Pectin in controlled drug delivery – a review

Pectin in controlled drug delivery – a review

LinShu Liu*, Marshall L. Fishman and Kevin B. HicksCrop Conversion Science and Engineering Research Unit, Eastern Regional Research Center, AgriculturalResearch Service, U.S. Department of Agriculture, 600 E. Mermaid Lane, Wyndmoor, PA 19038, USA;*Author for correspondence (e-mail: [email protected]; phone: +1-215-233-6486; fax: +1-215-233-6406)

Received 23 May 2006; accepted in revised form 26 September 2006

Key words: Pectin, Nasal delivery, Oral delivery, Fragrance delivery, Controlled drug delivery

Abstract

Controlled drug delivery remains a research focus for public health to enhance patient compliance, drugefficiency and reduce the side effects of drugs. Pectin, an edible plant polysaccharide, has been shown to beuseful for the construction of drug delivery systems for specific drug delivery. Several pectin derivedformulations have been developed in our laboratory and tested in vitro, ex vivo, and in vivo for the ability todeliver bioactive substances for therapeutic purposes in the context of interactions with living tissues. Pectinderivatives carrying primary amine groups were more mucoadhesive and have shown potential in nasaldrug delivery and other mucosal drug delivery. Pectin derivatives with highly esterified galacturonic acidresidues are more hydrophobic and able to sustain the release of incorporated fragrances for a prolongedduration. Less esterified pectin derivatives are able to penetrate deeper into the skin and may be useful inaromatherapy formulations. Pectin, in combination with zein, a corn protein, forms hydrogel beads. Thebound zein restricts bead swelling and retains the porosity of the beads; the pectin networks shield the zeinfrom protease attack. The complex beads are ideal vehicles for colon-specific drug delivery. Studiespresented in this paper indicate the flexibility and possibility to tailor pectin macromolecules into a varietyof drug delivery systems to meet different clinical requirements.

Introduction

This review outlines the recent developments ofpectin as a drug delivery system, which were con-ducted in the Eastern Regional Research Center,Agricultural Research Service, US Department ofAgriculture. Pectin, extracted from the cell walls ofhigher plants, contains smooth regions (also calledlinear regions), and hairy, branched regions(Figure 1). The smooth regions are primarily madeup of a polymer of a-1,4-linked D-galacturonic acid(GalpA) residues, some of which are partiallyesterified with methanol at the C-6 carboxyl group

andmay be esterifiedwith acetyl groups atC-2 orC-3. The degree of esterification (D.E.) of the galact-uronic acid residues is an important parameter indetermining the solubility of pectin and its gellingand film forming properties. The D.E. varies withthe origin of the plant source, when and where theplant is harvested, and the processing conditions,such as storage, extraction, isolation, and purifica-tion etc. The hairy region in Figure 1, also referredto as rhamnogalacturonan-I (RG-I), contains abackbone of the repeating disaccharide [ fi 4)-a-D-GalpA-(1 fi 2)- a-L-Rhap-( fi ]. The GalpA resi-dues are not substituted with side chains; while, the

(2007) 14:15 –24 � Springer 2006

DOI 10.1007/s10570-006-9095-7

Rhap residues are substituted at C-4 with neutraland acidic oligosaccharide side chains composed ofmainly arabinose and galactose, with fucoseand glucuronic acid also present depending on thepectin source (Ridley et al. 2001). The structureof pectin existing in the plant cell wall is morecomplicated. It also contains a substituted galac-turonan, referred to as rhamnogalacturonan-II(RG-II). The backbone of RG-II is composed ofat least seven 1,4-linked a-D-GalpA residues, towhich are attached four structurally differentoligosaccharide side chains containing uncommonmonosaccharides such as apiose, aceric acid,3-deoxy-D-manno-2-octulosonic acid and 3-deoxy-D-lyxo-2-heptulosaric acid (Mohnen 1999; Perezet al. 2000; Ridley et al. 2001). RG-II is greatlyreduced or absent in commercial pectin due to theextraction and purification procedures used.

