An Attractive Biocompatible Polymer for Pharmaceutical Application in Various Dosage Forms : Chitosan

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Shridhar J Pandya

Shridhar J Pandya

Chitosan comes from chitin a natural biopolymer originating from crustacean shells. Chitin is similar to cellulose in morphology; a bountiful natural polysaccharide that contains amino sugars.

Partial deacetylation of chitin gives rise to chitosan, a linear polysaccharide with interspersed D-glucosamine, and acetyl-D-glucosamine units. The preponderance and distribution of acetyl-D-glucosamine residues lead to differing physicochemical properties and biological responses. Chitosan is a weak cationic polysaccharide composed essentially of β(1→4) linked glucosamine units together with some N-acetylglucosamine units. It is obtained by extensive deacetylation of chitin, a polysaccharide common in nature. Chitosan is a biocompatible, biodegradable, and nontoxic natural polymer that exhibits excellent film-forming ability. As a result of its cationic character, chitosan is able to react with polyanions giving rise to polyelectrolyte complexes. Therefore, because of these interesting properties, it has become the subject of numerous scientific reports and patents on the preparation of microspheres and microcapsules. The techniques employed to microencapsulate with chitosan include, among others, ionotropic gelation, spray drying, emulsion phase separation, simple and complex coacervation, and polymerization of a vinyl monomer in the presence of chitosan. The aim of this work is to review is for a taste masking by various methods.

 

Chemistry :

Chemical structure of Chitosan :

Chemical structure of Chitosan

Preparation of Chitosan :

Figure: - 1. Preparation of Chitin and Chitosan Shellfish wastes from food processing (shrimp, crab, squid, lobster,)

Image

The crude chitosan is dissolved in aqueous 2 % w/v acetic acid. Then the insoluble material is removed giving a clear supernatant solution, which is neutralized with NaOH solution resulting in a purified sample of chitosan as a white precipitate. Further purification may be necessary to prepare medical and pharmaceutical-grade chitosan.

The crude chitosan is dissolved in aqueous 2 % w/v acetic acid. Then the insoluble material is removed giving a clear supernatant solution, which is neutralized with NaOH solution resulting in a purified sample of chitosan as a white precipitate. Further purification may be necessary to prepare medical and pharmaceutical-grade chitosan.

Deravative of Chitosan :

While chitosan provides a number of excellent properties, further derivatization of the amine functionalities can be carried out to obtain polymers with a range of properties. A number of approaches, both chemical and enzymatic, have been tried to exploit the reactivity of the amine functional groups. 1

N-Trimethylene Chloride Chitosan (TMC)

A number of studies demonstrated that the charge on chitosan has a role in providing intestinal permeability. Hence, a quaternary derivatized chitosan (N-trimethylene chloride chitosan) was shown to demonstrate higher intestinal permeability than chitosan alone. The TMC derivative was used as a permeation enhancer for large molecules, such as octreotide, a cyclic peptide. Hamman and coworkers showed that the degree of quaternization of TMC influences its drug absorption-enhancing properties. 8 Polymers with higher degrees of quaternization (> 22%) were able to reduce the transepithelial electrical resistance and thereby epithelial transport (in vitro) in a neutral environment (pH 7.4). The maximum reduction in transepithelial resistance was reached with TMC with a degree of quaternization of 48%. This degree of quaternization was also seen to be optimum for in vitro transport of model drugs across a Caco-2 monolayer.

Chitosan Esters

Chitosan esters, such as chitosan succinate and chitosan phthalate have been used successfully as potential matrices for the colon-specific oral delivery of sodium diclofenac. 9 By converting the polymer from an amine to a succinate form, the solubility profile is changed significantly. The modified polymers were insoluble under acidic conditions and provided sustained release of the encapsulated agent under basic conditions. The same researchers also synthesized an iron cross-linked derivative of hydroxamated chitosan succinate, as a matrix for oral theophylline beads. 10 A similar colon-targeting application was suggested for this polymer as well.

