CHITOSAN: A MUCOADHESIVE POLYMER

www.wjpps.com Vol 4, Issue 04, 2015.

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Prajakta et al. World Journal of Pharmacy and Pharmaceutical Sciences

CHITOSAN: A MUCOADHESIVE POLYMER

Prajakta K.Khobragade1* and Prashant K.Puranik

2

1Govt. College of Pharmacy, Vedant Road, Osmanpura, Aurangabad-431005 (M.S).

2SRTM Nagpur University Nagpur.

ABSTRACT

Chitosan is polymer having mucoadhesion properties. Being biological

origin it have less toxic effect than other polymers. Present article

review on various physicochemical biological properties, and its

method of preparation. Chitosan have the property to get modified or

make the complex with other excipients leads to enhancing its

properties. Chitosan is a versatile natural polymer. This article

reviewed different aspects of Chitosan with their applicability in

pharmaceutical formulations. This review emphasized that research on

Chitosan based systems containing various drugs for various

therapeutic applications have increased in recent years. So this article

has fullfill the requirement of a review on this naturally derived polymer in present

scenario.

KEYWORDS: Chitosan, mucoadhesion, formulation.

INTRODUCTION

Polymers

Polymers are macromolecules composed of repeating structural units of monomers concluded

by covalent chemical bonds and their process is known as polymerization. Polymers can be

classified as natural or synthetic polymers. Natural polymer for example protein (Collagens,

silk, and keratin), carbohydrate (Starch, glycogen) are widely used materials for conventional

and novel dosage form. These materials are inert, nontoxic, less expensive, biodegradable,

eco friendly and widely available.

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Article Received on

17 Feb 2015,

Revised on 09 March 2015,

Accepted on 31 March 2015

*Correspondence for

Author

Prajakta K.Khobragade

Govt. College of

Pharmacy, Vedant Road,

Osmanpura, Aurangabad-

431005 (M.S).


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Chitosan

Chitosan is no longer considered as just a waste product from seafood industries. This

material is now being utilized by industry to solve problem and to improve existing product

as well as create new once.[1]

Officially chitosan having non-proprietary names are according to BP, chitosan

hydrochloride, and according to the Ph Eur, chitosan hydrochloridum. Chitosan having

synonym as 2-Amino-2-deoxy-(1,4)- β - D-glucopyranan; deacetylated chitin; deacetylchitin;

β -1,4-poly-D-glucosamine; poly- D-glucosamine; poly-(1,4- β - D-glucopyranosamine).

Chemical Name and CAS Registry Number

Poly-β -(1,4)-2-Amino-2-deoxy-D-glucose [9012-76-4].

Empirical Formula and Molecular Weight

Partial deacetylation of chitin results in the production of chitosan, which is a polysaccharide

comprising copolymers of glucosamine and N-acetylglucosamine. Chitosan is the term

applied to deacetylated chitins in various stages of deacetylation and depolymerization and it

is therefore not easily defined in terms of its exact chemical composition. A clear

nomenclature with respect to the different degrees of N-deacetylation between chitin and

chitosan has not been defined, and as such chitosan is not one chemical entity but varies in

composition depending on the manufacturer. In essence, chitosan is chitin sufficiently

deacetylated to form soluble amine salts. The degree of deacetylation necessary to obtain a

soluble product must be greater than 80–85%. Chitosan is commercially available in several

types and grades that vary in molecular weight by 10000–1000000, and vary in degree of

deacetylation and viscosity.

Chitosan occurs as odourless, white or creamy-white powder or flakes. Fibre formation is

quite common during precipitation and the chitosan may look 'cottonlike'.[2

] The

pharmaceutical specification for chitosan is given in Table 1.

Table 1: Pharmacopeial specifications for chitosan.[2]

Test PhEur 2005

Identification +

Characters +

Appearance of solution +

Matter insoluble in water ≤ 0.5%

pH (1% w/v solution) 4.0–6.0


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Viscosity +

Degree of deacetylation +

Chlorides 10.0–20.0%

Heavy metals ≤ 40 ppm

Loss on drying ≤ 10%

Sulfated ash ≤ 1.0%

Chitin is the second most abounded natural polymer in nature after cellulose and it is found in

the structure of wide number of invertebrates (Crustaceans, exoskeleton, and insect cuticles)

and cell wall of fungi.

