a brief overview on chitosan applications - eJManager

Indo American Journal of Pharmaceutical Research, 2013

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INDO AMERICAN JOURNAL OF PHARMACEUTICAL RESEARCH

A BRIEF OVERVIEW ON CHITOSAN APPLICATIONS Ambore Sandeep*, Kanthale Sangameshwar, Gavit Mukesh, Rathod Chandrakant, Dhadwe Avinash School of Pharmacy, Swami Ramanand Teerth Marathwada University Nanded.

Copy right © 2013 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Please cite this article in press as Ambore S. M et al. A brief overview on chitosan applications.Indo American Journal Of Pharm Research.2013:3(12).

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ARTICLE INFO ABSTRACT The Chitosan is obtained by the alkaline deacetylation of chitin, which is the major Article history Received 15/12/2013 component of protective cuticles of various crustaceans like crabs, shrimps, prawns, lobsters Available online etc. A lot of work is done on the chitosan to explore its clinical, biomedical, food, agricultural 04/01/2014 and horticultural use. The chitosan is Biodegradable, non-toxic, Bacteriostatic, fungistatic hence it have wide application in the pharmaceutical field. The current review gives the Keywords detailed information about chitosan properties, application and its future applications in Chitosan, properties, pharmaceutical field. application, general recommendation, Chitosan as Natural Biocontrol and Elicitor. Corresponding author Mr. Ambore S. M. (M. Pharm, PhD Student) School of Pharmacy, Swami Ramanand Teerth Marathwada University, Nanded. Maharashtra. [email protected] Mob. No: 9822916966.

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Mr. Ambore S. M. , et. al.

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INTRODUCTION Chitosan, a natural linear bio-polyaminosaccharide is derived by the alkaline deacetylation of chitin, which is the major component of protective cuticles of various crustaceans like crabs, shrimps, prawns, lobsters and cell walls of some fungi such as aspergillus and mucor [2]. Chitosan is cheap, biodegradable and nontoxic to mammals. This makes it applicable for use as an additive in food industry [3], as a hydrating agent in cosmetics, more recently as pharmaceutical agent in preparation of biomedicine and as antimicrobial agent in clinical application [4]. Chitosan is weak base and insoluble in water and organic solvent. However it is soluble in dilute aqueous acidic medium (pH < 6.5). It get precipitated in alkaline solution or with the polyanions and forms gel at low pH. Nowadays starch conjugated chitosan microparticle are used in sustained/controlled release system [5]. These microparticle prepared by a reductive alkylation crosslinking method. It has been studied in broad range of biomedical application, because of its biocompatibility and biodegredation properties[6]. Chitosan and starch are employed for microencapsulation of bioactive material and as carrier in drug delivery systems[7,8,9]. Chitosan nanoparticles are generally prepared by ionotropic gelation, self-assembling or microemulsion methods (Agnihotri, Mallikarjuna, & Aminabhavi, 2004)[10]. The microemulsion method can produce nanoparticles with narrow size distribution, but large quantities of organic solvent must be used (Mitra, Gaur, Ghosh, & Maitra, 2001). Though self-assembling is a simple method, must be modified by introducing new chemical groups (Yinsong, Lingrong, Jian, & Zhang, 2007) [11,12,13]. Ionotropic gelation offers a mild preparation method in the aqueous environment, without the introduction of chemical groups into chitosan molecules. Nanotechnology is an emerging technology that holds great promises for the future. Nanosizing gives materials new characteristics as a result of surface and small size/quantum effects. Chitosan nanoparticles have been extensively explored for pharmaceutical applications, as carriers for drug, gene and vaccine delivery (Dev et al., 2010; Yang, Yuan, Cai, Wang, & Zong, 2009; Zheng et al., 2007). Furthermore, chitosan nanoparticles have been shown to have effective antitumor activity (Qi & Xu, 2006; Qi, Xu, & Chen, 2007) and hypochelosterolemic activity (Tao et al., 2011; Zhang, Tao, Guo, Hu, & Su, 2011) [14]. Solubility of Chitosan[3,15]: a) Soluble in nearly all diluted acids b) Insoluble in sulfuric acid and water c) Not thermo-elastic, decomposes at 280° c d) pKa is 6.3 e)

