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8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
Lei Gao 1 Guiyang Liu 1 Jianli Ma Xiaoqing Wang Liang Zhou Xiang Li
Department of Pharmacy The First Af 1047297liated Hospital of General Hospital of PLA No 51 Fucheng Road Beijing 100048 China
a b s t r a c ta r t i c l e i n f o
Article history
Received 1 December 2011
Accepted 8 March 2012
Available online 20 March 2012
Keywords
Poorly soluble drugs
Drug nanocrystals
Bioavailability
Pharmacokinetics
Pharmacodynamics
Targeting drug delivery
Over the past few decades there has been a considerable research interest in drug nanocrystal system as a
pharmaceutical approach for poorly soluble drugs At the beginning lots of works have been done to study
various technologies associated with production of drug nanocrystals and their in vitro physical and chemical
properties such as morphology formulation composition stabilities crystalline structure and enhanced sol-ubility and dissolution velocity Recently in vivo behaviors of the nanocrystals have been generally studied in
animals (including human) and the results proved that drug nanocrystals could be used as a versatile formu-
lation to alter and improve the pharmacokinetic pharmacodynamic and targeting properties of poorly solu-
ble drugs In this paper in vivo performances of drug nanocrystals exhibited in animals in different
administration route were reviewed and the advantages of drug nanocrystals in the aspect ofsafety pharma-
codynamics pharmacokinetics and targeting delivery were discussed in detail
copy 2012 Elsevier BV All rights reserved
Contents
1 Introduction 419
2 In vivo performances of nanocrystals in different administration route 419
21 Safety and toxicity 419
211 Safety issues of poorly soluble drugs 419
212 Advantages of nanocrystal formulations in terms of safety 419
22 Effects on the pharmacokinetic properties 420
221 Oral administration route 420
222 Injection administration route 423
223 Ophthalmic administration route 424
224 Pulmonary administration route 424
23 Effects on the pharmacodynamic properties 425
24 Targeting delivery 425
241 Passive targeting 426
242 Speci1047297c organs targeting 426
243 Cell-based drug delivery of drug nanocrystals 427
3 Conclusions 427
Acknowledgment 427
References 427
Journal of Controlled Release 160 (2012) 418ndash430
Abbreviations AN aqueous nanosuspension Apo apolipoprotein AUC area under the blood concentrationndashtime curve BCS biopharmaceutics classi1047297cation system BMM
bone marrow-derived macrophage CL clearance rate Cmax maximum plasma concentration CNV choroidal neovascularization EPR enhanced permeability and retention GI
gastrointestinal GIT gastrointestinal tract ICS Inhaled corticosteroids iv intravenous IVIVC in vitrondashin vivo correlation MPS mononuclear phagocyte system MRT mean res-
idence time MTT methyl thiazolyl tetrazolium NSAIDs non-steroidal anti-in1047298ammatory drugs PEG polyethylene glycol RBCs red blood cells RES reticuloendothelial system
RITC rhodamine B isothiocyanate SDS sodium dodecyl sulfate Tmax time to maximum plasma concentration Vd volume of distribution
Corresponding author Telfax +86 10 66867405
Corresponding author Telfax +86 10 66867081
E-mail addresses business_gaoleiyahoocn (L Gao) liuguiygmailcom (G Liu)1 Contributed equally to this paper
0168-3659$ ndash see front matter copy 2012 Elsevier BV All rights reserved
doi101016jjconrel201203013
Contents lists available at SciVerse ScienceDirect
Journal of Controlled Release
j o u r n a l h o m e p a g e w w w e l s e v i e r c o m l o c a t e j c o n r e l
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
It should be bear in mind that most drug nanocrystal formulations
used in the in vivo experiments are aqueous dispersions (Table 3)
however when it comes to the clinical application solid dosage
forms are usually more acceptable by patients [82] It can be seen
that most of the marketed nanoparticles formulations are solid
forms (Table 1) In order to solidi1047297cation 1047297rst the aqueous nanosus-
pensions should be transformed into dry powders suitable to gener-
ate tablets capsules pellets etc This transformation can be
achieved using different methods including lyophilization spray dry-ing granulation and pelletization [83ndash86] The drying process should
be well designed to avoid particle aggregation If aggregation occurs
the bene1047297ts that can be gained from large surface of the original
nanometer-sized particles would be greatly compromised In general
protectants (usually sugars) are often added to nanosuspensions to
minimize the particle size growth during a drying process
The redispersion progress of a solid formulation containing drug
nanocrystals in the GIT is more complex Physiological factors (in-
cluding pH variation compositions of the digestive juice and GI peri-
stalsis etc) affecting dispersion of nanocrystals are complicated [87]
Nanocrystals of basic drugs are more easily affected by pH variation in
the GIT For weak bases a nanometer-sized drug formulation will dis-
solve fast and more ef 1047297ciently in the low stomach pH environment
During transit from stomach to duodenum the rise in pH may illicit
uncontrolled precipitation of drug substance [88] In addition stabi-
lizer type should be screened by monitoring the change of particle
size after reconstitution in different pH media [89] After rehydration
in GI 1047298uid the nanocomplex disperses into separated nanocrystals
following the dissolution of 1047297llers Stabilizer molecules attached on
the surface of nanocrystals will offer ionic or steric repulsion among
nanocrystals given that they are not affected by the GIT environment
[690] In general ionic stabilizers are effective in aqueous environ-
ment but during the drying they may become less effective because
the ionized state is not maintained in dry material In addition ionic
stabilizers are also sensitive to changes in pH and ionic strength
when the dried powders redisperse in the GI 1047298uid [90] On the con-
trary in most cases the polymer and non-ionic surfactant stabilizers
can be effective to support suf 1047297cient steric repulsion in GI 1047298uid
given that the amount of stabilizers is enough [91]
The establishment of an in vitrondash
in vivo correlation (IVIVC) is anessential part for the study of oral formulations For the Class II
drugs dissolution is a rate-limiting step in the GIT so in general
they have a good IVIVC result [92] When they are processed into
nanocrystal formulations an IVIVC should be reevaluated again
since their dissolution velocity has been markedly enhanced In the
other hand the IVIVC data also help modulate the process and the
amount of matrix in the progress of drying nanosuspensions Howev-
er research on the IVIVC of nanocrystal formulations has not been
reported but we believe it will be the next focus in this 1047297eld
222 Injection administration route
For many cases intravenous injection is requested to meet some
treatment purpose such as immediate effects overcoming the 1047297rst
pass effect targeting effect and so on Due to its suf 1047297ciently small
size and safe aqueous composition nanosuspensions can be injected
intravenously and achieve 100 bioavailability [86] Compared with
other carrier-based solid nanoparticles such as solid lipid nanoparti-
cles polymer-based nanoparticles and liposomes carrier-free nano-
crystals would experience a much faster particle size reduction
during the process of dissolution This may lead to a distinct pharma-
cokinetic progress after iv administration because particle size is an
Table 4
Changes of pharmacokinetic properties of intravenous nanosuspensions compared with the conventional partners
Drug Methods Dosage form
(mean particle size)
Control
(mean particle size)
Comparison of the
pharmacokinetic parameters
Animals References
Asulac rine High p ressur e hom ogeniz at ion AN ( 13 3 nm) Organic solut ion 15- fold r edu ction in Cmax23-fold increase in t12 62-fold
increase in Vd 27-fold increase in
CL 27-fold increase in MRT
25-fold reduction in AUC
Rats [34]
Melar sopr ol High p ressur e hom ogeniz at ion AN ( 29 5 nm) Organic solut ion 22- fold inc rease in t12 14-fold
increase in Vd 14-fold reduction
in CL 2-fold reduction in AUC
Rats [41]
AN (409 nm) 3-fold increase in t12 13-fold reduction
in Vd 45-fold reduction in CL 42-fold
reduction in AUC
13-Dicyclohexylurea Media milling AN (NR)a Organic solution All parameters were similar to
those of solution
Rats [94]
Oridonin High p ressur e hom ogeniz at ion AN ( 10 33 nm) Organic solut ion All p ara meters w ere sim ilar to
those of solution 17-fold reduction
in Cmax 7-fold increase in t12 51-fold
increase in Vd 19-fold reduction in CL
62-fold increase in MRT 18-foldincrease in AUC
Rabbits [32]
AN (8972 nm)
It rac onaz ole High p ressur e hom ogeniz at ion AN ( 58 1 nm) Organic solut ion 17- fold inc rease in Cmax 31-fold
increase in t12 18 reduction in AUC 18
increase in CL 28 increase in MRT 79
increase in Vd
Rats [19]
AZ68 Precipitation AN (125 nm) Organic solution No signi1047297cant differences with
solution by means of plasma pro1047297les
Rats [35]
Media milling AN (200 nm)
Cyclosporine Precipitation AN (NR) Organic solution All parameters were similar to
those of solution
Rats [93]
Cu rc um in High p ressur e hom ogeniz at ion AN ( 21 02 nm) Organic solut ion 31- fold inc rease in Cmax
112-fold increase in MRT
48-fold increase in AUC
Rabbits [95]
Flu rb ip rofen High p ressur e hom ogeniz at ion AN ( NR ) Organic solut ion All p ara meters w ere sim ilar
to those of solution
Rats [96]
Vd volume of distribution CL clearance rate MRT mean retention time AUC area under the concentration ndashtime curve Cmax maximum plasma concentration Tmax time to max-
imum plasma concentration t12 plasma half lifea
NR Not reported
423L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
nanocrystals show clear potential for clinical development compared
with both the solution and the non-targeting nanocrystals formulations
243 Cell-based drug delivery of drug nanocrystals
The signi1047297cantly increased dissolution velocity which is a distinct
advantage of nanocrystals simultaneously implies the problem that
drug nanocrystals might dissolve before reaching the target Cell-
based drug delivery approach canbe employed to deal with this prob-
lem Cell based delivery systems are identi1047297
ed as cell carriers (includ-ing bacteria cells and animal cells) which can be loaded with drugs or
therapeutics The systems can release the drug content in circulation
or at selected sites or could target the drug to other relevant cells in
the body [147] Among the animal cells of special relevance are mac-
rophages and red blood cells (RBCs) Macrophages are differentiated
cells of the immune system able to phagocytize microorganisms as
well as nanoparticulate materials So nanoparticulate systems are
particularly useful for the delivery of therapeutic agents to macro-
phages [148149] When macrophages are used as drug delivery sys-
tems they should be 1047297rst loaded with the nanoparticulate drug ex
vivo and then re-infused into the host where their content is distrib-
uted to tissues that favor homing of macrophages such as parasites
bacteria and viruses [150151] RBCs constitute potential biocompati-
ble carriers for different bioactive substances including protein drugs
as well as nanoparticulates They have unique properties such as bio-
degradability biocompatibility and long-term drug releasing and thus
are well suited for drug encapsulation [152] They can be easily han-
dled ex vivo by means of several techniques for the encapsulation of
different molecules and nanoparticulates [153]
For drug nanocrystals few studies related on cell based drug deliv-
ery have been reported but the existing results proved the feasibility
Dou et al designed a novel bone marrow-derived macrophage (BMM)
indinavir nanocrystals delivery system for antiretroviral treatment
[154] Light microscopic examination proved that indinavir nanocrys-
tals were successfully loaded into BMMs after culture in the presence
of indinavir nanosuspensions for 12 h Following iv administration
into naive mice the indinavir nanocrystal loaded BMMs acted as ldquoTro-
jan horsesrdquo for transport of drug into tissues which were known to be
targets for HIV due to the parallel BMM migration and viral tissue tro-pism Administration of indinavir nanocrystal-BMMs sustained indina-
vir in tissue and sera for up to 10 days in comparison with 6 h for the
non-wrapped nanosuspensions Amphotericin B nanocrystal-loaded
RBCs systems were developed by Staedtke et al in order to improvean-
tifungal treatment [155] Amphotericin B nanocrystals encapsulation in
RBCs wasachieved by using hypotonichemolysis methodleading to in-
tracellularamphotericin B amounts of 381plusmn047 pg RBCminus1andanen-
trapment ef 1047297cacy of 15ndash18 Upon phagocytosis of amphotericin B
nanocrystal-RBCs leukocytes show a slow amphotericin B release
over 10 days and no alteration in cell viability
3 Conclusions
The researchon colloidal drug delivery systems may be the hottest1047297eld in pharmaceutics in the last several decades Due to the unique
advantage and pharmaeconomical value drug nanocrystals are paid
increasing attentions as a promising approach Drug nanocrystals
can be applied to all the poorly soluble drugs to overcome the solubil-
ity and bioavailability problems because all the poorly soluble drugs
can be comminuted into drug nanocrystals Researches on drug nano-
crystals within recent years fully exhibit their excellent in vivo perfor-
mances in different administration routes Among these the most
exciting information is that properties of drug nanocrystals can be
conveniently altered to meet various treatment demands of different
diseases With the number of insoluble drug compounds in develop-
ment increasing it is anticipated that nanocrystals technology will at-
tract increasing attentions as a viable formulation option However
though drug nanocrystals demonstrate superiority over the carrier
colloid drug delivery systems such as easier production safer compo-
sition and higher drug loading correspondingly they also confront
some problems For example how to obtain a more controllable
drug dissolution rate in order to meet the treatment requirements
of different diseases or reduce the drug release in the progress of de-
livering the drugs into target sites How can we get a more 1047297rm con-
junction between ligand-linked stabilizers and nanocrystal surfaces
without the loss of their properties We believe that many studies
will focus on handling these problems in the future
Acknowledgment
This work was partially supported by the Scienti1047297c Foundation of
the First Af 1047297liated Hospital of General Hospital of PLA the project
number is QN201105
References
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[2] ER Cooper Nanoparticles a personal experience for formulating poorly watersoluble drugs J Control Release 141 (2010) 300ndash302
[3] CM Keck RH Muumlller Drug nanocrystals of poorly soluble drugs produced by
high pressure homogenisation Eur J Pharm Biopharm 62 (2006) 3ndash
16[4] BE Rabinow Nanosuspensions in drug delivery Nat Rev Drug Discov 3 (2004)785ndash796
[5] L Gao D Zhang M Chen Drug nanocrystals for the formulation of poorly solu-ble drugs and its application as a potential drug delivery system J NanopartRes 10 (2008) 845ndash862
[6] GG Liversidge KC Cundy Particle size reduction for improvement of oral bio-availability of hydrophobic drugs I Absolute oral bioavailability of nanocrystal-line danazol in beagle dogs Int J Pharm 125 (1995) 91ndash97
[7] K Peters S Leitzke J Diederichs K Borner H Hahn RH Muumlller S Ehlers Prep-aration of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic ef 1047297cacy in murine Mycobacterium avium infection J AntimicrobChemother 45 (2000) 77ndash83
[8] P Rosario B Claudio F Piera M Adriana P Antonina P Giovanni EudragitRS100 nanosuspensions for the ophthalmic controlled delivery of ibuprofenEur J Pharm Sci 16 (2002) 53ndash61
[9] C Jacobs RH Muumlller Production and characterization of a budesonide nanosus-pension for pulmonary administration Pharm Res 19 (2002) 189ndash194
[10] RH Muumlller C Jacobs O Kayser Nanosuspensions as particulate drug formula-
tions in therapy rationale for development and what we can expect for the fu-ture Adv Drug Deliv Rev 47 (2001) 3ndash19
[11] B Van Eerdenbrugh G Van den Mooter P Augustijns Topndashdown production of drug nanocrystals nanosuspension stabilization miniaturization and transfor-mation into solid products Int J Pharm 364 (2008) 64ndash75
[12] E Merisko-Liversidge GG Liversidge ER Cooper Nanosizing a formulationapproach for poorly-water-soluble compounds Eur J Pharm Sci 18 (2003)113ndash120
[13] J Hu KP Johnston RO Williams Nanoparticle engineering processes for en-hancing the dissolution rates of poorly water soluble drugs Drug Dev IndPharm 30 (2004) 233ndash245
[14] JAH Junghanns RH Muumlller Nanocrystal technology drug delivery and clinicalapplications Int J Nanomedicine 3 (2008) 295ndash310
[15] GA Brazeau HL Fung Mechanisms of creatine kinase release from isolated ratskeletal muscles damaged by propylene glycol and ethanol J Pharm Sci 79(1990) 393ndash397
[16] K Korttila A Sothman P Andersson Polyethylene glycol as a solvent for diaze-pam bioavailability and clinical effects after intramuscular administrationcomparison of oral intramuscular and rectal administration and precipitationfrom intravenous solutions Acta Pharmacol Toxicol (Copenh) 39 (1976)104ndash117
[17] R Budden UG Kuhl J Bahlsen Experiments on toxic sedative and muscle re-laxant potency of various drug solvents in mice Pharmacol Ther 5 (1979)467ndash474
[18] F Liu JY Park Y Zhang C Conwell Y Liu SR Bathula L Huang Targeted can-cer therapy with novel high drug-loading nanocrystals J Pharm Sci 99 (2010)3542ndash3551
[19] B Rabinow J Kipp P Papadopoulos J Wong J Glosson J Gass CS Sun TWielgos R White C Cook K Barker K Wood Itraconazole IV nanosuspensionenhances ef 1047297cacy through altered pharmacokinetics in the rat Int J Pharm 339(2007) 251ndash260
[20] F Kesisoglou S Panmai Y Wu Nanosizingmdashoral formulation development andbiopharmaceutical evaluation Adv Drug Deliv Rev 59 (2007) 631ndash644
[22] GG Liversidge P Conzentino Drug particle size reduction for decreasing gastricirritancy and enhancing absorption of naproxen in rats Int J Pharm 125 (1995)
309ndash
313
427L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[23] E Merisko-Liversidge GG Liversidge Nanosizing for oral and parenteral drugdelivery a perspective on formulating poorly-water soluble compounds usingwet media milling technology Adv Drug Deliv Rev 30 (2011) 427ndash440
[24] BHL Boumlhm RH Muumlller Lab-scale production unit design for nanosuspensions of sparingly soluble cytotoxic drugs Pharm Sci Technol Today 2 (1999) 336ndash339
[25] RH Drew E Dodds Ashley DK Benjamin Jr R Duane Davis SM Palmer JRPerfect Comparative safety of amphotericin B lipid complex and amphotericinB deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipi-ents Transplantation 77 (2004) 232ndash237
[26] J Dubois T Bartter J Gryn MR Pratter The physiologic effects of inhaledamphotericin B Chest 108 (1995) 750ndash753
[27] SM Palmer RH Drew JD Whitehouse VF Tapson RD Davis RR McConnellSS Kanj JR Perfect Safety of aerosolized amphotericin B lipid complex in lungtransplant recipients Transplantation 72 (2001) 545ndash548
[28] RO Williams III J Liu Formulation of a protein with propellant HFA 134a foraerosol delivery Eur J Pharm Sci 7 (1999) 137ndash144
[29] IC Ashurst CV Ambrose DJ Russell Pharmaceutical evaluation of a new spac-er device for delivery of metered-dose inhalers to infants and young children JAerosol Sci 23 (1992) 499ndash502
[30] GC Na HJ Stevens B Yuan N Rajagopalan Physical stability of ethyl diatrizoatenanocrystalline suspension in steam sterilization Pharm Res 16 (1999) 569ndash574
[31] H Lou X Zhang L Gao F Feng J Wang X Wei Z Yu D Zhang Q Zhang Invitro and in vivo antitumor activity of oridonin nanosuspension Int J Pharm379 (2009) 181ndash186
[32] L Gao D Zhang M Chen C Duan W Dai L Jia W Zhao Studies on pharmaco-kinetics and tissue distribution of oridonin nanosuspensions Int J Pharm 355(2008) 321ndash327
[33] SM Moghimi AC Hunter JC Murray Long circulating and target-speci1047297cnanoparticles theory to practice Pharmacol Rev 53 (2001) 283ndash381
[34] S Ganta JW Paxton BC Baguley S Garg Formulation and pharmacokinetic
evaluation of an asulacrine nanocrystalline suspension for intravenous deliveryInt J Pharm 367 (2009) 179ndash186
[35] K Sigfridsson S Forsseacuten P Hollaumlnder U Skantze J de Verdier A formulationcomparison using a solution and different nanosuspensions of a poorly solublecompound Eur J Pharm Biopharm 67 (2007) 540ndash547
[36] K Sigfridsson AJ Lundqvist M Strimfors Particle size reduction for improve-ment of oral absorption absorption of the poorly soluble drug UG558 in rats dur-ing early development Drug Dev Ind Pharm 35 (2009) 1479ndash1486
[37] S Kim J Lee Folate-targeted drug-delivery systems prepared by nano-comminution Drug Dev Ind Pharm 37 (2011) 131ndash138
[38] R Xiong W Lu J Li P Wang R Xu T Chen Preparation and characterization of intravenously injectable nimodipine nanosuspension Int J Pharm 350 (2008)338ndash343
[39] Y Gao Z Li M Sun C Guo A Yu Y Xi J Cui H Lou G Zhai Preparation andcharacterization of intravenously injectable curcumin nanosuspension DrugDeliv 18 (2011) 131ndash142
[40] RH Muumlller K Peters Nanosuspensions for the formulation of poorly solubledrugs I Preparation by a size-reduction technique Int J Pharm 160 (1998)229ndash237
[41] SB Zirar A Astier M Muchow S Gibaud Comparison of nanosuspensions andhydroxypropyl-b-cyclodextrin complex of melarsoprol pharmacokinetics andtissue distribution in mice Eur J Pharm Biopharm 70 (2008) 649 ndash656
[42] M Salzberg M Pless C Rochlitz K Ambrus P Scigalla R Herrmann A phase Istudy with oral SU5416 in patients with advanced solid tumors a drug inducingits clearance Invest New Drugs 24 (2006) 299ndash304
[43] WK Kraft B Steiger D Beussink JN Quiring N Fitzgerald HE Greenberg SAWaldman The pharmacokinetics of nebulized nanocrystal budesonide suspen-sion in healthy volunteers J Clin Pharmacol 44 (2004) 67ndash72
[44] JM Vaughn NP Wiederhold JT McConville JJ Coalson RL Talbert DSBurgess KP Johnston RO Williams III JI Peters Murine airway histologyand intracellular uptake of inhaled amorphous itraconazole Int J Pharm 338(2007) 219ndash224
[45] JM Vaughn JT McConville D Burgess JI Peters KP Johnston RL Talbert ROWilliams III Single dose and multiple dose studies of itraconazole nanoparticlesEur J Pharm Biopharm 63 (2006) 95ndash102
[46] BJ Hoeben DS Burgess JT McConville LK Najvar RL Talbert JI Peters NPWiederhold BL Frei JR Graybill R Bocanegra KA Overhoff P Sinswat KP
Johnston RO Williams III In vivo ef 1047297cacy of aerosolized nanostructured itraco-nazole formulations for prevention of invasive pulmonary aspergillosis Antimi-crob Agents Chemother 50 (2006) 1552ndash1554
[47] CA Alvarez NP Wiederhold JT McConville JI Peters LK Najvar JR Graybill JJ Coalson RL Talbert DS Burgess R Bocanegra KP Johnston RO WilliamsIII Aerosolized nanostructured itraconazole as prophylaxis against invasive pul-monary aspergillosis J Infect 55 (2007) 68ndash74
[48] SB Shrewsbury AP Bosco PS Uster Pharmacokinetics of a novel submicronbudesonide dispersion for nebulized delivery in asthma Int J Pharm 365(2009) 12ndash17
[49] RH Muumlller KH Wallis Surface modi1047297cation of iv injectable biodegradablenanoparticles with poloxamer polymers and poloxamine 908 Int J Pharm 89(1993) 25ndash31
[50] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy and diagno-sis Adv Drug Deliv Rev 54 (2002) 631ndash651
[51] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (2000) 73ndash80
[52] M Wang M Thanou Targeting nanoparticles to cancer Pharmacol Res 62(2010) 90ndash99
[53] L Gao G Liu X Wang F Liu Y Xu J Ma Preparation of a chemically stablequercetin formulation using nanosuspension technology Int J Pharm 404(2011) 231ndash237
[54] M Sarkari J Brown X Chen S Swinnea RO Williams III KP Johnston En-hanced drug dissolution using evaporative precipitation into aqueous solutionInt J Pharm 243 (2002) 17ndash31
[55] X Li L Gu Y Xu Y Wang Preparation of feno1047297brate nanosuspension and studyof its pharmacokinetic behavior in rats Drug Dev Ind Pharm 35 (2009)827ndash833
[56] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Pharmacokinetic evaluation of oral feno1047297brate nanosus-
pensions and SLN in comparison to conventional suspensions of micronizeddrug Adv Drug Deliv Rev 59 (2007) 419ndash426[57] GJ Vergote C Vervaet I Van Driessche S Hoste S De Smedt J Demeester RA
Jain S Ruddy JP Remon In vivo evaluation of matrix pellets containing nano-crystalline ketoprofen Int J Pharm 240 (2002) 79ndash84
[58] S Ghosh P Chiang JL Wahlstrom H Fujiwara JG Selbo SL Roberds Oral de-livery of 13-dicyclohexylurea nanosuspension enhances exposure and lowersblood pressure in hypertensive rats Basic Clin Pharmacol Toxicol 102 (2008)453ndash458
[59] P Langguth A Hanafy D Frenzel P Grenier A Nhamias T Ohlig G VergnaultH Spahn-Langguth Nanosuspension formulations for low-soluble drugs phar-macokinetic evaluation using spironolactone as model compound Drug DevInd Pharm 31 (2005) 319ndash329
[60] MG Fakesa Blisse J Vakkalagaddab Feng Qiana Sridhar Desikana Rajesh BGandhi C Lai A Hsieha MK Franchini H Toaled J Brown Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amor-phous formulation approaches Int J Pharm 370 (2009) 167ndash174
[61] K Sigfridsson A Nordmark S Theilig A Lindah A formulation comparison be-tween micro- and nanosuspensions the importance of particle size for absorp-
tion of a model compound following repeated oral administration to rats duringearly development Drug Dev Ind Pharm 37 (2011) 185ndash192
[62] J Jinno N Kamada M Miyake K Yamada T Mukai M Odomi H Toguchi GGLiversidge K Higaki T Kimura Effect of particle size reduction on dissolutionand oral absorption of a poorly water-soluble drug cilostazol in beagle dogs JControl Release 111 (2006) 56ndash64
[63] Y Wu A Loper E Landis L Hettrick L Novak K Lynn C Chen K Thompson RHiggins U Batra S Shelukar G Kwei D Storey The role of biopharmaceutics inthe development of a clinical nanoparticle formulation of MK-0869 a beagledog model predicts improved bioavailability and diminished food effect on ab-sorption in human Int J Pharm 285 (2004) 135ndash146
[64] RH Muumlller S Runge V Ravelli W Mehnert AF Thuumlnemann EB Souto Oralbioavailability of cyclosporine solid lipid nanoparticles (SLNreg) versus drugnanocrystals Int J Pharm 317 (2006) 82ndash89
[65] G Ponchel MJ Montisci A Dembri C Durrer D Duchecircne Mucoadhesion of colloidal particulate systems in the gastro-intestinal tract Eur J Pharm Bio-pharm 44 (1997) 25ndash31
[66] D Duchecircne G Ponchel Bioadhesion of solid oral dosage forms why and howEur J Pharm Biopharm 44 (1997) 15ndash23
[67] D Dodou P Breedveld PA Wieringa Mucoadhesives in the gastrointestinaltract revisiting the literature for novel applications Eur J Pharm Biopharm60 (2005) 1ndash16
[68] JD Smart The basics and underlying mechanisms of mucoadhesion Adv DrugDeliv Rev 57 (2005) 1556ndash1568
[69] O Kayser A newapproach fortargetingto Cryptosporidium parvum using mucoadhe-sive nanosuspensions research and applications Int J Pharm 214 (2001) 83ndash85
[70] A des Rieux V Fievez M Garinot YJ Schneider V Preacuteat Nanoparticles as po-tential oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[71] A Lamprecht P Koenig N Ubrich P Maincent D Neumann Low molecularweight heparin nanoparticles mucoadhesion and behaviour in Caco-2 cellsNanotechnology 17 (2006) 3673ndash3680
[72] F Delie Evaluation of nano- and microparticle uptake by the gastrointestinaltract Adv Drug Deliv Rev 34 (1998) 221ndash233
[73] CN Grama DD Ankola MNV Ravi Kumar Poly(lactide-co-glycolide) nano-particles for peroral delivery of bioactives Curr Opin Colloid Interface Sci 16(2011) 238ndash245
[74] MP Desai V Labhasetwar GL Amidon RJ Levy Gastrointestinal Uptake of biodegradable microparticles effect of particle size Pharm Res 13 (1996)1838ndash1845
[75] A des Rieux V Fievez M Garinot YJ Scheider V Preat Nanoparticles as poten-tial oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[76] JM Dintaman JA Silverman Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) Pharm Res 16 (1999)1550ndash1556
[77] J Goole DJ Lindley W Roth SM Carl K Amighi JM Kauffmann GT KnippThe effects of excipients on transporter mediated absorption Int J Pharm 393(2010) 17ndash31
[78] J Huang L Si L Jiang Z Fan J Qiu G Li Effect of pluronic F68 block copolymeron P-glycoprotein transport and CYP3A4 metabolism Int J Pharm 356 (2008)351ndash353
[79] MF Wempe C Wright JL Little JW Lightner SE Large GB Ca1047298isch CMBuchanan PJ Rice VJ Wacher KM Ruble KJ Edgar Inhibiting ef 1047298ux withnovel non-ionic surfactants rational design based on vitamin E TPGS Int JPharm 370 (2009) 93ndash102
428 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[81] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Absence of a food effect with a 145 mg nanoparticle feno-1047297brate tablet formulation Int J Clin Pharmacol Ther 44 (2006) 64ndash70
[82] MV Chaubal C Popescu Conversion of nanosuspensions into dry powders byspray drying a case study Pharm Res 25 (2008) 2302ndash2308
[83] F Lai E Pini G Angioni ML Manca J Perricci C Sinico AM Fadda Nanocrys-tals as tool to improve piroxicam dissolution rate in novel orally disintegratingtablets Eur J Pharm Biopharm 79 (2011) 552ndash558
[84] D Mou H Chen J Wan H Xu X Yang Potent dried drug nanosuspensions for
oral bioavailability enhancement of poorly soluble drugs with pH-dependentsolubility Int J Pharm 413 (2011) 237ndash244[85] A Ain-Ai PK Gupta Effect of arginine hydrochloride and hydroxypropyl cellu-
lose as stabilizers on the physical stability of high drug loading nanosuspensionsof a poorly soluble compound Int J Pharm 351 (2008) 282 ndash288
[86] Z Guo T Pereira O Choi Y Wang HT Hahn Surface functionalized aluminananoparticle 1047297lled polymeric nanocomposites with enhanced mechanical prop-erties J Mater Chem 16 (2006) 2800ndash2808
[87] DR Kalaria G Sharma V Beniwal MN Ravi Kumar Design of biodegradablenanoparticles for oral delivery of doxorubicin in vivo pharmacokinetics and tox-icity studies in rats Pharm Res 26 (2009) 492ndash501
[88] JE Kipp The role of solid nanoparticle technology in parenteral delivery of poorly water soluble drugs Int J Pharm 284 (2004) 109ndash122
[89] HM Shubar S Lachenmaier MM Heimesaat U Lohman R Mauludin RHMuumlller R Fitzner K Borner O Liesenfeld SDS-coated atovaquone nanosuspen-sions show improved therapeutic ef 1047297cacy against experimental acquired andreactivated toxoplasmosis by improving passage of gastrointestinal and bloodndash
brain barriers J Drug Target 19 (2011) 114ndash124[90] L Peltonen J Hirvonen Pharmaceutical nanocrystals by nanomilling critical
process parameters particle fracturing and stabilization method J Pharm Phar-macol 62 (2010) 1569ndash1579
[91] F Lai C Sinico G Ennas F Marongiu G Marongiu AM Fadda Diclofenac nano-suspensions in1047298uence of preparation procedure and crystal form on drug disso-lution behavior Int J Pharm 373 (2009) 124ndash132
[92] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (Suppl 2) (2000) S73ndashS80
[93] RH Muller CM Keck Challenges and solutions for the delivery of biotech drugsmdasha review of drug nanocrystal technology and lipid nanoparticles J Biotechnol113 (2004) 151ndash170
[94] JL Wahlstrom P Chiang S Ghosh CJ Warren SP Wene LA Albin ME SmithSL Roberds Pharmacokinetic evaluation of a 13-dicyclohexylurea nanosuspen-sion formulation to support early ef 1047297cacy assessment Nanoscale Res Lett 2(2007) 291ndash296
[95] Y GaoZ LiM SunH Li CGuoJ CuiA LiF CaoY XiH Lou GZhai Preparationcharacterization pharmacokinetics and tissue distribution of curcumin nanosus-pension with TPGS as stabilizer Drug Dev Ind Pharm 36 (2010) 1225ndash1234
[96] M Clement W Pugh I Parikh Tissue distribution and plasma clearance of a novelmicrocrystalline-coated 1047298urbiprofen formulation Pharmacologist 34 (1992)204ndash211
[97] RC Nagarwal S Kant PN Singh P Maiti JK Pandit Polymeric nanoparticulate sys-tem a potential approach for ocular drug delivery J Control Release 136 (2009)2ndash13
[98] H Gupta M Aqil RK Khar A Ali A Bhatnagar G Mittal Spar1047298oxacin loadedPLGA nanoparticles for sustained ocular drug delivery Nanomedicine 6 (2010)324ndash333
[99] HS Ali P York AM Ali N Blagden Hydrocortisone nanosuspensions for oph-thalmic delivery a comparative study between micro1047298uidic nanoprecipitationand media milling J Control Release 149 (2011) 175ndash181
[100] SK Sahoo F Dilnawaz S Krishnakumar Nanotechnology in ocular drug deliv-ery Drug Discov Today 13 (2008) 144ndash151
[101] O Kayser A Lemke N Hernaacutendez-Trejo The impact of nanobiotechnology on thedevelopment of newdrug deliverysystems Curr Pharm Biotechnol6 (2005) 3ndash5
[102] R Pignatello C Bucolo G Spedalieri A Maltese G Puglisi Flurbiprofen-loadedacrylate polymer nanosuspensions for ophthalmic application Biomaterials 23(2002) 3247ndash3255
[103] R Ravichandran Nanoparticles in drug delivery potential green nanobiomedi-
cine applications Int J Green Nanotechnol Biomed 1 (2009) B108ndash
B130[104] AM Cerdeira M Mazzotti B Gander Miconazole nanosuspensions in1047298uence
of formulation variables on particle size reduction and physical stability Int JPharm 396 (2010) 210ndash218
[105] MA Kassem AA Abdel Rahman MM Ghorab MB Ahmed RM Khalil Nano-suspension as an ophthalmic delivery system for certain glucocorticoid drugsInt J Pharm 340 (2007) 126ndash133
[106] P Chiang JW Alsup Y Lai Y Hu BR Heyde D Tung Evaluation of aerosol de-livery of nanosuspension for pre-clinical pulmonary drug delivery NanoscaleRes Lett 4 (2009) 254ndash261
[107] W Yang JI Peters RO Williams III Inhaled nanoparticlesmdasha current reviewInt J Pharm 356 (2008) 239ndash247
[108] J Zhang L Wu H Chan W Watanabe Formation characterization and fate of inhaled drug nanoparticles Adv Drug Deliv Rev 63 (2011) 441ndash455
[109] HM Mansour YS Rhee X Wu Nanomedicine in pulmonary delivery Int JNanomedicine 4 (2009) 299ndash319
[110] NR Labiris MB Dolovich Pulmonary drug delivery Part I physiological factorsaffecting therapeutic effectiveness of aerosolized medications Br J Clin Phar-macol 56 (2003) 588ndash599
[111] JS Patton PR Byron Inhaling medicines delivering drugs to the body throughthe lungs Nat Rev Drug Discov 6 (2007) 67ndash74
[112] DA Edwards C Dunbar Bioengineering of therapeutic aerosols Annu RevBiomed Eng 4 (2002) 93ndash107
[113] W Yang JTam DA Miller J Zhou JT McConville KP Johnstonb RO WilliamsIII High bioavailability from nebulized itraconazole nanoparticle dispersionswith biocompatible stabilizers Int J Pharm 361 (2008) 177ndash188
[114] S Gill R Lobenberg T Ku S Azarmi W Roa EJ Prenner Nanoparticles char-acteristics mechanisms of action and toxicity in pulmonary drug deliverymdasha re-view J Biomed Nanotechnol 3 (2007) 107ndash119
[115] SJ Sze1047298er Pharmacodynamics and pharmacokinetics of budesonide a new
S183[116] W Yang KP Johnston RO Williams III Comparison of bioavailability of amor-phous versus crystalline itraconazole nanoparticles via pulmonary administra-tion in rats Eur J Pharm Biopharm 75 (2010) 33 ndash41
[117] R Ali GK Jain Z Iqbal S Talegaonkar P Pandit S Sule G Malhotra RK KharA Bhatnagar FJ Ahmad Development and clinical trial of nano-atropine sulfatedry powder inhaler as a novel organophosphorous poisoning antidote Nanome-dicine 5 (2009) 55ndash63
[118] D Andes Minireview in vivo pharmacodynamics of antifungal drugs in treat-ment of candidiasis Antimicrob Agents Chemother 47 (2003) 1179ndash1186
[119] D Andes K Marchillo R Conklin G Krishna F Ezzet A Cacciapuoti DLoebenberg Pharmacodynamics of a new triazole posaconazole in a murinemodel of disseminated candidiasis Antimicrob Agents Chemother 48 (2004)137ndash142
[120] O Kayser C Olbrich V Yardley AF Kiderlen SL Croft Formulation of ampho-tericin B as nanosuspension for oral administration Int J Pharm 254 (2003)73ndash75
[121] L Zhang S Hou S Mao D Wei X Song Y Lu Uptake of folate-conjugated albu-min nanoparticles to the SKOV3 cells Int J Pharm 287 (2004) 155ndash162
[122] J Sudimack RJ Lee Targeted drug delivery via folate receptor Adv Drug DelivRev 41 (2000) 147ndash162
[123] P Vader LJ van der Aa G Storm RM Schiffelers JF Engbersen Polymeric car-rier systems for siRNA delivery Curr Top Med Chem 12 (2012) 108 ndash119
[124] O Veiseh FM Kievit RG Ellenbogen M Zhang Cancer cell invasion treatmentand monitoring opportunities in nanomedicine Adv Drug Deliv Rev 63 (2011)582ndash596
[125] J Kreuter VE Petrov DA Kharkevich RN Alyautdin In1047298uence of the type of surfactant on the analgesic effects induced by the peptide dalargin after its de-livery across the bloodndashbrain barrier using surfactant-coated nanoparticles JControl Release 49 (1997) 81ndash87
[126] J Ye Q Wang X Zhou N Zhang Injectable actarit-loaded solid lipid nanoparti-cles as passive targeting therapeutic agents for rheumatoid arthritis Int JPharm 352 (2008) 273ndash279
[127] SM Moghimi AC Hunter JC Murray Nanomedicine current status and futureprospects FASEB J 19 (2005) 311ndash330
[128] K Park To PEGylate or not PEGylate that is not the question J Control Release142 (2010) 147ndash148
[129] M Socha P Bartecki C Passitani A Sapin C Damge T Lecompte J BarreE Ghazouani P Maincent Stealth nanoparticles coated with heparin aspeptide or peptide carriers J Drug Target 17 (2009) 575ndash585
[130] D Shenoy S Little R Langer M Amiji Poly(ethylene oxide)-modi1047297ed poly(-beta-amino ester) nanoparticles as a pH-sensitive system for tumor targeted de-livery of hydrophobic drugs part 2 In vivo distribution and tumor localizationstudies Pharm Res 22 (2005) 2107ndash2114
[131] R Shegokara KK Singha Surface modi1047297ed nevirapinenanosuspensions for viralreservoir targeting in vitro and in vivo evaluation Int J Pharm 421 (2011)341ndash352
[132] Y Matsumura H Maeda A new concept for macromolecular therapeutics incancer chemotherapy mechanism of tumoritropic accumulation of proteinsand the antitumor agent SMANCS Cancer Res 46 (1986) 6387ndash6392
[133] H Zhang CP Hollis Q Zhang T Li Preparation and antitumor study of camp-tothecin nanocrystals Int J Pharm 415 (2011) 293ndash300
[134] H Lou L Gao X Wei Z Zhang D Zheng D Zhang X Zhang Y Li Q Zhang Ori-donin nanosuspension enhances anti-tumor ef 1047297cacy in SMMC-7721 cells andH22 tumor bearing mice Colloids Surf B Biointerfaces 87 (2011) 319ndash325
[135] TM Goppert RH Muumlller Adsorption kinetics of plasma proteins on solid lipid
nanoparticles for drug targeting Int J Pharm 302 (2005) 172ndash
186[136] X Pu J Sun M Li Z He Formulation of nanosuspensions as a new approach for
the delivery of poorly soluble drugs Curr Nanosci 5 (2009) 417ndash427[137] R Gaudana J Jwala SHS Boddu AK Mitra Recent perspectives in ocular drug
delivery Pharm Res 26 (2009) 1197ndash1216[138] T Yasukawa H Kimura Y Tabata H Miyamoto Y Honda Y Ikada Y Ogura
Targeted delivery of anti-angiogenic agent TNP-470 using water-soluble poly-mer in the treatment of choroidal neovascularization Invest Ophthalmol VisSci 40 (1999) 2690ndash2696
[139] A Lemke AF Kiderlen B Petri O Kayser Delivery of amphotericin B nanosus-pensions to the brain and determination of activity against Balamuthia mandril-laris amebas Nanomedicine 6 (2010) 597ndash603
[140] HL Wong XY Wu R Bendayan Nanotechnological advances forthe delivery of CNS therapeutics Adv Drug Deliv Rev (2011) doi101016jaddr201110007
[141] J Kreuter S Gelperina Use of nanoparticles for cerebral cancer Tumori 94(2008) 271ndash277
[142] J Kreuter RN Alyautdin DA Kharkevich AA Ivanov Passage of peptidesthrough the bloodndashbrain barrier with colloidal polymer particles (nanoparti-cles) Brain Res 674 (1995) 171ndash174
429L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[143] J Kreuter Nanoparticulate systems for brain delivery of drugs Adv Drug DelivRev 47 (2001) 65ndash81
[144] TM Goumlppert RH Muumlller Polysorbate-stabilized solid lipid nanoparticles as col-loidal carriers for intravenous targeting of drugs to the brain comparison of plasma protein adsorption patterns J Drug Target 13 (2005) 179ndash187
[145] S Mansouri Y Cuie F Winnik Q Shi P Lavigne M Benderdour E Beaumont JC Fernandes Characterization of folate-chitosan-DNA nanoparticles for genetherapy Biomaterials 27 (2006) 2060ndash2065
[146] AR Hilgenbrink PS Low Folate receptor-mediated drug targeting from thera-peutics to diagnostics J Pharm Sci 94 (2005) 2135ndash2146
[147] F Pierigegrave S Sera1047297ni L Rossi M Magnani Cell-based drug delivery Adv Drug
Deliv Rev 60 (2008) 286ndash
295[148] F Chellat Y Merhi A Moreau L Yahia Therapeutic potential of nanoparticulatesystems for macrophage targeting Biomaterials 26 (2005) 7260ndash7275
[149] SS Hall S Mitragotri PS Daugherty Identi1047297cation of peptide ligands facilitatingnanoparticle at attachment to erythrocytes Biotechnol Prog 23 (2007) 749ndash754
[150] S Gorantla H Dou M Boska CJ Destache J Nelson L Poluektova BERabinow HE Gendelman RL Mosley Quantitative magnetic resonance and
SPECT imaging for macrophage tissue migration and nanoformulated drug de-livery J Leukoc Biol 80 (2006) 1165ndash1174
[151] LA Lotero G Olmos JC Diez Delivery to macrophages and toxic action of etopo-sidecarried in mouse redblood cells Biochim Biophys Acta 1620 (2003) 160ndash166
[152] L Rossi S Sera1047297ni F Pierigeacute A Antonelli A Cerasi A Fraternale L ChiarantiniM Magnani Erythrocyte-based drug delivery Expert Opin Drug Deliv 2 (2005)311ndash322
[153] S Sera1047297ni L Rossi A Antonelli A Fraternale A Cerasi R Crinelli L ChiarantiniGF Schiavano M Magnani Drug delivery through phagocytosis of red bloodcells Transfus Med Hemother 31 (2004) 92ndash101
[154] H Dou CJ Destache JR Morehead R Lee Mosley MD Boska J Kingsley S
Gorantla L Poluektova JA Nelson M Chaubal J Werling J Kipp BERabinow HE Gendelman Development of a macrophage-based nanoparticleplatform for antiretroviral drug delivery Blood 108 (2006) 2827ndash2835
[155] V Staedtke M Braumller A Muumlller R Georgieva S Bauer N Sternberg A Voigt ALemke C Keck J Moumlschwitzer H Baumlumler In vitro inhibition of fungal activityby macrophage-mediated sequestration and release of encapsulated amphoter-icin B nanosuspension in red blood cells Small 6 (2010) 96ndash103
430 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
It should be bear in mind that most drug nanocrystal formulations
used in the in vivo experiments are aqueous dispersions (Table 3)
however when it comes to the clinical application solid dosage
forms are usually more acceptable by patients [82] It can be seen
that most of the marketed nanoparticles formulations are solid
forms (Table 1) In order to solidi1047297cation 1047297rst the aqueous nanosus-
pensions should be transformed into dry powders suitable to gener-
ate tablets capsules pellets etc This transformation can be
achieved using different methods including lyophilization spray dry-ing granulation and pelletization [83ndash86] The drying process should
be well designed to avoid particle aggregation If aggregation occurs
the bene1047297ts that can be gained from large surface of the original
nanometer-sized particles would be greatly compromised In general
protectants (usually sugars) are often added to nanosuspensions to
minimize the particle size growth during a drying process
The redispersion progress of a solid formulation containing drug
nanocrystals in the GIT is more complex Physiological factors (in-
cluding pH variation compositions of the digestive juice and GI peri-
stalsis etc) affecting dispersion of nanocrystals are complicated [87]
Nanocrystals of basic drugs are more easily affected by pH variation in
the GIT For weak bases a nanometer-sized drug formulation will dis-
solve fast and more ef 1047297ciently in the low stomach pH environment
During transit from stomach to duodenum the rise in pH may illicit
uncontrolled precipitation of drug substance [88] In addition stabi-
lizer type should be screened by monitoring the change of particle
size after reconstitution in different pH media [89] After rehydration
in GI 1047298uid the nanocomplex disperses into separated nanocrystals
following the dissolution of 1047297llers Stabilizer molecules attached on
the surface of nanocrystals will offer ionic or steric repulsion among
nanocrystals given that they are not affected by the GIT environment
[690] In general ionic stabilizers are effective in aqueous environ-
ment but during the drying they may become less effective because
the ionized state is not maintained in dry material In addition ionic
stabilizers are also sensitive to changes in pH and ionic strength
when the dried powders redisperse in the GI 1047298uid [90] On the con-
trary in most cases the polymer and non-ionic surfactant stabilizers
can be effective to support suf 1047297cient steric repulsion in GI 1047298uid
given that the amount of stabilizers is enough [91]
The establishment of an in vitrondash
in vivo correlation (IVIVC) is anessential part for the study of oral formulations For the Class II
drugs dissolution is a rate-limiting step in the GIT so in general
they have a good IVIVC result [92] When they are processed into
nanocrystal formulations an IVIVC should be reevaluated again
since their dissolution velocity has been markedly enhanced In the
other hand the IVIVC data also help modulate the process and the
amount of matrix in the progress of drying nanosuspensions Howev-
er research on the IVIVC of nanocrystal formulations has not been
reported but we believe it will be the next focus in this 1047297eld
222 Injection administration route
For many cases intravenous injection is requested to meet some
treatment purpose such as immediate effects overcoming the 1047297rst
pass effect targeting effect and so on Due to its suf 1047297ciently small
size and safe aqueous composition nanosuspensions can be injected
intravenously and achieve 100 bioavailability [86] Compared with
other carrier-based solid nanoparticles such as solid lipid nanoparti-
cles polymer-based nanoparticles and liposomes carrier-free nano-
crystals would experience a much faster particle size reduction
during the process of dissolution This may lead to a distinct pharma-
cokinetic progress after iv administration because particle size is an
Table 4
Changes of pharmacokinetic properties of intravenous nanosuspensions compared with the conventional partners
Drug Methods Dosage form
(mean particle size)
Control
(mean particle size)
Comparison of the
pharmacokinetic parameters
Animals References
Asulac rine High p ressur e hom ogeniz at ion AN ( 13 3 nm) Organic solut ion 15- fold r edu ction in Cmax23-fold increase in t12 62-fold
increase in Vd 27-fold increase in
CL 27-fold increase in MRT
25-fold reduction in AUC
Rats [34]
Melar sopr ol High p ressur e hom ogeniz at ion AN ( 29 5 nm) Organic solut ion 22- fold inc rease in t12 14-fold
increase in Vd 14-fold reduction
in CL 2-fold reduction in AUC
Rats [41]
AN (409 nm) 3-fold increase in t12 13-fold reduction
in Vd 45-fold reduction in CL 42-fold
reduction in AUC
13-Dicyclohexylurea Media milling AN (NR)a Organic solution All parameters were similar to
those of solution
Rats [94]
Oridonin High p ressur e hom ogeniz at ion AN ( 10 33 nm) Organic solut ion All p ara meters w ere sim ilar to
those of solution 17-fold reduction
in Cmax 7-fold increase in t12 51-fold
increase in Vd 19-fold reduction in CL
62-fold increase in MRT 18-foldincrease in AUC
Rabbits [32]
AN (8972 nm)
It rac onaz ole High p ressur e hom ogeniz at ion AN ( 58 1 nm) Organic solut ion 17- fold inc rease in Cmax 31-fold
increase in t12 18 reduction in AUC 18
increase in CL 28 increase in MRT 79
increase in Vd
Rats [19]
AZ68 Precipitation AN (125 nm) Organic solution No signi1047297cant differences with
solution by means of plasma pro1047297les
Rats [35]
Media milling AN (200 nm)
Cyclosporine Precipitation AN (NR) Organic solution All parameters were similar to
those of solution
Rats [93]
Cu rc um in High p ressur e hom ogeniz at ion AN ( 21 02 nm) Organic solut ion 31- fold inc rease in Cmax
112-fold increase in MRT
48-fold increase in AUC
Rabbits [95]
Flu rb ip rofen High p ressur e hom ogeniz at ion AN ( NR ) Organic solut ion All p ara meters w ere sim ilar
to those of solution
Rats [96]
Vd volume of distribution CL clearance rate MRT mean retention time AUC area under the concentration ndashtime curve Cmax maximum plasma concentration Tmax time to max-
imum plasma concentration t12 plasma half lifea
NR Not reported
423L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
nanocrystals show clear potential for clinical development compared
with both the solution and the non-targeting nanocrystals formulations
243 Cell-based drug delivery of drug nanocrystals
The signi1047297cantly increased dissolution velocity which is a distinct
advantage of nanocrystals simultaneously implies the problem that
drug nanocrystals might dissolve before reaching the target Cell-
based drug delivery approach canbe employed to deal with this prob-
lem Cell based delivery systems are identi1047297
ed as cell carriers (includ-ing bacteria cells and animal cells) which can be loaded with drugs or
therapeutics The systems can release the drug content in circulation
or at selected sites or could target the drug to other relevant cells in
the body [147] Among the animal cells of special relevance are mac-
rophages and red blood cells (RBCs) Macrophages are differentiated
cells of the immune system able to phagocytize microorganisms as
well as nanoparticulate materials So nanoparticulate systems are
particularly useful for the delivery of therapeutic agents to macro-
phages [148149] When macrophages are used as drug delivery sys-
tems they should be 1047297rst loaded with the nanoparticulate drug ex
vivo and then re-infused into the host where their content is distrib-
uted to tissues that favor homing of macrophages such as parasites
bacteria and viruses [150151] RBCs constitute potential biocompati-
ble carriers for different bioactive substances including protein drugs
as well as nanoparticulates They have unique properties such as bio-
degradability biocompatibility and long-term drug releasing and thus
are well suited for drug encapsulation [152] They can be easily han-
dled ex vivo by means of several techniques for the encapsulation of