Pectin has a long safe history of use in foods.Particularly, it is used as a texturizer or stabilizerin acid food products because of its desirablestability in acidic conditions even at highertemperature. As an additive in pharmaceuticalapplications, researchers have attempted todevelop pectin as a drug delivery system (DDS)for controlled drug release. However, the com-mercial potential of this technology has yet to berealized. This is, partially, because of the lack ofreproducible performance of pectin formulations.Obstacles include the large diversity in pectin’smolecular characteristics, which generates diffi-culty in quality control and quality assurance

during intermediate preparation of pectin deriva-tives and in the final products. Solutions toresolve the problem fall into two categories: thedevelopment of new technologies for pectinisolation, purification, and characterization(Fishman et al. 2003, 2004), and the modificationof pectin macromolecules. For the secondapproach, a series of pectin derivatives has beendeveloped in our laboratory by chemical andphysical methods. The resultant pectin formula-tions (Figure 2) are currently being evaluated fordrug-controlled delivery in the context of inter-actions with various tissues. These include nasaland oral drug delivery, and the controlled fra-grance release for skin care.

The newly developed pectin composites have anumber of improved properties in comparisonwith existing pectin-based formulations. Theseinclude: (i) higher drug loading efficiency; (ii) lesspre-mature drug release; (iii) greater efficiency forthe controlled release of peptide and protein drugs;(iv) increased biocompatibility because only bio-polymers are used for composite fabrication; (v)their swelling and degradation behaviors can beeasily tailored to meet the requirements of incor-porated drugs and targeted tissue sites. Thecontrollable swellability and degradability aremainly realized through the alteration of compo-sitions and/or physical characteristics, such asporosity and wall thickness. The functionalities ofnewly developed pectin derivatives are summa-rized in following sections.

OOH

OH

CO2MeO

OH

OH

CO 2- H

OOH

OAc

CO2MeO

OH

OH

CO 2- H

O OH

OH

CO 2Me

O O

OH

CO 2Me

O O O O O O OAc

Figure 1. A co-linear model for pectin organization (top, cited from Perez et al. 2000 Plant Physiol Biochem with permission) and the

structure of smooth region – homogalacturonan (bottom, cited from Carpita et al. 2000 in ‘‘Biochemistry & Molecular Biology of

Plants’’ pp. 52 –108 with permission).

16

Pectin formulations for nasal drug delivery

Drug administration via the nasal route is analternative to injection. Nasal drug delivery hasbeen used traditionally for the treatment of localnasal diseases, such as congestion, allergy, infec-tion, and inflammation. Now, nasal drug admin-istration is under intensive study for systemicdrug delivery. The entire nasal cavity, except forthe vestibule of the nose, is lined with mucosaltissues, which function in filtering out small air-borne particles, warming, and humidifyinginhaled air before the air reaches the lung. Forthese purposes, the nasal cavity is rich in bloodvessels. The veins of the nasal mucosa form avenous plexus in the connective tissue of the nose.Due to the high degree of vascularization, themajor advantage offered by nasal drug delivery isthe high nasal permeability. It only takes about15 min for a vaccine to transport through thenasal mucosa into the circulatory system (Jabbal-

Gill et al. 1998). In addition to rapid absorption,advantages of nasal drug administration includehigh patient compliance, self-medication, mildenvironmental conditions, such as no exposure toacid/basic pH solutions and no protease attack,and the avoidance of liver metabolism (Gozes2001; Dale et al. 2002; Born et al. 2002). Thelimitations of nasal drug delivery are mainly dueto the small absorption area in the nasal cavityand short residence time. The maximum dose togive is normally less than 150 ll and the givendosage formulations are quickly cleared. There-fore, drugs with low aqueous solubility needadequate formulations in order to be sufficientlyabsorbed by nasal mucosa. For therapeutics thatdemand a constant drug blood level, drugs inprolongable release formulations are required;otherwise, frequent nasal administration isrequired. From this point of view, nasal drugadministration is still a complicated processrequiring sophisticated formulations.

Figure 2. Pectin derived Drug Delivery Systems developed at the Eastern Regional Research Center, Agricultural Research Service,

Department of Agriculture, USA. (a) microspheres of pectin cross-linked with calcium, (b) comb-like structure created by lyophil-

ization, (c, d) multi-particulate tablet and (e, f) ‘shrapnel-like’ structure composed of pectin and poly(lactide-co-glycolide), (g) pectin

gels, (h) calcium initiated hydrogel bead, (i) coacervate of pectin with zein. Field width: a, 10.0 lm; b, f, h, and i, 1.0 mm; c, d, and e,

0.12 mm; g, 1.0 lm.

