磷酸川芎嗪微孔渗透泵控释片研究
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摘要
磷酸川芎嗪(Tetramethlprazine Phophate, TMPP)是一种新型的钙拮抗剂,目前临床上主要用于治疗心脑血管系统疾病。在充分考察药物及各种辅料性质的基础上,本研究以聚乙烯吡咯烷酮(PVP)、乳糖、酒石酸、氯化钠(NaCl)等辅料为片芯材料,以醋酸纤维素(CA)、邻苯二甲酸二乙酯(DEP)、聚乙二醇-400 (PEG-400)为包衣材料,以丙酮:异丙醇(80:20)为包衣溶剂,制备了水易溶性药物水杨酸钠微孔渗透泵控释片(Solium Salicylic Controlled Porosity Osmotic Pump tablets,SOSA CPOP)和磷酸川芎嗪微孔渗透泵控释片(Tetramethlprazine Phophate Controlled Porosity Osmotic Pump tablets, TMPP CPOP)。
本研究以水杨酸钠为模型药物制备微孔渗透泵控释片,摸索了微孔渗透泵控释片的基本的处方、工艺和释药规律。考察各种因素对水杨酸钠微孔渗透泵控释片的影响,结果显示释药速度受pH调节剂种类和用量、致孔剂、增塑剂、包衣膜厚度影响较大,受渗透压促进剂种类和用量,高分子阻滞剂影响较小。利用均匀设计优化处方,通过均匀软件处理数据,得到回归方程和优化处方。F检验证明回归方程显著有效,优化处方验证结果显示,释放曲线相关系数r大于0.99,12h释放90%以上。
制备磷酸川芎嗪微孔渗透泵控释片,考察各种因素对药物释放速度的影响,结果显示渗透压促进剂、致孔剂、增塑剂、包衣膜厚度影响较大,利用均匀设计优化处方,均匀设计软件处理数据,得到回归方程和优化处方,F检验显示回归方程显著有效,优化处方验证结果显示,释放曲线相关系数r大于0.99,12h释放90%以上。考察不同释放条件对TMPP CPOP体外释放的影响,结果显示药物释放速度不受外界环境如pH值、转速、溶出方法等条件的影响。对最优处方进行释药模型拟合,释药曲线符合零级释放规律。
通过游离膜扩散动力学试验对磷酸川芎嗪微孔渗透泵控释片的片芯和包衣膜性质进行了基础研究,测定了TMPP在不同渗透压促进剂中的溶解度和药物通过游离膜的扩散速度,并利用渗透压计测定不同溶液系统的渗透压值,对三者相互关系做了初步探讨。以理论的经典公式为原型,以实验数据为根据拟合出一条适用于微孔渗透泵控释片的经验公式,用于预测不同包衣膜处方下药物的释放速度。结果验证,经验公式能很好的预测药物的释放速度。
The tetramethlprazine phosphate (TMPP) is a new calcium antagonist which has been widely used in clinic for cardiovascular and cerebrovascular diseases. On this study, two controlled porosity osmotic pump tablets (CPOP) were prepared, taking Solium Salicylic (SOSA) and Tetramthlprazine as the main drug respectively. Based on comprehensive pre-formulation research, polyvinylpyrrolidone (PVP), lactose, tartaric acid, sodium chloride etc were used as tablet core. Cellulose acetate(CA), Diethyl phthalate (DEP), Polyethylene Glycol-400(PEG-400) were selected as the coating material and acetone-isopropranol (4:1) co-solvent was employed as the coating medium.
SOSA CPOP were prepared to study the basic formulation, preparation process and release rules of controlled porosity osmotic pump tablets. On this study, various factors which may effect drug release were investigated. The result indicated the acid substance, pore formers, plasticizer, coating thickness had great influence on drug release, while osmotic agents and polymer blokers had little influence on drug release. In order to optimize the formulation, uniform design was adopted. Regression equation and the best formulation were calculated by uniform design software. F test proved the regression equation was significant. Cumulative drug release of the best formulation at 12 h exceeded 90% and the linear correlation coefficient exceeded 0.99.