different molecules and nanoparticulates [153]
For drug nanocrystals few studies related on cell based drug deliv-
ery have been reported but the existing results proved the feasibility
Dou et al designed a novel bone marrow-derived macrophage (BMM)
indinavir nanocrystals delivery system for antiretroviral treatment
[154] Light microscopic examination proved that indinavir nanocrys-
tals were successfully loaded into BMMs after culture in the presence
of indinavir nanosuspensions for 12 h Following iv administration
into naive mice the indinavir nanocrystal loaded BMMs acted as ldquoTro-
jan horsesrdquo for transport of drug into tissues which were known to be
targets for HIV due to the parallel BMM migration and viral tissue tro-pism Administration of indinavir nanocrystal-BMMs sustained indina-
vir in tissue and sera for up to 10 days in comparison with 6 h for the
non-wrapped nanosuspensions Amphotericin B nanocrystal-loaded
RBCs systems were developed by Staedtke et al in order to improvean-
tifungal treatment [155] Amphotericin B nanocrystals encapsulation in
RBCs wasachieved by using hypotonichemolysis methodleading to in-
tracellularamphotericin B amounts of 381plusmn047 pg RBCminus1andanen-
trapment ef 1047297cacy of 15ndash18 Upon phagocytosis of amphotericin B
nanocrystal-RBCs leukocytes show a slow amphotericin B release
over 10 days and no alteration in cell viability
3 Conclusions
The researchon colloidal drug delivery systems may be the hottest1047297eld in pharmaceutics in the last several decades Due to the unique
advantage and pharmaeconomical value drug nanocrystals are paid
increasing attentions as a promising approach Drug nanocrystals
can be applied to all the poorly soluble drugs to overcome the solubil-
ity and bioavailability problems because all the poorly soluble drugs
can be comminuted into drug nanocrystals Researches on drug nano-
crystals within recent years fully exhibit their excellent in vivo perfor-
mances in different administration routes Among these the most
exciting information is that properties of drug nanocrystals can be
conveniently altered to meet various treatment demands of different
diseases With the number of insoluble drug compounds in develop-
ment increasing it is anticipated that nanocrystals technology will at-
tract increasing attentions as a viable formulation option However
though drug nanocrystals demonstrate superiority over the carrier
colloid drug delivery systems such as easier production safer compo-
sition and higher drug loading correspondingly they also confront
some problems For example how to obtain a more controllable
drug dissolution rate in order to meet the treatment requirements
of different diseases or reduce the drug release in the progress of de-
livering the drugs into target sites How can we get a more 1047297rm con-
junction between ligand-linked stabilizers and nanocrystal surfaces
without the loss of their properties We believe that many studies
will focus on handling these problems in the future
Acknowledgment
This work was partially supported by the Scienti1047297c Foundation of
the First Af 1047297liated Hospital of General Hospital of PLA the project
number is QN201105
References
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[2] ER Cooper Nanoparticles a personal experience for formulating poorly watersoluble drugs J Control Release 141 (2010) 300ndash302
[3] CM Keck RH Muumlller Drug nanocrystals of poorly soluble drugs produced by
high pressure homogenisation Eur J Pharm Biopharm 62 (2006) 3ndash
16[4] BE Rabinow Nanosuspensions in drug delivery Nat Rev Drug Discov 3 (2004)785ndash796
[5] L Gao D Zhang M Chen Drug nanocrystals for the formulation of poorly solu-ble drugs and its application as a potential drug delivery system J NanopartRes 10 (2008) 845ndash862
[6] GG Liversidge KC Cundy Particle size reduction for improvement of oral bio-availability of hydrophobic drugs I Absolute oral bioavailability of nanocrystal-line danazol in beagle dogs Int J Pharm 125 (1995) 91ndash97
[7] K Peters S Leitzke J Diederichs K Borner H Hahn RH Muumlller S Ehlers Prep-aration of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic ef 1047297cacy in murine Mycobacterium avium infection J AntimicrobChemother 45 (2000) 77ndash83
[8] P Rosario B Claudio F Piera M Adriana P Antonina P Giovanni EudragitRS100 nanosuspensions for the ophthalmic controlled delivery of ibuprofenEur J Pharm Sci 16 (2002) 53ndash61
[9] C Jacobs RH Muumlller Production and characterization of a budesonide nanosus-pension for pulmonary administration Pharm Res 19 (2002) 189ndash194
[10] RH Muumlller C Jacobs O Kayser Nanosuspensions as particulate drug formula-
tions in therapy rationale for development and what we can expect for the fu-ture Adv Drug Deliv Rev 47 (2001) 3ndash19
[11] B Van Eerdenbrugh G Van den Mooter P Augustijns Topndashdown production of drug nanocrystals nanosuspension stabilization miniaturization and transfor-mation into solid products Int J Pharm 364 (2008) 64ndash75
[12] E Merisko-Liversidge GG Liversidge ER Cooper Nanosizing a formulationapproach for poorly-water-soluble compounds Eur J Pharm Sci 18 (2003)113ndash120
[13] J Hu KP Johnston RO Williams Nanoparticle engineering processes for en-hancing the dissolution rates of poorly water soluble drugs Drug Dev IndPharm 30 (2004) 233ndash245
[14] JAH Junghanns RH Muumlller Nanocrystal technology drug delivery and clinicalapplications Int J Nanomedicine 3 (2008) 295ndash310
[15] GA Brazeau HL Fung Mechanisms of creatine kinase release from isolated ratskeletal muscles damaged by propylene glycol and ethanol J Pharm Sci 79(1990) 393ndash397
[16] K Korttila A Sothman P Andersson Polyethylene glycol as a solvent for diaze-pam bioavailability and clinical effects after intramuscular administrationcomparison of oral intramuscular and rectal administration and precipitationfrom intravenous solutions Acta Pharmacol Toxicol (Copenh) 39 (1976)104ndash117
[17] R Budden UG Kuhl J Bahlsen Experiments on toxic sedative and muscle re-laxant potency of various drug solvents in mice Pharmacol Ther 5 (1979)467ndash474
[18] F Liu JY Park Y Zhang C Conwell Y Liu SR Bathula L Huang Targeted can-cer therapy with novel high drug-loading nanocrystals J Pharm Sci 99 (2010)3542ndash3551
[19] B Rabinow J Kipp P Papadopoulos J Wong J Glosson J Gass CS Sun TWielgos R White C Cook K Barker K Wood Itraconazole IV nanosuspensionenhances ef 1047297cacy through altered pharmacokinetics in the rat Int J Pharm 339(2007) 251ndash260
[20] F Kesisoglou S Panmai Y Wu Nanosizingmdashoral formulation development andbiopharmaceutical evaluation Adv Drug Deliv Rev 59 (2007) 631ndash644
[22] GG Liversidge P Conzentino Drug particle size reduction for decreasing gastricirritancy and enhancing absorption of naproxen in rats Int J Pharm 125 (1995)
309ndash
313
427L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[23] E Merisko-Liversidge GG Liversidge Nanosizing for oral and parenteral drugdelivery a perspective on formulating poorly-water soluble compounds usingwet media milling technology Adv Drug Deliv Rev 30 (2011) 427ndash440
[24] BHL Boumlhm RH Muumlller Lab-scale production unit design for nanosuspensions of sparingly soluble cytotoxic drugs Pharm Sci Technol Today 2 (1999) 336ndash339
[25] RH Drew E Dodds Ashley DK Benjamin Jr R Duane Davis SM Palmer JRPerfect Comparative safety of amphotericin B lipid complex and amphotericinB deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipi-ents Transplantation 77 (2004) 232ndash237
[26] J Dubois T Bartter J Gryn MR Pratter The physiologic effects of inhaledamphotericin B Chest 108 (1995) 750ndash753
[27] SM Palmer RH Drew JD Whitehouse VF Tapson RD Davis RR McConnellSS Kanj JR Perfect Safety of aerosolized amphotericin B lipid complex in lungtransplant recipients Transplantation 72 (2001) 545ndash548
[28] RO Williams III J Liu Formulation of a protein with propellant HFA 134a foraerosol delivery Eur J Pharm Sci 7 (1999) 137ndash144
[29] IC Ashurst CV Ambrose DJ Russell Pharmaceutical evaluation of a new spac-er device for delivery of metered-dose inhalers to infants and young children JAerosol Sci 23 (1992) 499ndash502
[30] GC Na HJ Stevens B Yuan N Rajagopalan Physical stability of ethyl diatrizoatenanocrystalline suspension in steam sterilization Pharm Res 16 (1999) 569ndash574
[31] H Lou X Zhang L Gao F Feng J Wang X Wei Z Yu D Zhang Q Zhang Invitro and in vivo antitumor activity of oridonin nanosuspension Int J Pharm379 (2009) 181ndash186
[32] L Gao D Zhang M Chen C Duan W Dai L Jia W Zhao Studies on pharmaco-kinetics and tissue distribution of oridonin nanosuspensions Int J Pharm 355(2008) 321ndash327
[33] SM Moghimi AC Hunter JC Murray Long circulating and target-speci1047297cnanoparticles theory to practice Pharmacol Rev 53 (2001) 283ndash381
[34] S Ganta JW Paxton BC Baguley S Garg Formulation and pharmacokinetic
evaluation of an asulacrine nanocrystalline suspension for intravenous deliveryInt J Pharm 367 (2009) 179ndash186
[35] K Sigfridsson S Forsseacuten P Hollaumlnder U Skantze J de Verdier A formulationcomparison using a solution and different nanosuspensions of a poorly solublecompound Eur J Pharm Biopharm 67 (2007) 540ndash547
[36] K Sigfridsson AJ Lundqvist M Strimfors Particle size reduction for improve-ment of oral absorption absorption of the poorly soluble drug UG558 in rats dur-ing early development Drug Dev Ind Pharm 35 (2009) 1479ndash1486
[37] S Kim J Lee Folate-targeted drug-delivery systems prepared by nano-comminution Drug Dev Ind Pharm 37 (2011) 131ndash138
[38] R Xiong W Lu J Li P Wang R Xu T Chen Preparation and characterization of intravenously injectable nimodipine nanosuspension Int J Pharm 350 (2008)338ndash343
[39] Y Gao Z Li M Sun C Guo A Yu Y Xi J Cui H Lou G Zhai Preparation andcharacterization of intravenously injectable curcumin nanosuspension DrugDeliv 18 (2011) 131ndash142
[40] RH Muumlller K Peters Nanosuspensions for the formulation of poorly solubledrugs I Preparation by a size-reduction technique Int J Pharm 160 (1998)229ndash237
[41] SB Zirar A Astier M Muchow S Gibaud Comparison of nanosuspensions andhydroxypropyl-b-cyclodextrin complex of melarsoprol pharmacokinetics andtissue distribution in mice Eur J Pharm Biopharm 70 (2008) 649 ndash656
[42] M Salzberg M Pless C Rochlitz K Ambrus P Scigalla R Herrmann A phase Istudy with oral SU5416 in patients with advanced solid tumors a drug inducingits clearance Invest New Drugs 24 (2006) 299ndash304
[43] WK Kraft B Steiger D Beussink JN Quiring N Fitzgerald HE Greenberg SAWaldman The pharmacokinetics of nebulized nanocrystal budesonide suspen-sion in healthy volunteers J Clin Pharmacol 44 (2004) 67ndash72
[44] JM Vaughn NP Wiederhold JT McConville JJ Coalson RL Talbert DSBurgess KP Johnston RO Williams III JI Peters Murine airway histologyand intracellular uptake of inhaled amorphous itraconazole Int J Pharm 338(2007) 219ndash224
[45] JM Vaughn JT McConville D Burgess JI Peters KP Johnston RL Talbert ROWilliams III Single dose and multiple dose studies of itraconazole nanoparticlesEur J Pharm Biopharm 63 (2006) 95ndash102
[46] BJ Hoeben DS Burgess JT McConville LK Najvar RL Talbert JI Peters NPWiederhold BL Frei JR Graybill R Bocanegra KA Overhoff P Sinswat KP
Johnston RO Williams III In vivo ef 1047297cacy of aerosolized nanostructured itraco-nazole formulations for prevention of invasive pulmonary aspergillosis Antimi-crob Agents Chemother 50 (2006) 1552ndash1554
[47] CA Alvarez NP Wiederhold JT McConville JI Peters LK Najvar JR Graybill JJ Coalson RL Talbert DS Burgess R Bocanegra KP Johnston RO WilliamsIII Aerosolized nanostructured itraconazole as prophylaxis against invasive pul-monary aspergillosis J Infect 55 (2007) 68ndash74
[48] SB Shrewsbury AP Bosco PS Uster Pharmacokinetics of a novel submicronbudesonide dispersion for nebulized delivery in asthma Int J Pharm 365(2009) 12ndash17
[49] RH Muumlller KH Wallis Surface modi1047297cation of iv injectable biodegradablenanoparticles with poloxamer polymers and poloxamine 908 Int J Pharm 89(1993) 25ndash31
[50] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy and diagno-sis Adv Drug Deliv Rev 54 (2002) 631ndash651
[51] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (2000) 73ndash80
[52] M Wang M Thanou Targeting nanoparticles to cancer Pharmacol Res 62(2010) 90ndash99
[53] L Gao G Liu X Wang F Liu Y Xu J Ma Preparation of a chemically stablequercetin formulation using nanosuspension technology Int J Pharm 404(2011) 231ndash237
[54] M Sarkari J Brown X Chen S Swinnea RO Williams III KP Johnston En-hanced drug dissolution using evaporative precipitation into aqueous solutionInt J Pharm 243 (2002) 17ndash31
[55] X Li L Gu Y Xu Y Wang Preparation of feno1047297brate nanosuspension and studyof its pharmacokinetic behavior in rats Drug Dev Ind Pharm 35 (2009)827ndash833
[56] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Pharmacokinetic evaluation of oral feno1047297brate nanosus-
pensions and SLN in comparison to conventional suspensions of micronizeddrug Adv Drug Deliv Rev 59 (2007) 419ndash426[57] GJ Vergote C Vervaet I Van Driessche S Hoste S De Smedt J Demeester RA
Jain S Ruddy JP Remon In vivo evaluation of matrix pellets containing nano-crystalline ketoprofen Int J Pharm 240 (2002) 79ndash84
[58] S Ghosh P Chiang JL Wahlstrom H Fujiwara JG Selbo SL Roberds Oral de-livery of 13-dicyclohexylurea nanosuspension enhances exposure and lowersblood pressure in hypertensive rats Basic Clin Pharmacol Toxicol 102 (2008)453ndash458
[59] P Langguth A Hanafy D Frenzel P Grenier A Nhamias T Ohlig G VergnaultH Spahn-Langguth Nanosuspension formulations for low-soluble drugs phar-macokinetic evaluation using spironolactone as model compound Drug DevInd Pharm 31 (2005) 319ndash329
[60] MG Fakesa Blisse J Vakkalagaddab Feng Qiana Sridhar Desikana Rajesh BGandhi C Lai A Hsieha MK Franchini H Toaled J Brown Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amor-phous formulation approaches Int J Pharm 370 (2009) 167ndash174
[61] K Sigfridsson A Nordmark S Theilig A Lindah A formulation comparison be-tween micro- and nanosuspensions the importance of particle size for absorp-
tion of a model compound following repeated oral administration to rats duringearly development Drug Dev Ind Pharm 37 (2011) 185ndash192
[62] J Jinno N Kamada M Miyake K Yamada T Mukai M Odomi H Toguchi GGLiversidge K Higaki T Kimura Effect of particle size reduction on dissolutionand oral absorption of a poorly water-soluble drug cilostazol in beagle dogs JControl Release 111 (2006) 56ndash64
[63] Y Wu A Loper E Landis L Hettrick L Novak K Lynn C Chen K Thompson RHiggins U Batra S Shelukar G Kwei D Storey The role of biopharmaceutics inthe development of a clinical nanoparticle formulation of MK-0869 a beagledog model predicts improved bioavailability and diminished food effect on ab-sorption in human Int J Pharm 285 (2004) 135ndash146
[64] RH Muumlller S Runge V Ravelli W Mehnert AF Thuumlnemann EB Souto Oralbioavailability of cyclosporine solid lipid nanoparticles (SLNreg) versus drugnanocrystals Int J Pharm 317 (2006) 82ndash89
[65] G Ponchel MJ Montisci A Dembri C Durrer D Duchecircne Mucoadhesion of colloidal particulate systems in the gastro-intestinal tract Eur J Pharm Bio-pharm 44 (1997) 25ndash31
[66] D Duchecircne G Ponchel Bioadhesion of solid oral dosage forms why and howEur J Pharm Biopharm 44 (1997) 15ndash23
[67] D Dodou P Breedveld PA Wieringa Mucoadhesives in the gastrointestinaltract revisiting the literature for novel applications Eur J Pharm Biopharm60 (2005) 1ndash16
[68] JD Smart The basics and underlying mechanisms of mucoadhesion Adv DrugDeliv Rev 57 (2005) 1556ndash1568
[69] O Kayser A newapproach fortargetingto Cryptosporidium parvum using mucoadhe-sive nanosuspensions research and applications Int J Pharm 214 (2001) 83ndash85
[70] A des Rieux V Fievez M Garinot YJ Schneider V Preacuteat Nanoparticles as po-tential oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[71] A Lamprecht P Koenig N Ubrich P Maincent D Neumann Low molecularweight heparin nanoparticles mucoadhesion and behaviour in Caco-2 cellsNanotechnology 17 (2006) 3673ndash3680
[72] F Delie Evaluation of nano- and microparticle uptake by the gastrointestinaltract Adv Drug Deliv Rev 34 (1998) 221ndash233
[73] CN Grama DD Ankola MNV Ravi Kumar Poly(lactide-co-glycolide) nano-particles for peroral delivery of bioactives Curr Opin Colloid Interface Sci 16(2011) 238ndash245
[74] MP Desai V Labhasetwar GL Amidon RJ Levy Gastrointestinal Uptake of biodegradable microparticles effect of particle size Pharm Res 13 (1996)1838ndash1845
[75] A des Rieux V Fievez M Garinot YJ Scheider V Preat Nanoparticles as poten-tial oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[76] JM Dintaman JA Silverman Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) Pharm Res 16 (1999)1550ndash1556
[77] J Goole DJ Lindley W Roth SM Carl K Amighi JM Kauffmann GT KnippThe effects of excipients on transporter mediated absorption Int J Pharm 393(2010) 17ndash31
[78] J Huang L Si L Jiang Z Fan J Qiu G Li Effect of pluronic F68 block copolymeron P-glycoprotein transport and CYP3A4 metabolism Int J Pharm 356 (2008)351ndash353
[79] MF Wempe C Wright JL Little JW Lightner SE Large GB Ca1047298isch CMBuchanan PJ Rice VJ Wacher KM Ruble KJ Edgar Inhibiting ef 1047298ux withnovel non-ionic surfactants rational design based on vitamin E TPGS Int JPharm 370 (2009) 93ndash102
428 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[81] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Absence of a food effect with a 145 mg nanoparticle feno-1047297brate tablet formulation Int J Clin Pharmacol Ther 44 (2006) 64ndash70
[82] MV Chaubal C Popescu Conversion of nanosuspensions into dry powders byspray drying a case study Pharm Res 25 (2008) 2302ndash2308
[83] F Lai E Pini G Angioni ML Manca J Perricci C Sinico AM Fadda Nanocrys-tals as tool to improve piroxicam dissolution rate in novel orally disintegratingtablets Eur J Pharm Biopharm 79 (2011) 552ndash558
[84] D Mou H Chen J Wan H Xu X Yang Potent dried drug nanosuspensions for
oral bioavailability enhancement of poorly soluble drugs with pH-dependentsolubility Int J Pharm 413 (2011) 237ndash244[85] A Ain-Ai PK Gupta Effect of arginine hydrochloride and hydroxypropyl cellu-
lose as stabilizers on the physical stability of high drug loading nanosuspensionsof a poorly soluble compound Int J Pharm 351 (2008) 282 ndash288
[86] Z Guo T Pereira O Choi Y Wang HT Hahn Surface functionalized aluminananoparticle 1047297lled polymeric nanocomposites with enhanced mechanical prop-erties J Mater Chem 16 (2006) 2800ndash2808
[87] DR Kalaria G Sharma V Beniwal MN Ravi Kumar Design of biodegradablenanoparticles for oral delivery of doxorubicin in vivo pharmacokinetics and tox-icity studies in rats Pharm Res 26 (2009) 492ndash501
[88] JE Kipp The role of solid nanoparticle technology in parenteral delivery of poorly water soluble drugs Int J Pharm 284 (2004) 109ndash122
[89] HM Shubar S Lachenmaier MM Heimesaat U Lohman R Mauludin RHMuumlller R Fitzner K Borner O Liesenfeld SDS-coated atovaquone nanosuspen-sions show improved therapeutic ef 1047297cacy against experimental acquired andreactivated toxoplasmosis by improving passage of gastrointestinal and bloodndash
brain barriers J Drug Target 19 (2011) 114ndash124[90] L Peltonen J Hirvonen Pharmaceutical nanocrystals by nanomilling critical
process parameters particle fracturing and stabilization method J Pharm Phar-macol 62 (2010) 1569ndash1579
[91] F Lai C Sinico G Ennas F Marongiu G Marongiu AM Fadda Diclofenac nano-suspensions in1047298uence of preparation procedure and crystal form on drug disso-lution behavior Int J Pharm 373 (2009) 124ndash132
[92] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (Suppl 2) (2000) S73ndashS80
[93] RH Muller CM Keck Challenges and solutions for the delivery of biotech drugsmdasha review of drug nanocrystal technology and lipid nanoparticles J Biotechnol113 (2004) 151ndash170
[94] JL Wahlstrom P Chiang S Ghosh CJ Warren SP Wene LA Albin ME SmithSL Roberds Pharmacokinetic evaluation of a 13-dicyclohexylurea nanosuspen-sion formulation to support early ef 1047297cacy assessment Nanoscale Res Lett 2(2007) 291ndash296
[95] Y GaoZ LiM SunH Li CGuoJ CuiA LiF CaoY XiH Lou GZhai Preparationcharacterization pharmacokinetics and tissue distribution of curcumin nanosus-pension with TPGS as stabilizer Drug Dev Ind Pharm 36 (2010) 1225ndash1234
[96] M Clement W Pugh I Parikh Tissue distribution and plasma clearance of a novelmicrocrystalline-coated 1047298urbiprofen formulation Pharmacologist 34 (1992)204ndash211
[97] RC Nagarwal S Kant PN Singh P Maiti JK Pandit Polymeric nanoparticulate sys-tem a potential approach for ocular drug delivery J Control Release 136 (2009)2ndash13
[98] H Gupta M Aqil RK Khar A Ali A Bhatnagar G Mittal Spar1047298oxacin loadedPLGA nanoparticles for sustained ocular drug delivery Nanomedicine 6 (2010)324ndash333
[99] HS Ali P York AM Ali N Blagden Hydrocortisone nanosuspensions for oph-thalmic delivery a comparative study between micro1047298uidic nanoprecipitationand media milling J Control Release 149 (2011) 175ndash181
[100] SK Sahoo F Dilnawaz S Krishnakumar Nanotechnology in ocular drug deliv-ery Drug Discov Today 13 (2008) 144ndash151
[101] O Kayser A Lemke N Hernaacutendez-Trejo The impact of nanobiotechnology on thedevelopment of newdrug deliverysystems Curr Pharm Biotechnol6 (2005) 3ndash5
[102] R Pignatello C Bucolo G Spedalieri A Maltese G Puglisi Flurbiprofen-loadedacrylate polymer nanosuspensions for ophthalmic application Biomaterials 23(2002) 3247ndash3255
[103] R Ravichandran Nanoparticles in drug delivery potential green nanobiomedi-
cine applications Int J Green Nanotechnol Biomed 1 (2009) B108ndash
B130[104] AM Cerdeira M Mazzotti B Gander Miconazole nanosuspensions in1047298uence
of formulation variables on particle size reduction and physical stability Int JPharm 396 (2010) 210ndash218
[105] MA Kassem AA Abdel Rahman MM Ghorab MB Ahmed RM Khalil Nano-suspension as an ophthalmic delivery system for certain glucocorticoid drugsInt J Pharm 340 (2007) 126ndash133
[106] P Chiang JW Alsup Y Lai Y Hu BR Heyde D Tung Evaluation of aerosol de-livery of nanosuspension for pre-clinical pulmonary drug delivery NanoscaleRes Lett 4 (2009) 254ndash261
[107] W Yang JI Peters RO Williams III Inhaled nanoparticlesmdasha current reviewInt J Pharm 356 (2008) 239ndash247
[108] J Zhang L Wu H Chan W Watanabe Formation characterization and fate of inhaled drug nanoparticles Adv Drug Deliv Rev 63 (2011) 441ndash455
[109] HM Mansour YS Rhee X Wu Nanomedicine in pulmonary delivery Int JNanomedicine 4 (2009) 299ndash319
[110] NR Labiris MB Dolovich Pulmonary drug delivery Part I physiological factorsaffecting therapeutic effectiveness of aerosolized medications Br J Clin Phar-macol 56 (2003) 588ndash599
[111] JS Patton PR Byron Inhaling medicines delivering drugs to the body throughthe lungs Nat Rev Drug Discov 6 (2007) 67ndash74
[112] DA Edwards C Dunbar Bioengineering of therapeutic aerosols Annu RevBiomed Eng 4 (2002) 93ndash107
[113] W Yang JTam DA Miller J Zhou JT McConville KP Johnstonb RO WilliamsIII High bioavailability from nebulized itraconazole nanoparticle dispersionswith biocompatible stabilizers Int J Pharm 361 (2008) 177ndash188
[114] S Gill R Lobenberg T Ku S Azarmi W Roa EJ Prenner Nanoparticles char-acteristics mechanisms of action and toxicity in pulmonary drug deliverymdasha re-view J Biomed Nanotechnol 3 (2007) 107ndash119
[115] SJ Sze1047298er Pharmacodynamics and pharmacokinetics of budesonide a new
S183[116] W Yang KP Johnston RO Williams III Comparison of bioavailability of amor-phous versus crystalline itraconazole nanoparticles via pulmonary administra-tion in rats Eur J Pharm Biopharm 75 (2010) 33 ndash41
[117] R Ali GK Jain Z Iqbal S Talegaonkar P Pandit S Sule G Malhotra RK KharA Bhatnagar FJ Ahmad Development and clinical trial of nano-atropine sulfatedry powder inhaler as a novel organophosphorous poisoning antidote Nanome-dicine 5 (2009) 55ndash63
[118] D Andes Minireview in vivo pharmacodynamics of antifungal drugs in treat-ment of candidiasis Antimicrob Agents Chemother 47 (2003) 1179ndash1186
[119] D Andes K Marchillo R Conklin G Krishna F Ezzet A Cacciapuoti DLoebenberg Pharmacodynamics of a new triazole posaconazole in a murinemodel of disseminated candidiasis Antimicrob Agents Chemother 48 (2004)137ndash142
[120] O Kayser C Olbrich V Yardley AF Kiderlen SL Croft Formulation of ampho-tericin B as nanosuspension for oral administration Int J Pharm 254 (2003)73ndash75
[121] L Zhang S Hou S Mao D Wei X Song Y Lu Uptake of folate-conjugated albu-min nanoparticles to the SKOV3 cells Int J Pharm 287 (2004) 155ndash162
[122] J Sudimack RJ Lee Targeted drug delivery via folate receptor Adv Drug DelivRev 41 (2000) 147ndash162
[123] P Vader LJ van der Aa G Storm RM Schiffelers JF Engbersen Polymeric car-rier systems for siRNA delivery Curr Top Med Chem 12 (2012) 108 ndash119
[124] O Veiseh FM Kievit RG Ellenbogen M Zhang Cancer cell invasion treatmentand monitoring opportunities in nanomedicine Adv Drug Deliv Rev 63 (2011)582ndash596
[125] J Kreuter VE Petrov DA Kharkevich RN Alyautdin In1047298uence of the type of surfactant on the analgesic effects induced by the peptide dalargin after its de-livery across the bloodndashbrain barrier using surfactant-coated nanoparticles JControl Release 49 (1997) 81ndash87
[126] J Ye Q Wang X Zhou N Zhang Injectable actarit-loaded solid lipid nanoparti-cles as passive targeting therapeutic agents for rheumatoid arthritis Int JPharm 352 (2008) 273ndash279
[127] SM Moghimi AC Hunter JC Murray Nanomedicine current status and futureprospects FASEB J 19 (2005) 311ndash330
[128] K Park To PEGylate or not PEGylate that is not the question J Control Release142 (2010) 147ndash148
[129] M Socha P Bartecki C Passitani A Sapin C Damge T Lecompte J BarreE Ghazouani P Maincent Stealth nanoparticles coated with heparin aspeptide or peptide carriers J Drug Target 17 (2009) 575ndash585
[130] D Shenoy S Little R Langer M Amiji Poly(ethylene oxide)-modi1047297ed poly(-beta-amino ester) nanoparticles as a pH-sensitive system for tumor targeted de-livery of hydrophobic drugs part 2 In vivo distribution and tumor localizationstudies Pharm Res 22 (2005) 2107ndash2114
[131] R Shegokara KK Singha Surface modi1047297ed nevirapinenanosuspensions for viralreservoir targeting in vitro and in vivo evaluation Int J Pharm 421 (2011)341ndash352
[132] Y Matsumura H Maeda A new concept for macromolecular therapeutics incancer chemotherapy mechanism of tumoritropic accumulation of proteinsand the antitumor agent SMANCS Cancer Res 46 (1986) 6387ndash6392
[133] H Zhang CP Hollis Q Zhang T Li Preparation and antitumor study of camp-tothecin nanocrystals Int J Pharm 415 (2011) 293ndash300
[134] H Lou L Gao X Wei Z Zhang D Zheng D Zhang X Zhang Y Li Q Zhang Ori-donin nanosuspension enhances anti-tumor ef 1047297cacy in SMMC-7721 cells andH22 tumor bearing mice Colloids Surf B Biointerfaces 87 (2011) 319ndash325
[135] TM Goppert RH Muumlller Adsorption kinetics of plasma proteins on solid lipid
nanoparticles for drug targeting Int J Pharm 302 (2005) 172ndash
186[136] X Pu J Sun M Li Z He Formulation of nanosuspensions as a new approach for
the delivery of poorly soluble drugs Curr Nanosci 5 (2009) 417ndash427[137] R Gaudana J Jwala SHS Boddu AK Mitra Recent perspectives in ocular drug
delivery Pharm Res 26 (2009) 1197ndash1216[138] T Yasukawa H Kimura Y Tabata H Miyamoto Y Honda Y Ikada Y Ogura
Targeted delivery of anti-angiogenic agent TNP-470 using water-soluble poly-mer in the treatment of choroidal neovascularization Invest Ophthalmol VisSci 40 (1999) 2690ndash2696
[139] A Lemke AF Kiderlen B Petri O Kayser Delivery of amphotericin B nanosus-pensions to the brain and determination of activity against Balamuthia mandril-laris amebas Nanomedicine 6 (2010) 597ndash603
[140] HL Wong XY Wu R Bendayan Nanotechnological advances forthe delivery of CNS therapeutics Adv Drug Deliv Rev (2011) doi101016jaddr201110007
[141] J Kreuter S Gelperina Use of nanoparticles for cerebral cancer Tumori 94(2008) 271ndash277
[142] J Kreuter RN Alyautdin DA Kharkevich AA Ivanov Passage of peptidesthrough the bloodndashbrain barrier with colloidal polymer particles (nanoparti-cles) Brain Res 674 (1995) 171ndash174
429L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[143] J Kreuter Nanoparticulate systems for brain delivery of drugs Adv Drug DelivRev 47 (2001) 65ndash81
[144] TM Goumlppert RH Muumlller Polysorbate-stabilized solid lipid nanoparticles as col-loidal carriers for intravenous targeting of drugs to the brain comparison of plasma protein adsorption patterns J Drug Target 13 (2005) 179ndash187
[145] S Mansouri Y Cuie F Winnik Q Shi P Lavigne M Benderdour E Beaumont JC Fernandes Characterization of folate-chitosan-DNA nanoparticles for genetherapy Biomaterials 27 (2006) 2060ndash2065
[146] AR Hilgenbrink PS Low Folate receptor-mediated drug targeting from thera-peutics to diagnostics J Pharm Sci 94 (2005) 2135ndash2146
[147] F Pierigegrave S Sera1047297ni L Rossi M Magnani Cell-based drug delivery Adv Drug
Deliv Rev 60 (2008) 286ndash
295[148] F Chellat Y Merhi A Moreau L Yahia Therapeutic potential of nanoparticulatesystems for macrophage targeting Biomaterials 26 (2005) 7260ndash7275
[149] SS Hall S Mitragotri PS Daugherty Identi1047297cation of peptide ligands facilitatingnanoparticle at attachment to erythrocytes Biotechnol Prog 23 (2007) 749ndash754
[150] S Gorantla H Dou M Boska CJ Destache J Nelson L Poluektova BERabinow HE Gendelman RL Mosley Quantitative magnetic resonance and
SPECT imaging for macrophage tissue migration and nanoformulated drug de-livery J Leukoc Biol 80 (2006) 1165ndash1174
[151] LA Lotero G Olmos JC Diez Delivery to macrophages and toxic action of etopo-sidecarried in mouse redblood cells Biochim Biophys Acta 1620 (2003) 160ndash166
[152] L Rossi S Sera1047297ni F Pierigeacute A Antonelli A Cerasi A Fraternale L ChiarantiniM Magnani Erythrocyte-based drug delivery Expert Opin Drug Deliv 2 (2005)311ndash322
[153] S Sera1047297ni L Rossi A Antonelli A Fraternale A Cerasi R Crinelli L ChiarantiniGF Schiavano M Magnani Drug delivery through phagocytosis of red bloodcells Transfus Med Hemother 31 (2004) 92ndash101
[154] H Dou CJ Destache JR Morehead R Lee Mosley MD Boska J Kingsley S
Gorantla L Poluektova JA Nelson M Chaubal J Werling J Kipp BERabinow HE Gendelman Development of a macrophage-based nanoparticleplatform for antiretroviral drug delivery Blood 108 (2006) 2827ndash2835
[155] V Staedtke M Braumller A Muumlller R Georgieva S Bauer N Sternberg A Voigt ALemke C Keck J Moumlschwitzer H Baumlumler In vitro inhibition of fungal activityby macrophage-mediated sequestration and release of encapsulated amphoter-icin B nanosuspension in red blood cells Small 6 (2010) 96ndash103
430 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
It should be bear in mind that most drug nanocrystal formulations
used in the in vivo experiments are aqueous dispersions (Table 3)
however when it comes to the clinical application solid dosage
forms are usually more acceptable by patients [82] It can be seen
that most of the marketed nanoparticles formulations are solid
forms (Table 1) In order to solidi1047297cation 1047297rst the aqueous nanosus-
pensions should be transformed into dry powders suitable to gener-
ate tablets capsules pellets etc This transformation can be
achieved using different methods including lyophilization spray dry-ing granulation and pelletization [83ndash86] The drying process should
be well designed to avoid particle aggregation If aggregation occurs
the bene1047297ts that can be gained from large surface of the original
nanometer-sized particles would be greatly compromised In general
protectants (usually sugars) are often added to nanosuspensions to
minimize the particle size growth during a drying process
The redispersion progress of a solid formulation containing drug
nanocrystals in the GIT is more complex Physiological factors (in-
cluding pH variation compositions of the digestive juice and GI peri-
stalsis etc) affecting dispersion of nanocrystals are complicated [87]
Nanocrystals of basic drugs are more easily affected by pH variation in
the GIT For weak bases a nanometer-sized drug formulation will dis-
solve fast and more ef 1047297ciently in the low stomach pH environment
During transit from stomach to duodenum the rise in pH may illicit
uncontrolled precipitation of drug substance [88] In addition stabi-
lizer type should be screened by monitoring the change of particle
size after reconstitution in different pH media [89] After rehydration
in GI 1047298uid the nanocomplex disperses into separated nanocrystals
following the dissolution of 1047297llers Stabilizer molecules attached on
the surface of nanocrystals will offer ionic or steric repulsion among
nanocrystals given that they are not affected by the GIT environment
[690] In general ionic stabilizers are effective in aqueous environ-
ment but during the drying they may become less effective because
the ionized state is not maintained in dry material In addition ionic
stabilizers are also sensitive to changes in pH and ionic strength
when the dried powders redisperse in the GI 1047298uid [90] On the con-
trary in most cases the polymer and non-ionic surfactant stabilizers
can be effective to support suf 1047297cient steric repulsion in GI 1047298uid
given that the amount of stabilizers is enough [91]
The establishment of an in vitrondash
in vivo correlation (IVIVC) is anessential part for the study of oral formulations For the Class II
drugs dissolution is a rate-limiting step in the GIT so in general
they have a good IVIVC result [92] When they are processed into
nanocrystal formulations an IVIVC should be reevaluated again
since their dissolution velocity has been markedly enhanced In the
other hand the IVIVC data also help modulate the process and the
amount of matrix in the progress of drying nanosuspensions Howev-
er research on the IVIVC of nanocrystal formulations has not been
reported but we believe it will be the next focus in this 1047297eld
222 Injection administration route
For many cases intravenous injection is requested to meet some
treatment purpose such as immediate effects overcoming the 1047297rst
pass effect targeting effect and so on Due to its suf 1047297ciently small
size and safe aqueous composition nanosuspensions can be injected
intravenously and achieve 100 bioavailability [86] Compared with
other carrier-based solid nanoparticles such as solid lipid nanoparti-
cles polymer-based nanoparticles and liposomes carrier-free nano-
crystals would experience a much faster particle size reduction
during the process of dissolution This may lead to a distinct pharma-
cokinetic progress after iv administration because particle size is an
Table 4
Changes of pharmacokinetic properties of intravenous nanosuspensions compared with the conventional partners
Drug Methods Dosage form
(mean particle size)
Control
(mean particle size)
Comparison of the
pharmacokinetic parameters
Animals References
Asulac rine High p ressur e hom ogeniz at ion AN ( 13 3 nm) Organic solut ion 15- fold r edu ction in Cmax23-fold increase in t12 62-fold
increase in Vd 27-fold increase in
CL 27-fold increase in MRT
25-fold reduction in AUC
Rats [34]
Melar sopr ol High p ressur e hom ogeniz at ion AN ( 29 5 nm) Organic solut ion 22- fold inc rease in t12 14-fold
increase in Vd 14-fold reduction
in CL 2-fold reduction in AUC
Rats [41]
AN (409 nm) 3-fold increase in t12 13-fold reduction
in Vd 45-fold reduction in CL 42-fold
reduction in AUC
13-Dicyclohexylurea Media milling AN (NR)a Organic solution All parameters were similar to
those of solution
Rats [94]
Oridonin High p ressur e hom ogeniz at ion AN ( 10 33 nm) Organic solut ion All p ara meters w ere sim ilar to
those of solution 17-fold reduction
in Cmax 7-fold increase in t12 51-fold
increase in Vd 19-fold reduction in CL
62-fold increase in MRT 18-foldincrease in AUC
Rabbits [32]
AN (8972 nm)
It rac onaz ole High p ressur e hom ogeniz at ion AN ( 58 1 nm) Organic solut ion 17- fold inc rease in Cmax 31-fold
increase in t12 18 reduction in AUC 18
increase in CL 28 increase in MRT 79
increase in Vd
Rats [19]
AZ68 Precipitation AN (125 nm) Organic solution No signi1047297cant differences with
solution by means of plasma pro1047297les
Rats [35]
Media milling AN (200 nm)
Cyclosporine Precipitation AN (NR) Organic solution All parameters were similar to
those of solution
Rats [93]
Cu rc um in High p ressur e hom ogeniz at ion AN ( 21 02 nm) Organic solut ion 31- fold inc rease in Cmax
112-fold increase in MRT
48-fold increase in AUC
Rabbits [95]
Flu rb ip rofen High p ressur e hom ogeniz at ion AN ( NR ) Organic solut ion All p ara meters w ere sim ilar
to those of solution
Rats [96]
Vd volume of distribution CL clearance rate MRT mean retention time AUC area under the concentration ndashtime curve Cmax maximum plasma concentration Tmax time to max-
imum plasma concentration t12 plasma half lifea
NR Not reported
423L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
nanocrystals show clear potential for clinical development compared
with both the solution and the non-targeting nanocrystals formulations
243 Cell-based drug delivery of drug nanocrystals
The signi1047297cantly increased dissolution velocity which is a distinct
advantage of nanocrystals simultaneously implies the problem that
drug nanocrystals might dissolve before reaching the target Cell-
based drug delivery approach canbe employed to deal with this prob-
lem Cell based delivery systems are identi1047297
ed as cell carriers (includ-ing bacteria cells and animal cells) which can be loaded with drugs or
therapeutics The systems can release the drug content in circulation
or at selected sites or could target the drug to other relevant cells in
the body [147] Among the animal cells of special relevance are mac-
rophages and red blood cells (RBCs) Macrophages are differentiated
cells of the immune system able to phagocytize microorganisms as
well as nanoparticulate materials So nanoparticulate systems are
particularly useful for the delivery of therapeutic agents to macro-
phages [148149] When macrophages are used as drug delivery sys-
tems they should be 1047297rst loaded with the nanoparticulate drug ex
vivo and then re-infused into the host where their content is distrib-
uted to tissues that favor homing of macrophages such as parasites
bacteria and viruses [150151] RBCs constitute potential biocompati-
ble carriers for different bioactive substances including protein drugs
as well as nanoparticulates They have unique properties such as bio-
degradability biocompatibility and long-term drug releasing and thus
are well suited for drug encapsulation [152] They can be easily han-
dled ex vivo by means of several techniques for the encapsulation of
different molecules and nanoparticulates [153]
For drug nanocrystals few studies related on cell based drug deliv-
ery have been reported but the existing results proved the feasibility
Dou et al designed a novel bone marrow-derived macrophage (BMM)
indinavir nanocrystals delivery system for antiretroviral treatment
[154] Light microscopic examination proved that indinavir nanocrys-
tals were successfully loaded into BMMs after culture in the presence
of indinavir nanosuspensions for 12 h Following iv administration
into naive mice the indinavir nanocrystal loaded BMMs acted as ldquoTro-
jan horsesrdquo for transport of drug into tissues which were known to be
targets for HIV due to the parallel BMM migration and viral tissue tro-pism Administration of indinavir nanocrystal-BMMs sustained indina-
vir in tissue and sera for up to 10 days in comparison with 6 h for the
non-wrapped nanosuspensions Amphotericin B nanocrystal-loaded
RBCs systems were developed by Staedtke et al in order to improvean-
tifungal treatment [155] Amphotericin B nanocrystals encapsulation in
RBCs wasachieved by using hypotonichemolysis methodleading to in-
tracellularamphotericin B amounts of 381plusmn047 pg RBCminus1andanen-
trapment ef 1047297cacy of 15ndash18 Upon phagocytosis of amphotericin B
nanocrystal-RBCs leukocytes show a slow amphotericin B release
over 10 days and no alteration in cell viability
3 Conclusions
The researchon colloidal drug delivery systems may be the hottest1047297eld in pharmaceutics in the last several decades Due to the unique
advantage and pharmaeconomical value drug nanocrystals are paid
increasing attentions as a promising approach Drug nanocrystals
can be applied to all the poorly soluble drugs to overcome the solubil-
ity and bioavailability problems because all the poorly soluble drugs
can be comminuted into drug nanocrystals Researches on drug nano-
crystals within recent years fully exhibit their excellent in vivo perfor-
mances in different administration routes Among these the most
exciting information is that properties of drug nanocrystals can be
conveniently altered to meet various treatment demands of different
diseases With the number of insoluble drug compounds in develop-
ment increasing it is anticipated that nanocrystals technology will at-
tract increasing attentions as a viable formulation option However
though drug nanocrystals demonstrate superiority over the carrier
colloid drug delivery systems such as easier production safer compo-
sition and higher drug loading correspondingly they also confront
some problems For example how to obtain a more controllable
drug dissolution rate in order to meet the treatment requirements
of different diseases or reduce the drug release in the progress of de-
livering the drugs into target sites How can we get a more 1047297rm con-
junction between ligand-linked stabilizers and nanocrystal surfaces
without the loss of their properties We believe that many studies
will focus on handling these problems in the future
Acknowledgment
This work was partially supported by the Scienti1047297c Foundation of
the First Af 1047297liated Hospital of General Hospital of PLA the project
number is QN201105
References
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[3] CM Keck RH Muumlller Drug nanocrystals of poorly soluble drugs produced by
high pressure homogenisation Eur J Pharm Biopharm 62 (2006) 3ndash
16[4] BE Rabinow Nanosuspensions in drug delivery Nat Rev Drug Discov 3 (2004)785ndash796
[5] L Gao D Zhang M Chen Drug nanocrystals for the formulation of poorly solu-ble drugs and its application as a potential drug delivery system J NanopartRes 10 (2008) 845ndash862
[6] GG Liversidge KC Cundy Particle size reduction for improvement of oral bio-availability of hydrophobic drugs I Absolute oral bioavailability of nanocrystal-line danazol in beagle dogs Int J Pharm 125 (1995) 91ndash97
[7] K Peters S Leitzke J Diederichs K Borner H Hahn RH Muumlller S Ehlers Prep-aration of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic ef 1047297cacy in murine Mycobacterium avium infection J AntimicrobChemother 45 (2000) 77ndash83
[8] P Rosario B Claudio F Piera M Adriana P Antonina P Giovanni EudragitRS100 nanosuspensions for the ophthalmic controlled delivery of ibuprofenEur J Pharm Sci 16 (2002) 53ndash61
[9] C Jacobs RH Muumlller Production and characterization of a budesonide nanosus-pension for pulmonary administration Pharm Res 19 (2002) 189ndash194
[10] RH Muumlller C Jacobs O Kayser Nanosuspensions as particulate drug formula-
tions in therapy rationale for development and what we can expect for the fu-ture Adv Drug Deliv Rev 47 (2001) 3ndash19
[11] B Van Eerdenbrugh G Van den Mooter P Augustijns Topndashdown production of drug nanocrystals nanosuspension stabilization miniaturization and transfor-mation into solid products Int J Pharm 364 (2008) 64ndash75
[12] E Merisko-Liversidge GG Liversidge ER Cooper Nanosizing a formulationapproach for poorly-water-soluble compounds Eur J Pharm Sci 18 (2003)113ndash120
[13] J Hu KP Johnston RO Williams Nanoparticle engineering processes for en-hancing the dissolution rates of poorly water soluble drugs Drug Dev IndPharm 30 (2004) 233ndash245
[14] JAH Junghanns RH Muumlller Nanocrystal technology drug delivery and clinicalapplications Int J Nanomedicine 3 (2008) 295ndash310
[15] GA Brazeau HL Fung Mechanisms of creatine kinase release from isolated ratskeletal muscles damaged by propylene glycol and ethanol J Pharm Sci 79(1990) 393ndash397
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[17] R Budden UG Kuhl J Bahlsen Experiments on toxic sedative and muscle re-laxant potency of various drug solvents in mice Pharmacol Ther 5 (1979)467ndash474
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[19] B Rabinow J Kipp P Papadopoulos J Wong J Glosson J Gass CS Sun TWielgos R White C Cook K Barker K Wood Itraconazole IV nanosuspensionenhances ef 1047297cacy through altered pharmacokinetics in the rat Int J Pharm 339(2007) 251ndash260
[20] F Kesisoglou S Panmai Y Wu Nanosizingmdashoral formulation development andbiopharmaceutical evaluation Adv Drug Deliv Rev 59 (2007) 631ndash644
[22] GG Liversidge P Conzentino Drug particle size reduction for decreasing gastricirritancy and enhancing absorption of naproxen in rats Int J Pharm 125 (1995)
309ndash
313
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[23] E Merisko-Liversidge GG Liversidge Nanosizing for oral and parenteral drugdelivery a perspective on formulating poorly-water soluble compounds usingwet media milling technology Adv Drug Deliv Rev 30 (2011) 427ndash440
[24] BHL Boumlhm RH Muumlller Lab-scale production unit design for nanosuspensions of sparingly soluble cytotoxic drugs Pharm Sci Technol Today 2 (1999) 336ndash339
[25] RH Drew E Dodds Ashley DK Benjamin Jr R Duane Davis SM Palmer JRPerfect Comparative safety of amphotericin B lipid complex and amphotericinB deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipi-ents Transplantation 77 (2004) 232ndash237
[26] J Dubois T Bartter J Gryn MR Pratter The physiologic effects of inhaledamphotericin B Chest 108 (1995) 750ndash753
[27] SM Palmer RH Drew JD Whitehouse VF Tapson RD Davis RR McConnellSS Kanj JR Perfect Safety of aerosolized amphotericin B lipid complex in lungtransplant recipients Transplantation 72 (2001) 545ndash548
[28] RO Williams III J Liu Formulation of a protein with propellant HFA 134a foraerosol delivery Eur J Pharm Sci 7 (1999) 137ndash144
[29] IC Ashurst CV Ambrose DJ Russell Pharmaceutical evaluation of a new spac-er device for delivery of metered-dose inhalers to infants and young children JAerosol Sci 23 (1992) 499ndash502
[30] GC Na HJ Stevens B Yuan N Rajagopalan Physical stability of ethyl diatrizoatenanocrystalline suspension in steam sterilization Pharm Res 16 (1999) 569ndash574
[31] H Lou X Zhang L Gao F Feng J Wang X Wei Z Yu D Zhang Q Zhang Invitro and in vivo antitumor activity of oridonin nanosuspension Int J Pharm379 (2009) 181ndash186
[32] L Gao D Zhang M Chen C Duan W Dai L Jia W Zhao Studies on pharmaco-kinetics and tissue distribution of oridonin nanosuspensions Int J Pharm 355(2008) 321ndash327
[33] SM Moghimi AC Hunter JC Murray Long circulating and target-speci1047297cnanoparticles theory to practice Pharmacol Rev 53 (2001) 283ndash381
[34] S Ganta JW Paxton BC Baguley S Garg Formulation and pharmacokinetic
evaluation of an asulacrine nanocrystalline suspension for intravenous deliveryInt J Pharm 367 (2009) 179ndash186
[35] K Sigfridsson S Forsseacuten P Hollaumlnder U Skantze J de Verdier A formulationcomparison using a solution and different nanosuspensions of a poorly solublecompound Eur J Pharm Biopharm 67 (2007) 540ndash547
[36] K Sigfridsson AJ Lundqvist M Strimfors Particle size reduction for improve-ment of oral absorption absorption of the poorly soluble drug UG558 in rats dur-ing early development Drug Dev Ind Pharm 35 (2009) 1479ndash1486
[37] S Kim J Lee Folate-targeted drug-delivery systems prepared by nano-comminution Drug Dev Ind Pharm 37 (2011) 131ndash138
[38] R Xiong W Lu J Li P Wang R Xu T Chen Preparation and characterization of intravenously injectable nimodipine nanosuspension Int J Pharm 350 (2008)338ndash343
[39] Y Gao Z Li M Sun C Guo A Yu Y Xi J Cui H Lou G Zhai Preparation andcharacterization of intravenously injectable curcumin nanosuspension DrugDeliv 18 (2011) 131ndash142
[40] RH Muumlller K Peters Nanosuspensions for the formulation of poorly solubledrugs I Preparation by a size-reduction technique Int J Pharm 160 (1998)229ndash237
[41] SB Zirar A Astier M Muchow S Gibaud Comparison of nanosuspensions andhydroxypropyl-b-cyclodextrin complex of melarsoprol pharmacokinetics andtissue distribution in mice Eur J Pharm Biopharm 70 (2008) 649 ndash656
[42] M Salzberg M Pless C Rochlitz K Ambrus P Scigalla R Herrmann A phase Istudy with oral SU5416 in patients with advanced solid tumors a drug inducingits clearance Invest New Drugs 24 (2006) 299ndash304
[43] WK Kraft B Steiger D Beussink JN Quiring N Fitzgerald HE Greenberg SAWaldman The pharmacokinetics of nebulized nanocrystal budesonide suspen-sion in healthy volunteers J Clin Pharmacol 44 (2004) 67ndash72
[44] JM Vaughn NP Wiederhold JT McConville JJ Coalson RL Talbert DSBurgess KP Johnston RO Williams III JI Peters Murine airway histologyand intracellular uptake of inhaled amorphous itraconazole Int J Pharm 338(2007) 219ndash224
[45] JM Vaughn JT McConville D Burgess JI Peters KP Johnston RL Talbert ROWilliams III Single dose and multiple dose studies of itraconazole nanoparticlesEur J Pharm Biopharm 63 (2006) 95ndash102
[46] BJ Hoeben DS Burgess JT McConville LK Najvar RL Talbert JI Peters NPWiederhold BL Frei JR Graybill R Bocanegra KA Overhoff P Sinswat KP
Johnston RO Williams III In vivo ef 1047297cacy of aerosolized nanostructured itraco-nazole formulations for prevention of invasive pulmonary aspergillosis Antimi-crob Agents Chemother 50 (2006) 1552ndash1554
[47] CA Alvarez NP Wiederhold JT McConville JI Peters LK Najvar JR Graybill JJ Coalson RL Talbert DS Burgess R Bocanegra KP Johnston RO WilliamsIII Aerosolized nanostructured itraconazole as prophylaxis against invasive pul-monary aspergillosis J Infect 55 (2007) 68ndash74
[48] SB Shrewsbury AP Bosco PS Uster Pharmacokinetics of a novel submicronbudesonide dispersion for nebulized delivery in asthma Int J Pharm 365(2009) 12ndash17
[49] RH Muumlller KH Wallis Surface modi1047297cation of iv injectable biodegradablenanoparticles with poloxamer polymers and poloxamine 908 Int J Pharm 89(1993) 25ndash31
[50] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy and diagno-sis Adv Drug Deliv Rev 54 (2002) 631ndash651
