吲哚美辛的海藻酸钠—壳聚糖缓释微囊的制备与性质研究
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摘要
1．选择海藻酸钠、壳聚糖为包埋药物的载体
天然材料一般无毒、免疫原性低、生物相容性好、可降解且产物无毒副作用，其中海藻酸盐、壳聚糖为天然多糖资源丰富、制备简单、价格便宜，可内服而无任何副作用，从而可作为理想的药物缓释膜材料。
壳聚糖还具有独特的抗酸、抗溃疡性能，能一定程度地阻挡吲哚美辛等药物对胃的刺激。
通过海藻酸钠与壳聚糖两种聚电解质间静电相互作用结合用乳化凝胶法制备微囊比单一选择其中的任何一种效果好。
2．选择吲哚美辛为药物模型
吲哚美辛为非甾体抗炎解热镇痛药。然而，吲哚美辛常见的副反应为胃肠道反应，严重时可引起胃出血及穿孔。有些病人因为副作用严重而中断治疗，严重影响了药效的发挥。吲哚美辛的半衰期短，服用不方便，为减少服药次数和副作用，需要将其制成缓释剂型。
3．本文主要研究的内容：
1．从虾蟹壳中提取甲壳素，并考察酸浓度、碱浓度、脱钙时间对提取工艺的影响。
2．用碱法对甲壳素脱乙酰化制备了壳聚糖，并考察反应时间、反应温度、碱浓度对脱乙酰度和分子量的影响。
3．用乳化凝胶法制备在缓释及消除其胃肠道刺激的双重目的吲哚美辛海藻酸钠-壳聚糖微囊，并测定回收率、包封率、载药量、溶出度。
1.Selecting chitosan and sodiumalginate as the carrier of embeding medicine Inartificial materical is usually nontoxic,biocompatible and biodegradable.
Because sodiumalginate and chitosan are low-cost, easily-prepared and can be taken orally, it can be used to make the film of sustained-release medicine. Furthermore, chitosan has the special property in anti-acid and anti-canker and preventing indomethacin from stimulating to stomach.
The property of microcapsules made by chitosan and sodiumalginate is better than the single one.
2.Selecting indomethacin as medical model
Indomethacin is an extensively used medicine which can be used to treat a lot of illness. Besides its short half life, it has some side-effect to patients, and even arouse gastricing perforation, so indomethacin should be made as sustained-release one.
3.The main study in this paper including:
(1) Chitin was distilled from the shell of shrimp and crab. The effect of the concentration of acid and alkali and the time of discalcium on the rate of distilling was investigated.
(2) The chitasan was prepared from the chitin by the method of deacetylation.The main factors influencing the degre of deacetylation and molecular weight were studied.
(3) The microcapsules of indomethacin-sodiumalginate-chitosan was prepared by emulsification-gelation method. The rate of recycling, medicine bearing capacity, encapsulation ratio and dissolution rate were mensurated
天然材料一般无毒、免疫原性低、生物相容性好、可降解且产物无毒副作用，其中海藻酸盐、壳聚糖为天然多糖资源丰富、制备简单、价格便宜，可内服而无任何副作用，从而可作为理想的药物缓释膜材料。
壳聚糖还具有独特的抗酸、抗溃疡性能，能一定程度地阻挡吲哚美辛等药物对胃的刺激。
通过海藻酸钠与壳聚糖两种聚电解质间静电相互作用结合用乳化凝胶法制备微囊比单一选择其中的任何一种效果好。
2．选择吲哚美辛为药物模型
吲哚美辛为非甾体抗炎解热镇痛药。然而，吲哚美辛常见的副反应为胃肠道反应，严重时可引起胃出血及穿孔。有些病人因为副作用严重而中断治疗，严重影响了药效的发挥。吲哚美辛的半衰期短，服用不方便，为减少服药次数和副作用，需要将其制成缓释剂型。
3．本文主要研究的内容：
1．从虾蟹壳中提取甲壳素，并考察酸浓度、碱浓度、脱钙时间对提取工艺的影响。
2．用碱法对甲壳素脱乙酰化制备了壳聚糖，并考察反应时间、反应温度、碱浓度对脱乙酰度和分子量的影响。
3．用乳化凝胶法制备在缓释及消除其胃肠道刺激的双重目的吲哚美辛海藻酸钠-壳聚糖微囊，并测定回收率、包封率、载药量、溶出度。
1.Selecting chitosan and sodiumalginate as the carrier of embeding medicine Inartificial materical is usually nontoxic,biocompatible and biodegradable.
