Recent Advances on Chitosan-based Micro- And Nano Particles

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Journal of Controlled Release 100 (2004) 5 – 28 www.elsevier.com/locate/jconrel Review Recent advances on chitosan-based micro- and nanoparticles in drug deliveryB Sunil A. Agnihotri, Nadagouda N. Mallikarjuna, Tejraj M. Aminabhavi* Drug Delivery Division, Center of Excellence in Polymer Science, Karnatak University, Dharwad 580 003, India Received 15 July 2004; accepted 12 August 2004 Abstract Considerable research efforts have been directed towards developing safe and efficient chitosan-bas
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  Review Recent advances on chitosan-based micro- and nanoparticlesin drug delivery B Sunil A. Agnihotri, Nadagouda N. Mallikarjuna, Tejraj M. Aminabhavi*  Drug Delivery Division, Center of Excellence in Polymer Science, Karnatak University, Dharwad 580 003, India Received 15 July 2004; accepted 12 August 2004 Abstract Considerable research efforts have been directed towards developing safe and efficient chitosan-based particulate drugdelivery systems. The present review outlines the major new findings on the pharmaceutical applications of chitosan-basedmicro/nanoparticulate drug delivery systems published over the past decade. Methods of their preparation, drug loading, releasecharacteristics, and applications are covered. Chemically modified chitosan or its derivatives used in drug delivery research arediscussed critically to evaluate the usefulness of these systems in delivering the bioactive molecules. From a literature survey, it is realized that research activities on chitosan micro/nanoparticulate systems containing various drugs for different therapeuticapplications have increased at the rapid rate. Hence, the present review is timely. D 2004 Elsevier B.V. All rights reserved.  Keywords: Microparticles; Nanoparticles; Chitosan; Chemically modified chitosan; Drug delivery Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62. Methods of preparation of micro/nanoparticles of chitosan . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82.1. Emulsion cross-linking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82.2. Coacervation/precipitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92.3. Spray-drying. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102.4. Emulsion-droplet coalescence method. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122.5. Ionic gelation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122.6. Reverse micellar method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142.7. Sieving method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 0168-3659/$ - see front matter  D 2004 Elsevier B.V. All rights reserved.doi:10.1016/j.jconrel.2004.08.010 B This paper is CEPS Communication # 23.* Corresponding author. Tel.: +91 836 2779983; fax: +91 836 2771275.  E-mail address: aminabhavi@yahoo.com (T.M. Aminabhavi).Journal of Controlled Release 100 (2004) 5–28www.elsevier.com/locate/jconrel  3. Drug loading into micro/nanoparticles of chitosan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154. Drug release and release kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165. Pharmaceutical applications of chitosan particulate systems. . . . . . . . . . . . . . . . . . . . . . . . . . . 185.1. Colon targeted drug delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185.2. Mucosal delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185.3. Cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195.4. Gene delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205.5. Topical delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225.6. Ocular delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225.7. Chitosan as a coating material . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226. Chemically modified chitosans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 1. Introduction Chitosan (CS) is a polysaccharide, similar instructure to cellulose. Both are madeby linear  h -(1 Y 4)-linked monosaccharides [seeFig. 1(a)].However, an important difference to cellulose is that CS is composed of 2-amino-2-deoxy- h - d -glucancombined with glycosidic linkages. The primaryamine groups render special properties that make CSvery useful in pharmaceutical applications. Comparedto many other natural polymers, chitosan has a positive charge and is mucoadhesive[1].Therefore, it is used extensively in drug delivery applications[2– 6]. Chitosan is obtained from the deacetylation of chitin, a naturally occurring and abundantly available(in marine crustaceans) biocompatible polysaccharide.However, applications of chitin are limited comparedto CS because chitin is structurally similar to cellulose, but chemically inert. Acetamide group of chitin can beconverted into amino group to give CS, which iscarried out by treating chitin with concentrated alkalisolution. Chitin and CS represent long-chain polymershaving molecular mass up to several million Daltons.Chitosan is relatively reactive and can be produced invarious forms such as powder, paste, film, fiber, etc.