-

Journal of Scientific & Industrial Research

Vol. 59, March 2000, pp. 20 1 -2 1 3

Trends in Controlled Drug Release Formulations Using Chitin and Chitosan

K. C. Gupta* and M. N. V. Ravi Kumar

Polymer Research Laboratory, Department of Chemistry, University of Roorkee, Roorkee 247 667 , India

Recently, the intel l igent drug delivery systems ( DDS) have attracted attention, because the release of drug can be control led via the system feedback, responding to the pathalogic environment signals. Muc

.h efto�t has concentrated on the

use of cheap raw materials and on simplifying the formulations for control led release t�erapl�s. USing natural polymers such as chitin and chitosan to compose this kind of pulsed DDS will be of immense benetlt. Chitin and chltos�n are among the abundantly avai lable polysaccharides in nature and are currently in use for the release of several drugs. ThiS review alms to present the recent developments in the usc of chitin and chitosan and their derivatives In the controlled drug release formulations.

Introduction

Of the several possible routes of introducing controlled release medication into the body, the oral administration of single dose medicinals is one of the simplest and safest, since it does not pose the steri lity problem and the risk of damage at the site of administration is also minimal . However, an oral controlled release formulation IS subjected to frequently changing environments during transit through the gastrointestinal tract , as it passes from the strongly acidic to the weakly alkaline medium in the lower part of the small intestine. The variable absorbing surfaces over the length of the GT tract adds further constraint to the design of oral dosage forms. Moreover, the stomach emptying period varies from person to person. These factors collectively introduce considerable variabi lity in the performance of oral controlled delivery systems. Several approaches have been taken in the past to prolong the retention of the dosage form in the stomach 1 , 2

.

The polymeric controlled delivery systems are being used for a wide range of reagents in various environments. The most popular application is the dl1lg delivery, in which tlie main objecti ve is to achieve an effective therapeutic adininistration for an extel ided

* Author for corrcsponden.:c: E-mai l : �s:gtS:..YSiLruJ:l<.LlJQ1]fLlD, Fax : +9 1 - 1 332-73560.

period of time. The technique is also termed as sustained release. These techniques have been used in the agricultural area for creating a continued environment of soil nutrients, insecticides, herbicides and other agro-expedient agents 3 using other polymers.

Chitin is a high molecular weight l inear polymer of N-acetyl-D-glucosamine (N-acetyl-2-amino-2-de­oxy-D-glucopyranose) units linked by �-D( 1 -74) bonds. It is highly insoluble in common solvents, resembling cellulose in its solubi lity and has low chemical reactivity. It may be regarded as cellulose with hydroxyl at position C-2 having being replaced by an acetamido group. Like cellulose, it naturally functions as a stlUctural polysaccharide. It is most abundant in clUstaceans, insects, and fungi . It is present in commercial quantities in the shells of lobsters, crabs and shrimps. The skeletal shells of these clUstaceans contain approximately 75% calcium carbonate and 1 5-20% chitin. Deacetylated chitin is a cationic polymer with many potential uses such as a textile sizer, adhesive, emulsifier and pharmaceutical component.

Chitosan is non-toxic and easily bioabsorbable4

with gel forming abil ity at low pH. Moreover, chitosan has antacid and antiulcer activities that prevent or weaken drug irritation in st0rtlach)' 6, Also, chi toSdl 1 matrix formulations appear to float and gradually swell in the acid medium. All theSe interesling {Jl operl ics of chitosan have made this natural polymer an ideal material for controlled dlUg release formulations.

202 J SCI INO RES VOL 59 MARCH 2000

Many excellent reviews and books have dealt the properties, chemistry, biochemistry and applications of chitin, chitosan and their derivatives7-? However, only a few reviews have reported the biomedical appli-. f h" / h ' 10- 1 2 d h ' catIOns 0 c 1tm c Itosan an no compre enSlve review has yet been publ ished on the controlled drug release formulations using chitin and chitosan . The purpose of this article is to take a closer look at the controlled drug release formulations made of chitin and chitosan.