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HISTORY OF CHITOSAN[20]: a) Chitosan (Kite-O-San) can be easily traced back to 1811 when the French scientist Braconnot discover the ―chitin‖, from which chitosan is derived. Braconnot was a professor of natural history in France. Braconnot was conducting research on mushrooms, from which he isolate substance which was later to be called as chitin. b) Chitosan is a substance which made from the chitin, a polysaccharide present in the exoskeletons of the various crustaceans. It is isolated from the shells of shellfish like lobster, shrimp and crab. Chitosan is popular as the ―fat magnet‖ in the scientific world, because of the reason that it inhibits the fat, which is beneficial for those who want to get rid of their body fat. c) After 20 years, there was scientist Lassaigne who authored an article on the insects where he found that identical substance was present in the structure of insects and the structure of plants. He called this amazing substance ―chitin‖. This name chitin is derived from Greek language, meaning ―tunic‖ or ―outer shell‖ or ―envelope‖. This same concept was further studied in 1843 when Lassaigne evaluated the presence of nitrogen in chitin structure. d) After the discovery of substance chitin, the name ―chitosan‖ emerged on. It was first discovered by scientist Rouget while experimenting with chitin. Rouget found that the compound of chitin could be easily derivatized by chemical and temperature treatments which made it soluble. In 1878 when Ledderhose report that chitin is combination of glucosamine and acetic acid molecules. In 1894 the scientists Hoppe-Seyler named the derivatized chitin, as the chitosan. e) After 1920, chitosan became the favorite issue of research by most of the researchers. They utilized sources of the chitin like crab shells and fungi. Rammelberg in the 1930 worked hard which result to the confirmation that chitosan is obtained from these natural sources. It was also found that by hydrolyzing chitin in a number of ways, the chitin is a polysaccharide of glucosamine. f) In the 1950, the use of x-ray analysis method had improved the study of the presence of chitin or chitosan in the fungi. It is only the most advanced technique that proved to be most reliable in proving the presence of chitin, as well as cellulose, in the cell walls of plants. After 140 years of the initial observation of Braconnot, first book on chitosan was published in the year 1951.

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Structure of Chitosan[19]:

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THE PREPARATION OF CHITOSAN[19]: According to some scientists and chitosan chemistry resources, chitosan is formed through N-deacylation of the chitin molecule.

Mycelium of Fungi

Crustacean Shell Washing and Grinding HCl Demineralization NaOH Deproteinization

Extraction with acetone and drying NaOCl Bleaching

Washing and drying

CHITIN NaOH Deacetylation

Washing and drying

CHITOSAN Fig. Preparation of chitin and chitosan from raw material

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The preparation of low molecular weight chitosan (LMWC)[22,23,24]: Dissolve the high molecular weight chitosan (HMWC) powder completely in 1% (w/v) acetic acid solution to make a chitosan solution of 2% (w/v). Then to above solution add thirty percent of (w/w) H2O2 (hydrogen peroxide) aqueous solution by 1:100 (v/v) ratio. After reaction at 60o C for 1.5 hr, adjust the solution to pH 8. The precipitated chitosan can be recovered by centrifugation and washed to pH 7 with deionized water. The chitosan paste may get freeze and thawed to separate the water, and then dried at 60o C.

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Preparation from raw material20,21]: Actually chitosan is a linear polysaccharide which is composed of randomly distributed B-(1, 4)-linked D-glucosamine (deacetylated unit; D) and N-acetyl-D-glucosamine (acetylated unit; A). With this kind of composition, chitosan is produced commercially by deacetylation of the chitin, which according to chitosan chemistry is found to be the structural element in the exoskeleton of crustaceans. The degree of deacetylation (% DA) can then be identified by NMR spectroscopy, and the % DA in commercial chitosan is in the range of 60 to 100 percent.