Chitosan Conjugates

Reactivity of the amine functionality can be exploited to covalently conjugate functional excipients to the polymer backbone. For example, Guggi and Bernkop attached an enzyme inhibitor to chitosan. The resulting polymer retained the mucoadhesivity of chitosan and further prevented drug degradation by inhibiting enzymes, such as trypsin and chymotrypsin. 11 This conjugated chitosan demonstrated promise for delivery of sensitive peptide drugs, such as calcitonin

Chitosan Pharmaceutical application in various dosage forms.

Preparation of microspheres:

A novel cellulose acetate/chitosan multimicrospheres (CACM) was prepared by the method of w/o/w emulsion. The concentration of cellulose acetate (CA) and the ratio of CA/chitosan (CS) had influence on the CACM size, and appearance. Ranitidine hydrochloride loading and releasing efficiency in vitro were investigated. The optimal condition for preparation of the microspheres was CA concentration at 2% and the ratio of CA/CS at 3/1. The microspheres size was 200–350 μm. The appearance of microspheres was spherical, porous, and nonaggregated. The highest loading efficiency was 21%. The ranitidine release from the CACM was 40% during 48 hr in buffers

Taste masked by spray drying:

Chitosan polymer and drug are dissolved in suitable solvent. Sonication done by ultracentrifuge, after stirring 24 hrs with magnetic stirrer, after completely loading polymer to drug, it way from sprays drying the complexes and evaluate for taste masking, threshold concentration of bitterness was determine and complexes was characterization with the help of XRPD, FT-IR, DSC and SEM. If Complexation was achieve, % of drug content was determine and equivalent weight of complexes taken and formulate it. Dissolution of the chitosan – drug complexes tablet give sustain released effect.

Preliminary study on film dosage form prepared from chitosan for oral drug delivery:

The potential of chitosan films containing diazepam as an oral drug delivery was investigated in rabbits. The results indicated that a film composed of a 1:0.5 drug-chitosan mixture might be an effective dosage form that is equivalent to the commercial tablet dosage forms. The ability of chitosan to form films may permit its use in the formulation of film dosage forms, as an alternative to pharmaceutical tablets.

Increase stability of drug :

Chitosan polymer is use to increase the stability of the drug in which the drug is complexes with chitosan and make slurry and kneading for 45 min. until dough mass. This dough mass is pass through sieve no.16 and make a granules is completely stable at different condition.

Solubility increase as well as taste masking:

Chitosan and cyclodextrins mixed in equal amount and make complexes with drug. The complexes were characterized by SEM, XRPD, FT-IR, & DSC. These complexes were check solubility in incubating shaking with different solvent so we identified that complexes solubility is more to compare pure drug. Chitosan is bio compatible polymer use for taste masking and cyclodextrins having cavity like structure so drug inclusion complex in cyclodextrins and make a complete complexes so it was not release in saliva so its complexes were also used for the taste masking purpose.

Orthopaedic patients :

It has been proven to be useful in promoting tissue growth in tissue repair and accelerating wound-healing and bone regeneration. Chitosan is a biopolymer that exhibits osteoconductive, enhanced wound healing and antimicrobial properties which make it attractive for use as a bioactive Coating to improve osseointegration of orthopaedic and craniofacial implant devices.

Cosmetics industry:

Cosmetic compositions are disclosed for the treatment of hair or skin, characterized by a content of new quaternary chitosan derivatives of the formula. Also disclosed are the new quaternary chitosan derivatives per se as well as processes for their preparation. The chitosan derivatives have a good substantively, particularly to hair keratin, and prove to have hair strengthening and hair conditioning characteristics. Eg. Hair setting lotion, Oxidation Hair-coloring Composition, Hair-toning Composition, Skin Cream, Hair-treatment Composition, Gel-form.

