Recent Perspectives of Chitosan: A Review

Vivek Jain*, Gopal Garg, U.K. Patil and Shailesh Jain

Department of Pharmaceutics, VNS Institute of Pharmacy, Bhopal, M.P. India- 462001

ABSTRACT:

Considerable research efforts have been directed towards mounting safe and competent chitosan-based particulate drug delivery systems. Chitosan is an abundant, naturally occurring polymer with versatile functionalities. Its non allergenicity, biocompatibility, biodegradability and cationic surface charges in acidic medium allow it to have applications in a variety of conventional and pharmaceutical areas. Over the years, numerous strategies for Chitosan and its derivatives have been explored. As evidenced by the literature, it was seen that the viability and prospect of chitosan-mediated drug delivery could be optimistic. The present review outlines the major new findings on the pharmaceutical applications of chitosan-based drug delivery systems published over the past decade and also reviews the recent reports on the preparation, properties and biomedical applications of chitin and Chitosan.

INTRODUCTION:

Ever since the discovery of the drugs, there has been a growing interest in developing a drug delivery system. A great deal of research is currently devoted to pharmaceutical preparations. There is rising curiosity in developing chemical and biochemical processes to acquire and amend bio polymers, and to other useful technical properties for their applications in different fields.¹ one of the latest and most interesting example is chitin which is mainly used for production of chitosan. Among the natural polymer, chitosan is the most abundant polysaccharide which is obtained by deacetylation of chitin.² Different chitosan formulations are extremely proficient in the enrichment of systemic and mucosal immune responses after nasal administrations.³ Chitosan is a polymer obtained from deacetylation of chitin, a naturally-occurring structural polymer abundant in crab and shrimp shells. Toxicity of chitosan depends on its high charge density but appears to be less affected by the molecular weight. It is a cationic polysaccharide with linear chain consisting of b-(1, 4)-linked 2-acetamido-2-deoxy-b-Dglucopyranose (GlcNAc) and 2-amino-2-deoxy-b- D-glucopyranose (GlcN).⁴ Structural properties of chitosans such as degree of acetylation and molecular weight are very important for its absorption enhancement of hydrophilic drugs. A low degree of acetylation (i.e. high percent deacetylation with greater charge density) and or a high molecular weight appear to be necessary for Chitosan to increase the epithelial permeability.⁵

Chemical Structure and Preparation of Chitosan:⁶

Chitin is a long and unbranched homopolymer which forms a major part of cell wall of shrimp, crab, lobster, krill, insects, fungi, annelids and coelenterates. Structurally, it is poly (N-acetyl-2-amino-2-deoxy-D-glycopyranose) in which the N-acetyl-2-amino-2-deoxy-D-glycopyranose units are linked by (1-4) β bonds. Its β (1-4) linked glucose-NAC units with a three dimensional α-helical configuration are stabilized by hydrogen bonding.

For the preparation of chitosan, shellfish wastes from food processing were decalcified in 3 to 5% dil. aqueous HCl solution w/v at room temperature and deproteination was performed in dil. aqueous 3% to 5 % w/v NaOH solution at 80°c to 900° C for a few hrs or at room temperature for overnight. Then it was decolorized in 0.5% KmnO₄ solution, which formed chitin. Deacetylation of chitin in hot concentration 40% to 50% w/v NaOH solution at 90°C to 120°C for 4 to 5 hrs yielded 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.

Scope and objective of the present review:

This review is an insight into the exploitation of the various properties of chitosan to drug delivery systems.

Specifications of pharmaceutical grade chitosan⁷

Appearance	White or yellow
Particle size	< 30 µm
Viscosity	a ≤ 5cps
Density	between 1.35to 1.40 g/cm^3
Molecular weight	50,000 to2,00,000 Da.
PH	6.5 to 7.5
Moisture content	> 10 %
Ash value	> 2 %
Mater insoluble in water	≤ 0.5 %
Degree of deacetylation	66 % to 99.8 %
Heavy metal (Pb)	< 10 ppm
Heavy metal (As)	< 10 ppm
Protein content	< 0.3 %
Loss on drying	≤ 10 %
Glass transition temperature	203° C

Recent contributions:

Ji wu and co-workers¹¹ have designed a thermo-sensitive hydrogel-based on quaternized chitosan and poly (ethylene glycol) for nasal drug delivery system. In the present work, a new thermo-sensitive hydrogel was deliberate and prepared by simply mixing N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride (HTCC) and poly(ethylene glycol) (PEG) with a small amount of a-b-glycerophosphate (a-b-GP)and the results concludes that hydrogel formulation decreased the blood glucose concentration apparently (40–50% of initial blood glucose concentration) for at least 4–5 h after administration, and no obvious cytoxicity was found after application.

