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. 2004 Sep 1;6(3):88–99. doi: 10.1208/aapsj060327

Development and characterization of biodegradable chitosan films for local delivery of paclitaxel

Anand Babu Dhanikula 1,✉, Ramesh Panchagnula 1
PMCID: PMC2751252  PMID: 15760112

Abstract

Intratumoral and local drug delivery strategies have gained momentum recently as a promising modality in cancer therapy. In order to deliver paclitaxel at the tumor site in therapeutically relevant concentrations, chitosan films were fabricated. Paclitaxel could be loaded at 31% wt/wt in films, which were translucent and flexible. Physicochemical characterization of paclitaxel via thermal, spectroscopic, x-ray diffraction, and electron microscopy techniques revealed information on solid-state properties of paclitaxel as well as chitosan in films. While chitosan was in amorphous form, paclitaxel seemed to be present in both amorphous and crystalline forms in film. The polymeric dispersion of paclitaxel in poloxamer formed fibrous structures generating discontinuities in the film matrix, thereby leading to the introduction of perturbations in the packing arrangement of polymer chains. These films released only 10% to 15% of loaded paclitaxel by a burst effect under in vitro testing conditions, with lysozyme having no effect on the release. However, films softened after implantation in mice and lost integrity over time. The implantable delivery system is not only biodegradable but also well tolerated in vivo and hence, biocompatible as revealed by histological studies. The lack of formulation-induced local inflammatory responses of paclitaxel chitosan films suggests a new paradigm for localized chemotherapy based on implantable systems.