[51] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (2000) 73ndash80
[52] M Wang M Thanou Targeting nanoparticles to cancer Pharmacol Res 62(2010) 90ndash99
[53] L Gao G Liu X Wang F Liu Y Xu J Ma Preparation of a chemically stablequercetin formulation using nanosuspension technology Int J Pharm 404(2011) 231ndash237
[54] M Sarkari J Brown X Chen S Swinnea RO Williams III KP Johnston En-hanced drug dissolution using evaporative precipitation into aqueous solutionInt J Pharm 243 (2002) 17ndash31
[55] X Li L Gu Y Xu Y Wang Preparation of feno1047297brate nanosuspension and studyof its pharmacokinetic behavior in rats Drug Dev Ind Pharm 35 (2009)827ndash833
[56] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Pharmacokinetic evaluation of oral feno1047297brate nanosus-
pensions and SLN in comparison to conventional suspensions of micronizeddrug Adv Drug Deliv Rev 59 (2007) 419ndash426[57] GJ Vergote C Vervaet I Van Driessche S Hoste S De Smedt J Demeester RA
Jain S Ruddy JP Remon In vivo evaluation of matrix pellets containing nano-crystalline ketoprofen Int J Pharm 240 (2002) 79ndash84
[58] S Ghosh P Chiang JL Wahlstrom H Fujiwara JG Selbo SL Roberds Oral de-livery of 13-dicyclohexylurea nanosuspension enhances exposure and lowersblood pressure in hypertensive rats Basic Clin Pharmacol Toxicol 102 (2008)453ndash458
[59] P Langguth A Hanafy D Frenzel P Grenier A Nhamias T Ohlig G VergnaultH Spahn-Langguth Nanosuspension formulations for low-soluble drugs phar-macokinetic evaluation using spironolactone as model compound Drug DevInd Pharm 31 (2005) 319ndash329
[60] MG Fakesa Blisse J Vakkalagaddab Feng Qiana Sridhar Desikana Rajesh BGandhi C Lai A Hsieha MK Franchini H Toaled J Brown Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amor-phous formulation approaches Int J Pharm 370 (2009) 167ndash174
[61] K Sigfridsson A Nordmark S Theilig A Lindah A formulation comparison be-tween micro- and nanosuspensions the importance of particle size for absorp-
tion of a model compound following repeated oral administration to rats duringearly development Drug Dev Ind Pharm 37 (2011) 185ndash192
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[63] Y Wu A Loper E Landis L Hettrick L Novak K Lynn C Chen K Thompson RHiggins U Batra S Shelukar G Kwei D Storey The role of biopharmaceutics inthe development of a clinical nanoparticle formulation of MK-0869 a beagledog model predicts improved bioavailability and diminished food effect on ab-sorption in human Int J Pharm 285 (2004) 135ndash146
[64] RH Muumlller S Runge V Ravelli W Mehnert AF Thuumlnemann EB Souto Oralbioavailability of cyclosporine solid lipid nanoparticles (SLNreg) versus drugnanocrystals Int J Pharm 317 (2006) 82ndash89
[65] G Ponchel MJ Montisci A Dembri C Durrer D Duchecircne Mucoadhesion of colloidal particulate systems in the gastro-intestinal tract Eur J Pharm Bio-pharm 44 (1997) 25ndash31
[66] D Duchecircne G Ponchel Bioadhesion of solid oral dosage forms why and howEur J Pharm Biopharm 44 (1997) 15ndash23
[67] D Dodou P Breedveld PA Wieringa Mucoadhesives in the gastrointestinaltract revisiting the literature for novel applications Eur J Pharm Biopharm60 (2005) 1ndash16
[68] JD Smart The basics and underlying mechanisms of mucoadhesion Adv DrugDeliv Rev 57 (2005) 1556ndash1568
[69] O Kayser A newapproach fortargetingto Cryptosporidium parvum using mucoadhe-sive nanosuspensions research and applications Int J Pharm 214 (2001) 83ndash85
[70] A des Rieux V Fievez M Garinot YJ Schneider V Preacuteat Nanoparticles as po-tential oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[71] A Lamprecht P Koenig N Ubrich P Maincent D Neumann Low molecularweight heparin nanoparticles mucoadhesion and behaviour in Caco-2 cellsNanotechnology 17 (2006) 3673ndash3680
[72] F Delie Evaluation of nano- and microparticle uptake by the gastrointestinaltract Adv Drug Deliv Rev 34 (1998) 221ndash233
[73] CN Grama DD Ankola MNV Ravi Kumar Poly(lactide-co-glycolide) nano-particles for peroral delivery of bioactives Curr Opin Colloid Interface Sci 16(2011) 238ndash245
[74] MP Desai V Labhasetwar GL Amidon RJ Levy Gastrointestinal Uptake of biodegradable microparticles effect of particle size Pharm Res 13 (1996)1838ndash1845
[75] A des Rieux V Fievez M Garinot YJ Scheider V Preat Nanoparticles as poten-tial oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
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[77] J Goole DJ Lindley W Roth SM Carl K Amighi JM Kauffmann GT KnippThe effects of excipients on transporter mediated absorption Int J Pharm 393(2010) 17ndash31
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[79] MF Wempe C Wright JL Little JW Lightner SE Large GB Ca1047298isch CMBuchanan PJ Rice VJ Wacher KM Ruble KJ Edgar Inhibiting ef 1047298ux withnovel non-ionic surfactants rational design based on vitamin E TPGS Int JPharm 370 (2009) 93ndash102
428 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
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[81] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Absence of a food effect with a 145 mg nanoparticle feno-1047297brate tablet formulation Int J Clin Pharmacol Ther 44 (2006) 64ndash70
[82] MV Chaubal C Popescu Conversion of nanosuspensions into dry powders byspray drying a case study Pharm Res 25 (2008) 2302ndash2308
[83] F Lai E Pini G Angioni ML Manca J Perricci C Sinico AM Fadda Nanocrys-tals as tool to improve piroxicam dissolution rate in novel orally disintegratingtablets Eur J Pharm Biopharm 79 (2011) 552ndash558
[84] D Mou H Chen J Wan H Xu X Yang Potent dried drug nanosuspensions for
oral bioavailability enhancement of poorly soluble drugs with pH-dependentsolubility Int J Pharm 413 (2011) 237ndash244[85] A Ain-Ai PK Gupta Effect of arginine hydrochloride and hydroxypropyl cellu-
lose as stabilizers on the physical stability of high drug loading nanosuspensionsof a poorly soluble compound Int J Pharm 351 (2008) 282 ndash288
[86] Z Guo T Pereira O Choi Y Wang HT Hahn Surface functionalized aluminananoparticle 1047297lled polymeric nanocomposites with enhanced mechanical prop-erties J Mater Chem 16 (2006) 2800ndash2808
[87] DR Kalaria G Sharma V Beniwal MN Ravi Kumar Design of biodegradablenanoparticles for oral delivery of doxorubicin in vivo pharmacokinetics and tox-icity studies in rats Pharm Res 26 (2009) 492ndash501
[88] JE Kipp The role of solid nanoparticle technology in parenteral delivery of poorly water soluble drugs Int J Pharm 284 (2004) 109ndash122
[89] HM Shubar S Lachenmaier MM Heimesaat U Lohman R Mauludin RHMuumlller R Fitzner K Borner O Liesenfeld SDS-coated atovaquone nanosuspen-sions show improved therapeutic ef 1047297cacy against experimental acquired andreactivated toxoplasmosis by improving passage of gastrointestinal and bloodndash
brain barriers J Drug Target 19 (2011) 114ndash124[90] L Peltonen J Hirvonen Pharmaceutical nanocrystals by nanomilling critical
process parameters particle fracturing and stabilization method J Pharm Phar-macol 62 (2010) 1569ndash1579
[91] F Lai C Sinico G Ennas F Marongiu G Marongiu AM Fadda Diclofenac nano-suspensions in1047298uence of preparation procedure and crystal form on drug disso-lution behavior Int J Pharm 373 (2009) 124ndash132
[92] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (Suppl 2) (2000) S73ndashS80
[93] RH Muller CM Keck Challenges and solutions for the delivery of biotech drugsmdasha review of drug nanocrystal technology and lipid nanoparticles J Biotechnol113 (2004) 151ndash170
[94] JL Wahlstrom P Chiang S Ghosh CJ Warren SP Wene LA Albin ME SmithSL Roberds Pharmacokinetic evaluation of a 13-dicyclohexylurea nanosuspen-sion formulation to support early ef 1047297cacy assessment Nanoscale Res Lett 2(2007) 291ndash296
[95] Y GaoZ LiM SunH Li CGuoJ CuiA LiF CaoY XiH Lou GZhai Preparationcharacterization pharmacokinetics and tissue distribution of curcumin nanosus-pension with TPGS as stabilizer Drug Dev Ind Pharm 36 (2010) 1225ndash1234
[96] M Clement W Pugh I Parikh Tissue distribution and plasma clearance of a novelmicrocrystalline-coated 1047298urbiprofen formulation Pharmacologist 34 (1992)204ndash211
[97] RC Nagarwal S Kant PN Singh P Maiti JK Pandit Polymeric nanoparticulate sys-tem a potential approach for ocular drug delivery J Control Release 136 (2009)2ndash13
[98] H Gupta M Aqil RK Khar A Ali A Bhatnagar G Mittal Spar1047298oxacin loadedPLGA nanoparticles for sustained ocular drug delivery Nanomedicine 6 (2010)324ndash333
[99] HS Ali P York AM Ali N Blagden Hydrocortisone nanosuspensions for oph-thalmic delivery a comparative study between micro1047298uidic nanoprecipitationand media milling J Control Release 149 (2011) 175ndash181
[100] SK Sahoo F Dilnawaz S Krishnakumar Nanotechnology in ocular drug deliv-ery Drug Discov Today 13 (2008) 144ndash151
[101] O Kayser A Lemke N Hernaacutendez-Trejo The impact of nanobiotechnology on thedevelopment of newdrug deliverysystems Curr Pharm Biotechnol6 (2005) 3ndash5
[102] R Pignatello C Bucolo G Spedalieri A Maltese G Puglisi Flurbiprofen-loadedacrylate polymer nanosuspensions for ophthalmic application Biomaterials 23(2002) 3247ndash3255
[103] R Ravichandran Nanoparticles in drug delivery potential green nanobiomedi-
cine applications Int J Green Nanotechnol Biomed 1 (2009) B108ndash
B130[104] AM Cerdeira M Mazzotti B Gander Miconazole nanosuspensions in1047298uence
of formulation variables on particle size reduction and physical stability Int JPharm 396 (2010) 210ndash218
[105] MA Kassem AA Abdel Rahman MM Ghorab MB Ahmed RM Khalil Nano-suspension as an ophthalmic delivery system for certain glucocorticoid drugsInt J Pharm 340 (2007) 126ndash133
[106] P Chiang JW Alsup Y Lai Y Hu BR Heyde D Tung Evaluation of aerosol de-livery of nanosuspension for pre-clinical pulmonary drug delivery NanoscaleRes Lett 4 (2009) 254ndash261
[107] W Yang JI Peters RO Williams III Inhaled nanoparticlesmdasha current reviewInt J Pharm 356 (2008) 239ndash247
[108] J Zhang L Wu H Chan W Watanabe Formation characterization and fate of inhaled drug nanoparticles Adv Drug Deliv Rev 63 (2011) 441ndash455
[109] HM Mansour YS Rhee X Wu Nanomedicine in pulmonary delivery Int JNanomedicine 4 (2009) 299ndash319
[110] NR Labiris MB Dolovich Pulmonary drug delivery Part I physiological factorsaffecting therapeutic effectiveness of aerosolized medications Br J Clin Phar-macol 56 (2003) 588ndash599
[111] JS Patton PR Byron Inhaling medicines delivering drugs to the body throughthe lungs Nat Rev Drug Discov 6 (2007) 67ndash74
[112] DA Edwards C Dunbar Bioengineering of therapeutic aerosols Annu RevBiomed Eng 4 (2002) 93ndash107
[113] W Yang JTam DA Miller J Zhou JT McConville KP Johnstonb RO WilliamsIII High bioavailability from nebulized itraconazole nanoparticle dispersionswith biocompatible stabilizers Int J Pharm 361 (2008) 177ndash188
[114] S Gill R Lobenberg T Ku S Azarmi W Roa EJ Prenner Nanoparticles char-acteristics mechanisms of action and toxicity in pulmonary drug deliverymdasha re-view J Biomed Nanotechnol 3 (2007) 107ndash119
[115] SJ Sze1047298er Pharmacodynamics and pharmacokinetics of budesonide a new
S183[116] W Yang KP Johnston RO Williams III Comparison of bioavailability of amor-phous versus crystalline itraconazole nanoparticles via pulmonary administra-tion in rats Eur J Pharm Biopharm 75 (2010) 33 ndash41
[117] R Ali GK Jain Z Iqbal S Talegaonkar P Pandit S Sule G Malhotra RK KharA Bhatnagar FJ Ahmad Development and clinical trial of nano-atropine sulfatedry powder inhaler as a novel organophosphorous poisoning antidote Nanome-dicine 5 (2009) 55ndash63
[118] D Andes Minireview in vivo pharmacodynamics of antifungal drugs in treat-ment of candidiasis Antimicrob Agents Chemother 47 (2003) 1179ndash1186
[119] D Andes K Marchillo R Conklin G Krishna F Ezzet A Cacciapuoti DLoebenberg Pharmacodynamics of a new triazole posaconazole in a murinemodel of disseminated candidiasis Antimicrob Agents Chemother 48 (2004)137ndash142
[120] O Kayser C Olbrich V Yardley AF Kiderlen SL Croft Formulation of ampho-tericin B as nanosuspension for oral administration Int J Pharm 254 (2003)73ndash75
[121] L Zhang S Hou S Mao D Wei X Song Y Lu Uptake of folate-conjugated albu-min nanoparticles to the SKOV3 cells Int J Pharm 287 (2004) 155ndash162
[122] J Sudimack RJ Lee Targeted drug delivery via folate receptor Adv Drug DelivRev 41 (2000) 147ndash162
[123] P Vader LJ van der Aa G Storm RM Schiffelers JF Engbersen Polymeric car-rier systems for siRNA delivery Curr Top Med Chem 12 (2012) 108 ndash119
[124] O Veiseh FM Kievit RG Ellenbogen M Zhang Cancer cell invasion treatmentand monitoring opportunities in nanomedicine Adv Drug Deliv Rev 63 (2011)582ndash596
[125] J Kreuter VE Petrov DA Kharkevich RN Alyautdin In1047298uence of the type of surfactant on the analgesic effects induced by the peptide dalargin after its de-livery across the bloodndashbrain barrier using surfactant-coated nanoparticles JControl Release 49 (1997) 81ndash87
[126] J Ye Q Wang X Zhou N Zhang Injectable actarit-loaded solid lipid nanoparti-cles as passive targeting therapeutic agents for rheumatoid arthritis Int JPharm 352 (2008) 273ndash279
[127] SM Moghimi AC Hunter JC Murray Nanomedicine current status and futureprospects FASEB J 19 (2005) 311ndash330
[128] K Park To PEGylate or not PEGylate that is not the question J Control Release142 (2010) 147ndash148
[129] M Socha P Bartecki C Passitani A Sapin C Damge T Lecompte J BarreE Ghazouani P Maincent Stealth nanoparticles coated with heparin aspeptide or peptide carriers J Drug Target 17 (2009) 575ndash585
[130] D Shenoy S Little R Langer M Amiji Poly(ethylene oxide)-modi1047297ed poly(-beta-amino ester) nanoparticles as a pH-sensitive system for tumor targeted de-livery of hydrophobic drugs part 2 In vivo distribution and tumor localizationstudies Pharm Res 22 (2005) 2107ndash2114
[131] R Shegokara KK Singha Surface modi1047297ed nevirapinenanosuspensions for viralreservoir targeting in vitro and in vivo evaluation Int J Pharm 421 (2011)341ndash352
[132] Y Matsumura H Maeda A new concept for macromolecular therapeutics incancer chemotherapy mechanism of tumoritropic accumulation of proteinsand the antitumor agent SMANCS Cancer Res 46 (1986) 6387ndash6392
[133] H Zhang CP Hollis Q Zhang T Li Preparation and antitumor study of camp-tothecin nanocrystals Int J Pharm 415 (2011) 293ndash300
[134] H Lou L Gao X Wei Z Zhang D Zheng D Zhang X Zhang Y Li Q Zhang Ori-donin nanosuspension enhances anti-tumor ef 1047297cacy in SMMC-7721 cells andH22 tumor bearing mice Colloids Surf B Biointerfaces 87 (2011) 319ndash325
[135] TM Goppert RH Muumlller Adsorption kinetics of plasma proteins on solid lipid
nanoparticles for drug targeting Int J Pharm 302 (2005) 172ndash
186[136] X Pu J Sun M Li Z He Formulation of nanosuspensions as a new approach for
the delivery of poorly soluble drugs Curr Nanosci 5 (2009) 417ndash427[137] R Gaudana J Jwala SHS Boddu AK Mitra Recent perspectives in ocular drug
delivery Pharm Res 26 (2009) 1197ndash1216[138] T Yasukawa H Kimura Y Tabata H Miyamoto Y Honda Y Ikada Y Ogura
Targeted delivery of anti-angiogenic agent TNP-470 using water-soluble poly-mer in the treatment of choroidal neovascularization Invest Ophthalmol VisSci 40 (1999) 2690ndash2696
[139] A Lemke AF Kiderlen B Petri O Kayser Delivery of amphotericin B nanosus-pensions to the brain and determination of activity against Balamuthia mandril-laris amebas Nanomedicine 6 (2010) 597ndash603
[140] HL Wong XY Wu R Bendayan Nanotechnological advances forthe delivery of CNS therapeutics Adv Drug Deliv Rev (2011) doi101016jaddr201110007
[141] J Kreuter S Gelperina Use of nanoparticles for cerebral cancer Tumori 94(2008) 271ndash277
[142] J Kreuter RN Alyautdin DA Kharkevich AA Ivanov Passage of peptidesthrough the bloodndashbrain barrier with colloidal polymer particles (nanoparti-cles) Brain Res 674 (1995) 171ndash174
429L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[143] J Kreuter Nanoparticulate systems for brain delivery of drugs Adv Drug DelivRev 47 (2001) 65ndash81
[144] TM Goumlppert RH Muumlller Polysorbate-stabilized solid lipid nanoparticles as col-loidal carriers for intravenous targeting of drugs to the brain comparison of plasma protein adsorption patterns J Drug Target 13 (2005) 179ndash187
[145] S Mansouri Y Cuie F Winnik Q Shi P Lavigne M Benderdour E Beaumont JC Fernandes Characterization of folate-chitosan-DNA nanoparticles for genetherapy Biomaterials 27 (2006) 2060ndash2065
[146] AR Hilgenbrink PS Low Folate receptor-mediated drug targeting from thera-peutics to diagnostics J Pharm Sci 94 (2005) 2135ndash2146
[147] F Pierigegrave S Sera1047297ni L Rossi M Magnani Cell-based drug delivery Adv Drug
Deliv Rev 60 (2008) 286ndash
295[148] F Chellat Y Merhi A Moreau L Yahia Therapeutic potential of nanoparticulatesystems for macrophage targeting Biomaterials 26 (2005) 7260ndash7275
[149] SS Hall S Mitragotri PS Daugherty Identi1047297cation of peptide ligands facilitatingnanoparticle at attachment to erythrocytes Biotechnol Prog 23 (2007) 749ndash754
[150] S Gorantla H Dou M Boska CJ Destache J Nelson L Poluektova BERabinow HE Gendelman RL Mosley Quantitative magnetic resonance and
SPECT imaging for macrophage tissue migration and nanoformulated drug de-livery J Leukoc Biol 80 (2006) 1165ndash1174
[151] LA Lotero G Olmos JC Diez Delivery to macrophages and toxic action of etopo-sidecarried in mouse redblood cells Biochim Biophys Acta 1620 (2003) 160ndash166
[152] L Rossi S Sera1047297ni F Pierigeacute A Antonelli A Cerasi A Fraternale L ChiarantiniM Magnani Erythrocyte-based drug delivery Expert Opin Drug Deliv 2 (2005)311ndash322
[153] S Sera1047297ni L Rossi A Antonelli A Fraternale A Cerasi R Crinelli L ChiarantiniGF Schiavano M Magnani Drug delivery through phagocytosis of red bloodcells Transfus Med Hemother 31 (2004) 92ndash101
[154] H Dou CJ Destache JR Morehead R Lee Mosley MD Boska J Kingsley S
Gorantla L Poluektova JA Nelson M Chaubal J Werling J Kipp BERabinow HE Gendelman Development of a macrophage-based nanoparticleplatform for antiretroviral drug delivery Blood 108 (2006) 2827ndash2835
[155] V Staedtke M Braumller A Muumlller R Georgieva S Bauer N Sternberg A Voigt ALemke C Keck J Moumlschwitzer H Baumlumler In vitro inhibition of fungal activityby macrophage-mediated sequestration and release of encapsulated amphoter-icin B nanosuspension in red blood cells Small 6 (2010) 96ndash103
430 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
It should be bear in mind that most drug nanocrystal formulations
used in the in vivo experiments are aqueous dispersions (Table 3)
however when it comes to the clinical application solid dosage
forms are usually more acceptable by patients [82] It can be seen
that most of the marketed nanoparticles formulations are solid
forms (Table 1) In order to solidi1047297cation 1047297rst the aqueous nanosus-
pensions should be transformed into dry powders suitable to gener-
ate tablets capsules pellets etc This transformation can be
achieved using different methods including lyophilization spray dry-ing granulation and pelletization [83ndash86] The drying process should
be well designed to avoid particle aggregation If aggregation occurs
the bene1047297ts that can be gained from large surface of the original
nanometer-sized particles would be greatly compromised In general
protectants (usually sugars) are often added to nanosuspensions to
minimize the particle size growth during a drying process
The redispersion progress of a solid formulation containing drug
nanocrystals in the GIT is more complex Physiological factors (in-
cluding pH variation compositions of the digestive juice and GI peri-
stalsis etc) affecting dispersion of nanocrystals are complicated [87]
Nanocrystals of basic drugs are more easily affected by pH variation in
the GIT For weak bases a nanometer-sized drug formulation will dis-
solve fast and more ef 1047297ciently in the low stomach pH environment
During transit from stomach to duodenum the rise in pH may illicit
uncontrolled precipitation of drug substance [88] In addition stabi-
lizer type should be screened by monitoring the change of particle
size after reconstitution in different pH media [89] After rehydration
in GI 1047298uid the nanocomplex disperses into separated nanocrystals
following the dissolution of 1047297llers Stabilizer molecules attached on
the surface of nanocrystals will offer ionic or steric repulsion among
nanocrystals given that they are not affected by the GIT environment
[690] In general ionic stabilizers are effective in aqueous environ-
ment but during the drying they may become less effective because
the ionized state is not maintained in dry material In addition ionic
stabilizers are also sensitive to changes in pH and ionic strength
when the dried powders redisperse in the GI 1047298uid [90] On the con-
trary in most cases the polymer and non-ionic surfactant stabilizers
can be effective to support suf 1047297cient steric repulsion in GI 1047298uid
given that the amount of stabilizers is enough [91]
The establishment of an in vitrondash
in vivo correlation (IVIVC) is anessential part for the study of oral formulations For the Class II
drugs dissolution is a rate-limiting step in the GIT so in general
they have a good IVIVC result [92] When they are processed into
nanocrystal formulations an IVIVC should be reevaluated again
since their dissolution velocity has been markedly enhanced In the
other hand the IVIVC data also help modulate the process and the
amount of matrix in the progress of drying nanosuspensions Howev-
er research on the IVIVC of nanocrystal formulations has not been
reported but we believe it will be the next focus in this 1047297eld
222 Injection administration route
For many cases intravenous injection is requested to meet some
treatment purpose such as immediate effects overcoming the 1047297rst
pass effect targeting effect and so on Due to its suf 1047297ciently small
size and safe aqueous composition nanosuspensions can be injected
intravenously and achieve 100 bioavailability [86] Compared with
other carrier-based solid nanoparticles such as solid lipid nanoparti-
cles polymer-based nanoparticles and liposomes carrier-free nano-
crystals would experience a much faster particle size reduction
during the process of dissolution This may lead to a distinct pharma-
cokinetic progress after iv administration because particle size is an
Table 4
Changes of pharmacokinetic properties of intravenous nanosuspensions compared with the conventional partners
Drug Methods Dosage form
(mean particle size)
Control
(mean particle size)
Comparison of the
pharmacokinetic parameters
Animals References
Asulac rine High p ressur e hom ogeniz at ion AN ( 13 3 nm) Organic solut ion 15- fold r edu ction in Cmax23-fold increase in t12 62-fold
increase in Vd 27-fold increase in
CL 27-fold increase in MRT
25-fold reduction in AUC
Rats [34]
Melar sopr ol High p ressur e hom ogeniz at ion AN ( 29 5 nm) Organic solut ion 22- fold inc rease in t12 14-fold
increase in Vd 14-fold reduction
in CL 2-fold reduction in AUC
Rats [41]
AN (409 nm) 3-fold increase in t12 13-fold reduction
in Vd 45-fold reduction in CL 42-fold
reduction in AUC
13-Dicyclohexylurea Media milling AN (NR)a Organic solution All parameters were similar to
those of solution
Rats [94]
Oridonin High p ressur e hom ogeniz at ion AN ( 10 33 nm) Organic solut ion All p ara meters w ere sim ilar to
those of solution 17-fold reduction
in Cmax 7-fold increase in t12 51-fold
increase in Vd 19-fold reduction in CL
62-fold increase in MRT 18-foldincrease in AUC
Rabbits [32]
AN (8972 nm)
It rac onaz ole High p ressur e hom ogeniz at ion AN ( 58 1 nm) Organic solut ion 17- fold inc rease in Cmax 31-fold
increase in t12 18 reduction in AUC 18
increase in CL 28 increase in MRT 79
increase in Vd
Rats [19]
AZ68 Precipitation AN (125 nm) Organic solution No signi1047297cant differences with
solution by means of plasma pro1047297les
Rats [35]
Media milling AN (200 nm)
Cyclosporine Precipitation AN (NR) Organic solution All parameters were similar to
those of solution
Rats [93]
Cu rc um in High p ressur e hom ogeniz at ion AN ( 21 02 nm) Organic solut ion 31- fold inc rease in Cmax
112-fold increase in MRT
48-fold increase in AUC
Rabbits [95]
Flu rb ip rofen High p ressur e hom ogeniz at ion AN ( NR ) Organic solut ion All p ara meters w ere sim ilar
to those of solution
Rats [96]
Vd volume of distribution CL clearance rate MRT mean retention time AUC area under the concentration ndashtime curve Cmax maximum plasma concentration Tmax time to max-
imum plasma concentration t12 plasma half lifea
NR Not reported
423L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
nanocrystals show clear potential for clinical development compared
with both the solution and the non-targeting nanocrystals formulations
243 Cell-based drug delivery of drug nanocrystals
The signi1047297cantly increased dissolution velocity which is a distinct
advantage of nanocrystals simultaneously implies the problem that
drug nanocrystals might dissolve before reaching the target Cell-
based drug delivery approach canbe employed to deal with this prob-
lem Cell based delivery systems are identi1047297
ed as cell carriers (includ-ing bacteria cells and animal cells) which can be loaded with drugs or
therapeutics The systems can release the drug content in circulation
or at selected sites or could target the drug to other relevant cells in
the body [147] Among the animal cells of special relevance are mac-
rophages and red blood cells (RBCs) Macrophages are differentiated
cells of the immune system able to phagocytize microorganisms as
well as nanoparticulate materials So nanoparticulate systems are
particularly useful for the delivery of therapeutic agents to macro-
phages [148149] When macrophages are used as drug delivery sys-
tems they should be 1047297rst loaded with the nanoparticulate drug ex
vivo and then re-infused into the host where their content is distrib-
uted to tissues that favor homing of macrophages such as parasites
bacteria and viruses [150151] RBCs constitute potential biocompati-
ble carriers for different bioactive substances including protein drugs
as well as nanoparticulates They have unique properties such as bio-
degradability biocompatibility and long-term drug releasing and thus
are well suited for drug encapsulation [152] They can be easily han-
dled ex vivo by means of several techniques for the encapsulation of
different molecules and nanoparticulates [153]
For drug nanocrystals few studies related on cell based drug deliv-
ery have been reported but the existing results proved the feasibility
Dou et al designed a novel bone marrow-derived macrophage (BMM)
indinavir nanocrystals delivery system for antiretroviral treatment
[154] Light microscopic examination proved that indinavir nanocrys-
tals were successfully loaded into BMMs after culture in the presence
of indinavir nanosuspensions for 12 h Following iv administration
into naive mice the indinavir nanocrystal loaded BMMs acted as ldquoTro-
jan horsesrdquo for transport of drug into tissues which were known to be
targets for HIV due to the parallel BMM migration and viral tissue tro-pism Administration of indinavir nanocrystal-BMMs sustained indina-
vir in tissue and sera for up to 10 days in comparison with 6 h for the
non-wrapped nanosuspensions Amphotericin B nanocrystal-loaded
RBCs systems were developed by Staedtke et al in order to improvean-
tifungal treatment [155] Amphotericin B nanocrystals encapsulation in
RBCs wasachieved by using hypotonichemolysis methodleading to in-
tracellularamphotericin B amounts of 381plusmn047 pg RBCminus1andanen-
trapment ef 1047297cacy of 15ndash18 Upon phagocytosis of amphotericin B
nanocrystal-RBCs leukocytes show a slow amphotericin B release
over 10 days and no alteration in cell viability
3 Conclusions
The researchon colloidal drug delivery systems may be the hottest1047297eld in pharmaceutics in the last several decades Due to the unique
advantage and pharmaeconomical value drug nanocrystals are paid
increasing attentions as a promising approach Drug nanocrystals
can be applied to all the poorly soluble drugs to overcome the solubil-
ity and bioavailability problems because all the poorly soluble drugs
can be comminuted into drug nanocrystals Researches on drug nano-
crystals within recent years fully exhibit their excellent in vivo perfor-
mances in different administration routes Among these the most
exciting information is that properties of drug nanocrystals can be
conveniently altered to meet various treatment demands of different
diseases With the number of insoluble drug compounds in develop-
ment increasing it is anticipated that nanocrystals technology will at-
tract increasing attentions as a viable formulation option However
though drug nanocrystals demonstrate superiority over the carrier
colloid drug delivery systems such as easier production safer compo-
sition and higher drug loading correspondingly they also confront
some problems For example how to obtain a more controllable
drug dissolution rate in order to meet the treatment requirements
of different diseases or reduce the drug release in the progress of de-
livering the drugs into target sites How can we get a more 1047297rm con-
junction between ligand-linked stabilizers and nanocrystal surfaces
without the loss of their properties We believe that many studies
will focus on handling these problems in the future
Acknowledgment
This work was partially supported by the Scienti1047297c Foundation of
the First Af 1047297liated Hospital of General Hospital of PLA the project
number is QN201105
References
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[3] CM Keck RH Muumlller Drug nanocrystals of poorly soluble drugs produced by
high pressure homogenisation Eur J Pharm Biopharm 62 (2006) 3ndash
16[4] BE Rabinow Nanosuspensions in drug delivery Nat Rev Drug Discov 3 (2004)785ndash796
[5] L Gao D Zhang M Chen Drug nanocrystals for the formulation of poorly solu-ble drugs and its application as a potential drug delivery system J NanopartRes 10 (2008) 845ndash862
[6] GG Liversidge KC Cundy Particle size reduction for improvement of oral bio-availability of hydrophobic drugs I Absolute oral bioavailability of nanocrystal-line danazol in beagle dogs Int J Pharm 125 (1995) 91ndash97
[7] K Peters S Leitzke J Diederichs K Borner H Hahn RH Muumlller S Ehlers Prep-aration of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic ef 1047297cacy in murine Mycobacterium avium infection J AntimicrobChemother 45 (2000) 77ndash83
[8] P Rosario B Claudio F Piera M Adriana P Antonina P Giovanni EudragitRS100 nanosuspensions for the ophthalmic controlled delivery of ibuprofenEur J Pharm Sci 16 (2002) 53ndash61
[9] C Jacobs RH Muumlller Production and characterization of a budesonide nanosus-pension for pulmonary administration Pharm Res 19 (2002) 189ndash194
[10] RH Muumlller C Jacobs O Kayser Nanosuspensions as particulate drug formula-
tions in therapy rationale for development and what we can expect for the fu-ture Adv Drug Deliv Rev 47 (2001) 3ndash19
[11] B Van Eerdenbrugh G Van den Mooter P Augustijns Topndashdown production of drug nanocrystals nanosuspension stabilization miniaturization and transfor-mation into solid products Int J Pharm 364 (2008) 64ndash75
[12] E Merisko-Liversidge GG Liversidge ER Cooper Nanosizing a formulationapproach for poorly-water-soluble compounds Eur J Pharm Sci 18 (2003)113ndash120
[13] J Hu KP Johnston RO Williams Nanoparticle engineering processes for en-hancing the dissolution rates of poorly water soluble drugs Drug Dev IndPharm 30 (2004) 233ndash245
[14] JAH Junghanns RH Muumlller Nanocrystal technology drug delivery and clinicalapplications Int J Nanomedicine 3 (2008) 295ndash310
[15] GA Brazeau HL Fung Mechanisms of creatine kinase release from isolated ratskeletal muscles damaged by propylene glycol and ethanol J Pharm Sci 79(1990) 393ndash397
[16] K Korttila A Sothman P Andersson Polyethylene glycol as a solvent for diaze-pam bioavailability and clinical effects after intramuscular administrationcomparison of oral intramuscular and rectal administration and precipitationfrom intravenous solutions Acta Pharmacol Toxicol (Copenh) 39 (1976)104ndash117
[17] R Budden UG Kuhl J Bahlsen Experiments on toxic sedative and muscle re-laxant potency of various drug solvents in mice Pharmacol Ther 5 (1979)467ndash474
[18] F Liu JY Park Y Zhang C Conwell Y Liu SR Bathula L Huang Targeted can-cer therapy with novel high drug-loading nanocrystals J Pharm Sci 99 (2010)3542ndash3551
[19] B Rabinow J Kipp P Papadopoulos J Wong J Glosson J Gass CS Sun TWielgos R White C Cook K Barker K Wood Itraconazole IV nanosuspensionenhances ef 1047297cacy through altered pharmacokinetics in the rat Int J Pharm 339(2007) 251ndash260
[20] F Kesisoglou S Panmai Y Wu Nanosizingmdashoral formulation development andbiopharmaceutical evaluation Adv Drug Deliv Rev 59 (2007) 631ndash644
[22] GG Liversidge P Conzentino Drug particle size reduction for decreasing gastricirritancy and enhancing absorption of naproxen in rats Int J Pharm 125 (1995)
309ndash
313
427L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[23] E Merisko-Liversidge GG Liversidge Nanosizing for oral and parenteral drugdelivery a perspective on formulating poorly-water soluble compounds usingwet media milling technology Adv Drug Deliv Rev 30 (2011) 427ndash440
[24] BHL Boumlhm RH Muumlller Lab-scale production unit design for nanosuspensions of sparingly soluble cytotoxic drugs Pharm Sci Technol Today 2 (1999) 336ndash339
[25] RH Drew E Dodds Ashley DK Benjamin Jr R Duane Davis SM Palmer JRPerfect Comparative safety of amphotericin B lipid complex and amphotericinB deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipi-ents Transplantation 77 (2004) 232ndash237
[26] J Dubois T Bartter J Gryn MR Pratter The physiologic effects of inhaledamphotericin B Chest 108 (1995) 750ndash753
[27] SM Palmer RH Drew JD Whitehouse VF Tapson RD Davis RR McConnellSS Kanj JR Perfect Safety of aerosolized amphotericin B lipid complex in lungtransplant recipients Transplantation 72 (2001) 545ndash548
[28] RO Williams III J Liu Formulation of a protein with propellant HFA 134a foraerosol delivery Eur J Pharm Sci 7 (1999) 137ndash144
[29] IC Ashurst CV Ambrose DJ Russell Pharmaceutical evaluation of a new spac-er device for delivery of metered-dose inhalers to infants and young children JAerosol Sci 23 (1992) 499ndash502
[30] GC Na HJ Stevens B Yuan N Rajagopalan Physical stability of ethyl diatrizoatenanocrystalline suspension in steam sterilization Pharm Res 16 (1999) 569ndash574
[31] H Lou X Zhang L Gao F Feng J Wang X Wei Z Yu D Zhang Q Zhang Invitro and in vivo antitumor activity of oridonin nanosuspension Int J Pharm379 (2009) 181ndash186
[32] L Gao D Zhang M Chen C Duan W Dai L Jia W Zhao Studies on pharmaco-kinetics and tissue distribution of oridonin nanosuspensions Int J Pharm 355(2008) 321ndash327
[33] SM Moghimi AC Hunter JC Murray Long circulating and target-speci1047297cnanoparticles theory to practice Pharmacol Rev 53 (2001) 283ndash381
[34] S Ganta JW Paxton BC Baguley S Garg Formulation and pharmacokinetic
evaluation of an asulacrine nanocrystalline suspension for intravenous deliveryInt J Pharm 367 (2009) 179ndash186
[35] K Sigfridsson S Forsseacuten P Hollaumlnder U Skantze J de Verdier A formulationcomparison using a solution and different nanosuspensions of a poorly solublecompound Eur J Pharm Biopharm 67 (2007) 540ndash547
[36] K Sigfridsson AJ Lundqvist M Strimfors Particle size reduction for improve-ment of oral absorption absorption of the poorly soluble drug UG558 in rats dur-ing early development Drug Dev Ind Pharm 35 (2009) 1479ndash1486
[37] S Kim J Lee Folate-targeted drug-delivery systems prepared by nano-comminution Drug Dev Ind Pharm 37 (2011) 131ndash138
[38] R Xiong W Lu J Li P Wang R Xu T Chen Preparation and characterization of intravenously injectable nimodipine nanosuspension Int J Pharm 350 (2008)338ndash343
[39] Y Gao Z Li M Sun C Guo A Yu Y Xi J Cui H Lou G Zhai Preparation andcharacterization of intravenously injectable curcumin nanosuspension DrugDeliv 18 (2011) 131ndash142
[40] RH Muumlller K Peters Nanosuspensions for the formulation of poorly solubledrugs I Preparation by a size-reduction technique Int J Pharm 160 (1998)229ndash237
[41] SB Zirar A Astier M Muchow S Gibaud Comparison of nanosuspensions andhydroxypropyl-b-cyclodextrin complex of melarsoprol pharmacokinetics andtissue distribution in mice Eur J Pharm Biopharm 70 (2008) 649 ndash656
[42] M Salzberg M Pless C Rochlitz K Ambrus P Scigalla R Herrmann A phase Istudy with oral SU5416 in patients with advanced solid tumors a drug inducingits clearance Invest New Drugs 24 (2006) 299ndash304
[43] WK Kraft B Steiger D Beussink JN Quiring N Fitzgerald HE Greenberg SAWaldman The pharmacokinetics of nebulized nanocrystal budesonide suspen-sion in healthy volunteers J Clin Pharmacol 44 (2004) 67ndash72
[44] JM Vaughn NP Wiederhold JT McConville JJ Coalson RL Talbert DSBurgess KP Johnston RO Williams III JI Peters Murine airway histologyand intracellular uptake of inhaled amorphous itraconazole Int J Pharm 338(2007) 219ndash224
[45] JM Vaughn JT McConville D Burgess JI Peters KP Johnston RL Talbert ROWilliams III Single dose and multiple dose studies of itraconazole nanoparticlesEur J Pharm Biopharm 63 (2006) 95ndash102
[46] BJ Hoeben DS Burgess JT McConville LK Najvar RL Talbert JI Peters NPWiederhold BL Frei JR Graybill R Bocanegra KA Overhoff P Sinswat KP
Johnston RO Williams III In vivo ef 1047297cacy of aerosolized nanostructured itraco-nazole formulations for prevention of invasive pulmonary aspergillosis Antimi-crob Agents Chemother 50 (2006) 1552ndash1554
[47] CA Alvarez NP Wiederhold JT McConville JI Peters LK Najvar JR Graybill JJ Coalson RL Talbert DS Burgess R Bocanegra KP Johnston RO WilliamsIII Aerosolized nanostructured itraconazole as prophylaxis against invasive pul-monary aspergillosis J Infect 55 (2007) 68ndash74
[48] SB Shrewsbury AP Bosco PS Uster Pharmacokinetics of a novel submicronbudesonide dispersion for nebulized delivery in asthma Int J Pharm 365(2009) 12ndash17
[49] RH Muumlller KH Wallis Surface modi1047297cation of iv injectable biodegradablenanoparticles with poloxamer polymers and poloxamine 908 Int J Pharm 89(1993) 25ndash31
[50] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy and diagno-sis Adv Drug Deliv Rev 54 (2002) 631ndash651
[51] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (2000) 73ndash80
[52] M Wang M Thanou Targeting nanoparticles to cancer Pharmacol Res 62(2010) 90ndash99
[53] L Gao G Liu X Wang F Liu Y Xu J Ma Preparation of a chemically stablequercetin formulation using nanosuspension technology Int J Pharm 404(2011) 231ndash237
[54] M Sarkari J Brown X Chen S Swinnea RO Williams III KP Johnston En-hanced drug dissolution using evaporative precipitation into aqueous solutionInt J Pharm 243 (2002) 17ndash31
[55] X Li L Gu Y Xu Y Wang Preparation of feno1047297brate nanosuspension and studyof its pharmacokinetic behavior in rats Drug Dev Ind Pharm 35 (2009)827ndash833
[56] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Pharmacokinetic evaluation of oral feno1047297brate nanosus-
pensions and SLN in comparison to conventional suspensions of micronizeddrug Adv Drug Deliv Rev 59 (2007) 419ndash426[57] GJ Vergote C Vervaet I Van Driessche S Hoste S De Smedt J Demeester RA
Jain S Ruddy JP Remon In vivo evaluation of matrix pellets containing nano-crystalline ketoprofen Int J Pharm 240 (2002) 79ndash84
[58] S Ghosh P Chiang JL Wahlstrom H Fujiwara JG Selbo SL Roberds Oral de-livery of 13-dicyclohexylurea nanosuspension enhances exposure and lowersblood pressure in hypertensive rats Basic Clin Pharmacol Toxicol 102 (2008)453ndash458
[59] P Langguth A Hanafy D Frenzel P Grenier A Nhamias T Ohlig G VergnaultH Spahn-Langguth Nanosuspension formulations for low-soluble drugs phar-macokinetic evaluation using spironolactone as model compound Drug DevInd Pharm 31 (2005) 319ndash329
[60] MG Fakesa Blisse J Vakkalagaddab Feng Qiana Sridhar Desikana Rajesh BGandhi C Lai A Hsieha MK Franchini H Toaled J Brown Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amor-phous formulation approaches Int J Pharm 370 (2009) 167ndash174
[61] K Sigfridsson A Nordmark S Theilig A Lindah A formulation comparison be-tween micro- and nanosuspensions the importance of particle size for absorp-
tion of a model compound following repeated oral administration to rats duringearly development Drug Dev Ind Pharm 37 (2011) 185ndash192
[62] J Jinno N Kamada M Miyake K Yamada T Mukai M Odomi H Toguchi GGLiversidge K Higaki T Kimura Effect of particle size reduction on dissolutionand oral absorption of a poorly water-soluble drug cilostazol in beagle dogs JControl Release 111 (2006) 56ndash64
[63] Y Wu A Loper E Landis L Hettrick L Novak K Lynn C Chen K Thompson RHiggins U Batra S Shelukar G Kwei D Storey The role of biopharmaceutics inthe development of a clinical nanoparticle formulation of MK-0869 a beagledog model predicts improved bioavailability and diminished food effect on ab-sorption in human Int J Pharm 285 (2004) 135ndash146
[64] RH Muumlller S Runge V Ravelli W Mehnert AF Thuumlnemann EB Souto Oralbioavailability of cyclosporine solid lipid nanoparticles (SLNreg) versus drugnanocrystals Int J Pharm 317 (2006) 82ndash89
[65] G Ponchel MJ Montisci A Dembri C Durrer D Duchecircne Mucoadhesion of colloidal particulate systems in the gastro-intestinal tract Eur J Pharm Bio-pharm 44 (1997) 25ndash31
[66] D Duchecircne G Ponchel Bioadhesion of solid oral dosage forms why and howEur J Pharm Biopharm 44 (1997) 15ndash23
[67] D Dodou P Breedveld PA Wieringa Mucoadhesives in the gastrointestinaltract revisiting the literature for novel applications Eur J Pharm Biopharm60 (2005) 1ndash16
[68] JD Smart The basics and underlying mechanisms of mucoadhesion Adv DrugDeliv Rev 57 (2005) 1556ndash1568
[69] O Kayser A newapproach fortargetingto Cryptosporidium parvum using mucoadhe-sive nanosuspensions research and applications Int J Pharm 214 (2001) 83ndash85
[70] A des Rieux V Fievez M Garinot YJ Schneider V Preacuteat Nanoparticles as po-tential oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[71] A Lamprecht P Koenig N Ubrich P Maincent D Neumann Low molecularweight heparin nanoparticles mucoadhesion and behaviour in Caco-2 cellsNanotechnology 17 (2006) 3673ndash3680
[72] F Delie Evaluation of nano- and microparticle uptake by the gastrointestinaltract Adv Drug Deliv Rev 34 (1998) 221ndash233
[73] CN Grama DD Ankola MNV Ravi Kumar Poly(lactide-co-glycolide) nano-particles for peroral delivery of bioactives Curr Opin Colloid Interface Sci 16(2011) 238ndash245
[74] MP Desai V Labhasetwar GL Amidon RJ Levy Gastrointestinal Uptake of biodegradable microparticles effect of particle size Pharm Res 13 (1996)1838ndash1845
[75] A des Rieux V Fievez M Garinot YJ Scheider V Preat Nanoparticles as poten-tial oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[76] JM Dintaman JA Silverman Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) Pharm Res 16 (1999)1550ndash1556
[77] J Goole DJ Lindley W Roth SM Carl K Amighi JM Kauffmann GT KnippThe effects of excipients on transporter mediated absorption Int J Pharm 393(2010) 17ndash31
[78] J Huang L Si L Jiang Z Fan J Qiu G Li Effect of pluronic F68 block copolymeron P-glycoprotein transport and CYP3A4 metabolism Int J Pharm 356 (2008)351ndash353
[79] MF Wempe C Wright JL Little JW Lightner SE Large GB Ca1047298isch CMBuchanan PJ Rice VJ Wacher KM Ruble KJ Edgar Inhibiting ef 1047298ux withnovel non-ionic surfactants rational design based on vitamin E TPGS Int JPharm 370 (2009) 93ndash102
428 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[81] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Absence of a food effect with a 145 mg nanoparticle feno-1047297brate tablet formulation Int J Clin Pharmacol Ther 44 (2006) 64ndash70
[82] MV Chaubal C Popescu Conversion of nanosuspensions into dry powders byspray drying a case study Pharm Res 25 (2008) 2302ndash2308
[83] F Lai E Pini G Angioni ML Manca J Perricci C Sinico AM Fadda Nanocrys-tals as tool to improve piroxicam dissolution rate in novel orally disintegratingtablets Eur J Pharm Biopharm 79 (2011) 552ndash558
[84] D Mou H Chen J Wan H Xu X Yang Potent dried drug nanosuspensions for
oral bioavailability enhancement of poorly soluble drugs with pH-dependentsolubility Int J Pharm 413 (2011) 237ndash244[85] A Ain-Ai PK Gupta Effect of arginine hydrochloride and hydroxypropyl cellu-
lose as stabilizers on the physical stability of high drug loading nanosuspensionsof a poorly soluble compound Int J Pharm 351 (2008) 282 ndash288
[86] Z Guo T Pereira O Choi Y Wang HT Hahn Surface functionalized aluminananoparticle 1047297lled polymeric nanocomposites with enhanced mechanical prop-erties J Mater Chem 16 (2006) 2800ndash2808
[87] DR Kalaria G Sharma V Beniwal MN Ravi Kumar Design of biodegradablenanoparticles for oral delivery of doxorubicin in vivo pharmacokinetics and tox-icity studies in rats Pharm Res 26 (2009) 492ndash501
[88] JE Kipp The role of solid nanoparticle technology in parenteral delivery of poorly water soluble drugs Int J Pharm 284 (2004) 109ndash122
[89] HM Shubar S Lachenmaier MM Heimesaat U Lohman R Mauludin RHMuumlller R Fitzner K Borner O Liesenfeld SDS-coated atovaquone nanosuspen-sions show improved therapeutic ef 1047297cacy against experimental acquired andreactivated toxoplasmosis by improving passage of gastrointestinal and bloodndash
brain barriers J Drug Target 19 (2011) 114ndash124[90] L Peltonen J Hirvonen Pharmaceutical nanocrystals by nanomilling critical
process parameters particle fracturing and stabilization method J Pharm Phar-macol 62 (2010) 1569ndash1579
[91] F Lai C Sinico G Ennas F Marongiu G Marongiu AM Fadda Diclofenac nano-suspensions in1047298uence of preparation procedure and crystal form on drug disso-lution behavior Int J Pharm 373 (2009) 124ndash132
[92] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (Suppl 2) (2000) S73ndashS80
[93] RH Muller CM Keck Challenges and solutions for the delivery of biotech drugsmdasha review of drug nanocrystal technology and lipid nanoparticles J Biotechnol113 (2004) 151ndash170
[94] JL Wahlstrom P Chiang S Ghosh CJ Warren SP Wene LA Albin ME SmithSL Roberds Pharmacokinetic evaluation of a 13-dicyclohexylurea nanosuspen-sion formulation to support early ef 1047297cacy assessment Nanoscale Res Lett 2(2007) 291ndash296
[95] Y GaoZ LiM SunH Li CGuoJ CuiA LiF CaoY XiH Lou GZhai Preparationcharacterization pharmacokinetics and tissue distribution of curcumin nanosus-pension with TPGS as stabilizer Drug Dev Ind Pharm 36 (2010) 1225ndash1234
[96] M Clement W Pugh I Parikh Tissue distribution and plasma clearance of a novelmicrocrystalline-coated 1047298urbiprofen formulation Pharmacologist 34 (1992)204ndash211
[97] RC Nagarwal S Kant PN Singh P Maiti JK Pandit Polymeric nanoparticulate sys-tem a potential approach for ocular drug delivery J Control Release 136 (2009)2ndash13
[98] H Gupta M Aqil RK Khar A Ali A Bhatnagar G Mittal Spar1047298oxacin loadedPLGA nanoparticles for sustained ocular drug delivery Nanomedicine 6 (2010)324ndash333
[99] HS Ali P York AM Ali N Blagden Hydrocortisone nanosuspensions for oph-thalmic delivery a comparative study between micro1047298uidic nanoprecipitationand media milling J Control Release 149 (2011) 175ndash181
[100] SK Sahoo F Dilnawaz S Krishnakumar Nanotechnology in ocular drug deliv-ery Drug Discov Today 13 (2008) 144ndash151
[101] O Kayser A Lemke N Hernaacutendez-Trejo The impact of nanobiotechnology on thedevelopment of newdrug deliverysystems Curr Pharm Biotechnol6 (2005) 3ndash5
[102] R Pignatello C Bucolo G Spedalieri A Maltese G Puglisi Flurbiprofen-loadedacrylate polymer nanosuspensions for ophthalmic application Biomaterials 23(2002) 3247ndash3255
[103] R Ravichandran Nanoparticles in drug delivery potential green nanobiomedi-
cine applications Int J Green Nanotechnol Biomed 1 (2009) B108ndash
B130[104] AM Cerdeira M Mazzotti B Gander Miconazole nanosuspensions in1047298uence
of formulation variables on particle size reduction and physical stability Int JPharm 396 (2010) 210ndash218
[105] MA Kassem AA Abdel Rahman MM Ghorab MB Ahmed RM Khalil Nano-suspension as an ophthalmic delivery system for certain glucocorticoid drugsInt J Pharm 340 (2007) 126ndash133
[106] P Chiang JW Alsup Y Lai Y Hu BR Heyde D Tung Evaluation of aerosol de-livery of nanosuspension for pre-clinical pulmonary drug delivery NanoscaleRes Lett 4 (2009) 254ndash261
[107] W Yang JI Peters RO Williams III Inhaled nanoparticlesmdasha current reviewInt J Pharm 356 (2008) 239ndash247
[108] J Zhang L Wu H Chan W Watanabe Formation characterization and fate of inhaled drug nanoparticles Adv Drug Deliv Rev 63 (2011) 441ndash455
[109] HM Mansour YS Rhee X Wu Nanomedicine in pulmonary delivery Int JNanomedicine 4 (2009) 299ndash319
[110] NR Labiris MB Dolovich Pulmonary drug delivery Part I physiological factorsaffecting therapeutic effectiveness of aerosolized medications Br J Clin Phar-macol 56 (2003) 588ndash599
[111] JS Patton PR Byron Inhaling medicines delivering drugs to the body throughthe lungs Nat Rev Drug Discov 6 (2007) 67ndash74
[112] DA Edwards C Dunbar Bioengineering of therapeutic aerosols Annu RevBiomed Eng 4 (2002) 93ndash107
[113] W Yang JTam DA Miller J Zhou JT McConville KP Johnstonb RO WilliamsIII High bioavailability from nebulized itraconazole nanoparticle dispersionswith biocompatible stabilizers Int J Pharm 361 (2008) 177ndash188
[114] S Gill R Lobenberg T Ku S Azarmi W Roa EJ Prenner Nanoparticles char-acteristics mechanisms of action and toxicity in pulmonary drug deliverymdasha re-view J Biomed Nanotechnol 3 (2007) 107ndash119
[115] SJ Sze1047298er Pharmacodynamics and pharmacokinetics of budesonide a new
S183[116] W Yang KP Johnston RO Williams III Comparison of bioavailability of amor-phous versus crystalline itraconazole nanoparticles via pulmonary administra-tion in rats Eur J Pharm Biopharm 75 (2010) 33 ndash41
[117] R Ali GK Jain Z Iqbal S Talegaonkar P Pandit S Sule G Malhotra RK KharA Bhatnagar FJ Ahmad Development and clinical trial of nano-atropine sulfatedry powder inhaler as a novel organophosphorous poisoning antidote Nanome-dicine 5 (2009) 55ndash63
[118] D Andes Minireview in vivo pharmacodynamics of antifungal drugs in treat-ment of candidiasis Antimicrob Agents Chemother 47 (2003) 1179ndash1186
