REVIEW OF LITERATURE - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/49545/10/10_chapter2.pdf · NE30D as time-dependent coat and Eudragit FS 30D as pH-dependent coat) Kulthe

REVIEW OF LITERATURE

Colon specific drug delivery

Lipid based drug delivery system

Drug Profile

Review of Literature

Faculty of Pharmaceutical Sciences, M.M. University, Mullana, Ambala, Haryana (India) 17

2. REVIEW OF LITERATURE

2.1. Colon-specific drug delivery system

Oral colon-specific drug delivery may be achieved by a wide variety of controlled release

technologies, which may be divided into the three main approaches. The first approach is the

programmed release. In this approach drug release (often a pre-designed release profile) will

start after a specific lag-time following ingestion of the drug product. A second approach is the

triggered release system, a system from which drug release starts after it encountered a

specific intraluminal condition. A third approach is targeted oral drug delivery, where the aim is

to target the location of disease. The different approaches may be based on the delivery of the

intact molecule or on pro-drugs of which the conversion principle to the active molecule may

add to the specificity of drug release (De et al., 2006). Targeted delivery of the intact drug

substance may also be achieved by formulation of micro- and nanoparticles (Lamprecht et al.,

2001), in a passive or active mode. Passive targeting is achieved by enhanced permeability

and retention-effect for micro- or nanoparticles in certain diseased conditions. The application

of micro- or nanoparticles is based on the uptake of small particulate drug carriers by immune

related cells in the inflammed tissue with the aim to achieve a more local effect through their

accumulation at the site of action (Lamprecht et al., 2001). Negatively charged liposomes have

been investigated for their ability to target inflammed tissues based on specific electrostatic

interaction (Tirosh et al., 2009). In active targeting the drug delivery system holds a ligand

which interacts with a disease-specific molecular target.

With the advancements in colon targeted drug delivery system, various formulation

technologies have been reported. These technologies may be broadly classified based on the

formulation approaches that have been exploited for the development of colon targeted drug

delivery, viz, pH-dependent, time-dependent, microflora-activated, pH- and time-dependent,

and pH- and microflora- activated systems. Amongst them, pH-dependent systems are most

widely used as far as the commercial availability of colonic delivery is concerned (Patel et al.,

2011). In 2007, the first and only FDA-approved once daily oral formulation of mesalamine,

MMS (Multi-Matrix System, Shire Pharmaceuticals Inc., Pennsylvania, USA) was developed for

the induction of remission of mild to moderate ulcerative colitis. Recently developed

technologies and formulations for colon targeted drug delivery system are summarized in Table

5 and Table 6 respectively.



Table 5: Recently developed technologies for colon targeting

Trade name Description Inventor/Reference

pH-dependent systems

Lialda® Mesalamine (MMX technology; pH-dependent gastro-resistant coating with tablet

core containing hydrophilic and lipophilic excipients)

Shire Pharmaceuticals Pennsylvania, USA

Asacol® Mesalamine (Eudragit

® S 100 coated tablets) Tillots Pharma AG, Rheinfelden, Switzerland

Claversal® Mesalamine (Eudragit

® L 100 coated tablets)

Merckle Recordati GmbH, Germany

Mesasal® GlaxoSmithKline Inc., Ontario, Canada

Calitoflak®

Time-dependent systems

Pentasa® Mesalamine (ethyl cellulose coated microgranules slowly dissolve throughout the

small intestine and colon in time-dependent fashion)

Ferring Pharmaceuticals, Saint-Prex,

Switzerland

Port®

system Captopril (hard gelatin capsule, film coated with semi-permeable membrane

(capsule body), an insoluble plug and an osmotic agent along with drug molecule)

Therapeutic System Research Laboratory

Ann Arbor, MI, USA

Egalet® Quinine (3K form of Egalet technology consists of an impermeable shell with two lag

plugs, enclosing a plug of active drug in middle of unit)

Egalet Ltd., Vaerlose, Denmark

Erodible plug, time-

delayed capsule

Chlorpheniramine (erodible compressed tablet is used in place of the swelling

hydrogel plug)

Krogel et al., 1998

Hydrophilic sandwich

capsule

Paracetamol (capsule-within-capsule system in which the inter-capsular space was

filled with a layer of hydrophilic polymer (HPMC)

Stevens et al., 2000

Contd….



Time controlled

explosion system

Metoprolol tartrate (expansion of swelling agent by water penetrating through outer

membrane causes destruction of the membrane by stress due to swelling force and

subsequent rapid drug release)

Ueda et al., 1994

Microflora-activated systems

Colazal®

Balsalazide (delivered to the colon intact then bacteria cleave the compound to

release 5-amino salicylic acid)

Salix Pharmaceuticals Inc., North Carolina,

USA

Dipentum® Olsalazine (rapidly converted in the colon to molecules of 5-amino salicylic acid by

bacteria and the colon‘s low prevailing redox potential)

Pharmacia AB Stockholm, Sweden

Salazopyrin® Sulfasalazine (metabolized by intestinal bacteria to 5-amino salicylic acid and

sulfapyridine)

Pfizer Australia Pty Ltd, West Ryde NSW,

Australia

Azulfidine® Sulfasalazine (azulfidine En-Tabs contain a cellulose acetatephthalate coating that

retards disintegration in the stomach)

Pfizer, Inc., New York, USA

Colal-Pred®

Prednisolone sodium metasulfobenzoate (COLAL involves a coating for drug

pellets, tablets or capsules, which is composed of ethyl cellulose and a form of

starch called ‗glassy amylose‘)

Alizyme plc, Cambridge, UK

pH and Time-dependent systems

Time Clock® Salbutamol (inner coating consists of hydrophobic surfactant layer to which a water-

soluble polymer is added to improve adhesion to the core)

Pozzi et al., 1994

Chronotopic® Antipyrine (composed of a drug-containing core and hydrophilic swellable polymeric

coating capable of delaying drug release through slow interaction with aqueous

fluids)

Gazzaniga et al., 1994

Contd……….