17

Pectin-based formulations are expected to beable to meet some of these challenges by facilitat-ing drug adsorption and bioavailability in nasalcavities, and as such to serve as a potentially idealnasal drug delivery system. We have investigatedthe effect of the side chain functional groups ofpectin derivatives on their interactions withmucosal tissues (Liu et al. 2005a). Pectin with theD.E. of 25% (P-25) or 93% (P-93) and pectinderivatives carrying primary amine groups (P-N)were used for the examination of negatively,neutrally, and positively charged pectins, respec-tively (Figure 3). P-N was prepared from P-25,after its de-esterification, according to the methoddescribed previously using 1-ethyl-3-(3-dimethyla-minopropyl)carbodiimide hydrochloride as a cou-pling reagent (Liu et al. 1991). All tested pectinderivatives reacted with mucin to form gel com-plexes. We demonstrated that pectin macromole-cules can diffuse into nasal mucosal tissues andpectin gel formulations can regulate the adsorp-tion of incorporated drugs (Liu et al. 2005b, c). Asshown in Figure 4a, pectin adsorption in nasaltissues was dependant on gel concentration andthe side chain functional groups of the pectin. Inthis experiment, the amounts of adsorbed pectinand bovine serum albumin (BSA) were determined

using fluorescence-labeled materials as tracers asdescribed previously (Liu et al. 2005a). Morepectin macromolecules penetrated into the mucinlayer of nasal cavity tissues from higher concen-trated pectin formulations. At the same gelconcentration, more pectin was adsorbed by nasalmucosal tissues from pectin derivatives carryingprimary amine groups (P-N) than from those withcarboxyl groups (P-25) or almost no charge (P-93).Due to its positive charge, P-N associates easilywith the negatively charged mucin. Resultsobtained from P-N drug formulations clearlyshowed the potency of pectin derivatives intargeting and functioning in nasal drug delivery

R =H or CH3P-25: CH3 = 25%P-93: CH3 = 93%

=

C-OR

O

PECTIN

=

C-OR

O

PECTIN P-25

EDCEthylenediamine

=

C-

OP-N

PECTIN N(CH2)2NH2H

(A)

(B)

Figure 3. Pectin derivatives with the D.E. of 25% (P-25), 93%

(P-93), or carrying –NH2 groups (P-N). The P-N was prepared

according to the method described previously using 1-ethyl-3-

(3-dimethylaminopropyl)carbodiimide hydrochloride as the

coupling reagent (Liu et al. 1991).

Gel concentration (mg/ml)

Pec

tin

adso

rpti

on (

mg/

cm2 )

0

1

2

3

4

5

Pectin concentration (mg/ml)0 5 10 15 20 25 30 35 40

Mas

s ad

sorp

tion

(%

)

0

10

20

30

40

50

60

70

0 15 30 45

A

B

Figure 4. (a) Pectin adsorption on nasal cavity tissue from

various formulations: P-N (�), P-25 (s), and P-93 (.); (b) Mass

uptake by nasal cavity tissues from P-N gel formulation: Pectin

(solid bar), BSA (open bar). Study was performed under stan-

dard tissue culture conditions (CO2 5%, O2 95%) at 37 �C for

4 h. The amounts of adsorbed pectin and BSA were determined

according to Ref. Liu et al. (2005a). Nasal cavity tissues were

harvested from a freshly slaughtered healthy adult swine from a

local slaughterhouse.

18

studies (Liu et al. 2005a, b, c). Drug deliveryprofiles from different pectin formulations areshown in Figure 4b. More BSA from the gels oflower pectin content adsorbed onto nasal cavitytissues than that from higher pectin gels. Theresults also suggested two different mechanismsfor drug release from pectin formulations: at alower pectin concentration, BSA was adsorbed bynasal cavity tissues at a higher rate than was pec-tin; thus, drug uptake obeys a diffusion controlmechanism. At a higher gel density, both BSAadsorption and pectin diffusion were found tooccur at the same rate; thus, drug adsorption isdetermined by gel dissolution. We also found thatnanoparticulates pre-incorporated in pectin gelscould be transported into nasal mucosal tissues(data not shown). The nanoparticulates can serveas drug carriers and efficiently release encapsu-lated drugs for a prolonged duration. The resultswill be discussed in an upcoming paper (Kendeand Liu, in preparation).