Naturally chitosan occurs only on some fungi (Mucoraceae). Commercially chitosan prepared

by the chemical deacetylation of chitin from crustacean source under alkaline condition.

Chitin is a beta (1-4) - 2- acetamido-2-deoxy-D-glucopyranose as a repetating unit.[3]

Structure

Structure of chitin and chitosan is shown in Figure 1

a. Chitin b. Chitosan

Fig. 1, Structure of chitin and chitosan

The percentage of chitin content varies with the source of supply. Industrially, the isolation of

chitin from crustacean shell mainly involves removal of proteins and dissolution of calcium

carbonate which present in crab shell in high concentration.

Chitin is water insoluble and insoluble in almost all organic solvent.[4]

Preparation methods of chitosan from chitin

1. Chemical manufacturing of chitin and chitosan

Chitosan is manufactured commercially by chemically treating the shells of crustaceans such

as shrimps and crabs. The basic manufacturing process involves the removal of proteins by

treatment with alkali and of minerals such as calcium carbonate and calcium phosphate by

treatment with acid. Before these treatments, the shells are ground to make them more


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accessible. The shells are initially deproteinized by treatment with aqueous sodium hydroxide

3–5% solution. The resulting product is neutralized and calcium is removed by treatment with

an aqueous hydrochloric acid 3–5% solution at room temperature to precipitate chitin. The

chitin is dried so that it can be stored as a stable intermediate for deacetylation to chitosan at a

later stage. N-deacetylation of chitin is achieved by treatment with an aqueous sodium

hydroxide 40–45% solution at elevated temperature (110°C), and the precipitate is washed

with water. The crude sample is dissolved in acetic acid 2% and the insoluble material is

removed. The resulting clear supernatant solution is neutralized with aqueous sodium

hydroxide solution to give a purified white precipitate of chitosan. The product can then be

further purified and ground to a fine uniform powder or granules. The animals from which

chitosan is derived must fulfil the requirements for the health of animals suitable for human

consumption to the satisfaction of the competent authority. The method of production must

consider inactivation or removal of any contamination by viruses or other infectious agents.[2]

2. Biotechnological method for chitin and chitosan

Shellfish waste obtained from crab shrimp etc were grind in the presence of water. Resulting

substance demineralised with the help of Pseudomonas argenosa F722. After

demineralization; obtained product get deproteinized by using enzyme or proteolytic bacteria.

After enzymatic degradation, enzyme should be deactivated. Deproteinized product washed it

and then dried to obtained chitin. Chitin is then deacetylated by using chitin deacetyalase or

lactic acid bacteria or by using hydrolysis using chitinolytic enzyme which produces chitosan

on washing and drying.

3. Biological process for chitin and chitosan production

Crustacean shell obtained from crab, shrimp etc. It is demineralised with the help of organic

acid producing bacteria. Then it is deproteinized by protease producing bacteria to produce

chitin. Chitin is then deacetylated in the presence of chitin deacetyalase to produce

Chitosan.[5]

Properties of chitosan

1. Physicochemical Properties

Chitosan is solid state, semicrystalline polymer. Chitosan is broadly classified as chitosan

oligomer having 2 monomer unit and chitosan polymer with more than 12 monomers which

further classified as chitosan polymer having low molecular weight greater than 150 KDa,

medium molecular weight in between 150- 700 KDa, and High molecular weight 700 – 1000


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KDa.[4

] It is notoxic, biodegradable, biocompatible, citocompatabilital, mucoadhesive,

haemostatic, analgesic, adsorption enhancer, antimicrobial activity, anticholetereolemic

activity, angiogenesis, granulation and scar formation, macrophage activation. [3

] The degree

of deacetylation of typical commercial chitosan is usually ranged between 66 – 95%. In solid

state, chitosan is a semicrystalline in nature which exhibit polymorphism. As the removal of

acetyl moieties that are present in the amine group.[4]