Pulsincap® Salbutamol sulphate (comprises an impermeable capsule body containing a drug

formulation sealed in the capsule with a hydrogel polymer plug)

R.P. Scherer International Corp., Michigan,

USA

OROS®-CT Aminosalicylates, Corticosteroids (push--pull units encapsulated within a hard

gelatin capsule)

Alza Corp., Palo Alto, California, USA

Osmet™ Anti-inflammatory, anti-hypertensive and receptor blocking agents (a miniature

osmotic pump that can be swallowed, which will pass through the stomach and small

intestine and then deliver its contents (240 μl) more than 8 h in the large bowel)

Chronset™ Acetaminophen (proprietary OROS®

delivery system that reproducibly delivers a

bolus drug dose (> 80% drug release within 15 min).

Alza Corp., Palo Alto, California, USA

Eudracol® Caffeine (multiparticulate, multilayer system that uses aqueous polymethacrylate

dispersion in the design of the release profile)

Evonik Rohm GmbH Pharma Polymers,

Darmstadt, Germany

Entocort® EC Budesonide (granules, coated to protect dissolution in gastric juice, but which

dissolve at pH > 5.5, i.e., normally when the granules reach the duodenum

AstraZeneca, Sodertalje, Sweden

pH and Microflora activated systems

CODES™ 5-Aminosalicylic acid, Insulin, salmon calcitonin (coupled with a pH-sensitive

polymer coating. On entry into the colon, the polysaccharide inside the core tablet

dissolves and diffuses through the coating. Bacteria enzymatically degrade the

polysaccharides into organic acids)

Yamanouchi Pharmaceuticals Co. Ltd., Japan

TARGIT® Budesonide (enteric-coated injection-moulded starch capsule, consists of a mixture

of Eudragit L and S)

West Pharmaceutical Services Drug Delivery

and Clinical Research Centre Ltd.,

Nottingham, UK



Table 6: Novel drug delivery systems for colon targeting

Delivery system Description Reference(s)

pH-dependent systems

Self micro-emulsifying

drug delivery system

Curcumin (system was filled into a capsular system and coated with Eudragit S 100)

Zhang et al., 2012

Nanogels 5- Fluorouracil (drug entrapment within the polymeric backbone was achieved using solvent

evaporation method)

Kumar et al., 2012

pH and time-dependent systems

Microparticles Celecoxib (dual coated microparticulate system; where Poly- ε- caprolactone was evaluated as time-

dependent coat and Eudragit S100 as pH-dependent coat)

Ghorab et al., 2011

Tablets Meloxicam (dual coated microparticulate system; where inner coat consists of ethyl cellulose

containing polyethylene glycol as time-dependent coat and Eudragit FS 30D as pH-dependent coat)

Patel et al., 2011

Multiparticulate systems

(pellets)

5- Fluorouracil (dual coated multiparticulate pellets; where inner coat consists of Eudragit

NE30D as time-dependent coat and Eudragit FS 30D as pH-dependent coat)

Kulthe et al., 2013

Microbially and/or enzymatically driven drug delivery systems

Mucoadhesive

Microsphere

5- Fluorouracil (assam Bora rise starch has been used due to its efficiency as CoDDS) Ahmad et al., 2012

Multiparticulate

System (Pellets)

5- Fluorouracil (multiparticulate system consisting of pectin as coat and core material whereas Ethyl

cellulose was employed as an in situ intracapsular coating Material)

Elyagoby et al., 2013

Contd……..



Nanoparticles Paclitaxel (paclitaxel-loaded chitin (amorphous) nanoparticulate system was prepared by ionic cross-

linking reaction technique)

Smitha et al., 2013

Methotrexate (methotrexate-FA-GGNP has been prepared by emulsification cross-linking technique) Sharma et al., 2013

Tableted Microsponges Meloxicam (modified quassi-emulsion solvent diffusion technique was used to formulate the

microsponges)

Srivastava et al., 2012

Tablets 5- Fluorouracil (compression-coated tablets containing 5-FU as drug candidate was evaluated as a

potential alternative for achieving CoDDS)

Dev et al., 2011

Azo-conjugates Methotrexate and gemcitabine (conjugates were stable in presence of acidic conditions and were

reported to release more than 89% of drug in presence of rat cecal contents)

Sharma et al., 2014

pH and microflora activated di-dependent systems

Mucoadhesive

Microsphere

Valdecoxib (in vitro cell line studies revealed that the transport of valdecoxib microspheres across

Caco-2 cell monolayers at pH 7.4 was found to be slower than that of solutions, thus providing a

prolonged and sustained release profile)

Thakral et al., 2011

Microsphere Curcumin (in vitro evaluation of the developed system revealed that the drug release was

significantly increased in presence of rat caecal content (1% w/v)

Zhang et al., 2011

Multiparticulate system Ginger extracts (in vitro evaluation of the developed systems revealed a super class II release

mechanism, controlled by swelling and polymer relaxation)

Deol et al., 2013



2.2. Lipid based drug delivery system

Most of the investigations described so far have evaluated the pharmacokinetics of the drug in

SEFs and very few reports demonstrates pharmacodynamic efficacy. Although pharmacokinetic

studies are sufficient to establish the proof of concept for SEFs, the result of the investigation

should be preferably corroborated by pharmacodynamic studies. This is particularly important

for drugs such as simvastatin, atorvastatin and ezetimibe, which do not show pharmacokinetic-

pharmacodynamic correlation. Although the potential of SEFs in improving oral bioavailability of

lipophilic drugs has been established, an increase in the drug bioavailability need not be

translated into an increase in the pharmacodynamic effects of these drugs. Such aspects

should be carefully considered while planning investigations on the SEFs. The key

investigations that describe the potential of SEFs in oral drug delivery are listed in Table 7 and

some of them have been discussed in the subsequent sections.