[7,8]. Commercially available CS has an averagemolecular weight ranging between 3800 and 20,000Daltons and is 66% to 95% deacetylated.Chitosan, being a cationic polysaccharide in neutralor basic pH conditions, contains free amino groups andhence,isinsolubleinwater.InacidicpH,aminogroupscan undergo protonation thus, making it soluble inwater.SolubilityofCSdependsuponthedistributionof free amino and N-acetyl groups[9].Usually 1–3% aqueous acetic acid solutions are used to solubilize CS.Chitosan is biocompatible with living tissues since it doesnotcauseallergicreactionsandrejection.Itbreaksdown slowly to harmless products (amino sugars),which are completely absorbed by the human body[10].Chitosan degrades under the action of ferments, it is nontoxic and easily removable from the organismwithout causing concurrent side reactions. It possessesantimicrobial property and absorbs toxic metals likemercury, cadmium, lead, etc. In addition, it has goodadhesion, coagulation ability, and immunostimulatingactivity.If degree of deacetylation and molecular weight of CS can be controlled, then it would be a material of choice for developing micro/nanoparticles. Chitosanhas many advantages, particularly for developingmicro/nanoparticles. These include: its ability tocontrol the release of active agents, it avoids the useof hazardous organic solvents while fabricating particles since it is soluble in aqueous acidic solution,it is a linear polyamine containing a number of freeamine groups that are readily available for cross-linking, its cationic nature allows for ionic cross-linking with multivalent anions, it has mucoadhesivecharacter, which increases residual time at the site of absorption, and so on. Chitin and CS have very lowtoxicity; LD 50 of CS in laboratory mice is 16 g/kg body weight, which is close to sugar or salt. Chitosanis proven to be safe in rats up 10% in the diet [11]. Various sterilization methods such as ionizing radia-tion, heat, steam and chemical methods can besuitably adopted for sterilization of CS in clinical S.A. Agnihotri et al. / Journal of Controlled Release 100 (2004) 5–28 6  applications[12]. In view of the above-mentioned properties, CS is extensively used in developing drugdelivery systems[7,8,13–18].Particularly, CS has  been used in thepreparation of mucoadhesiveformulations[19–22],improving the dissolution rate of the poorly soluble drugs[14,23,24],drug targeting [25,26]and enhancement of peptide absorption[20,21,27].Many reports are available on the preparation of CSmicrospheres[23,25,26,28,29].Many methods used in the development of microparticulate polymeric drugdelivery devices canalso be used to prepareCS microspheres[30–35].Dodane and Vilivalam[3] reviewed new approaches on pharmaceutical applica-tions of CS and discussed its mechanisms of action invariousin vitro and in vivo models. Recent reviews[36,37]addressed the issues on biomedical, pharma-ceutical and biological aspects of chitin, CS and their derivatives. Chitosan and its derivatives as a non-viralvector for gene delivery[38]and CS-based gastro- intestinal delivery systems[39]have been discussed. The recent review by Sinha et al.[40]covers various methods of preparation and evaluation of CS micro-spheres, but no attempt has been made to discussnanoparticulate CS systems. Different typesof CS- baseddrugdeliverysystemsaresummarizedinTable1. Fig. 1. (a) Structure of chitosan [poly ( h 1– 4- d -glucosamine)]. (b)Structure of cross-linked chitosan.Table 1Chitosan-based drug delivery systems prepared by different methods for various kinds of drugsType of system Method of preparation DrugTablets matrix diclofenac sodium, pentoxyphylline, salicylic acid, theophyllinecoating propranolol HClCapsules capsule shell insulin, 5-amino salicylic acidMicrospheres/Microparticles emulsion cross-linking theophylline, cisplatin, pentazocine, phenobarbitone, theophylline,insulin, 5-fluorouracil, diclofenac sodium, griseofulvin, aspirin,diphtheria toxoid, pamidronate, suberoylbisphosphonate,mitoxantrone, progesteronecoacervation/precipitation prednisolone, interleukin-2, propranolol-HClspray-drying cimetidine, famotidine, nizatidine, vitamin D-2, diclofenacsodium, ketoprofen, metoclopramide-HCl, bovine