Because sodiumalginate and chitosan are low-cost, easily-prepared and can be taken orally, it can be used to make the film of sustained-release medicine. Furthermore, chitosan has the special property in anti-acid and anti-canker and preventing indomethacin from stimulating to stomach.
The property of microcapsules made by chitosan and sodiumalginate is better than the single one.
2.Selecting indomethacin as medical model
Indomethacin is an extensively used medicine which can be used to treat a lot of illness. Besides its short half life, it has some side-effect to patients, and even arouse gastricing perforation, so indomethacin should be made as sustained-release one.
3.The main study in this paper including:
(1) Chitin was distilled from the shell of shrimp and crab. The effect of the concentration of acid and alkali and the time of discalcium on the rate of distilling was investigated.
(2) The chitasan was prepared from the chitin by the method of deacetylation.The main factors influencing the degre of deacetylation and molecular weight were studied.
(3) The microcapsules of indomethacin-sodiumalginate-chitosan was prepared by emulsification-gelation method. The rate of recycling, medicine bearing capacity, encapsulation ratio and dissolution rate were mensurated
引文
[1] Ranney MW, "Microencapsulation Technology", Noyes Development, ParkRidge,NJ,1969.
[2] Yolles S,Leafe D I,Meyer FJ,J Pharm,Sci,1975,64:115
[3] Jani P, Halbert G W, Langrige J,et al.J Pharm,1990,41:821
[4] 王建明．《分散体系理论在制剂学中的应用》．北京医科大学，中国协和医科大学联合出版社，1995年4月第一版：120
[5] 周洁．微胶囊技术及其在食品工业中应用．粮食与油脂，2003，9：10-12
[6] 刘袖洞．微胶囊及其在生物医学领域的应用．科学通报，2000，45(23)：2476-2483．
[7] 谈金辉 等．药物微胶囊技术及其应用．天津化工，2003，17(6)：4-6
[8] 郝红等．微胶囊技术及其应用．现代化工，2002，22(3)：60-67
[9] Tyler J E.Microencapsulation of mammalian cells.Bioprocess Technoi, 1990,10:343-361
[10] Knorr D,Pandya Y, Doemenbrug H. Food Biotechnol, 1990,4(1):409～420.
[11] Yuet P K,Harris T J, et al. Art Cells Blood Subs Imob Biotechnol, 1995,23(1): 109～133.
[12] Awrey D E,Tse M, et al. Biotechnol Bioeng,1996,52:472～484.
[13] Tin S S H, Boadi D K, et al. Biotechnol Bioeng,1997,56:464～470.
[14] Goosen M F A,Achaw, O W, Grandmaison E W. Appl Chitin Chitosan,1997,233-254.