Hydrogels Based on Chitin and Chitosan

Hydrogels are highly swol len, hydrophi l ic polymer networks that can absorb large amounts of water and increase drastical ly in volume. It is wel l known that the physicochemical properties of the hydrogels depend not only on the molecular structure, the gel structure, and the degree of crossl inking but also on the content and state of water in the hydrogel . Hydrogels have been widely used in the controlled

P 1 \ release systems -. . . Recently, hydrogels, which swel l and contract in

response to external pHI4- 1 6, are being explored . The pH-sensitive hydrogels have a potential use in site­specific del ivery of drugs to specific regions of GI tract and have been prepared for low molecular weight and protein drug delivery l 7. It is known that the release of drugs from the hydrogels depends on their structure or their chemical properties in response to environmental pHIs. These polymers, in certain cases, are expected to reside in the body for a longer period and respond to local environmental stimul i to modulate drug release l ? On the other hand, it i s sometimes expected that the polymers shou ld be biodegradable to obtain a desirable device to control the drug release20. Thus, to be able to design hydrogel s for a particular application, it is important to know the nature of systems in their environmental conditions to design them under proper situation. Some recent advances in the controlled release formulations using gels of chitin and chitosan are presented here.

Chitosanipolyether Interpenetrating Polymer Network (IPN) Hydrogel

Yao et al. 2 1 reported a procedure for the preparation of semi-IPN hydrogels based on crosslinked chitosan with glutaraldehyde interpene­trating polyether polymer network. They investigated

the pH-sensitivity, swel l ing and release kinetics and structural changes of the gel in different pH solutions""-24. It is wel l known that physiochemical properties of the hydrogel depend not only on the molecular structure, the gel structure and the degree of crosslinking but also on the content and state of water in the hydrogel . Since the inclusion of water significantly affects the performance of hydrogels, a study on the physical state of water in the hydrogels is of great importance because it offers useful suggestion on their microstructure and enables to understand the nature of interactions between absorbed water and polymers. Yao et al.2:; studied the dynamic water absorption characteristics, state of water, correlation between state of water and swel ling kinetics of chitosan-polyether hydrogels by applying techniques like DSC and some novel techniques l ike positron annihi lation life-time spectroscopy.

While studying the effect of ionic strength on the rate of hydrolysis of the gel, Yao et al. 23 observed rapid hydrolysis of the gel with decrease in the ionic strength, i .e. , a higher degree of swelling in lower ionic strength solution23 (Figure I ) . The hydrolysis of the gel can be controlled by the amount of the cross linker added and the effect of crosslinker on the swel ling behavior of gel has been studied (Figure 2). From the studies it is clear that more is the added crosslinker, the higher is the crosslink density of the semi-IPNs, which results in a lower degree of swell ing and difficulty in hydrolysis23 .

8 0

70 0> 60 c: a; 50 � '" '0 1.0 '" t 0> 30 '" 0

20

1 0

0 0 10 20 30 1.0 50 60 70 80

Per i od ( hour 1

Figure 1 - The effect of ionic strength (I) 011 the hydrolysis of sample I at pH 4.84 and 37 "C,

1 = 0. 1 . 0: 1 = 0.032' . ;1

.....

-

GUPTA & RA V I KUMAR: TRENDS IN CONTROLLED DRUG RELEASE FORMULATION 203

50

LO

]' 3 5

! 3 0

-: 25 � g' 20 a

1 5

1 0

6 • • .. 11 -6-

o 1 0 7 0 )0 L O 50 6 0 7 0 8 0 90 10 0 110 170 130 140

Piriod ( hour)

D. L - Lac t i d�

o 0 0 ° "- [ ' + f LI' 1. " UV CHr CH- ClO -R - C , 0 C flr CflrOJnlC - R y C - CH,CHl �

o W h. , . , R , C H-(CH) ),O . /: .CH.(CH3 )

Figure 2 - The effect crosslinker on the hydrolysis of the OR (CH7)S semi-IPN hydrogels at pH = 1 ,0 at 37 "c Sample I , 0;

Sample 323, V

Chlorhexidini acetas and Cimetidine were used as model drugs for the drug release studies. A fast swell ing of gels resulting in higher drug release at pH < 6 in comparison to that at pH > 6 was observed 2 1 . 22 .