A review work entitled chitosan for mucosal vaccination was performed by I.M. Vander Lubben and co-workers.¹² They summaries mucosal vaccination, chitosan nano and micro particles for mucosal vaccine delivery, chitosan for nasal vaccine delivery and concluded that chitosan particles, powders and solutions are promising candidates for mucosal vaccine delivery.

T. J. Aspedan and co-workers:¹³ have evaluated the effect of chitosan on mucociliary clearance rate in the frog palate method. In this study, mucociliary transport velocity (MTV) was determined by monitoring the speed of movement of graphite particles and a large number of particles can be tracked and identified.

Alexander H. Krauland and co-workers were developed:¹⁴ a micro-particulate delivery system based on a thiolated chitosan conjugate for the nasal application of peptides. The results stated that micro-particles comprising chitosan TBA and reduced glutathione seem to represent a useful formulation for the nasal administration of peptides.

Barbara C. Baudner and co-workers:¹⁵ evaluated chitosan micro-particles as a vaccine delivery system as well as the mucosal adjuvant and the results demonstrate that the concomitant use of chitosan micro-particles and the LTK63 mutant significantly enhances the immunogenicity and the protective efficacy of vaccines given intranasally.

Krum Kafedjiisk and co-workers:¹⁶ have performed the synthesis and in vitro evaluation of a novel thiolated chitosan. The aim of this study was to evaluate the imidoester reaction of isopropyl-S-acetylthioacetimidate for the chemical modification of chitosan and to study the properties of the resulting chitosan-thioethylamidine (TEA) derivative. The results of this study stated that, the chitosan-thioethylamidine conjugate appears to be a promising novel excipient for the development of various drug delivery systems.

The surface carboxylation of glutaraldehyde cross linked chitosan (CS-GA) membrane was successfully achieved by the reaction of amine groups on the CS-GA membrane surface with anhydride groups of maleic anhydride (MA) in acetone solution.

Chitosan based formulations: ^{8 -10}

Type of Systems	Drugs incorporated	Method of preparation	Applications
Chitosan Micro-particles Chitosan bile salt micro- particles	Chitosan-TBA-insulin micro particles Chitosan with surfactant solution	Emulsification solvent evaporation technique Micro-encapsulation technique	In nasal peptide delivery Preparation of micro-particulate systems for drug administration.
Chitosan Nanoparticles O-HTCC nanoparticles BSA Loaded Chitosan nanoparticles	Chitosan, O-HTCC solution and Sodium tripolyphosphate Sodium tripolyphosphate, Chitosan solution & O-HTCC solution containing bovine serum albumin	Ionic gelation technique Ionic gelation technique	Absorption enhancing effect In nasal vaccine delivery
Chitosan Liposomes	Ferric chloride, Chitosan matrix	Embedding method	For the development of prolong released dosage form
Chitosan based Hydrogels	Doxorubicin and Chitosan	Incorporation method	Synergistic antitumor effect

This work was performed by Wei Zhang and co-workers¹⁷ and the results indicated that the surface carboxylation was a very effective method to improve pervaporation performance of CS-GA membrane for the separation of aqueous organic mixtures.

Palladium supported on chitosan hollow fiber for nitrotoluene hydrogenation was prepared by F. Peirano and co-workers.¹⁸ Chitosan hollow fibers was used for the continuous catalytic hydrogenation of nitrotoluene into o-toluidine. The results explain the differences observed in the catalytic properties of fibers prepared with different metal contents.

The ultraviolet radiation-induced accelerated degradation of chitosan was demonstrated by Wu Yue and co-workers.¹⁹ the results conclude the accelerated degradation of chitosan is probably due to the excessive production of hydroxyl radical generated by the radiolysis of ozone in the presence of ultraviolet irradiation.

Guogen Liu and co-workers:²⁰ were prepared ultrafine chitosan particles by reverse micro-emulsion consisting of water, Triton X-100, octanol and cyclohexane.

Experimental outcomes showed that, the method which combined ionic gelation and cross-linking, gave uniformly sized chitosan nano-particles with an average diameter of 92 nm, while the cross-linking without ionic gelation produced spindly chitosan particles with an average length of 943 nm and width of 188 nm.

The asymmetric chitosan guided tissue regeneration (GTR) membranes were fabricated by Ming-Hua Ho and co-workers²¹ and the results showed that asymmetric chitosan GTR membranes prepared in this study are promising for the treatment of periodontal diseases.

Guiping Ma and co-workers:²² were synthesized and characterize organic-soluble acylated chitosan and the results demonstrated that thermal stability of the prepared compounds was lower than chitosan.

Chutima Vanichvattanadecha and co-workers:²³ have assessed the effect of gamma radiation on dilute aqueous solutions and thin films of N-succinyl chitosan. The results of present work suggested that the radiolysis of chitosan and N-SC products occurred at the glycosidic linkages and ray radiation affected both the N-acetyl and N-substituted groups on the polymer chains.