The effect of various factors on drug release of TMPP CPOP was investigated. The result showed that osmotic agents, pore formers, plasticizer, coating thickness had great influence on drug release. In order to optimize the formulation, uniform design was adopted. Regression equation and the best formulation were calculated by uniform design software. F test proved the regression equation was significant. The verification of the best formulation proved drug cumulative release conformed to model of zero order, the cumulative release at 12 h exceeded 90% and the linear correction coefficient exceeded 0.99. It was proved the drug release was not influenced by the pH of dissolution medium, dissolution method and rotate speed.
Free film diffusion experiment were employed to investigate the basic properties on tablet core and coating film of CPOP. The drug’solubility, solution’osmotic pressure and the rate of drug diffusion in different solution with different osmotic agent were determined. Using theoretical formula as a model, a new empirical formula had been deduced from experiments. It was proved calculation results from the formulae fit the test data satisfactorily.
本研究以水杨酸钠为模型药物制备微孔渗透泵控释片,摸索了微孔渗透泵控释片的基本的处方、工艺和释药规律。考察各种因素对水杨酸钠微孔渗透泵控释片的影响,结果显示释药速度受pH调节剂种类和用量、致孔剂、增塑剂、包衣膜厚度影响较大,受渗透压促进剂种类和用量,高分子阻滞剂影响较小。利用均匀设计优化处方,通过均匀软件处理数据,得到回归方程和优化处方。F检验证明回归方程显著有效,优化处方验证结果显示,释放曲线相关系数r大于0.99,12h释放90%以上。
制备磷酸川芎嗪微孔渗透泵控释片,考察各种因素对药物释放速度的影响,结果显示渗透压促进剂、致孔剂、增塑剂、包衣膜厚度影响较大,利用均匀设计优化处方,均匀设计软件处理数据,得到回归方程和优化处方,F检验显示回归方程显著有效,优化处方验证结果显示,释放曲线相关系数r大于0.99,12h释放90%以上。考察不同释放条件对TMPP CPOP体外释放的影响,结果显示药物释放速度不受外界环境如pH值、转速、溶出方法等条件的影响。对最优处方进行释药模型拟合,释药曲线符合零级释放规律。
通过游离膜扩散动力学试验对磷酸川芎嗪微孔渗透泵控释片的片芯和包衣膜性质进行了基础研究,测定了TMPP在不同渗透压促进剂中的溶解度和药物通过游离膜的扩散速度,并利用渗透压计测定不同溶液系统的渗透压值,对三者相互关系做了初步探讨。以理论的经典公式为原型,以实验数据为根据拟合出一条适用于微孔渗透泵控释片的经验公式,用于预测不同包衣膜处方下药物的释放速度。结果验证,经验公式能很好的预测药物的释放速度。
The tetramethlprazine phosphate (TMPP) is a new calcium antagonist which has been widely used in clinic for cardiovascular and cerebrovascular diseases. On this study, two controlled porosity osmotic pump tablets (CPOP) were prepared, taking Solium Salicylic (SOSA) and Tetramthlprazine as the main drug respectively. Based on comprehensive pre-formulation research, polyvinylpyrrolidone (PVP), lactose, tartaric acid, sodium chloride etc were used as tablet core. Cellulose acetate(CA), Diethyl phthalate (DEP), Polyethylene Glycol-400(PEG-400) were selected as the coating material and acetone-isopropranol (4:1) co-solvent was employed as the coating medium.
SOSA CPOP were prepared to study the basic formulation, preparation process and release rules of controlled porosity osmotic pump tablets. On this study, various factors which may effect drug release were investigated. The result indicated the acid substance, pore formers, plasticizer, coating thickness had great influence on drug release, while osmotic agents and polymer blokers had little influence on drug release. In order to optimize the formulation, uniform design was adopted. Regression equation and the best formulation were calculated by uniform design software. F test proved the regression equation was significant. Cumulative drug release of the best formulation at 12 h exceeded 90% and the linear correlation coefficient exceeded 0.99.
The effect of various factors on drug release of TMPP CPOP was investigated. The result showed that osmotic agents, pore formers, plasticizer, coating thickness had great influence on drug release. In order to optimize the formulation, uniform design was adopted. Regression equation and the best formulation were calculated by uniform design software. F test proved the regression equation was significant. The verification of the best formulation proved drug cumulative release conformed to model of zero order, the cumulative release at 12 h exceeded 90% and the linear correction coefficient exceeded 0.99. It was proved the drug release was not influenced by the pH of dissolution medium, dissolution method and rotate speed.