Semi-IPN Hydrogel Polymer Networks of p-Chitin and Poly(ethylene glycol) Macromer

Semi-IPN polymer network hydrogels composed of �-chitin and poly(ethylene glycol) macromer have been synthesized for the biomedical applications by Kim et al. 26. 27 . The thermal and mechanical properties of these hydrogels have also been studied. The tensile strengths of semi-IPNs in the swollen state were found to be between 1 .35 and 2.4 1 Mpa, the highest reported values to date for crosslinked hydrogels. These hydrogels have been used as wound covering materials and their drug release behavior has been studied using silver dulfadiazine as a model drug28.

Hydrogels of Poly( ethylene glycol)-co­poly (lactone) Diacrylate Macromers (PEGLM) and p-Chitin

Lee and Kim2? reported a procedure for preparing poly(ester-ether-ester) triblock copolymers. The synthesis of the triblock copolymers was carried out by bulk polymerization using low toxic stannous octoate as catalyst or without catalyst. The synthesis of PEGLM or PEGCM/�-chit in semi-IPNs is depicted in Figure 3. Investigations on the thermal and rnechal J ical properties have also been carried oul. Vitamin A, vitamin E and riboflavin were used as model drugs'O' 3 1 .

Figure 3 - Synthetic scheme of PEGLM or PEGCM/p­chitin semi-IPNs"

However, there are no reports on the swel l ing kinetics and solubi lity parameters of these gels.

Hydrogels of Poly(ethylene glycol) Macromer (PEGM) and P-Chitosan

In their studies on ehitosan for biomedical appl ications, Lee et al. 32 reported a procedure for preparing semi-IPN polymer network hydrogels composed of �-chitosan and poly(ethylene glycol) diacrylate macromer. The hydrogels were prepared by dissolving the mixture of PEGM and �-chitosan in aqueous acetic acid. The resu lting mixture was then cast to fi lms, followed by subsequent crossl inking with 2, 2-dimethoxy-2-phenylacetophenone as non-toxic photo initiator by uv irradiation . They studied the crystal l inity and thermal and mechanical properties of these gels.

Hydrogels of ChitosaniGelatin Hybrid Polymer Network

'n Yao et al.· reported a novel hydrogel based on crosslinked chitosan/gelatin with glutaraldehyde hybrid polymer network. They observed drastic swel ling of the gels in acidic pH in comparison to basic solutions (Figure 4). They used levamisole, cimetidine and chlormphenicol as model drugs in their studies. The pH-dependent release of cimetid ine (Figure S), levamisole and chloramphenicol from the gel was also reported by them.

204 J SCI INO RES VOL 59 MARCH 2000

10 01 C

� 8 � VI

0 6 0-� 01 0-

"U � E ... '-

..0 � 2 ::l g

O �I�-r-r�'i�i�'-ri-rl-ri �i �i�l�i o 2 3 I., 5 6 7 8 9 10 1 1 12 13 11.,

p H

Figure 4 - Swell ing behavior of gel at different pH. ionic strength 1 = 0. 1 M. Temp. = 37 °C33

1 00 0 0 0 0 0 00 0 •

0 . . N 0 0 . . 't:i eo . C1I 0 , " VI 0 0 . C1I 6.0 a; • .... <pO • (7l � o ::J 0 . 0 0 0 .

20 . •

0 0 500 1000 1500 2000 (Time)'/2/Thickness/( slh1c m )

Figure 5 - Cimetidine release performance from drug loaded matrix of chitosan/gelatin hydrogel in di fferent pH

butTers at 37 °C (0) pH 1 .0; (e) pH 7.S31

Chitosan-amine Oxide Gel ',4 .