SOLUBILITY

Chitosan is soluble in acidic medium and poor soluble in neutral and basic pH. Soluble in

dilute organic acid solution such as acidic acid, formic acid, succinic acid and lactic acid at

pH below 6.5. Low solubility at pH 7.4 and higher pH. Solubilisation occurs through

protonation of -NH2 group of D-glucosamine derivative which give polycation in acidic

medium.

a. Chitosan with more than 50% deacetylation soluble in acidic medium

b. Chitosan with 50% deacetylation soluble in neutral medium

c. Chitosan with less than 50% deacetylation soluble in aqueous medium at pH 9.

The solution properties of chitosan are depends upon distribution pattern of acetyl group

along the main chain and mol. wt. The concentration of the CH+ needed to dissolve chitosan

must at least be equal to conc. of NH2 unit participating in solubilisation process. In the

presence of excessive HCl salting out of the chitosan takes place. The aqueous solubility of

chitosan is greatly influence by the addition of electrolyte to the solution. It forms the

extended conformation in the solution form of chitosan. It is due to repulsion of positively

charge deacetylated unit on the neighbouring glucosamine units. Addition of electrolyte

reduces the interchain repulsion and induces a more random coil like conformation in the

molecule which eventually results in salting out and precipitation of chitosan.[4]

pKa - 6.2 - 7

Acidity/alkalinity: pH = 4.0–6.0 (1% w/v aqueous solution)

Density: 1.35–1.40 g/cm3

Glass transition temperature: 203°C

Moisture content: chitosan adsorbs moisture from the atmosphere, the amount of water

adsorbed depending upon the initial moisture cont ent and the temperature and relative

humidity of the surrounding air.

Particle size distribution: <30 μm,2


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VISCOSITY

The viscosity of the chitosan greatly affected by molecular weight, ionic strength, pH, and

temperature of the solution. The viscosity of the solution increases with increase in

concentration of the chitosan and degree of deacetylation, but decrease in temperature and

pH. It possesses peudoplastic behaviour with solution viscosity decreases with an increase in

shear rate. Typical viscosity values are shown in Table 2.

Table 2: Typical viscosity (dynamic) values for chitosan 1% W/V solutions in different

acids.[2]

Typical viscosity (dynamic) values for chitosan 1% w/v solutions in different acids.

Acid 1% acid concentration 5% acid concentration 10% acid concentration

Viscosity (mPa) pH Viscosity (mPa) pH Viscosity (mPa) pH

Acetic 260 4.2 260 3.3 260 2.9

Adipic 190 4.11 - - - -

Citric 35 3.0 195 2.3 215 3

Formic 240 2.6 185 2.0 185 1.7

Lactic 235 3.3 235 2.7 270 2.1

Malic 180 3.3 205 2.3 220 2.1

Malonic 195 2.5 - - - -

Oxalic 12 1.8 100 1.1 100 0.8

Tartaric 52 2.8 135 2.0 160 1.7

Chitosan is known to possessed good complexing capacity It has good complexing capacity.

The presence of C-NH2 group involved in specific interaction with metal. A higher degree of

chitosan is attained with chitosan characterized by greater degree of deacetylation. The

affinity of chitosan for divalent and trivalent cation of chloride salts as

Cu2+

>> Hg2+

>> Zn2+

>>Cd2+

> Ni2+

> Co2+

- Ca2+

> Eur3+

> Nd3+

> Cr3+

- Pr3+

.

Chitosan is able to form electrostatic complexes under acidic condition with oppositely

charged surfactant (SLS). Chitosan can complex with oppositely charged polymer such as

polyacrylic acid, Na salt of polyacrylic acid, CMC, xanthum, carrageenan, alginate, pectin,

heparin, hyluronan, sulfonated cellulose, dextron, and chondrotoin sulfate. Chitosan may be

cross linked with reagent such as epichlorhydrin, genipin, disocynate and 1, 4- butandiol

diglycidyl ether. Starch chitosan blend can be cross linked through oxidizing the starch to

produce polyaldehyde which react with NH2 in the presence of reducing agent.