[119] D Andes K Marchillo R Conklin G Krishna F Ezzet A Cacciapuoti DLoebenberg Pharmacodynamics of a new triazole posaconazole in a murinemodel of disseminated candidiasis Antimicrob Agents Chemother 48 (2004)137ndash142
[120] O Kayser C Olbrich V Yardley AF Kiderlen SL Croft Formulation of ampho-tericin B as nanosuspension for oral administration Int J Pharm 254 (2003)73ndash75
[121] L Zhang S Hou S Mao D Wei X Song Y Lu Uptake of folate-conjugated albu-min nanoparticles to the SKOV3 cells Int J Pharm 287 (2004) 155ndash162
[122] J Sudimack RJ Lee Targeted drug delivery via folate receptor Adv Drug DelivRev 41 (2000) 147ndash162
[123] P Vader LJ van der Aa G Storm RM Schiffelers JF Engbersen Polymeric car-rier systems for siRNA delivery Curr Top Med Chem 12 (2012) 108 ndash119
[124] O Veiseh FM Kievit RG Ellenbogen M Zhang Cancer cell invasion treatmentand monitoring opportunities in nanomedicine Adv Drug Deliv Rev 63 (2011)582ndash596
[125] J Kreuter VE Petrov DA Kharkevich RN Alyautdin In1047298uence of the type of surfactant on the analgesic effects induced by the peptide dalargin after its de-livery across the bloodndashbrain barrier using surfactant-coated nanoparticles JControl Release 49 (1997) 81ndash87
[126] J Ye Q Wang X Zhou N Zhang Injectable actarit-loaded solid lipid nanoparti-cles as passive targeting therapeutic agents for rheumatoid arthritis Int JPharm 352 (2008) 273ndash279
[127] SM Moghimi AC Hunter JC Murray Nanomedicine current status and futureprospects FASEB J 19 (2005) 311ndash330
[128] K Park To PEGylate or not PEGylate that is not the question J Control Release142 (2010) 147ndash148
[129] M Socha P Bartecki C Passitani A Sapin C Damge T Lecompte J BarreE Ghazouani P Maincent Stealth nanoparticles coated with heparin aspeptide or peptide carriers J Drug Target 17 (2009) 575ndash585
[130] D Shenoy S Little R Langer M Amiji Poly(ethylene oxide)-modi1047297ed poly(-beta-amino ester) nanoparticles as a pH-sensitive system for tumor targeted de-livery of hydrophobic drugs part 2 In vivo distribution and tumor localizationstudies Pharm Res 22 (2005) 2107ndash2114
[131] R Shegokara KK Singha Surface modi1047297ed nevirapinenanosuspensions for viralreservoir targeting in vitro and in vivo evaluation Int J Pharm 421 (2011)341ndash352
[132] Y Matsumura H Maeda A new concept for macromolecular therapeutics incancer chemotherapy mechanism of tumoritropic accumulation of proteinsand the antitumor agent SMANCS Cancer Res 46 (1986) 6387ndash6392
[133] H Zhang CP Hollis Q Zhang T Li Preparation and antitumor study of camp-tothecin nanocrystals Int J Pharm 415 (2011) 293ndash300
[134] H Lou L Gao X Wei Z Zhang D Zheng D Zhang X Zhang Y Li Q Zhang Ori-donin nanosuspension enhances anti-tumor ef 1047297cacy in SMMC-7721 cells andH22 tumor bearing mice Colloids Surf B Biointerfaces 87 (2011) 319ndash325
[135] TM Goppert RH Muumlller Adsorption kinetics of plasma proteins on solid lipid
nanoparticles for drug targeting Int J Pharm 302 (2005) 172ndash
186[136] X Pu J Sun M Li Z He Formulation of nanosuspensions as a new approach for
the delivery of poorly soluble drugs Curr Nanosci 5 (2009) 417ndash427[137] R Gaudana J Jwala SHS Boddu AK Mitra Recent perspectives in ocular drug
delivery Pharm Res 26 (2009) 1197ndash1216[138] T Yasukawa H Kimura Y Tabata H Miyamoto Y Honda Y Ikada Y Ogura
Targeted delivery of anti-angiogenic agent TNP-470 using water-soluble poly-mer in the treatment of choroidal neovascularization Invest Ophthalmol VisSci 40 (1999) 2690ndash2696
[139] A Lemke AF Kiderlen B Petri O Kayser Delivery of amphotericin B nanosus-pensions to the brain and determination of activity against Balamuthia mandril-laris amebas Nanomedicine 6 (2010) 597ndash603
[140] HL Wong XY Wu R Bendayan Nanotechnological advances forthe delivery of CNS therapeutics Adv Drug Deliv Rev (2011) doi101016jaddr201110007
[141] J Kreuter S Gelperina Use of nanoparticles for cerebral cancer Tumori 94(2008) 271ndash277
[142] J Kreuter RN Alyautdin DA Kharkevich AA Ivanov Passage of peptidesthrough the bloodndashbrain barrier with colloidal polymer particles (nanoparti-cles) Brain Res 674 (1995) 171ndash174
429L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[143] J Kreuter Nanoparticulate systems for brain delivery of drugs Adv Drug DelivRev 47 (2001) 65ndash81
[144] TM Goumlppert RH Muumlller Polysorbate-stabilized solid lipid nanoparticles as col-loidal carriers for intravenous targeting of drugs to the brain comparison of plasma protein adsorption patterns J Drug Target 13 (2005) 179ndash187
[145] S Mansouri Y Cuie F Winnik Q Shi P Lavigne M Benderdour E Beaumont JC Fernandes Characterization of folate-chitosan-DNA nanoparticles for genetherapy Biomaterials 27 (2006) 2060ndash2065
[146] AR Hilgenbrink PS Low Folate receptor-mediated drug targeting from thera-peutics to diagnostics J Pharm Sci 94 (2005) 2135ndash2146
[147] F Pierigegrave S Sera1047297ni L Rossi M Magnani Cell-based drug delivery Adv Drug
Deliv Rev 60 (2008) 286ndash
295[148] F Chellat Y Merhi A Moreau L Yahia Therapeutic potential of nanoparticulatesystems for macrophage targeting Biomaterials 26 (2005) 7260ndash7275
[149] SS Hall S Mitragotri PS Daugherty Identi1047297cation of peptide ligands facilitatingnanoparticle at attachment to erythrocytes Biotechnol Prog 23 (2007) 749ndash754
[150] S Gorantla H Dou M Boska CJ Destache J Nelson L Poluektova BERabinow HE Gendelman RL Mosley Quantitative magnetic resonance and
SPECT imaging for macrophage tissue migration and nanoformulated drug de-livery J Leukoc Biol 80 (2006) 1165ndash1174
[151] LA Lotero G Olmos JC Diez Delivery to macrophages and toxic action of etopo-sidecarried in mouse redblood cells Biochim Biophys Acta 1620 (2003) 160ndash166
[152] L Rossi S Sera1047297ni F Pierigeacute A Antonelli A Cerasi A Fraternale L ChiarantiniM Magnani Erythrocyte-based drug delivery Expert Opin Drug Deliv 2 (2005)311ndash322
[153] S Sera1047297ni L Rossi A Antonelli A Fraternale A Cerasi R Crinelli L ChiarantiniGF Schiavano M Magnani Drug delivery through phagocytosis of red bloodcells Transfus Med Hemother 31 (2004) 92ndash101
[154] H Dou CJ Destache JR Morehead R Lee Mosley MD Boska J Kingsley S
Gorantla L Poluektova JA Nelson M Chaubal J Werling J Kipp BERabinow HE Gendelman Development of a macrophage-based nanoparticleplatform for antiretroviral drug delivery Blood 108 (2006) 2827ndash2835
[155] V Staedtke M Braumller A Muumlller R Georgieva S Bauer N Sternberg A Voigt ALemke C Keck J Moumlschwitzer H Baumlumler In vitro inhibition of fungal activityby macrophage-mediated sequestration and release of encapsulated amphoter-icin B nanosuspension in red blood cells Small 6 (2010) 96ndash103
430 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
It should be bear in mind that most drug nanocrystal formulations
used in the in vivo experiments are aqueous dispersions (Table 3)
however when it comes to the clinical application solid dosage
forms are usually more acceptable by patients [82] It can be seen
that most of the marketed nanoparticles formulations are solid
forms (Table 1) In order to solidi1047297cation 1047297rst the aqueous nanosus-
pensions should be transformed into dry powders suitable to gener-
ate tablets capsules pellets etc This transformation can be
achieved using different methods including lyophilization spray dry-ing granulation and pelletization [83ndash86] The drying process should
be well designed to avoid particle aggregation If aggregation occurs
the bene1047297ts that can be gained from large surface of the original
nanometer-sized particles would be greatly compromised In general
protectants (usually sugars) are often added to nanosuspensions to
minimize the particle size growth during a drying process
The redispersion progress of a solid formulation containing drug
nanocrystals in the GIT is more complex Physiological factors (in-
cluding pH variation compositions of the digestive juice and GI peri-
stalsis etc) affecting dispersion of nanocrystals are complicated [87]
Nanocrystals of basic drugs are more easily affected by pH variation in
the GIT For weak bases a nanometer-sized drug formulation will dis-
solve fast and more ef 1047297ciently in the low stomach pH environment
During transit from stomach to duodenum the rise in pH may illicit
uncontrolled precipitation of drug substance [88] In addition stabi-
lizer type should be screened by monitoring the change of particle
size after reconstitution in different pH media [89] After rehydration
in GI 1047298uid the nanocomplex disperses into separated nanocrystals
following the dissolution of 1047297llers Stabilizer molecules attached on
the surface of nanocrystals will offer ionic or steric repulsion among
nanocrystals given that they are not affected by the GIT environment
[690] In general ionic stabilizers are effective in aqueous environ-
ment but during the drying they may become less effective because
the ionized state is not maintained in dry material In addition ionic
stabilizers are also sensitive to changes in pH and ionic strength
when the dried powders redisperse in the GI 1047298uid [90] On the con-
trary in most cases the polymer and non-ionic surfactant stabilizers
can be effective to support suf 1047297cient steric repulsion in GI 1047298uid
given that the amount of stabilizers is enough [91]
The establishment of an in vitrondash
in vivo correlation (IVIVC) is anessential part for the study of oral formulations For the Class II
drugs dissolution is a rate-limiting step in the GIT so in general
they have a good IVIVC result [92] When they are processed into
nanocrystal formulations an IVIVC should be reevaluated again
since their dissolution velocity has been markedly enhanced In the
other hand the IVIVC data also help modulate the process and the
amount of matrix in the progress of drying nanosuspensions Howev-
er research on the IVIVC of nanocrystal formulations has not been
reported but we believe it will be the next focus in this 1047297eld
222 Injection administration route
For many cases intravenous injection is requested to meet some
treatment purpose such as immediate effects overcoming the 1047297rst
pass effect targeting effect and so on Due to its suf 1047297ciently small
size and safe aqueous composition nanosuspensions can be injected
intravenously and achieve 100 bioavailability [86] Compared with
other carrier-based solid nanoparticles such as solid lipid nanoparti-
cles polymer-based nanoparticles and liposomes carrier-free nano-
crystals would experience a much faster particle size reduction
during the process of dissolution This may lead to a distinct pharma-
cokinetic progress after iv administration because particle size is an
Table 4
Changes of pharmacokinetic properties of intravenous nanosuspensions compared with the conventional partners
Drug Methods Dosage form
(mean particle size)
Control
(mean particle size)
Comparison of the
pharmacokinetic parameters
Animals References
Asulac rine High p ressur e hom ogeniz at ion AN ( 13 3 nm) Organic solut ion 15- fold r edu ction in Cmax23-fold increase in t12 62-fold
increase in Vd 27-fold increase in
CL 27-fold increase in MRT
25-fold reduction in AUC
Rats [34]
Melar sopr ol High p ressur e hom ogeniz at ion AN ( 29 5 nm) Organic solut ion 22- fold inc rease in t12 14-fold
increase in Vd 14-fold reduction
in CL 2-fold reduction in AUC
Rats [41]
AN (409 nm) 3-fold increase in t12 13-fold reduction
in Vd 45-fold reduction in CL 42-fold
reduction in AUC
13-Dicyclohexylurea Media milling AN (NR)a Organic solution All parameters were similar to
those of solution
Rats [94]
Oridonin High p ressur e hom ogeniz at ion AN ( 10 33 nm) Organic solut ion All p ara meters w ere sim ilar to
those of solution 17-fold reduction
in Cmax 7-fold increase in t12 51-fold
increase in Vd 19-fold reduction in CL
62-fold increase in MRT 18-foldincrease in AUC
Rabbits [32]
AN (8972 nm)
It rac onaz ole High p ressur e hom ogeniz at ion AN ( 58 1 nm) Organic solut ion 17- fold inc rease in Cmax 31-fold
increase in t12 18 reduction in AUC 18
increase in CL 28 increase in MRT 79
increase in Vd
Rats [19]
AZ68 Precipitation AN (125 nm) Organic solution No signi1047297cant differences with
solution by means of plasma pro1047297les
Rats [35]
Media milling AN (200 nm)
Cyclosporine Precipitation AN (NR) Organic solution All parameters were similar to
those of solution
Rats [93]
Cu rc um in High p ressur e hom ogeniz at ion AN ( 21 02 nm) Organic solut ion 31- fold inc rease in Cmax
112-fold increase in MRT
48-fold increase in AUC
Rabbits [95]
Flu rb ip rofen High p ressur e hom ogeniz at ion AN ( NR ) Organic solut ion All p ara meters w ere sim ilar
to those of solution
Rats [96]
Vd volume of distribution CL clearance rate MRT mean retention time AUC area under the concentration ndashtime curve Cmax maximum plasma concentration Tmax time to max-
imum plasma concentration t12 plasma half lifea
NR Not reported
423L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
nanocrystals show clear potential for clinical development compared
with both the solution and the non-targeting nanocrystals formulations
243 Cell-based drug delivery of drug nanocrystals
The signi1047297cantly increased dissolution velocity which is a distinct
advantage of nanocrystals simultaneously implies the problem that
drug nanocrystals might dissolve before reaching the target Cell-
based drug delivery approach canbe employed to deal with this prob-
lem Cell based delivery systems are identi1047297
ed as cell carriers (includ-ing bacteria cells and animal cells) which can be loaded with drugs or
therapeutics The systems can release the drug content in circulation
or at selected sites or could target the drug to other relevant cells in
the body [147] Among the animal cells of special relevance are mac-
rophages and red blood cells (RBCs) Macrophages are differentiated
cells of the immune system able to phagocytize microorganisms as
well as nanoparticulate materials So nanoparticulate systems are
particularly useful for the delivery of therapeutic agents to macro-
phages [148149] When macrophages are used as drug delivery sys-
tems they should be 1047297rst loaded with the nanoparticulate drug ex
vivo and then re-infused into the host where their content is distrib-
uted to tissues that favor homing of macrophages such as parasites
bacteria and viruses [150151] RBCs constitute potential biocompati-
ble carriers for different bioactive substances including protein drugs
as well as nanoparticulates They have unique properties such as bio-
degradability biocompatibility and long-term drug releasing and thus
are well suited for drug encapsulation [152] They can be easily han-
dled ex vivo by means of several techniques for the encapsulation of
different molecules and nanoparticulates [153]
For drug nanocrystals few studies related on cell based drug deliv-
ery have been reported but the existing results proved the feasibility
Dou et al designed a novel bone marrow-derived macrophage (BMM)
indinavir nanocrystals delivery system for antiretroviral treatment
[154] Light microscopic examination proved that indinavir nanocrys-
tals were successfully loaded into BMMs after culture in the presence
of indinavir nanosuspensions for 12 h Following iv administration
into naive mice the indinavir nanocrystal loaded BMMs acted as ldquoTro-
jan horsesrdquo for transport of drug into tissues which were known to be
targets for HIV due to the parallel BMM migration and viral tissue tro-pism Administration of indinavir nanocrystal-BMMs sustained indina-
vir in tissue and sera for up to 10 days in comparison with 6 h for the
non-wrapped nanosuspensions Amphotericin B nanocrystal-loaded
RBCs systems were developed by Staedtke et al in order to improvean-
tifungal treatment [155] Amphotericin B nanocrystals encapsulation in
RBCs wasachieved by using hypotonichemolysis methodleading to in-
tracellularamphotericin B amounts of 381plusmn047 pg RBCminus1andanen-
trapment ef 1047297cacy of 15ndash18 Upon phagocytosis of amphotericin B
nanocrystal-RBCs leukocytes show a slow amphotericin B release
over 10 days and no alteration in cell viability
3 Conclusions
The researchon colloidal drug delivery systems may be the hottest1047297eld in pharmaceutics in the last several decades Due to the unique
advantage and pharmaeconomical value drug nanocrystals are paid
increasing attentions as a promising approach Drug nanocrystals
can be applied to all the poorly soluble drugs to overcome the solubil-
ity and bioavailability problems because all the poorly soluble drugs
can be comminuted into drug nanocrystals Researches on drug nano-
crystals within recent years fully exhibit their excellent in vivo perfor-
mances in different administration routes Among these the most
exciting information is that properties of drug nanocrystals can be
conveniently altered to meet various treatment demands of different
diseases With the number of insoluble drug compounds in develop-
ment increasing it is anticipated that nanocrystals technology will at-
tract increasing attentions as a viable formulation option However
though drug nanocrystals demonstrate superiority over the carrier
colloid drug delivery systems such as easier production safer compo-
sition and higher drug loading correspondingly they also confront
some problems For example how to obtain a more controllable
drug dissolution rate in order to meet the treatment requirements
of different diseases or reduce the drug release in the progress of de-
livering the drugs into target sites How can we get a more 1047297rm con-
junction between ligand-linked stabilizers and nanocrystal surfaces
without the loss of their properties We believe that many studies
will focus on handling these problems in the future
Acknowledgment
This work was partially supported by the Scienti1047297c Foundation of
the First Af 1047297liated Hospital of General Hospital of PLA the project
number is QN201105
References
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[2] ER Cooper Nanoparticles a personal experience for formulating poorly watersoluble drugs J Control Release 141 (2010) 300ndash302
[3] CM Keck RH Muumlller Drug nanocrystals of poorly soluble drugs produced by
high pressure homogenisation Eur J Pharm Biopharm 62 (2006) 3ndash
16[4] BE Rabinow Nanosuspensions in drug delivery Nat Rev Drug Discov 3 (2004)785ndash796
[5] L Gao D Zhang M Chen Drug nanocrystals for the formulation of poorly solu-ble drugs and its application as a potential drug delivery system J NanopartRes 10 (2008) 845ndash862
[6] GG Liversidge KC Cundy Particle size reduction for improvement of oral bio-availability of hydrophobic drugs I Absolute oral bioavailability of nanocrystal-line danazol in beagle dogs Int J Pharm 125 (1995) 91ndash97
[7] K Peters S Leitzke J Diederichs K Borner H Hahn RH Muumlller S Ehlers Prep-aration of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic ef 1047297cacy in murine Mycobacterium avium infection J AntimicrobChemother 45 (2000) 77ndash83
[8] P Rosario B Claudio F Piera M Adriana P Antonina P Giovanni EudragitRS100 nanosuspensions for the ophthalmic controlled delivery of ibuprofenEur J Pharm Sci 16 (2002) 53ndash61
[9] C Jacobs RH Muumlller Production and characterization of a budesonide nanosus-pension for pulmonary administration Pharm Res 19 (2002) 189ndash194
[10] RH Muumlller C Jacobs O Kayser Nanosuspensions as particulate drug formula-
tions in therapy rationale for development and what we can expect for the fu-ture Adv Drug Deliv Rev 47 (2001) 3ndash19
[11] B Van Eerdenbrugh G Van den Mooter P Augustijns Topndashdown production of drug nanocrystals nanosuspension stabilization miniaturization and transfor-mation into solid products Int J Pharm 364 (2008) 64ndash75
[12] E Merisko-Liversidge GG Liversidge ER Cooper Nanosizing a formulationapproach for poorly-water-soluble compounds Eur J Pharm Sci 18 (2003)113ndash120
[13] J Hu KP Johnston RO Williams Nanoparticle engineering processes for en-hancing the dissolution rates of poorly water soluble drugs Drug Dev IndPharm 30 (2004) 233ndash245
[14] JAH Junghanns RH Muumlller Nanocrystal technology drug delivery and clinicalapplications Int J Nanomedicine 3 (2008) 295ndash310
[15] GA Brazeau HL Fung Mechanisms of creatine kinase release from isolated ratskeletal muscles damaged by propylene glycol and ethanol J Pharm Sci 79(1990) 393ndash397
[16] K Korttila A Sothman P Andersson Polyethylene glycol as a solvent for diaze-pam bioavailability and clinical effects after intramuscular administrationcomparison of oral intramuscular and rectal administration and precipitationfrom intravenous solutions Acta Pharmacol Toxicol (Copenh) 39 (1976)104ndash117
[17] R Budden UG Kuhl J Bahlsen Experiments on toxic sedative and muscle re-laxant potency of various drug solvents in mice Pharmacol Ther 5 (1979)467ndash474
[18] F Liu JY Park Y Zhang C Conwell Y Liu SR Bathula L Huang Targeted can-cer therapy with novel high drug-loading nanocrystals J Pharm Sci 99 (2010)3542ndash3551
[19] B Rabinow J Kipp P Papadopoulos J Wong J Glosson J Gass CS Sun TWielgos R White C Cook K Barker K Wood Itraconazole IV nanosuspensionenhances ef 1047297cacy through altered pharmacokinetics in the rat Int J Pharm 339(2007) 251ndash260
[20] F Kesisoglou S Panmai Y Wu Nanosizingmdashoral formulation development andbiopharmaceutical evaluation Adv Drug Deliv Rev 59 (2007) 631ndash644
[22] GG Liversidge P Conzentino Drug particle size reduction for decreasing gastricirritancy and enhancing absorption of naproxen in rats Int J Pharm 125 (1995)
309ndash
313
427L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[23] E Merisko-Liversidge GG Liversidge Nanosizing for oral and parenteral drugdelivery a perspective on formulating poorly-water soluble compounds usingwet media milling technology Adv Drug Deliv Rev 30 (2011) 427ndash440
[24] BHL Boumlhm RH Muumlller Lab-scale production unit design for nanosuspensions of sparingly soluble cytotoxic drugs Pharm Sci Technol Today 2 (1999) 336ndash339
[25] RH Drew E Dodds Ashley DK Benjamin Jr R Duane Davis SM Palmer JRPerfect Comparative safety of amphotericin B lipid complex and amphotericinB deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipi-ents Transplantation 77 (2004) 232ndash237
[26] J Dubois T Bartter J Gryn MR Pratter The physiologic effects of inhaledamphotericin B Chest 108 (1995) 750ndash753
[27] SM Palmer RH Drew JD Whitehouse VF Tapson RD Davis RR McConnellSS Kanj JR Perfect Safety of aerosolized amphotericin B lipid complex in lungtransplant recipients Transplantation 72 (2001) 545ndash548
[28] RO Williams III J Liu Formulation of a protein with propellant HFA 134a foraerosol delivery Eur J Pharm Sci 7 (1999) 137ndash144
[29] IC Ashurst CV Ambrose DJ Russell Pharmaceutical evaluation of a new spac-er device for delivery of metered-dose inhalers to infants and young children JAerosol Sci 23 (1992) 499ndash502
[30] GC Na HJ Stevens B Yuan N Rajagopalan Physical stability of ethyl diatrizoatenanocrystalline suspension in steam sterilization Pharm Res 16 (1999) 569ndash574
[31] H Lou X Zhang L Gao F Feng J Wang X Wei Z Yu D Zhang Q Zhang Invitro and in vivo antitumor activity of oridonin nanosuspension Int J Pharm379 (2009) 181ndash186
[32] L Gao D Zhang M Chen C Duan W Dai L Jia W Zhao Studies on pharmaco-kinetics and tissue distribution of oridonin nanosuspensions Int J Pharm 355(2008) 321ndash327
[33] SM Moghimi AC Hunter JC Murray Long circulating and target-speci1047297cnanoparticles theory to practice Pharmacol Rev 53 (2001) 283ndash381
[34] S Ganta JW Paxton BC Baguley S Garg Formulation and pharmacokinetic
evaluation of an asulacrine nanocrystalline suspension for intravenous deliveryInt J Pharm 367 (2009) 179ndash186
[35] K Sigfridsson S Forsseacuten P Hollaumlnder U Skantze J de Verdier A formulationcomparison using a solution and different nanosuspensions of a poorly solublecompound Eur J Pharm Biopharm 67 (2007) 540ndash547
[36] K Sigfridsson AJ Lundqvist M Strimfors Particle size reduction for improve-ment of oral absorption absorption of the poorly soluble drug UG558 in rats dur-ing early development Drug Dev Ind Pharm 35 (2009) 1479ndash1486
[37] S Kim J Lee Folate-targeted drug-delivery systems prepared by nano-comminution Drug Dev Ind Pharm 37 (2011) 131ndash138
[38] R Xiong W Lu J Li P Wang R Xu T Chen Preparation and characterization of intravenously injectable nimodipine nanosuspension Int J Pharm 350 (2008)338ndash343
[39] Y Gao Z Li M Sun C Guo A Yu Y Xi J Cui H Lou G Zhai Preparation andcharacterization of intravenously injectable curcumin nanosuspension DrugDeliv 18 (2011) 131ndash142
[40] RH Muumlller K Peters Nanosuspensions for the formulation of poorly solubledrugs I Preparation by a size-reduction technique Int J Pharm 160 (1998)229ndash237
[41] SB Zirar A Astier M Muchow S Gibaud Comparison of nanosuspensions andhydroxypropyl-b-cyclodextrin complex of melarsoprol pharmacokinetics andtissue distribution in mice Eur J Pharm Biopharm 70 (2008) 649 ndash656
[42] M Salzberg M Pless C Rochlitz K Ambrus P Scigalla R Herrmann A phase Istudy with oral SU5416 in patients with advanced solid tumors a drug inducingits clearance Invest New Drugs 24 (2006) 299ndash304
[43] WK Kraft B Steiger D Beussink JN Quiring N Fitzgerald HE Greenberg SAWaldman The pharmacokinetics of nebulized nanocrystal budesonide suspen-sion in healthy volunteers J Clin Pharmacol 44 (2004) 67ndash72
[44] JM Vaughn NP Wiederhold JT McConville JJ Coalson RL Talbert DSBurgess KP Johnston RO Williams III JI Peters Murine airway histologyand intracellular uptake of inhaled amorphous itraconazole Int J Pharm 338(2007) 219ndash224
[45] JM Vaughn JT McConville D Burgess JI Peters KP Johnston RL Talbert ROWilliams III Single dose and multiple dose studies of itraconazole nanoparticlesEur J Pharm Biopharm 63 (2006) 95ndash102
[46] BJ Hoeben DS Burgess JT McConville LK Najvar RL Talbert JI Peters NPWiederhold BL Frei JR Graybill R Bocanegra KA Overhoff P Sinswat KP
Johnston RO Williams III In vivo ef 1047297cacy of aerosolized nanostructured itraco-nazole formulations for prevention of invasive pulmonary aspergillosis Antimi-crob Agents Chemother 50 (2006) 1552ndash1554
[47] CA Alvarez NP Wiederhold JT McConville JI Peters LK Najvar JR Graybill JJ Coalson RL Talbert DS Burgess R Bocanegra KP Johnston RO WilliamsIII Aerosolized nanostructured itraconazole as prophylaxis against invasive pul-monary aspergillosis J Infect 55 (2007) 68ndash74
[48] SB Shrewsbury AP Bosco PS Uster Pharmacokinetics of a novel submicronbudesonide dispersion for nebulized delivery in asthma Int J Pharm 365(2009) 12ndash17
[49] RH Muumlller KH Wallis Surface modi1047297cation of iv injectable biodegradablenanoparticles with poloxamer polymers and poloxamine 908 Int J Pharm 89(1993) 25ndash31
[50] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy and diagno-sis Adv Drug Deliv Rev 54 (2002) 631ndash651
[51] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (2000) 73ndash80
[52] M Wang M Thanou Targeting nanoparticles to cancer Pharmacol Res 62(2010) 90ndash99
[53] L Gao G Liu X Wang F Liu Y Xu J Ma Preparation of a chemically stablequercetin formulation using nanosuspension technology Int J Pharm 404(2011) 231ndash237
[54] M Sarkari J Brown X Chen S Swinnea RO Williams III KP Johnston En-hanced drug dissolution using evaporative precipitation into aqueous solutionInt J Pharm 243 (2002) 17ndash31
[55] X Li L Gu Y Xu Y Wang Preparation of feno1047297brate nanosuspension and studyof its pharmacokinetic behavior in rats Drug Dev Ind Pharm 35 (2009)827ndash833
[56] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Pharmacokinetic evaluation of oral feno1047297brate nanosus-
pensions and SLN in comparison to conventional suspensions of micronizeddrug Adv Drug Deliv Rev 59 (2007) 419ndash426[57] GJ Vergote C Vervaet I Van Driessche S Hoste S De Smedt J Demeester RA
Jain S Ruddy JP Remon In vivo evaluation of matrix pellets containing nano-crystalline ketoprofen Int J Pharm 240 (2002) 79ndash84
[58] S Ghosh P Chiang JL Wahlstrom H Fujiwara JG Selbo SL Roberds Oral de-livery of 13-dicyclohexylurea nanosuspension enhances exposure and lowersblood pressure in hypertensive rats Basic Clin Pharmacol Toxicol 102 (2008)453ndash458
[59] P Langguth A Hanafy D Frenzel P Grenier A Nhamias T Ohlig G VergnaultH Spahn-Langguth Nanosuspension formulations for low-soluble drugs phar-macokinetic evaluation using spironolactone as model compound Drug DevInd Pharm 31 (2005) 319ndash329
[60] MG Fakesa Blisse J Vakkalagaddab Feng Qiana Sridhar Desikana Rajesh BGandhi C Lai A Hsieha MK Franchini H Toaled J Brown Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amor-phous formulation approaches Int J Pharm 370 (2009) 167ndash174
[61] K Sigfridsson A Nordmark S Theilig A Lindah A formulation comparison be-tween micro- and nanosuspensions the importance of particle size for absorp-
tion of a model compound following repeated oral administration to rats duringearly development Drug Dev Ind Pharm 37 (2011) 185ndash192
[62] J Jinno N Kamada M Miyake K Yamada T Mukai M Odomi H Toguchi GGLiversidge K Higaki T Kimura Effect of particle size reduction on dissolutionand oral absorption of a poorly water-soluble drug cilostazol in beagle dogs JControl Release 111 (2006) 56ndash64
[63] Y Wu A Loper E Landis L Hettrick L Novak K Lynn C Chen K Thompson RHiggins U Batra S Shelukar G Kwei D Storey The role of biopharmaceutics inthe development of a clinical nanoparticle formulation of MK-0869 a beagledog model predicts improved bioavailability and diminished food effect on ab-sorption in human Int J Pharm 285 (2004) 135ndash146
[64] RH Muumlller S Runge V Ravelli W Mehnert AF Thuumlnemann EB Souto Oralbioavailability of cyclosporine solid lipid nanoparticles (SLNreg) versus drugnanocrystals Int J Pharm 317 (2006) 82ndash89
[65] G Ponchel MJ Montisci A Dembri C Durrer D Duchecircne Mucoadhesion of colloidal particulate systems in the gastro-intestinal tract Eur J Pharm Bio-pharm 44 (1997) 25ndash31
[66] D Duchecircne G Ponchel Bioadhesion of solid oral dosage forms why and howEur J Pharm Biopharm 44 (1997) 15ndash23
[67] D Dodou P Breedveld PA Wieringa Mucoadhesives in the gastrointestinaltract revisiting the literature for novel applications Eur J Pharm Biopharm60 (2005) 1ndash16
[68] JD Smart The basics and underlying mechanisms of mucoadhesion Adv DrugDeliv Rev 57 (2005) 1556ndash1568
[69] O Kayser A newapproach fortargetingto Cryptosporidium parvum using mucoadhe-sive nanosuspensions research and applications Int J Pharm 214 (2001) 83ndash85
[70] A des Rieux V Fievez M Garinot YJ Schneider V Preacuteat Nanoparticles as po-tential oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[71] A Lamprecht P Koenig N Ubrich P Maincent D Neumann Low molecularweight heparin nanoparticles mucoadhesion and behaviour in Caco-2 cellsNanotechnology 17 (2006) 3673ndash3680
[72] F Delie Evaluation of nano- and microparticle uptake by the gastrointestinaltract Adv Drug Deliv Rev 34 (1998) 221ndash233
[73] CN Grama DD Ankola MNV Ravi Kumar Poly(lactide-co-glycolide) nano-particles for peroral delivery of bioactives Curr Opin Colloid Interface Sci 16(2011) 238ndash245
[74] MP Desai V Labhasetwar GL Amidon RJ Levy Gastrointestinal Uptake of biodegradable microparticles effect of particle size Pharm Res 13 (1996)1838ndash1845
[75] A des Rieux V Fievez M Garinot YJ Scheider V Preat Nanoparticles as poten-tial oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[76] JM Dintaman JA Silverman Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) Pharm Res 16 (1999)1550ndash1556
[77] J Goole DJ Lindley W Roth SM Carl K Amighi JM Kauffmann GT KnippThe effects of excipients on transporter mediated absorption Int J Pharm 393(2010) 17ndash31
[78] J Huang L Si L Jiang Z Fan J Qiu G Li Effect of pluronic F68 block copolymeron P-glycoprotein transport and CYP3A4 metabolism Int J Pharm 356 (2008)351ndash353
[79] MF Wempe C Wright JL Little JW Lightner SE Large GB Ca1047298isch CMBuchanan PJ Rice VJ Wacher KM Ruble KJ Edgar Inhibiting ef 1047298ux withnovel non-ionic surfactants rational design based on vitamin E TPGS Int JPharm 370 (2009) 93ndash102
428 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[81] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Absence of a food effect with a 145 mg nanoparticle feno-1047297brate tablet formulation Int J Clin Pharmacol Ther 44 (2006) 64ndash70
[82] MV Chaubal C Popescu Conversion of nanosuspensions into dry powders byspray drying a case study Pharm Res 25 (2008) 2302ndash2308
[83] F Lai E Pini G Angioni ML Manca J Perricci C Sinico AM Fadda Nanocrys-tals as tool to improve piroxicam dissolution rate in novel orally disintegratingtablets Eur J Pharm Biopharm 79 (2011) 552ndash558
[84] D Mou H Chen J Wan H Xu X Yang Potent dried drug nanosuspensions for
oral bioavailability enhancement of poorly soluble drugs with pH-dependentsolubility Int J Pharm 413 (2011) 237ndash244[85] A Ain-Ai PK Gupta Effect of arginine hydrochloride and hydroxypropyl cellu-
lose as stabilizers on the physical stability of high drug loading nanosuspensionsof a poorly soluble compound Int J Pharm 351 (2008) 282 ndash288
[86] Z Guo T Pereira O Choi Y Wang HT Hahn Surface functionalized aluminananoparticle 1047297lled polymeric nanocomposites with enhanced mechanical prop-erties J Mater Chem 16 (2006) 2800ndash2808
[87] DR Kalaria G Sharma V Beniwal MN Ravi Kumar Design of biodegradablenanoparticles for oral delivery of doxorubicin in vivo pharmacokinetics and tox-icity studies in rats Pharm Res 26 (2009) 492ndash501
[88] JE Kipp The role of solid nanoparticle technology in parenteral delivery of poorly water soluble drugs Int J Pharm 284 (2004) 109ndash122
[89] HM Shubar S Lachenmaier MM Heimesaat U Lohman R Mauludin RHMuumlller R Fitzner K Borner O Liesenfeld SDS-coated atovaquone nanosuspen-sions show improved therapeutic ef 1047297cacy against experimental acquired andreactivated toxoplasmosis by improving passage of gastrointestinal and bloodndash
brain barriers J Drug Target 19 (2011) 114ndash124[90] L Peltonen J Hirvonen Pharmaceutical nanocrystals by nanomilling critical
process parameters particle fracturing and stabilization method J Pharm Phar-macol 62 (2010) 1569ndash1579
[91] F Lai C Sinico G Ennas F Marongiu G Marongiu AM Fadda Diclofenac nano-suspensions in1047298uence of preparation procedure and crystal form on drug disso-lution behavior Int J Pharm 373 (2009) 124ndash132
[92] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (Suppl 2) (2000) S73ndashS80
[93] RH Muller CM Keck Challenges and solutions for the delivery of biotech drugsmdasha review of drug nanocrystal technology and lipid nanoparticles J Biotechnol113 (2004) 151ndash170
[94] JL Wahlstrom P Chiang S Ghosh CJ Warren SP Wene LA Albin ME SmithSL Roberds Pharmacokinetic evaluation of a 13-dicyclohexylurea nanosuspen-sion formulation to support early ef 1047297cacy assessment Nanoscale Res Lett 2(2007) 291ndash296
[95] Y GaoZ LiM SunH Li CGuoJ CuiA LiF CaoY XiH Lou GZhai Preparationcharacterization pharmacokinetics and tissue distribution of curcumin nanosus-pension with TPGS as stabilizer Drug Dev Ind Pharm 36 (2010) 1225ndash1234
[96] M Clement W Pugh I Parikh Tissue distribution and plasma clearance of a novelmicrocrystalline-coated 1047298urbiprofen formulation Pharmacologist 34 (1992)204ndash211
[97] RC Nagarwal S Kant PN Singh P Maiti JK Pandit Polymeric nanoparticulate sys-tem a potential approach for ocular drug delivery J Control Release 136 (2009)2ndash13
[98] H Gupta M Aqil RK Khar A Ali A Bhatnagar G Mittal Spar1047298oxacin loadedPLGA nanoparticles for sustained ocular drug delivery Nanomedicine 6 (2010)324ndash333
[99] HS Ali P York AM Ali N Blagden Hydrocortisone nanosuspensions for oph-thalmic delivery a comparative study between micro1047298uidic nanoprecipitationand media milling J Control Release 149 (2011) 175ndash181
[100] SK Sahoo F Dilnawaz S Krishnakumar Nanotechnology in ocular drug deliv-ery Drug Discov Today 13 (2008) 144ndash151
[101] O Kayser A Lemke N Hernaacutendez-Trejo The impact of nanobiotechnology on thedevelopment of newdrug deliverysystems Curr Pharm Biotechnol6 (2005) 3ndash5
[102] R Pignatello C Bucolo G Spedalieri A Maltese G Puglisi Flurbiprofen-loadedacrylate polymer nanosuspensions for ophthalmic application Biomaterials 23(2002) 3247ndash3255
[103] R Ravichandran Nanoparticles in drug delivery potential green nanobiomedi-
cine applications Int J Green Nanotechnol Biomed 1 (2009) B108ndash
B130[104] AM Cerdeira M Mazzotti B Gander Miconazole nanosuspensions in1047298uence
of formulation variables on particle size reduction and physical stability Int JPharm 396 (2010) 210ndash218
[105] MA Kassem AA Abdel Rahman MM Ghorab MB Ahmed RM Khalil Nano-suspension as an ophthalmic delivery system for certain glucocorticoid drugsInt J Pharm 340 (2007) 126ndash133
[106] P Chiang JW Alsup Y Lai Y Hu BR Heyde D Tung Evaluation of aerosol de-livery of nanosuspension for pre-clinical pulmonary drug delivery NanoscaleRes Lett 4 (2009) 254ndash261
[107] W Yang JI Peters RO Williams III Inhaled nanoparticlesmdasha current reviewInt J Pharm 356 (2008) 239ndash247
[108] J Zhang L Wu H Chan W Watanabe Formation characterization and fate of inhaled drug nanoparticles Adv Drug Deliv Rev 63 (2011) 441ndash455
[109] HM Mansour YS Rhee X Wu Nanomedicine in pulmonary delivery Int JNanomedicine 4 (2009) 299ndash319
[110] NR Labiris MB Dolovich Pulmonary drug delivery Part I physiological factorsaffecting therapeutic effectiveness of aerosolized medications Br J Clin Phar-macol 56 (2003) 588ndash599
[111] JS Patton PR Byron Inhaling medicines delivering drugs to the body throughthe lungs Nat Rev Drug Discov 6 (2007) 67ndash74
[112] DA Edwards C Dunbar Bioengineering of therapeutic aerosols Annu RevBiomed Eng 4 (2002) 93ndash107
[113] W Yang JTam DA Miller J Zhou JT McConville KP Johnstonb RO WilliamsIII High bioavailability from nebulized itraconazole nanoparticle dispersionswith biocompatible stabilizers Int J Pharm 361 (2008) 177ndash188
[114] S Gill R Lobenberg T Ku S Azarmi W Roa EJ Prenner Nanoparticles char-acteristics mechanisms of action and toxicity in pulmonary drug deliverymdasha re-view J Biomed Nanotechnol 3 (2007) 107ndash119
[115] SJ Sze1047298er Pharmacodynamics and pharmacokinetics of budesonide a new
S183[116] W Yang KP Johnston RO Williams III Comparison of bioavailability of amor-phous versus crystalline itraconazole nanoparticles via pulmonary administra-tion in rats Eur J Pharm Biopharm 75 (2010) 33 ndash41
[117] R Ali GK Jain Z Iqbal S Talegaonkar P Pandit S Sule G Malhotra RK KharA Bhatnagar FJ Ahmad Development and clinical trial of nano-atropine sulfatedry powder inhaler as a novel organophosphorous poisoning antidote Nanome-dicine 5 (2009) 55ndash63
[118] D Andes Minireview in vivo pharmacodynamics of antifungal drugs in treat-ment of candidiasis Antimicrob Agents Chemother 47 (2003) 1179ndash1186
[119] D Andes K Marchillo R Conklin G Krishna F Ezzet A Cacciapuoti DLoebenberg Pharmacodynamics of a new triazole posaconazole in a murinemodel of disseminated candidiasis Antimicrob Agents Chemother 48 (2004)137ndash142
[120] O Kayser C Olbrich V Yardley AF Kiderlen SL Croft Formulation of ampho-tericin B as nanosuspension for oral administration Int J Pharm 254 (2003)73ndash75
[121] L Zhang S Hou S Mao D Wei X Song Y Lu Uptake of folate-conjugated albu-min nanoparticles to the SKOV3 cells Int J Pharm 287 (2004) 155ndash162
[122] J Sudimack RJ Lee Targeted drug delivery via folate receptor Adv Drug DelivRev 41 (2000) 147ndash162
[123] P Vader LJ van der Aa G Storm RM Schiffelers JF Engbersen Polymeric car-rier systems for siRNA delivery Curr Top Med Chem 12 (2012) 108 ndash119
[124] O Veiseh FM Kievit RG Ellenbogen M Zhang Cancer cell invasion treatmentand monitoring opportunities in nanomedicine Adv Drug Deliv Rev 63 (2011)582ndash596
[125] J Kreuter VE Petrov DA Kharkevich RN Alyautdin In1047298uence of the type of surfactant on the analgesic effects induced by the peptide dalargin after its de-livery across the bloodndashbrain barrier using surfactant-coated nanoparticles JControl Release 49 (1997) 81ndash87
[126] J Ye Q Wang X Zhou N Zhang Injectable actarit-loaded solid lipid nanoparti-cles as passive targeting therapeutic agents for rheumatoid arthritis Int JPharm 352 (2008) 273ndash279
[127] SM Moghimi AC Hunter JC Murray Nanomedicine current status and futureprospects FASEB J 19 (2005) 311ndash330
[128] K Park To PEGylate or not PEGylate that is not the question J Control Release142 (2010) 147ndash148
[129] M Socha P Bartecki C Passitani A Sapin C Damge T Lecompte J BarreE Ghazouani P Maincent Stealth nanoparticles coated with heparin aspeptide or peptide carriers J Drug Target 17 (2009) 575ndash585
[130] D Shenoy S Little R Langer M Amiji Poly(ethylene oxide)-modi1047297ed poly(-beta-amino ester) nanoparticles as a pH-sensitive system for tumor targeted de-livery of hydrophobic drugs part 2 In vivo distribution and tumor localizationstudies Pharm Res 22 (2005) 2107ndash2114
[131] R Shegokara KK Singha Surface modi1047297ed nevirapinenanosuspensions for viralreservoir targeting in vitro and in vivo evaluation Int J Pharm 421 (2011)341ndash352
[132] Y Matsumura H Maeda A new concept for macromolecular therapeutics incancer chemotherapy mechanism of tumoritropic accumulation of proteinsand the antitumor agent SMANCS Cancer Res 46 (1986) 6387ndash6392
[133] H Zhang CP Hollis Q Zhang T Li Preparation and antitumor study of camp-tothecin nanocrystals Int J Pharm 415 (2011) 293ndash300
[134] H Lou L Gao X Wei Z Zhang D Zheng D Zhang X Zhang Y Li Q Zhang Ori-donin nanosuspension enhances anti-tumor ef 1047297cacy in SMMC-7721 cells andH22 tumor bearing mice Colloids Surf B Biointerfaces 87 (2011) 319ndash325
[135] TM Goppert RH Muumlller Adsorption kinetics of plasma proteins on solid lipid
nanoparticles for drug targeting Int J Pharm 302 (2005) 172ndash
186[136] X Pu J Sun M Li Z He Formulation of nanosuspensions as a new approach for
the delivery of poorly soluble drugs Curr Nanosci 5 (2009) 417ndash427[137] R Gaudana J Jwala SHS Boddu AK Mitra Recent perspectives in ocular drug
delivery Pharm Res 26 (2009) 1197ndash1216[138] T Yasukawa H Kimura Y Tabata H Miyamoto Y Honda Y Ikada Y Ogura
Targeted delivery of anti-angiogenic agent TNP-470 using water-soluble poly-mer in the treatment of choroidal neovascularization Invest Ophthalmol VisSci 40 (1999) 2690ndash2696
[139] A Lemke AF Kiderlen B Petri O Kayser Delivery of amphotericin B nanosus-pensions to the brain and determination of activity against Balamuthia mandril-laris amebas Nanomedicine 6 (2010) 597ndash603
[140] HL Wong XY Wu R Bendayan Nanotechnological advances forthe delivery of CNS therapeutics Adv Drug Deliv Rev (2011) doi101016jaddr201110007
[141] J Kreuter S Gelperina Use of nanoparticles for cerebral cancer Tumori 94(2008) 271ndash277
[142] J Kreuter RN Alyautdin DA Kharkevich AA Ivanov Passage of peptidesthrough the bloodndashbrain barrier with colloidal polymer particles (nanoparti-cles) Brain Res 674 (1995) 171ndash174
429L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[143] J Kreuter Nanoparticulate systems for brain delivery of drugs Adv Drug DelivRev 47 (2001) 65ndash81
[144] TM Goumlppert RH Muumlller Polysorbate-stabilized solid lipid nanoparticles as col-loidal carriers for intravenous targeting of drugs to the brain comparison of plasma protein adsorption patterns J Drug Target 13 (2005) 179ndash187
[145] S Mansouri Y Cuie F Winnik Q Shi P Lavigne M Benderdour E Beaumont JC Fernandes Characterization of folate-chitosan-DNA nanoparticles for genetherapy Biomaterials 27 (2006) 2060ndash2065
[146] AR Hilgenbrink PS Low Folate receptor-mediated drug targeting from thera-peutics to diagnostics J Pharm Sci 94 (2005) 2135ndash2146
[147] F Pierigegrave S Sera1047297ni L Rossi M Magnani Cell-based drug delivery Adv Drug
Deliv Rev 60 (2008) 286ndash
295[148] F Chellat Y Merhi A Moreau L Yahia Therapeutic potential of nanoparticulatesystems for macrophage targeting Biomaterials 26 (2005) 7260ndash7275
[149] SS Hall S Mitragotri PS Daugherty Identi1047297cation of peptide ligands facilitatingnanoparticle at attachment to erythrocytes Biotechnol Prog 23 (2007) 749ndash754
[150] S Gorantla H Dou M Boska CJ Destache J Nelson L Poluektova BERabinow HE Gendelman RL Mosley Quantitative magnetic resonance and
SPECT imaging for macrophage tissue migration and nanoformulated drug de-livery J Leukoc Biol 80 (2006) 1165ndash1174
[151] LA Lotero G Olmos JC Diez Delivery to macrophages and toxic action of etopo-sidecarried in mouse redblood cells Biochim Biophys Acta 1620 (2003) 160ndash166
[152] L Rossi S Sera1047297ni F Pierigeacute A Antonelli A Cerasi A Fraternale L ChiarantiniM Magnani Erythrocyte-based drug delivery Expert Opin Drug Deliv 2 (2005)311ndash322
[153] S Sera1047297ni L Rossi A Antonelli A Fraternale A Cerasi R Crinelli L ChiarantiniGF Schiavano M Magnani Drug delivery through phagocytosis of red bloodcells Transfus Med Hemother 31 (2004) 92ndash101
[154] H Dou CJ Destache JR Morehead R Lee Mosley MD Boska J Kingsley S
Gorantla L Poluektova JA Nelson M Chaubal J Werling J Kipp BERabinow HE Gendelman Development of a macrophage-based nanoparticleplatform for antiretroviral drug delivery Blood 108 (2006) 2827ndash2835
[155] V Staedtke M Braumller A Muumlller R Georgieva S Bauer N Sternberg A Voigt ALemke C Keck J Moumlschwitzer H Baumlumler In vitro inhibition of fungal activityby macrophage-mediated sequestration and release of encapsulated amphoter-icin B nanosuspension in red blood cells Small 6 (2010) 96ndash103
430 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
It should be bear in mind that most drug nanocrystal formulations
used in the in vivo experiments are aqueous dispersions (Table 3)
however when it comes to the clinical application solid dosage
forms are usually more acceptable by patients [82] It can be seen
that most of the marketed nanoparticles formulations are solid
forms (Table 1) In order to solidi1047297cation 1047297rst the aqueous nanosus-
pensions should be transformed into dry powders suitable to gener-
ate tablets capsules pellets etc This transformation can be
achieved using different methods including lyophilization spray dry-ing granulation and pelletization [83ndash86] The drying process should
be well designed to avoid particle aggregation If aggregation occurs
the bene1047297ts that can be gained from large surface of the original
nanometer-sized particles would be greatly compromised In general
protectants (usually sugars) are often added to nanosuspensions to
minimize the particle size growth during a drying process
The redispersion progress of a solid formulation containing drug
nanocrystals in the GIT is more complex Physiological factors (in-
cluding pH variation compositions of the digestive juice and GI peri-
stalsis etc) affecting dispersion of nanocrystals are complicated [87]
Nanocrystals of basic drugs are more easily affected by pH variation in
the GIT For weak bases a nanometer-sized drug formulation will dis-
solve fast and more ef 1047297ciently in the low stomach pH environment
During transit from stomach to duodenum the rise in pH may illicit
uncontrolled precipitation of drug substance [88] In addition stabi-
lizer type should be screened by monitoring the change of particle
size after reconstitution in different pH media [89] After rehydration
in GI 1047298uid the nanocomplex disperses into separated nanocrystals
following the dissolution of 1047297llers Stabilizer molecules attached on
the surface of nanocrystals will offer ionic or steric repulsion among
nanocrystals given that they are not affected by the GIT environment
[690] In general ionic stabilizers are effective in aqueous environ-
ment but during the drying they may become less effective because
the ionized state is not maintained in dry material In addition ionic
stabilizers are also sensitive to changes in pH and ionic strength
when the dried powders redisperse in the GI 1047298uid [90] On the con-
trary in most cases the polymer and non-ionic surfactant stabilizers
can be effective to support suf 1047297cient steric repulsion in GI 1047298uid
given that the amount of stabilizers is enough [91]
The establishment of an in vitrondash
in vivo correlation (IVIVC) is anessential part for the study of oral formulations For the Class II
drugs dissolution is a rate-limiting step in the GIT so in general
they have a good IVIVC result [92] When they are processed into
nanocrystal formulations an IVIVC should be reevaluated again
since their dissolution velocity has been markedly enhanced In the
other hand the IVIVC data also help modulate the process and the
amount of matrix in the progress of drying nanosuspensions Howev-
er research on the IVIVC of nanocrystal formulations has not been
reported but we believe it will be the next focus in this 1047297eld
222 Injection administration route
For many cases intravenous injection is requested to meet some
treatment purpose such as immediate effects overcoming the 1047297rst
pass effect targeting effect and so on Due to its suf 1047297ciently small
size and safe aqueous composition nanosuspensions can be injected
intravenously and achieve 100 bioavailability [86] Compared with
other carrier-based solid nanoparticles such as solid lipid nanoparti-
cles polymer-based nanoparticles and liposomes carrier-free nano-
crystals would experience a much faster particle size reduction
during the process of dissolution This may lead to a distinct pharma-
cokinetic progress after iv administration because particle size is an
Table 4
Changes of pharmacokinetic properties of intravenous nanosuspensions compared with the conventional partners
Drug Methods Dosage form
(mean particle size)
Control
(mean particle size)
Comparison of the
pharmacokinetic parameters
Animals References
Asulac rine High p ressur e hom ogeniz at ion AN ( 13 3 nm) Organic solut ion 15- fold r edu ction in Cmax23-fold increase in t12 62-fold
increase in Vd 27-fold increase in
CL 27-fold increase in MRT
25-fold reduction in AUC
Rats [34]
Melar sopr ol High p ressur e hom ogeniz at ion AN ( 29 5 nm) Organic solut ion 22- fold inc rease in t12 14-fold
increase in Vd 14-fold reduction
in CL 2-fold reduction in AUC
Rats [41]
AN (409 nm) 3-fold increase in t12 13-fold reduction
in Vd 45-fold reduction in CL 42-fold
reduction in AUC
13-Dicyclohexylurea Media milling AN (NR)a Organic solution All parameters were similar to
those of solution
Rats [94]
Oridonin High p ressur e hom ogeniz at ion AN ( 10 33 nm) Organic solut ion All p ara meters w ere sim ilar to
