氟脲嘧啶微粒-壳聚糖微敏性水凝胶复合释药系统的制备

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氟脲嘧啶微粒-壳聚糖微敏性水凝胶复合释药系统的制备

昝佳^a; 朱德权^a; 谭丰苹^b; 蒋国强^a; 林莹^a; 丁富新^a

^a Department of Chemical Engineering, Tsinghua University, Beijing 100084, China
^b School of Pharmacy, Tianjin University, Tianjin 300072, China

收稿日期:1900-01-01 修回日期:1900-01-01 出版日期:2006-04-28 发布日期:2006-04-28
通讯作者: 丁富新

Preparation of Thermosensitive Chitosan Formulations Containing
5-Fluorouracil/Poly-3-hydroxybutyrate Microparticles Used as
Injectable Drug Delivery System

ZAN Jia^a; ZHU Dequan^a; TAN Fengping^b; JIANG Guoqiang^a; LIN Ying^a; DING Fuxin^a

^aDepartment of Chemical Engineering, Tsinghua University, Beijing 100084, China
^b School of Pharmacy, Tianjin University, Tianjin 300072, China

Received:1900-01-01 Revised:1900-01-01 Online:2006-04-28 Published:2006-04-28
Contact: DING Fuxin

摘要/Abstract

摘要： The auto-gelling and drug release properties of the thermosensitive chitosan-β-glycerophosphate formulation were investigated. According to rheological study, gelation lag time of chitosan/β-glycerophosphate (GP) solutions varied from 2 to 60min with different deacetylation degree of chitosan, pH, gelation temperature, and the particles in the sol. The gelation properties were also found to influence the release profiles of a hydrophilic drug, 5-fluorouracil (5-FU). Morphological examination by scanning electron microphotography demonstrated that large “pores” occurred during the gel-forming process, which created hydrophilic environment and led to the rapid initial release of the drug (85% in first 8h). Poly-3-hydroxybutyrate (PHB), a biodegradable material, was applied here as scaffold to capture 5-FU into microparticles with high encapsulation efficiency by solvent-nonsolvent method. Combination of these microparticles into the chitosan-β-GP formulation could drop the rapid initial release from 85% down to 29% in the optimized PHB content (75%, by mass). The release could sustain for about 10 months. This study provided an understanding of the potential of injectable implant using thermosensitive chitosan-β-GP formulation containing PHB based particles for the water soluble drugs that need the property of long-term delivery.

关键词: hydrogel;chitosan;injectables;microparticle;drug release

Abstract: The auto-gelling and drug release properties of the thermosensitive chitosan-β-glycerophosphate formulation were investigated. According to rheological study, gelation lag time of chitosan/β-glycerophosphate (GP) solutions varied from 2 to 60min with different deacetylation degree of chitosan, pH, gelation temperature, and the particles in the sol. The gelation properties were also found to influence the release profiles of a hydrophilic drug, 5-fluorouracil (5-FU). Morphological examination by scanning electron microphotography demonstrated that large “pores” occurred during the gel-forming process, which created hydrophilic environment and led to the rapid initial release of the drug (85% in first 8h). Poly-3-hydroxybutyrate (PHB), a biodegradable material, was applied here as scaffold to capture 5-FU into microparticles with high encapsulation efficiency by solvent-nonsolvent method. Combination of these microparticles into the chitosan-β-GP formulation could drop the rapid initial release from 85% down to 29% in the optimized PHB content (75%, by mass). The release could sustain for about 10 months. This study provided an understanding of the potential of injectable implant using thermosensitive chitosan-β-GP formulation containing PHB based particles for the water soluble drugs that need the property of long-term delivery.

Key words: hydrogel, chitosan, injectables, microparticle, drug release

昝佳, 朱德权, 谭丰苹, 蒋国强, 林莹, 丁富新. 氟脲嘧啶微粒-壳聚糖微敏性水凝胶复合释药系统的制备
[J]. , DOI: .

ZAN Jia, ZHU Dequan, TAN Fengping, JIANG Guoqiang, LIN Ying, DING Fuxin. Preparation of Thermosensitive Chitosan Formulations Containing
5-Fluorouracil/Poly-3-hydroxybutyrate Microparticles Used as
Injectable Drug Delivery System
[J]. , DOI: .