Chitosan form the hydrogel when polymer react with multivalent amino such as glycerol

phosphate, oxalic acid, pyrophosphate, tripolyphosphate, tetraposphate, hexapohosphate,

metaphosphate and Fe (CN6)-4

/ Fe (CN6)-3

.


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1.Biological Properties

It is a natural, biodegradable, biocompatible, degraded by lysosome or enzyme chitinase

producing N- acetyl glucosamine. Chitosan have low level of toxicity. LD50 values found to

be in excess of 16gm/kg body wt. of mouse, higher than that of sucrose. Low deacetylated

have high toxicity than high deacetylated. Chitosan is lack of irritant and allergic effect. It has

immunostimulant properties. It have high capacity to adhere to mucosa, owing to ionic

interaction between NH2 and negatively charged mucus gel layer, it enhances transmucosal

drug absorption and is known to reversible membrane damage. The primary mechanism of

adhesion at the molecule level is affected via electrostatic attraction. Higher mol.wt. of

chitosan 1400kDa produces higher mucoadhesion than low mol. wt.

Modification of chitosan

1.Quternization of NH2 Group

Solubility of chitosan can be increased by quarterisatipn. Chitosan have NH2 group, on

quarterisation it form no. of derivative such as

1. O, N carboxy methyl chitosan – The NH- group of chitosan is reacted with carbonyl

group of aldehyde and glyoxylic acid and then hydrogenated by the reaction with NaBH4 or

NaCNBH3 to give N carboxy methyl chitosan. Another method is solubilised chitosan with

1% acetic acid solution which get approximately 1-1.5 %w/v solution. This solution is treated

with glyoxylic acid in molar ration 1:1 to 1:3 followed by reduction with portions of sodium

borohydride to obtain pH of 4-5 without precipitation in reaction mixture. The viscous

solution is then dialyzed against water and lyophilized to get N-carboxymethyl chitosan. Use

of the reductive alkylation process gave a product having approximately 70% N,N-

dicarboxymethyl chitosan units.[6]

The chitosan is soaked in alkaline solution at freezing or

room temperature for 2-24 h. The concentration of chitosan for this purpose commonly

reported is 4% -20% w/v in 40-50% w/v solution of NaOH. The activated chitosan is then

reacted with monochloroacetic acid in solid or solution form. The concentration of

monochloroacetic acid used is 1:1 -1:6 by weight in isopropanol/ethanol and reaction is

carried at 0–60°C for 2–24 h. The product is precipitated by solvent as acetone, ethanol and

desalted by pH adjustment or dialysis.[7][8][9]

2. Chitosan 6-o-sulfate: Chitosan (65000 D) (1.0 g) was suspended in 50 ml methanol with

stirring at room temperature, then octaldehyde (1.02 g) was added. After 24 h, KBH4 (0.5 g)

dissolved in 5 ml water was slowly added to the solution. After a further 24 h continuous


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stirring, the reaction solution was neutralized with 2N hydrochloric acid and the product was

precipitated with methanol. The precipitate was filtered and repeatedly washed with methanol

and water. The product, N-octylchitosan (OC1) was dried under vacuum at 60 - 800C

overnight. OC2 was prepared with chitosan (25000 D) as the starting material using the same

method as above. Different N-alkyl substituents DC1 (chitosan 65000 D), DC2 (chitosan

25000 D), LC1 (chitosan 65000 D) and LC2 (chitosan 25000 D) were synthesized using

decanal and lauryl aldehyde, respectively. OC1 (1.05 g) was suspended in DMF (40 ml), and

magnetically stirred overnight. Chlorsulphanic acid (20 ml) was added dropwise into DMF

(40 ml) with stirring at 1080C under N2 atmosphere. After completely dripped, the solution

was kept in agitation for 1 h, and then the suspension of OC1 and DMF was added to the

above solution. The mixture was reacted at 1080C under N2 atmosphere for 24 h. The

reaction solution was neutralized with 20% NaOH to pH 7, and the filtered solution was

dialyzed (MWCO 10000) against distilled water, then lyophilized and the OCS1 powder was

obtained. Different chitosan derivatives, OCS2, DCS1, DCS2; LCS1, LCS2 were obtained

using the same method.