2.2.1. Self-emulsifying formulations

Self-emulsifying tablets (SE tablets)

Incorporation of lipid formulation into a solid dosage form combines the advantages of lipid-

based drug delivery systems with those of solid dosage forms. Attama, 2003 formulated a solid

self-emulsifying formulation using goat fat and tween for the delivery of diclofenac. Fatty

material was melted and mixed with surfactant and the drug incorporated into this mixture. This

wet mass was poured into plastic molds and cooled to form a tablet. During the processing of

this formulation it was observed that agitation during fabrication of tablets reduced the

liquification time, resulting in faster emulsification. These results demonstrated that different

formulation ratios possess varying dissolution profiles at constant speed/agitation, and the

optimized formulation showed good release profiles with acceptable tablet properties.

Nazzal and Khan 2002, evaluated the effect of some parameters (colloidal silicates, magnesium

stearate mixing time, and compression force) on coenzyme Q10 (CoQ10) dissolution from

tablets of eutectic-based SMEFs. The optimized conditions were achieved by a face centred

cubic design. In order to significantly reduce the amount of solidifying excipients required for

transformation of SEFs into solid dosage forms, gelled SEFs have been developed by Patil,

2004. In this study, colloidal silicon dioxide (Aerosil 200) was selected as a gelling agent for the

oil-based systems. Colloidal silicon dioxide served a dual purpose: (i) reducing the amount of

solidifying excipients required; and (ii) aiding in reducing drug release.

In a clinical study, it was found that SE tablets may be of use in reducing adverse effects

(Schwarz, 2003). The incorporation of indomethacin (or other hydrophobic NSAIDs) in SE

tablets was found to increase the penetration efficacy of the drug through the GI mucosal

membranes, potentially reducing GI bleeding. The SEF in this study composed of glycerol

monolaurate and Tyloxapol TM (a copolymer of alkyl phenol and formaldehyde). The tablets



consistently maintained a higher active ingredient concentration in blood plasma over the same

time period compared with a non-emulsifying tablet.

Self-emulsifying powder formulation (SE powder formulation)

Arida et al. 2007 formulated an SE powder formulation in order to enhance the dissolution and

absorption of the poorly water-soluble drug griseofulvin. Capmul GMO- 50, poloxamer and

myvacet were used as surfactants and co-surfactants. A significant enhancement in dissolution

(without ultra-micronisation) and bioavailability of griseofulvin was observed. Balakrishnan et al.,

2009, developed a novel solid SEF of dexibuprofen using spray drying. Aerosil 200 was used as

an inert solid carrier. Both in vitro and in vivo studies were carried out. The optimization of the

SEF composition was carried out by assessing solubility, preparation of phase diagram, particle

size analysis, drug release studies etc. The study showed that Labrafil M 1944 CS, Labrafil M

2125, Labrasol, Capryol 90 and Lauroglycol FCC could enhance the solubility of CoQ10 and

provide the desired drug loading.

Self-emulsifying pellets (SE pellets)

Oral pellets are known to overcome the poor and variable GIT absorption of drugs and have

shown the ability to reduce or eliminate the influence of food on bioavailability. Thus, it appears

highly appealing to combine the advantages of pellets with those of SETs by formulating SE

pellets. Kang et al., 2004 as part of their study to develop a self-emulsifying drug delivery

system, have reported considerable differences in the solubility of simvastatin in a range of

surfactants. The authors suggest that the properties of surfactants need to be considered when

selecting them for the formulation of SE pellets.

Franceschinis et al., 2005 developed a new method for preparing self-emulsifying pellets by wet

granulation consisting of a binder solution containing an oil (mono and diglycerides),

polysorbate 80 and nimesulide as a model drug. The oil surfactant mixture was added to water

to obtain binder solution. The prepared binder solutions were sprayed onto the granules

(prepared from microcrystalline cellulose and lactose) to give pellets. In vivo studies indicated

significantly higher bioavailability with the prepared pellets in comparison to the corresponding

emulsions.

Tuleu, 2004 conducted a comparative bioavailability study of progesterone from SE pellet

formulation, SE solution, capsule and an aqueous suspension in dogs. Complete drug release

was seen within 30 min of capsule administration and within 5 min of administration of the self-

emulsifying system. However, in the case of aqueous suspension the drug release was very low

(~50% of the dose in 60 min). Plasma drug concentration was significantly higher when the drug

was orally administered from self-emulsifying pellets and self-emulsifying solution when

compared to aqueous suspension at the same dose. Abdalla and Mader, 2007, prepared three

self-emulsifying pellet formulations by melting cithrol GMS (mono and diglycerides) and solutol



HS 15. To this molten blend, the drug (diazepam) and dry microcrystalline cellulose (MCC) were

added to obtain a suitable mass for extrusion. A dye was incorporated for assessment of self-

emulsification and spin probe was added to assess the release kinetics and microenvironment

of pellets. The results from the release study, with higher load of diazepam and lower volume of

the dissolution media, indicated that the formulation was able to create and maintain a state of

supersaturation for the poorly water-soluble diazepam. Nearly 90% of the drug was released

within an hour while only 55% was released from the GMS/MCC pellets.

Wang et al., 2010 demonstrated that the extrusion/ spheronization technique is a large-scale

production method for preparing solid SE pellets from the liquid SEF to improve oral absorption.

SE pellets of a hydrophobic drug (nitrendipine) were prepared. Formulation stability and

solubilisation capacity were noted. The system was optimized on the basis of equilibrium

solubility, pseudo-ternary phase diagram and supersaturation studies. The liquid SEFs were

solidified using adsorbents (porous silicon dioxide), MCC and lactose to form fine flowable

powder. Crospovidone was added to the formulation. The AUC of nitrendipine from the SE

pellets was two-fold greater than the conventional tablets and was comparable with the liquid

SEFs.

Controlled release self-emulsifying pellets

Serratoni and Newton, 2007, observed that the release of methyl paraben (MP) and propyl

parabens (PP) from pellet formulations could be controlled by incorporating them into self-

emulsifying systems containing water soluble plasticiser and talc. Oil and surfactant were mixed

and added to the damp mass of MCC and lactose monohydrate. Extrusion spheronization of the

wet mass was carried out. The pellets obtained were initially coated with ethyl cellulose and

subsequently with an aqueous solution of hydroxy propyl methyl cellulose in a fluid bed coater.