Dutta ef al. have reported the preparatIon procedure for homogeneous chitosan-amine oxide gel . The swelling behavior and release characteristics of the gel were studied by them in buffer solutions (pH 7.4) at room temperature. The homogenous erosion of the matrix and nearly zero order release of ampicil l in trihydrate (Figure 6) were observed in their studies. They also reported the thermal properties of chitosan­amine oxide gel in a further study's

11.00

'" 1200 E

e 0> 1000 e

u ·f 800 .= 0:: 600 . Q -,g 1. 00 " '" u

200 c: 8 0

0 2 3 I. 5 6 7 8

No of days

Figure 6 - Release of ampici l l in trihydrate from chitosan amine-oxide gel in (pH 7.4) phosphate butTer3�

Chitin and Chitosan Tablets

Many direct-compression di luents have been reported in the l iterature, but every di luent has some disadvantages'6. Crystalline cellulose (MCC) has been used widely as a tablet diluent in Japan. Chitin and chitosan, because of their versatil ity, have been reported to be useful di luents in pharmaceutical preparations,7. :1R.

Directly Compressed Tablets Containing Chitin or Chitosan in Addition to Lactose or Potato Starch

Sawayanagi ef al. 39 reported the fluidity and compressibi l ity of combined powders of lactose with chitin (lactose/chitin), with chitosan (Iactose/chitosan) and potato starch with chitin (potato starch/chitin), with chitosan (potato starch/chitosan). The disintegration properties of tablets made from these powders, in comparison with those of combined powders of lactose with MCC (IactoselMCC) and potato starch with MCC (potato starchIMCC) in order to develop new direct­compression di luents, were also reported by them as a part of their studies on pharmaceutical applications or chitin and chitosanw. They found that the fluidity of combined powders with chitin and chitosan was greater than that of the powder with crystal l ine cellulose. The reported hardness of the tablets fol lows the order: chitosan tablets > MCC > chitin. In the disintegration studies, tablets containing less than 70% chitin or chitosan have passed the test. Moreover, the ejection

GUPTA & RAYI KUMAR : TRENDS I N CONTROLLED DRUG RELEASE FORMULATION 205

force of the tablets of lactose/chitin and lactose/chitosan was significantly smaller than that of lactose/crystall ine cellulose tablets39. However, no reports are available on the controlled drug release formulations using these tablets.

Chitosan Tablets for Controlled Release: Anionic-Cationic Interpolymer Complex

Recently, chitosan is gaining importance as a disintegration agent due to its strong abi l ity to absorb water. It has been observed that chitosan contained in tablets at levels below 70% acts as a disintegration

19 40 N' I 1 4 1 . . d h . d agenr ' . Iga aye et a . mvestIgate t e sustame release characteristics of chitosan in the presence of citric acid or carbomer-934 P in tablets containing theophyll ine as the model drug. The rate of drug release was slower in the tablets containing citric acid or carbomer-934 P used as anionic complex agents than containing chitosan alone.

Recently, Mi et al.42 have reported chitosan tablets ' for the controlled release of theophyl l ine. Alginate was used as an anionic polyelectrolyte to control the swel ling and erosion rates of the chitosan tablets in acidic medium. Investigations on the drug release mechanism of various tablets have been carried Ollt based on Peppas' s modeI43. 44 and nuclear magnetic resonance imaging microscopy was used to examine the swelling/diffusion mechanism of various tablets42.

Microcapsules/Microspheres of Chitosan

The tern1 "microcapsule" is defined as a spherical particle with size varying from 50 nm to 2 mm, containing a core substance. Microspheres are, in strict sense, spherical empty particles. However, the terms microcapsules and microspheres are often used synonymously. In addition, some related terms are used as wel l . For example, "microbeads" and "beads" are used alternatively. Spheres and spherical particles are also used for a large size and rigid morphology. Recently, Yao et al.45 highlighted the preparation and properties of microcapsules and microspheres related to chitosan. Due to attractive properties and wider applications of chitosan-based microcapsules and microspheres, a survey of their applications in controlled drug release formulations is appropriate. Moreover, microcapsule and microsphere forms have an edge over other forms in handling and administration. Therefore, an up-to-date information on

chitosan microcapsules and microspheres is presented here.