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Ultrafine milling of chitosan[20]: In this method, mill the chitosan in TJH-2-4L multidimensional swing high-energy nano-ball-mill (Qinghuangdao Taiji Ring Nano-Products Co., Ltd., Hebei, China), with a driving motor of 7 kW. Mix this chitosan powder (80 g) and ZrO2 balls (6–10 mm in diameter) in a volume ratio of 1:2 in a 4000 ml strengthened stain-less steel grinding bowl. Carry out this experiment in a dry mode for 12 hr without any milling aid. Maintain the temperature at 30o C by cold water recirculation method. The obtained powders can be sealed in aluminum foil for the storage. The milling products of HMWC and LMWC will be abbreviated as HMWC-NP and LMWCNP, respectively. Synthesis of Chitosan Nanogels by Controlled Regeneration Chemistry[21-27] In this method, stirr well the chitin solution of 10 ml (Tamura, Nagahama, & Tokura, 2006; Tamura, Furuike, Nair, & Jayakumar, 2011) for 1 hr, and treat it with the methanol till chitin is regenerated as gel. Wash this gel several times with water till methanol is completely removed from the chitosan nanogels. Centrifuge this product, followed by higher amplitude (75%) probe sonication for 5 min, and then resuspended in the water for further studies. The probe sonication should be done after each centrifugation for 5 min. The whole probe sonication is needed to be done in an enclosed wooden cabin. Thus, by using this preparation method we can easily prepare the chitosan nanogels with desired pharmaceutical applications. Starch Conjugated Chitosan Microparticle Preparation[28,29]:

Fig. Procedure for starch conjugated chitosan microparticle preparation EVALUATION OF THE CHITOSAN[27,28]: Determination of molecular weight: The molecular weight of chitosan can be measured in a solvent of 0.2 M NaCl / 0.1 M CH3 COOH at 25 0 C using an Ubbelohde viscometer, as described by the scientists No, Park, Lee, and Meyers (2002). The viscosity from average molecular weight (mw) is calculated by using the Mark–Houwink equation, [η] = KMx Eqn (1) Where k and x, were 1.81 × 10−3 cm3 g−1 and 0.93, respectively. Each measurement was carried out in triplicate to eliminate

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Particle size determination: The particle size distribution of original chitosan powder can be easily determined using the instrument Mastersizer 2000 (Malvern Instrument Co., UK). Then, particle size distribution of chitosan nanopowder is determined according to the China National Standard GB/T 13321 (2004). Before measuring the particle size, disperse the chitosan nanopowder in celloidin–acetone solution, and acetone will be removed by drying the mixture at 20 to 50 0 C. The sample will be analyzed by small angle X-ray scattering (SAXS) (Rigaku-3014, Rigaku, Japan) under the following conditions: Cu-K radiation, 35 kV, 20 mA and measurement range 2_ 0–3◦. In this way we can determine the particle size of chitosan powder.

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Electron microscopy: Morphological characterization of particles in the original chitosan powder should be performed using a scanning electron microscope (Quanta-200 SEM, FEI, Netherlands). For this evaluation, coat the sample with spraying gold powder to make it conductive. Then, the chitosan nanopowder is analyzed under a transmitting electron microscope (TEM) to have the images of the particles. For this the chitosan nanopowder is suspended in water for 3 min and sonicated to obtain a dilute suspension. Then, deposit a drop of this dilute suspension onto a glow discharged carbon-coated microscopy grid and allowed to dry. The sample is observed by using Hitachi H-7000 TEM (Japan) and particle size of the chitosan nanopowder is determined. Thermogravimetric analysis (TGA)[29]: In this case, thermal stability of powder will be checked. The Mettler Toledo TGA/SDTA851 Thermo gravimeter (Mettler Toledo Corp., Zurich, Switzerland) with STARe software (version 9.01) can be used to analyze the thermal stability of the chitosan samples. The Samples are heated from 30 to 500 0 C at a heating rate of 100C/min under N2 at 30 ml/min during the analysis. In this way thermogravimetric analysis can be done. This thermogravimetric analysis will be useful incase of thermo labile compounds, which shows change in their properties with increase in temperature. FT-IR(Fourier Transform Infrared) spectroscopy: In this method, the FTIR (Fourier transform infrared) is used to analyze the chitosan sample. Fourier transform infrared (FTIR) spectrum is very reliable method to analyze any type of compound. The chitosan samples are prepared as KBr pellet and scanned against a blank KBr pellet background at wave number range 4000–400 cm−1 with resolution of 4.0 cm−1. The KBr spectrum is taken as the background and chitosan-KBr complex is considered as the main sample. UV–visible spectroscopy: The chitosan sample can be prepared by dissolving 0.1g of chitosan in 50 ml 1% (w/v) HCl solution. After complete dissolution, centrifuge this solution at 3000 rpm for 10 min to remove the insoluble material. UV–visible absorption spectra may be obtained using a UV1000 spectrophotometer (Tech-comp Ltd., China) in the range of 200–500 nm. Thus, the data can be analyzed to check spectroscopic properties of the chitosan powder. Statistical analysis: The test data are statistically analyzed using DPS 7.05 software for windows (Zhejiang University, Hangzhou, China). Duncan’s multiple range tests are generally used to determine the difference among means at the level of 0.05. Multiple test data can be utilized to have correct result. Physicochemical Charecterization Methods of Chitosan: Physicochemical properties Determination methods Deacetylation Degree (DD) Infra-red Spectroscopy First derivaive UV-Sectrophotometry NMR Specroscopy Conductometric titration Potentiometric titration Differential scanning colorimetry 2 Average mw or mw distribution Viscometry Light scattering Gel permeation chromatography 3 Crystanility X-ray Diffraction 4 Moisture content Gravimetric analysis 5 Ash content Gravimetric analysis 6 Protein Bradford method DD: Deacetylation Degree, mw: molecular weight Sr. No. 1