Free film diffusion experiment were employed to investigate the basic properties on tablet core and coating film of CPOP. The drug’solubility, solution’osmotic pressure and the rate of drug diffusion in different solution with different osmotic agent were determined. Using theoretical formula as a model, a new empirical formula had been deduced from experiments. It was proved calculation results from the formulae fit the test data satisfactorily.
引文
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[2]吴涛, 潘卫三, 庄殿友等. 硫酸沙丁胺醇口服渗透泵片的制备及体外释放率考察. 沈阳药科大学学报, 1999, 16(2): 79-82.
[3]曹德英, 张立德, 李伟等. 氨茶碱渗透泵片剂的研制. 中国药学杂志, 1991, 26 (7): 409-412.
[4]Ritschel WA, Johnson RD, Young DA. Evaluation of a controlled release osmotic pump type of dosage form for chlorpheniramine melate. Eur J Pharm Biopharm, 1994, 40(3): 122-127.
[5]Vyas SP, Guleria R, Singh R. Development and in-vitro characterization of elementary osmotic pump bearing ciprofloxacin hydrochloride. East Pharm, 1996, 39(457):167-176.
[6]Mccleeland GA, Stubbs RJ, Fix JA, et al. Enhancement of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)redutase inhibitor efficacy through administration of a controlled-porosity osmotic pump dosage form. Pharm Res, 1991, 8(7): 873-882.
[7]Vandenberg G, Vansteveninck F, Gubben JM. Influence of food on the bioavailability of metoprolol from an OROS system: a study in healthyvolunteers. Eur J Clin Pharmacol, 1990 39(3): 315-326.
[8]Elliott HL,Vicent J, Meredith PA. Relationship between plasma prazosin concentions and a-antagonism in humans:comparison of conventional and rate-controlled (OROS) formulayions. Clin Pharmacol Ther, 1988, 43(5): 82-587.
[9]Sykes RS, Reese ME, Meyer MC, et al. Relative bioavailability of a controlled-release albuterol formulation for twice-daily use. Biopharm Drug Disposition, 1988, 9: 551-556.
[10]Sawichi W, Depulski T, Janicki S. Bioavailability of isosorbide dinitrate form an oral therapeutic system and from tablet sorbonit prolongatum in human volunteers. Pharmazie 1989, 44(4): 280-281.
[11]Soons PA, Deboer AG, Vanbrummelen P. Oral absorption profile of nitrendipine in healthy subjects:a kinetic and dynamic study. Br J Clin Phannacol, 1989, 27(2): 179-189.
[12]Theeuwes F. Elemently osmotic pump. Pharm Sci, 1975, 64(12): 1987-1991.
[13]Stevens RE, Limsakun T, Evans G, et al. Controlled, multidose, pharmacokinetic evaluation of two extended-release carbamazepine formulation (Carbatrol and Tegretol-XR. J pharm Sci, 998, 7(12): 1531-1 534.
[14]Abrahamsson B, Alpsten M, Bake B, et al. Drug absorption from nifedipine hydrophilic matrix extended-release (ER) tablet-comparison with an osmotic pump tablet and effect of food. Controlled Release, 1998, 52(3): 301-310.
[15]梨洪珊, 柳翠敬. 渗透泵制剂的研究进展. 国外医药一合成药、生化药、制剂分册, 1999, 20(1): 9-13.
[16]Davis SS, Hardy JG, Taylor MJ. The effect of food on the gastrointestinal transit of pellets and an osmotic device(Osmot). Int J Pharm. 1984, 21: 331-340.
[17]Verma RK, Krishna DM, Garg S. Formulation aspects in the development of osmotically controlled oral drug delivery systems. Controlled Release, 2002, 79: 7-27.
[18]Thombre AG, Appel LE, Chidlaw MB, et al. Osmotic drug delivery using swellable-core technology. Controlled Release, 2004,94(1):75-89.
[19]Verma RK, Mishra B, Gang S. Osmotically controlled oral drug delivery. Drug Dev Ind Pharm, 2000, 26(7): 695-708.
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