Results obtained from the in vitro study revealed that the presence of self-emulsifying system

enhanced drug release of MP and PP while the film coating considerably reduced the drug

release from pellets.

Iosio et al., 2008 prepared two types of pellets containing vinpocetine (model insoluble drug)

where Type I pellets contained a self-emulsifying system internally and an inert matrix

externally, whereas Type II contained an inert matrix internally and a self-emulsifying system

externally. Formulations were prepared in two steps. In the first step, the oil-surfactant mixture

was added to water to form self-emulsifying systems whereas in the next stage this mixture was

loaded onto MCC and lactose to form extrusion-spheronization mass for pellets. Results indica-

ted that Type I pellets released 90% of vinpocetine within 30 min while the same quantity was

released within 20 min from Type II pellets. The physical mixture of the excipients with drug was

able to release around 25% of the drug in 60 min. Although both types of pellets demonstrated

adequate morphological and technological characteristics, type II pellets showed better drug



solubility and in vivo bioavailability. The above investigations suggest that a solid dosage form

containing a self-emulsifying system is a promising approach for the formulation of drug

compounds with poor aqueous solubility.

Self-emulsifying beads (SE beads)

Self-emulsifying beads can be formulated as a solid dosage form using smaller amounts of

different excipients. Patil and Paradkar formulated an isotropic formulation of loratadine

consisting of Captex 200, Cremophore EL and Capmul MCM. The SE mixture was loaded onto

poly propylene beads (PPB) using the solvent evaporation method. Formulations were optimi-

zed for loading efficiency and in vitro drug release by evaluating their geometrical features such

as bead size and pore architecture. Results indicated that the poly propylene beads are

potential carriers for solidification of SE mixture, with sufficiently high SE mixture to PPB ratios

for the solid form. The results indicated that self-emulsifying beads can be formulated as a solid

dosage form with a minimal amount of solidifying agents.

Self-emulsifying sustained-release microspheres

You et al., 2006 prepared solid SE sustained-release microspheres of zedoary turmeric oil (oil

phase) using the quasi-emulsion-solvent-diffusion method involving spherical crystallization.

The release behaviour of zedoary turmeric oil from the formulation was found to be dependent

upon the hydroxyl propyl methylcellulose acetate succinate to aerosil 200 ratio. The plasma

concentration time profiles after oral administration in rabbits showed a bioavailability of 135.6%

compared with the conventional liquid SEFs.

Self-emulsifying implants (SE implants)

Research in the field of implants has greatly increased the use and application of solid self-

emulsifying formulation (S-SEF). Carmustine (BCNU) is a chemotherapeutic agent used to treat

malignant brain tumours. However, its effectiveness is hindered by its short half-life. In order to

enhance its stability, the SEF of carmustine was formulated using tributyrin, Cremophor RH 40

(polyoxyl 40 hydrogenated castor oil) and Labrafil 1944 (polyglycolyzed glyceride). The self-

emulsified BCNU was fabricated into wafers with a flat and smooth surface by compression

moulding. The release profile was compared with a wafer implant fabricated using poly (d, l-

lactide-co-glycolide) acetic acid. It was found that SEF increased the in vitro half-life of BCNU to

130 min compared with 45 min with intact BCNU. The in vitro release of BCNU from self-

emulsifying PLGA wafers was prolonged up to 7 days and was found to have higher in vitro

anti-tumor activity (Chae et al., 2005).



2.2.2. Self-microemulsifying formulations

Self-micro emulsifying formulations (SMEFs) have attracted great attention recently. In an

attempt to combine the advantages of SMEFs with those of solid dosage forms and overcome

the shortcomings of liquid formulations, increasing attention has been focused on solid self-

(micro) emulsifying formulations. The thermotropic stability of SMEFs and their high drug

loading efficiency make them a promising system for low aqueous soluble drugs (Jannin et al.,

2007). SMEFs are usually placed in soft gelatin capsules, but can also be transformed into

granules, pellets, powders for dry filled capsules or tablet preparations (Nazzal, Khan, 2006;

Serratoni, Newton, 2007; Abdalla et al., 2008; Tan et al., 2009). The commercial success of the

SMEF, Neoral® drew greater attention to the development of SMEFs. Many poorly water-soluble

drugs such as acyclovir, atorvastatin, and fenofibrate have been reported to offer improved oral

bioavailability by SMEFs (Wang et al., 2006; Shen, Zhong, 2006; Patel, Vavia, 2007).

Postolache et al., 2002 compared the bioavailability of two cyclosporine capsule products with

different pharmaceutical formulations. Results showed that the test cyclosporine non-SMEFs

formulation was not bioequivalent to the cyclosporine SMEFs formulation due to a statistically

significantly lower absorption rate. These authors demonstrated that the non-self

microemulsifying capsules are not totally interchangeable with the self microemulsifying

capsules unless validated clinical and laboratory conversion protocols for each kind of organ

transplantation are enforced.

Zvonar et al., 2010 suggested that, SMEFs possessing a composition similar to microcapsules

with Ca-pectinate shell and a drug loaded SMEFs as the core phase, would be a potential

approach for enhancing low permeability and solubility of BCS class II drugs.

2.2.3. Self nanoemulsifying formulations (SNEFs)

The classical lipid nanoparticles that have been proposed for drug delivery are composed of

solid lipids. A distinct advantage of SNEFs over polymeric nanoparticles is that the lipid matrix is

made from physiologically tolerated lipid components, which decreases potential acute and

chronic toxicity. Nazzal et al., 2002 developed a SNEF based on the eutectic properties of

ubiquinone (CoQ10) and also studied the progress of emulsion formation and drug release

mechanisms by turbidimetry and droplet size analysis. Results obtained from study revealed

that eutectic-based semisolid SEFs can overcome the drawbacks of the traditional emulsified

systems such as low solubility and irreversible precipitation of the active drug in the vehicle with

time.