PROPERTEIS OF CHITOSAN[17,18,33]:

Chemical Properties Linear polyamine (poly-D-glucosamine), Reactive amino groups , Form chelates with many transitional metal ions, Basteriostatic and fungistatic effect, Separation of protein,

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Biological Properties Biodegradibility, Biocompatibilty, Heamostatic, Analgesic effect, Analgesic effect, Antitumor activity, Mucoadhesion , Permeation enhancing effect, Anticholesterolemicic effect, Antimicrobial activity, Antioxidant activity

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Sr. No. 1

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Chemical and Bilogical properties[16-19, 34]:

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Physical properties[33,34]: Sr.No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

Parameters Appearance Particle size Viscosity Density Molecular Weight pH Moisture content Ash value Matter insoluble in water Degree of deacetylation Heavy metal (Pb/ As) Protein content Loss on drying Glass trnsition temperature

Description White or yellow 10% > 2% 0.5%

Instrument External shape estimation Optical microscopy Capillary test Densitometer HPLC pH meter Gravimetric analysis Gravimetric analysis

66% -- 99.8% < 10 ppm < 0.3% < 10% 2030C

FTIR test Kjeldal method

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Waste Water Treatment: The chemical contamination of water from wide range of toxic materials like heavy metals, aromatic materials, dyes and so on. This is serious environmental problem which may lead to serious consequences to human health. So nowadays low cost chitin and chitosan are widely recommended for waste water treatment. Giabl and his co-workers have studied effect of chitosan properties on adsorption of heavy metals, dyes and organic compounds. The use of chitosan based material to remove ananionic dyes has been recently derived by Crinni and Badot. The Chitosan has been used as adsorbent, coagulant and bactericide intreatment of aquaculture waste water. The effectiveness of chitosan in coagulating and flocculating organic suspensions at pH close to neutrality and low ionic strengh is improved by high DD (Deacetylation degree) and low molecular weight chitosan samples.

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APPLICATIONS OF THE CHITOSAN: Clinical appliction of chitosan[36-48]: a) Chitosan in the Scar Differentiation b) Chitosan hydrogels is useful in the photo-chemistry and experimental surgery c) Inhibition of Matrix proteinases by chitosan d) Chitosan dressings are useful in hemostasis and angiogenesis e) The Chitosan activates microphages for tumoricidal activity and for production of Interleukin-1 f) Chitosan used for scaffold and hydrogel preparation g) Chitosan acetate bandages acts as strong bactericide and thus reduce number of inflamatory cells in wound & bone defects. h) Biomedical Applications of chitosan[49-56] : a) In wound healing b) In different drug delivery systems c) In gene delivery d) Tissue engineering. e) Food Applications of chitosan[57,58] : a) Dietary ingredient b) Food preservatives c) Emulsifying agent ( Food emulsion, Aqueous system, Solid matrix system, Edible films and coatings. d) Chitosan In Biocatalysis: The Chitosan has been widely used as support for enzyme and cell immibilization due to its specific charecterstics. Extraction of chitin from shells and subsequent deacetylation of chitin to produce chitosan is relatively low cost process. Several studies covering the field of immobilization of enzyme on chitosan have been published in 2007-09, but the effect of chitosan charecterstic is not issued.  Immobilization of enzymes and cells on chitosan (adsorption and covalent bonding)  Entrapment of biocatalyst on chitosan and its derivative systems.