Crosslinked Chitosan Microspheres Coated with Polysaccharides or Lipid

Ohya and Takei46 studied 5-f1uorouraci l (S-FU) and its amino derivatives (Figure 7), and loaded crosslinked chitosan microspheres coated with polysaccharide or lipid (Figure 8) for intell igent drug del ivery systems. The microspheres were prepared with an inverse emulsion of 5-FU or its derivative solution of hydrochloric acid of chitosan in toluene containing SPAN 80. Chitosan was crosslinked through Schiff' s salt formation by adding glutaraldehyde toluene solution. At the same time, the amino derivatives of 5-FU were immobil ized, obviously resulting in an increase in the amount of drug within the microspheres. The microspheres were coated with anionIC

Aminopentyl - corbo moyl ·S·F U

Ami nopenty l - este r - methy llme -S-F U

Figure 7 - Amino derivati ves of 5-fiuorouracil (5-FU)�('

M S (C M.) polysacc h a r ide M S ( C M L )

Figure 8 - Theoretical stnrcture o f chitosan gel microsphere coated with polysaccharide and l ipid46

206 1 SCI [NO RES VOL 59 MARCH 2000

polysaccharides (e.g. carboxymethylchitin, etc.) through a polyion complex formation reaction. In the case of l ipid coated microsphere, the microspheres along with dipalmitoyl phosphalidyl choline (DPPC) were dispersed in chloroform. After evaporation of the solvent, microspheres were obtained coated with a DPPC lipid multi layer, which exhibited a transition temperature of a l iquid crystal phase at 4 1 .4 DC. The diameter range of microspheres was 250-300 nm with a narrow distribution . The stabil ity of the dispersion was improved by coating the microsphere with anionic polysaccharide or a lipid multilayer (Figure 9).

A comparative study on the release of 5-FU and its derivatives from polysaccharide-coated micro­spheres MS (CM) was carried out in physiological saline at 37 "c. Data indicated that the 5-FU-release rate decreased in the order: free-5-FU > carboxymethyl type 5-FU > ester type 5-FU. The results revealed that the coating layers on the microspheres were effective barriers to 5-FU release.

The lipid mutilayers with a homogeneous composition general ly show transition of gel-liquid crysta l . When the temperature was raised to 42 DC, which was higher than the phase transition of 4 1 .4 "c. the release amount of 5-Fu increased, the amount of drug del ivered decreased at 37 nC, which is lower than the transition temperature (Figure 1 0) . Due to the improved recognition function of polysaccharide

I I Upid � Io'((jr jAddition of wat"r a nd sonication

t8;;i � M S (CML)

C£0IU'no ( 50 mU Conta i n i n g 'O� Spon 80

Chito�Q.n / He! sclution ( 1 mU containing SFUor 5 - FU derjllotlv� (0-0 8 nlmolJ j ����a:�o�

LlSinQ t:B-:: .; ;". : . . . ' . sonicator : - �':<·'.�o PolysQcCharlde. �� . ' . . ... 'qu.ous solutIon

I SO'.'licotion uSing p:rotx> tVPf sonicator �

� � 0 e. e I Incubation

I addition of toue e saturated glutol1lldohyd. � �oo �

o . • o ! Centrifugation

I CentriflJ9Otion waShing drying washing drying e @) • • • 8

... M S (C M ) M S Ie M} Polysocchorid�

Figure 9 - Preparation of MS (CM), M S (CML) and MS (CM)-polysaccharide - A schematic diagram"('

5 0 3 7 ·C

N � u.. t..fl

"0 2 5 <l> VI 0 <l>

a; cr

0 .U 1.0 a. E � 3 5

0 5 Per iod ( hour )

Figure 1 0 - On-ofT control via change in temrerature for 5-FU release from amino rentyl-carbamoyl-5-FU

immobi l ized loaded microsrheres coated with lirid I11lI i t i layel.46

chains for animal cell membranes, it is reasonable to develop targeting delivery systems from polysaccharide-coated microspheres, MS (CM) .

ChitosaniGelatin Network Polymer Microspheres

In their studies on pharmaceutical applications of chitin and chitosan, Yao and coworkers47 reported chitosan/gelatin network polymer microspheres for controlled release of cimetidine. The drug loaded microspheres were prepared by dissolving chitosan, gelatin ( I : I by weight) and cimetidine in 5% acetic acid. A certain amount of tween-80 and l iquid paraffin at a water to oi I ratio of I : 1 0 were added to the chitosanlgelatin mixture under agitation at 650 RPM at 30 °C. A suitable amount of 25% aqueous glutaraldehyde solution was added to the inverse emulsion and maintained for 2 h . Finally, the liquid paraffin was vaporized under vacuum to obtain microspheres.