Cyclosporine lipid nanoparticles (lipospheres) consisting of phospholipids, Span 80, Tween 80,

Tricaprin, and Cremophor RH 40 were prepared (Bekerman et al., 2004). The CsA dispersion

systems prepared had a particle size ranging from 25 nm to 400 nm. Particles with a size of 25

nm showed maximum oral bioavailability. In a study surfactant–co-surfactant blend (Witepsol®



H35 and Solutol® HS15) at a ratio of 1:4 led to sufficient reduction in free energy of the system

to resist thermodynamic instability of the nano-emulsion as well as providing a sufficient

mechanical barrier to coalescence oil droplets (Nepal et al., 2010). Koynova et al., 2010

suggested the use of nanosized self-emulsifying lipid vesicles as carriers for the inclusion of

lipophilic dietary supplements. These were proposed as good alternatives to liposomal

preparations which pose problems in stability, sterilization, and non-reproducibility between

batches.

2.2.4. Supersaturable self-emulsifying formulation

Supersaturation represents a potent technique for enhancing absorption by generating and

maintaining a supersaturated state in the intestine. Such formulations contain both a reduced

amount of surfactant(s) and a polymeric precipitation inhibitor (e.g., water-soluble cellulosic

polymers, such as HPMC). These maintain a suggested, directly supersaturating a system with

a drug during manufacture adds to the risk of recrystallization of the product. Various ways of

inhibiting recrystallization have been identified. Thermodynamic ―freezing‖ inside a polymer is

one such option. Under storage conditions, the drug is mobilized by thermodynamic changes in

the polymeric structure. To avoid risk of direct super saturation, several strategies can be

employed, such as, evaporation of a solvent from the system, activation of thermodynamically

―frozen‖ drug-supersaturated islands by hydration.

However, attaining full knowledge of these processes, especially in a multi- component

formulation, requires extensive research. Recently, authors investigated the mechanism

responsible for the enhanced intestinal absorption of hydrophobic drugs from supersaturable

SEFs containing HPMC (Gao et al., 2008). This effect could be attributed to enhanced

permeation of drug to the enterocyte brush border region through the aqueous pathway by

mimicking, or equilibrating with, the bile acid /bile acid mixed micelle pathway.

2.2.5. Marketed formulations

The successful commercialization of oral lipid- and surfactant-based formulations of poorly

soluble drugs in the market has encouraged researchers to explore the field further.

Sandimmune®, Sandimmune Neoral®, Norvir® (ritonavir), and Fortovase® (saquinavir) have

been formulated as SEFs. Sandimmune® and Sandimmune Neoral® formulations of CsA are

perhaps the best known examples of marketed lipid and surfactant based systems and the

pharmacokinetic has been studied and reviewed extensively (Ritschel, 1996). When diluted with

water, these form a polydispersed oil-in-water macro/microemulsion. Table 8 lists selected

commercially available self-emulsifying formulations along with their characteristics.



Table 7: Different categories of drugs, formulations and excipients used in self-emulsifying formulations

Drug (s) Formulation type

Excipients

Comments References

Halofantrine SEF (Powder) Soybean oil: Maisine

Cremophor EL

Absolute ethanol

Developed formulation improved the oral bioavailability significantly (~6-8

fold) relative to previous data of the solid Halofantrine HCl tablet formulation.

Khoo et al., 1999

Loratadine SEF (Beads) Captex 200

Cremophore EL

Capmul MCM

SEF migrated to the surface of PPB to form a fine oil droplet that readily

dispersed in the bulk to form oil-in-water microemulsion.

Patil et al., 2006

Itraconazole SMEFs Tocopherol acetate

Pluronic L64, Transcutol

Greatly enhanced bioavailability of itraconazole. Hong et al., 2006

Griseofulvin SEF (Powder) Castor oil

Capmul GMO-50,

Myvacet 945

The mean AUC and Cmax after oral administration of GRIS-PEG formulation

in rats were 1.28 and 1.15 fold higher, respectively, compared to SEFS.

Arida et al., 2009

Probucol SNEF Sesame oil

Cremophor RH40

Ethanol

The bioavailability from the surfactant solution and the oil solution were

slightly lower compared to the self-nanoemulsifying drug delivery system.

Nielsen, Gibault

2007

Paclitaxel Super

saturable SEF

Glyceryldioleate ,

Cremophor EL

Cremophor EL

Ethanol, PEG 400

The paclitaxel S-SEFS formulation shows 10-fold higher Cmax and 5-fold

higher oral bioavailability compared to orally dosed Taxol formulation.

Gao et al., 2006

Acyclovir SMEF Sunflower oil

Tween 60, Glycerol

SMEFs increased the oral bioavailability of acyclovir by 3.5-fold compared

with the pure drug solution.

Patel et al., 2007

Diazepam SEF (pellets) C18 mono and di-

glycerides, Solutol HS15

Significant improvement in the in vitro dissolution of diazepam compared to

the release from the non-emulsifying formulation.

Abdalla, Mader

2007

Contd….




Excipients

Comments References

Coenzyme

Q10 (CoQ10)

SNEFs Witepsol H35

Solutol HS15

Lauroglycol

Result observed from SNEDDS vs reported SEFS were AUC (4.6 fold vs 2.4

fold), Cmax (5.5 fold vs 1.7 fold) and reduction in Tmax (2.0 fold).

Nepal et al., 2010

Lemon oil,

Cremophor EL,

Capmul MCM-C8

The extent of dissolution for the samples stored at 40 °C/75% RH was

comparable.

Nazzal et al., 2002

SEF (Tablet) Lemon oil

Cremophor EL,

Capmul MCM-C8

Cumulative percent of CoQ10 released within 8 h ranged from 40.6% to 90%. Nazzal, Khan 2006

Nitrendipine

(NTD)

SEF (pellets) Miglyol 812

Cremophor® RH40 and

Tween80 (2:1)

Transcutol P

AUC of NTD of SE pellets was 1.6-fold greater than the conventional tablets

and were comparable with the liquid SEFs.