Dental Medicine 9

Chitin / chitosan has a variety of biological activities and advertised as a healthy food that is effective for improvement and/or care of various disorders, arthritis, cancer, diabetes, hepatitis, etc. In Japan , it is renowned since a three-year old Russian boy whose skin was burnt 90 % in total area dramatically recovered thanks to the chitin / chitosan dressing (Beschitin-WR, Unitika , Japan ) in August, 1990.
Chitin / chitosan have been recognized to accelerate wound healing to attain an aesthetically valid skin surface, and to prevent excess scar formation. In dental medicine, chitin / chitosan is also applied as a dressing for oral mucous wound and a tampon following radical treatment of maxillary sinusitis. Furthermore, it is being investigated as an absorbing membrane for periodontal surgery.

Enhanced bone formation by transforming growth factor 10 :

Chitosan composite microgranules were fabricated as bone substitutes for the purpose of obtaining high bone-forming efficacy. The microgranules have the flexibility to fill various types of defect sites with closer packing. The interconnected pores formed spaces between the microgranules, which allowed new bone ingrowth and vascularization. In addition, the transforming growth factor-beta 1 (TGF-pl) was incorporated into the microgranules in order to improve bone-healing efficacy. The chitosan microgranules were fabricated by dropping a mixed solution into a NaOH/ethanol solution. TGF-pl was loaded into the chitosan microgranules by soaking the microgranules in a TGF-pl solution. Scanning electron microscopy (SEM) observations and experiments examining the release of TGF-pl from chitosan and the collagen/chitosan microgranules were performed. SEM was used to examine the cell morphologies on the microgranules and cell proliferation was evaluated using a dimethylthiazole tetrazolium bromide assay. The differentiated cell function was assessed by measuring the alkaline phosphatase (ALPase) activity as well as detecting an osteocalcin assay. The in vivo bone-regeneration experiments were performed using a rabbit calvarial defect model. TGF-pl was released from the collagen/chitosan microgranules at a therapeutic concentration for 4 weeks. SEM indicated that the seeded osteoblastic cells were firmly attached to the microgranules and proliferated in a multilayer manner. The proliferation of the osteoblasts on the TGF-pl-loaded microgranules was the highest among the different types of microgranules tested. The ALPase activity and osteocalcin level of all the samples increased during the culture period, and the TGF-pl-loaded microgranules had a significantly higher ALPase activity and osteocalcin content than the other microgranules. The TGF-pl-loaded microgranules demonstrated a higher bone-regenerative capacity in the rabbit calvarial defects after 4 weeks than the TGF-pl-unloaded microgranules

Cholesterol-lowering effects 13

Fibres with a range of abilities to perturb cholesterol homeostasis were used to nvestigate how the serum cholesterol-lowering effects of insoluble dietary fibres are related to parameters of intestinal cholesterol absorption and hepatic cholesterol homeostasis in mice. Cholestyramine, chitosan and cellulose were used as examples of fibres with high, intermediate and low bile acid-binding capacities, respectively. The serum cholesterol levels in a control group of mice fed a high fat/high cholesterol (HFHC) diet for 3 weeks increased about 2-fold to 4·3mM and inclusion of any of these fibres at 7·5% of the diet prevented this increase from occurring. In addition, the amount of cholesterol ccumulated in hepatic stores due to the HFHC diet was reduced by treatment with these fibres. The three kinds of fibres showed similar hypocholesterolaemic activity; however, cholesterol depletion of liver tissue was greatest with cholestyramine. The mechanisms underlying the cholesterol-lowering effect of cholestyramine were (1) decreased cholesterol (food) intake, (2) decreased cholesterol absorption efficiency, and (3) increased faecal bile acid and cholesterol excretion. The latter effects can be attributed to the high bile acid-binding capacity of cholestyramine. In contrast, incorporation of chitosan or cellulose in the diet reduced cholesterol (food) intake, but did not affect either intestinal cholesterol absorption or faecal sterol output. The present study provides strong evidence that above all satiation and satiety effects underlie the cholesterol-lowering.

Chitosan as Permeation Enhancer

It has been reported that chitosan, due to its cationic nature is capable of opening tight junctions in a cell membrane. This property has led to a number of studies to investigate the use of chitosan as a permeation enhancer for hydrophilic drugs that may otherwise have poor oral bioavailability, such as peptides. 6 Because the absorption enhancement is caused by interactions between the cell membrane and positive charges on the polymer, the phenomenon is pH and concentration dependant. Furthermore increasing the charge density on the polymer would lead to higher permeability. This has been studied by quaternizing the amine functionality on chitosan. Further details are discussed in the chitosan derivatives section.