those of solution 17-fold reduction
in Cmax 7-fold increase in t12 51-fold
increase in Vd 19-fold reduction in CL
62-fold increase in MRT 18-foldincrease in AUC
Rabbits [32]
AN (8972 nm)
It rac onaz ole High p ressur e hom ogeniz at ion AN ( 58 1 nm) Organic solut ion 17- fold inc rease in Cmax 31-fold
increase in t12 18 reduction in AUC 18
increase in CL 28 increase in MRT 79
increase in Vd
Rats [19]
AZ68 Precipitation AN (125 nm) Organic solution No signi1047297cant differences with
solution by means of plasma pro1047297les
Rats [35]
Media milling AN (200 nm)
Cyclosporine Precipitation AN (NR) Organic solution All parameters were similar to
those of solution
Rats [93]
Cu rc um in High p ressur e hom ogeniz at ion AN ( 21 02 nm) Organic solut ion 31- fold inc rease in Cmax
112-fold increase in MRT
48-fold increase in AUC
Rabbits [95]
Flu rb ip rofen High p ressur e hom ogeniz at ion AN ( NR ) Organic solut ion All p ara meters w ere sim ilar
to those of solution
Rats [96]
Vd volume of distribution CL clearance rate MRT mean retention time AUC area under the concentration ndashtime curve Cmax maximum plasma concentration Tmax time to max-
imum plasma concentration t12 plasma half lifea
NR Not reported
423L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
nanocrystals show clear potential for clinical development compared
with both the solution and the non-targeting nanocrystals formulations
243 Cell-based drug delivery of drug nanocrystals
The signi1047297cantly increased dissolution velocity which is a distinct
advantage of nanocrystals simultaneously implies the problem that
drug nanocrystals might dissolve before reaching the target Cell-
based drug delivery approach canbe employed to deal with this prob-
lem Cell based delivery systems are identi1047297
ed as cell carriers (includ-ing bacteria cells and animal cells) which can be loaded with drugs or
therapeutics The systems can release the drug content in circulation
or at selected sites or could target the drug to other relevant cells in
the body [147] Among the animal cells of special relevance are mac-
rophages and red blood cells (RBCs) Macrophages are differentiated
cells of the immune system able to phagocytize microorganisms as
well as nanoparticulate materials So nanoparticulate systems are
particularly useful for the delivery of therapeutic agents to macro-
phages [148149] When macrophages are used as drug delivery sys-
tems they should be 1047297rst loaded with the nanoparticulate drug ex
vivo and then re-infused into the host where their content is distrib-
uted to tissues that favor homing of macrophages such as parasites
bacteria and viruses [150151] RBCs constitute potential biocompati-
ble carriers for different bioactive substances including protein drugs
as well as nanoparticulates They have unique properties such as bio-
degradability biocompatibility and long-term drug releasing and thus
are well suited for drug encapsulation [152] They can be easily han-
dled ex vivo by means of several techniques for the encapsulation of
different molecules and nanoparticulates [153]
For drug nanocrystals few studies related on cell based drug deliv-
ery have been reported but the existing results proved the feasibility
Dou et al designed a novel bone marrow-derived macrophage (BMM)
indinavir nanocrystals delivery system for antiretroviral treatment
[154] Light microscopic examination proved that indinavir nanocrys-
tals were successfully loaded into BMMs after culture in the presence
of indinavir nanosuspensions for 12 h Following iv administration
into naive mice the indinavir nanocrystal loaded BMMs acted as ldquoTro-
jan horsesrdquo for transport of drug into tissues which were known to be
targets for HIV due to the parallel BMM migration and viral tissue tro-pism Administration of indinavir nanocrystal-BMMs sustained indina-
vir in tissue and sera for up to 10 days in comparison with 6 h for the
non-wrapped nanosuspensions Amphotericin B nanocrystal-loaded
RBCs systems were developed by Staedtke et al in order to improvean-
tifungal treatment [155] Amphotericin B nanocrystals encapsulation in
RBCs wasachieved by using hypotonichemolysis methodleading to in-
tracellularamphotericin B amounts of 381plusmn047 pg RBCminus1andanen-
trapment ef 1047297cacy of 15ndash18 Upon phagocytosis of amphotericin B
nanocrystal-RBCs leukocytes show a slow amphotericin B release
over 10 days and no alteration in cell viability
3 Conclusions
The researchon colloidal drug delivery systems may be the hottest1047297eld in pharmaceutics in the last several decades Due to the unique
advantage and pharmaeconomical value drug nanocrystals are paid
increasing attentions as a promising approach Drug nanocrystals
can be applied to all the poorly soluble drugs to overcome the solubil-
ity and bioavailability problems because all the poorly soluble drugs
can be comminuted into drug nanocrystals Researches on drug nano-
crystals within recent years fully exhibit their excellent in vivo perfor-
mances in different administration routes Among these the most
exciting information is that properties of drug nanocrystals can be
conveniently altered to meet various treatment demands of different
diseases With the number of insoluble drug compounds in develop-
ment increasing it is anticipated that nanocrystals technology will at-
tract increasing attentions as a viable formulation option However
though drug nanocrystals demonstrate superiority over the carrier
colloid drug delivery systems such as easier production safer compo-
sition and higher drug loading correspondingly they also confront
some problems For example how to obtain a more controllable
drug dissolution rate in order to meet the treatment requirements
of different diseases or reduce the drug release in the progress of de-
livering the drugs into target sites How can we get a more 1047297rm con-
junction between ligand-linked stabilizers and nanocrystal surfaces
without the loss of their properties We believe that many studies
will focus on handling these problems in the future
Acknowledgment
This work was partially supported by the Scienti1047297c Foundation of
the First Af 1047297liated Hospital of General Hospital of PLA the project
number is QN201105
References
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[2] ER Cooper Nanoparticles a personal experience for formulating poorly watersoluble drugs J Control Release 141 (2010) 300ndash302
[3] CM Keck RH Muumlller Drug nanocrystals of poorly soluble drugs produced by
high pressure homogenisation Eur J Pharm Biopharm 62 (2006) 3ndash
16[4] BE Rabinow Nanosuspensions in drug delivery Nat Rev Drug Discov 3 (2004)785ndash796
[5] L Gao D Zhang M Chen Drug nanocrystals for the formulation of poorly solu-ble drugs and its application as a potential drug delivery system J NanopartRes 10 (2008) 845ndash862
[6] GG Liversidge KC Cundy Particle size reduction for improvement of oral bio-availability of hydrophobic drugs I Absolute oral bioavailability of nanocrystal-line danazol in beagle dogs Int J Pharm 125 (1995) 91ndash97
[7] K Peters S Leitzke J Diederichs K Borner H Hahn RH Muumlller S Ehlers Prep-aration of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic ef 1047297cacy in murine Mycobacterium avium infection J AntimicrobChemother 45 (2000) 77ndash83
[8] P Rosario B Claudio F Piera M Adriana P Antonina P Giovanni EudragitRS100 nanosuspensions for the ophthalmic controlled delivery of ibuprofenEur J Pharm Sci 16 (2002) 53ndash61
[9] C Jacobs RH Muumlller Production and characterization of a budesonide nanosus-pension for pulmonary administration Pharm Res 19 (2002) 189ndash194
[10] RH Muumlller C Jacobs O Kayser Nanosuspensions as particulate drug formula-
tions in therapy rationale for development and what we can expect for the fu-ture Adv Drug Deliv Rev 47 (2001) 3ndash19
[11] B Van Eerdenbrugh G Van den Mooter P Augustijns Topndashdown production of drug nanocrystals nanosuspension stabilization miniaturization and transfor-mation into solid products Int J Pharm 364 (2008) 64ndash75
[12] E Merisko-Liversidge GG Liversidge ER Cooper Nanosizing a formulationapproach for poorly-water-soluble compounds Eur J Pharm Sci 18 (2003)113ndash120
[13] J Hu KP Johnston RO Williams Nanoparticle engineering processes for en-hancing the dissolution rates of poorly water soluble drugs Drug Dev IndPharm 30 (2004) 233ndash245
[14] JAH Junghanns RH Muumlller Nanocrystal technology drug delivery and clinicalapplications Int J Nanomedicine 3 (2008) 295ndash310
[15] GA Brazeau HL Fung Mechanisms of creatine kinase release from isolated ratskeletal muscles damaged by propylene glycol and ethanol J Pharm Sci 79(1990) 393ndash397
[16] K Korttila A Sothman P Andersson Polyethylene glycol as a solvent for diaze-pam bioavailability and clinical effects after intramuscular administrationcomparison of oral intramuscular and rectal administration and precipitationfrom intravenous solutions Acta Pharmacol Toxicol (Copenh) 39 (1976)104ndash117
[17] R Budden UG Kuhl J Bahlsen Experiments on toxic sedative and muscle re-laxant potency of various drug solvents in mice Pharmacol Ther 5 (1979)467ndash474
[18] F Liu JY Park Y Zhang C Conwell Y Liu SR Bathula L Huang Targeted can-cer therapy with novel high drug-loading nanocrystals J Pharm Sci 99 (2010)3542ndash3551
[19] B Rabinow J Kipp P Papadopoulos J Wong J Glosson J Gass CS Sun TWielgos R White C Cook K Barker K Wood Itraconazole IV nanosuspensionenhances ef 1047297cacy through altered pharmacokinetics in the rat Int J Pharm 339(2007) 251ndash260
[20] F Kesisoglou S Panmai Y Wu Nanosizingmdashoral formulation development andbiopharmaceutical evaluation Adv Drug Deliv Rev 59 (2007) 631ndash644
[22] GG Liversidge P Conzentino Drug particle size reduction for decreasing gastricirritancy and enhancing absorption of naproxen in rats Int J Pharm 125 (1995)
309ndash
313
427L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[23] E Merisko-Liversidge GG Liversidge Nanosizing for oral and parenteral drugdelivery a perspective on formulating poorly-water soluble compounds usingwet media milling technology Adv Drug Deliv Rev 30 (2011) 427ndash440
[24] BHL Boumlhm RH Muumlller Lab-scale production unit design for nanosuspensions of sparingly soluble cytotoxic drugs Pharm Sci Technol Today 2 (1999) 336ndash339
[25] RH Drew E Dodds Ashley DK Benjamin Jr R Duane Davis SM Palmer JRPerfect Comparative safety of amphotericin B lipid complex and amphotericinB deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipi-ents Transplantation 77 (2004) 232ndash237
[26] J Dubois T Bartter J Gryn MR Pratter The physiologic effects of inhaledamphotericin B Chest 108 (1995) 750ndash753
[27] SM Palmer RH Drew JD Whitehouse VF Tapson RD Davis RR McConnellSS Kanj JR Perfect Safety of aerosolized amphotericin B lipid complex in lungtransplant recipients Transplantation 72 (2001) 545ndash548
[28] RO Williams III J Liu Formulation of a protein with propellant HFA 134a foraerosol delivery Eur J Pharm Sci 7 (1999) 137ndash144
[29] IC Ashurst CV Ambrose DJ Russell Pharmaceutical evaluation of a new spac-er device for delivery of metered-dose inhalers to infants and young children JAerosol Sci 23 (1992) 499ndash502
[30] GC Na HJ Stevens B Yuan N Rajagopalan Physical stability of ethyl diatrizoatenanocrystalline suspension in steam sterilization Pharm Res 16 (1999) 569ndash574
[31] H Lou X Zhang L Gao F Feng J Wang X Wei Z Yu D Zhang Q Zhang Invitro and in vivo antitumor activity of oridonin nanosuspension Int J Pharm379 (2009) 181ndash186
[32] L Gao D Zhang M Chen C Duan W Dai L Jia W Zhao Studies on pharmaco-kinetics and tissue distribution of oridonin nanosuspensions Int J Pharm 355(2008) 321ndash327
[33] SM Moghimi AC Hunter JC Murray Long circulating and target-speci1047297cnanoparticles theory to practice Pharmacol Rev 53 (2001) 283ndash381
[34] S Ganta JW Paxton BC Baguley S Garg Formulation and pharmacokinetic
evaluation of an asulacrine nanocrystalline suspension for intravenous deliveryInt J Pharm 367 (2009) 179ndash186
[35] K Sigfridsson S Forsseacuten P Hollaumlnder U Skantze J de Verdier A formulationcomparison using a solution and different nanosuspensions of a poorly solublecompound Eur J Pharm Biopharm 67 (2007) 540ndash547
[36] K Sigfridsson AJ Lundqvist M Strimfors Particle size reduction for improve-ment of oral absorption absorption of the poorly soluble drug UG558 in rats dur-ing early development Drug Dev Ind Pharm 35 (2009) 1479ndash1486
[37] S Kim J Lee Folate-targeted drug-delivery systems prepared by nano-comminution Drug Dev Ind Pharm 37 (2011) 131ndash138
[38] R Xiong W Lu J Li P Wang R Xu T Chen Preparation and characterization of intravenously injectable nimodipine nanosuspension Int J Pharm 350 (2008)338ndash343
[39] Y Gao Z Li M Sun C Guo A Yu Y Xi J Cui H Lou G Zhai Preparation andcharacterization of intravenously injectable curcumin nanosuspension DrugDeliv 18 (2011) 131ndash142
[40] RH Muumlller K Peters Nanosuspensions for the formulation of poorly solubledrugs I Preparation by a size-reduction technique Int J Pharm 160 (1998)229ndash237
[41] SB Zirar A Astier M Muchow S Gibaud Comparison of nanosuspensions andhydroxypropyl-b-cyclodextrin complex of melarsoprol pharmacokinetics andtissue distribution in mice Eur J Pharm Biopharm 70 (2008) 649 ndash656
[42] M Salzberg M Pless C Rochlitz K Ambrus P Scigalla R Herrmann A phase Istudy with oral SU5416 in patients with advanced solid tumors a drug inducingits clearance Invest New Drugs 24 (2006) 299ndash304
[43] WK Kraft B Steiger D Beussink JN Quiring N Fitzgerald HE Greenberg SAWaldman The pharmacokinetics of nebulized nanocrystal budesonide suspen-sion in healthy volunteers J Clin Pharmacol 44 (2004) 67ndash72
[44] JM Vaughn NP Wiederhold JT McConville JJ Coalson RL Talbert DSBurgess KP Johnston RO Williams III JI Peters Murine airway histologyand intracellular uptake of inhaled amorphous itraconazole Int J Pharm 338(2007) 219ndash224
[45] JM Vaughn JT McConville D Burgess JI Peters KP Johnston RL Talbert ROWilliams III Single dose and multiple dose studies of itraconazole nanoparticlesEur J Pharm Biopharm 63 (2006) 95ndash102
[46] BJ Hoeben DS Burgess JT McConville LK Najvar RL Talbert JI Peters NPWiederhold BL Frei JR Graybill R Bocanegra KA Overhoff P Sinswat KP
Johnston RO Williams III In vivo ef 1047297cacy of aerosolized nanostructured itraco-nazole formulations for prevention of invasive pulmonary aspergillosis Antimi-crob Agents Chemother 50 (2006) 1552ndash1554
[47] CA Alvarez NP Wiederhold JT McConville JI Peters LK Najvar JR Graybill JJ Coalson RL Talbert DS Burgess R Bocanegra KP Johnston RO WilliamsIII Aerosolized nanostructured itraconazole as prophylaxis against invasive pul-monary aspergillosis J Infect 55 (2007) 68ndash74
[48] SB Shrewsbury AP Bosco PS Uster Pharmacokinetics of a novel submicronbudesonide dispersion for nebulized delivery in asthma Int J Pharm 365(2009) 12ndash17
[49] RH Muumlller KH Wallis Surface modi1047297cation of iv injectable biodegradablenanoparticles with poloxamer polymers and poloxamine 908 Int J Pharm 89(1993) 25ndash31
[50] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy and diagno-sis Adv Drug Deliv Rev 54 (2002) 631ndash651
[51] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (2000) 73ndash80
[52] M Wang M Thanou Targeting nanoparticles to cancer Pharmacol Res 62(2010) 90ndash99
[53] L Gao G Liu X Wang F Liu Y Xu J Ma Preparation of a chemically stablequercetin formulation using nanosuspension technology Int J Pharm 404(2011) 231ndash237
[54] M Sarkari J Brown X Chen S Swinnea RO Williams III KP Johnston En-hanced drug dissolution using evaporative precipitation into aqueous solutionInt J Pharm 243 (2002) 17ndash31
[55] X Li L Gu Y Xu Y Wang Preparation of feno1047297brate nanosuspension and studyof its pharmacokinetic behavior in rats Drug Dev Ind Pharm 35 (2009)827ndash833
[56] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Pharmacokinetic evaluation of oral feno1047297brate nanosus-
pensions and SLN in comparison to conventional suspensions of micronizeddrug Adv Drug Deliv Rev 59 (2007) 419ndash426[57] GJ Vergote C Vervaet I Van Driessche S Hoste S De Smedt J Demeester RA
Jain S Ruddy JP Remon In vivo evaluation of matrix pellets containing nano-crystalline ketoprofen Int J Pharm 240 (2002) 79ndash84
[58] S Ghosh P Chiang JL Wahlstrom H Fujiwara JG Selbo SL Roberds Oral de-livery of 13-dicyclohexylurea nanosuspension enhances exposure and lowersblood pressure in hypertensive rats Basic Clin Pharmacol Toxicol 102 (2008)453ndash458
[59] P Langguth A Hanafy D Frenzel P Grenier A Nhamias T Ohlig G VergnaultH Spahn-Langguth Nanosuspension formulations for low-soluble drugs phar-macokinetic evaluation using spironolactone as model compound Drug DevInd Pharm 31 (2005) 319ndash329
[60] MG Fakesa Blisse J Vakkalagaddab Feng Qiana Sridhar Desikana Rajesh BGandhi C Lai A Hsieha MK Franchini H Toaled J Brown Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amor-phous formulation approaches Int J Pharm 370 (2009) 167ndash174
[61] K Sigfridsson A Nordmark S Theilig A Lindah A formulation comparison be-tween micro- and nanosuspensions the importance of particle size for absorp-
tion of a model compound following repeated oral administration to rats duringearly development Drug Dev Ind Pharm 37 (2011) 185ndash192
[62] J Jinno N Kamada M Miyake K Yamada T Mukai M Odomi H Toguchi GGLiversidge K Higaki T Kimura Effect of particle size reduction on dissolutionand oral absorption of a poorly water-soluble drug cilostazol in beagle dogs JControl Release 111 (2006) 56ndash64
[63] Y Wu A Loper E Landis L Hettrick L Novak K Lynn C Chen K Thompson RHiggins U Batra S Shelukar G Kwei D Storey The role of biopharmaceutics inthe development of a clinical nanoparticle formulation of MK-0869 a beagledog model predicts improved bioavailability and diminished food effect on ab-sorption in human Int J Pharm 285 (2004) 135ndash146
[64] RH Muumlller S Runge V Ravelli W Mehnert AF Thuumlnemann EB Souto Oralbioavailability of cyclosporine solid lipid nanoparticles (SLNreg) versus drugnanocrystals Int J Pharm 317 (2006) 82ndash89
[65] G Ponchel MJ Montisci A Dembri C Durrer D Duchecircne Mucoadhesion of colloidal particulate systems in the gastro-intestinal tract Eur J Pharm Bio-pharm 44 (1997) 25ndash31
[66] D Duchecircne G Ponchel Bioadhesion of solid oral dosage forms why and howEur J Pharm Biopharm 44 (1997) 15ndash23
[67] D Dodou P Breedveld PA Wieringa Mucoadhesives in the gastrointestinaltract revisiting the literature for novel applications Eur J Pharm Biopharm60 (2005) 1ndash16
[68] JD Smart The basics and underlying mechanisms of mucoadhesion Adv DrugDeliv Rev 57 (2005) 1556ndash1568
[69] O Kayser A newapproach fortargetingto Cryptosporidium parvum using mucoadhe-sive nanosuspensions research and applications Int J Pharm 214 (2001) 83ndash85
[70] A des Rieux V Fievez M Garinot YJ Schneider V Preacuteat Nanoparticles as po-tential oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[71] A Lamprecht P Koenig N Ubrich P Maincent D Neumann Low molecularweight heparin nanoparticles mucoadhesion and behaviour in Caco-2 cellsNanotechnology 17 (2006) 3673ndash3680
[72] F Delie Evaluation of nano- and microparticle uptake by the gastrointestinaltract Adv Drug Deliv Rev 34 (1998) 221ndash233
[73] CN Grama DD Ankola MNV Ravi Kumar Poly(lactide-co-glycolide) nano-particles for peroral delivery of bioactives Curr Opin Colloid Interface Sci 16(2011) 238ndash245
[74] MP Desai V Labhasetwar GL Amidon RJ Levy Gastrointestinal Uptake of biodegradable microparticles effect of particle size Pharm Res 13 (1996)1838ndash1845
[75] A des Rieux V Fievez M Garinot YJ Scheider V Preat Nanoparticles as poten-tial oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[76] JM Dintaman JA Silverman Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) Pharm Res 16 (1999)1550ndash1556
[77] J Goole DJ Lindley W Roth SM Carl K Amighi JM Kauffmann GT KnippThe effects of excipients on transporter mediated absorption Int J Pharm 393(2010) 17ndash31
[78] J Huang L Si L Jiang Z Fan J Qiu G Li Effect of pluronic F68 block copolymeron P-glycoprotein transport and CYP3A4 metabolism Int J Pharm 356 (2008)351ndash353
[79] MF Wempe C Wright JL Little JW Lightner SE Large GB Ca1047298isch CMBuchanan PJ Rice VJ Wacher KM Ruble KJ Edgar Inhibiting ef 1047298ux withnovel non-ionic surfactants rational design based on vitamin E TPGS Int JPharm 370 (2009) 93ndash102
428 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[81] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Absence of a food effect with a 145 mg nanoparticle feno-1047297brate tablet formulation Int J Clin Pharmacol Ther 44 (2006) 64ndash70
[82] MV Chaubal C Popescu Conversion of nanosuspensions into dry powders byspray drying a case study Pharm Res 25 (2008) 2302ndash2308
[83] F Lai E Pini G Angioni ML Manca J Perricci C Sinico AM Fadda Nanocrys-tals as tool to improve piroxicam dissolution rate in novel orally disintegratingtablets Eur J Pharm Biopharm 79 (2011) 552ndash558
[84] D Mou H Chen J Wan H Xu X Yang Potent dried drug nanosuspensions for
oral bioavailability enhancement of poorly soluble drugs with pH-dependentsolubility Int J Pharm 413 (2011) 237ndash244[85] A Ain-Ai PK Gupta Effect of arginine hydrochloride and hydroxypropyl cellu-
lose as stabilizers on the physical stability of high drug loading nanosuspensionsof a poorly soluble compound Int J Pharm 351 (2008) 282 ndash288
[86] Z Guo T Pereira O Choi Y Wang HT Hahn Surface functionalized aluminananoparticle 1047297lled polymeric nanocomposites with enhanced mechanical prop-erties J Mater Chem 16 (2006) 2800ndash2808
[87] DR Kalaria G Sharma V Beniwal MN Ravi Kumar Design of biodegradablenanoparticles for oral delivery of doxorubicin in vivo pharmacokinetics and tox-icity studies in rats Pharm Res 26 (2009) 492ndash501
[88] JE Kipp The role of solid nanoparticle technology in parenteral delivery of poorly water soluble drugs Int J Pharm 284 (2004) 109ndash122
[89] HM Shubar S Lachenmaier MM Heimesaat U Lohman R Mauludin RHMuumlller R Fitzner K Borner O Liesenfeld SDS-coated atovaquone nanosuspen-sions show improved therapeutic ef 1047297cacy against experimental acquired andreactivated toxoplasmosis by improving passage of gastrointestinal and bloodndash
brain barriers J Drug Target 19 (2011) 114ndash124[90] L Peltonen J Hirvonen Pharmaceutical nanocrystals by nanomilling critical
process parameters particle fracturing and stabilization method J Pharm Phar-macol 62 (2010) 1569ndash1579
[91] F Lai C Sinico G Ennas F Marongiu G Marongiu AM Fadda Diclofenac nano-suspensions in1047298uence of preparation procedure and crystal form on drug disso-lution behavior Int J Pharm 373 (2009) 124ndash132
[92] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (Suppl 2) (2000) S73ndashS80
[93] RH Muller CM Keck Challenges and solutions for the delivery of biotech drugsmdasha review of drug nanocrystal technology and lipid nanoparticles J Biotechnol113 (2004) 151ndash170
[94] JL Wahlstrom P Chiang S Ghosh CJ Warren SP Wene LA Albin ME SmithSL Roberds Pharmacokinetic evaluation of a 13-dicyclohexylurea nanosuspen-sion formulation to support early ef 1047297cacy assessment Nanoscale Res Lett 2(2007) 291ndash296
[95] Y GaoZ LiM SunH Li CGuoJ CuiA LiF CaoY XiH Lou GZhai Preparationcharacterization pharmacokinetics and tissue distribution of curcumin nanosus-pension with TPGS as stabilizer Drug Dev Ind Pharm 36 (2010) 1225ndash1234
[96] M Clement W Pugh I Parikh Tissue distribution and plasma clearance of a novelmicrocrystalline-coated 1047298urbiprofen formulation Pharmacologist 34 (1992)204ndash211
[97] RC Nagarwal S Kant PN Singh P Maiti JK Pandit Polymeric nanoparticulate sys-tem a potential approach for ocular drug delivery J Control Release 136 (2009)2ndash13
[98] H Gupta M Aqil RK Khar A Ali A Bhatnagar G Mittal Spar1047298oxacin loadedPLGA nanoparticles for sustained ocular drug delivery Nanomedicine 6 (2010)324ndash333
[99] HS Ali P York AM Ali N Blagden Hydrocortisone nanosuspensions for oph-thalmic delivery a comparative study between micro1047298uidic nanoprecipitationand media milling J Control Release 149 (2011) 175ndash181
[100] SK Sahoo F Dilnawaz S Krishnakumar Nanotechnology in ocular drug deliv-ery Drug Discov Today 13 (2008) 144ndash151
[101] O Kayser A Lemke N Hernaacutendez-Trejo The impact of nanobiotechnology on thedevelopment of newdrug deliverysystems Curr Pharm Biotechnol6 (2005) 3ndash5
[102] R Pignatello C Bucolo G Spedalieri A Maltese G Puglisi Flurbiprofen-loadedacrylate polymer nanosuspensions for ophthalmic application Biomaterials 23(2002) 3247ndash3255
[103] R Ravichandran Nanoparticles in drug delivery potential green nanobiomedi-
cine applications Int J Green Nanotechnol Biomed 1 (2009) B108ndash
B130[104] AM Cerdeira M Mazzotti B Gander Miconazole nanosuspensions in1047298uence
of formulation variables on particle size reduction and physical stability Int JPharm 396 (2010) 210ndash218
[105] MA Kassem AA Abdel Rahman MM Ghorab MB Ahmed RM Khalil Nano-suspension as an ophthalmic delivery system for certain glucocorticoid drugsInt J Pharm 340 (2007) 126ndash133
[106] P Chiang JW Alsup Y Lai Y Hu BR Heyde D Tung Evaluation of aerosol de-livery of nanosuspension for pre-clinical pulmonary drug delivery NanoscaleRes Lett 4 (2009) 254ndash261
[107] W Yang JI Peters RO Williams III Inhaled nanoparticlesmdasha current reviewInt J Pharm 356 (2008) 239ndash247
[108] J Zhang L Wu H Chan W Watanabe Formation characterization and fate of inhaled drug nanoparticles Adv Drug Deliv Rev 63 (2011) 441ndash455
[109] HM Mansour YS Rhee X Wu Nanomedicine in pulmonary delivery Int JNanomedicine 4 (2009) 299ndash319
[110] NR Labiris MB Dolovich Pulmonary drug delivery Part I physiological factorsaffecting therapeutic effectiveness of aerosolized medications Br J Clin Phar-macol 56 (2003) 588ndash599
[111] JS Patton PR Byron Inhaling medicines delivering drugs to the body throughthe lungs Nat Rev Drug Discov 6 (2007) 67ndash74
[112] DA Edwards C Dunbar Bioengineering of therapeutic aerosols Annu RevBiomed Eng 4 (2002) 93ndash107
[113] W Yang JTam DA Miller J Zhou JT McConville KP Johnstonb RO WilliamsIII High bioavailability from nebulized itraconazole nanoparticle dispersionswith biocompatible stabilizers Int J Pharm 361 (2008) 177ndash188
[114] S Gill R Lobenberg T Ku S Azarmi W Roa EJ Prenner Nanoparticles char-acteristics mechanisms of action and toxicity in pulmonary drug deliverymdasha re-view J Biomed Nanotechnol 3 (2007) 107ndash119
[115] SJ Sze1047298er Pharmacodynamics and pharmacokinetics of budesonide a new
S183[116] W Yang KP Johnston RO Williams III Comparison of bioavailability of amor-phous versus crystalline itraconazole nanoparticles via pulmonary administra-tion in rats Eur J Pharm Biopharm 75 (2010) 33 ndash41
[117] R Ali GK Jain Z Iqbal S Talegaonkar P Pandit S Sule G Malhotra RK KharA Bhatnagar FJ Ahmad Development and clinical trial of nano-atropine sulfatedry powder inhaler as a novel organophosphorous poisoning antidote Nanome-dicine 5 (2009) 55ndash63
[118] D Andes Minireview in vivo pharmacodynamics of antifungal drugs in treat-ment of candidiasis Antimicrob Agents Chemother 47 (2003) 1179ndash1186
[119] D Andes K Marchillo R Conklin G Krishna F Ezzet A Cacciapuoti DLoebenberg Pharmacodynamics of a new triazole posaconazole in a murinemodel of disseminated candidiasis Antimicrob Agents Chemother 48 (2004)137ndash142
[120] O Kayser C Olbrich V Yardley AF Kiderlen SL Croft Formulation of ampho-tericin B as nanosuspension for oral administration Int J Pharm 254 (2003)73ndash75
[121] L Zhang S Hou S Mao D Wei X Song Y Lu Uptake of folate-conjugated albu-min nanoparticles to the SKOV3 cells Int J Pharm 287 (2004) 155ndash162
[122] J Sudimack RJ Lee Targeted drug delivery via folate receptor Adv Drug DelivRev 41 (2000) 147ndash162
[123] P Vader LJ van der Aa G Storm RM Schiffelers JF Engbersen Polymeric car-rier systems for siRNA delivery Curr Top Med Chem 12 (2012) 108 ndash119
[124] O Veiseh FM Kievit RG Ellenbogen M Zhang Cancer cell invasion treatmentand monitoring opportunities in nanomedicine Adv Drug Deliv Rev 63 (2011)582ndash596
[125] J Kreuter VE Petrov DA Kharkevich RN Alyautdin In1047298uence of the type of surfactant on the analgesic effects induced by the peptide dalargin after its de-livery across the bloodndashbrain barrier using surfactant-coated nanoparticles JControl Release 49 (1997) 81ndash87
[126] J Ye Q Wang X Zhou N Zhang Injectable actarit-loaded solid lipid nanoparti-cles as passive targeting therapeutic agents for rheumatoid arthritis Int JPharm 352 (2008) 273ndash279
[127] SM Moghimi AC Hunter JC Murray Nanomedicine current status and futureprospects FASEB J 19 (2005) 311ndash330
[128] K Park To PEGylate or not PEGylate that is not the question J Control Release142 (2010) 147ndash148
[129] M Socha P Bartecki C Passitani A Sapin C Damge T Lecompte J BarreE Ghazouani P Maincent Stealth nanoparticles coated with heparin aspeptide or peptide carriers J Drug Target 17 (2009) 575ndash585
[130] D Shenoy S Little R Langer M Amiji Poly(ethylene oxide)-modi1047297ed poly(-beta-amino ester) nanoparticles as a pH-sensitive system for tumor targeted de-livery of hydrophobic drugs part 2 In vivo distribution and tumor localizationstudies Pharm Res 22 (2005) 2107ndash2114
[131] R Shegokara KK Singha Surface modi1047297ed nevirapinenanosuspensions for viralreservoir targeting in vitro and in vivo evaluation Int J Pharm 421 (2011)341ndash352
[132] Y Matsumura H Maeda A new concept for macromolecular therapeutics incancer chemotherapy mechanism of tumoritropic accumulation of proteinsand the antitumor agent SMANCS Cancer Res 46 (1986) 6387ndash6392
[133] H Zhang CP Hollis Q Zhang T Li Preparation and antitumor study of camp-tothecin nanocrystals Int J Pharm 415 (2011) 293ndash300
[134] H Lou L Gao X Wei Z Zhang D Zheng D Zhang X Zhang Y Li Q Zhang Ori-donin nanosuspension enhances anti-tumor ef 1047297cacy in SMMC-7721 cells andH22 tumor bearing mice Colloids Surf B Biointerfaces 87 (2011) 319ndash325
[135] TM Goppert RH Muumlller Adsorption kinetics of plasma proteins on solid lipid
nanoparticles for drug targeting Int J Pharm 302 (2005) 172ndash
186[136] X Pu J Sun M Li Z He Formulation of nanosuspensions as a new approach for
the delivery of poorly soluble drugs Curr Nanosci 5 (2009) 417ndash427[137] R Gaudana J Jwala SHS Boddu AK Mitra Recent perspectives in ocular drug
delivery Pharm Res 26 (2009) 1197ndash1216[138] T Yasukawa H Kimura Y Tabata H Miyamoto Y Honda Y Ikada Y Ogura
Targeted delivery of anti-angiogenic agent TNP-470 using water-soluble poly-mer in the treatment of choroidal neovascularization Invest Ophthalmol VisSci 40 (1999) 2690ndash2696
[139] A Lemke AF Kiderlen B Petri O Kayser Delivery of amphotericin B nanosus-pensions to the brain and determination of activity against Balamuthia mandril-laris amebas Nanomedicine 6 (2010) 597ndash603
[140] HL Wong XY Wu R Bendayan Nanotechnological advances forthe delivery of CNS therapeutics Adv Drug Deliv Rev (2011) doi101016jaddr201110007
[141] J Kreuter S Gelperina Use of nanoparticles for cerebral cancer Tumori 94(2008) 271ndash277
[142] J Kreuter RN Alyautdin DA Kharkevich AA Ivanov Passage of peptidesthrough the bloodndashbrain barrier with colloidal polymer particles (nanoparti-cles) Brain Res 674 (1995) 171ndash174
429L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[143] J Kreuter Nanoparticulate systems for brain delivery of drugs Adv Drug DelivRev 47 (2001) 65ndash81
[144] TM Goumlppert RH Muumlller Polysorbate-stabilized solid lipid nanoparticles as col-loidal carriers for intravenous targeting of drugs to the brain comparison of plasma protein adsorption patterns J Drug Target 13 (2005) 179ndash187
[145] S Mansouri Y Cuie F Winnik Q Shi P Lavigne M Benderdour E Beaumont JC Fernandes Characterization of folate-chitosan-DNA nanoparticles for genetherapy Biomaterials 27 (2006) 2060ndash2065
[146] AR Hilgenbrink PS Low Folate receptor-mediated drug targeting from thera-peutics to diagnostics J Pharm Sci 94 (2005) 2135ndash2146
[147] F Pierigegrave S Sera1047297ni L Rossi M Magnani Cell-based drug delivery Adv Drug
Deliv Rev 60 (2008) 286ndash
295[148] F Chellat Y Merhi A Moreau L Yahia Therapeutic potential of nanoparticulatesystems for macrophage targeting Biomaterials 26 (2005) 7260ndash7275
[149] SS Hall S Mitragotri PS Daugherty Identi1047297cation of peptide ligands facilitatingnanoparticle at attachment to erythrocytes Biotechnol Prog 23 (2007) 749ndash754
[150] S Gorantla H Dou M Boska CJ Destache J Nelson L Poluektova BERabinow HE Gendelman RL Mosley Quantitative magnetic resonance and
SPECT imaging for macrophage tissue migration and nanoformulated drug de-livery J Leukoc Biol 80 (2006) 1165ndash1174
[151] LA Lotero G Olmos JC Diez Delivery to macrophages and toxic action of etopo-sidecarried in mouse redblood cells Biochim Biophys Acta 1620 (2003) 160ndash166
[152] L Rossi S Sera1047297ni F Pierigeacute A Antonelli A Cerasi A Fraternale L ChiarantiniM Magnani Erythrocyte-based drug delivery Expert Opin Drug Deliv 2 (2005)311ndash322
[153] S Sera1047297ni L Rossi A Antonelli A Fraternale A Cerasi R Crinelli L ChiarantiniGF Schiavano M Magnani Drug delivery through phagocytosis of red bloodcells Transfus Med Hemother 31 (2004) 92ndash101
[154] H Dou CJ Destache JR Morehead R Lee Mosley MD Boska J Kingsley S
Gorantla L Poluektova JA Nelson M Chaubal J Werling J Kipp BERabinow HE Gendelman Development of a macrophage-based nanoparticleplatform for antiretroviral drug delivery Blood 108 (2006) 2827ndash2835
[155] V Staedtke M Braumller A Muumlller R Georgieva S Bauer N Sternberg A Voigt ALemke C Keck J Moumlschwitzer H Baumlumler In vitro inhibition of fungal activityby macrophage-mediated sequestration and release of encapsulated amphoter-icin B nanosuspension in red blood cells Small 6 (2010) 96ndash103
430 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
nanocrystals show clear potential for clinical development compared
with both the solution and the non-targeting nanocrystals formulations
243 Cell-based drug delivery of drug nanocrystals
The signi1047297cantly increased dissolution velocity which is a distinct
advantage of nanocrystals simultaneously implies the problem that
drug nanocrystals might dissolve before reaching the target Cell-
based drug delivery approach canbe employed to deal with this prob-
lem Cell based delivery systems are identi1047297
ed as cell carriers (includ-ing bacteria cells and animal cells) which can be loaded with drugs or
therapeutics The systems can release the drug content in circulation
or at selected sites or could target the drug to other relevant cells in
the body [147] Among the animal cells of special relevance are mac-
rophages and red blood cells (RBCs) Macrophages are differentiated
cells of the immune system able to phagocytize microorganisms as
well as nanoparticulate materials So nanoparticulate systems are
particularly useful for the delivery of therapeutic agents to macro-
phages [148149] When macrophages are used as drug delivery sys-
tems they should be 1047297rst loaded with the nanoparticulate drug ex
vivo and then re-infused into the host where their content is distrib-
uted to tissues that favor homing of macrophages such as parasites
bacteria and viruses [150151] RBCs constitute potential biocompati-
ble carriers for different bioactive substances including protein drugs
as well as nanoparticulates They have unique properties such as bio-
degradability biocompatibility and long-term drug releasing and thus
are well suited for drug encapsulation [152] They can be easily han-
dled ex vivo by means of several techniques for the encapsulation of
different molecules and nanoparticulates [153]
For drug nanocrystals few studies related on cell based drug deliv-
ery have been reported but the existing results proved the feasibility
Dou et al designed a novel bone marrow-derived macrophage (BMM)
indinavir nanocrystals delivery system for antiretroviral treatment
[154] Light microscopic examination proved that indinavir nanocrys-
tals were successfully loaded into BMMs after culture in the presence
of indinavir nanosuspensions for 12 h Following iv administration
into naive mice the indinavir nanocrystal loaded BMMs acted as ldquoTro-
jan horsesrdquo for transport of drug into tissues which were known to be
targets for HIV due to the parallel BMM migration and viral tissue tro-pism Administration of indinavir nanocrystal-BMMs sustained indina-
vir in tissue and sera for up to 10 days in comparison with 6 h for the
non-wrapped nanosuspensions Amphotericin B nanocrystal-loaded
RBCs systems were developed by Staedtke et al in order to improvean-
tifungal treatment [155] Amphotericin B nanocrystals encapsulation in
RBCs wasachieved by using hypotonichemolysis methodleading to in-
tracellularamphotericin B amounts of 381plusmn047 pg RBCminus1andanen-
trapment ef 1047297cacy of 15ndash18 Upon phagocytosis of amphotericin B
nanocrystal-RBCs leukocytes show a slow amphotericin B release
over 10 days and no alteration in cell viability
3 Conclusions
The researchon colloidal drug delivery systems may be the hottest1047297eld in pharmaceutics in the last several decades Due to the unique
advantage and pharmaeconomical value drug nanocrystals are paid
increasing attentions as a promising approach Drug nanocrystals
can be applied to all the poorly soluble drugs to overcome the solubil-
ity and bioavailability problems because all the poorly soluble drugs
can be comminuted into drug nanocrystals Researches on drug nano-
crystals within recent years fully exhibit their excellent in vivo perfor-
mances in different administration routes Among these the most
exciting information is that properties of drug nanocrystals can be
conveniently altered to meet various treatment demands of different
diseases With the number of insoluble drug compounds in develop-
ment increasing it is anticipated that nanocrystals technology will at-
tract increasing attentions as a viable formulation option However
though drug nanocrystals demonstrate superiority over the carrier
colloid drug delivery systems such as easier production safer compo-
sition and higher drug loading correspondingly they also confront
some problems For example how to obtain a more controllable
drug dissolution rate in order to meet the treatment requirements
of different diseases or reduce the drug release in the progress of de-
livering the drugs into target sites How can we get a more 1047297rm con-
junction between ligand-linked stabilizers and nanocrystal surfaces
without the loss of their properties We believe that many studies
will focus on handling these problems in the future
Acknowledgment
This work was partially supported by the Scienti1047297c Foundation of
the First Af 1047297liated Hospital of General Hospital of PLA the project
number is QN201105
References
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high pressure homogenisation Eur J Pharm Biopharm 62 (2006) 3ndash
16[4] BE Rabinow Nanosuspensions in drug delivery Nat Rev Drug Discov 3 (2004)785ndash796
[5] L Gao D Zhang M Chen Drug nanocrystals for the formulation of poorly solu-ble drugs and its application as a potential drug delivery system J NanopartRes 10 (2008) 845ndash862
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[7] K Peters S Leitzke J Diederichs K Borner H Hahn RH Muumlller S Ehlers Prep-aration of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic ef 1047297cacy in murine Mycobacterium avium infection J AntimicrobChemother 45 (2000) 77ndash83
[8] P Rosario B Claudio F Piera M Adriana P Antonina P Giovanni EudragitRS100 nanosuspensions for the ophthalmic controlled delivery of ibuprofenEur J Pharm Sci 16 (2002) 53ndash61
[9] C Jacobs RH Muumlller Production and characterization of a budesonide nanosus-pension for pulmonary administration Pharm Res 19 (2002) 189ndash194
[10] RH Muumlller C Jacobs O Kayser Nanosuspensions as particulate drug formula-
tions in therapy rationale for development and what we can expect for the fu-ture Adv Drug Deliv Rev 47 (2001) 3ndash19
[11] B Van Eerdenbrugh G Van den Mooter P Augustijns Topndashdown production of drug nanocrystals nanosuspension stabilization miniaturization and transfor-mation into solid products Int J Pharm 364 (2008) 64ndash75
[12] E Merisko-Liversidge GG Liversidge ER Cooper Nanosizing a formulationapproach for poorly-water-soluble compounds Eur J Pharm Sci 18 (2003)113ndash120
[13] J Hu KP Johnston RO Williams Nanoparticle engineering processes for en-hancing the dissolution rates of poorly water soluble drugs Drug Dev IndPharm 30 (2004) 233ndash245
[14] JAH Junghanns RH Muumlller Nanocrystal technology drug delivery and clinicalapplications Int J Nanomedicine 3 (2008) 295ndash310
[15] GA Brazeau HL Fung Mechanisms of creatine kinase release from isolated ratskeletal muscles damaged by propylene glycol and ethanol J Pharm Sci 79(1990) 393ndash397
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[17] R Budden UG Kuhl J Bahlsen Experiments on toxic sedative and muscle re-laxant potency of various drug solvents in mice Pharmacol Ther 5 (1979)467ndash474
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[19] B Rabinow J Kipp P Papadopoulos J Wong J Glosson J Gass CS Sun TWielgos R White C Cook K Barker K Wood Itraconazole IV nanosuspensionenhances ef 1047297cacy through altered pharmacokinetics in the rat Int J Pharm 339(2007) 251ndash260
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[22] GG Liversidge P Conzentino Drug particle size reduction for decreasing gastricirritancy and enhancing absorption of naproxen in rats Int J Pharm 125 (1995)
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[27] SM Palmer RH Drew JD Whitehouse VF Tapson RD Davis RR McConnellSS Kanj JR Perfect Safety of aerosolized amphotericin B lipid complex in lungtransplant recipients Transplantation 72 (2001) 545ndash548
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[32] L Gao D Zhang M Chen C Duan W Dai L Jia W Zhao Studies on pharmaco-kinetics and tissue distribution of oridonin nanosuspensions Int J Pharm 355(2008) 321ndash327
[33] SM Moghimi AC Hunter JC Murray Long circulating and target-speci1047297cnanoparticles theory to practice Pharmacol Rev 53 (2001) 283ndash381
[34] S Ganta JW Paxton BC Baguley S Garg Formulation and pharmacokinetic
evaluation of an asulacrine nanocrystalline suspension for intravenous deliveryInt J Pharm 367 (2009) 179ndash186
[35] K Sigfridsson S Forsseacuten P Hollaumlnder U Skantze J de Verdier A formulationcomparison using a solution and different nanosuspensions of a poorly solublecompound Eur J Pharm Biopharm 67 (2007) 540ndash547
[36] K Sigfridsson AJ Lundqvist M Strimfors Particle size reduction for improve-ment of oral absorption absorption of the poorly soluble drug UG558 in rats dur-ing early development Drug Dev Ind Pharm 35 (2009) 1479ndash1486
[37] S Kim J Lee Folate-targeted drug-delivery systems prepared by nano-comminution Drug Dev Ind Pharm 37 (2011) 131ndash138
[38] R Xiong W Lu J Li P Wang R Xu T Chen Preparation and characterization of intravenously injectable nimodipine nanosuspension Int J Pharm 350 (2008)338ndash343
[39] Y Gao Z Li M Sun C Guo A Yu Y Xi J Cui H Lou G Zhai Preparation andcharacterization of intravenously injectable curcumin nanosuspension DrugDeliv 18 (2011) 131ndash142
[40] RH Muumlller K Peters Nanosuspensions for the formulation of poorly solubledrugs I Preparation by a size-reduction technique Int J Pharm 160 (1998)229ndash237
[41] SB Zirar A Astier M Muchow S Gibaud Comparison of nanosuspensions andhydroxypropyl-b-cyclodextrin complex of melarsoprol pharmacokinetics andtissue distribution in mice Eur J Pharm Biopharm 70 (2008) 649 ndash656
[42] M Salzberg M Pless C Rochlitz K Ambrus P Scigalla R Herrmann A phase Istudy with oral SU5416 in patients with advanced solid tumors a drug inducingits clearance Invest New Drugs 24 (2006) 299ndash304
[43] WK Kraft B Steiger D Beussink JN Quiring N Fitzgerald HE Greenberg SAWaldman The pharmacokinetics of nebulized nanocrystal budesonide suspen-sion in healthy volunteers J Clin Pharmacol 44 (2004) 67ndash72
[44] JM Vaughn NP Wiederhold JT McConville JJ Coalson RL Talbert DSBurgess KP Johnston RO Williams III JI Peters Murine airway histologyand intracellular uptake of inhaled amorphous itraconazole Int J Pharm 338(2007) 219ndash224
[45] JM Vaughn JT McConville D Burgess JI Peters KP Johnston RL Talbert ROWilliams III Single dose and multiple dose studies of itraconazole nanoparticlesEur J Pharm Biopharm 63 (2006) 95ndash102
[46] BJ Hoeben DS Burgess JT McConville LK Najvar RL Talbert JI Peters NPWiederhold BL Frei JR Graybill R Bocanegra KA Overhoff P Sinswat KP
Johnston RO Williams III In vivo ef 1047297cacy of aerosolized nanostructured itraco-nazole formulations for prevention of invasive pulmonary aspergillosis Antimi-crob Agents Chemother 50 (2006) 1552ndash1554
[47] CA Alvarez NP Wiederhold JT McConville JI Peters LK Najvar JR Graybill JJ Coalson RL Talbert DS Burgess R Bocanegra KP Johnston RO WilliamsIII Aerosolized nanostructured itraconazole as prophylaxis against invasive pul-monary aspergillosis J Infect 55 (2007) 68ndash74
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[49] RH Muumlller KH Wallis Surface modi1047297cation of iv injectable biodegradablenanoparticles with poloxamer polymers and poloxamine 908 Int J Pharm 89(1993) 25ndash31
[50] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy and diagno-sis Adv Drug Deliv Rev 54 (2002) 631ndash651
[51] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (2000) 73ndash80
[52] M Wang M Thanou Targeting nanoparticles to cancer Pharmacol Res 62(2010) 90ndash99
[53] L Gao G Liu X Wang F Liu Y Xu J Ma Preparation of a chemically stablequercetin formulation using nanosuspension technology Int J Pharm 404(2011) 231ndash237
[54] M Sarkari J Brown X Chen S Swinnea RO Williams III KP Johnston En-hanced drug dissolution using evaporative precipitation into aqueous solutionInt J Pharm 243 (2002) 17ndash31
[55] X Li L Gu Y Xu Y Wang Preparation of feno1047297brate nanosuspension and studyof its pharmacokinetic behavior in rats Drug Dev Ind Pharm 35 (2009)827ndash833
[56] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Pharmacokinetic evaluation of oral feno1047297brate nanosus-
pensions and SLN in comparison to conventional suspensions of micronizeddrug Adv Drug Deliv Rev 59 (2007) 419ndash426[57] GJ Vergote C Vervaet I Van Driessche S Hoste S De Smedt J Demeester RA
Jain S Ruddy JP Remon In vivo evaluation of matrix pellets containing nano-crystalline ketoprofen Int J Pharm 240 (2002) 79ndash84
[58] S Ghosh P Chiang JL Wahlstrom H Fujiwara JG Selbo SL Roberds Oral de-livery of 13-dicyclohexylurea nanosuspension enhances exposure and lowersblood pressure in hypertensive rats Basic Clin Pharmacol Toxicol 102 (2008)453ndash458
[59] P Langguth A Hanafy D Frenzel P Grenier A Nhamias T Ohlig G VergnaultH Spahn-Langguth Nanosuspension formulations for low-soluble drugs phar-macokinetic evaluation using spironolactone as model compound Drug DevInd Pharm 31 (2005) 319ndash329
[60] MG Fakesa Blisse J Vakkalagaddab Feng Qiana Sridhar Desikana Rajesh BGandhi C Lai A Hsieha MK Franchini H Toaled J Brown Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amor-phous formulation approaches Int J Pharm 370 (2009) 167ndash174
[61] K Sigfridsson A Nordmark S Theilig A Lindah A formulation comparison be-tween micro- and nanosuspensions the importance of particle size for absorp-
tion of a model compound following repeated oral administration to rats duringearly development Drug Dev Ind Pharm 37 (2011) 185ndash192
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[63] Y Wu A Loper E Landis L Hettrick L Novak K Lynn C Chen K Thompson RHiggins U Batra S Shelukar G Kwei D Storey The role of biopharmaceutics inthe development of a clinical nanoparticle formulation of MK-0869 a beagledog model predicts improved bioavailability and diminished food effect on ab-sorption in human Int J Pharm 285 (2004) 135ndash146
[64] RH Muumlller S Runge V Ravelli W Mehnert AF Thuumlnemann EB Souto Oralbioavailability of cyclosporine solid lipid nanoparticles (SLNreg) versus drugnanocrystals Int J Pharm 317 (2006) 82ndash89
[65] G Ponchel MJ Montisci A Dembri C Durrer D Duchecircne Mucoadhesion of colloidal particulate systems in the gastro-intestinal tract Eur J Pharm Bio-pharm 44 (1997) 25ndash31
[66] D Duchecircne G Ponchel Bioadhesion of solid oral dosage forms why and howEur J Pharm Biopharm 44 (1997) 15ndash23
[67] D Dodou P Breedveld PA Wieringa Mucoadhesives in the gastrointestinaltract revisiting the literature for novel applications Eur J Pharm Biopharm60 (2005) 1ndash16
[68] JD Smart The basics and underlying mechanisms of mucoadhesion Adv DrugDeliv Rev 57 (2005) 1556ndash1568
[69] O Kayser A newapproach fortargetingto Cryptosporidium parvum using mucoadhe-sive nanosuspensions research and applications Int J Pharm 214 (2001) 83ndash85
[70] A des Rieux V Fievez M Garinot YJ Schneider V Preacuteat Nanoparticles as po-tential oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[71] A Lamprecht P Koenig N Ubrich P Maincent D Neumann Low molecularweight heparin nanoparticles mucoadhesion and behaviour in Caco-2 cellsNanotechnology 17 (2006) 3673ndash3680
[72] F Delie Evaluation of nano- and microparticle uptake by the gastrointestinaltract Adv Drug Deliv Rev 34 (1998) 221ndash233
[73] CN Grama DD Ankola MNV Ravi Kumar Poly(lactide-co-glycolide) nano-particles for peroral delivery of bioactives Curr Opin Colloid Interface Sci 16(2011) 238ndash245
[74] MP Desai V Labhasetwar GL Amidon RJ Levy Gastrointestinal Uptake of biodegradable microparticles effect of particle size Pharm Res 13 (1996)1838ndash1845
[75] A des Rieux V Fievez M Garinot YJ Scheider V Preat Nanoparticles as poten-tial oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[76] JM Dintaman JA Silverman Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) Pharm Res 16 (1999)1550ndash1556
[77] J Goole DJ Lindley W Roth SM Carl K Amighi JM Kauffmann GT KnippThe effects of excipients on transporter mediated absorption Int J Pharm 393(2010) 17ndash31
[78] J Huang L Si L Jiang Z Fan J Qiu G Li Effect of pluronic F68 block copolymeron P-glycoprotein transport and CYP3A4 metabolism Int J Pharm 356 (2008)351ndash353
[79] MF Wempe C Wright JL Little JW Lightner SE Large GB Ca1047298isch CMBuchanan PJ Rice VJ Wacher KM Ruble KJ Edgar Inhibiting ef 1047298ux withnovel non-ionic surfactants rational design based on vitamin E TPGS Int JPharm 370 (2009) 93ndash102