Wang et al., 2010

Nimodipine SMEF Ethyl Oleate, Labrasol

Cremophor RH 40

AUC and Cmax after oral administration of the solid SMEFs were 2.6 and 6.6

fold higher, respectively, compared with those of the conventional tablet.

Yi et al., 2008

Furosemide SMEF Mygliol 812®

Caprylocaproyl macrogol

glycerides, Labrasol®

polyglyceryl-6 dioleate

Plurol Oleique®

Self-microemulsifying cores with completely solubilized drug (SMEFs with 1

and 5% furosemide) exhibited the fastest release profiles with pronounced

initial release.

Zvonar et al., 2010

Ezetimibe SNEF Capryol 90

Cremophor EL

Lauroglycol FCC

The SNGs filled into hard gelatin capsules showed 2-3 fold increase in the

dissolution rate as compared to plain drug filled capsules.

Dixit, Nagarsenker

2008

Contd……




Excipients

Comments References

Cyclosporine A SNEFs Phospholipids

Chremophor RH 40,

Tween 80, Span 80

Higher AUC and Cmax with lipospheres of small diameter. Bekerman et al.,

2004

SMEFs Hydrogenated castor oil,

medium chain

triglycerides

Polyethylene glycol

Sucrose monolaurate

Solid micellar solution exhibited significant higher Cmax bioavailability (141%

and 139% of Sandimmune, respectively).

Drewe et al., 1992

Silymarin

SEF (Pellets) Migliol®812, Tween80

Propylene glycol

Developed formulation containing (phototherapeutic extract of silymarin)

enhanced the oral bioavailability of its main active compounds.

Iosio et al., 2010

Diclofenac SEF (Tablet) Goat fat

Tween 65

Batches with higher Tween 65: goat fat content ratios yielded better release

rates.

Attama 2003

Dexibuprofen SEF (Powder) Transcutol P, Labrasol

Labrafac CC, Capryol 90

AUC of solid SEFS was about two-fold higher than that of dexibuprofen

powder.

Balakrishnan et al.,

2009

Nimesulide SEF (Pellets) Mono and diglycerides

Polysorbate 80

Bioavailability: Pellets>Emulsions. Franceschinis et

al., 2005

Piroxicam SEF (Pellets) Lauroglycol 90

Cremophor EL

Transcutol HP

Piroxicam release was significantly enhanced with respect to pure drug. Franceschinis et

al., 2010

Curcumin SMEFs Ethyl oleate, Cremorphor

EL, Poloxamer 188

Propylene glycol 400,

Tween 80

Solubility: SMEFs>curcumin suspension. The solubility of curcumin in SMEFs

was found as 21mg/g.

Cui et al., 2009

Contd……




Excipients

Comments References

Ligusticum-

chuanxiong oil

(VOC)

SMEF Chuanxiong oil, Tween-80

Propylene glycol

The absorption rate of VOC-SMEFs capsules was 2.53 and 1.59 times higher

than that of VOC and VOC/β-Cyclodextrin inclusion (β-CD), and the per cent

absorption was 1.55 and 28.19 times higher than that of VOC and VOC/β-

CD, respectively.

Yao et al., 2010

Curcumin SMEF Labrafac PG and Capryol

90, Cremophor EL,

Labrasol, Propylene

glycol, polyethylene glycol

400

Bioavailability of curcumin from liquid SMEFs and SMEFs pellets was about

16-fold higher than that of unformulated curcumin.

Setthacheewakul et

al., 2010

Progesterone SEF (Pellets) Captex 355, Capmul

MCM Solutol HS 15

Solubilization capacity strongly depends on the concentration of

endogenously secreted materials such as bile salts and phospholipids.

Abdalla et al., 2008

Exemestane SMEF Capryol 90, Transcutol P

Cremophore EL

The relative bioavailability of exemestane of SMEFs was enhanced 2.9 fold. Singh et al., 2009

Vitamin E SEF (Powder) Palm oil, Tween, Span AUC: SEFS> soft gelatin capsule. Julianto et al., 2000

Methyl and

Propyl Paraben

SEF

(Controlled

release

Pellets)

Mono- and diglycerides of

capric and caprylic acids

Tween 80, Ethanol

and glycerol

Water-soluble polymer can refine the control of the in vitro release of drug

from such pellets.

Serratoni, Newton

2007

Vinpocetine Peanut oil, mono- and di-

glycerides

Croscarmellose Sodium,

Microcrystalline Cellulose

Polysorbate 80

Bi-layered pellets resulted in plasma levels 2.4 fold higher than the physical

mixture.

Iosio et al., 2008



Table 8: List of selected commercially available lipid-based formulations for oral administration

Active moiety Trade name/

Company Dosage forms Indication

Cyclosporin A Neoral (Novartis) Soft gelatin capsule, 50 and 100 mg Immuno-suppressant

Sandimmune (Novartis) Soft gelatin capsule, 25, 50 and 100 mg

Gengraf (Abbott) Hard gelatin capsule

Panimumbioral (Panacea Biotec) Capsule, 50 and 100 mg

Ritonavir Norvir (Abbott) Soft gelatin capsule, 50 and 100 mg HIV antiviral

Isotretinoin Accutane (Roche) Soft gelatin capsule, 10, 20 and 40 mg Acute promyelocytic leukemia

Sanquinavir Fortovase (Roche) Soft gelatin capsule, 200 mg HIV antiviral

Lopinavir and Ritonavir

Kaletra (Abbott) Soft gelatin capsule, 133.33 mg and Ritonavir 33.3 mg

HIV-1 antiviral

Tipranavir Aptivus (Boehringer Ingelheim) Soft gelatin capsule, 250 mg HIV-1 Antiviral

Amprenavir Agenerase (Glaxo Smithkline) Soft gelatin capsule, 50 mg HIV antiviral

Valproic acid Convulex (Pharmacia) Soft gelatin capsule, 150, 300, 500 mg Antiepileptic

Bexarotene Targretin (Ligand) Soft gelatin capsule, 75 mg Antineoplastic

Calcitriol Rocaltrol (Roche) Soft gelatin capsule, 0.25, 0.50 mcg Calcium regulator



