甲磺酸多沙唑嗪微孔渗透泵片的研制
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摘要
目的:甲磺酸多沙唑嗪为喹啉类衍生物,是选择性突触后α1-肾上腺受体阻滞剂。通过阻滞α1-受体达到扩张血管,减少血管阻力,降低血压的作用,对心排出量影响不大。适用于原发性轻、中度高血压及伴有良性前列腺肥大的高血压患者。与其他的α1-受体阻滞剂一样,甲磺酸多沙唑嗪对立位血压和心率影响较大,在使用普通片剂时,若直接采用治疗剂量,则可能因血药浓度突然升高而使血压骤降从而引起昏厥、体位性低血压等不良反应,因此必须从小剂量开始逐步调定剂量,给应用带来一定不便。渗透泵控释制剂作为控释制剂的典型代表,具有零级释药特征,释药行为不受介质环境pH值、胃肠蠕动和食物等因素的影响,以及体内外释药相关性好等特点。因此本文将甲磺酸多沙唑嗪制成微孔渗透泵片,通过控制释药速率,使血药浓度平稳化,不仅改善了病人的耐受性,而且简化了剂量调整过程,显示出较好的临床优越性。
方法:以酒石酸、乳糖、甘露醇为主要辅料用单冲压片机制备片芯,以醋酸纤维素为包衣材料,PEG400为致孔剂,邻苯二甲酸二乙酯为增塑剂,丙酮为溶剂配制包衣液,锅包衣法制备甲磺酸多沙唑嗪微孔渗透泵片。在文献和预实验的基础上,对片芯中的助溶剂种类及用量、粘合剂种类、渗透压活性物质种类及用量、包衣液浓度、致孔剂的用量、增塑剂的用量和包衣膜重量进行考察,并以相似因子法评价其体外释药曲线的相似性。在上述单因素实验基础上选择渗透压促进剂的用量、致孔剂的用量和包衣膜重量作为3个影响因素,分别选取3个水平,按L_9(3~4)正交实验,采用加权评分法,以2、12、24h的累积释放度及0~24小时药物累积释放度与时间t的释放曲线进行直线拟合得到的相关系数r为评分点优化处方。
在文献和预实验基础上,建立了高效液相色谱分析方法测定甲磺酸多沙唑嗪。色谱条件:色谱柱为Hypersil OSD2 (4.6mm×150mm,5μm);流动相为甲醇-醋酸缓冲液(冰醋酸15ml,三乙胺1ml,加水至500ml)(52:48);流速为1.0 ml/min;柱温为30℃;检测波长为246nm。
对甲磺酸多沙唑嗪微孔渗透泵片进行了初步稳定性考察,影响因素实验包括高温、高湿、强光照射3个影响因素实验,分别在0、5、10天取样对其外观、含量、释放度进行考察,并用上述色谱方法进行测定。
体内药代动力学实验:以市售控释片(辉瑞)为对照,对甲磺酸多沙唑嗪微孔渗透泵片进行了Begael犬体内药物动力学研究。采用双周期自身交叉实验设计,以高效液相色谱法对6只健康Baegle犬体内血药浓度进行测定。采用非隔室模型方法计算各种药动学参数。
结果:通过单因素考察和正交实验,筛选出压片工艺为片芯直径9mm,硬度8kg,采用深弧度冲压片,片重0.3g/片。包衣工艺为:包衣温度35~40℃,包衣锅转速60rpm,喷雾压力2kg/cm2。最佳处方为:酒石酸作助溶剂,渗透压活性物质选用乳糖-甘露醇(1:1)150mg,包衣液为醋酸纤维素的丙酮溶液,其中PEG400为醋酸纤维素的100%(g/g),邻苯二甲酸二乙酯为醋酸纤维素的20%(g/g),包衣膜增重为片芯重量的3%,醋酸纤维素的浓度为3%(w/v)。
用HPLC法对甲磺酸多沙唑嗪进行体外含量测定,其保留时间约为7min,辅料对测定无干扰,线性回归方程为A=69126C-777.49(r=0.9999),线性范围为0.25~5.0μg/ml,日内精密度的平均RSD值为0.35%,日间精密度的平均RSD值为0.79%,平均回收率为99.64%。
影响因素实验中,在92.5%的相对湿度下样品在5天和10天时增重较大,而在75%的相对湿度下样品在5天后外观和含量均无明显变化,释放行为也无明显差异;10天后有轻度吸湿现象,外观和释放行为无明显差异,含量有少许下降;在60℃和4500Lx强光照射条件下,10天后样品外观、含量和释放都不变。
以辉瑞市售控释片为参比制剂进行Beagle犬体内的药物动力学研究,根据所选液相条件进行实验,其主要的药动学参数分别为:受试制剂参比制剂tmax(h) 7.67±1.51 9.67±0.82 Cmax(ng/ml) 55.84±2.69 54.37±1.72 AUC(ng·h/ml) 1208.36±44.54 1175.33±64.66 AUMC 20977.5±2499.5 23647.0±2179.4 MRT 17.33±1.55 20.09±0.77 F (%) 103.03 100
与市售控释片相比,药物达峰浓度和药时曲线下面积均无明显差异,药物的达峰时间稍有提前。
结论:甲磺酸多沙唑嗪微孔渗透泵片具有显著控释制剂的释药特征,符合零级释放动力学模型,能够恒速释药24h,重现性好,温度、光照不影响制剂的质量,湿度对制剂有影响,应注意防潮保存。同时建立了含量测定、释放度测定的方法,为考察质量提供了可靠方法。体内实验表明,与市售控释片相比,药物达峰浓度和药时曲线下面积均无明显差异,药物的达峰时间稍有提前。
Objectives: Mesylate doxazosin (DOX) for quinoline derivatives, are selective postsynapticα1-adrenergic receptors blockers. By blocking theα1-recepters to expand blood vessels, reduce vascular resistance,in order to decrease the blood pressure. It has little effect on cardiac output which is applicable to primary mild to moderate hypertension and accompanied by high blood pressure in patients with benign prostatic hyperplasia. As otherα1-recepter blockers, DOX has great impacts on orthostatic blood pressure and heart rate. In the application of ordinary tablets, if take the therapeutic doses directly,it may cause a sharp fall in blood pressure which led to syncope, orthostatic hypotension and other adverse