复方盐酸曲马多缓释微丸的研制
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摘要
本文进行了复方盐酸曲马多缓释微丸的处方前、制剂学、稳定性及药动学研究。
建立了紫外分光光度法分别测定曲马多缓释微丸、异丙嗪缓释微丸的体外释放度及两个主药的基本性质。建立了高效液相色谱法测定复方曲马多缓释微丸的制剂含量和释放度。考察了主药间的配伍变化，结果表明两者间有配伍禁忌。制备了异丙嗪-β-环糊精，稳定性实验结果表明，与异丙嗪原料相比，包合物对光、热、湿度的稳定性增强。
采用挤出-滚圆法分别制备曲马多、异丙嗪素丸，通过单因素试验考察了粘合剂用量、捏合时间、筛板孔径、挤出速度、滚圆速度、滚圆时间、滚圆载物量对微丸收率的影响。结果表明，粘合剂用量、滚圆速度和滚圆时间对微丸收率有较大影响。2~3析因试验优化结果表明，在三种因素的高水平条件下能获得圆整度好、收率高的微丸。
以Eudragit NE30D为包衣材料对素丸包衣，对影响微丸释放度的包衣工艺因素和包衣液处方因素进行考察，选出了较佳的工艺参数：投料量为13～18g，包衣温度为21～24℃，喷雾压力为中压，喷液速度为1.0ml／min。对包衣液处方的单因素考察结果表明，以8％的包衣液浓度，3％的致孔剂用量，20％的抗粘剂用量进行包衣所得包衣微丸的缓释效果较好。对制剂稳定性考察的结果表明，复方制剂稳定性好。
以高效液相色谱法测定体内血药浓度，以普通复方制剂为对照，研究了复方曲马多缓释胶囊在家犬体内相对生物利用度和药代动力学。结果表明，普通胶囊与缓释胶囊的AUC分别为曲马多1168.52±163.14ng·mL~(-1)·h、1279.85±132.76ng·mL~(-1)·h，异丙嗪588.88±102.96ng·mL~(-1)·h、606.52±75.90ng·mL~(-1)·h；普通胶囊的C_(max)、T_(max)分别为曲马多136.67±27.42ng·mL~(-1)、2.02±0.22h，异丙嗪35.00±2.30ng·mL~(-1)、
沈阳药科大学硕士学位论文 摘要
2．31士0．34h；缓释胶囊的Cm叫、Tm拙分别为曲马多97刀1士23．16ng·mL1、
6．48士0．34h，异丙嗓20＊7士1．45ng·mL’、6．02士0．22h。表明与普通胶囊
相比，缓释胶囊血药浓度相对平稳，达峰时间有所延长，峰浓度下降。
缓释胶囊与普通胶囊生物利用度相近。缓释胶囊体内吸收和体外释放度
之间具有良好的相关性。
The research was aiming at the preparation of compound tramadol 12h sustained-release pellets and validation in vivo,consisting of preparation methods for pellets, the sustained-release system of coated pellets, stability, pharmacokinetics. The results show: the sustained-release pellets exhibited a marked sustained-release property and principal drugs were released in vivo over 12h.
A reversed-phase HPLC method was established for determination of drug content and accumulative release quantity. Preformulation studies illustrated that principal drugs can affect alternately, which implies they should be prepared separately. Inclusion complex of promethazine with p-cyclodextrin was made to improve the stability of promethazine.
A single-factor design was employed to isolate critical parameters that influenced the yield of pellets by extrusion-spheronization method. The result of this study found that amount of water, spheronization speed and spheronization time had greater influences on the yield of pellets. Then, 23 full factorical design had been used to investigate the main effects and their interactive of amount of water, spheronization speed and spheronization time on the yield, sphericity and friability. Pellets with good sphericity, high yield and appropriate hardness was produced.
Pellets were coated with aqueous dispersion(Eudragit NE30D)using mini-fluidized bed spray coater. The effects of process variables and formulation variables on coating pellets preparation were investigated. The results showed: the coated pellets had a marked sustained release property.
The process variables were optimized as followed: 21~24癈 coating temperature, middle pressure of atomization air and l.0ml/min spray rate. The coating level, amount of pore-forming agent could alter the release rate of the drug. The stability of the preparation was investigated under 4500Lx light condition, 40癈, 60癈, 92.5% RH, 75% RH, 40癈 and 75% RH. The results showed that the preparation was stable.