The drug release studies were performed in hydrochloric acid solution (pH 1 .0) and potassium dihydrogen phosphate (pH 7.8) buffer at ionic strength 0. 1 M. A pH dependent pulsed-release behavior of the HPN matrix was observed47. Moreover, the release rate

"' . ..

..

GUPTA & RAYI KUMAR: TRENDS IN CONTROLLED DRUG RELEASE FORMULATION 207

can be controlled through the composition of the HPN and the degree of deacetylation of chitosan.

Chitosan Microspheres for Controlled Release of DicIofenac Sodium

Gohel et al.48 reported the preparation of chitosan microspheres containing diclofenac sodium, by the coacervation phase separation method. Chitosan and glutaraldehyde were used as the coating material and crosslinking agent respectively. In vivo studies were performed on New Zealand white rabbits. Moreover, the microspheres were found to be stable at 45 DC for 30 days. The student 't' test was performed for the results of in vitro dissolution data of fresh and aged samples (30 days at 45 °C) and no significance difference was noticed due to the storage.

Chitosan-polyethylene Oxide NanoparticIes as Protein Carriers

Hydrophilic nanoparticulate carriers have many potential applications for the administration of therapeutics molecules. The recently developed hydrophobic-hydrophilic carriers require organic solvents for their preparation and have a limited protein-loading capacit/9-52. To address these limitations, Calvo et at. 5:1 reported a new approach for the preparation of nanoparticles made solely of hydrophilic polymer. The preparation technique, based on an ionic gelation process, is extremely mild and involves the mixture of two aqueous phases at room temperature. One phase contains the polysaccharide chitosan (CS) and a diblock copolymer of ethylene oxide and polyanion sodium tripolyphosphate (TPP) (Figure I I ) . Size (200- 1 000 n) and zeta potential (20 -60 mv) of nanoparticles can be conventionally modulated by varying the CSIPEO-PPO ratio. Furthermore, using bovine serum albumin (BSA) as a

Chitoson P E O

model protein, it was shown that these new nanoparticles have great protein loading capacity (entrapment efficiency up to 80% of the protein) and can provide a continuous release of the entrapped protein up to I week.

ChitosanlCalcium Alginate Beads

The encapsulation process of chitosan and calcium alginate as applied to encapsulation of hemoglobin was reported by Huguet et al.54. In the first process, the mixture of hemoglobin and sodium alginate was added dropwise to the solution of chitosan and the interior of capsules thus formed in the presence of CaCI2 was hardened. In the second method, the droplets were directly pulled off in a chitosan-CaCl2 mixture. Both procedures led to the formation of beads containing a high concentration of hemoglobin (more than 90% of the initial concentration of 1 50 gIL) was retained (inside the beads), provided the chitosan concentration was sufficiently h igh.

The molecular weight of chitosan (mol wt 245000 or 390000) and the pH (2, 4, or 5.4) had only a slight effect on the entrapment of hemoglobin, the best retention being obtained with beads prepared at pH 5 .4. The release of hemoglobin concentration during the bead storage in water was found to be dependent on the molecular weight of chitosan. The best retention during storage in water was obtained with beads prepared with the h igh molecular weight chitosan solution at pH 2.0. Considering the total loss in hemoglobin during the bead formation and after I month of storage in water, the best results were obtained by preparing the beads in an 8 gIL solution of a 390000 chitosan at pH 4 (less than 7% loss with regard to the 1 50 giL in itial concentration). The ionic interactions existing between alginate and chitosan at pH 5 .4 and pH 2.0 are presented in Figure 1 2.

I NSTANTANEOUS FORMAT ION OF CS/PEO · P PO NANOPARTICLES

Figure I I - The preparation of CS nanoparticles - A schematic diagrams.1

208 1 SCI INO RES VOL 59 MARCH 2000

eOOH

lb)

Figurc 1 2 - Schcmatic rcprcsentalion of lhc ion ic interaclions between algi nate and chitosan (a ) pH

5 .4; (b) pH 2.054

S i mi l arly, the encapsu lation of various molecu les [Hb, bovine serum albumin (BSA) and dextrans with various molecu lar weights] in calcium alginate beads

d .

h h ' I b j'i'i 'i6 TI . coate Wit c I tosan las een reportee · · · . . lelr release has been compared and the influence of the conformati on, the c hemical compositi on and molecu lar wei ght of the encapsulated materials have been analysed55.