Chitosan as Mucoadhesive Excipient

Bioadhesivity is often used as an approach to enhance the residence time of a drug in the GI tract, thereby increasing the oral bioavailability. A comparison between chitosan and other commonly used polymeric excipients indicates that the cationic polymer has higher bioadhesivity compared to other natural polymers, such as cellulose, Xantham gum, and starch. 7

Aloe Vera Toothpaste 4

Use daily to fight cavities, plaque, tartar and gum problems. A unique combination of natural active ingredients include: Aloe Vera (naturally soothing gel), CoQ10 for healthy gums, Tea tree oil (natural antiseptic), Chitosan to attack bacteria, Silica (a natural whitener), Escin for healthy gums, and Peppermint and Menthol for natural flavor.

Ophthalmic Drug Delivery

Chitosan exhibits favorable biological behavior, such as bioadhesion, permeability-enhancing properties, and interesting physico-chemical characteristics, which make it a unique material for the design of ocular drug delivery vehicles. 19 Due to their elastic properties, chitosan hydrogels offer better acceptability, with respect to solid or semisolid formulation, for ophthalmic delivery, such as suspensions or ointments, ophthalmic chitosan gels improve adhesion to the mucin, which coats the conjunctiva and the corneal surface of the eye, and increase precorneal drug residence times, showing down drug elimination by the lachrymal flow. In addition, its penetration enhancement has more targeted effect and allows lower doses of the drugs. 20 In contrast, chitosan based colloidal system were found to work as transmucosal drug carriers, either facilitating the transport of drugs to the inner eye (chitosan-coated colloidal system containing indomethacin) or their accumulation into the corneal/conjunctival epithelia (chitosan nanoparticulate containing cyclosporin). The microparticulate drug- carrier (micropsheres) seems a promising means of topical administration of acyclovir to the eye. 21 The duration of efficacy of the ofloxacin was increased by using high MW (1930 kd) chitosan. 22

Gene Delivery

The course of many hereditary diseases could be reversed by gene delivery. In addition, many acquired diseases such as multigenetic disorders and those diseases caused by viral genes could be treated by genetic therapy. 28 Gene delivery systems include viral vectors, cationic liposomes, polycation complexes, and microencapsulated systems. 29,30 Viral vectors are advantageous for gene delivery because they are highly efficient and have a wide range of cell targets. However, when used in vivo they cause immune responses and oncogenic effects. To overcome the limitations of viral vectors, non-viral delivery systems are considered for gene therapy. Non-viral delivery system has advantages such as ease of preparation, cell/tissue targeting, low immune response, unrestricted plasmid size, and large-scale reproducible production. 31 Chitosan has been used as a carrier of DNA for gene delivery applications. Also, Chitosan could be a useful oral gene carrier because of its adhesive and transport properties in the GI tract. MacLaughlin et al. 32 Showed that plasmid DNA containing cytomegalo virus promoter sequence and a luciferase reporter gene could be delivered in vivo by Chitosan and depolymerized Chitosan oligomers to express a luciferase gene in the intestinal tract.

Due to its natural abundance and specific biological properties, chitosan is an attractive material for multiple applications including the following :

Application

Summary

 

Biomedical

- Drug delivery

- Cell delivery

- Orthopedics

- Wound healing

- Surgical sutures

- Ophthalmology

- Skin treatments

- Pharmaceuticals

- Dentistry

- Bone healing

 

 

Chitosan is biocompatible, 1-3 shows antimicrobial and antifungal activities 4-5 which makes it a favorable option for biomedical applications.

 

It has been proven to be useful in promoting tissue growth in tissue repair and accelerating wound-healing and bone regeneration. 6-7

 

Moreover, chitosan can be incorporated into hydrogels and microspheres which demonstrate large potential in delivery systems for drugs, proteins or genes.