Using HPLC to determine the plasma drug concentration and using compound conventional capsule as the reference, the relative bioavailability and pharmacokinetics study of compound tramadol slow release capsule was perfomed in three healthy dogs. The AUC of compound conventional capsule and compound sustained-release capsule were tramadol 1168.52 ?163.14ng.mL-1.h , 1279.85 ?132.76ng.mL-1.h, promethazine 588.88 ?102.96ng.mL-1.h 606.52?5.90ng.mL-1.h, The Cmax and Tmax of compound conventional capsule were tramadol 136.67 ?7.42ngTnL'\ 2.02?.22h, promethazine 35.00 ?.30ng.mL-12.31?.34h, The Cmax and Tmax of compound slow release capsule were tramadol 97.01 ?3.16ng-mL-1 , 6.48 ?.34h, promethazine 20.67 + 1.45ng.mL-1A 6.02?.22h. The relative bioavailability of compound slow release capsule was 109.53% compared with tramadol and 103.00% compared with promethazine in compound conventional capsule. It was very significant between in vivo absorption and dissolution in vitro using Wagner-Nelson equation to ca
lculate the in vivo absorption fraction. Consequently, sustained-release capsule dosed 2 times a day was expected to show a more efficiency than its reference dosed 3-4 times a day.
建立了紫外分光光度法分别测定曲马多缓释微丸、异丙嗪缓释微丸的体外释放度及两个主药的基本性质。建立了高效液相色谱法测定复方曲马多缓释微丸的制剂含量和释放度。考察了主药间的配伍变化，结果表明两者间有配伍禁忌。制备了异丙嗪-β-环糊精，稳定性实验结果表明，与异丙嗪原料相比，包合物对光、热、湿度的稳定性增强。
采用挤出-滚圆法分别制备曲马多、异丙嗪素丸，通过单因素试验考察了粘合剂用量、捏合时间、筛板孔径、挤出速度、滚圆速度、滚圆时间、滚圆载物量对微丸收率的影响。结果表明，粘合剂用量、滚圆速度和滚圆时间对微丸收率有较大影响。2~3析因试验优化结果表明，在三种因素的高水平条件下能获得圆整度好、收率高的微丸。
以Eudragit NE30D为包衣材料对素丸包衣，对影响微丸释放度的包衣工艺因素和包衣液处方因素进行考察，选出了较佳的工艺参数：投料量为13～18g，包衣温度为21～24℃，喷雾压力为中压，喷液速度为1.0ml／min。对包衣液处方的单因素考察结果表明，以8％的包衣液浓度，3％的致孔剂用量，20％的抗粘剂用量进行包衣所得包衣微丸的缓释效果较好。对制剂稳定性考察的结果表明，复方制剂稳定性好。
以高效液相色谱法测定体内血药浓度，以普通复方制剂为对照，研究了复方曲马多缓释胶囊在家犬体内相对生物利用度和药代动力学。结果表明，普通胶囊与缓释胶囊的AUC分别为曲马多1168.52±163.14ng·mL~(-1)·h、1279.85±132.76ng·mL~(-1)·h，异丙嗪588.88±102.96ng·mL~(-1)·h、606.52±75.90ng·mL~(-1)·h；普通胶囊的C_(max)、T_(max)分别为曲马多136.67±27.42ng·mL~(-1)、2.02±0.22h，异丙嗪35.00±2.30ng·mL~(-1)、
沈阳药科大学硕士学位论文 摘要
2．31士0．34h；缓释胶囊的Cm叫、Tm拙分别为曲马多97刀1士23．16ng·mL1、
6．48士0．34h，异丙嗓20＊7士1．45ng·mL’、6．02士0．22h。表明与普通胶囊
相比，缓释胶囊血药浓度相对平稳，达峰时间有所延长，峰浓度下降。
缓释胶囊与普通胶囊生物利用度相近。缓释胶囊体内吸收和体外释放度
之间具有良好的相关性。
The research was aiming at the preparation of compound tramadol 12h sustained-release pellets and validation in vivo,consisting of preparation methods for pellets, the sustained-release system of coated pellets, stability, pharmacokinetics. The results show: the sustained-release pellets exhibited a marked sustained-release property and principal drugs were released in vivo over 12h.