428 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[81] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Absence of a food effect with a 145 mg nanoparticle feno-1047297brate tablet formulation Int J Clin Pharmacol Ther 44 (2006) 64ndash70
[82] MV Chaubal C Popescu Conversion of nanosuspensions into dry powders byspray drying a case study Pharm Res 25 (2008) 2302ndash2308
[83] F Lai E Pini G Angioni ML Manca J Perricci C Sinico AM Fadda Nanocrys-tals as tool to improve piroxicam dissolution rate in novel orally disintegratingtablets Eur J Pharm Biopharm 79 (2011) 552ndash558
[84] D Mou H Chen J Wan H Xu X Yang Potent dried drug nanosuspensions for
oral bioavailability enhancement of poorly soluble drugs with pH-dependentsolubility Int J Pharm 413 (2011) 237ndash244[85] A Ain-Ai PK Gupta Effect of arginine hydrochloride and hydroxypropyl cellu-
lose as stabilizers on the physical stability of high drug loading nanosuspensionsof a poorly soluble compound Int J Pharm 351 (2008) 282 ndash288
[86] Z Guo T Pereira O Choi Y Wang HT Hahn Surface functionalized aluminananoparticle 1047297lled polymeric nanocomposites with enhanced mechanical prop-erties J Mater Chem 16 (2006) 2800ndash2808
[87] DR Kalaria G Sharma V Beniwal MN Ravi Kumar Design of biodegradablenanoparticles for oral delivery of doxorubicin in vivo pharmacokinetics and tox-icity studies in rats Pharm Res 26 (2009) 492ndash501
[88] JE Kipp The role of solid nanoparticle technology in parenteral delivery of poorly water soluble drugs Int J Pharm 284 (2004) 109ndash122
[89] HM Shubar S Lachenmaier MM Heimesaat U Lohman R Mauludin RHMuumlller R Fitzner K Borner O Liesenfeld SDS-coated atovaquone nanosuspen-sions show improved therapeutic ef 1047297cacy against experimental acquired andreactivated toxoplasmosis by improving passage of gastrointestinal and bloodndash
brain barriers J Drug Target 19 (2011) 114ndash124[90] L Peltonen J Hirvonen Pharmaceutical nanocrystals by nanomilling critical
process parameters particle fracturing and stabilization method J Pharm Phar-macol 62 (2010) 1569ndash1579
[91] F Lai C Sinico G Ennas F Marongiu G Marongiu AM Fadda Diclofenac nano-suspensions in1047298uence of preparation procedure and crystal form on drug disso-lution behavior Int J Pharm 373 (2009) 124ndash132
[92] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (Suppl 2) (2000) S73ndashS80
[93] RH Muller CM Keck Challenges and solutions for the delivery of biotech drugsmdasha review of drug nanocrystal technology and lipid nanoparticles J Biotechnol113 (2004) 151ndash170
[94] JL Wahlstrom P Chiang S Ghosh CJ Warren SP Wene LA Albin ME SmithSL Roberds Pharmacokinetic evaluation of a 13-dicyclohexylurea nanosuspen-sion formulation to support early ef 1047297cacy assessment Nanoscale Res Lett 2(2007) 291ndash296
[95] Y GaoZ LiM SunH Li CGuoJ CuiA LiF CaoY XiH Lou GZhai Preparationcharacterization pharmacokinetics and tissue distribution of curcumin nanosus-pension with TPGS as stabilizer Drug Dev Ind Pharm 36 (2010) 1225ndash1234
[96] M Clement W Pugh I Parikh Tissue distribution and plasma clearance of a novelmicrocrystalline-coated 1047298urbiprofen formulation Pharmacologist 34 (1992)204ndash211
[97] RC Nagarwal S Kant PN Singh P Maiti JK Pandit Polymeric nanoparticulate sys-tem a potential approach for ocular drug delivery J Control Release 136 (2009)2ndash13
[98] H Gupta M Aqil RK Khar A Ali A Bhatnagar G Mittal Spar1047298oxacin loadedPLGA nanoparticles for sustained ocular drug delivery Nanomedicine 6 (2010)324ndash333
[99] HS Ali P York AM Ali N Blagden Hydrocortisone nanosuspensions for oph-thalmic delivery a comparative study between micro1047298uidic nanoprecipitationand media milling J Control Release 149 (2011) 175ndash181
[100] SK Sahoo F Dilnawaz S Krishnakumar Nanotechnology in ocular drug deliv-ery Drug Discov Today 13 (2008) 144ndash151
[101] O Kayser A Lemke N Hernaacutendez-Trejo The impact of nanobiotechnology on thedevelopment of newdrug deliverysystems Curr Pharm Biotechnol6 (2005) 3ndash5
[102] R Pignatello C Bucolo G Spedalieri A Maltese G Puglisi Flurbiprofen-loadedacrylate polymer nanosuspensions for ophthalmic application Biomaterials 23(2002) 3247ndash3255
[103] R Ravichandran Nanoparticles in drug delivery potential green nanobiomedi-
cine applications Int J Green Nanotechnol Biomed 1 (2009) B108ndash
B130[104] AM Cerdeira M Mazzotti B Gander Miconazole nanosuspensions in1047298uence
of formulation variables on particle size reduction and physical stability Int JPharm 396 (2010) 210ndash218
[105] MA Kassem AA Abdel Rahman MM Ghorab MB Ahmed RM Khalil Nano-suspension as an ophthalmic delivery system for certain glucocorticoid drugsInt J Pharm 340 (2007) 126ndash133
[106] P Chiang JW Alsup Y Lai Y Hu BR Heyde D Tung Evaluation of aerosol de-livery of nanosuspension for pre-clinical pulmonary drug delivery NanoscaleRes Lett 4 (2009) 254ndash261
[107] W Yang JI Peters RO Williams III Inhaled nanoparticlesmdasha current reviewInt J Pharm 356 (2008) 239ndash247
[108] J Zhang L Wu H Chan W Watanabe Formation characterization and fate of inhaled drug nanoparticles Adv Drug Deliv Rev 63 (2011) 441ndash455
[109] HM Mansour YS Rhee X Wu Nanomedicine in pulmonary delivery Int JNanomedicine 4 (2009) 299ndash319
[110] NR Labiris MB Dolovich Pulmonary drug delivery Part I physiological factorsaffecting therapeutic effectiveness of aerosolized medications Br J Clin Phar-macol 56 (2003) 588ndash599
[111] JS Patton PR Byron Inhaling medicines delivering drugs to the body throughthe lungs Nat Rev Drug Discov 6 (2007) 67ndash74
[112] DA Edwards C Dunbar Bioengineering of therapeutic aerosols Annu RevBiomed Eng 4 (2002) 93ndash107
[113] W Yang JTam DA Miller J Zhou JT McConville KP Johnstonb RO WilliamsIII High bioavailability from nebulized itraconazole nanoparticle dispersionswith biocompatible stabilizers Int J Pharm 361 (2008) 177ndash188
[114] S Gill R Lobenberg T Ku S Azarmi W Roa EJ Prenner Nanoparticles char-acteristics mechanisms of action and toxicity in pulmonary drug deliverymdasha re-view J Biomed Nanotechnol 3 (2007) 107ndash119
[115] SJ Sze1047298er Pharmacodynamics and pharmacokinetics of budesonide a new
S183[116] W Yang KP Johnston RO Williams III Comparison of bioavailability of amor-phous versus crystalline itraconazole nanoparticles via pulmonary administra-tion in rats Eur J Pharm Biopharm 75 (2010) 33 ndash41
[117] R Ali GK Jain Z Iqbal S Talegaonkar P Pandit S Sule G Malhotra RK KharA Bhatnagar FJ Ahmad Development and clinical trial of nano-atropine sulfatedry powder inhaler as a novel organophosphorous poisoning antidote Nanome-dicine 5 (2009) 55ndash63
[118] D Andes Minireview in vivo pharmacodynamics of antifungal drugs in treat-ment of candidiasis Antimicrob Agents Chemother 47 (2003) 1179ndash1186
[119] D Andes K Marchillo R Conklin G Krishna F Ezzet A Cacciapuoti DLoebenberg Pharmacodynamics of a new triazole posaconazole in a murinemodel of disseminated candidiasis Antimicrob Agents Chemother 48 (2004)137ndash142
[120] O Kayser C Olbrich V Yardley AF Kiderlen SL Croft Formulation of ampho-tericin B as nanosuspension for oral administration Int J Pharm 254 (2003)73ndash75
[121] L Zhang S Hou S Mao D Wei X Song Y Lu Uptake of folate-conjugated albu-min nanoparticles to the SKOV3 cells Int J Pharm 287 (2004) 155ndash162
[122] J Sudimack RJ Lee Targeted drug delivery via folate receptor Adv Drug DelivRev 41 (2000) 147ndash162
[123] P Vader LJ van der Aa G Storm RM Schiffelers JF Engbersen Polymeric car-rier systems for siRNA delivery Curr Top Med Chem 12 (2012) 108 ndash119
[124] O Veiseh FM Kievit RG Ellenbogen M Zhang Cancer cell invasion treatmentand monitoring opportunities in nanomedicine Adv Drug Deliv Rev 63 (2011)582ndash596
[125] J Kreuter VE Petrov DA Kharkevich RN Alyautdin In1047298uence of the type of surfactant on the analgesic effects induced by the peptide dalargin after its de-livery across the bloodndashbrain barrier using surfactant-coated nanoparticles JControl Release 49 (1997) 81ndash87
[126] J Ye Q Wang X Zhou N Zhang Injectable actarit-loaded solid lipid nanoparti-cles as passive targeting therapeutic agents for rheumatoid arthritis Int JPharm 352 (2008) 273ndash279
[127] SM Moghimi AC Hunter JC Murray Nanomedicine current status and futureprospects FASEB J 19 (2005) 311ndash330
[128] K Park To PEGylate or not PEGylate that is not the question J Control Release142 (2010) 147ndash148
[129] M Socha P Bartecki C Passitani A Sapin C Damge T Lecompte J BarreE Ghazouani P Maincent Stealth nanoparticles coated with heparin aspeptide or peptide carriers J Drug Target 17 (2009) 575ndash585
[130] D Shenoy S Little R Langer M Amiji Poly(ethylene oxide)-modi1047297ed poly(-beta-amino ester) nanoparticles as a pH-sensitive system for tumor targeted de-livery of hydrophobic drugs part 2 In vivo distribution and tumor localizationstudies Pharm Res 22 (2005) 2107ndash2114
[131] R Shegokara KK Singha Surface modi1047297ed nevirapinenanosuspensions for viralreservoir targeting in vitro and in vivo evaluation Int J Pharm 421 (2011)341ndash352
[132] Y Matsumura H Maeda A new concept for macromolecular therapeutics incancer chemotherapy mechanism of tumoritropic accumulation of proteinsand the antitumor agent SMANCS Cancer Res 46 (1986) 6387ndash6392
[133] H Zhang CP Hollis Q Zhang T Li Preparation and antitumor study of camp-tothecin nanocrystals Int J Pharm 415 (2011) 293ndash300
[134] H Lou L Gao X Wei Z Zhang D Zheng D Zhang X Zhang Y Li Q Zhang Ori-donin nanosuspension enhances anti-tumor ef 1047297cacy in SMMC-7721 cells andH22 tumor bearing mice Colloids Surf B Biointerfaces 87 (2011) 319ndash325
[135] TM Goppert RH Muumlller Adsorption kinetics of plasma proteins on solid lipid
nanoparticles for drug targeting Int J Pharm 302 (2005) 172ndash
186[136] X Pu J Sun M Li Z He Formulation of nanosuspensions as a new approach for
the delivery of poorly soluble drugs Curr Nanosci 5 (2009) 417ndash427[137] R Gaudana J Jwala SHS Boddu AK Mitra Recent perspectives in ocular drug
delivery Pharm Res 26 (2009) 1197ndash1216[138] T Yasukawa H Kimura Y Tabata H Miyamoto Y Honda Y Ikada Y Ogura
Targeted delivery of anti-angiogenic agent TNP-470 using water-soluble poly-mer in the treatment of choroidal neovascularization Invest Ophthalmol VisSci 40 (1999) 2690ndash2696
[139] A Lemke AF Kiderlen B Petri O Kayser Delivery of amphotericin B nanosus-pensions to the brain and determination of activity against Balamuthia mandril-laris amebas Nanomedicine 6 (2010) 597ndash603
[140] HL Wong XY Wu R Bendayan Nanotechnological advances forthe delivery of CNS therapeutics Adv Drug Deliv Rev (2011) doi101016jaddr201110007
[141] J Kreuter S Gelperina Use of nanoparticles for cerebral cancer Tumori 94(2008) 271ndash277
[142] J Kreuter RN Alyautdin DA Kharkevich AA Ivanov Passage of peptidesthrough the bloodndashbrain barrier with colloidal polymer particles (nanoparti-cles) Brain Res 674 (1995) 171ndash174
429L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[143] J Kreuter Nanoparticulate systems for brain delivery of drugs Adv Drug DelivRev 47 (2001) 65ndash81
[144] TM Goumlppert RH Muumlller Polysorbate-stabilized solid lipid nanoparticles as col-loidal carriers for intravenous targeting of drugs to the brain comparison of plasma protein adsorption patterns J Drug Target 13 (2005) 179ndash187
[145] S Mansouri Y Cuie F Winnik Q Shi P Lavigne M Benderdour E Beaumont JC Fernandes Characterization of folate-chitosan-DNA nanoparticles for genetherapy Biomaterials 27 (2006) 2060ndash2065
[146] AR Hilgenbrink PS Low Folate receptor-mediated drug targeting from thera-peutics to diagnostics J Pharm Sci 94 (2005) 2135ndash2146
[147] F Pierigegrave S Sera1047297ni L Rossi M Magnani Cell-based drug delivery Adv Drug
Deliv Rev 60 (2008) 286ndash
295[148] F Chellat Y Merhi A Moreau L Yahia Therapeutic potential of nanoparticulatesystems for macrophage targeting Biomaterials 26 (2005) 7260ndash7275
[149] SS Hall S Mitragotri PS Daugherty Identi1047297cation of peptide ligands facilitatingnanoparticle at attachment to erythrocytes Biotechnol Prog 23 (2007) 749ndash754
[150] S Gorantla H Dou M Boska CJ Destache J Nelson L Poluektova BERabinow HE Gendelman RL Mosley Quantitative magnetic resonance and
SPECT imaging for macrophage tissue migration and nanoformulated drug de-livery J Leukoc Biol 80 (2006) 1165ndash1174
[151] LA Lotero G Olmos JC Diez Delivery to macrophages and toxic action of etopo-sidecarried in mouse redblood cells Biochim Biophys Acta 1620 (2003) 160ndash166
[152] L Rossi S Sera1047297ni F Pierigeacute A Antonelli A Cerasi A Fraternale L ChiarantiniM Magnani Erythrocyte-based drug delivery Expert Opin Drug Deliv 2 (2005)311ndash322
[153] S Sera1047297ni L Rossi A Antonelli A Fraternale A Cerasi R Crinelli L ChiarantiniGF Schiavano M Magnani Drug delivery through phagocytosis of red bloodcells Transfus Med Hemother 31 (2004) 92ndash101
[154] H Dou CJ Destache JR Morehead R Lee Mosley MD Boska J Kingsley S
Gorantla L Poluektova JA Nelson M Chaubal J Werling J Kipp BERabinow HE Gendelman Development of a macrophage-based nanoparticleplatform for antiretroviral drug delivery Blood 108 (2006) 2827ndash2835
[155] V Staedtke M Braumller A Muumlller R Georgieva S Bauer N Sternberg A Voigt ALemke C Keck J Moumlschwitzer H Baumlumler In vitro inhibition of fungal activityby macrophage-mediated sequestration and release of encapsulated amphoter-icin B nanosuspension in red blood cells Small 6 (2010) 96ndash103
430 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
nanocrystals show clear potential for clinical development compared
with both the solution and the non-targeting nanocrystals formulations
243 Cell-based drug delivery of drug nanocrystals
The signi1047297cantly increased dissolution velocity which is a distinct
advantage of nanocrystals simultaneously implies the problem that
drug nanocrystals might dissolve before reaching the target Cell-
based drug delivery approach canbe employed to deal with this prob-
lem Cell based delivery systems are identi1047297
ed as cell carriers (includ-ing bacteria cells and animal cells) which can be loaded with drugs or
therapeutics The systems can release the drug content in circulation
or at selected sites or could target the drug to other relevant cells in
the body [147] Among the animal cells of special relevance are mac-
rophages and red blood cells (RBCs) Macrophages are differentiated
cells of the immune system able to phagocytize microorganisms as
well as nanoparticulate materials So nanoparticulate systems are
particularly useful for the delivery of therapeutic agents to macro-
phages [148149] When macrophages are used as drug delivery sys-
tems they should be 1047297rst loaded with the nanoparticulate drug ex
vivo and then re-infused into the host where their content is distrib-
uted to tissues that favor homing of macrophages such as parasites
bacteria and viruses [150151] RBCs constitute potential biocompati-
ble carriers for different bioactive substances including protein drugs
as well as nanoparticulates They have unique properties such as bio-
degradability biocompatibility and long-term drug releasing and thus
are well suited for drug encapsulation [152] They can be easily han-
dled ex vivo by means of several techniques for the encapsulation of
different molecules and nanoparticulates [153]
For drug nanocrystals few studies related on cell based drug deliv-
ery have been reported but the existing results proved the feasibility
Dou et al designed a novel bone marrow-derived macrophage (BMM)
indinavir nanocrystals delivery system for antiretroviral treatment
[154] Light microscopic examination proved that indinavir nanocrys-
tals were successfully loaded into BMMs after culture in the presence
of indinavir nanosuspensions for 12 h Following iv administration
into naive mice the indinavir nanocrystal loaded BMMs acted as ldquoTro-
jan horsesrdquo for transport of drug into tissues which were known to be
targets for HIV due to the parallel BMM migration and viral tissue tro-pism Administration of indinavir nanocrystal-BMMs sustained indina-
vir in tissue and sera for up to 10 days in comparison with 6 h for the
non-wrapped nanosuspensions Amphotericin B nanocrystal-loaded
RBCs systems were developed by Staedtke et al in order to improvean-
tifungal treatment [155] Amphotericin B nanocrystals encapsulation in
RBCs wasachieved by using hypotonichemolysis methodleading to in-
tracellularamphotericin B amounts of 381plusmn047 pg RBCminus1andanen-
trapment ef 1047297cacy of 15ndash18 Upon phagocytosis of amphotericin B
nanocrystal-RBCs leukocytes show a slow amphotericin B release
over 10 days and no alteration in cell viability
3 Conclusions
The researchon colloidal drug delivery systems may be the hottest1047297eld in pharmaceutics in the last several decades Due to the unique
advantage and pharmaeconomical value drug nanocrystals are paid
increasing attentions as a promising approach Drug nanocrystals
can be applied to all the poorly soluble drugs to overcome the solubil-
ity and bioavailability problems because all the poorly soluble drugs
can be comminuted into drug nanocrystals Researches on drug nano-
crystals within recent years fully exhibit their excellent in vivo perfor-
mances in different administration routes Among these the most
exciting information is that properties of drug nanocrystals can be
conveniently altered to meet various treatment demands of different
diseases With the number of insoluble drug compounds in develop-
ment increasing it is anticipated that nanocrystals technology will at-
tract increasing attentions as a viable formulation option However
though drug nanocrystals demonstrate superiority over the carrier
colloid drug delivery systems such as easier production safer compo-
sition and higher drug loading correspondingly they also confront
some problems For example how to obtain a more controllable
drug dissolution rate in order to meet the treatment requirements
of different diseases or reduce the drug release in the progress of de-
livering the drugs into target sites How can we get a more 1047297rm con-
junction between ligand-linked stabilizers and nanocrystal surfaces
without the loss of their properties We believe that many studies
will focus on handling these problems in the future
Acknowledgment
This work was partially supported by the Scienti1047297c Foundation of
the First Af 1047297liated Hospital of General Hospital of PLA the project
number is QN201105
References
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[3] CM Keck RH Muumlller Drug nanocrystals of poorly soluble drugs produced by
high pressure homogenisation Eur J Pharm Biopharm 62 (2006) 3ndash
16[4] BE Rabinow Nanosuspensions in drug delivery Nat Rev Drug Discov 3 (2004)785ndash796
[5] L Gao D Zhang M Chen Drug nanocrystals for the formulation of poorly solu-ble drugs and its application as a potential drug delivery system J NanopartRes 10 (2008) 845ndash862
[6] GG Liversidge KC Cundy Particle size reduction for improvement of oral bio-availability of hydrophobic drugs I Absolute oral bioavailability of nanocrystal-line danazol in beagle dogs Int J Pharm 125 (1995) 91ndash97
[7] K Peters S Leitzke J Diederichs K Borner H Hahn RH Muumlller S Ehlers Prep-aration of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic ef 1047297cacy in murine Mycobacterium avium infection J AntimicrobChemother 45 (2000) 77ndash83
[8] P Rosario B Claudio F Piera M Adriana P Antonina P Giovanni EudragitRS100 nanosuspensions for the ophthalmic controlled delivery of ibuprofenEur J Pharm Sci 16 (2002) 53ndash61
[9] C Jacobs RH Muumlller Production and characterization of a budesonide nanosus-pension for pulmonary administration Pharm Res 19 (2002) 189ndash194
[10] RH Muumlller C Jacobs O Kayser Nanosuspensions as particulate drug formula-
tions in therapy rationale for development and what we can expect for the fu-ture Adv Drug Deliv Rev 47 (2001) 3ndash19
[11] B Van Eerdenbrugh G Van den Mooter P Augustijns Topndashdown production of drug nanocrystals nanosuspension stabilization miniaturization and transfor-mation into solid products Int J Pharm 364 (2008) 64ndash75
[12] E Merisko-Liversidge GG Liversidge ER Cooper Nanosizing a formulationapproach for poorly-water-soluble compounds Eur J Pharm Sci 18 (2003)113ndash120
[13] J Hu KP Johnston RO Williams Nanoparticle engineering processes for en-hancing the dissolution rates of poorly water soluble drugs Drug Dev IndPharm 30 (2004) 233ndash245
[14] JAH Junghanns RH Muumlller Nanocrystal technology drug delivery and clinicalapplications Int J Nanomedicine 3 (2008) 295ndash310
[15] GA Brazeau HL Fung Mechanisms of creatine kinase release from isolated ratskeletal muscles damaged by propylene glycol and ethanol J Pharm Sci 79(1990) 393ndash397
[16] K Korttila A Sothman P Andersson Polyethylene glycol as a solvent for diaze-pam bioavailability and clinical effects after intramuscular administrationcomparison of oral intramuscular and rectal administration and precipitationfrom intravenous solutions Acta Pharmacol Toxicol (Copenh) 39 (1976)104ndash117
[17] R Budden UG Kuhl J Bahlsen Experiments on toxic sedative and muscle re-laxant potency of various drug solvents in mice Pharmacol Ther 5 (1979)467ndash474
[18] F Liu JY Park Y Zhang C Conwell Y Liu SR Bathula L Huang Targeted can-cer therapy with novel high drug-loading nanocrystals J Pharm Sci 99 (2010)3542ndash3551
[19] B Rabinow J Kipp P Papadopoulos J Wong J Glosson J Gass CS Sun TWielgos R White C Cook K Barker K Wood Itraconazole IV nanosuspensionenhances ef 1047297cacy through altered pharmacokinetics in the rat Int J Pharm 339(2007) 251ndash260
[20] F Kesisoglou S Panmai Y Wu Nanosizingmdashoral formulation development andbiopharmaceutical evaluation Adv Drug Deliv Rev 59 (2007) 631ndash644
[22] GG Liversidge P Conzentino Drug particle size reduction for decreasing gastricirritancy and enhancing absorption of naproxen in rats Int J Pharm 125 (1995)
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[23] E Merisko-Liversidge GG Liversidge Nanosizing for oral and parenteral drugdelivery a perspective on formulating poorly-water soluble compounds usingwet media milling technology Adv Drug Deliv Rev 30 (2011) 427ndash440
[24] BHL Boumlhm RH Muumlller Lab-scale production unit design for nanosuspensions of sparingly soluble cytotoxic drugs Pharm Sci Technol Today 2 (1999) 336ndash339
[25] RH Drew E Dodds Ashley DK Benjamin Jr R Duane Davis SM Palmer JRPerfect Comparative safety of amphotericin B lipid complex and amphotericinB deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipi-ents Transplantation 77 (2004) 232ndash237
[26] J Dubois T Bartter J Gryn MR Pratter The physiologic effects of inhaledamphotericin B Chest 108 (1995) 750ndash753
[27] SM Palmer RH Drew JD Whitehouse VF Tapson RD Davis RR McConnellSS Kanj JR Perfect Safety of aerosolized amphotericin B lipid complex in lungtransplant recipients Transplantation 72 (2001) 545ndash548
[28] RO Williams III J Liu Formulation of a protein with propellant HFA 134a foraerosol delivery Eur J Pharm Sci 7 (1999) 137ndash144
[29] IC Ashurst CV Ambrose DJ Russell Pharmaceutical evaluation of a new spac-er device for delivery of metered-dose inhalers to infants and young children JAerosol Sci 23 (1992) 499ndash502
[30] GC Na HJ Stevens B Yuan N Rajagopalan Physical stability of ethyl diatrizoatenanocrystalline suspension in steam sterilization Pharm Res 16 (1999) 569ndash574
[31] H Lou X Zhang L Gao F Feng J Wang X Wei Z Yu D Zhang Q Zhang Invitro and in vivo antitumor activity of oridonin nanosuspension Int J Pharm379 (2009) 181ndash186
[32] L Gao D Zhang M Chen C Duan W Dai L Jia W Zhao Studies on pharmaco-kinetics and tissue distribution of oridonin nanosuspensions Int J Pharm 355(2008) 321ndash327
[33] SM Moghimi AC Hunter JC Murray Long circulating and target-speci1047297cnanoparticles theory to practice Pharmacol Rev 53 (2001) 283ndash381
[34] S Ganta JW Paxton BC Baguley S Garg Formulation and pharmacokinetic
evaluation of an asulacrine nanocrystalline suspension for intravenous deliveryInt J Pharm 367 (2009) 179ndash186
[35] K Sigfridsson S Forsseacuten P Hollaumlnder U Skantze J de Verdier A formulationcomparison using a solution and different nanosuspensions of a poorly solublecompound Eur J Pharm Biopharm 67 (2007) 540ndash547
[36] K Sigfridsson AJ Lundqvist M Strimfors Particle size reduction for improve-ment of oral absorption absorption of the poorly soluble drug UG558 in rats dur-ing early development Drug Dev Ind Pharm 35 (2009) 1479ndash1486
[37] S Kim J Lee Folate-targeted drug-delivery systems prepared by nano-comminution Drug Dev Ind Pharm 37 (2011) 131ndash138
[38] R Xiong W Lu J Li P Wang R Xu T Chen Preparation and characterization of intravenously injectable nimodipine nanosuspension Int J Pharm 350 (2008)338ndash343
[39] Y Gao Z Li M Sun C Guo A Yu Y Xi J Cui H Lou G Zhai Preparation andcharacterization of intravenously injectable curcumin nanosuspension DrugDeliv 18 (2011) 131ndash142
[40] RH Muumlller K Peters Nanosuspensions for the formulation of poorly solubledrugs I Preparation by a size-reduction technique Int J Pharm 160 (1998)229ndash237
[41] SB Zirar A Astier M Muchow S Gibaud Comparison of nanosuspensions andhydroxypropyl-b-cyclodextrin complex of melarsoprol pharmacokinetics andtissue distribution in mice Eur J Pharm Biopharm 70 (2008) 649 ndash656
[42] M Salzberg M Pless C Rochlitz K Ambrus P Scigalla R Herrmann A phase Istudy with oral SU5416 in patients with advanced solid tumors a drug inducingits clearance Invest New Drugs 24 (2006) 299ndash304
[43] WK Kraft B Steiger D Beussink JN Quiring N Fitzgerald HE Greenberg SAWaldman The pharmacokinetics of nebulized nanocrystal budesonide suspen-sion in healthy volunteers J Clin Pharmacol 44 (2004) 67ndash72
[44] JM Vaughn NP Wiederhold JT McConville JJ Coalson RL Talbert DSBurgess KP Johnston RO Williams III JI Peters Murine airway histologyand intracellular uptake of inhaled amorphous itraconazole Int J Pharm 338(2007) 219ndash224
[45] JM Vaughn JT McConville D Burgess JI Peters KP Johnston RL Talbert ROWilliams III Single dose and multiple dose studies of itraconazole nanoparticlesEur J Pharm Biopharm 63 (2006) 95ndash102
[46] BJ Hoeben DS Burgess JT McConville LK Najvar RL Talbert JI Peters NPWiederhold BL Frei JR Graybill R Bocanegra KA Overhoff P Sinswat KP
Johnston RO Williams III In vivo ef 1047297cacy of aerosolized nanostructured itraco-nazole formulations for prevention of invasive pulmonary aspergillosis Antimi-crob Agents Chemother 50 (2006) 1552ndash1554
[47] CA Alvarez NP Wiederhold JT McConville JI Peters LK Najvar JR Graybill JJ Coalson RL Talbert DS Burgess R Bocanegra KP Johnston RO WilliamsIII Aerosolized nanostructured itraconazole as prophylaxis against invasive pul-monary aspergillosis J Infect 55 (2007) 68ndash74
[48] SB Shrewsbury AP Bosco PS Uster Pharmacokinetics of a novel submicronbudesonide dispersion for nebulized delivery in asthma Int J Pharm 365(2009) 12ndash17
[49] RH Muumlller KH Wallis Surface modi1047297cation of iv injectable biodegradablenanoparticles with poloxamer polymers and poloxamine 908 Int J Pharm 89(1993) 25ndash31
[50] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy and diagno-sis Adv Drug Deliv Rev 54 (2002) 631ndash651
[51] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (2000) 73ndash80
[52] M Wang M Thanou Targeting nanoparticles to cancer Pharmacol Res 62(2010) 90ndash99
[53] L Gao G Liu X Wang F Liu Y Xu J Ma Preparation of a chemically stablequercetin formulation using nanosuspension technology Int J Pharm 404(2011) 231ndash237
[54] M Sarkari J Brown X Chen S Swinnea RO Williams III KP Johnston En-hanced drug dissolution using evaporative precipitation into aqueous solutionInt J Pharm 243 (2002) 17ndash31
[55] X Li L Gu Y Xu Y Wang Preparation of feno1047297brate nanosuspension and studyof its pharmacokinetic behavior in rats Drug Dev Ind Pharm 35 (2009)827ndash833
[56] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Pharmacokinetic evaluation of oral feno1047297brate nanosus-
pensions and SLN in comparison to conventional suspensions of micronizeddrug Adv Drug Deliv Rev 59 (2007) 419ndash426[57] GJ Vergote C Vervaet I Van Driessche S Hoste S De Smedt J Demeester RA
Jain S Ruddy JP Remon In vivo evaluation of matrix pellets containing nano-crystalline ketoprofen Int J Pharm 240 (2002) 79ndash84
[58] S Ghosh P Chiang JL Wahlstrom H Fujiwara JG Selbo SL Roberds Oral de-livery of 13-dicyclohexylurea nanosuspension enhances exposure and lowersblood pressure in hypertensive rats Basic Clin Pharmacol Toxicol 102 (2008)453ndash458
[59] P Langguth A Hanafy D Frenzel P Grenier A Nhamias T Ohlig G VergnaultH Spahn-Langguth Nanosuspension formulations for low-soluble drugs phar-macokinetic evaluation using spironolactone as model compound Drug DevInd Pharm 31 (2005) 319ndash329
[60] MG Fakesa Blisse J Vakkalagaddab Feng Qiana Sridhar Desikana Rajesh BGandhi C Lai A Hsieha MK Franchini H Toaled J Brown Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amor-phous formulation approaches Int J Pharm 370 (2009) 167ndash174
[61] K Sigfridsson A Nordmark S Theilig A Lindah A formulation comparison be-tween micro- and nanosuspensions the importance of particle size for absorp-
tion of a model compound following repeated oral administration to rats duringearly development Drug Dev Ind Pharm 37 (2011) 185ndash192
[62] J Jinno N Kamada M Miyake K Yamada T Mukai M Odomi H Toguchi GGLiversidge K Higaki T Kimura Effect of particle size reduction on dissolutionand oral absorption of a poorly water-soluble drug cilostazol in beagle dogs JControl Release 111 (2006) 56ndash64
[63] Y Wu A Loper E Landis L Hettrick L Novak K Lynn C Chen K Thompson RHiggins U Batra S Shelukar G Kwei D Storey The role of biopharmaceutics inthe development of a clinical nanoparticle formulation of MK-0869 a beagledog model predicts improved bioavailability and diminished food effect on ab-sorption in human Int J Pharm 285 (2004) 135ndash146
[64] RH Muumlller S Runge V Ravelli W Mehnert AF Thuumlnemann EB Souto Oralbioavailability of cyclosporine solid lipid nanoparticles (SLNreg) versus drugnanocrystals Int J Pharm 317 (2006) 82ndash89
[65] G Ponchel MJ Montisci A Dembri C Durrer D Duchecircne Mucoadhesion of colloidal particulate systems in the gastro-intestinal tract Eur J Pharm Bio-pharm 44 (1997) 25ndash31
[66] D Duchecircne G Ponchel Bioadhesion of solid oral dosage forms why and howEur J Pharm Biopharm 44 (1997) 15ndash23
[67] D Dodou P Breedveld PA Wieringa Mucoadhesives in the gastrointestinaltract revisiting the literature for novel applications Eur J Pharm Biopharm60 (2005) 1ndash16
[68] JD Smart The basics and underlying mechanisms of mucoadhesion Adv DrugDeliv Rev 57 (2005) 1556ndash1568
[69] O Kayser A newapproach fortargetingto Cryptosporidium parvum using mucoadhe-sive nanosuspensions research and applications Int J Pharm 214 (2001) 83ndash85
[70] A des Rieux V Fievez M Garinot YJ Schneider V Preacuteat Nanoparticles as po-tential oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[71] A Lamprecht P Koenig N Ubrich P Maincent D Neumann Low molecularweight heparin nanoparticles mucoadhesion and behaviour in Caco-2 cellsNanotechnology 17 (2006) 3673ndash3680
[72] F Delie Evaluation of nano- and microparticle uptake by the gastrointestinaltract Adv Drug Deliv Rev 34 (1998) 221ndash233
[73] CN Grama DD Ankola MNV Ravi Kumar Poly(lactide-co-glycolide) nano-particles for peroral delivery of bioactives Curr Opin Colloid Interface Sci 16(2011) 238ndash245
[74] MP Desai V Labhasetwar GL Amidon RJ Levy Gastrointestinal Uptake of biodegradable microparticles effect of particle size Pharm Res 13 (1996)1838ndash1845
[75] A des Rieux V Fievez M Garinot YJ Scheider V Preat Nanoparticles as poten-tial oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[76] JM Dintaman JA Silverman Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) Pharm Res 16 (1999)1550ndash1556
[77] J Goole DJ Lindley W Roth SM Carl K Amighi JM Kauffmann GT KnippThe effects of excipients on transporter mediated absorption Int J Pharm 393(2010) 17ndash31
[78] J Huang L Si L Jiang Z Fan J Qiu G Li Effect of pluronic F68 block copolymeron P-glycoprotein transport and CYP3A4 metabolism Int J Pharm 356 (2008)351ndash353
[79] MF Wempe C Wright JL Little JW Lightner SE Large GB Ca1047298isch CMBuchanan PJ Rice VJ Wacher KM Ruble KJ Edgar Inhibiting ef 1047298ux withnovel non-ionic surfactants rational design based on vitamin E TPGS Int JPharm 370 (2009) 93ndash102
428 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[81] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Absence of a food effect with a 145 mg nanoparticle feno-1047297brate tablet formulation Int J Clin Pharmacol Ther 44 (2006) 64ndash70
[82] MV Chaubal C Popescu Conversion of nanosuspensions into dry powders byspray drying a case study Pharm Res 25 (2008) 2302ndash2308
[83] F Lai E Pini G Angioni ML Manca J Perricci C Sinico AM Fadda Nanocrys-tals as tool to improve piroxicam dissolution rate in novel orally disintegratingtablets Eur J Pharm Biopharm 79 (2011) 552ndash558
[84] D Mou H Chen J Wan H Xu X Yang Potent dried drug nanosuspensions for
oral bioavailability enhancement of poorly soluble drugs with pH-dependentsolubility Int J Pharm 413 (2011) 237ndash244[85] A Ain-Ai PK Gupta Effect of arginine hydrochloride and hydroxypropyl cellu-
lose as stabilizers on the physical stability of high drug loading nanosuspensionsof a poorly soluble compound Int J Pharm 351 (2008) 282 ndash288
[86] Z Guo T Pereira O Choi Y Wang HT Hahn Surface functionalized aluminananoparticle 1047297lled polymeric nanocomposites with enhanced mechanical prop-erties J Mater Chem 16 (2006) 2800ndash2808
[87] DR Kalaria G Sharma V Beniwal MN Ravi Kumar Design of biodegradablenanoparticles for oral delivery of doxorubicin in vivo pharmacokinetics and tox-icity studies in rats Pharm Res 26 (2009) 492ndash501
[88] JE Kipp The role of solid nanoparticle technology in parenteral delivery of poorly water soluble drugs Int J Pharm 284 (2004) 109ndash122
[89] HM Shubar S Lachenmaier MM Heimesaat U Lohman R Mauludin RHMuumlller R Fitzner K Borner O Liesenfeld SDS-coated atovaquone nanosuspen-sions show improved therapeutic ef 1047297cacy against experimental acquired andreactivated toxoplasmosis by improving passage of gastrointestinal and bloodndash
brain barriers J Drug Target 19 (2011) 114ndash124[90] L Peltonen J Hirvonen Pharmaceutical nanocrystals by nanomilling critical
process parameters particle fracturing and stabilization method J Pharm Phar-macol 62 (2010) 1569ndash1579
[91] F Lai C Sinico G Ennas F Marongiu G Marongiu AM Fadda Diclofenac nano-suspensions in1047298uence of preparation procedure and crystal form on drug disso-lution behavior Int J Pharm 373 (2009) 124ndash132
[92] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (Suppl 2) (2000) S73ndashS80
[93] RH Muller CM Keck Challenges and solutions for the delivery of biotech drugsmdasha review of drug nanocrystal technology and lipid nanoparticles J Biotechnol113 (2004) 151ndash170
[94] JL Wahlstrom P Chiang S Ghosh CJ Warren SP Wene LA Albin ME SmithSL Roberds Pharmacokinetic evaluation of a 13-dicyclohexylurea nanosuspen-sion formulation to support early ef 1047297cacy assessment Nanoscale Res Lett 2(2007) 291ndash296
[95] Y GaoZ LiM SunH Li CGuoJ CuiA LiF CaoY XiH Lou GZhai Preparationcharacterization pharmacokinetics and tissue distribution of curcumin nanosus-pension with TPGS as stabilizer Drug Dev Ind Pharm 36 (2010) 1225ndash1234
[96] M Clement W Pugh I Parikh Tissue distribution and plasma clearance of a novelmicrocrystalline-coated 1047298urbiprofen formulation Pharmacologist 34 (1992)204ndash211
[97] RC Nagarwal S Kant PN Singh P Maiti JK Pandit Polymeric nanoparticulate sys-tem a potential approach for ocular drug delivery J Control Release 136 (2009)2ndash13
[98] H Gupta M Aqil RK Khar A Ali A Bhatnagar G Mittal Spar1047298oxacin loadedPLGA nanoparticles for sustained ocular drug delivery Nanomedicine 6 (2010)324ndash333
[99] HS Ali P York AM Ali N Blagden Hydrocortisone nanosuspensions for oph-thalmic delivery a comparative study between micro1047298uidic nanoprecipitationand media milling J Control Release 149 (2011) 175ndash181
[100] SK Sahoo F Dilnawaz S Krishnakumar Nanotechnology in ocular drug deliv-ery Drug Discov Today 13 (2008) 144ndash151
[101] O Kayser A Lemke N Hernaacutendez-Trejo The impact of nanobiotechnology on thedevelopment of newdrug deliverysystems Curr Pharm Biotechnol6 (2005) 3ndash5
[102] R Pignatello C Bucolo G Spedalieri A Maltese G Puglisi Flurbiprofen-loadedacrylate polymer nanosuspensions for ophthalmic application Biomaterials 23(2002) 3247ndash3255
[103] R Ravichandran Nanoparticles in drug delivery potential green nanobiomedi-
cine applications Int J Green Nanotechnol Biomed 1 (2009) B108ndash
B130[104] AM Cerdeira M Mazzotti B Gander Miconazole nanosuspensions in1047298uence
of formulation variables on particle size reduction and physical stability Int JPharm 396 (2010) 210ndash218
[105] MA Kassem AA Abdel Rahman MM Ghorab MB Ahmed RM Khalil Nano-suspension as an ophthalmic delivery system for certain glucocorticoid drugsInt J Pharm 340 (2007) 126ndash133
[106] P Chiang JW Alsup Y Lai Y Hu BR Heyde D Tung Evaluation of aerosol de-livery of nanosuspension for pre-clinical pulmonary drug delivery NanoscaleRes Lett 4 (2009) 254ndash261
[107] W Yang JI Peters RO Williams III Inhaled nanoparticlesmdasha current reviewInt J Pharm 356 (2008) 239ndash247
[108] J Zhang L Wu H Chan W Watanabe Formation characterization and fate of inhaled drug nanoparticles Adv Drug Deliv Rev 63 (2011) 441ndash455
[109] HM Mansour YS Rhee X Wu Nanomedicine in pulmonary delivery Int JNanomedicine 4 (2009) 299ndash319
[110] NR Labiris MB Dolovich Pulmonary drug delivery Part I physiological factorsaffecting therapeutic effectiveness of aerosolized medications Br J Clin Phar-macol 56 (2003) 588ndash599
[111] JS Patton PR Byron Inhaling medicines delivering drugs to the body throughthe lungs Nat Rev Drug Discov 6 (2007) 67ndash74
[112] DA Edwards C Dunbar Bioengineering of therapeutic aerosols Annu RevBiomed Eng 4 (2002) 93ndash107
[113] W Yang JTam DA Miller J Zhou JT McConville KP Johnstonb RO WilliamsIII High bioavailability from nebulized itraconazole nanoparticle dispersionswith biocompatible stabilizers Int J Pharm 361 (2008) 177ndash188
[114] S Gill R Lobenberg T Ku S Azarmi W Roa EJ Prenner Nanoparticles char-acteristics mechanisms of action and toxicity in pulmonary drug deliverymdasha re-view J Biomed Nanotechnol 3 (2007) 107ndash119
[115] SJ Sze1047298er Pharmacodynamics and pharmacokinetics of budesonide a new
S183[116] W Yang KP Johnston RO Williams III Comparison of bioavailability of amor-phous versus crystalline itraconazole nanoparticles via pulmonary administra-tion in rats Eur J Pharm Biopharm 75 (2010) 33 ndash41
[117] R Ali GK Jain Z Iqbal S Talegaonkar P Pandit S Sule G Malhotra RK KharA Bhatnagar FJ Ahmad Development and clinical trial of nano-atropine sulfatedry powder inhaler as a novel organophosphorous poisoning antidote Nanome-dicine 5 (2009) 55ndash63
[118] D Andes Minireview in vivo pharmacodynamics of antifungal drugs in treat-ment of candidiasis Antimicrob Agents Chemother 47 (2003) 1179ndash1186
[119] D Andes K Marchillo R Conklin G Krishna F Ezzet A Cacciapuoti DLoebenberg Pharmacodynamics of a new triazole posaconazole in a murinemodel of disseminated candidiasis Antimicrob Agents Chemother 48 (2004)137ndash142
[120] O Kayser C Olbrich V Yardley AF Kiderlen SL Croft Formulation of ampho-tericin B as nanosuspension for oral administration Int J Pharm 254 (2003)73ndash75
[121] L Zhang S Hou S Mao D Wei X Song Y Lu Uptake of folate-conjugated albu-min nanoparticles to the SKOV3 cells Int J Pharm 287 (2004) 155ndash162
[122] J Sudimack RJ Lee Targeted drug delivery via folate receptor Adv Drug DelivRev 41 (2000) 147ndash162
[123] P Vader LJ van der Aa G Storm RM Schiffelers JF Engbersen Polymeric car-rier systems for siRNA delivery Curr Top Med Chem 12 (2012) 108 ndash119
[124] O Veiseh FM Kievit RG Ellenbogen M Zhang Cancer cell invasion treatmentand monitoring opportunities in nanomedicine Adv Drug Deliv Rev 63 (2011)582ndash596
[125] J Kreuter VE Petrov DA Kharkevich RN Alyautdin In1047298uence of the type of surfactant on the analgesic effects induced by the peptide dalargin after its de-livery across the bloodndashbrain barrier using surfactant-coated nanoparticles JControl Release 49 (1997) 81ndash87
[126] J Ye Q Wang X Zhou N Zhang Injectable actarit-loaded solid lipid nanoparti-cles as passive targeting therapeutic agents for rheumatoid arthritis Int JPharm 352 (2008) 273ndash279
[127] SM Moghimi AC Hunter JC Murray Nanomedicine current status and futureprospects FASEB J 19 (2005) 311ndash330
[128] K Park To PEGylate or not PEGylate that is not the question J Control Release142 (2010) 147ndash148
[129] M Socha P Bartecki C Passitani A Sapin C Damge T Lecompte J BarreE Ghazouani P Maincent Stealth nanoparticles coated with heparin aspeptide or peptide carriers J Drug Target 17 (2009) 575ndash585
[130] D Shenoy S Little R Langer M Amiji Poly(ethylene oxide)-modi1047297ed poly(-beta-amino ester) nanoparticles as a pH-sensitive system for tumor targeted de-livery of hydrophobic drugs part 2 In vivo distribution and tumor localizationstudies Pharm Res 22 (2005) 2107ndash2114
[131] R Shegokara KK Singha Surface modi1047297ed nevirapinenanosuspensions for viralreservoir targeting in vitro and in vivo evaluation Int J Pharm 421 (2011)341ndash352
[132] Y Matsumura H Maeda A new concept for macromolecular therapeutics incancer chemotherapy mechanism of tumoritropic accumulation of proteinsand the antitumor agent SMANCS Cancer Res 46 (1986) 6387ndash6392
[133] H Zhang CP Hollis Q Zhang T Li Preparation and antitumor study of camp-tothecin nanocrystals Int J Pharm 415 (2011) 293ndash300
[134] H Lou L Gao X Wei Z Zhang D Zheng D Zhang X Zhang Y Li Q Zhang Ori-donin nanosuspension enhances anti-tumor ef 1047297cacy in SMMC-7721 cells andH22 tumor bearing mice Colloids Surf B Biointerfaces 87 (2011) 319ndash325
[135] TM Goppert RH Muumlller Adsorption kinetics of plasma proteins on solid lipid
nanoparticles for drug targeting Int J Pharm 302 (2005) 172ndash
186[136] X Pu J Sun M Li Z He Formulation of nanosuspensions as a new approach for
the delivery of poorly soluble drugs Curr Nanosci 5 (2009) 417ndash427[137] R Gaudana J Jwala SHS Boddu AK Mitra Recent perspectives in ocular drug
delivery Pharm Res 26 (2009) 1197ndash1216[138] T Yasukawa H Kimura Y Tabata H Miyamoto Y Honda Y Ikada Y Ogura
Targeted delivery of anti-angiogenic agent TNP-470 using water-soluble poly-mer in the treatment of choroidal neovascularization Invest Ophthalmol VisSci 40 (1999) 2690ndash2696
[139] A Lemke AF Kiderlen B Petri O Kayser Delivery of amphotericin B nanosus-pensions to the brain and determination of activity against Balamuthia mandril-laris amebas Nanomedicine 6 (2010) 597ndash603
[140] HL Wong XY Wu R Bendayan Nanotechnological advances forthe delivery of CNS therapeutics Adv Drug Deliv Rev (2011) doi101016jaddr201110007
[141] J Kreuter S Gelperina Use of nanoparticles for cerebral cancer Tumori 94(2008) 271ndash277
[142] J Kreuter RN Alyautdin DA Kharkevich AA Ivanov Passage of peptidesthrough the bloodndashbrain barrier with colloidal polymer particles (nanoparti-cles) Brain Res 674 (1995) 171ndash174
429L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[143] J Kreuter Nanoparticulate systems for brain delivery of drugs Adv Drug DelivRev 47 (2001) 65ndash81
[144] TM Goumlppert RH Muumlller Polysorbate-stabilized solid lipid nanoparticles as col-loidal carriers for intravenous targeting of drugs to the brain comparison of plasma protein adsorption patterns J Drug Target 13 (2005) 179ndash187
[145] S Mansouri Y Cuie F Winnik Q Shi P Lavigne M Benderdour E Beaumont JC Fernandes Characterization of folate-chitosan-DNA nanoparticles for genetherapy Biomaterials 27 (2006) 2060ndash2065
[146] AR Hilgenbrink PS Low Folate receptor-mediated drug targeting from thera-peutics to diagnostics J Pharm Sci 94 (2005) 2135ndash2146
[147] F Pierigegrave S Sera1047297ni L Rossi M Magnani Cell-based drug delivery Adv Drug
Deliv Rev 60 (2008) 286ndash
295[148] F Chellat Y Merhi A Moreau L Yahia Therapeutic potential of nanoparticulatesystems for macrophage targeting Biomaterials 26 (2005) 7260ndash7275
[149] SS Hall S Mitragotri PS Daugherty Identi1047297cation of peptide ligands facilitatingnanoparticle at attachment to erythrocytes Biotechnol Prog 23 (2007) 749ndash754
[150] S Gorantla H Dou M Boska CJ Destache J Nelson L Poluektova BERabinow HE Gendelman RL Mosley Quantitative magnetic resonance and
SPECT imaging for macrophage tissue migration and nanoformulated drug de-livery J Leukoc Biol 80 (2006) 1165ndash1174
[151] LA Lotero G Olmos JC Diez Delivery to macrophages and toxic action of etopo-sidecarried in mouse redblood cells Biochim Biophys Acta 1620 (2003) 160ndash166
[152] L Rossi S Sera1047297ni F Pierigeacute A Antonelli A Cerasi A Fraternale L ChiarantiniM Magnani Erythrocyte-based drug delivery Expert Opin Drug Deliv 2 (2005)311ndash322
[153] S Sera1047297ni L Rossi A Antonelli A Fraternale A Cerasi R Crinelli L ChiarantiniGF Schiavano M Magnani Drug delivery through phagocytosis of red bloodcells Transfus Med Hemother 31 (2004) 92ndash101
[154] H Dou CJ Destache JR Morehead R Lee Mosley MD Boska J Kingsley S
Gorantla L Poluektova JA Nelson M Chaubal J Werling J Kipp BERabinow HE Gendelman Development of a macrophage-based nanoparticleplatform for antiretroviral drug delivery Blood 108 (2006) 2827ndash2835
[155] V Staedtke M Braumller A Muumlller R Georgieva S Bauer N Sternberg A Voigt ALemke C Keck J Moumlschwitzer H Baumlumler In vitro inhibition of fungal activityby macrophage-mediated sequestration and release of encapsulated amphoter-icin B nanosuspension in red blood cells Small 6 (2010) 96ndash103
430 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
nanocrystals show clear potential for clinical development compared
with both the solution and the non-targeting nanocrystals formulations
243 Cell-based drug delivery of drug nanocrystals
The signi1047297cantly increased dissolution velocity which is a distinct
advantage of nanocrystals simultaneously implies the problem that
drug nanocrystals might dissolve before reaching the target Cell-
based drug delivery approach canbe employed to deal with this prob-
lem Cell based delivery systems are identi1047297
ed as cell carriers (includ-ing bacteria cells and animal cells) which can be loaded with drugs or
therapeutics The systems can release the drug content in circulation
or at selected sites or could target the drug to other relevant cells in
the body [147] Among the animal cells of special relevance are mac-
rophages and red blood cells (RBCs) Macrophages are differentiated
cells of the immune system able to phagocytize microorganisms as
well as nanoparticulate materials So nanoparticulate systems are
particularly useful for the delivery of therapeutic agents to macro-
phages [148149] When macrophages are used as drug delivery sys-
tems they should be 1047297rst loaded with the nanoparticulate drug ex
vivo and then re-infused into the host where their content is distrib-
uted to tissues that favor homing of macrophages such as parasites
bacteria and viruses [150151] RBCs constitute potential biocompati-
ble carriers for different bioactive substances including protein drugs
as well as nanoparticulates They have unique properties such as bio-
degradability biocompatibility and long-term drug releasing and thus
are well suited for drug encapsulation [152] They can be easily han-
dled ex vivo by means of several techniques for the encapsulation of
different molecules and nanoparticulates [153]
For drug nanocrystals few studies related on cell based drug deliv-
ery have been reported but the existing results proved the feasibility
Dou et al designed a novel bone marrow-derived macrophage (BMM)
indinavir nanocrystals delivery system for antiretroviral treatment
[154] Light microscopic examination proved that indinavir nanocrys-
tals were successfully loaded into BMMs after culture in the presence
of indinavir nanosuspensions for 12 h Following iv administration
into naive mice the indinavir nanocrystal loaded BMMs acted as ldquoTro-
jan horsesrdquo for transport of drug into tissues which were known to be
targets for HIV due to the parallel BMM migration and viral tissue tro-pism Administration of indinavir nanocrystal-BMMs sustained indina-
vir in tissue and sera for up to 10 days in comparison with 6 h for the
non-wrapped nanosuspensions Amphotericin B nanocrystal-loaded
RBCs systems were developed by Staedtke et al in order to improvean-
tifungal treatment [155] Amphotericin B nanocrystals encapsulation in
RBCs wasachieved by using hypotonichemolysis methodleading to in-
tracellularamphotericin B amounts of 381plusmn047 pg RBCminus1andanen-
trapment ef 1047297cacy of 15ndash18 Upon phagocytosis of amphotericin B
nanocrystal-RBCs leukocytes show a slow amphotericin B release
over 10 days and no alteration in cell viability
3 Conclusions
The researchon colloidal drug delivery systems may be the hottest1047297eld in pharmaceutics in the last several decades Due to the unique
advantage and pharmaeconomical value drug nanocrystals are paid
increasing attentions as a promising approach Drug nanocrystals
can be applied to all the poorly soluble drugs to overcome the solubil-
ity and bioavailability problems because all the poorly soluble drugs
can be comminuted into drug nanocrystals Researches on drug nano-
crystals within recent years fully exhibit their excellent in vivo perfor-
mances in different administration routes Among these the most
exciting information is that properties of drug nanocrystals can be
conveniently altered to meet various treatment demands of different
diseases With the number of insoluble drug compounds in develop-
ment increasing it is anticipated that nanocrystals technology will at-
tract increasing attentions as a viable formulation option However
though drug nanocrystals demonstrate superiority over the carrier
colloid drug delivery systems such as easier production safer compo-
sition and higher drug loading correspondingly they also confront
some problems For example how to obtain a more controllable