Multiporous Beads of Chitosan

Several researchers57-w have studied s imple coacervation of chitosan i n the production of chitosan beads. In general , chitosan is d issolved in aqueous acetic acid or formic ac id . Using a compressed air nozzle, this solution is blown into NaOH, NaOH-

.... a. ...-a. E o

"0 VI ::J o .... a a...

0·6

0'1.

o o

, • " - -<» -'> - � -£a - -<»-= ca

' .... ,. ,

-D-OJ�

5 10 A l ka l i ne concen t ra t ion

Figure 1 3 - Thc elTr.et of N-deacetylation degrec anu alkal inc conccll trJl ioll on the porous di ameter of chitosJn beads (0 e )

7VY" N-deacetylaled chi losa n ; C - 0 ) 95% N-deacctylalcd chitosan , (0 0) surfacc of thc hCJds (e -) ccntrc of the heads" )

methanol , or et hanediamine solution to form coacervate drops. The drops are then fil tered and washed wit hot and cold water successi vely. Varying the exc lusion rate of the ch i tosan solution or the nozzle di ameter can control t he diameter of the droplets. The porosity and strength of the beads correspond to the concentrat ion of the ch itosan-acid soluti on, the degree of N-deacetylation of chitosan , and the type and concentration of coacervation agents used . Figure 1 3 shows the effect of the degree of N-deacetylation and alkaline concentration on the porous diameter of chitosan beads obtained by simple coacervat ion . Some properties of the beads reported by Nishimura5x and Kinemura60 are l isted in Table I .

Thes� chitosan beads have been ut i l ized for enzymatic i mmob i l i zation5'l, chromatograph support(,(),

d b f I · 6 1 I ' . (,? d I I a sor e n t 0 meta I ons , or Ipoproteill -, a n ce

cultures60. It was confi rmed that the porous surfaces of chitosan beads make good cel l culture carrier60. Hayashi and Ikada6.1 i mmobi l i zed protease onto the

Researcher

Table I - Properties of chitosan beads prepared by simple coacervation

Phvsical Properties Chcmical propert ies

Kinemura60

Nishimura5x

Mean diameter

( mm)

0. 1 -3

0.22-0.73

Relative surface area

m2/g

1 5-90

52.4-82.6

Aacid/alkali resistance

Soluble in acid

Stable in neutral and

Alkali solution

GUPTA & �AVI KUMAR: TRENDS IN CONTROLLED DRUG RELEASE FORMULATION

Figure 1 4 - Scanning electron micrographs of crosslinked chitosan-glycine beads (AI -A5) shape and size, (A 1 *-A *5) morphology of the bead&

209

210 J SCI IND RES VOL 59 MARCH 2000

porous chitosan beads which carry active groups with a spacer and found that the immobilized protease had higher pH, thermal storage stability, and gave rather higher activity toward the small ester substrate, N­benzyl-L-arginine ethyl ester. In addition, Nishimura et at. 58 . investigated the possibilities of using chitosan beads as a cancer chemotherapeutic carrier for adriamycin. Recently, Sharma et at. 64-66 prepared chitosan microbeads for oral sustained delivery of nefedipine, ampicillin and various steroids by adding to chitosan and then going through a simple coacervation process. These coacervate beads can be hardened by cross linking with glutaraldehyde or epoxychloro­propane to produce microcapsules containing rotundine67. The release profiles of the drugs from all these chitosan delivery systems were monitored and showed in general the higher release rates at pH 1 -2 than that at. pH 7 .2-7.4. The effect of the amount of drug loaded, the molecular weight of chitosan and the crossliriking agent on the drug delivery profiles have been discussed well64-67.

