复方盐酸二甲双胍缓释微丸的研制
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摘要
本文采用挤出滚圆工艺制备盐酸二甲双胍素丸，采用缓释包衣材料和普通薄膜包衣材料制备盐酸二甲双胍及格列本脲的复方缓释微丸。对微丸的制备工艺及其影响因素、稳定性、生物利用度进行了较为全面、深入的研究。结果表明，制备的复方缓释微丸圆整度好，粒径均匀，性质稳定，缓释部分体内作用平稳、持久。
建立了紫外分光光度法测定盐酸二甲双胍的药物浓度，用于含量测定及释放度测定，方法简单，结果准确，不受辅料影响。以蒸馏水为溶剂，在232nm处测定吸收度，经方法学验证，适用于该晶体外控制。建立了高效液相法测定格列本脲的药物浓度，用于含量、含量均匀度测定及溶出度测定，经方法学验证，适用于该晶体外控制。
盐酸二甲双胍缓释微丸的制备，首先进行了素丸的工艺和处方的考察，在单因素实验的基础上，采用正交设计进行优化，所得素丸圆整度好，粒度分布集中，收率高。采用微型流化床包衣机，以Eudragit~(?) NE30D为包衣材料对素丸包衣，对包衣微丸释放度的影响因素进行考察，确定了最佳包衣工艺和包衣液处方组成。结果表明，盐酸二甲双胍缓释微丸体外释药具有明显的缓释特性，释药规律符合一级释药模型。
对所制得的盐酸二甲双胍缓释微丸再进行包衣，即在其外层继续包上含有格列本脲的普通薄膜衣制备复方缓释微丸。在确定包衣工艺和包衣液处方组成的基础上制备了衣膜增重为3％的复方缓释微丸，考察了微丸中格列本脲的体外溶出度及含量均匀度。结果表明，复方缓释微丸中的格列本脲在45分钟内能够达到理想的溶出，其含量均匀度符合要求。进一步的实验表明外层普通薄膜衣对盐酸二甲双胍缓释微丸的释放行为没有影响。
采用相似因子法研究了微丸的稳定性，结果表明，微丸中药物含量、格列本脲的溶出度及盐酸二甲双胍的释放度均无明显变化，说明微丸在高温、
沈阳药科大学硕士学位论文 摘要
高湿、光照及加速试验条件下基本稳定。家犬体内动力学表明，复方缓释胶
囊剂中的缓释部分在测定时间范围内血药浓度曲线与速释胶囊剂相比，较为
平稳，达峰时间有所延长，峰浓度下降；其相对生物利用度为96．27％。体内
外相关性结果表明，其缓释部分体外释放与体内吸收具有良好相关性。
In this thesis, Metformin Hydrochloride pellets were prepared by extrusion-spheronisation. Compound sustained-release pellets of Metformin Hydrochloride and Glibenclamide were prepared by coating with sustained-release and normal coating materials. The preparation methods for pellets and influence factors involved, stability, pharmacokinetics and bioavailability on pellets were studied completely and thoroughly. Results show: the compound sustained-release pellets had good appearance and stability, the sustained-release property of pellets was marked.
Ultraviolet spetrophotometry method was developed for assaying content and drug release of Metformin Hydrochloride. The method was monitored by methodology and was simple, accurate to be used in vitro. High performance liquid chromatography method was developed to determine content, content uniformity and dissolution of Glibenclamide.
The formulation and technology of Metformin Hydrochloride prompt-release pellets were optimized with orthogonal experiment design. Aqueous disperdion (Eudragit?NE30D) was used as coating material and coating process was performed on a mini-fluidized bed spary coater. The effects of process varibles and formulation varibles on pellets preparation were investigated. The formulation and technology of Metformin Hydrochloride sustained-release pellets were optimized. Results show: the coated pellets had a marked sustained-release property, the drug release profile in vitro followed first order kinetics.
The Metformin Hydrochloride sustained-release pellets were further coated to prepare compound sustained-release pellets with normal coating material
which contained Glibenclamide. The formulation and technology were optimized. Dissolution and content uniformity of Glibenclamide were also invetigated. Results show: Glibenclamide could dissolute completely within 45 min in vitro and content uniformity of it was ideal. Further test indicated that outer coating had no influence on the release behaviour of Metformin Hydrochloride.