A reversed-phase HPLC method was established for determination of drug content and accumulative release quantity. Preformulation studies illustrated that principal drugs can affect alternately, which implies they should be prepared separately. Inclusion complex of promethazine with p-cyclodextrin was made to improve the stability of promethazine.
A single-factor design was employed to isolate critical parameters that influenced the yield of pellets by extrusion-spheronization method. The result of this study found that amount of water, spheronization speed and spheronization time had greater influences on the yield of pellets. Then, 23 full factorical design had been used to investigate the main effects and their interactive of amount of water, spheronization speed and spheronization time on the yield, sphericity and friability. Pellets with good sphericity, high yield and appropriate hardness was produced.
Pellets were coated with aqueous dispersion(Eudragit NE30D)using mini-fluidized bed spray coater. The effects of process variables and formulation variables on coating pellets preparation were investigated. The results showed: the coated pellets had a marked sustained release property.
The process variables were optimized as followed: 21~24癈 coating temperature, middle pressure of atomization air and l.0ml/min spray rate. The coating level, amount of pore-forming agent could alter the release rate of the drug. The stability of the preparation was investigated under 4500Lx light condition, 40癈, 60癈, 92.5% RH, 75% RH, 40癈 and 75% RH. The results showed that the preparation was stable.
Using HPLC to determine the plasma drug concentration and using compound conventional capsule as the reference, the relative bioavailability and pharmacokinetics study of compound tramadol slow release capsule was perfomed in three healthy dogs. The AUC of compound conventional capsule and compound sustained-release capsule were tramadol 1168.52 ?163.14ng.mL-1.h , 1279.85 ?132.76ng.mL-1.h, promethazine 588.88 ?102.96ng.mL-1.h 606.52?5.90ng.mL-1.h, The Cmax and Tmax of compound conventional capsule were tramadol 136.67 ?7.42ngTnL'\ 2.02?.22h, promethazine 35.00 ?.30ng.mL-12.31?.34h, The Cmax and Tmax of compound slow release capsule were tramadol 97.01 ?3.16ng-mL-1 , 6.48 ?.34h, promethazine 20.67 + 1.45ng.mL-1A 6.02?.22h. The relative bioavailability of compound slow release capsule was 109.53% compared with tramadol and 103.00% compared with promethazine in compound conventional capsule. It was very significant between in vivo absorption and dissolution in vitro using Wagner-Nelson equation to ca
lculate the in vivo absorption fraction. Consequently, sustained-release capsule dosed 2 times a day was expected to show a more efficiency than its reference dosed 3-4 times a day.
引文
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[2]车胜荣，于丽璇，郭鹏举等．新编临床药用指南．陕西科学技术出版社，1998．117．
[3]Miller J, Ronald D, Brown R et al. Pharmaceutical Formulation. WO97/18801.
[4]陈化纯，漆先凤，李明秀．曲马多治疗癌痛86例．新药与临床，1993，12(4)：240-241．
[5]平其能．口服缓释及控释制剂发展动态．药学进展，1995，19(3)：140-144．
[6]阳长明，侯世祥，张志荣等．缓释与控释小丸的研究进展．华西药学杂志，2001，16(2)：121-123．
[7]Lee C, Mctavish D, Sorkin E. Tramadol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs, 1993,46:313-340.
[8]Underberg W. Oxidative Degradation of Pharmaceutically Important Phenothiazine Ⅰ:Isolation and Identification of Oxidation Products of Promethazine. J Pharm Sci, 1978, 67(8): 1128 -1131.
[9]Underberg W. Oxidative Degradation of Pharmaceutically Important Phenothiazine Ⅱ: Quantitative Determination of Promethazine and Some Degradation Products. J Pharm Sci, 1978, 67(8): 1131-1133.
[10]Underberg W. Oxidative Degradation of Pharmaceutically Important Phenothiazine Ⅲ:Kinetics and Mechanism of Promethazine Oxidation. J Pharm Sci, 1978,67(8): 1133-1138.
[11]孙伟张，刘明蓉，曾仁杰等．盐酸异丙嗪-β-环糊精包合物的制备及其稳定性的初步研究．中国医药工业杂志，1996，27(11)：500-502．
[12]stevens J, Meakin B J, Davies D. The stability of aqueous solutions of promethazine hydrochloride as a function of pH. J Pharm Pharmac, 1972, 24(suppl.): 133-134.