drug dissolution rate in order to meet the treatment requirements
of different diseases or reduce the drug release in the progress of de-
livering the drugs into target sites How can we get a more 1047297rm con-
junction between ligand-linked stabilizers and nanocrystal surfaces
without the loss of their properties We believe that many studies
will focus on handling these problems in the future
Acknowledgment
This work was partially supported by the Scienti1047297c Foundation of
the First Af 1047297liated Hospital of General Hospital of PLA the project
number is QN201105
References
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[3] CM Keck RH Muumlller Drug nanocrystals of poorly soluble drugs produced by
high pressure homogenisation Eur J Pharm Biopharm 62 (2006) 3ndash
16[4] BE Rabinow Nanosuspensions in drug delivery Nat Rev Drug Discov 3 (2004)785ndash796
[5] L Gao D Zhang M Chen Drug nanocrystals for the formulation of poorly solu-ble drugs and its application as a potential drug delivery system J NanopartRes 10 (2008) 845ndash862
[6] GG Liversidge KC Cundy Particle size reduction for improvement of oral bio-availability of hydrophobic drugs I Absolute oral bioavailability of nanocrystal-line danazol in beagle dogs Int J Pharm 125 (1995) 91ndash97
[7] K Peters S Leitzke J Diederichs K Borner H Hahn RH Muumlller S Ehlers Prep-aration of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic ef 1047297cacy in murine Mycobacterium avium infection J AntimicrobChemother 45 (2000) 77ndash83
[8] P Rosario B Claudio F Piera M Adriana P Antonina P Giovanni EudragitRS100 nanosuspensions for the ophthalmic controlled delivery of ibuprofenEur J Pharm Sci 16 (2002) 53ndash61
[9] C Jacobs RH Muumlller Production and characterization of a budesonide nanosus-pension for pulmonary administration Pharm Res 19 (2002) 189ndash194
[10] RH Muumlller C Jacobs O Kayser Nanosuspensions as particulate drug formula-
tions in therapy rationale for development and what we can expect for the fu-ture Adv Drug Deliv Rev 47 (2001) 3ndash19
[11] B Van Eerdenbrugh G Van den Mooter P Augustijns Topndashdown production of drug nanocrystals nanosuspension stabilization miniaturization and transfor-mation into solid products Int J Pharm 364 (2008) 64ndash75
[12] E Merisko-Liversidge GG Liversidge ER Cooper Nanosizing a formulationapproach for poorly-water-soluble compounds Eur J Pharm Sci 18 (2003)113ndash120
[13] J Hu KP Johnston RO Williams Nanoparticle engineering processes for en-hancing the dissolution rates of poorly water soluble drugs Drug Dev IndPharm 30 (2004) 233ndash245
[14] JAH Junghanns RH Muumlller Nanocrystal technology drug delivery and clinicalapplications Int J Nanomedicine 3 (2008) 295ndash310
[15] GA Brazeau HL Fung Mechanisms of creatine kinase release from isolated ratskeletal muscles damaged by propylene glycol and ethanol J Pharm Sci 79(1990) 393ndash397
[16] K Korttila A Sothman P Andersson Polyethylene glycol as a solvent for diaze-pam bioavailability and clinical effects after intramuscular administrationcomparison of oral intramuscular and rectal administration and precipitationfrom intravenous solutions Acta Pharmacol Toxicol (Copenh) 39 (1976)104ndash117
[17] R Budden UG Kuhl J Bahlsen Experiments on toxic sedative and muscle re-laxant potency of various drug solvents in mice Pharmacol Ther 5 (1979)467ndash474
[18] F Liu JY Park Y Zhang C Conwell Y Liu SR Bathula L Huang Targeted can-cer therapy with novel high drug-loading nanocrystals J Pharm Sci 99 (2010)3542ndash3551
[19] B Rabinow J Kipp P Papadopoulos J Wong J Glosson J Gass CS Sun TWielgos R White C Cook K Barker K Wood Itraconazole IV nanosuspensionenhances ef 1047297cacy through altered pharmacokinetics in the rat Int J Pharm 339(2007) 251ndash260
[20] F Kesisoglou S Panmai Y Wu Nanosizingmdashoral formulation development andbiopharmaceutical evaluation Adv Drug Deliv Rev 59 (2007) 631ndash644
[22] GG Liversidge P Conzentino Drug particle size reduction for decreasing gastricirritancy and enhancing absorption of naproxen in rats Int J Pharm 125 (1995)
309ndash
313
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8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[23] E Merisko-Liversidge GG Liversidge Nanosizing for oral and parenteral drugdelivery a perspective on formulating poorly-water soluble compounds usingwet media milling technology Adv Drug Deliv Rev 30 (2011) 427ndash440
[24] BHL Boumlhm RH Muumlller Lab-scale production unit design for nanosuspensions of sparingly soluble cytotoxic drugs Pharm Sci Technol Today 2 (1999) 336ndash339
[25] RH Drew E Dodds Ashley DK Benjamin Jr R Duane Davis SM Palmer JRPerfect Comparative safety of amphotericin B lipid complex and amphotericinB deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipi-ents Transplantation 77 (2004) 232ndash237
[26] J Dubois T Bartter J Gryn MR Pratter The physiologic effects of inhaledamphotericin B Chest 108 (1995) 750ndash753
[27] SM Palmer RH Drew JD Whitehouse VF Tapson RD Davis RR McConnellSS Kanj JR Perfect Safety of aerosolized amphotericin B lipid complex in lungtransplant recipients Transplantation 72 (2001) 545ndash548
[28] RO Williams III J Liu Formulation of a protein with propellant HFA 134a foraerosol delivery Eur J Pharm Sci 7 (1999) 137ndash144
[29] IC Ashurst CV Ambrose DJ Russell Pharmaceutical evaluation of a new spac-er device for delivery of metered-dose inhalers to infants and young children JAerosol Sci 23 (1992) 499ndash502
[30] GC Na HJ Stevens B Yuan N Rajagopalan Physical stability of ethyl diatrizoatenanocrystalline suspension in steam sterilization Pharm Res 16 (1999) 569ndash574
[31] H Lou X Zhang L Gao F Feng J Wang X Wei Z Yu D Zhang Q Zhang Invitro and in vivo antitumor activity of oridonin nanosuspension Int J Pharm379 (2009) 181ndash186
[32] L Gao D Zhang M Chen C Duan W Dai L Jia W Zhao Studies on pharmaco-kinetics and tissue distribution of oridonin nanosuspensions Int J Pharm 355(2008) 321ndash327
[33] SM Moghimi AC Hunter JC Murray Long circulating and target-speci1047297cnanoparticles theory to practice Pharmacol Rev 53 (2001) 283ndash381
[34] S Ganta JW Paxton BC Baguley S Garg Formulation and pharmacokinetic
evaluation of an asulacrine nanocrystalline suspension for intravenous deliveryInt J Pharm 367 (2009) 179ndash186
[35] K Sigfridsson S Forsseacuten P Hollaumlnder U Skantze J de Verdier A formulationcomparison using a solution and different nanosuspensions of a poorly solublecompound Eur J Pharm Biopharm 67 (2007) 540ndash547
[36] K Sigfridsson AJ Lundqvist M Strimfors Particle size reduction for improve-ment of oral absorption absorption of the poorly soluble drug UG558 in rats dur-ing early development Drug Dev Ind Pharm 35 (2009) 1479ndash1486
[37] S Kim J Lee Folate-targeted drug-delivery systems prepared by nano-comminution Drug Dev Ind Pharm 37 (2011) 131ndash138
[38] R Xiong W Lu J Li P Wang R Xu T Chen Preparation and characterization of intravenously injectable nimodipine nanosuspension Int J Pharm 350 (2008)338ndash343
[39] Y Gao Z Li M Sun C Guo A Yu Y Xi J Cui H Lou G Zhai Preparation andcharacterization of intravenously injectable curcumin nanosuspension DrugDeliv 18 (2011) 131ndash142
[40] RH Muumlller K Peters Nanosuspensions for the formulation of poorly solubledrugs I Preparation by a size-reduction technique Int J Pharm 160 (1998)229ndash237
[41] SB Zirar A Astier M Muchow S Gibaud Comparison of nanosuspensions andhydroxypropyl-b-cyclodextrin complex of melarsoprol pharmacokinetics andtissue distribution in mice Eur J Pharm Biopharm 70 (2008) 649 ndash656
[42] M Salzberg M Pless C Rochlitz K Ambrus P Scigalla R Herrmann A phase Istudy with oral SU5416 in patients with advanced solid tumors a drug inducingits clearance Invest New Drugs 24 (2006) 299ndash304
[43] WK Kraft B Steiger D Beussink JN Quiring N Fitzgerald HE Greenberg SAWaldman The pharmacokinetics of nebulized nanocrystal budesonide suspen-sion in healthy volunteers J Clin Pharmacol 44 (2004) 67ndash72
[44] JM Vaughn NP Wiederhold JT McConville JJ Coalson RL Talbert DSBurgess KP Johnston RO Williams III JI Peters Murine airway histologyand intracellular uptake of inhaled amorphous itraconazole Int J Pharm 338(2007) 219ndash224
[45] JM Vaughn JT McConville D Burgess JI Peters KP Johnston RL Talbert ROWilliams III Single dose and multiple dose studies of itraconazole nanoparticlesEur J Pharm Biopharm 63 (2006) 95ndash102
[46] BJ Hoeben DS Burgess JT McConville LK Najvar RL Talbert JI Peters NPWiederhold BL Frei JR Graybill R Bocanegra KA Overhoff P Sinswat KP
Johnston RO Williams III In vivo ef 1047297cacy of aerosolized nanostructured itraco-nazole formulations for prevention of invasive pulmonary aspergillosis Antimi-crob Agents Chemother 50 (2006) 1552ndash1554
[47] CA Alvarez NP Wiederhold JT McConville JI Peters LK Najvar JR Graybill JJ Coalson RL Talbert DS Burgess R Bocanegra KP Johnston RO WilliamsIII Aerosolized nanostructured itraconazole as prophylaxis against invasive pul-monary aspergillosis J Infect 55 (2007) 68ndash74
[48] SB Shrewsbury AP Bosco PS Uster Pharmacokinetics of a novel submicronbudesonide dispersion for nebulized delivery in asthma Int J Pharm 365(2009) 12ndash17
[49] RH Muumlller KH Wallis Surface modi1047297cation of iv injectable biodegradablenanoparticles with poloxamer polymers and poloxamine 908 Int J Pharm 89(1993) 25ndash31
[50] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy and diagno-sis Adv Drug Deliv Rev 54 (2002) 631ndash651
[51] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (2000) 73ndash80
[52] M Wang M Thanou Targeting nanoparticles to cancer Pharmacol Res 62(2010) 90ndash99
[53] L Gao G Liu X Wang F Liu Y Xu J Ma Preparation of a chemically stablequercetin formulation using nanosuspension technology Int J Pharm 404(2011) 231ndash237
[54] M Sarkari J Brown X Chen S Swinnea RO Williams III KP Johnston En-hanced drug dissolution using evaporative precipitation into aqueous solutionInt J Pharm 243 (2002) 17ndash31
[55] X Li L Gu Y Xu Y Wang Preparation of feno1047297brate nanosuspension and studyof its pharmacokinetic behavior in rats Drug Dev Ind Pharm 35 (2009)827ndash833
[56] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Pharmacokinetic evaluation of oral feno1047297brate nanosus-
pensions and SLN in comparison to conventional suspensions of micronizeddrug Adv Drug Deliv Rev 59 (2007) 419ndash426[57] GJ Vergote C Vervaet I Van Driessche S Hoste S De Smedt J Demeester RA
Jain S Ruddy JP Remon In vivo evaluation of matrix pellets containing nano-crystalline ketoprofen Int J Pharm 240 (2002) 79ndash84
[58] S Ghosh P Chiang JL Wahlstrom H Fujiwara JG Selbo SL Roberds Oral de-livery of 13-dicyclohexylurea nanosuspension enhances exposure and lowersblood pressure in hypertensive rats Basic Clin Pharmacol Toxicol 102 (2008)453ndash458
[59] P Langguth A Hanafy D Frenzel P Grenier A Nhamias T Ohlig G VergnaultH Spahn-Langguth Nanosuspension formulations for low-soluble drugs phar-macokinetic evaluation using spironolactone as model compound Drug DevInd Pharm 31 (2005) 319ndash329
[60] MG Fakesa Blisse J Vakkalagaddab Feng Qiana Sridhar Desikana Rajesh BGandhi C Lai A Hsieha MK Franchini H Toaled J Brown Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amor-phous formulation approaches Int J Pharm 370 (2009) 167ndash174
[61] K Sigfridsson A Nordmark S Theilig A Lindah A formulation comparison be-tween micro- and nanosuspensions the importance of particle size for absorp-
tion of a model compound following repeated oral administration to rats duringearly development Drug Dev Ind Pharm 37 (2011) 185ndash192
[62] J Jinno N Kamada M Miyake K Yamada T Mukai M Odomi H Toguchi GGLiversidge K Higaki T Kimura Effect of particle size reduction on dissolutionand oral absorption of a poorly water-soluble drug cilostazol in beagle dogs JControl Release 111 (2006) 56ndash64
[63] Y Wu A Loper E Landis L Hettrick L Novak K Lynn C Chen K Thompson RHiggins U Batra S Shelukar G Kwei D Storey The role of biopharmaceutics inthe development of a clinical nanoparticle formulation of MK-0869 a beagledog model predicts improved bioavailability and diminished food effect on ab-sorption in human Int J Pharm 285 (2004) 135ndash146
[64] RH Muumlller S Runge V Ravelli W Mehnert AF Thuumlnemann EB Souto Oralbioavailability of cyclosporine solid lipid nanoparticles (SLNreg) versus drugnanocrystals Int J Pharm 317 (2006) 82ndash89
[65] G Ponchel MJ Montisci A Dembri C Durrer D Duchecircne Mucoadhesion of colloidal particulate systems in the gastro-intestinal tract Eur J Pharm Bio-pharm 44 (1997) 25ndash31
[66] D Duchecircne G Ponchel Bioadhesion of solid oral dosage forms why and howEur J Pharm Biopharm 44 (1997) 15ndash23
[67] D Dodou P Breedveld PA Wieringa Mucoadhesives in the gastrointestinaltract revisiting the literature for novel applications Eur J Pharm Biopharm60 (2005) 1ndash16
[68] JD Smart The basics and underlying mechanisms of mucoadhesion Adv DrugDeliv Rev 57 (2005) 1556ndash1568
[69] O Kayser A newapproach fortargetingto Cryptosporidium parvum using mucoadhe-sive nanosuspensions research and applications Int J Pharm 214 (2001) 83ndash85
[70] A des Rieux V Fievez M Garinot YJ Schneider V Preacuteat Nanoparticles as po-tential oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[71] A Lamprecht P Koenig N Ubrich P Maincent D Neumann Low molecularweight heparin nanoparticles mucoadhesion and behaviour in Caco-2 cellsNanotechnology 17 (2006) 3673ndash3680
[72] F Delie Evaluation of nano- and microparticle uptake by the gastrointestinaltract Adv Drug Deliv Rev 34 (1998) 221ndash233
[73] CN Grama DD Ankola MNV Ravi Kumar Poly(lactide-co-glycolide) nano-particles for peroral delivery of bioactives Curr Opin Colloid Interface Sci 16(2011) 238ndash245
[74] MP Desai V Labhasetwar GL Amidon RJ Levy Gastrointestinal Uptake of biodegradable microparticles effect of particle size Pharm Res 13 (1996)1838ndash1845
[75] A des Rieux V Fievez M Garinot YJ Scheider V Preat Nanoparticles as poten-tial oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[76] JM Dintaman JA Silverman Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) Pharm Res 16 (1999)1550ndash1556
[77] J Goole DJ Lindley W Roth SM Carl K Amighi JM Kauffmann GT KnippThe effects of excipients on transporter mediated absorption Int J Pharm 393(2010) 17ndash31
[78] J Huang L Si L Jiang Z Fan J Qiu G Li Effect of pluronic F68 block copolymeron P-glycoprotein transport and CYP3A4 metabolism Int J Pharm 356 (2008)351ndash353
[79] MF Wempe C Wright JL Little JW Lightner SE Large GB Ca1047298isch CMBuchanan PJ Rice VJ Wacher KM Ruble KJ Edgar Inhibiting ef 1047298ux withnovel non-ionic surfactants rational design based on vitamin E TPGS Int JPharm 370 (2009) 93ndash102
428 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[81] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Absence of a food effect with a 145 mg nanoparticle feno-1047297brate tablet formulation Int J Clin Pharmacol Ther 44 (2006) 64ndash70
[82] MV Chaubal C Popescu Conversion of nanosuspensions into dry powders byspray drying a case study Pharm Res 25 (2008) 2302ndash2308
[83] F Lai E Pini G Angioni ML Manca J Perricci C Sinico AM Fadda Nanocrys-tals as tool to improve piroxicam dissolution rate in novel orally disintegratingtablets Eur J Pharm Biopharm 79 (2011) 552ndash558
[84] D Mou H Chen J Wan H Xu X Yang Potent dried drug nanosuspensions for
oral bioavailability enhancement of poorly soluble drugs with pH-dependentsolubility Int J Pharm 413 (2011) 237ndash244[85] A Ain-Ai PK Gupta Effect of arginine hydrochloride and hydroxypropyl cellu-
lose as stabilizers on the physical stability of high drug loading nanosuspensionsof a poorly soluble compound Int J Pharm 351 (2008) 282 ndash288
[86] Z Guo T Pereira O Choi Y Wang HT Hahn Surface functionalized aluminananoparticle 1047297lled polymeric nanocomposites with enhanced mechanical prop-erties J Mater Chem 16 (2006) 2800ndash2808
[87] DR Kalaria G Sharma V Beniwal MN Ravi Kumar Design of biodegradablenanoparticles for oral delivery of doxorubicin in vivo pharmacokinetics and tox-icity studies in rats Pharm Res 26 (2009) 492ndash501
[88] JE Kipp The role of solid nanoparticle technology in parenteral delivery of poorly water soluble drugs Int J Pharm 284 (2004) 109ndash122
[89] HM Shubar S Lachenmaier MM Heimesaat U Lohman R Mauludin RHMuumlller R Fitzner K Borner O Liesenfeld SDS-coated atovaquone nanosuspen-sions show improved therapeutic ef 1047297cacy against experimental acquired andreactivated toxoplasmosis by improving passage of gastrointestinal and bloodndash
brain barriers J Drug Target 19 (2011) 114ndash124[90] L Peltonen J Hirvonen Pharmaceutical nanocrystals by nanomilling critical
process parameters particle fracturing and stabilization method J Pharm Phar-macol 62 (2010) 1569ndash1579
[91] F Lai C Sinico G Ennas F Marongiu G Marongiu AM Fadda Diclofenac nano-suspensions in1047298uence of preparation procedure and crystal form on drug disso-lution behavior Int J Pharm 373 (2009) 124ndash132
[92] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (Suppl 2) (2000) S73ndashS80
[93] RH Muller CM Keck Challenges and solutions for the delivery of biotech drugsmdasha review of drug nanocrystal technology and lipid nanoparticles J Biotechnol113 (2004) 151ndash170
[94] JL Wahlstrom P Chiang S Ghosh CJ Warren SP Wene LA Albin ME SmithSL Roberds Pharmacokinetic evaluation of a 13-dicyclohexylurea nanosuspen-sion formulation to support early ef 1047297cacy assessment Nanoscale Res Lett 2(2007) 291ndash296
[95] Y GaoZ LiM SunH Li CGuoJ CuiA LiF CaoY XiH Lou GZhai Preparationcharacterization pharmacokinetics and tissue distribution of curcumin nanosus-pension with TPGS as stabilizer Drug Dev Ind Pharm 36 (2010) 1225ndash1234
[96] M Clement W Pugh I Parikh Tissue distribution and plasma clearance of a novelmicrocrystalline-coated 1047298urbiprofen formulation Pharmacologist 34 (1992)204ndash211
[97] RC Nagarwal S Kant PN Singh P Maiti JK Pandit Polymeric nanoparticulate sys-tem a potential approach for ocular drug delivery J Control Release 136 (2009)2ndash13
[98] H Gupta M Aqil RK Khar A Ali A Bhatnagar G Mittal Spar1047298oxacin loadedPLGA nanoparticles for sustained ocular drug delivery Nanomedicine 6 (2010)324ndash333
[99] HS Ali P York AM Ali N Blagden Hydrocortisone nanosuspensions for oph-thalmic delivery a comparative study between micro1047298uidic nanoprecipitationand media milling J Control Release 149 (2011) 175ndash181
[100] SK Sahoo F Dilnawaz S Krishnakumar Nanotechnology in ocular drug deliv-ery Drug Discov Today 13 (2008) 144ndash151
[101] O Kayser A Lemke N Hernaacutendez-Trejo The impact of nanobiotechnology on thedevelopment of newdrug deliverysystems Curr Pharm Biotechnol6 (2005) 3ndash5
[102] R Pignatello C Bucolo G Spedalieri A Maltese G Puglisi Flurbiprofen-loadedacrylate polymer nanosuspensions for ophthalmic application Biomaterials 23(2002) 3247ndash3255
[103] R Ravichandran Nanoparticles in drug delivery potential green nanobiomedi-
cine applications Int J Green Nanotechnol Biomed 1 (2009) B108ndash
B130[104] AM Cerdeira M Mazzotti B Gander Miconazole nanosuspensions in1047298uence
of formulation variables on particle size reduction and physical stability Int JPharm 396 (2010) 210ndash218
[105] MA Kassem AA Abdel Rahman MM Ghorab MB Ahmed RM Khalil Nano-suspension as an ophthalmic delivery system for certain glucocorticoid drugsInt J Pharm 340 (2007) 126ndash133
[106] P Chiang JW Alsup Y Lai Y Hu BR Heyde D Tung Evaluation of aerosol de-livery of nanosuspension for pre-clinical pulmonary drug delivery NanoscaleRes Lett 4 (2009) 254ndash261
[107] W Yang JI Peters RO Williams III Inhaled nanoparticlesmdasha current reviewInt J Pharm 356 (2008) 239ndash247
[108] J Zhang L Wu H Chan W Watanabe Formation characterization and fate of inhaled drug nanoparticles Adv Drug Deliv Rev 63 (2011) 441ndash455
[109] HM Mansour YS Rhee X Wu Nanomedicine in pulmonary delivery Int JNanomedicine 4 (2009) 299ndash319
[110] NR Labiris MB Dolovich Pulmonary drug delivery Part I physiological factorsaffecting therapeutic effectiveness of aerosolized medications Br J Clin Phar-macol 56 (2003) 588ndash599
[111] JS Patton PR Byron Inhaling medicines delivering drugs to the body throughthe lungs Nat Rev Drug Discov 6 (2007) 67ndash74
[112] DA Edwards C Dunbar Bioengineering of therapeutic aerosols Annu RevBiomed Eng 4 (2002) 93ndash107
[113] W Yang JTam DA Miller J Zhou JT McConville KP Johnstonb RO WilliamsIII High bioavailability from nebulized itraconazole nanoparticle dispersionswith biocompatible stabilizers Int J Pharm 361 (2008) 177ndash188
[114] S Gill R Lobenberg T Ku S Azarmi W Roa EJ Prenner Nanoparticles char-acteristics mechanisms of action and toxicity in pulmonary drug deliverymdasha re-view J Biomed Nanotechnol 3 (2007) 107ndash119
[115] SJ Sze1047298er Pharmacodynamics and pharmacokinetics of budesonide a new
S183[116] W Yang KP Johnston RO Williams III Comparison of bioavailability of amor-phous versus crystalline itraconazole nanoparticles via pulmonary administra-tion in rats Eur J Pharm Biopharm 75 (2010) 33 ndash41
[117] R Ali GK Jain Z Iqbal S Talegaonkar P Pandit S Sule G Malhotra RK KharA Bhatnagar FJ Ahmad Development and clinical trial of nano-atropine sulfatedry powder inhaler as a novel organophosphorous poisoning antidote Nanome-dicine 5 (2009) 55ndash63
[118] D Andes Minireview in vivo pharmacodynamics of antifungal drugs in treat-ment of candidiasis Antimicrob Agents Chemother 47 (2003) 1179ndash1186
[119] D Andes K Marchillo R Conklin G Krishna F Ezzet A Cacciapuoti DLoebenberg Pharmacodynamics of a new triazole posaconazole in a murinemodel of disseminated candidiasis Antimicrob Agents Chemother 48 (2004)137ndash142
[120] O Kayser C Olbrich V Yardley AF Kiderlen SL Croft Formulation of ampho-tericin B as nanosuspension for oral administration Int J Pharm 254 (2003)73ndash75
[121] L Zhang S Hou S Mao D Wei X Song Y Lu Uptake of folate-conjugated albu-min nanoparticles to the SKOV3 cells Int J Pharm 287 (2004) 155ndash162
[122] J Sudimack RJ Lee Targeted drug delivery via folate receptor Adv Drug DelivRev 41 (2000) 147ndash162
[123] P Vader LJ van der Aa G Storm RM Schiffelers JF Engbersen Polymeric car-rier systems for siRNA delivery Curr Top Med Chem 12 (2012) 108 ndash119
[124] O Veiseh FM Kievit RG Ellenbogen M Zhang Cancer cell invasion treatmentand monitoring opportunities in nanomedicine Adv Drug Deliv Rev 63 (2011)582ndash596
[125] J Kreuter VE Petrov DA Kharkevich RN Alyautdin In1047298uence of the type of surfactant on the analgesic effects induced by the peptide dalargin after its de-livery across the bloodndashbrain barrier using surfactant-coated nanoparticles JControl Release 49 (1997) 81ndash87
[126] J Ye Q Wang X Zhou N Zhang Injectable actarit-loaded solid lipid nanoparti-cles as passive targeting therapeutic agents for rheumatoid arthritis Int JPharm 352 (2008) 273ndash279
[127] SM Moghimi AC Hunter JC Murray Nanomedicine current status and futureprospects FASEB J 19 (2005) 311ndash330
[128] K Park To PEGylate or not PEGylate that is not the question J Control Release142 (2010) 147ndash148
[129] M Socha P Bartecki C Passitani A Sapin C Damge T Lecompte J BarreE Ghazouani P Maincent Stealth nanoparticles coated with heparin aspeptide or peptide carriers J Drug Target 17 (2009) 575ndash585
[130] D Shenoy S Little R Langer M Amiji Poly(ethylene oxide)-modi1047297ed poly(-beta-amino ester) nanoparticles as a pH-sensitive system for tumor targeted de-livery of hydrophobic drugs part 2 In vivo distribution and tumor localizationstudies Pharm Res 22 (2005) 2107ndash2114
[131] R Shegokara KK Singha Surface modi1047297ed nevirapinenanosuspensions for viralreservoir targeting in vitro and in vivo evaluation Int J Pharm 421 (2011)341ndash352
[132] Y Matsumura H Maeda A new concept for macromolecular therapeutics incancer chemotherapy mechanism of tumoritropic accumulation of proteinsand the antitumor agent SMANCS Cancer Res 46 (1986) 6387ndash6392
[133] H Zhang CP Hollis Q Zhang T Li Preparation and antitumor study of camp-tothecin nanocrystals Int J Pharm 415 (2011) 293ndash300
[134] H Lou L Gao X Wei Z Zhang D Zheng D Zhang X Zhang Y Li Q Zhang Ori-donin nanosuspension enhances anti-tumor ef 1047297cacy in SMMC-7721 cells andH22 tumor bearing mice Colloids Surf B Biointerfaces 87 (2011) 319ndash325
[135] TM Goppert RH Muumlller Adsorption kinetics of plasma proteins on solid lipid
nanoparticles for drug targeting Int J Pharm 302 (2005) 172ndash
186[136] X Pu J Sun M Li Z He Formulation of nanosuspensions as a new approach for
the delivery of poorly soluble drugs Curr Nanosci 5 (2009) 417ndash427[137] R Gaudana J Jwala SHS Boddu AK Mitra Recent perspectives in ocular drug
delivery Pharm Res 26 (2009) 1197ndash1216[138] T Yasukawa H Kimura Y Tabata H Miyamoto Y Honda Y Ikada Y Ogura
Targeted delivery of anti-angiogenic agent TNP-470 using water-soluble poly-mer in the treatment of choroidal neovascularization Invest Ophthalmol VisSci 40 (1999) 2690ndash2696
[139] A Lemke AF Kiderlen B Petri O Kayser Delivery of amphotericin B nanosus-pensions to the brain and determination of activity against Balamuthia mandril-laris amebas Nanomedicine 6 (2010) 597ndash603
[140] HL Wong XY Wu R Bendayan Nanotechnological advances forthe delivery of CNS therapeutics Adv Drug Deliv Rev (2011) doi101016jaddr201110007
[141] J Kreuter S Gelperina Use of nanoparticles for cerebral cancer Tumori 94(2008) 271ndash277
[142] J Kreuter RN Alyautdin DA Kharkevich AA Ivanov Passage of peptidesthrough the bloodndashbrain barrier with colloidal polymer particles (nanoparti-cles) Brain Res 674 (1995) 171ndash174
429L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[143] J Kreuter Nanoparticulate systems for brain delivery of drugs Adv Drug DelivRev 47 (2001) 65ndash81
[144] TM Goumlppert RH Muumlller Polysorbate-stabilized solid lipid nanoparticles as col-loidal carriers for intravenous targeting of drugs to the brain comparison of plasma protein adsorption patterns J Drug Target 13 (2005) 179ndash187
[145] S Mansouri Y Cuie F Winnik Q Shi P Lavigne M Benderdour E Beaumont JC Fernandes Characterization of folate-chitosan-DNA nanoparticles for genetherapy Biomaterials 27 (2006) 2060ndash2065
[146] AR Hilgenbrink PS Low Folate receptor-mediated drug targeting from thera-peutics to diagnostics J Pharm Sci 94 (2005) 2135ndash2146
[147] F Pierigegrave S Sera1047297ni L Rossi M Magnani Cell-based drug delivery Adv Drug
Deliv Rev 60 (2008) 286ndash
295[148] F Chellat Y Merhi A Moreau L Yahia Therapeutic potential of nanoparticulatesystems for macrophage targeting Biomaterials 26 (2005) 7260ndash7275
[149] SS Hall S Mitragotri PS Daugherty Identi1047297cation of peptide ligands facilitatingnanoparticle at attachment to erythrocytes Biotechnol Prog 23 (2007) 749ndash754
[150] S Gorantla H Dou M Boska CJ Destache J Nelson L Poluektova BERabinow HE Gendelman RL Mosley Quantitative magnetic resonance and
SPECT imaging for macrophage tissue migration and nanoformulated drug de-livery J Leukoc Biol 80 (2006) 1165ndash1174
[151] LA Lotero G Olmos JC Diez Delivery to macrophages and toxic action of etopo-sidecarried in mouse redblood cells Biochim Biophys Acta 1620 (2003) 160ndash166
[152] L Rossi S Sera1047297ni F Pierigeacute A Antonelli A Cerasi A Fraternale L ChiarantiniM Magnani Erythrocyte-based drug delivery Expert Opin Drug Deliv 2 (2005)311ndash322
[153] S Sera1047297ni L Rossi A Antonelli A Fraternale A Cerasi R Crinelli L ChiarantiniGF Schiavano M Magnani Drug delivery through phagocytosis of red bloodcells Transfus Med Hemother 31 (2004) 92ndash101
[154] H Dou CJ Destache JR Morehead R Lee Mosley MD Boska J Kingsley S
Gorantla L Poluektova JA Nelson M Chaubal J Werling J Kipp BERabinow HE Gendelman Development of a macrophage-based nanoparticleplatform for antiretroviral drug delivery Blood 108 (2006) 2827ndash2835
[155] V Staedtke M Braumller A Muumlller R Georgieva S Bauer N Sternberg A Voigt ALemke C Keck J Moumlschwitzer H Baumlumler In vitro inhibition of fungal activityby macrophage-mediated sequestration and release of encapsulated amphoter-icin B nanosuspension in red blood cells Small 6 (2010) 96ndash103
430 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
nanocrystals show clear potential for clinical development compared
with both the solution and the non-targeting nanocrystals formulations
243 Cell-based drug delivery of drug nanocrystals
The signi1047297cantly increased dissolution velocity which is a distinct
advantage of nanocrystals simultaneously implies the problem that
drug nanocrystals might dissolve before reaching the target Cell-
based drug delivery approach canbe employed to deal with this prob-
lem Cell based delivery systems are identi1047297
ed as cell carriers (includ-ing bacteria cells and animal cells) which can be loaded with drugs or
therapeutics The systems can release the drug content in circulation
or at selected sites or could target the drug to other relevant cells in
the body [147] Among the animal cells of special relevance are mac-
rophages and red blood cells (RBCs) Macrophages are differentiated
cells of the immune system able to phagocytize microorganisms as
well as nanoparticulate materials So nanoparticulate systems are
particularly useful for the delivery of therapeutic agents to macro-
phages [148149] When macrophages are used as drug delivery sys-
tems they should be 1047297rst loaded with the nanoparticulate drug ex
vivo and then re-infused into the host where their content is distrib-
uted to tissues that favor homing of macrophages such as parasites
bacteria and viruses [150151] RBCs constitute potential biocompati-
ble carriers for different bioactive substances including protein drugs
as well as nanoparticulates They have unique properties such as bio-
degradability biocompatibility and long-term drug releasing and thus
are well suited for drug encapsulation [152] They can be easily han-
dled ex vivo by means of several techniques for the encapsulation of
different molecules and nanoparticulates [153]
For drug nanocrystals few studies related on cell based drug deliv-
ery have been reported but the existing results proved the feasibility
Dou et al designed a novel bone marrow-derived macrophage (BMM)
indinavir nanocrystals delivery system for antiretroviral treatment
[154] Light microscopic examination proved that indinavir nanocrys-
tals were successfully loaded into BMMs after culture in the presence
of indinavir nanosuspensions for 12 h Following iv administration
into naive mice the indinavir nanocrystal loaded BMMs acted as ldquoTro-
jan horsesrdquo for transport of drug into tissues which were known to be
targets for HIV due to the parallel BMM migration and viral tissue tro-pism Administration of indinavir nanocrystal-BMMs sustained indina-
vir in tissue and sera for up to 10 days in comparison with 6 h for the
non-wrapped nanosuspensions Amphotericin B nanocrystal-loaded
RBCs systems were developed by Staedtke et al in order to improvean-
tifungal treatment [155] Amphotericin B nanocrystals encapsulation in
RBCs wasachieved by using hypotonichemolysis methodleading to in-
tracellularamphotericin B amounts of 381plusmn047 pg RBCminus1andanen-
trapment ef 1047297cacy of 15ndash18 Upon phagocytosis of amphotericin B
nanocrystal-RBCs leukocytes show a slow amphotericin B release
over 10 days and no alteration in cell viability
3 Conclusions
The researchon colloidal drug delivery systems may be the hottest1047297eld in pharmaceutics in the last several decades Due to the unique
advantage and pharmaeconomical value drug nanocrystals are paid
increasing attentions as a promising approach Drug nanocrystals
can be applied to all the poorly soluble drugs to overcome the solubil-
ity and bioavailability problems because all the poorly soluble drugs
can be comminuted into drug nanocrystals Researches on drug nano-
crystals within recent years fully exhibit their excellent in vivo perfor-
mances in different administration routes Among these the most
exciting information is that properties of drug nanocrystals can be
conveniently altered to meet various treatment demands of different
diseases With the number of insoluble drug compounds in develop-
ment increasing it is anticipated that nanocrystals technology will at-
tract increasing attentions as a viable formulation option However
though drug nanocrystals demonstrate superiority over the carrier
colloid drug delivery systems such as easier production safer compo-
sition and higher drug loading correspondingly they also confront
some problems For example how to obtain a more controllable
drug dissolution rate in order to meet the treatment requirements
of different diseases or reduce the drug release in the progress of de-
livering the drugs into target sites How can we get a more 1047297rm con-
junction between ligand-linked stabilizers and nanocrystal surfaces
without the loss of their properties We believe that many studies
will focus on handling these problems in the future
Acknowledgment
This work was partially supported by the Scienti1047297c Foundation of
the First Af 1047297liated Hospital of General Hospital of PLA the project
number is QN201105
References
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[3] CM Keck RH Muumlller Drug nanocrystals of poorly soluble drugs produced by
high pressure homogenisation Eur J Pharm Biopharm 62 (2006) 3ndash
16[4] BE Rabinow Nanosuspensions in drug delivery Nat Rev Drug Discov 3 (2004)785ndash796
[5] L Gao D Zhang M Chen Drug nanocrystals for the formulation of poorly solu-ble drugs and its application as a potential drug delivery system J NanopartRes 10 (2008) 845ndash862
[6] GG Liversidge KC Cundy Particle size reduction for improvement of oral bio-availability of hydrophobic drugs I Absolute oral bioavailability of nanocrystal-line danazol in beagle dogs Int J Pharm 125 (1995) 91ndash97
[7] K Peters S Leitzke J Diederichs K Borner H Hahn RH Muumlller S Ehlers Prep-aration of a clofazimine nanosuspension for intravenous use and evaluation of its therapeutic ef 1047297cacy in murine Mycobacterium avium infection J AntimicrobChemother 45 (2000) 77ndash83
[8] P Rosario B Claudio F Piera M Adriana P Antonina P Giovanni EudragitRS100 nanosuspensions for the ophthalmic controlled delivery of ibuprofenEur J Pharm Sci 16 (2002) 53ndash61
[9] C Jacobs RH Muumlller Production and characterization of a budesonide nanosus-pension for pulmonary administration Pharm Res 19 (2002) 189ndash194
[10] RH Muumlller C Jacobs O Kayser Nanosuspensions as particulate drug formula-
tions in therapy rationale for development and what we can expect for the fu-ture Adv Drug Deliv Rev 47 (2001) 3ndash19
[11] B Van Eerdenbrugh G Van den Mooter P Augustijns Topndashdown production of drug nanocrystals nanosuspension stabilization miniaturization and transfor-mation into solid products Int J Pharm 364 (2008) 64ndash75
[12] E Merisko-Liversidge GG Liversidge ER Cooper Nanosizing a formulationapproach for poorly-water-soluble compounds Eur J Pharm Sci 18 (2003)113ndash120
[13] J Hu KP Johnston RO Williams Nanoparticle engineering processes for en-hancing the dissolution rates of poorly water soluble drugs Drug Dev IndPharm 30 (2004) 233ndash245
[14] JAH Junghanns RH Muumlller Nanocrystal technology drug delivery and clinicalapplications Int J Nanomedicine 3 (2008) 295ndash310
[15] GA Brazeau HL Fung Mechanisms of creatine kinase release from isolated ratskeletal muscles damaged by propylene glycol and ethanol J Pharm Sci 79(1990) 393ndash397
[16] K Korttila A Sothman P Andersson Polyethylene glycol as a solvent for diaze-pam bioavailability and clinical effects after intramuscular administrationcomparison of oral intramuscular and rectal administration and precipitationfrom intravenous solutions Acta Pharmacol Toxicol (Copenh) 39 (1976)104ndash117
[17] R Budden UG Kuhl J Bahlsen Experiments on toxic sedative and muscle re-laxant potency of various drug solvents in mice Pharmacol Ther 5 (1979)467ndash474
[18] F Liu JY Park Y Zhang C Conwell Y Liu SR Bathula L Huang Targeted can-cer therapy with novel high drug-loading nanocrystals J Pharm Sci 99 (2010)3542ndash3551
[19] B Rabinow J Kipp P Papadopoulos J Wong J Glosson J Gass CS Sun TWielgos R White C Cook K Barker K Wood Itraconazole IV nanosuspensionenhances ef 1047297cacy through altered pharmacokinetics in the rat Int J Pharm 339(2007) 251ndash260
[20] F Kesisoglou S Panmai Y Wu Nanosizingmdashoral formulation development andbiopharmaceutical evaluation Adv Drug Deliv Rev 59 (2007) 631ndash644
[22] GG Liversidge P Conzentino Drug particle size reduction for decreasing gastricirritancy and enhancing absorption of naproxen in rats Int J Pharm 125 (1995)
309ndash
313
427L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[23] E Merisko-Liversidge GG Liversidge Nanosizing for oral and parenteral drugdelivery a perspective on formulating poorly-water soluble compounds usingwet media milling technology Adv Drug Deliv Rev 30 (2011) 427ndash440
[24] BHL Boumlhm RH Muumlller Lab-scale production unit design for nanosuspensions of sparingly soluble cytotoxic drugs Pharm Sci Technol Today 2 (1999) 336ndash339
[25] RH Drew E Dodds Ashley DK Benjamin Jr R Duane Davis SM Palmer JRPerfect Comparative safety of amphotericin B lipid complex and amphotericinB deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipi-ents Transplantation 77 (2004) 232ndash237
[26] J Dubois T Bartter J Gryn MR Pratter The physiologic effects of inhaledamphotericin B Chest 108 (1995) 750ndash753
[27] SM Palmer RH Drew JD Whitehouse VF Tapson RD Davis RR McConnellSS Kanj JR Perfect Safety of aerosolized amphotericin B lipid complex in lungtransplant recipients Transplantation 72 (2001) 545ndash548
[28] RO Williams III J Liu Formulation of a protein with propellant HFA 134a foraerosol delivery Eur J Pharm Sci 7 (1999) 137ndash144
[29] IC Ashurst CV Ambrose DJ Russell Pharmaceutical evaluation of a new spac-er device for delivery of metered-dose inhalers to infants and young children JAerosol Sci 23 (1992) 499ndash502
[30] GC Na HJ Stevens B Yuan N Rajagopalan Physical stability of ethyl diatrizoatenanocrystalline suspension in steam sterilization Pharm Res 16 (1999) 569ndash574
[31] H Lou X Zhang L Gao F Feng J Wang X Wei Z Yu D Zhang Q Zhang Invitro and in vivo antitumor activity of oridonin nanosuspension Int J Pharm379 (2009) 181ndash186
[32] L Gao D Zhang M Chen C Duan W Dai L Jia W Zhao Studies on pharmaco-kinetics and tissue distribution of oridonin nanosuspensions Int J Pharm 355(2008) 321ndash327
[33] SM Moghimi AC Hunter JC Murray Long circulating and target-speci1047297cnanoparticles theory to practice Pharmacol Rev 53 (2001) 283ndash381
[34] S Ganta JW Paxton BC Baguley S Garg Formulation and pharmacokinetic
evaluation of an asulacrine nanocrystalline suspension for intravenous deliveryInt J Pharm 367 (2009) 179ndash186
[35] K Sigfridsson S Forsseacuten P Hollaumlnder U Skantze J de Verdier A formulationcomparison using a solution and different nanosuspensions of a poorly solublecompound Eur J Pharm Biopharm 67 (2007) 540ndash547
[36] K Sigfridsson AJ Lundqvist M Strimfors Particle size reduction for improve-ment of oral absorption absorption of the poorly soluble drug UG558 in rats dur-ing early development Drug Dev Ind Pharm 35 (2009) 1479ndash1486
[37] S Kim J Lee Folate-targeted drug-delivery systems prepared by nano-comminution Drug Dev Ind Pharm 37 (2011) 131ndash138
[38] R Xiong W Lu J Li P Wang R Xu T Chen Preparation and characterization of intravenously injectable nimodipine nanosuspension Int J Pharm 350 (2008)338ndash343
[39] Y Gao Z Li M Sun C Guo A Yu Y Xi J Cui H Lou G Zhai Preparation andcharacterization of intravenously injectable curcumin nanosuspension DrugDeliv 18 (2011) 131ndash142
[40] RH Muumlller K Peters Nanosuspensions for the formulation of poorly solubledrugs I Preparation by a size-reduction technique Int J Pharm 160 (1998)229ndash237
[41] SB Zirar A Astier M Muchow S Gibaud Comparison of nanosuspensions andhydroxypropyl-b-cyclodextrin complex of melarsoprol pharmacokinetics andtissue distribution in mice Eur J Pharm Biopharm 70 (2008) 649 ndash656
[42] M Salzberg M Pless C Rochlitz K Ambrus P Scigalla R Herrmann A phase Istudy with oral SU5416 in patients with advanced solid tumors a drug inducingits clearance Invest New Drugs 24 (2006) 299ndash304
[43] WK Kraft B Steiger D Beussink JN Quiring N Fitzgerald HE Greenberg SAWaldman The pharmacokinetics of nebulized nanocrystal budesonide suspen-sion in healthy volunteers J Clin Pharmacol 44 (2004) 67ndash72
[44] JM Vaughn NP Wiederhold JT McConville JJ Coalson RL Talbert DSBurgess KP Johnston RO Williams III JI Peters Murine airway histologyand intracellular uptake of inhaled amorphous itraconazole Int J Pharm 338(2007) 219ndash224
[45] JM Vaughn JT McConville D Burgess JI Peters KP Johnston RL Talbert ROWilliams III Single dose and multiple dose studies of itraconazole nanoparticlesEur J Pharm Biopharm 63 (2006) 95ndash102
[46] BJ Hoeben DS Burgess JT McConville LK Najvar RL Talbert JI Peters NPWiederhold BL Frei JR Graybill R Bocanegra KA Overhoff P Sinswat KP
Johnston RO Williams III In vivo ef 1047297cacy of aerosolized nanostructured itraco-nazole formulations for prevention of invasive pulmonary aspergillosis Antimi-crob Agents Chemother 50 (2006) 1552ndash1554
[47] CA Alvarez NP Wiederhold JT McConville JI Peters LK Najvar JR Graybill JJ Coalson RL Talbert DS Burgess R Bocanegra KP Johnston RO WilliamsIII Aerosolized nanostructured itraconazole as prophylaxis against invasive pul-monary aspergillosis J Infect 55 (2007) 68ndash74
[48] SB Shrewsbury AP Bosco PS Uster Pharmacokinetics of a novel submicronbudesonide dispersion for nebulized delivery in asthma Int J Pharm 365(2009) 12ndash17
[49] RH Muumlller KH Wallis Surface modi1047297cation of iv injectable biodegradablenanoparticles with poloxamer polymers and poloxamine 908 Int J Pharm 89(1993) 25ndash31
[50] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy and diagno-sis Adv Drug Deliv Rev 54 (2002) 631ndash651
[51] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (2000) 73ndash80
[52] M Wang M Thanou Targeting nanoparticles to cancer Pharmacol Res 62(2010) 90ndash99
[53] L Gao G Liu X Wang F Liu Y Xu J Ma Preparation of a chemically stablequercetin formulation using nanosuspension technology Int J Pharm 404(2011) 231ndash237
[54] M Sarkari J Brown X Chen S Swinnea RO Williams III KP Johnston En-hanced drug dissolution using evaporative precipitation into aqueous solutionInt J Pharm 243 (2002) 17ndash31
[55] X Li L Gu Y Xu Y Wang Preparation of feno1047297brate nanosuspension and studyof its pharmacokinetic behavior in rats Drug Dev Ind Pharm 35 (2009)827ndash833
[56] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Pharmacokinetic evaluation of oral feno1047297brate nanosus-
pensions and SLN in comparison to conventional suspensions of micronizeddrug Adv Drug Deliv Rev 59 (2007) 419ndash426[57] GJ Vergote C Vervaet I Van Driessche S Hoste S De Smedt J Demeester RA
Jain S Ruddy JP Remon In vivo evaluation of matrix pellets containing nano-crystalline ketoprofen Int J Pharm 240 (2002) 79ndash84
[58] S Ghosh P Chiang JL Wahlstrom H Fujiwara JG Selbo SL Roberds Oral de-livery of 13-dicyclohexylurea nanosuspension enhances exposure and lowersblood pressure in hypertensive rats Basic Clin Pharmacol Toxicol 102 (2008)453ndash458
[59] P Langguth A Hanafy D Frenzel P Grenier A Nhamias T Ohlig G VergnaultH Spahn-Langguth Nanosuspension formulations for low-soluble drugs phar-macokinetic evaluation using spironolactone as model compound Drug DevInd Pharm 31 (2005) 319ndash329
[60] MG Fakesa Blisse J Vakkalagaddab Feng Qiana Sridhar Desikana Rajesh BGandhi C Lai A Hsieha MK Franchini H Toaled J Brown Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amor-phous formulation approaches Int J Pharm 370 (2009) 167ndash174
[61] K Sigfridsson A Nordmark S Theilig A Lindah A formulation comparison be-tween micro- and nanosuspensions the importance of particle size for absorp-
tion of a model compound following repeated oral administration to rats duringearly development Drug Dev Ind Pharm 37 (2011) 185ndash192
[62] J Jinno N Kamada M Miyake K Yamada T Mukai M Odomi H Toguchi GGLiversidge K Higaki T Kimura Effect of particle size reduction on dissolutionand oral absorption of a poorly water-soluble drug cilostazol in beagle dogs JControl Release 111 (2006) 56ndash64
[63] Y Wu A Loper E Landis L Hettrick L Novak K Lynn C Chen K Thompson RHiggins U Batra S Shelukar G Kwei D Storey The role of biopharmaceutics inthe development of a clinical nanoparticle formulation of MK-0869 a beagledog model predicts improved bioavailability and diminished food effect on ab-sorption in human Int J Pharm 285 (2004) 135ndash146
[64] RH Muumlller S Runge V Ravelli W Mehnert AF Thuumlnemann EB Souto Oralbioavailability of cyclosporine solid lipid nanoparticles (SLNreg) versus drugnanocrystals Int J Pharm 317 (2006) 82ndash89
[65] G Ponchel MJ Montisci A Dembri C Durrer D Duchecircne Mucoadhesion of colloidal particulate systems in the gastro-intestinal tract Eur J Pharm Bio-pharm 44 (1997) 25ndash31
[66] D Duchecircne G Ponchel Bioadhesion of solid oral dosage forms why and howEur J Pharm Biopharm 44 (1997) 15ndash23
[67] D Dodou P Breedveld PA Wieringa Mucoadhesives in the gastrointestinaltract revisiting the literature for novel applications Eur J Pharm Biopharm60 (2005) 1ndash16
[68] JD Smart The basics and underlying mechanisms of mucoadhesion Adv DrugDeliv Rev 57 (2005) 1556ndash1568
[69] O Kayser A newapproach fortargetingto Cryptosporidium parvum using mucoadhe-sive nanosuspensions research and applications Int J Pharm 214 (2001) 83ndash85
[70] A des Rieux V Fievez M Garinot YJ Schneider V Preacuteat Nanoparticles as po-tential oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[71] A Lamprecht P Koenig N Ubrich P Maincent D Neumann Low molecularweight heparin nanoparticles mucoadhesion and behaviour in Caco-2 cellsNanotechnology 17 (2006) 3673ndash3680
[72] F Delie Evaluation of nano- and microparticle uptake by the gastrointestinaltract Adv Drug Deliv Rev 34 (1998) 221ndash233
[73] CN Grama DD Ankola MNV Ravi Kumar Poly(lactide-co-glycolide) nano-particles for peroral delivery of bioactives Curr Opin Colloid Interface Sci 16(2011) 238ndash245
[74] MP Desai V Labhasetwar GL Amidon RJ Levy Gastrointestinal Uptake of biodegradable microparticles effect of particle size Pharm Res 13 (1996)1838ndash1845
[75] A des Rieux V Fievez M Garinot YJ Scheider V Preat Nanoparticles as poten-tial oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[76] JM Dintaman JA Silverman Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) Pharm Res 16 (1999)1550ndash1556
[77] J Goole DJ Lindley W Roth SM Carl K Amighi JM Kauffmann GT KnippThe effects of excipients on transporter mediated absorption Int J Pharm 393(2010) 17ndash31
[78] J Huang L Si L Jiang Z Fan J Qiu G Li Effect of pluronic F68 block copolymeron P-glycoprotein transport and CYP3A4 metabolism Int J Pharm 356 (2008)351ndash353
[79] MF Wempe C Wright JL Little JW Lightner SE Large GB Ca1047298isch CMBuchanan PJ Rice VJ Wacher KM Ruble KJ Edgar Inhibiting ef 1047298ux withnovel non-ionic surfactants rational design based on vitamin E TPGS Int JPharm 370 (2009) 93ndash102
428 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[81] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Absence of a food effect with a 145 mg nanoparticle feno-1047297brate tablet formulation Int J Clin Pharmacol Ther 44 (2006) 64ndash70
[82] MV Chaubal C Popescu Conversion of nanosuspensions into dry powders byspray drying a case study Pharm Res 25 (2008) 2302ndash2308
[83] F Lai E Pini G Angioni ML Manca J Perricci C Sinico AM Fadda Nanocrys-tals as tool to improve piroxicam dissolution rate in novel orally disintegratingtablets Eur J Pharm Biopharm 79 (2011) 552ndash558
[84] D Mou H Chen J Wan H Xu X Yang Potent dried drug nanosuspensions for
oral bioavailability enhancement of poorly soluble drugs with pH-dependentsolubility Int J Pharm 413 (2011) 237ndash244[85] A Ain-Ai PK Gupta Effect of arginine hydrochloride and hydroxypropyl cellu-
lose as stabilizers on the physical stability of high drug loading nanosuspensionsof a poorly soluble compound Int J Pharm 351 (2008) 282 ndash288
[86] Z Guo T Pereira O Choi Y Wang HT Hahn Surface functionalized aluminananoparticle 1047297lled polymeric nanocomposites with enhanced mechanical prop-erties J Mater Chem 16 (2006) 2800ndash2808
[87] DR Kalaria G Sharma V Beniwal MN Ravi Kumar Design of biodegradablenanoparticles for oral delivery of doxorubicin in vivo pharmacokinetics and tox-icity studies in rats Pharm Res 26 (2009) 492ndash501
[88] JE Kipp The role of solid nanoparticle technology in parenteral delivery of poorly water soluble drugs Int J Pharm 284 (2004) 109ndash122
[89] HM Shubar S Lachenmaier MM Heimesaat U Lohman R Mauludin RHMuumlller R Fitzner K Borner O Liesenfeld SDS-coated atovaquone nanosuspen-sions show improved therapeutic ef 1047297cacy against experimental acquired andreactivated toxoplasmosis by improving passage of gastrointestinal and bloodndash
brain barriers J Drug Target 19 (2011) 114ndash124[90] L Peltonen J Hirvonen Pharmaceutical nanocrystals by nanomilling critical
process parameters particle fracturing and stabilization method J Pharm Phar-macol 62 (2010) 1569ndash1579
[91] F Lai C Sinico G Ennas F Marongiu G Marongiu AM Fadda Diclofenac nano-suspensions in1047298uence of preparation procedure and crystal form on drug disso-lution behavior Int J Pharm 373 (2009) 124ndash132
[92] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (Suppl 2) (2000) S73ndashS80
[93] RH Muller CM Keck Challenges and solutions for the delivery of biotech drugsmdasha review of drug nanocrystal technology and lipid nanoparticles J Biotechnol113 (2004) 151ndash170
[94] JL Wahlstrom P Chiang S Ghosh CJ Warren SP Wene LA Albin ME SmithSL Roberds Pharmacokinetic evaluation of a 13-dicyclohexylurea nanosuspen-sion formulation to support early ef 1047297cacy assessment Nanoscale Res Lett 2(2007) 291ndash296
[95] Y GaoZ LiM SunH Li CGuoJ CuiA LiF CaoY XiH Lou GZhai Preparationcharacterization pharmacokinetics and tissue distribution of curcumin nanosus-pension with TPGS as stabilizer Drug Dev Ind Pharm 36 (2010) 1225ndash1234
[96] M Clement W Pugh I Parikh Tissue distribution and plasma clearance of a novelmicrocrystalline-coated 1047298urbiprofen formulation Pharmacologist 34 (1992)204ndash211
[97] RC Nagarwal S Kant PN Singh P Maiti JK Pandit Polymeric nanoparticulate sys-tem a potential approach for ocular drug delivery J Control Release 136 (2009)2ndash13