3. Trimethyl chitosan ammonium: N,N,N-trimethyl chitosan (TMC) is a cationic

polyelectrolyte obtained by extensive methylation of chitosan parent polymer.[11]

The

resulting derivative is a water-soluble polysaccharide useful for a variety of applications. The

TMC was obtained by methylation of chitosan with dimethylsulfate at 700C. Reaction is

carried out as 1.g of chitosan (0.005 mol) in 16 mL of dimethylsulfate and 4 mL of deionized

water.[12][13]

Methylation leads to increase solubility of chitosan in water at neutral and basic

pH values. The increase in solubility is achieved by replacing the primary amino group on the

C-2 position of chitosan with quaternary amino groups.[14][15]

TMC was investigated for

permeation enhancing properties and toxicity, using the Caco-2 cells as a model for intestinal

epithelium. Synthesis of TCM is shown in Figure2.

Fig. 2, Synthesis of N-Trimethyl chitosan chloride (TMC).[16]

5. Carbohydrate branched chitosan- By reductive alkylation carbohydrates can be grafted

on the chitosan backbone at the C-2 position: Disaccharides (cellobiose, lactose, etc.) having


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a reducing end group, are introduced, in the presence of a reluctant, on chitosan in the open

chain form. [17][18]

These derivatives are water soluble. Carbohydrates can also be introduced

without ring opening on the C-6 position.[19][20]

These derivatives are important as they are

recognized by the corresponding specific lectins and thus could be used for drug targeting.

[21], [22]

6. Polyethylene grafted chitosan - Poly(ethylene glycol) (PEG) is a highly water- soluble,

amphipathic polymer and frequently used for chemical modification of natural and artificial

macromolecules for biomedical applications. Grafting PEG onto chitosan should be a

promising approach to obtain water-soluble chitosan derivatives. 6-O-triphenylmethyl-

chitosan was prepared from chitosan by the method reported by Kurita et al. PEG-g- chitosan

was prepared according to the following methods.

The coupling reaction of 6-O-triphenylmethyl-chitosan with MeO-PEG acid was carried out

by using the water-soluble carbodiimide (WSC)-hydroxybenzotriazole (HOBO method in

N,N-dimethylformamide (DMF) to give PEG-grafted-6-O-triphenylmethyl-chitosan. The

reaction mixture was subjected to gel-filtration chromatography (column: Sephadex LH-60, 2

× 100 cm, eluent: DMF) monitored by UV. detector at 265 nm to afford the conjugate. The

high molecular weight fraction was separated and evaporated under reduced pressure. The

yellow solid obtained was treated by 50% (v/v) acetic acid for 2h to deprotect its

triphenylmethyl groups. Then the acidic solution was neutralized with triethylamine (TEA),

and dialyzed in cellulose tube against water, and freeze-dried to give the objective PEG-g-

chitosan. Deprotection of triphenylmethyl groups was confirmed by disappearance of

absorption at 265 nm using UV. spectrophotometer. The purity of PEG-g-chitosan obtained

was confirmed by gel-permeation chromatography (GPC) (column: Shodex OH pack SB-

803, Showa Denko, eluent 1/15 M phosphate buffer, standard: pullulan) monitored by

refractive index (r.i.) detector.[23]

7. Cyclodextrin linked chitosan- To a solution of chitosan (200 mg) in 0.2 M acetate buffer

at pH 4.4 (100 ml) was added a solution (50 ml) of 2 that was prepared form 1 (1 g) was

added by portions. The mixture was stirred for 1h at room temperature. Sodium

cyanoborohydride (260 mg) was added to the resulting solution. The mixture was stirred for 4

days at room temperature, neutralized with 5% ammonia water, subjected to ultrafiltration

through a membrane, and lyophilized to give the 3-CD-linked chitosan. [24]


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Strategies in chitosan derivative

1. Functional group modification

a. Thiolated chitosan - Chitosan when treated with thioglycolic acid, it form thiolated

chitosan shown in Figure 3.