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Agricultural and Horticultural use[59]: Chitosan as Natural Biocontrol and Elicitor In agriculture, chitosan is used mainly as a natural seed treatment agent and plant growth enhancer, and which is an ecologically friendly biopesticide substance. It boosts the self ability of plants to protect themselves against various fungal infections. This naturally occurring biocontrolling active ingredients, chitin/chitosan are found in the shells of crustaceans, such as lobsters, crabs, and shrimp, and many other organisms, including insects and fungi. These are one of the most abundant biodegradable substances in the world, which are easily accessible. Degraded molecules of chitin/chitosan exist in the soil and water. Chitosan applications in case of plants and crops are generally regulated by the Environment Pollution Act (EPA), and the USDA National Organic Program regulates its use on organic certified farms and crops. EPA approved that biodegradable chitosan products are allowed for use on different kinds of plants and crops grown commercially and by various consumers. The NASA first flew a chitosan experiment to protect adzuki beans grown aboard the space shuttle and Mir space station in 1997 (see photo above). NASA results concluded that chitosan induces increased growth (biomass) and pathogen resistance due to elevated levels of beta 1-3 glucanase enzymes within the plant cells. NASA confirmed that chitosan delivers the same effect in plants on earth also. Hence after more than 20 years of research and development by DuPont/ConAgra Ventures (DCV) and AgriHouse, have made into developing nontoxic, low molecular weight chitosan polymer solutions which are safe enough for broad-spectrum use in agricultural and horticultural field. In the year 2008, AgriHouse, Inc, Denver (Berthoud), Colorado, was granted Environment Pollution Act (EPA) natural broad-spectrum elicitor position for YEA (Yield Enhancing Agent), which is a liquid solution consists of an ultralow molecular active ingredient of 0.25% chitosan. (Yield Enhancing Agent) YEA is a next-generation, natural chitosan elicitor solution for the agriculture and horticultural uses. This was approved as an amended label for foliar and irrigation applications by the EPA authority in June, 2009. Potential Industrial use[58-60]: The self-healing coatings have chitosan containing polymer materials, such as those used in coatings on cars, to protect paint. When a scratch damages the chemical structure of the paint, the chitosan responds to ultraviolet light by forming chemical chains that begin to form bonding with other materials in the substance, leading to removing the scratch. The process may take less than an hour. A scientist Marek W. Urban, working on this project reported that the polymer can only repair itself in the same spot at single time only, and would not work after repeated scratches. This technology can be applied to industrial materials, however it may depends on a various external factors (long-term persistence of "healability", stiffness and heat resistance of coating, knowledge of the exact mechanism of healing, etc.) not present initial studies; further investigation into these factors might potentially take decades to show the results. New Applications of Chitosan[57-67]: Imprinted chitosan based matrixes: Molecularly imprinted polymer for creating selective binding sites.

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Chitosan metal nano-composites[67,68]: As we have already studied that, chitosan have high affinity for metal ions. This property has been used to prepare Chitosan metal nano-composites, which have potential applications in several fields such as, biomedicine, catalyst, electronics, non-linear optics and so on. Researcher Murugodoss and Chattopadhyay have also prepared silver chitosan metal nano-composites in basic medium at higher temperature using high molecular weight.

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Fig. Schematic representaion of Imprinted chitosan based matrixes preparation

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Fig. Effect of Chitosan mw on morphology of gold nano-composites (A) nanoplates(1000 kda) (B) single nano particles (50 kDa), (C) 2D chains ( 5 kDa) The chitosan metal nano-composites can be prepared in three different paricle size like nanoplates(1000 kda), single nano particles (50 kDa) and 2D chains ( 5 kDa). GENERAL RECOMMENDATION FOR CHITOSAN USE: Sr. no. 1.

APPLICATION Wound healing

2. 3.

Drug delivery system

4.

Scaffolds(gene engineering)

5.

Gene delivery

Cell immobilization

6. Enzyme immobilization

7. 8. 9. 10. 11. 12.