Keywords: paclitaxel, local delivery, film, solid-state, histology, mice

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References

  • 1.Angelova N, Hunkeler D. Rationalizing the design of polymeric biomaterials. Trends Biotechnol. 1999;17:409–421. doi: 10.1016/S0167-7799(99)01356-6. [DOI] [PubMed] [Google Scholar]
  • 2.Pillai O, Panchagnula R. Polymers in drug delivery. Curr Opin Chem Biol. 2001;5:447–451. doi: 10.1016/S1367-5931(00)00227-1. [DOI] [PubMed] [Google Scholar]
  • 3.Pangburn SH, Trescony PV, Heller J. Lysozyme degradation of partially deacetylated chitin, its films and hydrogels. Biomaterials. 1982;3:105–108. doi: 10.1016/0142-9612(82)90043-6. [DOI] [PubMed] [Google Scholar]
  • 4.Janes KA, Fresnean MP, Marazuela A, et al. Chitosan nanoparticles as delivery systems for doxorubicin. J Control Release. 2001;73:255–267. doi: 10.1016/S0168-3659(01)00294-2. [DOI] [PubMed] [Google Scholar]
  • 5.Ruel-Gariepy E, Chenite A, Chaput C, et al. Characterization of thermosensitive chitosan gels for the sustained delivery of drugs. Int J Pharm. 2000;203:89–98. doi: 10.1016/S0378-5173(00)00428-2. [DOI] [PubMed] [Google Scholar]
  • 6.Muzarelli R, Baldassarre V, Conti F, et al. Biological activity of chitosan: ultra structural study. Biomaterials. 1998;9:247–252. doi: 10.1016/0142-9612(88)90092-0. [DOI] [PubMed] [Google Scholar]
  • 7.Senel S, Ikinci G, Kas S, et al. Chitosan films and hydrogels of cholhexidine gluconate for oral mucosal delivery. Int J Pharm. 2000;193:197–203. doi: 10.1016/S0378-5173(99)00334-8. [DOI] [PubMed] [Google Scholar]
  • 8.Ouchi T, Banba T, Fujimoto M, et al. Synthesis and antitumor activity of chitosan canying 5-fluorouracil. Makromol Chem. 1989;190:1817–1825. doi: 10.1002/macp.1989.021900807. [DOI] [Google Scholar]
  • 9.Jameela SR, Jayakrisnan A. Glutaraldehyde cross-linked chitosan microspheres as a long acting biodegradable drug delivery vehicle: studies on the in vitro release of mitoxantrone and in vivo degradation of microspheres in rat muscle. Biomaterials. 1995;16:769–775. doi: 10.1016/0142-9612(95)99639-4. [DOI] [PubMed] [Google Scholar]
  • 10.Blanco MD, Gomez C, Olmo R, et al. Chitosan microspheres in PLG films as devices for cytarabine release. Int J Pharm. 2000;202:29–39. doi: 10.1016/S0378-5173(00)00408-7. [DOI] [PubMed] [Google Scholar]
  • 11.Miwa A, Ishibe A, Nakano M, et al. Development of novel chitosan derivatives as micellar carriers of taxol. Pharm Res. 1998;15:1844–1850. doi: 10.1023/A:1011901921995. [DOI] [PubMed] [Google Scholar]
  • 12.Ma J, Wang H, He B, et al. A preliminary in vitro study on the fabrication and tissue engineering applications of a novel chitosan bilayer materials as a scaffold of human neofetal dermal fibroblasts. Biomaterials. 2001;22:331–336. doi: 10.1016/S0142-9612(00)00188-5. [DOI] [PubMed] [Google Scholar]
  • 13.Miyazaki S, Yamaguchi H, Takada M, et al. Pharmaceutical application of biomedical polymers. XXIX. Preliminary study on film dosage form prepared from chitosan for oral drug delivery. Acta Pharm Nord. 1990;2:401–406. [PubMed] [Google Scholar]
  • 14.Chandy T, Sharma CP. Biodegradable chitosan matrix for the controlled release of steroids. Biomater Artif Cells Immobilization Biotechnol. 1991;19:745–760. doi: 10.3109/10731199109117852. [DOI] [PubMed] [Google Scholar]
  • 15.Lesser GJ, Grossman SA, Eller S, et al. The distribution of systemically administered [3H]-paclitaxel in rats: a quantitative autoradiographic study. Cancer Chemother Pharmacol. 1995;37:173–178. doi: 10.1007/BF00685646. [DOI] [PubMed] [Google Scholar]
  • 16.Brem H, Gabikian P. Biodegradable polymer implants to treat brain tumors. J Control Release. 2001;74:63–67. doi: 10.1016/S0168-3659(01)00311-X. [DOI] [PubMed] [Google Scholar]
  • 17.Ringel I, Horwitz SB. Taxol is converted to 7-epitaxol, a biologically active isomer, in cell culture medium. J Pharmacol Exp Ther. 1987;242:692–698. [PubMed] [Google Scholar]
  • 18.Horisawa E, Hirota T, Kawajoe S, et al. Prolonged anti-inflammatory action of D,L-lactide/glycolide copolymer nanospheres containing betamethasone sodium phosphate for intra-articular delivery system in antigen-induced arthritic rabbit. Pharm Res. 2002;19:403–410. doi: 10.1023/A:1015123024113. [DOI] [PubMed] [Google Scholar]
  • 19.Liggins RT, Hunter WL, Burt HM. Solid-state characterization of paclitaxel. J Pharm Sci. 1997;86:1458–1463. doi: 10.1021/js9605226. [DOI] [PubMed] [Google Scholar]
  • 20.Kemp W. Organic Spectroscopy. London, UK: Macmillan Press; 1996. Infrared spectroscopy; pp. 19–100. [Google Scholar]
  • 21.Ratner BD, Kwok C. Characterization of delivery systems surface analysis and controlled release systems. In: Mathiowitz E, editor. Encyclopedia of Controlled Drug Delivery. New York, NY: John Wiley and Sons; 1999. pp. 261–269. [Google Scholar]
  • 22.Chenite A, Chaput C, Wang D, et al. Novel injectable neutral solutions of chitosan form biodegradable gels in situ. Biomaterials. 2000;21:2155–2161. doi: 10.1016/S0142-9612(00)00116-2. [DOI] [PubMed] [Google Scholar]
  • 23.Grit M, Crommelin DJ. Chemical stability of liposomes: implications for their physical stability. Chem Phys Lipids. 1993;64:3–18. doi: 10.1016/0009-3084(93)90053-6. [DOI] [PubMed] [Google Scholar]
  • 24.Zuidam NJ, Crommelin DJ. Chemical hydrolysis of phospholipids. J Pharm Sci. 1995;84:1113–1119. doi: 10.1002/jps.2600840915. [DOI] [PubMed] [Google Scholar]
  • 25.Kofuji K, Shibata K, Murata Y, et al. Preparation and drug retention of biodegradable chitosan gel beads. Chem Pharm Bull (Tokyo) 1999;47:1494–1496. doi: 10.1248/cpb.47.1494. [DOI] [PubMed] [Google Scholar]
  • 26.Schwendeman SP, Costantino HR, Gupta RK, et al. Strategies for stabilising tetanus toxoid towards the development of a single-dose tetanus vaccine. Dev Biol Stand. 1996;87:293–306. [PubMed] [Google Scholar]
  • 27.Tomihata K, Ikada Y. In vitro and in vivo degradation of films of chitin and its deacetylated derivatives. Biomaterials. 1997;18:567–575. doi: 10.1016/S0142-9612(96)00167-6. [DOI] [PubMed] [Google Scholar]
  • 28.Martin A. Physical Pharmacy:Physical Chemical Principles in the Pharmaceutical Sciences. Baltimore, MD: Waverly International; 1994. Polymer science; pp. 556–594. [Google Scholar]
  • 29.Ford JL, Timmins P. Pharmaceutical Thermal Analysis: Techniques and Applications. Chichester, UK: Ellis Horwood; 1989. pp. 180–200. [Google Scholar]
  • 30.Nunthanid J, Puttipipatkhachorn S, Yamamoto K, et al. Physical properties and molecular behavior of chitosan films. Drug Dev Ind Pharm. 2001;27:143–157. doi: 10.1081/DDC-100000481. [DOI] [PubMed] [Google Scholar]
  • 31.Puttipipatkhachorn S, Nunthanid J, Yamamoto K, et al. Drug physical state and drug-polymer interaction on drug release from chitosan matrix films. J Control Release. 2001;75:143–153. doi: 10.1016/S0168-3659(01)00389-3. [DOI] [PubMed] [Google Scholar]

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