[15] Kank.e. M,Simmons G H,et al.J Pharm Sci,1990,69:755
[16] Chang T M S.Semipermeable microcapsules.Science,1964,146:524-525
[17] Lim F, Sun A M. Science, 1980,210:908-909
[18] Basic D,Vacek I,Sun A M. Art Cells Blood Subs Immob Biotechnol, 1996,24(3):219-255
[19] Sanchez A,Gupta R K,Alonso M J,et al. J Pharm Sci,1996,85(6):547-552
[20] 卢凤琦，曹宗顺，王春香，等．壳聚糖-海藻酸盐微囊对尼莫地平的缓释作用．中国药学杂志，1996，31(9)：555-556
[21] 冯鹏，王亦农，马建标，等．肽类药物口服剂型材料及控制释放研究：Ⅰ．壳聚糖-海藻酸盐微囊对胰岛素的控制释放作用．离子交换与吸附，1999，15(1)：64-70
[22] Kader A,Jalil R. Drug Dev Ind Pharm, 1999,25(2): 141-151
[23] 姚善泾．新型生物微胶囊体系的生物相容性研究．生物工程学报，1998，21(3)：391-398．
[24] 于鹰．缓释药物—患者的福音．化学教育，2003，6：1-2
[25] 周洁．微胶囊技术及其在食品工业中应用．粮食与油脂，2003，9：10-12
[26] 黄守坚．约物的控释制剂．新医学，1996，27(10)：556-557
[27] 刘会臣．约物控／缓释制剂生物等效性评价．解放军药学学报，1999，15(6)：45-47
[28] 侯俊伦．约物控释剂及其释药方式的类型分析．天津药学，2001，13(6)
[29] Machluf M,Orsola A,Atala A. World J Urol,2000,18(1):80-83
[30] Shiraishi S,I mai T, Otagiri M, Biol Pharm Bull,1993,16(11):1164-1168
[31] Kim H J,Lee H C,Oh J S,et al. J Biomater Sci Polyrn Ed,1999,10(5):543-556
[32] Curt T. Newyork: WileyPress,1987.9.34.
[33] Curt T. Newyork: WileyPress,1987.7.24.
[34] 刘袖洞、何洋，等．微胶囊及其在生物医学领域的应用．科学通报．2000，45(23)：2476-2483．
[35] Aicheal C,Aprahamain M,Defontaine L,et al J Pharm Pharmacol, 1991,43:1-5
[36] 施良和，胡汉杰．高分子科学的今天与明天．北京：化学工业出版社，1994．108．
[37] 甘景镐，甘纯矶，胡炳环．天然高分子．高等教育出版社，1993：203-205
[38] Felt O, Buri P, Gumy R. Chitosan. Drug Dev Ind Pharm, 1998, 24(11): 979
[39] Richardson SCW, Kolbe VJH, Duncan. Int. J Pharm, 1999, 178:231
[40] 夏文水，吴焱楠．甲壳素／壳聚糖水解酶的研究进展．中国海洋药物杂志，1997(2)：315
[41] Schipper NM, Varum KM, A rtusson P, et al. Pharm Res, 1996,13(11):1686
[42] Lueben HL, Rental CO, Kotze AF, et al. J Contr Rel,1997,45:15
[43] Awie FK, Henrik LL, Bas JD, et al. J Contr Rel,1998,51:35
[44] Muzzarelli. R.A.A. Carbohydrate Polymers, 1996.29:309
[45] Chandy. T..Biomater. Artif. Cells Artif. Organs. 1990.18(1):1
[46] Shi Yongchang,JiangYongming.Sui Dexin et al.,J.Chromatography,1996,742:107
[2] Yolles S,Leafe D I,Meyer FJ,J Pharm,Sci,1975,64:115
[3] Jani P, Halbert G W, Langrige J,et al.J Pharm,1990,41:821
[4] 王建明．《分散体系理论在制剂学中的应用》．北京医科大学，中国协和医科大学联合出版社，1995年4月第一版：120
[5] 周洁．微胶囊技术及其在食品工业中应用．粮食与油脂，2003，9：10-12
[6] 刘袖洞．微胶囊及其在生物医学领域的应用．科学通报，2000，45(23)：2476-2483．
[7] 谈金辉 等．药物微胶囊技术及其应用．天津化工，2003，17(6)：4-6
[8] 郝红等．微胶囊技术及其应用．现代化工，2002，22(3)：60-67
[9] Tyler J E.Microencapsulation of mammalian cells.Bioprocess Technoi, 1990,10:343-361
[10] Knorr D,Pandya Y, Doemenbrug H. Food Biotechnol, 1990,4(1):409～420.
[11] Yuet P K,Harris T J, et al. Art Cells Blood Subs Imob Biotechnol, 1995,23(1): 109～133.