Because of pectin –mucin complex formation,pectin is mucoadhesive. The epithelia of the nasalcavity secrete a mucous substance to coat thewalls, aiding in mucociliary clearance of smallparticles trapped on the mucosal surface. There-fore, the drug residence time in nasal cavities isusually very short. The interaction of pectin withmucin should cause a synergistic increase in vis-cosity, which is followed by an ‘interdiffusion andinterpenetration’ process (Hassan and Gallo 1990;Rossi et al. 1996; Tamburic and Craig 1997; Liuet al. 2005a). This process initiates intimate con-tact between the polymer and the mucus layer.Therefore, pectin formulations possess a relativelylonger residence time at the nasal cavity. Themeasurement of the interaction between pectin andmucus layer, synergism parameter (DG¢), is calcu-lated from

DG0 ¼ G0mix � ðG0p þ G0mÞ

where G¢p, G¢m, and G¢mix are the elastic moduli ofpectin formulation, mucin, and their mixture,respectively. The positive value of DG¢, the inter-action term, indicates the strength of adhesion. Wehave demonstrated that P-N gel formulationscould introduce the highest value of DG¢, indicatingthe strongest mucoadhesive property (Liu et al.2005a, b). P-N is now under investigation as avaccine carrier for nasal immunization.

Another important advantage of pectin formu-lations is the exclusion of the use of organic sol-vents in dosage preparation. This biopolymer is awell-known gelling material. It gels in aqueoussolutions under mild conditions; pectin derivativesalso coacervated easily with calcium, proteins,polypeptides, and polyphosphates. A large numberof drugs can be simply incorporated into pectinformulations by various physical methods, such asdiffusion, mixing, encapsulation, or co-precipita-tion. These lead to the avoidance of drug dena-turation and possible irritation of the dosageforms to mucosal tissues.

Biocompatibility has been examined in a ratmodel using pectin formulations without drug. Noadverse effects related to the intranasal adminis-tration of P-N, in the forms of gels or micro-spheres, could be identified by visual observationor histological examinations (data not shown). Inaddition, there were no negative histologicalappearances, such as swelling and epithelial cellloss post administration. This will be discussed indetail in a forthcoming paper (Kende and Liu, inpreparation).

Pectin formulations for oral drug delivery

Although many parenteral drug delivery systemshave been developed, the importance of oral drugdelivery has not faded. Oral delivery is still the mostpopular and conventional way of drug adminis-tration, because of its higher likelihood of compli-ance and the convenience of self-administration.The development of oral drug delivery systems hasbeen fostered at an accelerated pace by the need todeliver drugs more efficiently and with fewer sideeffects. In contrast to nasal drug delivery, orallyadministered drugs have to transport over a longdistance and experience different environmentalconditions, mainly, the low pH and constantmechanical pressure in the stomach, proteaseattack in the small intestine, and microflora diges-tion in the colon, and variation in residence time atdifferent segments of the gastrointestinal (GI) tract(Meyer et al. 1985;Davis et al. 1986). The impact ofenvironmental variation on drug stability is a con-cern, especially, for protein or polypeptide drugsthat are used increasingly. To protect drugs againstdegradation, drugs are encapsulated or incorpo-rated in tablets, capsules, ormicro- or nanoparticles

19

prior to administration. Encapsulation technologyis also used for drug modified-release and taste-masking. Pectins have been suggested as useful rawmaterials to construct drug carriers for oral drugdelivery. A series of studies have been performed toexplore this possibility (Sinha and Kumira 2001;Vandammer et al. 2002; Liu et al. 2003). This isbecause, as mentioned above, pectin is an ediblepolysaccharide and has a long safe use history in thefood industry. Furthermore, pectin passes intactthrough the upper gastrointestinal tract and isdegraded by colonic microflora, which remainrelatively consistent across diverse human popula-tions. This has directed researchers to focus on thedevelopment of pectin as a drug carrier for colon-specific drug delivery. One obstacle to overcomewith pectin application for colon-specific drugdelivery is that pectin formulations swell consider-ably in physiological conditions. Drugs with highsolubility in physiological conditions may display apre-mature release due to the expanded pore size ofpectin formulations. The use of pectin in the com-bination with other polymers to form more stablestructures is a strategy to overcome this problem(Semde et al. 2000; Kwabena and Fell 2001;Turkoglu and Ugurlu 2002).