serum albumin,ampicillin, cetylpyridinium chloride, oxytetracycline, betamethasoneionic gelation felodipinesieving method clozapine Nanoparticles emulsion-droplet coalescence gadopentetic acidcoacervation/precipitation DNA, doxorubicinionic gelation insulin, ricin, bovine serum albumin, cyclosporin Areverse micellar method doxorubicinBeads coacervation/precipitation adriamycin, nifedipine, bovine serum albumin, salbutamolsulfate, lidocaine–HCl, riboflavinFilms solution casting isosorbide dinitrate, chlorhexidine gluconate, trypsin,granulocyte-macrophage colony-stimulating factor, acyclovir,riboflavine, testosterone, progesterone, beta-oestradiolGel cross-linking chlorpheniramine maleate, aspirin, theophylline, caffeine,lidocaine–HCl, hydrocortisone acetate, 5-fluorouracil S.A. Agnihotri et al. / Journal of Controlled Release 100 (2004) 5–28 7  However, the micro/nanoparticulate drug deliverysystems offer numerous advantages over the conven-tional dosage forms. These include improved efficacy,reduced toxicity and improved patient compliance[35,41–43]. The present review addresses the recent trends in the area of micro/nanoparticulate CS-baseddrugdelivery systems.Literature ofthepast decade has been covered and results are critically evaluated. 2. Methods of preparation of micro/nanoparticlesof chitosan Different methods have been used to prepare CS particulate systems. Selection of any of the methodsdepends upon factors such as particle size require-ment, thermal and chemical stability of the activeagent, reproducibility of the release kinetic profiles,stability of the final product and residual toxicityassociated with the final product. Different methodsused in the preparation of CS micro/nanoparticles arediscussed in this review. However, selection of any of these methods depends upon the nature of the activemolecule as well as the type of the delivery device.Since we are concerned only with the micro/nano- particulate systems of CS and its derivatives, we willrestrict our discussions only on these aspects. 2.1. Emulsion cross-linking  This method utilizes the reactive functional aminegroup of CS to cross-link with aldehyde groups of thecross-linking agent (seeFig. 1 b). In this method, awater-in-oil (w/o) emulsion is prepared by emulsify-ing the CS aqueous solution in the oil phase. Aqueousdroplets are stabilized using a suitable surfactant. Thestable emulsion is cross-linked by using an appro- priate cross-linking agent such as glutaraldehyde toharden the droplets. Microspheres are filtered andwashed repeatedly with n-hexane followed by alcoholand then dried[44].By this method, size of the  particles can be controlled by controlling the size of aqueous droplets. However, the particle size of final product depends upon the extent of cross-linkingagent used while hardening in addition to speed of stirring during the formation of emulsion. Thismethod is schematically represented inFig. 2.The emulsion cross-linking method has few drawbackssince it involves tedious procedures as well as use of harsh cross-linking agents, which might possiblyinduce chemical reactions with the active agent.However, complete removal of the un-reacted cross-linking agent maybe difficult in this process.Recently,[33]we have used the emulsion cross-linking method to prepare chitosan microspheres toencapsulate diclofenac sodium using three cross-linking agents viz, glutaraldehyde, sulfuric acid andheat treatment. Microspheres were spherical withsmooth surfaces as shown inFig. 3.The size of the microparticles ranged between 40 and 230 A m.Among the three cross-linking agents used, glutaral-dehyde cross-linked microspheres showed the slowest release rates while a quick release of diclofenacsodium was observed by the heat cross-linked micro-spheres. In our continuing study on CS-basedderivatives[34],we have also prepared the nifedi-  pine-loaded microspheres of polyacrylamide-g-chito-san using three concentrations of glutaraldehyde asthe cross-linking agent. Microspheres were sphericalwith the mean particle size of 450 A m.Glutaraldehyde extracted in toluene was used as across-linking agent by Al-Helw et al.[45]to prepare CS microspheres encapsulated with phenobarbitone.Uniform and spherical microspheres with loadingefficiency up to 57.2% were produced. Loadingefficiency was dependent upon the preparationconditions. Parameters affecting the preparation and performance of microspheres are molecular weight  Fig. 2. Schematic representation of preparation of chitosan particulate systems by emulsion cross-linking method. S.A. Agnihotri et al. / Journal of Controlled Release 100 (2004) 5–28 8
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