[12] Awrey D E,Tse M, et al. Biotechnol Bioeng,1996,52:472～484.
[13] Tin S S H, Boadi D K, et al. Biotechnol Bioeng,1997,56:464～470.
[14] Goosen M F A,Achaw, O W, Grandmaison E W. Appl Chitin Chitosan,1997,233-254.
[15] Kank.e. M,Simmons G H,et al.J Pharm Sci,1990,69:755
[16] Chang T M S.Semipermeable microcapsules.Science,1964,146:524-525
[17] Lim F, Sun A M. Science, 1980,210:908-909
[18] Basic D,Vacek I,Sun A M. Art Cells Blood Subs Immob Biotechnol, 1996,24(3):219-255
[19] Sanchez A,Gupta R K,Alonso M J,et al. J Pharm Sci,1996,85(6):547-552
[20] 卢凤琦，曹宗顺，王春香，等．壳聚糖-海藻酸盐微囊对尼莫地平的缓释作用．中国药学杂志，1996，31(9)：555-556
[21] 冯鹏，王亦农，马建标，等．肽类药物口服剂型材料及控制释放研究：Ⅰ．壳聚糖-海藻酸盐微囊对胰岛素的控制释放作用．离子交换与吸附，1999，15(1)：64-70
[22] Kader A,Jalil R. Drug Dev Ind Pharm, 1999,25(2): 141-151
[23] 姚善泾．新型生物微胶囊体系的生物相容性研究．生物工程学报，1998，21(3)：391-398．
[24] 于鹰．缓释药物—患者的福音．化学教育，2003，6：1-2
[25] 周洁．微胶囊技术及其在食品工业中应用．粮食与油脂，2003，9：10-12
[26] 黄守坚．约物的控释制剂．新医学，1996，27(10)：556-557
[27] 刘会臣．约物控／缓释制剂生物等效性评价．解放军药学学报，1999，15(6)：45-47
[28] 侯俊伦．约物控释剂及其释药方式的类型分析．天津药学，2001，13(6)
[29] Machluf M,Orsola A,Atala A. World J Urol,2000,18(1):80-83
[30] Shiraishi S,I mai T, Otagiri M, Biol Pharm Bull,1993,16(11):1164-1168
[31] Kim H J,Lee H C,Oh J S,et al. J Biomater Sci Polyrn Ed,1999,10(5):543-556
[32] Curt T. Newyork: WileyPress,1987.9.34.
[33] Curt T. Newyork: WileyPress,1987.7.24.
[34] 刘袖洞、何洋，等．微胶囊及其在生物医学领域的应用．科学通报．2000，45(23)：2476-2483．
[35] Aicheal C,Aprahamain M,Defontaine L,et al J Pharm Pharmacol, 1991,43:1-5
[36] 施良和，胡汉杰．高分子科学的今天与明天．北京：化学工业出版社，1994．108．
[37] 甘景镐，甘纯矶，胡炳环．天然高分子．高等教育出版社，1993：203-205
[38] Felt O, Buri P, Gumy R. Chitosan. Drug Dev Ind Pharm, 1998, 24(11): 979
[39] Richardson SCW, Kolbe VJH, Duncan. Int. J Pharm, 1999, 178:231
[40] 夏文水，吴焱楠．甲壳素／壳聚糖水解酶的研究进展．中国海洋药物杂志，1997(2)：315
[41] Schipper NM, Varum KM, A rtusson P, et al. Pharm Res, 1996,13(11):1686
[42] Lueben HL, Rental CO, Kotze AF, et al. J Contr Rel,1997,45:15
[43] Awie FK, Henrik LL, Bas JD, et al. J Contr Rel,1998,51:35
[44] Muzzarelli. R.A.A. Carbohydrate Polymers, 1996.29:309
[45] Chandy. T..Biomater. Artif. Cells Artif. Organs. 1990.18(1):1
[46] Shi Yongchang,JiangYongming.Sui Dexin et al.,J.Chromatography,1996,742:107
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