In our laboratory, several pectin compositeshave been developed for this purpose (Figure 2).Pectin/zein complex hydrogel beads are one ofthese composites showing promise. Zein is a majorstorage protein of corn kernels, is a hydrophobicpolymer and attractive for several industrial pur-poses due to its capability to adhere to or coat toother surfaces (Shukla and Munir 2001; Mathio-witz et al. 1993). The pectin/zein complex hydrogelbeads were prepared by pumping pectin gel into anethanol solution containing zein and calciumchloride at designed ratios (Liu et al. 2005b, c,2006). Confocal laser scanning microscopyrevealed a porous, roughly spherical structure forthe beads. The zein was mainly located around theperiphery of the beads to form a shell-like struc-ture, but also migrated into the beads, where theprotein macromolecules were either bound to thepectin networks or aligned to densely packed fibers(Figure 2). Dissolution experiments showed animproved stability of the complex beads in theenvironments that mimic the upper GI tract. Theinclusion of a small portion of zein into the pectinnetworks not only suppressed the swelling behaviorof pectin (Figure 5a), but also offered the beads

great protease resistance (Figure 5b). The ‘shell’around the beads restricted the swelling of pectinnetworks, in turn; the steric hindrance of pectinnetworks shielded the bound zein from proteasedigestion. Meanwhile, the in vitro study showed noeffect of zein coating on pectinase-induced degra-dation of beads in a medium mimicking the lowerGI tract.

Incubation time (hrs)

Incr

ease

in b

ead

diam

eter

(%

)

0

50

100

150

200

250

0

0 20 40 60

2 4 6 8 10

A

B

Concentration of pepsin (mg/100 ml)

zfo

%e

niam er

nied

ebeht

nisd a

0

5

10

15

Figure 5. (a) Swelling measurement of drug-free pectin hydro-

gel beads in solutions with different pH at ambient temperature.

For calcium pectinate, a pH-dependent swelling behavior could

be clearly seen at pH 3.5 (dash line), pH 5.0 (solid line), and pH

7.4 (dotted line). For pectin/zein complex (dash-dotted line), no

obvious changes in beads size could be recorded at pH 7.4; the

same at pH 3.5 and pH 5.0 (data not shown). Cited from Drug

Delivery 2006; 13: 1 –7 with permission. (b) Effect of pepsin on

pectin/zein degradation. Complex beads with zein content at

5.4% (s) and 16.8% (�) were incubated in KH2PO4 –citrate –

pepsin buffer containing pepsin of different concentrations at

pH 3.5 at 37 �C for 4 h. A constant amount, about 4% of total

zein, was remained to bound on the beads. Cited from Drug

Delivery 2006; 13: 417 –423 with permission.

20

As delivery vehicles, the pectin/zein complexhydrogels have shown great potential in carryingthe encapsulated drugs to the colon and specifi-cally releasing them at the site. Figure 6 shows thekinetics of protein released from pectin/zein beadsusing bovine serum albumin as a model proteindrug. For the complex beads, the release of BSAwas suppressed in pectinase-free media (Figure 6,zones I and II), while a highly concentrated BSAwas detected in the buffer containing Pectinex 3XL(Figure 6, zone III). Furthermore, by adjusting theamount of bound zein, the BSA release profilecould be controlled.

In practice, a single dose of a mixture of complexbeads with different zein contents can be used todeliver drugs at several different time points. Such asystem may be useful for oral vaccine or antibioticdelivery. Oral vaccine delivery requires stimula-tion of antibody producing cells at two to threesuccessive time points within a day or two. A singleadministration of a cocktail of different pectin/zeinbeads is expected to provide such stimulation. Anexample is to deliver antibiotics such as ciproflox-acin against Bacillus anthraces or anthracis. Forthis case, a single administration of a cocktail ofselective pectin and pectin/zein beads is expected to

provide a sufficiently high serum level of the drugfor prolonged periods (Liu et al. 2006).