 

 

Nutritional

- Cholesterol-lowering effects

- Fiber and weight loss effects

 

 

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Chitosan has a strong positive charge; studies indicate that Chitosan’s charge helps it bind to fats and cholesterol and initiates clotting of red blood cells. 2

 

it acts as a fiber; these fiber-like properties can be used to replace calories in foods

 

Cosmetic

- Hair care

- Skin care

- Oral care

 

 

 

Chitosan's strong positive charge allows it to bind to negatively charged surfaces such as hair and skin which makes it a useful ingredient in hair and skin products

References:

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2. Park HS, Lee JY, Cho SH, Baek HJ, Lee SJ. Colon delivery of prednisolone based on chitosan-coated polysaccharide tablets. Arch Pharm Res. 2002;25(6): 964-968.

3. Sakkinen M, Linna A, Ojala S, Jurjenson H, Veski P, Marvola M. In vivo evaluation of matrix granules containing microcrystalline chitosan as a gel-forming excipient. Int J Pharm. 2003;250(1):227-237.

4. Tozaki H, Odoriba T, Okada N, Fujita T, Terabe A, Suzuki T, Okabe S, Muranishi S, Yamamoto A. Chitosan capsules for colon-specific drug delivery: enhanced localization of 5-aminosalicylic acid in the large intestine accelerates healing of TNBS-induced colitis in rats. J Controlled Release. 2002;82(1):51-61.

5. Sinha VR, Kumria R. Polysaccharides in colon-specific drug delivery. Int J Pharm. 2001; 224(1-2):19-38.

6. Thanou M, Verhoef JC, Marbach P, Junginger HE. Intestinal absorption of octreotide: N-trimethyl chitosan chloride (TMC) ameliorates the permeability and absorption properties of the somatostatin analogue in vitro and in vivo. J Pharm Sci. 2000;89(7):951-957.

7. Kotze AF, Luessen HL, Thanou M, Verhoef JC, de Boer AG, Juninger HE, Lehr CM. Chitosan and chitosan derivatives as absorption enhancers for peptide drugs across mucosal epithelia. In: Matiowitz E, Chickering DE, Lehr CM, eds. Bioadhesive Drug Delivery Systems. New York , NY : Marcel Dekker;1999.

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12.National Toxicology Program Document. http://ntp-server.niehs.nih.gov/htdocs/ Chem_Background/ExSumPdf/Chitosan.pdf.

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About Authors:

Shridhar J Pandya

Shridhar J Pandya completed B.Pharmacy form TVES College of Pharmacy, faizpur, Jalgaon. Presently he is pursing M.Pharmacy at AISSMS College of Pharmacy, Pune, he is working on “Taste masked formulations of various bitter taste drugs. He also worked on orodispersible tablets of bitter drugs”.

D Harinarayana

D Harinarayana completed D.Pharmacy from SV College of Pharmacy, Hyderabad. B.Pharmacy form SSR College of Pharmacy, Mahabubnagar. Presently he is pursing M.Pharmacy at AISSMS College of Pharmacy, Pune, he is working on projects “Improvement of photostability of various pharmaceutical agents in formulation”.

Devendra Jain

Devendra Jain completed B.Pharmacy form MGV’s College of Pharmacy, Nashik. Presently he is pursing M.Pharmacy at AISSMS College of Pharmacy, Pune, he is working on projects “Formulation development and evaluation of topical drug delivery system of antifungal drug-Fluconazole”.

Sushant Kulthe

Sushant Kulthe completed B.Pharmacy form MGV’s College of Pharmacy, Nashik. Presently he is pursing M.Pharmacy at AISSMS College of Pharmacy, Pune.

Shital. J. Bidkar

Shital. J. Bidkar completed B.Pharmacy form NPC College of Pharmacy, Nanded. Presently she is pursing M.Pharmacy at AISSMS College of Pharmacy, Pune.

Nitin M. Kadam

Nitin M. Kadam completed B.Pharmacy form Satara College of Pharmacy, satara. Presently he is pursing M.Pharmacy at AISSMS College of Pharmacy, Pune.

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