[98] H Gupta M Aqil RK Khar A Ali A Bhatnagar G Mittal Spar1047298oxacin loadedPLGA nanoparticles for sustained ocular drug delivery Nanomedicine 6 (2010)324ndash333
[99] HS Ali P York AM Ali N Blagden Hydrocortisone nanosuspensions for oph-thalmic delivery a comparative study between micro1047298uidic nanoprecipitationand media milling J Control Release 149 (2011) 175ndash181
[100] SK Sahoo F Dilnawaz S Krishnakumar Nanotechnology in ocular drug deliv-ery Drug Discov Today 13 (2008) 144ndash151
[101] O Kayser A Lemke N Hernaacutendez-Trejo The impact of nanobiotechnology on thedevelopment of newdrug deliverysystems Curr Pharm Biotechnol6 (2005) 3ndash5
[102] R Pignatello C Bucolo G Spedalieri A Maltese G Puglisi Flurbiprofen-loadedacrylate polymer nanosuspensions for ophthalmic application Biomaterials 23(2002) 3247ndash3255
[103] R Ravichandran Nanoparticles in drug delivery potential green nanobiomedi-
cine applications Int J Green Nanotechnol Biomed 1 (2009) B108ndash
B130[104] AM Cerdeira M Mazzotti B Gander Miconazole nanosuspensions in1047298uence
of formulation variables on particle size reduction and physical stability Int JPharm 396 (2010) 210ndash218
[105] MA Kassem AA Abdel Rahman MM Ghorab MB Ahmed RM Khalil Nano-suspension as an ophthalmic delivery system for certain glucocorticoid drugsInt J Pharm 340 (2007) 126ndash133
[106] P Chiang JW Alsup Y Lai Y Hu BR Heyde D Tung Evaluation of aerosol de-livery of nanosuspension for pre-clinical pulmonary drug delivery NanoscaleRes Lett 4 (2009) 254ndash261
[107] W Yang JI Peters RO Williams III Inhaled nanoparticlesmdasha current reviewInt J Pharm 356 (2008) 239ndash247
[108] J Zhang L Wu H Chan W Watanabe Formation characterization and fate of inhaled drug nanoparticles Adv Drug Deliv Rev 63 (2011) 441ndash455
[109] HM Mansour YS Rhee X Wu Nanomedicine in pulmonary delivery Int JNanomedicine 4 (2009) 299ndash319
[110] NR Labiris MB Dolovich Pulmonary drug delivery Part I physiological factorsaffecting therapeutic effectiveness of aerosolized medications Br J Clin Phar-macol 56 (2003) 588ndash599
[111] JS Patton PR Byron Inhaling medicines delivering drugs to the body throughthe lungs Nat Rev Drug Discov 6 (2007) 67ndash74
[112] DA Edwards C Dunbar Bioengineering of therapeutic aerosols Annu RevBiomed Eng 4 (2002) 93ndash107
[113] W Yang JTam DA Miller J Zhou JT McConville KP Johnstonb RO WilliamsIII High bioavailability from nebulized itraconazole nanoparticle dispersionswith biocompatible stabilizers Int J Pharm 361 (2008) 177ndash188
[114] S Gill R Lobenberg T Ku S Azarmi W Roa EJ Prenner Nanoparticles char-acteristics mechanisms of action and toxicity in pulmonary drug deliverymdasha re-view J Biomed Nanotechnol 3 (2007) 107ndash119
[115] SJ Sze1047298er Pharmacodynamics and pharmacokinetics of budesonide a new
S183[116] W Yang KP Johnston RO Williams III Comparison of bioavailability of amor-phous versus crystalline itraconazole nanoparticles via pulmonary administra-tion in rats Eur J Pharm Biopharm 75 (2010) 33 ndash41
[117] R Ali GK Jain Z Iqbal S Talegaonkar P Pandit S Sule G Malhotra RK KharA Bhatnagar FJ Ahmad Development and clinical trial of nano-atropine sulfatedry powder inhaler as a novel organophosphorous poisoning antidote Nanome-dicine 5 (2009) 55ndash63
[118] D Andes Minireview in vivo pharmacodynamics of antifungal drugs in treat-ment of candidiasis Antimicrob Agents Chemother 47 (2003) 1179ndash1186
[119] D Andes K Marchillo R Conklin G Krishna F Ezzet A Cacciapuoti DLoebenberg Pharmacodynamics of a new triazole posaconazole in a murinemodel of disseminated candidiasis Antimicrob Agents Chemother 48 (2004)137ndash142
[120] O Kayser C Olbrich V Yardley AF Kiderlen SL Croft Formulation of ampho-tericin B as nanosuspension for oral administration Int J Pharm 254 (2003)73ndash75
[121] L Zhang S Hou S Mao D Wei X Song Y Lu Uptake of folate-conjugated albu-min nanoparticles to the SKOV3 cells Int J Pharm 287 (2004) 155ndash162
[122] J Sudimack RJ Lee Targeted drug delivery via folate receptor Adv Drug DelivRev 41 (2000) 147ndash162
[123] P Vader LJ van der Aa G Storm RM Schiffelers JF Engbersen Polymeric car-rier systems for siRNA delivery Curr Top Med Chem 12 (2012) 108 ndash119
[124] O Veiseh FM Kievit RG Ellenbogen M Zhang Cancer cell invasion treatmentand monitoring opportunities in nanomedicine Adv Drug Deliv Rev 63 (2011)582ndash596
[125] J Kreuter VE Petrov DA Kharkevich RN Alyautdin In1047298uence of the type of surfactant on the analgesic effects induced by the peptide dalargin after its de-livery across the bloodndashbrain barrier using surfactant-coated nanoparticles JControl Release 49 (1997) 81ndash87
[126] J Ye Q Wang X Zhou N Zhang Injectable actarit-loaded solid lipid nanoparti-cles as passive targeting therapeutic agents for rheumatoid arthritis Int JPharm 352 (2008) 273ndash279
[127] SM Moghimi AC Hunter JC Murray Nanomedicine current status and futureprospects FASEB J 19 (2005) 311ndash330
[128] K Park To PEGylate or not PEGylate that is not the question J Control Release142 (2010) 147ndash148
[129] M Socha P Bartecki C Passitani A Sapin C Damge T Lecompte J BarreE Ghazouani P Maincent Stealth nanoparticles coated with heparin aspeptide or peptide carriers J Drug Target 17 (2009) 575ndash585
[130] D Shenoy S Little R Langer M Amiji Poly(ethylene oxide)-modi1047297ed poly(-beta-amino ester) nanoparticles as a pH-sensitive system for tumor targeted de-livery of hydrophobic drugs part 2 In vivo distribution and tumor localizationstudies Pharm Res 22 (2005) 2107ndash2114
[131] R Shegokara KK Singha Surface modi1047297ed nevirapinenanosuspensions for viralreservoir targeting in vitro and in vivo evaluation Int J Pharm 421 (2011)341ndash352
[132] Y Matsumura H Maeda A new concept for macromolecular therapeutics incancer chemotherapy mechanism of tumoritropic accumulation of proteinsand the antitumor agent SMANCS Cancer Res 46 (1986) 6387ndash6392
[133] H Zhang CP Hollis Q Zhang T Li Preparation and antitumor study of camp-tothecin nanocrystals Int J Pharm 415 (2011) 293ndash300
[134] H Lou L Gao X Wei Z Zhang D Zheng D Zhang X Zhang Y Li Q Zhang Ori-donin nanosuspension enhances anti-tumor ef 1047297cacy in SMMC-7721 cells andH22 tumor bearing mice Colloids Surf B Biointerfaces 87 (2011) 319ndash325
[135] TM Goppert RH Muumlller Adsorption kinetics of plasma proteins on solid lipid
nanoparticles for drug targeting Int J Pharm 302 (2005) 172ndash
186[136] X Pu J Sun M Li Z He Formulation of nanosuspensions as a new approach for
the delivery of poorly soluble drugs Curr Nanosci 5 (2009) 417ndash427[137] R Gaudana J Jwala SHS Boddu AK Mitra Recent perspectives in ocular drug
delivery Pharm Res 26 (2009) 1197ndash1216[138] T Yasukawa H Kimura Y Tabata H Miyamoto Y Honda Y Ikada Y Ogura
Targeted delivery of anti-angiogenic agent TNP-470 using water-soluble poly-mer in the treatment of choroidal neovascularization Invest Ophthalmol VisSci 40 (1999) 2690ndash2696
[139] A Lemke AF Kiderlen B Petri O Kayser Delivery of amphotericin B nanosus-pensions to the brain and determination of activity against Balamuthia mandril-laris amebas Nanomedicine 6 (2010) 597ndash603
[140] HL Wong XY Wu R Bendayan Nanotechnological advances forthe delivery of CNS therapeutics Adv Drug Deliv Rev (2011) doi101016jaddr201110007
[141] J Kreuter S Gelperina Use of nanoparticles for cerebral cancer Tumori 94(2008) 271ndash277
[142] J Kreuter RN Alyautdin DA Kharkevich AA Ivanov Passage of peptidesthrough the bloodndashbrain barrier with colloidal polymer particles (nanoparti-cles) Brain Res 674 (1995) 171ndash174
429L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[143] J Kreuter Nanoparticulate systems for brain delivery of drugs Adv Drug DelivRev 47 (2001) 65ndash81
[144] TM Goumlppert RH Muumlller Polysorbate-stabilized solid lipid nanoparticles as col-loidal carriers for intravenous targeting of drugs to the brain comparison of plasma protein adsorption patterns J Drug Target 13 (2005) 179ndash187
[145] S Mansouri Y Cuie F Winnik Q Shi P Lavigne M Benderdour E Beaumont JC Fernandes Characterization of folate-chitosan-DNA nanoparticles for genetherapy Biomaterials 27 (2006) 2060ndash2065
[146] AR Hilgenbrink PS Low Folate receptor-mediated drug targeting from thera-peutics to diagnostics J Pharm Sci 94 (2005) 2135ndash2146
[147] F Pierigegrave S Sera1047297ni L Rossi M Magnani Cell-based drug delivery Adv Drug
Deliv Rev 60 (2008) 286ndash
295[148] F Chellat Y Merhi A Moreau L Yahia Therapeutic potential of nanoparticulatesystems for macrophage targeting Biomaterials 26 (2005) 7260ndash7275
[149] SS Hall S Mitragotri PS Daugherty Identi1047297cation of peptide ligands facilitatingnanoparticle at attachment to erythrocytes Biotechnol Prog 23 (2007) 749ndash754
[150] S Gorantla H Dou M Boska CJ Destache J Nelson L Poluektova BERabinow HE Gendelman RL Mosley Quantitative magnetic resonance and
SPECT imaging for macrophage tissue migration and nanoformulated drug de-livery J Leukoc Biol 80 (2006) 1165ndash1174
[151] LA Lotero G Olmos JC Diez Delivery to macrophages and toxic action of etopo-sidecarried in mouse redblood cells Biochim Biophys Acta 1620 (2003) 160ndash166
[152] L Rossi S Sera1047297ni F Pierigeacute A Antonelli A Cerasi A Fraternale L ChiarantiniM Magnani Erythrocyte-based drug delivery Expert Opin Drug Deliv 2 (2005)311ndash322
[153] S Sera1047297ni L Rossi A Antonelli A Fraternale A Cerasi R Crinelli L ChiarantiniGF Schiavano M Magnani Drug delivery through phagocytosis of red bloodcells Transfus Med Hemother 31 (2004) 92ndash101
[154] H Dou CJ Destache JR Morehead R Lee Mosley MD Boska J Kingsley S
Gorantla L Poluektova JA Nelson M Chaubal J Werling J Kipp BERabinow HE Gendelman Development of a macrophage-based nanoparticleplatform for antiretroviral drug delivery Blood 108 (2006) 2827ndash2835
[155] V Staedtke M Braumller A Muumlller R Georgieva S Bauer N Sternberg A Voigt ALemke C Keck J Moumlschwitzer H Baumlumler In vitro inhibition of fungal activityby macrophage-mediated sequestration and release of encapsulated amphoter-icin B nanosuspension in red blood cells Small 6 (2010) 96ndash103
430 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[23] E Merisko-Liversidge GG Liversidge Nanosizing for oral and parenteral drugdelivery a perspective on formulating poorly-water soluble compounds usingwet media milling technology Adv Drug Deliv Rev 30 (2011) 427ndash440
[24] BHL Boumlhm RH Muumlller Lab-scale production unit design for nanosuspensions of sparingly soluble cytotoxic drugs Pharm Sci Technol Today 2 (1999) 336ndash339
[25] RH Drew E Dodds Ashley DK Benjamin Jr R Duane Davis SM Palmer JRPerfect Comparative safety of amphotericin B lipid complex and amphotericinB deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipi-ents Transplantation 77 (2004) 232ndash237
[26] J Dubois T Bartter J Gryn MR Pratter The physiologic effects of inhaledamphotericin B Chest 108 (1995) 750ndash753
[27] SM Palmer RH Drew JD Whitehouse VF Tapson RD Davis RR McConnellSS Kanj JR Perfect Safety of aerosolized amphotericin B lipid complex in lungtransplant recipients Transplantation 72 (2001) 545ndash548
[28] RO Williams III J Liu Formulation of a protein with propellant HFA 134a foraerosol delivery Eur J Pharm Sci 7 (1999) 137ndash144
[29] IC Ashurst CV Ambrose DJ Russell Pharmaceutical evaluation of a new spac-er device for delivery of metered-dose inhalers to infants and young children JAerosol Sci 23 (1992) 499ndash502
[30] GC Na HJ Stevens B Yuan N Rajagopalan Physical stability of ethyl diatrizoatenanocrystalline suspension in steam sterilization Pharm Res 16 (1999) 569ndash574
[31] H Lou X Zhang L Gao F Feng J Wang X Wei Z Yu D Zhang Q Zhang Invitro and in vivo antitumor activity of oridonin nanosuspension Int J Pharm379 (2009) 181ndash186
[32] L Gao D Zhang M Chen C Duan W Dai L Jia W Zhao Studies on pharmaco-kinetics and tissue distribution of oridonin nanosuspensions Int J Pharm 355(2008) 321ndash327
[33] SM Moghimi AC Hunter JC Murray Long circulating and target-speci1047297cnanoparticles theory to practice Pharmacol Rev 53 (2001) 283ndash381
[34] S Ganta JW Paxton BC Baguley S Garg Formulation and pharmacokinetic
evaluation of an asulacrine nanocrystalline suspension for intravenous deliveryInt J Pharm 367 (2009) 179ndash186
[35] K Sigfridsson S Forsseacuten P Hollaumlnder U Skantze J de Verdier A formulationcomparison using a solution and different nanosuspensions of a poorly solublecompound Eur J Pharm Biopharm 67 (2007) 540ndash547
[36] K Sigfridsson AJ Lundqvist M Strimfors Particle size reduction for improve-ment of oral absorption absorption of the poorly soluble drug UG558 in rats dur-ing early development Drug Dev Ind Pharm 35 (2009) 1479ndash1486
[37] S Kim J Lee Folate-targeted drug-delivery systems prepared by nano-comminution Drug Dev Ind Pharm 37 (2011) 131ndash138
[38] R Xiong W Lu J Li P Wang R Xu T Chen Preparation and characterization of intravenously injectable nimodipine nanosuspension Int J Pharm 350 (2008)338ndash343
[39] Y Gao Z Li M Sun C Guo A Yu Y Xi J Cui H Lou G Zhai Preparation andcharacterization of intravenously injectable curcumin nanosuspension DrugDeliv 18 (2011) 131ndash142
[40] RH Muumlller K Peters Nanosuspensions for the formulation of poorly solubledrugs I Preparation by a size-reduction technique Int J Pharm 160 (1998)229ndash237
[41] SB Zirar A Astier M Muchow S Gibaud Comparison of nanosuspensions andhydroxypropyl-b-cyclodextrin complex of melarsoprol pharmacokinetics andtissue distribution in mice Eur J Pharm Biopharm 70 (2008) 649 ndash656
[42] M Salzberg M Pless C Rochlitz K Ambrus P Scigalla R Herrmann A phase Istudy with oral SU5416 in patients with advanced solid tumors a drug inducingits clearance Invest New Drugs 24 (2006) 299ndash304
[43] WK Kraft B Steiger D Beussink JN Quiring N Fitzgerald HE Greenberg SAWaldman The pharmacokinetics of nebulized nanocrystal budesonide suspen-sion in healthy volunteers J Clin Pharmacol 44 (2004) 67ndash72
[44] JM Vaughn NP Wiederhold JT McConville JJ Coalson RL Talbert DSBurgess KP Johnston RO Williams III JI Peters Murine airway histologyand intracellular uptake of inhaled amorphous itraconazole Int J Pharm 338(2007) 219ndash224
[45] JM Vaughn JT McConville D Burgess JI Peters KP Johnston RL Talbert ROWilliams III Single dose and multiple dose studies of itraconazole nanoparticlesEur J Pharm Biopharm 63 (2006) 95ndash102
[46] BJ Hoeben DS Burgess JT McConville LK Najvar RL Talbert JI Peters NPWiederhold BL Frei JR Graybill R Bocanegra KA Overhoff P Sinswat KP
Johnston RO Williams III In vivo ef 1047297cacy of aerosolized nanostructured itraco-nazole formulations for prevention of invasive pulmonary aspergillosis Antimi-crob Agents Chemother 50 (2006) 1552ndash1554
[47] CA Alvarez NP Wiederhold JT McConville JI Peters LK Najvar JR Graybill JJ Coalson RL Talbert DS Burgess R Bocanegra KP Johnston RO WilliamsIII Aerosolized nanostructured itraconazole as prophylaxis against invasive pul-monary aspergillosis J Infect 55 (2007) 68ndash74
[48] SB Shrewsbury AP Bosco PS Uster Pharmacokinetics of a novel submicronbudesonide dispersion for nebulized delivery in asthma Int J Pharm 365(2009) 12ndash17
[49] RH Muumlller KH Wallis Surface modi1047297cation of iv injectable biodegradablenanoparticles with poloxamer polymers and poloxamine 908 Int J Pharm 89(1993) 25ndash31
[50] I Brigger C Dubernet P Couvreur Nanoparticles in cancer therapy and diagno-sis Adv Drug Deliv Rev 54 (2002) 631ndash651
[51] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (2000) 73ndash80
[52] M Wang M Thanou Targeting nanoparticles to cancer Pharmacol Res 62(2010) 90ndash99
[53] L Gao G Liu X Wang F Liu Y Xu J Ma Preparation of a chemically stablequercetin formulation using nanosuspension technology Int J Pharm 404(2011) 231ndash237
[54] M Sarkari J Brown X Chen S Swinnea RO Williams III KP Johnston En-hanced drug dissolution using evaporative precipitation into aqueous solutionInt J Pharm 243 (2002) 17ndash31
[55] X Li L Gu Y Xu Y Wang Preparation of feno1047297brate nanosuspension and studyof its pharmacokinetic behavior in rats Drug Dev Ind Pharm 35 (2009)827ndash833
[56] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Pharmacokinetic evaluation of oral feno1047297brate nanosus-
pensions and SLN in comparison to conventional suspensions of micronizeddrug Adv Drug Deliv Rev 59 (2007) 419ndash426[57] GJ Vergote C Vervaet I Van Driessche S Hoste S De Smedt J Demeester RA
Jain S Ruddy JP Remon In vivo evaluation of matrix pellets containing nano-crystalline ketoprofen Int J Pharm 240 (2002) 79ndash84
[58] S Ghosh P Chiang JL Wahlstrom H Fujiwara JG Selbo SL Roberds Oral de-livery of 13-dicyclohexylurea nanosuspension enhances exposure and lowersblood pressure in hypertensive rats Basic Clin Pharmacol Toxicol 102 (2008)453ndash458
[59] P Langguth A Hanafy D Frenzel P Grenier A Nhamias T Ohlig G VergnaultH Spahn-Langguth Nanosuspension formulations for low-soluble drugs phar-macokinetic evaluation using spironolactone as model compound Drug DevInd Pharm 31 (2005) 319ndash329
[60] MG Fakesa Blisse J Vakkalagaddab Feng Qiana Sridhar Desikana Rajesh BGandhi C Lai A Hsieha MK Franchini H Toaled J Brown Enhancement of oral bioavailability of an HIV-attachment inhibitor by nanosizing and amor-phous formulation approaches Int J Pharm 370 (2009) 167ndash174
[61] K Sigfridsson A Nordmark S Theilig A Lindah A formulation comparison be-tween micro- and nanosuspensions the importance of particle size for absorp-
tion of a model compound following repeated oral administration to rats duringearly development Drug Dev Ind Pharm 37 (2011) 185ndash192
[62] J Jinno N Kamada M Miyake K Yamada T Mukai M Odomi H Toguchi GGLiversidge K Higaki T Kimura Effect of particle size reduction on dissolutionand oral absorption of a poorly water-soluble drug cilostazol in beagle dogs JControl Release 111 (2006) 56ndash64
[63] Y Wu A Loper E Landis L Hettrick L Novak K Lynn C Chen K Thompson RHiggins U Batra S Shelukar G Kwei D Storey The role of biopharmaceutics inthe development of a clinical nanoparticle formulation of MK-0869 a beagledog model predicts improved bioavailability and diminished food effect on ab-sorption in human Int J Pharm 285 (2004) 135ndash146
[64] RH Muumlller S Runge V Ravelli W Mehnert AF Thuumlnemann EB Souto Oralbioavailability of cyclosporine solid lipid nanoparticles (SLNreg) versus drugnanocrystals Int J Pharm 317 (2006) 82ndash89
[65] G Ponchel MJ Montisci A Dembri C Durrer D Duchecircne Mucoadhesion of colloidal particulate systems in the gastro-intestinal tract Eur J Pharm Bio-pharm 44 (1997) 25ndash31
[66] D Duchecircne G Ponchel Bioadhesion of solid oral dosage forms why and howEur J Pharm Biopharm 44 (1997) 15ndash23
[67] D Dodou P Breedveld PA Wieringa Mucoadhesives in the gastrointestinaltract revisiting the literature for novel applications Eur J Pharm Biopharm60 (2005) 1ndash16
[68] JD Smart The basics and underlying mechanisms of mucoadhesion Adv DrugDeliv Rev 57 (2005) 1556ndash1568
[69] O Kayser A newapproach fortargetingto Cryptosporidium parvum using mucoadhe-sive nanosuspensions research and applications Int J Pharm 214 (2001) 83ndash85
[70] A des Rieux V Fievez M Garinot YJ Schneider V Preacuteat Nanoparticles as po-tential oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[71] A Lamprecht P Koenig N Ubrich P Maincent D Neumann Low molecularweight heparin nanoparticles mucoadhesion and behaviour in Caco-2 cellsNanotechnology 17 (2006) 3673ndash3680
[72] F Delie Evaluation of nano- and microparticle uptake by the gastrointestinaltract Adv Drug Deliv Rev 34 (1998) 221ndash233
[73] CN Grama DD Ankola MNV Ravi Kumar Poly(lactide-co-glycolide) nano-particles for peroral delivery of bioactives Curr Opin Colloid Interface Sci 16(2011) 238ndash245
[74] MP Desai V Labhasetwar GL Amidon RJ Levy Gastrointestinal Uptake of biodegradable microparticles effect of particle size Pharm Res 13 (1996)1838ndash1845
[75] A des Rieux V Fievez M Garinot YJ Scheider V Preat Nanoparticles as poten-tial oral delivery systems of proteins and vaccines a mechanistic approach JControl Release 116 (2006) 1ndash27
[76] JM Dintaman JA Silverman Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) Pharm Res 16 (1999)1550ndash1556
[77] J Goole DJ Lindley W Roth SM Carl K Amighi JM Kauffmann GT KnippThe effects of excipients on transporter mediated absorption Int J Pharm 393(2010) 17ndash31
[78] J Huang L Si L Jiang Z Fan J Qiu G Li Effect of pluronic F68 block copolymeron P-glycoprotein transport and CYP3A4 metabolism Int J Pharm 356 (2008)351ndash353
[79] MF Wempe C Wright JL Little JW Lightner SE Large GB Ca1047298isch CMBuchanan PJ Rice VJ Wacher KM Ruble KJ Edgar Inhibiting ef 1047298ux withnovel non-ionic surfactants rational design based on vitamin E TPGS Int JPharm 370 (2009) 93ndash102
428 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[81] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Absence of a food effect with a 145 mg nanoparticle feno-1047297brate tablet formulation Int J Clin Pharmacol Ther 44 (2006) 64ndash70
[82] MV Chaubal C Popescu Conversion of nanosuspensions into dry powders byspray drying a case study Pharm Res 25 (2008) 2302ndash2308
[83] F Lai E Pini G Angioni ML Manca J Perricci C Sinico AM Fadda Nanocrys-tals as tool to improve piroxicam dissolution rate in novel orally disintegratingtablets Eur J Pharm Biopharm 79 (2011) 552ndash558
[84] D Mou H Chen J Wan H Xu X Yang Potent dried drug nanosuspensions for
oral bioavailability enhancement of poorly soluble drugs with pH-dependentsolubility Int J Pharm 413 (2011) 237ndash244[85] A Ain-Ai PK Gupta Effect of arginine hydrochloride and hydroxypropyl cellu-
lose as stabilizers on the physical stability of high drug loading nanosuspensionsof a poorly soluble compound Int J Pharm 351 (2008) 282 ndash288
[86] Z Guo T Pereira O Choi Y Wang HT Hahn Surface functionalized aluminananoparticle 1047297lled polymeric nanocomposites with enhanced mechanical prop-erties J Mater Chem 16 (2006) 2800ndash2808
[87] DR Kalaria G Sharma V Beniwal MN Ravi Kumar Design of biodegradablenanoparticles for oral delivery of doxorubicin in vivo pharmacokinetics and tox-icity studies in rats Pharm Res 26 (2009) 492ndash501
[88] JE Kipp The role of solid nanoparticle technology in parenteral delivery of poorly water soluble drugs Int J Pharm 284 (2004) 109ndash122
[89] HM Shubar S Lachenmaier MM Heimesaat U Lohman R Mauludin RHMuumlller R Fitzner K Borner O Liesenfeld SDS-coated atovaquone nanosuspen-sions show improved therapeutic ef 1047297cacy against experimental acquired andreactivated toxoplasmosis by improving passage of gastrointestinal and bloodndash
brain barriers J Drug Target 19 (2011) 114ndash124[90] L Peltonen J Hirvonen Pharmaceutical nanocrystals by nanomilling critical
process parameters particle fracturing and stabilization method J Pharm Phar-macol 62 (2010) 1569ndash1579
[91] F Lai C Sinico G Ennas F Marongiu G Marongiu AM Fadda Diclofenac nano-suspensions in1047298uence of preparation procedure and crystal form on drug disso-lution behavior Int J Pharm 373 (2009) 124ndash132
[92] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (Suppl 2) (2000) S73ndashS80
[93] RH Muller CM Keck Challenges and solutions for the delivery of biotech drugsmdasha review of drug nanocrystal technology and lipid nanoparticles J Biotechnol113 (2004) 151ndash170
[94] JL Wahlstrom P Chiang S Ghosh CJ Warren SP Wene LA Albin ME SmithSL Roberds Pharmacokinetic evaluation of a 13-dicyclohexylurea nanosuspen-sion formulation to support early ef 1047297cacy assessment Nanoscale Res Lett 2(2007) 291ndash296
[95] Y GaoZ LiM SunH Li CGuoJ CuiA LiF CaoY XiH Lou GZhai Preparationcharacterization pharmacokinetics and tissue distribution of curcumin nanosus-pension with TPGS as stabilizer Drug Dev Ind Pharm 36 (2010) 1225ndash1234
[96] M Clement W Pugh I Parikh Tissue distribution and plasma clearance of a novelmicrocrystalline-coated 1047298urbiprofen formulation Pharmacologist 34 (1992)204ndash211
[97] RC Nagarwal S Kant PN Singh P Maiti JK Pandit Polymeric nanoparticulate sys-tem a potential approach for ocular drug delivery J Control Release 136 (2009)2ndash13
[98] H Gupta M Aqil RK Khar A Ali A Bhatnagar G Mittal Spar1047298oxacin loadedPLGA nanoparticles for sustained ocular drug delivery Nanomedicine 6 (2010)324ndash333
[99] HS Ali P York AM Ali N Blagden Hydrocortisone nanosuspensions for oph-thalmic delivery a comparative study between micro1047298uidic nanoprecipitationand media milling J Control Release 149 (2011) 175ndash181
[100] SK Sahoo F Dilnawaz S Krishnakumar Nanotechnology in ocular drug deliv-ery Drug Discov Today 13 (2008) 144ndash151
[101] O Kayser A Lemke N Hernaacutendez-Trejo The impact of nanobiotechnology on thedevelopment of newdrug deliverysystems Curr Pharm Biotechnol6 (2005) 3ndash5
[102] R Pignatello C Bucolo G Spedalieri A Maltese G Puglisi Flurbiprofen-loadedacrylate polymer nanosuspensions for ophthalmic application Biomaterials 23(2002) 3247ndash3255
[103] R Ravichandran Nanoparticles in drug delivery potential green nanobiomedi-
cine applications Int J Green Nanotechnol Biomed 1 (2009) B108ndash
B130[104] AM Cerdeira M Mazzotti B Gander Miconazole nanosuspensions in1047298uence
of formulation variables on particle size reduction and physical stability Int JPharm 396 (2010) 210ndash218
[105] MA Kassem AA Abdel Rahman MM Ghorab MB Ahmed RM Khalil Nano-suspension as an ophthalmic delivery system for certain glucocorticoid drugsInt J Pharm 340 (2007) 126ndash133
[106] P Chiang JW Alsup Y Lai Y Hu BR Heyde D Tung Evaluation of aerosol de-livery of nanosuspension for pre-clinical pulmonary drug delivery NanoscaleRes Lett 4 (2009) 254ndash261
[107] W Yang JI Peters RO Williams III Inhaled nanoparticlesmdasha current reviewInt J Pharm 356 (2008) 239ndash247
[108] J Zhang L Wu H Chan W Watanabe Formation characterization and fate of inhaled drug nanoparticles Adv Drug Deliv Rev 63 (2011) 441ndash455
[109] HM Mansour YS Rhee X Wu Nanomedicine in pulmonary delivery Int JNanomedicine 4 (2009) 299ndash319
[110] NR Labiris MB Dolovich Pulmonary drug delivery Part I physiological factorsaffecting therapeutic effectiveness of aerosolized medications Br J Clin Phar-macol 56 (2003) 588ndash599
[111] JS Patton PR Byron Inhaling medicines delivering drugs to the body throughthe lungs Nat Rev Drug Discov 6 (2007) 67ndash74
[112] DA Edwards C Dunbar Bioengineering of therapeutic aerosols Annu RevBiomed Eng 4 (2002) 93ndash107
[113] W Yang JTam DA Miller J Zhou JT McConville KP Johnstonb RO WilliamsIII High bioavailability from nebulized itraconazole nanoparticle dispersionswith biocompatible stabilizers Int J Pharm 361 (2008) 177ndash188
[114] S Gill R Lobenberg T Ku S Azarmi W Roa EJ Prenner Nanoparticles char-acteristics mechanisms of action and toxicity in pulmonary drug deliverymdasha re-view J Biomed Nanotechnol 3 (2007) 107ndash119
[115] SJ Sze1047298er Pharmacodynamics and pharmacokinetics of budesonide a new
S183[116] W Yang KP Johnston RO Williams III Comparison of bioavailability of amor-phous versus crystalline itraconazole nanoparticles via pulmonary administra-tion in rats Eur J Pharm Biopharm 75 (2010) 33 ndash41
[117] R Ali GK Jain Z Iqbal S Talegaonkar P Pandit S Sule G Malhotra RK KharA Bhatnagar FJ Ahmad Development and clinical trial of nano-atropine sulfatedry powder inhaler as a novel organophosphorous poisoning antidote Nanome-dicine 5 (2009) 55ndash63
[118] D Andes Minireview in vivo pharmacodynamics of antifungal drugs in treat-ment of candidiasis Antimicrob Agents Chemother 47 (2003) 1179ndash1186
[119] D Andes K Marchillo R Conklin G Krishna F Ezzet A Cacciapuoti DLoebenberg Pharmacodynamics of a new triazole posaconazole in a murinemodel of disseminated candidiasis Antimicrob Agents Chemother 48 (2004)137ndash142
[120] O Kayser C Olbrich V Yardley AF Kiderlen SL Croft Formulation of ampho-tericin B as nanosuspension for oral administration Int J Pharm 254 (2003)73ndash75
[121] L Zhang S Hou S Mao D Wei X Song Y Lu Uptake of folate-conjugated albu-min nanoparticles to the SKOV3 cells Int J Pharm 287 (2004) 155ndash162
[122] J Sudimack RJ Lee Targeted drug delivery via folate receptor Adv Drug DelivRev 41 (2000) 147ndash162
[123] P Vader LJ van der Aa G Storm RM Schiffelers JF Engbersen Polymeric car-rier systems for siRNA delivery Curr Top Med Chem 12 (2012) 108 ndash119
[124] O Veiseh FM Kievit RG Ellenbogen M Zhang Cancer cell invasion treatmentand monitoring opportunities in nanomedicine Adv Drug Deliv Rev 63 (2011)582ndash596
[125] J Kreuter VE Petrov DA Kharkevich RN Alyautdin In1047298uence of the type of surfactant on the analgesic effects induced by the peptide dalargin after its de-livery across the bloodndashbrain barrier using surfactant-coated nanoparticles JControl Release 49 (1997) 81ndash87
[126] J Ye Q Wang X Zhou N Zhang Injectable actarit-loaded solid lipid nanoparti-cles as passive targeting therapeutic agents for rheumatoid arthritis Int JPharm 352 (2008) 273ndash279
[127] SM Moghimi AC Hunter JC Murray Nanomedicine current status and futureprospects FASEB J 19 (2005) 311ndash330
[128] K Park To PEGylate or not PEGylate that is not the question J Control Release142 (2010) 147ndash148
[129] M Socha P Bartecki C Passitani A Sapin C Damge T Lecompte J BarreE Ghazouani P Maincent Stealth nanoparticles coated with heparin aspeptide or peptide carriers J Drug Target 17 (2009) 575ndash585
[130] D Shenoy S Little R Langer M Amiji Poly(ethylene oxide)-modi1047297ed poly(-beta-amino ester) nanoparticles as a pH-sensitive system for tumor targeted de-livery of hydrophobic drugs part 2 In vivo distribution and tumor localizationstudies Pharm Res 22 (2005) 2107ndash2114
[131] R Shegokara KK Singha Surface modi1047297ed nevirapinenanosuspensions for viralreservoir targeting in vitro and in vivo evaluation Int J Pharm 421 (2011)341ndash352
[132] Y Matsumura H Maeda A new concept for macromolecular therapeutics incancer chemotherapy mechanism of tumoritropic accumulation of proteinsand the antitumor agent SMANCS Cancer Res 46 (1986) 6387ndash6392
[133] H Zhang CP Hollis Q Zhang T Li Preparation and antitumor study of camp-tothecin nanocrystals Int J Pharm 415 (2011) 293ndash300
[134] H Lou L Gao X Wei Z Zhang D Zheng D Zhang X Zhang Y Li Q Zhang Ori-donin nanosuspension enhances anti-tumor ef 1047297cacy in SMMC-7721 cells andH22 tumor bearing mice Colloids Surf B Biointerfaces 87 (2011) 319ndash325
[135] TM Goppert RH Muumlller Adsorption kinetics of plasma proteins on solid lipid
nanoparticles for drug targeting Int J Pharm 302 (2005) 172ndash
186[136] X Pu J Sun M Li Z He Formulation of nanosuspensions as a new approach for
the delivery of poorly soluble drugs Curr Nanosci 5 (2009) 417ndash427[137] R Gaudana J Jwala SHS Boddu AK Mitra Recent perspectives in ocular drug
delivery Pharm Res 26 (2009) 1197ndash1216[138] T Yasukawa H Kimura Y Tabata H Miyamoto Y Honda Y Ikada Y Ogura
Targeted delivery of anti-angiogenic agent TNP-470 using water-soluble poly-mer in the treatment of choroidal neovascularization Invest Ophthalmol VisSci 40 (1999) 2690ndash2696
[139] A Lemke AF Kiderlen B Petri O Kayser Delivery of amphotericin B nanosus-pensions to the brain and determination of activity against Balamuthia mandril-laris amebas Nanomedicine 6 (2010) 597ndash603
[140] HL Wong XY Wu R Bendayan Nanotechnological advances forthe delivery of CNS therapeutics Adv Drug Deliv Rev (2011) doi101016jaddr201110007
[141] J Kreuter S Gelperina Use of nanoparticles for cerebral cancer Tumori 94(2008) 271ndash277
[142] J Kreuter RN Alyautdin DA Kharkevich AA Ivanov Passage of peptidesthrough the bloodndashbrain barrier with colloidal polymer particles (nanoparti-cles) Brain Res 674 (1995) 171ndash174
429L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[143] J Kreuter Nanoparticulate systems for brain delivery of drugs Adv Drug DelivRev 47 (2001) 65ndash81
[144] TM Goumlppert RH Muumlller Polysorbate-stabilized solid lipid nanoparticles as col-loidal carriers for intravenous targeting of drugs to the brain comparison of plasma protein adsorption patterns J Drug Target 13 (2005) 179ndash187
[145] S Mansouri Y Cuie F Winnik Q Shi P Lavigne M Benderdour E Beaumont JC Fernandes Characterization of folate-chitosan-DNA nanoparticles for genetherapy Biomaterials 27 (2006) 2060ndash2065
[146] AR Hilgenbrink PS Low Folate receptor-mediated drug targeting from thera-peutics to diagnostics J Pharm Sci 94 (2005) 2135ndash2146
[147] F Pierigegrave S Sera1047297ni L Rossi M Magnani Cell-based drug delivery Adv Drug
Deliv Rev 60 (2008) 286ndash
295[148] F Chellat Y Merhi A Moreau L Yahia Therapeutic potential of nanoparticulatesystems for macrophage targeting Biomaterials 26 (2005) 7260ndash7275
[149] SS Hall S Mitragotri PS Daugherty Identi1047297cation of peptide ligands facilitatingnanoparticle at attachment to erythrocytes Biotechnol Prog 23 (2007) 749ndash754
[150] S Gorantla H Dou M Boska CJ Destache J Nelson L Poluektova BERabinow HE Gendelman RL Mosley Quantitative magnetic resonance and
SPECT imaging for macrophage tissue migration and nanoformulated drug de-livery J Leukoc Biol 80 (2006) 1165ndash1174
[151] LA Lotero G Olmos JC Diez Delivery to macrophages and toxic action of etopo-sidecarried in mouse redblood cells Biochim Biophys Acta 1620 (2003) 160ndash166
[152] L Rossi S Sera1047297ni F Pierigeacute A Antonelli A Cerasi A Fraternale L ChiarantiniM Magnani Erythrocyte-based drug delivery Expert Opin Drug Deliv 2 (2005)311ndash322
[153] S Sera1047297ni L Rossi A Antonelli A Fraternale A Cerasi R Crinelli L ChiarantiniGF Schiavano M Magnani Drug delivery through phagocytosis of red bloodcells Transfus Med Hemother 31 (2004) 92ndash101
[154] H Dou CJ Destache JR Morehead R Lee Mosley MD Boska J Kingsley S
Gorantla L Poluektova JA Nelson M Chaubal J Werling J Kipp BERabinow HE Gendelman Development of a macrophage-based nanoparticleplatform for antiretroviral drug delivery Blood 108 (2006) 2827ndash2835
[155] V Staedtke M Braumller A Muumlller R Georgieva S Bauer N Sternberg A Voigt ALemke C Keck J Moumlschwitzer H Baumlumler In vitro inhibition of fungal activityby macrophage-mediated sequestration and release of encapsulated amphoter-icin B nanosuspension in red blood cells Small 6 (2010) 96ndash103
430 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[81] A Hanafy H Spahn-Langguth G Vergnault P Grenier M Tubic Grozdanis TLenhardt P Langguth Absence of a food effect with a 145 mg nanoparticle feno-1047297brate tablet formulation Int J Clin Pharmacol Ther 44 (2006) 64ndash70
[82] MV Chaubal C Popescu Conversion of nanosuspensions into dry powders byspray drying a case study Pharm Res 25 (2008) 2302ndash2308
[83] F Lai E Pini G Angioni ML Manca J Perricci C Sinico AM Fadda Nanocrys-tals as tool to improve piroxicam dissolution rate in novel orally disintegratingtablets Eur J Pharm Biopharm 79 (2011) 552ndash558
[84] D Mou H Chen J Wan H Xu X Yang Potent dried drug nanosuspensions for
oral bioavailability enhancement of poorly soluble drugs with pH-dependentsolubility Int J Pharm 413 (2011) 237ndash244[85] A Ain-Ai PK Gupta Effect of arginine hydrochloride and hydroxypropyl cellu-
lose as stabilizers on the physical stability of high drug loading nanosuspensionsof a poorly soluble compound Int J Pharm 351 (2008) 282 ndash288
[86] Z Guo T Pereira O Choi Y Wang HT Hahn Surface functionalized aluminananoparticle 1047297lled polymeric nanocomposites with enhanced mechanical prop-erties J Mater Chem 16 (2006) 2800ndash2808
[87] DR Kalaria G Sharma V Beniwal MN Ravi Kumar Design of biodegradablenanoparticles for oral delivery of doxorubicin in vivo pharmacokinetics and tox-icity studies in rats Pharm Res 26 (2009) 492ndash501
[88] JE Kipp The role of solid nanoparticle technology in parenteral delivery of poorly water soluble drugs Int J Pharm 284 (2004) 109ndash122
[89] HM Shubar S Lachenmaier MM Heimesaat U Lohman R Mauludin RHMuumlller R Fitzner K Borner O Liesenfeld SDS-coated atovaquone nanosuspen-sions show improved therapeutic ef 1047297cacy against experimental acquired andreactivated toxoplasmosis by improving passage of gastrointestinal and bloodndash
brain barriers J Drug Target 19 (2011) 114ndash124[90] L Peltonen J Hirvonen Pharmaceutical nanocrystals by nanomilling critical
process parameters particle fracturing and stabilization method J Pharm Phar-macol 62 (2010) 1569ndash1579
[91] F Lai C Sinico G Ennas F Marongiu G Marongiu AM Fadda Diclofenac nano-suspensions in1047298uence of preparation procedure and crystal form on drug disso-lution behavior Int J Pharm 373 (2009) 124ndash132
[92] JB Dressman C Reppas In vitrondashin vivo correlations for lipophilic poorlywater-soluble drugs Eur J Pharm Sci 11 (Suppl 2) (2000) S73ndashS80
[93] RH Muller CM Keck Challenges and solutions for the delivery of biotech drugsmdasha review of drug nanocrystal technology and lipid nanoparticles J Biotechnol113 (2004) 151ndash170
[94] JL Wahlstrom P Chiang S Ghosh CJ Warren SP Wene LA Albin ME SmithSL Roberds Pharmacokinetic evaluation of a 13-dicyclohexylurea nanosuspen-sion formulation to support early ef 1047297cacy assessment Nanoscale Res Lett 2(2007) 291ndash296
[95] Y GaoZ LiM SunH Li CGuoJ CuiA LiF CaoY XiH Lou GZhai Preparationcharacterization pharmacokinetics and tissue distribution of curcumin nanosus-pension with TPGS as stabilizer Drug Dev Ind Pharm 36 (2010) 1225ndash1234
[96] M Clement W Pugh I Parikh Tissue distribution and plasma clearance of a novelmicrocrystalline-coated 1047298urbiprofen formulation Pharmacologist 34 (1992)204ndash211
[97] RC Nagarwal S Kant PN Singh P Maiti JK Pandit Polymeric nanoparticulate sys-tem a potential approach for ocular drug delivery J Control Release 136 (2009)2ndash13
[98] H Gupta M Aqil RK Khar A Ali A Bhatnagar G Mittal Spar1047298oxacin loadedPLGA nanoparticles for sustained ocular drug delivery Nanomedicine 6 (2010)324ndash333
[99] HS Ali P York AM Ali N Blagden Hydrocortisone nanosuspensions for oph-thalmic delivery a comparative study between micro1047298uidic nanoprecipitationand media milling J Control Release 149 (2011) 175ndash181
[100] SK Sahoo F Dilnawaz S Krishnakumar Nanotechnology in ocular drug deliv-ery Drug Discov Today 13 (2008) 144ndash151
[101] O Kayser A Lemke N Hernaacutendez-Trejo The impact of nanobiotechnology on thedevelopment of newdrug deliverysystems Curr Pharm Biotechnol6 (2005) 3ndash5
[102] R Pignatello C Bucolo G Spedalieri A Maltese G Puglisi Flurbiprofen-loadedacrylate polymer nanosuspensions for ophthalmic application Biomaterials 23(2002) 3247ndash3255
[103] R Ravichandran Nanoparticles in drug delivery potential green nanobiomedi-
cine applications Int J Green Nanotechnol Biomed 1 (2009) B108ndash
B130[104] AM Cerdeira M Mazzotti B Gander Miconazole nanosuspensions in1047298uence
of formulation variables on particle size reduction and physical stability Int JPharm 396 (2010) 210ndash218
[105] MA Kassem AA Abdel Rahman MM Ghorab MB Ahmed RM Khalil Nano-suspension as an ophthalmic delivery system for certain glucocorticoid drugsInt J Pharm 340 (2007) 126ndash133
[106] P Chiang JW Alsup Y Lai Y Hu BR Heyde D Tung Evaluation of aerosol de-livery of nanosuspension for pre-clinical pulmonary drug delivery NanoscaleRes Lett 4 (2009) 254ndash261
[107] W Yang JI Peters RO Williams III Inhaled nanoparticlesmdasha current reviewInt J Pharm 356 (2008) 239ndash247
[108] J Zhang L Wu H Chan W Watanabe Formation characterization and fate of inhaled drug nanoparticles Adv Drug Deliv Rev 63 (2011) 441ndash455
[109] HM Mansour YS Rhee X Wu Nanomedicine in pulmonary delivery Int JNanomedicine 4 (2009) 299ndash319
[110] NR Labiris MB Dolovich Pulmonary drug delivery Part I physiological factorsaffecting therapeutic effectiveness of aerosolized medications Br J Clin Phar-macol 56 (2003) 588ndash599
[111] JS Patton PR Byron Inhaling medicines delivering drugs to the body throughthe lungs Nat Rev Drug Discov 6 (2007) 67ndash74
[112] DA Edwards C Dunbar Bioengineering of therapeutic aerosols Annu RevBiomed Eng 4 (2002) 93ndash107
[113] W Yang JTam DA Miller J Zhou JT McConville KP Johnstonb RO WilliamsIII High bioavailability from nebulized itraconazole nanoparticle dispersionswith biocompatible stabilizers Int J Pharm 361 (2008) 177ndash188
[114] S Gill R Lobenberg T Ku S Azarmi W Roa EJ Prenner Nanoparticles char-acteristics mechanisms of action and toxicity in pulmonary drug deliverymdasha re-view J Biomed Nanotechnol 3 (2007) 107ndash119
[115] SJ Sze1047298er Pharmacodynamics and pharmacokinetics of budesonide a new
S183[116] W Yang KP Johnston RO Williams III Comparison of bioavailability of amor-phous versus crystalline itraconazole nanoparticles via pulmonary administra-tion in rats Eur J Pharm Biopharm 75 (2010) 33 ndash41
[117] R Ali GK Jain Z Iqbal S Talegaonkar P Pandit S Sule G Malhotra RK KharA Bhatnagar FJ Ahmad Development and clinical trial of nano-atropine sulfatedry powder inhaler as a novel organophosphorous poisoning antidote Nanome-dicine 5 (2009) 55ndash63
[118] D Andes Minireview in vivo pharmacodynamics of antifungal drugs in treat-ment of candidiasis Antimicrob Agents Chemother 47 (2003) 1179ndash1186
[119] D Andes K Marchillo R Conklin G Krishna F Ezzet A Cacciapuoti DLoebenberg Pharmacodynamics of a new triazole posaconazole in a murinemodel of disseminated candidiasis Antimicrob Agents Chemother 48 (2004)137ndash142
[120] O Kayser C Olbrich V Yardley AF Kiderlen SL Croft Formulation of ampho-tericin B as nanosuspension for oral administration Int J Pharm 254 (2003)73ndash75
[121] L Zhang S Hou S Mao D Wei X Song Y Lu Uptake of folate-conjugated albu-min nanoparticles to the SKOV3 cells Int J Pharm 287 (2004) 155ndash162
[122] J Sudimack RJ Lee Targeted drug delivery via folate receptor Adv Drug DelivRev 41 (2000) 147ndash162
[123] P Vader LJ van der Aa G Storm RM Schiffelers JF Engbersen Polymeric car-rier systems for siRNA delivery Curr Top Med Chem 12 (2012) 108 ndash119
[124] O Veiseh FM Kievit RG Ellenbogen M Zhang Cancer cell invasion treatmentand monitoring opportunities in nanomedicine Adv Drug Deliv Rev 63 (2011)582ndash596
[125] J Kreuter VE Petrov DA Kharkevich RN Alyautdin In1047298uence of the type of surfactant on the analgesic effects induced by the peptide dalargin after its de-livery across the bloodndashbrain barrier using surfactant-coated nanoparticles JControl Release 49 (1997) 81ndash87
[126] J Ye Q Wang X Zhou N Zhang Injectable actarit-loaded solid lipid nanoparti-cles as passive targeting therapeutic agents for rheumatoid arthritis Int JPharm 352 (2008) 273ndash279
[127] SM Moghimi AC Hunter JC Murray Nanomedicine current status and futureprospects FASEB J 19 (2005) 311ndash330
[128] K Park To PEGylate or not PEGylate that is not the question J Control Release142 (2010) 147ndash148
[129] M Socha P Bartecki C Passitani A Sapin C Damge T Lecompte J BarreE Ghazouani P Maincent Stealth nanoparticles coated with heparin aspeptide or peptide carriers J Drug Target 17 (2009) 575ndash585
[130] D Shenoy S Little R Langer M Amiji Poly(ethylene oxide)-modi1047297ed poly(-beta-amino ester) nanoparticles as a pH-sensitive system for tumor targeted de-livery of hydrophobic drugs part 2 In vivo distribution and tumor localizationstudies Pharm Res 22 (2005) 2107ndash2114
[131] R Shegokara KK Singha Surface modi1047297ed nevirapinenanosuspensions for viralreservoir targeting in vitro and in vivo evaluation Int J Pharm 421 (2011)341ndash352
[132] Y Matsumura H Maeda A new concept for macromolecular therapeutics incancer chemotherapy mechanism of tumoritropic accumulation of proteinsand the antitumor agent SMANCS Cancer Res 46 (1986) 6387ndash6392
[133] H Zhang CP Hollis Q Zhang T Li Preparation and antitumor study of camp-tothecin nanocrystals Int J Pharm 415 (2011) 293ndash300
[134] H Lou L Gao X Wei Z Zhang D Zheng D Zhang X Zhang Y Li Q Zhang Ori-donin nanosuspension enhances anti-tumor ef 1047297cacy in SMMC-7721 cells andH22 tumor bearing mice Colloids Surf B Biointerfaces 87 (2011) 319ndash325
[135] TM Goppert RH Muumlller Adsorption kinetics of plasma proteins on solid lipid
nanoparticles for drug targeting Int J Pharm 302 (2005) 172ndash
186[136] X Pu J Sun M Li Z He Formulation of nanosuspensions as a new approach for
the delivery of poorly soluble drugs Curr Nanosci 5 (2009) 417ndash427[137] R Gaudana J Jwala SHS Boddu AK Mitra Recent perspectives in ocular drug
delivery Pharm Res 26 (2009) 1197ndash1216[138] T Yasukawa H Kimura Y Tabata H Miyamoto Y Honda Y Ikada Y Ogura
Targeted delivery of anti-angiogenic agent TNP-470 using water-soluble poly-mer in the treatment of choroidal neovascularization Invest Ophthalmol VisSci 40 (1999) 2690ndash2696
[139] A Lemke AF Kiderlen B Petri O Kayser Delivery of amphotericin B nanosus-pensions to the brain and determination of activity against Balamuthia mandril-laris amebas Nanomedicine 6 (2010) 597ndash603
[140] HL Wong XY Wu R Bendayan Nanotechnological advances forthe delivery of CNS therapeutics Adv Drug Deliv Rev (2011) doi101016jaddr201110007
[141] J Kreuter S Gelperina Use of nanoparticles for cerebral cancer Tumori 94(2008) 271ndash277
[142] J Kreuter RN Alyautdin DA Kharkevich AA Ivanov Passage of peptidesthrough the bloodndashbrain barrier with colloidal polymer particles (nanoparti-cles) Brain Res 674 (1995) 171ndash174
429L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[143] J Kreuter Nanoparticulate systems for brain delivery of drugs Adv Drug DelivRev 47 (2001) 65ndash81
[144] TM Goumlppert RH Muumlller Polysorbate-stabilized solid lipid nanoparticles as col-loidal carriers for intravenous targeting of drugs to the brain comparison of plasma protein adsorption patterns J Drug Target 13 (2005) 179ndash187
[145] S Mansouri Y Cuie F Winnik Q Shi P Lavigne M Benderdour E Beaumont JC Fernandes Characterization of folate-chitosan-DNA nanoparticles for genetherapy Biomaterials 27 (2006) 2060ndash2065
[146] AR Hilgenbrink PS Low Folate receptor-mediated drug targeting from thera-peutics to diagnostics J Pharm Sci 94 (2005) 2135ndash2146
[147] F Pierigegrave S Sera1047297ni L Rossi M Magnani Cell-based drug delivery Adv Drug
Deliv Rev 60 (2008) 286ndash
295[148] F Chellat Y Merhi A Moreau L Yahia Therapeutic potential of nanoparticulatesystems for macrophage targeting Biomaterials 26 (2005) 7260ndash7275
[149] SS Hall S Mitragotri PS Daugherty Identi1047297cation of peptide ligands facilitatingnanoparticle at attachment to erythrocytes Biotechnol Prog 23 (2007) 749ndash754
[150] S Gorantla H Dou M Boska CJ Destache J Nelson L Poluektova BERabinow HE Gendelman RL Mosley Quantitative magnetic resonance and
SPECT imaging for macrophage tissue migration and nanoformulated drug de-livery J Leukoc Biol 80 (2006) 1165ndash1174
[151] LA Lotero G Olmos JC Diez Delivery to macrophages and toxic action of etopo-sidecarried in mouse redblood cells Biochim Biophys Acta 1620 (2003) 160ndash166
[152] L Rossi S Sera1047297ni F Pierigeacute A Antonelli A Cerasi A Fraternale L ChiarantiniM Magnani Erythrocyte-based drug delivery Expert Opin Drug Deliv 2 (2005)311ndash322
[153] S Sera1047297ni L Rossi A Antonelli A Fraternale A Cerasi R Crinelli L ChiarantiniGF Schiavano M Magnani Drug delivery through phagocytosis of red bloodcells Transfus Med Hemother 31 (2004) 92ndash101
[154] H Dou CJ Destache JR Morehead R Lee Mosley MD Boska J Kingsley S
Gorantla L Poluektova JA Nelson M Chaubal J Werling J Kipp BERabinow HE Gendelman Development of a macrophage-based nanoparticleplatform for antiretroviral drug delivery Blood 108 (2006) 2827ndash2835
[155] V Staedtke M Braumller A Muumlller R Georgieva S Bauer N Sternberg A Voigt ALemke C Keck J Moumlschwitzer H Baumlumler In vitro inhibition of fungal activityby macrophage-mediated sequestration and release of encapsulated amphoter-icin B nanosuspension in red blood cells Small 6 (2010) 96ndash103
430 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430
8202019 Drug Nanocrystals in Vivo Performances 2012 Journal of Controlled Release
[143] J Kreuter Nanoparticulate systems for brain delivery of drugs Adv Drug DelivRev 47 (2001) 65ndash81
[144] TM Goumlppert RH Muumlller Polysorbate-stabilized solid lipid nanoparticles as col-loidal carriers for intravenous targeting of drugs to the brain comparison of plasma protein adsorption patterns J Drug Target 13 (2005) 179ndash187
[145] S Mansouri Y Cuie F Winnik Q Shi P Lavigne M Benderdour E Beaumont JC Fernandes Characterization of folate-chitosan-DNA nanoparticles for genetherapy Biomaterials 27 (2006) 2060ndash2065
[146] AR Hilgenbrink PS Low Folate receptor-mediated drug targeting from thera-peutics to diagnostics J Pharm Sci 94 (2005) 2135ndash2146
[147] F Pierigegrave S Sera1047297ni L Rossi M Magnani Cell-based drug delivery Adv Drug
Deliv Rev 60 (2008) 286ndash
295[148] F Chellat Y Merhi A Moreau L Yahia Therapeutic potential of nanoparticulatesystems for macrophage targeting Biomaterials 26 (2005) 7260ndash7275
[149] SS Hall S Mitragotri PS Daugherty Identi1047297cation of peptide ligands facilitatingnanoparticle at attachment to erythrocytes Biotechnol Prog 23 (2007) 749ndash754
[150] S Gorantla H Dou M Boska CJ Destache J Nelson L Poluektova BERabinow HE Gendelman RL Mosley Quantitative magnetic resonance and
SPECT imaging for macrophage tissue migration and nanoformulated drug de-livery J Leukoc Biol 80 (2006) 1165ndash1174
[151] LA Lotero G Olmos JC Diez Delivery to macrophages and toxic action of etopo-sidecarried in mouse redblood cells Biochim Biophys Acta 1620 (2003) 160ndash166
[152] L Rossi S Sera1047297ni F Pierigeacute A Antonelli A Cerasi A Fraternale L ChiarantiniM Magnani Erythrocyte-based drug delivery Expert Opin Drug Deliv 2 (2005)311ndash322
[153] S Sera1047297ni L Rossi A Antonelli A Fraternale A Cerasi R Crinelli L ChiarantiniGF Schiavano M Magnani Drug delivery through phagocytosis of red bloodcells Transfus Med Hemother 31 (2004) 92ndash101
[154] H Dou CJ Destache JR Morehead R Lee Mosley MD Boska J Kingsley S
Gorantla L Poluektova JA Nelson M Chaubal J Werling J Kipp BERabinow HE Gendelman Development of a macrophage-based nanoparticleplatform for antiretroviral drug delivery Blood 108 (2006) 2827ndash2835
[155] V Staedtke M Braumller A Muumlller R Georgieva S Bauer N Sternberg A Voigt ALemke C Keck J Moumlschwitzer H Baumlumler In vitro inhibition of fungal activityby macrophage-mediated sequestration and release of encapsulated amphoter-icin B nanosuspension in red blood cells Small 6 (2010) 96ndash103
430 L Gao et al Journal of Controlled Release 160 (2012) 418ndash430