[13]Meakin B J, stevens J, Davies D. The effect of drug concentration on the thermal(dark) degradation of promethazine hydrochloride in aqueous solution. J Pharm Pharmac, 1978,30:75-80.
[14]王文刚，崔光华．挤出-滚圆制微丸工艺的进展．中国新药杂志，2001，10(9)：661-664．
[15]Varshosaz J,Kennedy R A,Gipps E M. Effect of Binder Level and Granulating
Liquid on Phenylbutazone Pellets Prepared by Extrusion-Spheronization. Drug Development and Industrial Pharmacy, 1997, 23 (6):611-618
[16]吴伟，崔光华，陆彬．实验设计中多指标的优化：星点设计和总评“归一值”的应用。中国药学杂志，2000，35(8)：530-533．
[17]Van S, Rhodos C. The Sustained Release Coating of Solid Dosage Forms: A Historical Review. Drug Dev and Pharm, 1995, 21 (1): 93-118.
[18]Mehta A. Scale-up Considerations in the fluid-bed process for controlled-release products. Pharm Tech, 1998,12(2):46-52.
[19]Yoshinori M, Masaharu M, Toru O et al. Coating of Small Particles by New Fluidized-bed Granulation and Coming Method. Pharm Tech Japan, 1993, 9(7):811-832.
[20]Dyer A M, Khan K A, Aulton M E. Effect of Polymer Loading on Drug Release from Film-Coated Ibuprofen Pellets Prepared by Extrusion-Spheronization. Drug Development and Industrial Pharmacy, 1995,21 (16):1841-1858.
[21]Sellassie G, Gordon R H, Middleton D L et al. A unique application and characterization of Eudragit E 30D film coatings in sustained release formulations. Int J Pharm, 1986,31:43-54.
[22]Porter S. Aqueous polymeric coatings for pharmaceutical dosage form. New York, Marcel Dekker, 1997.327-372.
[23]Herbert A L, Martin M R, Gilbert S B. Aqueous Polymeric Dispersion as Film Formers. Aqueous Polymeric Disperdion as Film Formers. New York, Marcel Dekker, 1991 .129-161.
[24]李静秋，许盛章．药用辅料-彩色包衣粉应用技术．化学工业出版社，1998．50．
[25]Korsmeyer R W, Gurny R, Doelker E. Mechanism of solute release from porous hydrophilic polymers. Int J Pharm, 1983,5:25-29.
[26]Dredan J, Antal I, Racz I. Evaluation of mathematical models describing drug release from lipophilic matrices. Int J Pharm, 1996,145:61-64.
[27]Wesselingh J A. Controlling diffusion. J Control Rel, 1993,24,47-60.
[28]Costa P, Lobo J M S. Modeling and comparison of dissolution profiles. Euro J Pharm Sci,2001,13,123-133.
[29]Ozturk A, Oztuk S, Palsson B et al. Mechanism of release from pellets coated with an ethylcellulose-based film. J Control Rel, 1990,14(3):203-213.
[30]卢元东，王登明，膜控释药的机理及影响因素．国外医药-合成药、生化药、制剂
分册，1992，13(5)：296-299．
[31]夏锦辉，刘昌孝．固体制剂的体外溶出度的统计学证价分析．中国药学杂志，2000，35(2)：345-349．
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[38]段金菊，孙效东，王中孝等．反相高效液相色谱法测定盐酸曲马多血浆浓度及其药物动力学．中国临床药学杂志，1997，6(2)：58-61．
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[43]Schwinghammer T, Juhl R, Ditter L et al. Comparison of the bioavailability of oral, rectal and intramuscular promethazine. Biopharm Drug Dispos, 1984,5:185-194.
[44]Zaman R, Honigberg I, Kotzan J et al. Bioequivalency and dose proportionality of three tableted promethazine products. Biopharm Drug Dispos, 1986, 7: 281-291.
[2]车胜荣，于丽璇，郭鹏举等．新编临床药用指南．陕西科学技术出版社，1998．117．
[3]Miller J, Ronald D, Brown R et al. Pharmaceutical Formulation. WO97/18801.