Fig.3, Thiolated polymers.[26]

It has better mucoadhesion and permeation enhancing properties in oral drug delivery.

Thiolated polymer can form disulfide bonds between the thiomer and the mucus gel layer

takes place either via thiol/disulfide exchange reactions or via a simple oxidation process of

free thiol groups. The different types of mucus glycolproteins or designated mucins

exhibiting cysteine-rich subdomains have been reviewed previously. [25]

Mechanism of

disulfide bond formation between thiomers and mucus glycoproteins (mucins) is shown in

Figure 4.

Fig. 4, Mechanism of disulfide bond formation between thiomers and mucus

glycoproteins (Mucins).[26]

b. N- acetylated chitosan- Generally useful in gene drug delivery. Fully de-N-acetylated

chitosan oligomers (dimer to hexamer) were prepared by nitrous acid, depolymerization of

chitosan takes place and separated by size exclusion chromatography (SEC). The oligomers

were then stored in aqueous 0.15M ammonium acetate solution at pH 4.5 until the time of the


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polymerization reaction. The de-N-acetylated dimer to hexamer fractions were each

polymerized (self-branched) by reductive N-alkylation of a 1% solution at pH 5.5 in 0.15M

ammonium acetate and 0.1M NaCl. NaCNBH3 was added in excess (approx. 50 mg) twice,

after 30 min and 24 h. The reaction was stopped after 4 days on stirring in room temperature

by adding concentrated HCl (pH < 2) to remove NaCNBH3. The products were then

lyophilized after adjusting the pH< 4 to obtain the derivatives in their HCl form. Following

scheme is given for nitrous acid degradation and subsequent reductive N-alkylation produce

branched chitosan. The process is shown in Figure 5.

Fig. 5, Nitrous acid degradation and subsequent reductive N-alkylation produce

branched chitosan.[27]

2. Copolymerization - A 250 ml three necked round bottomed flask, filled with a magnetic

stirrer, thermometer, and reflux condenser in a temperature-controlled oil bath, was used for

the graft reaction. Firstly, a desired quantity of chitosan was dissolved in 1 wt% of acet ic acid

aqueous solution at 600C. The total volume of the aqueous solution was 80 ml in all

experiments. After the chitosan was fully dissolved, temperature of the system was strictly

controlled at a required value. Then ammonium persulfate powder was added into the

solution. The mixture was continuously stirred at the desired temperature until completion of

the copolymerization reaction. At the end of the graft copolymerization, the mixture was

continuously stirred for 15 min at room temperature, and then neutralized to pH 10 to

precipitate the product with 1 M NaOH solution. Then the mixture was centrifuged to obtain

the solid. The solid mixture was washed by the distilled water and centrifuged repeatedly to

pH 7, then washed by anhydrous alcohol to remove the salts and centrifuged for 2 times. The


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centrifugate was dried at 700C to a constant weight. After filtration and washed by DMF for

several times, the pure chitosan-g-polyacrylonitrile (CS-g-PAN) was obtained by thoroughly

washed with anhydrous alcohol, and dried at 700C to reach a constant weight. All the samples

were absolutely dried before used for characterization. Grafting rate (%G), which designates

the amount of polymer grafted on the substrate backbone (chitosan), and efficiency of

grafting (%E), which indicates the efficiency of conversion of the initial polymer to the

grafted PAN, were calculated from the increase in weight of the chitosan after graft

copolymerization [28]

:

%Grafting (%G) =

% Efficiency (%E) =

Where W1, W0 and W2 denote the weight of the grafted chitosan, the weight of original

chitosan and weight of the monomer used, respectively. The experiments of graft

polymerization were performed with two parallel experiments, and the data was the average

value of the two results. When the two data were quite different, we carried out the third one

to confirm it.

Mucoadhesion properties

Chitosan structure possesses cationic group, due to this group it has mucoadhesive property.