Dietary ingredients Food preservative Emulsifying agent Waste water treatment Molecular imprinting Metal reduction

GENERAL RECOMMENDATION High DD chitosan prefered over chitin Low molecular weight samples High DD high mw DD ≤ 80 Low Mw (Around 10 KDa) DD around 85 (good proliferation and structure) HIGH mw (prolonged bidegredation) Chitosan preferred over chitin( high dd) Β chitin preferred over α-chitin in organic reaction media Adsorption: chitosan for negatively charged proteins, high DD Covalent: chitosan for multipoint immobilization high DD Encapsulation: 1) chitosan-TPP high Mw. High DD retention 2) Chitosan-alginate PECs medium Mw stability High DD, highMw( viscosity), fine particle.

better more

High DD, Medium-low Mw(5-80kDa) Low DD for emulsion stability, high viscosity Generally chitosan preferred over chitin high DD, low viscosity Cross-linking is improved by high DD. low Mw chitosan is used High DD and low Mw chitosan stabilize nanoparticles

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REFERENCE: 1) Caiqin Q, Huirong L, Xiao Q, Liu Y, Juncheng Z, Yumin D, Water-solubility of chitosan and its antimicrobial activity, Carbohydrate Polymers 63 (2006) 367–374. 2) Kumar M. N. V. R., Muzzarelli, R. A. A., Muzzarelli, C., Sashiwa, H., & Domb, A. J. Chitosan chemistry and pharmaceutical perspectives, Chemical Reviews 2004, 104, 6017–6084. 3) Koide, S. S., Chitin–chitosan, properties, benefits and risks. Nutrition Research, 1998 (18), 1091–1101. 4) Dodane V, Vilivalam V D, Pharmaceutical applications of chitosan. Pharmaceutical Science and Technology Today 1998, 1,

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CONCLUSION: From the information given in above review, we can easily conclude that, the chitosan is the easily accessible, cheap and biodegradable natural source. This chitosan have wide application: in clinical, biomedical, food industry, pharmaceutical field etc. Thus by having proper method of preparation, with appropriate conjugate it will certainly deliver desired action. Chitosan is the ideal area to study on and nowadays it is favorite topic under study by many researchers. It is found that, when chitosan is compared with traditional excipient for use in certain purpose, it is evident that the chitosan have superior properties than traditional one. Furthermore, chitosan is widely used in many delivery systems like controlled drug delivery system for extended hormone release effect. It is also used in oral and nasal drug delivery system. In future chitosan can be useful for novel drug delivery system. The characteristics explained above with safe toxicity profile, makes the chitosan excellent excipient in pharmaceutical field for present and future application.

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246–253. 5) Balmayor E R, Barana E T, Azevedoa H S, Reisa R L, Injectable biodegradable starch/chitosan delivery system for the sustained release of gentamicin to treat bone infections. Carbohydrate polymer 2011 87, 32-39. 6) Illum L. Chitosan and its use as a pharmaceutical excipient. Pharmaceutical Research, 1998 15(9), 1326–1331. 7) Illum L, Farraj N F, Davis S S. Chitosan as a novel nasal delivery system for peptide drugs Pharm. Res. 1994, 11:1186–1189. 8) Chandy T, Mooradian D L, Rao G H R, Chitosan polyethylene glycol alginate microcapsules for oral delivery of hirudin. Journal of Applied Polymer Science, 1998 70(11), 2143–2153. 9) Agnihotri S. A., Mallikarjuna N. N., & Aminabhavi T. M.,Recent advances on chitosan-based micro- and nanoparticles in drug delivery. Journal of Controlled Release 2004, 100(1), 5–28. 10) Lin Y. H., Mi F. L, Chen C. T., Chang W. C., Peng S. F., Liang H. F., and Sung H. W.. 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67) Vimala K., Mohan Y. M., Sivudu K. S., Varaprasad K., Ravindra S., Reddy N. N., et al. Fabrication of porous chitosan films impregnated with silver nanoparticles: A facile approach for superior antibacterial application. Colloids and Surfaces B: Biointerfaces 2010, 76, 248–258. 68) Warayuth S, Tantayanon S., Tangpasuthadol V., Thatte M., & Daly W. H. Synthesis and characterization of N-benzyl chitosan derivatives. Polymer Preprints 2006, 47(1), 294–295.

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