Narayan Bhattarai and co-workers:²⁴ proposed the development of chitosan hydrogel has led to new drug delivery systems that release their payloads under varying environmental stimuli. In addition, thermosensitive hydrogel variants have been developed to form a chitosan hydrogel in situ, precluding the need for surgical implantation.

Ana Grenha and co-workers:²⁵ developed a new drug delivery system consisting of complexes formed between preformed chitosan/tripolyphosphate nanoparticles and phospholipids, named as lipid/Chitosan nanoparticles (L/CS-NP) complexes and results demonstrates that protein-loaded L/CS-NP complexes can be efficiently microencapsulated, resulting in microspheres with adequate properties to provide a deep inhalation pattern.

Pharmaceutical applications: ^26-28

Ophthalmic Drug Delivery:

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.

Buccal and Sublingual Drug Delivery:

Chitosan has a good muco-adhesive property so it is used in buccal drug delivery. Buccal tablets based on chitosan microspheres containing chlorhexidine diacetate showed a prolonged release of the drug in the buccal cavity.

Periodontal Drug Delivery:

Local delivery of drugs and other bioactive agents directly into the periodontal pocket has received a lot of attention lately. For example for moderate to severe periodontal diseases.

Nasal Drug Delivery:

The nasal mucosa presents an ideal site for bioadhesive drug delivery systems. Bioavailability and residence time of the drugs that are administered via the nasal route can be increased by bioadhesive drug delivery systems.

Gastrointestinal (Floating) Drug Delivery:

Chitosan granules and chitosan-laminated preparations could be helpful in developing drug delivery systems that will reduce the effect of gastrointestinal transit time.

Peroral Drug Delivery:

The co-administration of chitosan and its derivatives leads to a sturdily improved bioavailability of many perorally given peptide drugs, such as insulin, calcitonin and buserelin.

Intestinal Drug Delivery:

A formulation was developed that could bypass the acidity of the stomach and release the loaded drug for long periods into the intestine by using the bioadhesiveness of polyacrylic acid, alginate, and chitosan.

Colon Drug Delivery:

Recently, it was found that chitosan is degraded by the micro flora that is available in the colon. As a result, this compound could be promising for colon-specific drug delivery. Chitosan esters, such as chitosan succinate and chitosan phthalate have been used successfully as potential matrices.

Transdermal Drug Delivery:

Chitosan has good film-forming properties. The drug release from the devices are depends on the membrane thickness and cross-linking of the film. These properties makes chitosan for potential applications in packaging, controlled release systems, and wound dressings.

Gene delivery:

Chitosan could be a useful oral gene carrier because of its adhesive and transport properties in the GI tract. Gene delivery systems include viral vectors, cationic liposomes, polycation complexes, and microencapsulated systems.

Vaccine Delivery:

Various Chitosan-antigen nasal vaccines have been prepared. These include cholera toxin, diphtheria toxoids, liposomes, nano-particles, attenuated virus and cells, and proteosomes. They induced significant serum IgG responses similar to and secretory IgA levels superior to what was induced by a parenteral administration of the vaccine.

Future prospects:

Despite enormous efforts to develop efficient chitosan-based vectors for drug delivery, the therapeutic effectiveness of chitosan-based drug therapy still needs to be improved in order to achieve clinical significance. By combining the factors using formulation parameter optimization and chitosan structure modifications, the chitosan-based drug delivery system can effectively address the challenges of extracellular and intracellular barriers.

Conclusion and outlook:

Chitosan is the most abundant polysaccharide, infect second only cellulose, it is obtained by alkaline N-deacetylation of chitin. Chitosan has been widely investigated as a drug carrier for many possible routes of administration because of chitosan has favorable biological properties, such as non-toxicity, biocompatibility, biodegradability, and antibacterial characteristics. The physical and chemical properties of chitosan, such as inter- and intermolecular hydrogen bonding and the cationic charge in acidic medium, makes this polymer more attractive for the development of conventional and novel pharmaceutical product. Chitosan can serve a number of purpose, including as a coating agent, gel former, controlled-release matrix, in addition to including desirable properties, such as mucoadhesion and permeation enhancement to improve oral bioavailability of drug. Chitosan is a good candidate for site-specific drug delivery. Chitosan has been found to be of use many clinical situations for ameliorating variety of human ailments, ranging from wound healing glomerulonephritis up to substitute of artificial red blood cells. These multiform aspects of chitosan parallel to those as a drug carrier make it a unique polymer in pharmaceutical field.

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Received on 28.02.2010

Accepted on 25.03.2010

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Research Journal of Pharmaceutical Dosage Forms and Technology. 2(3): May-June 2010, 220-224