The fit factors method was used in this thesis to study the stability of compound sustained-release capsule. The drug content and release stability of the capsule were both good under high temperature, high humidity and intensive light tests. Pharmacokinetics and bioavailability studies of compound sustained-release capsule and Metformin Hydrochloride prompt-release capsule in dogs
were performed based on determination of plasma concentration of drugs at different intervals after a single oral administration. Tmax of compound sustained-release capsule was 3.98 hours and that of prompt-release capsule was 1.94 hours. The relative bioavailability of Metformin Hydrochloride was 96.27% compared with prompt-release capsule. Obvious correlation existed between absorption fraction in vivo and the release percentage in vitro.
建立了紫外分光光度法测定盐酸二甲双胍的药物浓度，用于含量测定及释放度测定，方法简单，结果准确，不受辅料影响。以蒸馏水为溶剂，在232nm处测定吸收度，经方法学验证，适用于该晶体外控制。建立了高效液相法测定格列本脲的药物浓度，用于含量、含量均匀度测定及溶出度测定，经方法学验证，适用于该晶体外控制。
盐酸二甲双胍缓释微丸的制备，首先进行了素丸的工艺和处方的考察，在单因素实验的基础上，采用正交设计进行优化，所得素丸圆整度好，粒度分布集中，收率高。采用微型流化床包衣机，以Eudragit~(?) NE30D为包衣材料对素丸包衣，对包衣微丸释放度的影响因素进行考察，确定了最佳包衣工艺和包衣液处方组成。结果表明，盐酸二甲双胍缓释微丸体外释药具有明显的缓释特性，释药规律符合一级释药模型。
对所制得的盐酸二甲双胍缓释微丸再进行包衣，即在其外层继续包上含有格列本脲的普通薄膜衣制备复方缓释微丸。在确定包衣工艺和包衣液处方组成的基础上制备了衣膜增重为3％的复方缓释微丸，考察了微丸中格列本脲的体外溶出度及含量均匀度。结果表明，复方缓释微丸中的格列本脲在45分钟内能够达到理想的溶出，其含量均匀度符合要求。进一步的实验表明外层普通薄膜衣对盐酸二甲双胍缓释微丸的释放行为没有影响。
采用相似因子法研究了微丸的稳定性，结果表明，微丸中药物含量、格列本脲的溶出度及盐酸二甲双胍的释放度均无明显变化，说明微丸在高温、
沈阳药科大学硕士学位论文 摘要
高湿、光照及加速试验条件下基本稳定。家犬体内动力学表明，复方缓释胶
囊剂中的缓释部分在测定时间范围内血药浓度曲线与速释胶囊剂相比，较为
平稳，达峰时间有所延长，峰浓度下降；其相对生物利用度为96．27％。体内
外相关性结果表明，其缓释部分体外释放与体内吸收具有良好相关性。
In this thesis, Metformin Hydrochloride pellets were prepared by extrusion-spheronisation. Compound sustained-release pellets of Metformin Hydrochloride and Glibenclamide were prepared by coating with sustained-release and normal coating materials. The preparation methods for pellets and influence factors involved, stability, pharmacokinetics and bioavailability on pellets were studied completely and thoroughly. Results show: the compound sustained-release pellets had good appearance and stability, the sustained-release property of pellets was marked.
Ultraviolet spetrophotometry method was developed for assaying content and drug release of Metformin Hydrochloride. The method was monitored by methodology and was simple, accurate to be used in vitro. High performance liquid chromatography method was developed to determine content, content uniformity and dissolution of Glibenclamide.
The formulation and technology of Metformin Hydrochloride prompt-release pellets were optimized with orthogonal experiment design. Aqueous disperdion (Eudragit?NE30D) was used as coating material and coating process was performed on a mini-fluidized bed spary coater. The effects of process varibles and formulation varibles on pellets preparation were investigated. The formulation and technology of Metformin Hydrochloride sustained-release pellets were optimized. Results show: the coated pellets had a marked sustained-release property, the drug release profile in vitro followed first order kinetics.
The Metformin Hydrochloride sustained-release pellets were further coated to prepare compound sustained-release pellets with normal coating material
which contained Glibenclamide. The formulation and technology were optimized. Dissolution and content uniformity of Glibenclamide were also invetigated. Results show: Glibenclamide could dissolute completely within 45 min in vitro and content uniformity of it was ideal. Further test indicated that outer coating had no influence on the release behaviour of Metformin Hydrochloride.