Chitosan mainly combine with anionic group of mucus i.e sialic acid and sulfonic group

substituent. Hence ionic interaction is take place in between cationic primary amino acid

group of chitosan with anionic sialic acid group of mucus, mucoadhesion can be achieved. In

addition, hydrophobic interactions might contribute to its mucoadhesive properties. In

comparison with various anionic polymeric excipients such as carbomer, polycarbophil, and

hyaluronic acid, however, its mucoadhesive properties are weak.[29]

To achieve better

mucoadhesive properties, polymer should have cohesive properties as that of adhesive. If not

then polymer fails to achieve mucoadhesion. Chitosan has weak cohesive properties but can

be improved by formation of complexes with multivalent anionic drug or other anionic

excipients. [30]

Trimethylation of the primary amino group of chitosan provides an even more

cationic character of the polymer. When trimethylated chitosan (TMC) is additionally

PEGylated, its mucoadhesive properties are even up to 3.4-fold improved.[31]

Due to the

immobilization of thiol groups on chitosan, its mucoadhesive properties can also be strongly

improved, as the thiolated polymer is capable of forming disulfide bonds with mucus

glycoprotein of the mucus gel layer, placing it among the most mucoadhesive polymers


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known so far. [32]

In addition, as inter- and intrachain disulfide bonds are also formed within

chitosan itself, thiolated chitosan exhibits substantially improved cohesive properties.

Recently, the mucoadhesive properties of thiolated chitosan were even significantly further

improved by the preactivation of thiol groups on chitosan via the formation of disulfide bonds

with mercaptonicotinamide.[33]

Application in the drug delivery

1. In conventional dosage form - It is used as binder, disintegrating agent, and coating

material. It has been formulated as core with acrylic coat in design of enteric coated.

2. Chitosan form a gel at low pH and exhibit antacid or antiulcer properties which prevent or

alleviate gastric discomfort induced by drug irritation.[34]

3. Chitosan dosage forms are given in Table 3.

Table 3 : List of chitosan based formulations prepared by different methods

Sr. No Dosage form Method of preparation Drug

1 Tablets Matrix Coating Theophylline,[35]

Propranolol HCl .[36]

2. Capsules Hard gelatine shell Insulin [37]

3. Microspheres/

Microparticles

Emulsion cross-linking,

Coacervation/precipitation

Spray-drying

Ionic gelation

Sieving method

Gentamicin Sulphate,[38]

Propranolol-HCl, [39]

Cimetidine,[40]

Bovine serum albumin (BSA), [41]

Famotidine,[40]

Bovine serum albumin. Clozapine. [42]

4. Nanoparticles Emulsion-droplet coalescence,

Coacervation/ precipitation

Ionic gelation

Reverse micellar method

Gadopentetic acid, [43]

Bovine serum albumin,[44]

Ascorbic acid,[45]

Doxorubicin [46]

5. Beads Coacervation/ precipitation Bovine serum albumin, Insulin [47]

6. Films Solution casting Ofloxacin[48]

7. Gel Cross-linking 5-Fluorouracil [49]

Various chitosan based drug delivery systems

1.Oral drug delivery

As liquid formulations are not favoured by patients and storage stability problems of drugs

such as peptide drugs have to be overcome, solid dosage forms are the delivery systems of

choice. Apart from capsules, tablets are therefore the likely most favourable dosage form. As

tablets provide an accurate dosage and are easy to manufacture and handle, numerous drug

delivery systems comprising chitosan are based on this type of dosage form. The drug can

thereby be homogenized with chitosan and directly compressed to tablets. As chitosan


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precipitates at pH above 6.5, it loses its mucoadhesive and permeation enhancing properties

in distal segments of the intestine. This effect reduces its applicability to drugs having their

absorption window in the proximal segment of the GI tract. [33]

Dhaliwal et al. for instance,

could improve the oral bioavailability of acyclovir 3-fold and 4-fold due to the incorporation

of this drug in chitosan and thiolated chitosan, respectively.[50]