Another formulation marketed as an amorphous, semi-solid dispersion was the hard gelatin

capsule of ritonavir (Norvir®). However, unexpected precipitation of amorphous ritonavir as a

less soluble crystalline form in the excipient matrix negatively impacted both the drug dissolution

rate and bioavailability, leading to a temporary withdrawal of the product from the market in

1998. Norvir® was reintroduced in 1999 after reformulation as a thermodynamically stable

solution containing 100 mg of ritonavir solubilized in a self-emulsifying excipient delivered in soft

gelatin capsules. Saquinavir was first introduced in 1996 as a solid oral dosage form (Invirase®)

and subsequently, as a self-emulsifying lipid-based formulation in a soft gelatin capsule

(Fortovase®) containing 200 mg of saquinavir. In 2006, Fortovase® was removed from the

market due to lack of demand. Saquinavir is still available as 200 mg and 500 mg Invirase hard

gelatin capsules.

2.3. Drug Profile

The growing public interest in traditional medicine, particularly plant based medicines, has led to

extensive research on the potentials of natural substances (Wadhwa et al., 2013). Hundreds of

studies were conducted to investigate the effects of natural compounds on human health and

prevention and treatment of chronic diseases (Schmidt et al., 2007). Among studied

compounds, polyphenols appear as one of the most promising groups. These have recently

received much attention in disease prevention and treatment due to their proven anticancer

capabilities (Zern and Fernandez, 2005). Polyphenols are mainly derived from human food

including peanuts, dark chocolate, green and black tea and turmeric. Among polyphenols,

curcumin is currently one of the most studied substances.

Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is a major chemical

component of turmeric powder, produced from the rhizome of the plant Curcuma longa

(Jayaprakasha et al., 2002), and is also known as diferyloylmethane. It contains two

parahydroxyl groups responsible for antioxidant activity, two keto groups and two double bonds

responsible for anti-inflammatory, anticancer and antimutagenic activity, two methoxy groups

and an active methylene group (

Figure 3) (Priyadarsini et al., 2003). Physicochemical properties of CUR are enlisted in Table 9.

CH

H3CO

OH

CH C

O

CH2 C

O

CH

CH

OH

OCH3

1

1

33

22

Figure 3: Structure of curcumin; 1. parahydroxyl groups; 2. double bonds; 3. keto groups



Table 9: Physicochemical properties of CUR

Parameter Specification Reference

Appearance Orange-yellow crystalline powder

Aggarwal et al., 2003 Molecular formula

(Molecular weight)

C21H20O6 (368.37 Daltons)

pKa 7.8, 8.5, and 9.0 Tonnesen et al.,1985

Melting point 183˚C Sharma et al., 2005

Solubility Ethanol (10 mg/ml)

Acetone (20 mg/ml)

Water (0.6 µg/ml)

Tonnesen et al.,2002

Log P 3.29 US 2009/0326275A1

BCS Class IV Tonnesen et al., 2002

Stability Unstable in neutral or alkaline conditions,

pH dependent

Tonnesen et al.,1985

2.3.1. Pharmacological aspects of selected drug

The pharmacodynamics and pharmacokinetic profile of CUR are described below:

Pharmacodynamics

CUR has been reported as one of the most promising candidates of natural origin (Aggarwal

and Sung, 2009) exerting a fascinating array of pharmacological effects in cells in vitro at

physiologically attainable and supra physiological concentrations. Studies indicated that

curcumin exerts hepato and nephroprotective, thrombosis suppressing and myocardial

infarction-protective properties. Figure 4 highlights some of these activities.

Figure 4: Highlights of therapeutic potentials of CUR



Additionally, its strong antioxidant, antimicrobial, anti-carcinogenic and anti-inflammatory

activities were also reported (Aggarwal and Harikumar, 2009). The mechanisms for anti-

inflammatory potential of CUR may include:

Suppression of the activation of the transcription factor (NF–κB), which regulates the

expression of pro-inflammatory gene products (Singh et al.,1995)

Down-regulation of the expression of cyclooxygenase-2 (COX-2), an enzyme linked with

most types of inflammations (Kawamori et al., 1999)

Decrease the activity and protein levels of inducible nitric oxide synthase (iNOS) enzymes

through reducing the expression of iNOS genes (Ben et al., 2011)

Inhibition of arachidonic acid metabolism via lipoxygenase and scavenging the free

radicals generated in this pathway (Menon and Sudheer, 2007)

Down-regulation of the expression of various cell surface adhesion molecules that have

been linked with inflammation

Decrease in the expression of various inflammatory cytokines, including TNF-α, IL-1, IL-6,

IL-8, and chemokines

All these effects lead to lowering the formation of inflammatory compounds and suppressing the

inflammatory response. This outcome is considered to be beneficial in many abnormal

conditions such as autoimmune diseases (Jagetia and Aggarwal, 2007). Furthermore, there are

growing evidences linking many of the targets mentioned above with tumor promotion. Studies

have shown that overexpression of enzymes such as COX-2 and iNOS have been implicated in

carcinogenesis of many tumors. Although it has not any direct effect on the human cells, it

should be noted that curcumin is potentially chemopreventive (Hasima et al., 2012).

Pharmacokinetics

Pharmacokinetic parameters of CUR are listed in Table 10. It has poor absorption, low

biodistribution, high metabolism and low bioavailability. Cmax is achieved after about 1-3 h.

Protein binding is approximately 97%. It is metabolized predominantly by demethylation and

conjugation, and is eliminated mainly as metabolites in the bile and faeces.

Table 10: Pharmacokinetic parameters of oral CUR (Anand et al., 2007)

Pharmacokinetic parameters* Value

AUC (ng.hr/ml) 461.86

Peak plasma concentration (Cmax) 149.8 ng/ml

Time to reach Cmax (Tmax) 1-3 h

Elimination half-life (t1/2) 2.3 h

Elimination rate constant 0.296 h-1



2.3.2 Research findings of the selected drug

More than 6000 articles published within the past two decades, researching the molecular basis

for antioxidant, anti-inflammatory, antibacterial, antiviral, antifungal, and anticancer activities of

curcumin (Figure 5). Over one hundred clinical trials conducted on this molecule, prove its

potential in various chronic conditions, including autoimmune, cardiovascular, neurological, and

psychological diseases, as well as diabetes and cancer.