Pectin formulations for controlled fragrance release

Fragrance, natural or synthetic, is made up ofvolatile compounds. For storage and applicationpurposes, fragrances are formulated in gels,ointments, films, or encapsulates. (Okabe et al.1992; Herrmann et al. 2000; Vaddi et al. 2002;Nakayama et al. 2003). In the pharmaceuticalindustry, fragrances are often used in dermato-logical formulations to make the formulation smellbetter, and to promote drug diffusion by changingthe structure of stratum corneum, a barrier layerof the skin (Williams and Barry 1991, 1993). Thereare also several fragrances used in aromatherapymassage, such as the treatment of viral hepatitisand to reduce anxiolytic influence (Cooke andErnst 2000; Zhai and Maibach 2001; Cal andSznitowaska 2003; Lahlou 2004; Giraud-Robert2005). Although aromatherapy has been lessstudied in controlled academic studies, its use isincreasing dramatically. Furthermore, fragrancesare used in many household products. Examplesinclude the use of essential oils and citronellal inmosquito repellant, which still is one of the mosteffective and inexpensive strategies in malariaprevention (Gbolade 2001; Burfield and Reekie2005). The sustained release of fragrances andtheir interaction with drugs or tissues can bemediated by the physical and chemical propertiesof formulations, such as dose, porosity, viscosity,and hydrophobic or hydrophilic properties.

Pectin is a well-known gelling and thickeningreagent. Pectin has demonstrated the ability tocarry fragrances in many food products. In thispreliminary research, we first investigated theeffect of pectin D.E. on the controlled release offragrances for non-food applications, using citro-nellal as a model compound. Four pectin gel for-mulations with different D.E. values were studied(Liu et al. 2005d). The released citronellal wasanalyzed by a headspace-sampling and GC-FIDmethod; the amount of citronellal was determinedby measuring the peak area on a correlated GCchart. As determined by measuring the contactangle of an air bubble on the surfaces of pectinfilms in ethanol, low D.E. pectin is more hydro-philic than high D.E. pectin. As the results in

Incubation time (hr)0 2 4 6 8 10 12 14 16

Cum

ulat

ive

rele

ase

(mg/

100m

l)

0

3

6

9

12

15

18ZONE I ZONE II ZONE III

Figure 6. Cumulative release of BSA from pectin beads (�) andpectin/zein beads (s, 5.4% zein; ., 16.8% zein) at 37 �C. Therelease media were changed in the sequence of (zone I) 0.01 M

KH2PO4 –citrate buffer (pH 3.5) for 2 h, (zone II) Sorensen’s

phosphate buffer (pH 7.4) for 4 h, and (zone III) 0.05 M

phosphate –citrate buffer (pH 5.0) containing with Pectinex

3XL (120 FDU/ml) for 8 h. The experiment was performed by

placing �75 mg dry beads in 100 ml release medium. BSA

content was 154±9 mg/g (�), 192±16 mg/g (s), and

191±5 mg/g (m). Cited from Drug Delivery 2006; 13: 417 –423

with permission.

21

Figure 7a show, the release of citronellal from thehigher D.E. pectin formulation was slow andrelatively constant. The release of citronellal fromthe lower D.E. pectin formulation was rapid, dis-playing an unsymmetrical bell-like curve. Since thetwo formulations have similar viscosity while dif-fering from each other only in their D.E. and theindex of hydrophilicity, the results indicate theeffect of the hydrophobic property of pectins onthe controlled release of a volatile fragrance. Theinfluence of the hydrophobic properties of gelformulations on citronellal release was confirmedby the following study using three other pectinformulations with the D.E. of 93, 65, and 25. The

rate of citronellal release decreased in the sequenceof pectin pectin(25)>pectin(65)>pectin(93)(Figure 7b).