The fit factors method was used in this thesis to study the stability of compound sustained-release capsule. The drug content and release stability of the capsule were both good under high temperature, high humidity and intensive light tests. Pharmacokinetics and bioavailability studies of compound sustained-release capsule and Metformin Hydrochloride prompt-release capsule in dogs
were performed based on determination of plasma concentration of drugs at different intervals after a single oral administration. Tmax of compound sustained-release capsule was 3.98 hours and that of prompt-release capsule was 1.94 hours. The relative bioavailability of Metformin Hydrochloride was 96.27% compared with prompt-release capsule. Obvious correlation existed between absorption fraction in vivo and the release percentage in vitro.
引文
(1)刘菊英．老年糖尿病现状及家庭治疗护理的思考．全科医生，2001，10(2)：96
(2)李兆寰，李红梅．口服降糖药合理选择与应用．医师进修杂志，2002，25(11)：8-10
(3)张圣雨，李翔云，周小菊等．合理选用口服降糖药．首都医药，1998，5(2)：23
(4)刘燕君．口服抗糖尿病药物的合理选择．国外医学药学分册，1998，25(6)：349-353
(5)张石革．口服降血糖药研究与临床应用的进展及其合理使用．当代医学，2000，5(6)：62-69
(6)宋儒年，田文足．双胍类降糖药物研究进展．山东医药工业，1999，18(6)：21-22
(7)扬根正，刘国利，崔国敏等．2型糖尿病的研究进展．医学综述，2000，6(11)：571-572
(8)丁禄霞．口服降糖药研究进展．西北药学杂志，2000，15(1)：37-38
(9)杜小莉，张翠莲．降血糖新约一格列本脲和盐酸二甲双胍复合片．中国药学杂志，2002，37(11)：869-871
(10)柏俊，孙备，吕凌等．盐酸二甲双胍与微粉化格列本脲复方片的制剂研究．安徽医药，200l，5(1)：9-10
(11)张玉，曾环想，袁鹰等．复方格列本脲片的试制．中国新药杂志，2002，11(6)：464-466
(12)金燕，冯利，庞静秋．常用口服降糖药药物动力学特点．黑龙江医药，2000，13(6)：356-358
(13)郭茜，马晓琴．口服降糖药物的临床评价．中国综合临床，2002，18(10)：870-871
(14)张宁．口服缓控秆制剂技术发展的新动向．国外医学药学分册，2000，27(4)：239-243
(15)于少云，王洪光．微丸的进展．中国新药杂志，1999，8(12)：802-805
(16)潘家祯，陈庆华．挤山滚圆法制备约川微丸：Ⅰ．设备的工作原理及特点．中国医药工业杂志，1998，29(8)：378-380
(17)钱方，蒋雪涛，王安文．微丸的进展．中国医药工业杂志，1996，27(1)：41-46
(18)陆彬．药物新剂型与新技术．人民卫生出版社，1998：294
(19)潘家祯，孙晓明．用挤出滚圆法制造球形微丸颗粒的基本方法和设备．化工进展，1998，17(3)：44-46
(20)陆彬．药物新剂型与新技术．人民卫生出版社，1998：266
(21)陈庆华．现代微丸制备与包衣装置的类型与应用．中国医药工业杂志，1996，27(3)：134-138
(22)Lippold BH, Sutter BK and Lippold BC. Parameters controlling drug release from pellets coated with aqueous ethyl cellulose dispersion. Int J Pharm 1989,54:15
(23)Turkoglu M and Sakr A. Mathematical modeling and optimization of a rotary fluidized-bed coating process. Int J Pharm 1992,88:75
(24)陈挺，陈庆华．聚合物水分散体包衣技术及其应用．中国现代应用药学，2000，17(5)：339-344
(25)张立超，胡晋红，连佳芳等．丙烯酸树脂在薄膜包衣中的应用．中国医院药学杂志，2001，2l(5)：301-302
(26)美国专利，专利号：WO9906035
(27)Graham Cole, John Hogan, Michael Aulton原著．郑俊民译．片剂包衣的工艺和原理．中国医药科技出版社，2000：10
(28)王文刚，崔光华．挤山滚圆制微丸工艺的进展．中国新药杂志，2001，10(9)：661-664
(29)陆彬．药物新剂型与新技术．人民卫生出版社，1998：301
(30)毕殿洲．药剂学．第四版．人民卫生出版社，1999：76