Figure 5: Trends in scientific publication(s) on CUR formulations over last 13 years (2000-2013)

2.2.3. Limitations in formulating dosage forms and delivery systems

Despite the demonstrated efficacy of curcumin its poor systemic bioavailability after oral dosing

compromises the therapeutic potential. Major reasons contributing to low bioavailability of

curcumin include poor absorption and rapid systemic elimination (Strimpakos and Sharma,

2008). Numerous previously reported studies have aimed at improving its poor aqueous

solubility, low bioavailability, poor alkaline stability and/or rapid intestinal metabolism of

curcumin. These include novel formulation containing curcumin impregnated soluble dietary

fibres dispersion, with enhanced bioavailability (20 times) than unformulated curcumin

(Rodriguez et al., 2008). Curcumin may also be combined with piperine, which inhibits

enzymatic conjugation and allows enhanced absorption of unchanged curcuminoids into the

portal blood (Chuah et al., 2013). Table 12 enlist various system developed to enhance the

bioavailability of CUR. In addition, various strategies have been undertaken to deliver CUR in

colon cancer with enhanced systemic bioavailability. Table 13 enlist various system developed

to deliver CUR in colon cancer.



However, these aforementioned systems have poor localization efficacy due to rapid drug

absorption into the systemic circulation. A review of literature suggests that the application of

carrier technology is not limited to scientific interest in such formulations, but underlines the

potential and versatility in addressing the problems associated with poorly aqueous soluble

drugs for localized delivery (Sylvester et al., 2013, Barrias et al., 2005). Newer approaches,

such as self-emulsifying drug delivery system, have also found its way in enhancing the

solubility of CUR in colonic conditions and have several advantages over the existing ones

(Zhang et al., 2012, Huang et al., 2013).

Table 11: Recent patents of curcumin (grant in 2014 only)

Patent Number Details

US20140193533 Formulation of curcuminoids with enhanced bioavailability of curcumin, demethoxycurcumin, bisdemethoxycurcumin and method of preparation and uses thereof

WO 2013016257 A8

Botanical antioxidant compositions and methods of preparation and use thereof

US 20140161915 A1

Solubilization of cucurminoid compounds and products thereof

US20140127179 Natural killer cell formulations

US20140099390 Formulation of curcumin with enhanced bioavailability of curcumin and method of preparation and treatment thereof

US20140093594 Composition to enhance the bioavailability of curcumin

US20140065061 Curcumin, a liposomal-PLGA sustained release nanocurcumin for minimizing the prolongation for cancer therapy

US20140051742 Lipophilic curcumin analogs and methods of inhibiting HIV-1, treating latent HIV in the brain, and preventing HIV-mediated cognitive decline and HIV dementia

US20140039031 Pharmaceutical formulations of acetyl-11-keto-b-boswellic acid, diindolylmethane and curcumin for pharmaceutical applications

US20140010903 Curcuminoid composition with enhanced bioavailability and process for its preparation



Table 12: Systems developed to enhance CUR bioavailability

Formulation Details Reference

Nanoparticles Significant delay in progression of diabetic cataract by nanocurcumin attributed to its ability to intervene the biochemical pathways of disease

Grama et al., 2013

Nanoemulsion

Increase in hydrophilicity, bioaccessibility and protection from degradation Sari et al., 2014

Phosphatidylcholine (EPC) liposomes

Curcumin formulated with phosphatidylcholine led to higher systemic levels of parent agent than unformulated curcumin.

Marczylo et al., 2007

Chitosan chloride liposomes

Enhanced bioavailability, compared with curcumin encapsulated by uncoated liposomes and curcumin suspension.

Chen et al., 2012

Self-emulsifying drug delivery system(SEDDS)

Castor oil-(tween-80) -ethanol = 28: 55: 20 (w/ w/w) was selected for optimum curcumin SEDDS.

Wang et al., 2010

Curcumin-SMEDDS in liquid and pellet formulations rapidly formed fine oil-in-water microemulsions

Setthacheewakul et al., 2010

Absorption of curcumin in SMEDDS was via passive transfer by diffusion across the lipid membranes.

Cui et al., 2009

β-cyclodextrin nanoparticle

Formulation increased the dissolution rate of curcumin upto10-fold (p < 0.01). Rachmawati et al., 2013



Table 13: Various systems developed to deliver CUR to intestine in colon cancer

Formulations Description References

PLGA nanoparticles Nanoparticulate curcumin was more bioavailable and had a longer half-life than

native curcumin as revealed from pharmacokinetics study.

Mohanty et al., 2010

N,O-carboxy methyl chitosan

nanoparticles

Improved plasma half-life of curcumin and 5-Fluorouracil up to 72 h. Anitha et al., 2014

pH-sensitive nanoparticles Formulation significantly decreased neutrophil infiltration and TNF-α secretion

while maintaining the colonic structure

Beloqui et al., 2014

Synergistic action of the curcumin-celecoxib drug combination, provide enhanced

efficacy for mitigating ulcerative colitis.

Gugulothu et al., 2014

Lyophilised egg phosphatidylcholine

(EPC) liposomes

Egg phosphatidylcholine liposomal formulation improved cytotoxic activity versus

free curcumin against colorectal cancer cell lines

Pandelidou et al., 2011

Calcium pectin microsphere Eudragit coated calcium pectinate microsphere formulation effectively protected

curcumin in the upper gastrointestinal tract, and then curcumin could be released

specifically in colon

Zhang et al., 2011

REVIEW OF LITERATURE - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/49545/10/10_chapter2.pdf · NE30D as time-dependent coat and Eudragit FS 30D as pH-dependent coat) Kulthe

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