The role of pectin derivatives on the interactionof citronellal with skin tissue was studied. Fourpectin/citronellal formulations were coated onhairless pigskin and exposed to air flow for 8 h; atthe conclusion of experiments, the adsorbed cit-ronellal was extracted with ethanol and measuredby GC-FID (Liu et al. 2005d). In this limited dataset, citronellal adsorption appeared to reach amaximum at a D.E. of 25%, then decreased as theD.E. increased further (Figure 8a). The release ofadsorbed citronellal from pectin-coated skin was

Incubation time (min)

0 100 200 300 400 500 600

0 100 200 300 400 500 600

Cit

rone

llal p

eak

area

0

500

1000

1500

2000

2500

Incubation time (min)

Cit

rone

llal p

eak

area

0

200

400

600

800

1000

A

B

Figure 7. (a) Comparison study on the kinetics of citronellal

released from two pectin formulations with same viscosity: P-93

(dash line) and P-10 (solid line). The citronellal content in the

headspace of gel formulations were measured by GC-FID

method. Cited from Drug Delivery 2005; 12: 149 –157 with

permission. (b) Effect of the D.E. of pectin on the constancy of

citronellal release. The pectin content in all formulations was

4%, w/v. P-25 (solid line), P-65 (dotted line), and P-93

(dash line). Cited from Drug Delivery 2005; 12: 149 –157 with

permission.

Effect of pectin D.E. on citronellal adsorptionpectin

(10)

pectin(25)

pectin(65)

pectin(93)

Am

ou

nt

of

citr

on

ella

l (n

g/c

m2 )

0

200

400

600

800

1000

Incubation time (hrs)

Cum

ulat

ive

citr

onel

lal r

elea

se (

%)

00 2 4 6 8 10

20

40

60

80

100

120

A

B

Figure 8. (a) Cumulative adsorption of citronellal from various

pectin formulations (4%, w/v) to the receptor skin layers after

8 h incubation. Data expressed as mean±SD (n = 5). Cited

from Drug Delivery 2005; 12: 149 –157 with permission. (b)

Cumulative release of citronellal from the host skin layers pre-

coated with P-93 (broken line), P-65 (dash line), P-25 (dotted

line), and P-10 (solid line). Cited from Drug Delivery 2005; 12:

149 –157 with permission.

22

also a function of pectin DE. Figure 8b shows therelease kinetics of adsorbed citronellal from theskin layers. Citronellal released at a much lowerrate from skin pre-coated with lower D.E. pectinformulations than from that pre-coated withhigher D.E. pectin formulations. This study sug-gested that the adsorption of citronellal to, andelimination from, the skin could be mediated bythe pectin formulations.

Conclusions

Because of its gelling, film forming and bindingproperties, biocompatibility, and non-toxicity,pectin is a very promising biopolymer to constructdrug carriers for controlled drug delivery. Pectinformulations are easily tailored into gels, 3-Dmatrices, films, micro- or nano-particles. Variousdrugs can be incorporated into pectin formula-tions with high loading efficiency by simple pro-cedures. Furthermore, chemical modifications ofpectin have improved the polysaccharide for sev-eral specific applications. Pectin derivatives carry-ing a higher charge density (either positive primaryamine or negative carboxyl groups) were able topenetrate deeply into tissue, thus, prolonging theresidual time to incorporate drugs and enhancingtheir penetration. High D.E. pectin derivativeswere able to better retain incorporated drugs.Pectin and zein composite gels are able to deliver adrug (or the combination of several drugs) tospecific G.I. segments at designed time points.Thus, pectin formulations seem to be importantpotential carrier systems for controlled drugdelivery.

Although pectin has a long use history in thefood industry, the application of pectin as a carrierfor controlled drug delivery still is in its infancy.Pectin must compete in DDS with other polysac-charides. Examples include chitosan, alginate,dextran, inulin, and derivatives of carboxymethylcellulose or (hydroxypropyl)methyl cellulose.Comparison studies with these biopolymers inwell-defined clinical applications will be helpful tounderstand the relative merits of pectin andderivatives. Systematic studies of the interactionsof pectin and living tissues are needed. Progress inthis aspect will certainly accelerate the clinicapplications of pectin formulations as drug carri-ers and drug absorption enhancers.

Acknowledgements

The authors gratefully acknowledge Dr PeterH. Cooke (USDA-ARS-ERRC) and Dr MyerKende (USAMRIID) for their technical assistance.

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