(31)C. W. Woodruff and N. O. Nuessle. Effect of processing variables on particles obtained by extrusion-spheronization process. J Pharm Sci,1972,61:787-790
(32)H. A. Doshi and R.Shricastava. Preparation of pellets: Extruding and Spheronizing Machines Study. Int J Pharm Sci,1993,55 (2): 55-58
(33)梁超峰，欧刚允，陈平等．润湿粘合剂对小丸制备的影响．中国医药工业杂志，2000，31(4)：159-161
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(43) Graham Cole, John Hogan, Michael Aulton原著．郑俊民译．片剂包衣的工艺和原理．中国医药科技出版社，2000：73
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(47) 何海霞，韩敏，黄萍．盐酸二甲双胍生物等效性研究．中国药房，2002，13(11)：669-671
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(2)李兆寰，李红梅．口服降糖药合理选择与应用．医师进修杂志，2002，25(11)：8-10
(3)张圣雨，李翔云，周小菊等．合理选用口服降糖药．首都医药，1998，5(2)：23
(4)刘燕君．口服抗糖尿病药物的合理选择．国外医学药学分册，1998，25(6)：349-353
(5)张石革．口服降血糖药研究与临床应用的进展及其合理使用．当代医学，2000，5(6)：62-69
(6)宋儒年，田文足．双胍类降糖药物研究进展．山东医药工业，1999，18(6)：21-22
(7)扬根正，刘国利，崔国敏等．2型糖尿病的研究进展．医学综述，2000，6(11)：571-572
(8)丁禄霞．口服降糖药研究进展．西北药学杂志，2000，15(1)：37-38
(9)杜小莉，张翠莲．降血糖新约一格列本脲和盐酸二甲双胍复合片．中国药学杂志，2002，37(11)：869-871
(10)柏俊，孙备，吕凌等．盐酸二甲双胍与微粉化格列本脲复方片的制剂研究．安徽医药，200l，5(1)：9-10
(11)张玉，曾环想，袁鹰等．复方格列本脲片的试制．中国新药杂志，2002，11(6)：464-466
(12)金燕，冯利，庞静秋．常用口服降糖药药物动力学特点．黑龙江医药，2000，13(6)：356-358
(13)郭茜，马晓琴．口服降糖药物的临床评价．中国综合临床，2002，18(10)：870-871
(14)张宁．口服缓控秆制剂技术发展的新动向．国外医学药学分册，2000，27(4)：239-243
(15)于少云，王洪光．微丸的进展．中国新药杂志，1999，8(12)：802-805
(16)潘家祯，陈庆华．挤山滚圆法制备约川微丸：Ⅰ．设备的工作原理及特点．中国医药工业杂志，1998，29(8)：378-380
(17)钱方，蒋雪涛，王安文．微丸的进展．中国医药工业杂志，1996，27(1)：41-46
(18)陆彬．药物新剂型与新技术．人民卫生出版社，1998：294
(19)潘家祯，孙晓明．用挤出滚圆法制造球形微丸颗粒的基本方法和设备．化工进展，1998，17(3)：44-46
(20)陆彬．药物新剂型与新技术．人民卫生出版社，1998：266
(21)陈庆华．现代微丸制备与包衣装置的类型与应用．中国医药工业杂志，1996，27(3)：134-138
(22)Lippold BH, Sutter BK and Lippold BC. Parameters controlling drug release from pellets coated with aqueous ethyl cellulose dispersion. Int J Pharm 1989,54:15
(23)Turkoglu M and Sakr A. Mathematical modeling and optimization of a rotary fluidized-bed coating process. Int J Pharm 1992,88:75
(24)陈挺，陈庆华．聚合物水分散体包衣技术及其应用．中国现代应用药学，2000，17(5)：339-344
(25)张立超，胡晋红，连佳芳等．丙烯酸树脂在薄膜包衣中的应用．中国医院药学杂志，2001，2l(5)：301-302
(26)美国专利，专利号：WO9906035
(27)Graham Cole, John Hogan, Michael Aulton原著．郑俊民译．片剂包衣的工艺和原理．中国医药科技出版社，2000：10
(28)王文刚，崔光华．挤山滚圆制微丸工艺的进展．中国新药杂志，2001，10(9)：661-664
(29)陆彬．药物新剂型与新技术．人民卫生出版社，1998：301
(30)毕殿洲．药剂学．第四版．人民卫生出版社，1999：76
(31)C. W. Woodruff and N. O. Nuessle. Effect of processing variables on particles obtained by extrusion-spheronization process. J Pharm Sci,1972,61:787-790
(32)H. A. Doshi and R.Shricastava. Preparation of pellets: Extruding and Spheronizing Machines Study. Int J Pharm Sci,1993,55 (2): 55-58
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