2.Ocular drug delivery

A model drug Cyclosporin A (CyA) was chosen. Chitosan and CyA is complexed in the form

of nanoparticle. Under sink condition in vitro studies are carried out which revealed that an

initial brust realease of the drug followed by gradual drug release upto 24 h. For in vivo

studies rabbits are chosen and CyA loaded chitosan nanoparticles instilled topically (i.e.,

cornea and conjunctiva). These levels were significantly higher than those obtained following

the instillation of CS solution containing CyA that CS nanoparticles could be used as a

vehicle to and an aqueous CyA suspension. The study indicated enhances the therapeutic

index of the clinically challenging drugs with potential application at the extra ocular level.[51]

3.Nasal Drug Delivery

Diabetes is routinely treated by injection of insulin. Insulin can administered via other route

of administration such as oral as well as nasal. But insulin has enzymatic degradation

problem and poor transmucosal absorption. So there is to need to develop new formulation

which includes insulin and excipients into dosage form, increase in physical stability and

bioavailability of insulin. Chitosan and its derivatives or salts have been widely investigated

as functional excipients of delivering insulin via oral, nasal and transdermal routes.

Characteristic of chitosan for its mucoadhesive and able to protect the insulin from enzymatic

degradation, prolong the retention time of insulin, as well as, open the inter-epithelial tight

junction to facilitate systemic insulin transport. The chitosan can be employed to strengthen

the physicochemical stability of insulin and multi-particulate matrix. On modification of

chitosan chemically, produces water soluble low molecular weight polymer protect the

insulin molecule and sulphated chitosan which markedly opens the paracellular channels for

insulin transport. Nanoparticles of chitosan and fatty acid as hydrophobic molecule promote

the insulin absorption via lymphoid tissue. Attainment of optimized formulations with higher

levels of pharmacological bioavailability is deemed possible in future through targeted

delivery of insulin using chitosan with specific adhesiveness to the intended absorption

mucosa.[4]


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4.Vaginal drug delivery

In the treatment of mycotic infection of genitourinary tract clotramazole is embeded in

modified chitosan thioglycolic acid derivatives. By introducing thiol groups, the

mucoadhesive properties of the polymer were strongly improved, and this resulted in an

increased residence time of the vaginal mucosa tissue (26 times longer than the

corresponding unmodified polymer). Vaginal tablets of chitosan containing metronidazole,

acriflavine, and other excipients showed adequate release and good adhesion properties.[52][53]

5.Buccal drug delivery

Biological properties of chitosan allow drug absorb through oral mucosa. Oral mucosal

bioadhesive tablets of diltiazem were prepared by directly compressing the drug with a

mixture of chitosan and sodium alginate. In vitro adhesion studies indicated adhesion

properties comparable to those of a commercial formulation. [54]

6.Parenteral drug delivery

Chitosan can administered intravenously, which has low molecular weight and high purity, its

use in injectable preparations has received considerable attention within the last years. In

controlled release technology, biodegradable polymeric carriers offer potential advantages for

prolonged release of low-molecular-weight compounds to macromolecular drugs. [55]

7.Targeted drug delivery

Chitosan has unique physicochemical and biological properties so it is safe and effective in

drug delivery system. Chemical modification of chitosan is due to presence of primary

hydroxyl and amine groups located on the backbone of chitosan to control its physical

properties. Chitosan conjugated with hydrophobic molecule, forming amphiphilic molecule

which may self assembled nanoparticle having encapsulating efficiency which deliver drug to

site specific. By chemical conjugation with drug form prodrug, exhibiting the appropriate

biological activity at the target site. Mucoadhesive and absorption enhancement properties of

chitosan increase the in vivo residence time of the dosage form in the gastrointestinal tract

and improve the bioavailability of various drugs. [56]

8.Gene therapy

Chitosan-based gene delivery systems have been proven to be effective for non-viral gene

therapy. [57]

The chitosan–DNA complexes are very easy to synthesise and are more effective


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compared to the commonly used polygalactosamine – DNA complexes, but, their use is

limited because of the lower transfection efficiency.[58]

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CHITOSAN: A MUCOADHESIVE POLYMER

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