参考文献

1    Langer, R., “Drug delivery and targeting”, Nature, 392,   5—10(1998).
2    Langer, R., “Drug delivery: Drugs on target”, Science, 293, 58—59(2001).
3    Kost, J., Langer, R., “Responsive polymeric delivery systems”, Adv. Drug Delivery Rev., 46, 125—148(2001).
4    Meyer, D.E., Shin, B.C., Kong, G.A., Dewhirst, M.W., Chilkoti, A., “Drug targeting using thermally responsive polymers and local hyperthermia”, J. Control Release, 74, 213—224(2001).
5    Chen, G.H., Hoffman, A.S., “Graft copolymers that ex-hibit temperature-induced phase transitions over a wide range of pH”, Nature, 373, 49—52(1995).
6    Jeong, B., Bae, Y.H., Kim, S.W., “Drug release from bio-degradable injectable thermosensitive hydrogel of PEG-PLGA- PEG triblock copolymers”, J. Control Re-lease, 63, 155—163(2000).
7    Jeong, B., Kim, S.W., Bae, Y.H., “Thermosensitive sol-gel reversible hydrogels”, Adv. Drug Delivery Rev., 54, 37—51(2002).
8    Muzzarelli, R.A.A., “Biochemical significance of ex-ogenous chitins and chitosans in animals and patients”, Carbohydrate Polymers, 20, 7—16(1993).
9    Molinaroa, G., Lerouxa, J.C., Damasb, J., Adama, A., “Biocompatibility of thermosensitive chitosan-based hy-drogels: An in vivo experimental approach to injectable biomaterials”, Biomaterials, 23, 2717—2722(2002).
10    Chenite, A., Chaput, C., Wang, D., Combes, C., Busch-mann, M.D., “Novel injectable neutral solutions of chi-tosan form biodegradable gels in situ”, Biomaterials, 21, 2155—2161(2000).
11    Ruel-Gariépy, E., Chenite, A., Chaput, C., Guirguis, S., “Characterization of thermosensitive chitosan gels for the sustained delivery of drugs”, Int. J. Pharmac., 203, 89—98(2000).
12    Ruel-Gariépy, E., Leclair, G., Hildgen, P., “Thermosensi-tive chitosan-based hydrogel containing liposomes for the delivery of hydrophilic molecules”, J. Control Re-lease, 82, 373—383(2002).
13    Grem, J.L., “Mechanisms of action and modulation of fluorouracil”, Seminars Radiat. Oncol., 7, 249—259(1997).
14    Denkba, E.B., Seyyal, M., Piskin, E., “Implantable 5-fluorouracil loaded chitosan scaffolds prepared by wet spinning”, J. Memb. Sci., 172, 33—38(2000).
15    Yu, H.M., Shi, Y., YIN, J., Shen, Z.Y., Yang, S.L., “Si-multaneous expression of vitreoscilla globin gene and lytic genes of phage λ in a novel recombinant rscherichia coli used for production of PHB”, Chinese J. Chem. Eng., 9, 407—411(2001).
16    Luengo, J.M., Ruel-Gariépy, G., Angel, S., Naharro, G., “Bioplastics from microorganisms”, Curr. Opin. in Mi-crobiol., 6, 251—260(2003).
17    Ramchandani, M., Robinson, D., “In vitro and in vivo release of ciprofloxacin from PLGA 50:50 implants”, J. Control Release, 54, 167—175(1998).
18    Doll, D.A., Sojka, P.E., HALLETT, S.G., “Effect of noz-zle type and pressure on the efficacy of spray applica-tions of the bioherbicidal fungus microsphaeropsis ama-ranthil”, Weed Technol., 19, 918—923(2005).
19    Wrightson, W.R., Myers, S.R., Galandiuk, S., “HPLC analysis of 5-Fu and FdUMP in tissue and serum”, Bio-chem. Biophys. Res. Commun., 216, 808—813(1995).
20    Chenite, A., Buschmann, M., Wang, D., Chaput, C., Kandani, N., “Rheological characterisation of ther-mogelling chitosan/glycerol-phosphate solutions”, Car-bohydrate Polymers, 46, 39—47(2001).
21    Kaiser, N., Kimpfler, A., “5-Fluorouracil in vesicular phos-pholipid gels for anticancer treatment: Entrapment and re-lease properties”, Int. J. Pharmac., 256, 123—131(2003).
22    Glavas-Dodov, M., Fredro-Kumbaradzi, E., “5-Fluorouracil in topical liposome gels for anticancer treatment - Formula-tion and evaluation”, Acta Pharmac., 53, 241—250(2003).