[4]陈化纯，漆先凤，李明秀．曲马多治疗癌痛86例．新药与临床，1993，12(4)：240-241．
[5]平其能．口服缓释及控释制剂发展动态．药学进展，1995，19(3)：140-144．
[6]阳长明，侯世祥，张志荣等．缓释与控释小丸的研究进展．华西药学杂志，2001，16(2)：121-123．
[7]Lee C, Mctavish D, Sorkin E. Tramadol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs, 1993,46:313-340.
[8]Underberg W. Oxidative Degradation of Pharmaceutically Important Phenothiazine Ⅰ:Isolation and Identification of Oxidation Products of Promethazine. J Pharm Sci, 1978, 67(8): 1128 -1131.
[9]Underberg W. Oxidative Degradation of Pharmaceutically Important Phenothiazine Ⅱ: Quantitative Determination of Promethazine and Some Degradation Products. J Pharm Sci, 1978, 67(8): 1131-1133.
[10]Underberg W. Oxidative Degradation of Pharmaceutically Important Phenothiazine Ⅲ:Kinetics and Mechanism of Promethazine Oxidation. J Pharm Sci, 1978,67(8): 1133-1138.
[11]孙伟张，刘明蓉，曾仁杰等．盐酸异丙嗪-β-环糊精包合物的制备及其稳定性的初步研究．中国医药工业杂志，1996，27(11)：500-502．
[12]stevens J, Meakin B J, Davies D. The stability of aqueous solutions of promethazine hydrochloride as a function of pH. J Pharm Pharmac, 1972, 24(suppl.): 133-134.
[13]Meakin B J, stevens J, Davies D. The effect of drug concentration on the thermal(dark) degradation of promethazine hydrochloride in aqueous solution. J Pharm Pharmac, 1978,30:75-80.
[14]王文刚，崔光华．挤出-滚圆制微丸工艺的进展．中国新药杂志，2001，10(9)：661-664．
[15]Varshosaz J,Kennedy R A,Gipps E M. Effect of Binder Level and Granulating
Liquid on Phenylbutazone Pellets Prepared by Extrusion-Spheronization. Drug Development and Industrial Pharmacy, 1997, 23 (6):611-618
[16]吴伟，崔光华，陆彬．实验设计中多指标的优化：星点设计和总评“归一值”的应用。中国药学杂志，2000，35(8)：530-533．
[17]Van S, Rhodos C. The Sustained Release Coating of Solid Dosage Forms: A Historical Review. Drug Dev and Pharm, 1995, 21 (1): 93-118.
[18]Mehta A. Scale-up Considerations in the fluid-bed process for controlled-release products. Pharm Tech, 1998,12(2):46-52.
[19]Yoshinori M, Masaharu M, Toru O et al. Coating of Small Particles by New Fluidized-bed Granulation and Coming Method. Pharm Tech Japan, 1993, 9(7):811-832.
[20]Dyer A M, Khan K A, Aulton M E. Effect of Polymer Loading on Drug Release from Film-Coated Ibuprofen Pellets Prepared by Extrusion-Spheronization. Drug Development and Industrial Pharmacy, 1995,21 (16):1841-1858.
[21]Sellassie G, Gordon R H, Middleton D L et al. A unique application and characterization of Eudragit E 30D film coatings in sustained release formulations. Int J Pharm, 1986,31:43-54.
[22]Porter S. Aqueous polymeric coatings for pharmaceutical dosage form. New York, Marcel Dekker, 1997.327-372.
[23]Herbert A L, Martin M R, Gilbert S B. Aqueous Polymeric Dispersion as Film Formers. Aqueous Polymeric Disperdion as Film Formers. New York, Marcel Dekker, 1991 .129-161.
[24]李静秋，许盛章．药用辅料-彩色包衣粉应用技术．化学工业出版社，1998．50．
[25]Korsmeyer R W, Gurny R, Doelker E. Mechanism of solute release from porous hydrophilic polymers. Int J Pharm, 1983,5:25-29.
[26]Dredan J, Antal I, Racz I. Evaluation of mathematical models describing drug release from lipophilic matrices. Int J Pharm, 1996,145:61-64.
[27]Wesselingh J A. Controlling diffusion. J Control Rel, 1993,24,47-60.
[28]Costa P, Lobo J M S. Modeling and comparison of dissolution profiles. Euro J Pharm Sci,2001,13,123-133.
[29]Ozturk A, Oztuk S, Palsson B et al. Mechanism of release from pellets coated with an ethylcellulose-based film. J Control Rel, 1990,14(3):203-213.
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