Crosslinked Chitosan-glycine semi IPN Polymer Network Beads

The authors have also prepared pH-sensitive beads of chitosan, as a part of the studies on controlled drug delivery applications of chitosan, wherein dic10fenac sodium, thyamine hydrochloride and chlorphenramine maleate w�re used as model drugs68-7o. In one of the techniques, glycine, an attractive product widely used in medical and pharmaceutical areas7l , was used as a spacer group to enhance the flexibility of the semi-IPN and influence the swelling behavior through macromolecular interactions. The coacervate beads were crosslinked with different concentrations of glutaraldehyde.

Figure 14 shows the size and morphology of the beads. The beads exhibit high pH sensitivity. The swelling ratio of the beads at pH 2.0 is higher than that at pH 7.4. This pH-sensitive swelling is due to the transition of bead network between the collapsed and the expended states, which is related to the degree of ionization of amino groups on chitosan at different pH72. Figure 1 5 shows the pH dependent swelling of beads crosslinked with different concentrations of glutaraldehyde at pH 2.0 and pH 7 .4. Chlorphenramine maleate was used as a model drug. The drug release from the drug loaded beads in acidic as well as basic

-+-A1 pH 2.0 -tl-A2pH 2.0 ___ A3 pH 2.0 -*,"M pH 2.0 ..... A5 pH 2.0 -+-Al pH 7.4 -+-A2pH 7A -A3 pH 7.4 -M pH 7A -+- A5 PH 7.4

D �_� ___ � _�_�_�_�_� a 2 3 4 5 Ptrlod (da)'J) 6 7 8

Figure 1 5 - Swelling behavior of crosslinked chitosan-glycine beads at pH 2.0 and 7.4 at 37 °C

solutions fol lowed . the order A5 > A4 > A3 > A2 > A2 > Al (AI with max.crosslinking)72. The effect of the amount of drug loaded and the crosslinking agent on the drug delivery profiles was reported as weU68, 69, 72.

Chitosan-based Transdermal Drug Delivery Systems

Thacharodi and Ra073-75 have reported the permeation-controlled trans dermal . drug delivery systems (TDS) using chitosan. Studies on propranolol hydrochloride (prop-HC!) delivery systems using various chitosan membranes with different crosslink densities as drug release controlling membranes and chitosan gel as the drug reservoir have been performed. The physicochemical properties of the membranes have been characterized . and the permeability characteristics of these membranes to both lipophilic and hydrophilic drugs have been reported73, 74 . The in vitro evaluations of the TDS devices while supported on rabbit pinna skin were carried out in modified Franz diffusion cells75. The in vitro drug release profiles showed that all devices released prop-HCI in a reliable, reproducible manner. The drug release was significantly reduced when crosslinked chitosan membranes were used to regulate drug release in the devices. Moreover, the drug release rate was found to depend on the crosslink density within the membranes. It has been observed that the device constructed with chitosan membrane with high crosslink density released the minimum amount of drug. This is due to

GUPTA & �AVI KUMAR: TRENDS IN CONTROLLED DRUG RELEASE FORMULATION

Figure 1 4 - Scanning electron micrographs of crosslinked t;hitosan-glycine beads (AI -A5) shape and size, (Al *-A *5) morphology of the beads

2 1 1

2 1 2 J SCI IND RES VOL 59 MARCH 2000

the decreased permeabil ity coefficient of the crosslinked membranes resulting from the crosslink points.

Conclusion

Chitin derivatives have high potential as polysaccharides for medical use. These derivatives, including partial ly deactylated chitosan, can be easily molded to various forms and are digested in vivo by Iysozomal enzymes. Thus, it appears this material can be a strong candidate for use as a carrier of a variety of drugs for controlled release applications. The bioactivities of chitosan itself and its formulations with drugs may have dual therapeutic effects. Chitosan has shown a wide range of applications including those in environmental and biomedical engineering.

Acknowledgement

The authors thank Dr K G Ramachandran Nair, Central Institute of Fisheries Technology, Kochi, India for providing the sample of chitosan. The financial assistance to the laboratory by the Al l India Council for Technical Education (AICTE), New Delhi, India is gratefully acknowledged. One of the authors (MNVRK) is gratefu l to the Council of Scientific and Industrial Research (CSIR, New Delhi) for awarding a Senior Research Fel lowship to him.

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