reactions due to a sudden increase in blood concentration. Therefore we must adjust the dosage from the beginning small dose, taking a lot of inconvenience in applications. As a typical representative of controlled-release formulations, osmotic pump controlled-release formulations with zero-order release characteristic, independ on the media environment, pH, gastric motility, food and other factors in drug release process, which have a good correlation as well as in vivo and in vitro drug release. The study prepared DOX porous osmotic pump tablets. By controlling the release rate to make the plasma concentration placidity, not only improved the patient's tolerance but also simplifies the process of dose adjustment, showing the more good clinical superiority.
Methods: With tartaric acid, lactose, mannitol as the main excipients prepared the core tablets by the sigle-punch machine. Cellulose acetate, PEG400, diethyl phthalate and acetone were respectively used as coating material, channeling agent, plasticizer and solvent. DOX porous osmotic pump tablets were coat by pan coating method. On the basis of pretesting and scientific literatures, the type and amount of consolvent, the type of adhesive, the type and amount of osmotic agent, the concentration of coating solution, the amount of porogen and plasticizer, the thickness of coating membrane were investigated and evaluated by similarity (f2). The orthogonal experiment was designed to optimize formula in which the amount of osmotic agent, PEG400 and the thickness of coating membrane were taken as three influential factors and three different levels were selected. Each of them was selected refer to the L_9(3~4) orthogonal design table. According to accumulative release percentage at 2h, 12h, 24h and the correlation coefficient (r) of the 0~24h drug release profile to select optimal formula with the colligation evaluation.
The concertration of DOX was determined using a HPLC system on the basis of pretesting and scientific literatures. Separation was achieved by using a Hypersil OSD2 column (4.6mm×150mm, 5μm). The mobile phase was methanol- acetic acid buffer(glacial acetic acid 15ml, triethylamine 1ml, add water to 500ml)(52:48)(v/v).The flow rate was 1.0ml/min. All chromatographic separations were performed at 30℃. The wavelength of detectionwas set at 246nm.
The chemical and physical stability of optimal formula was investigated under following circumstances: high humidity, high temperature, and strong illumination. At the end of the study period, the formula was observed for change in physical appearance, drug content and drug release characteristics.
Pharmacokinetics study in vivo: With the commercial DOX tablet as the reference, the pharmacokinetic study of self-prepared DOX porous osmotic pump controlled-release tablets was performed in six Beagle dogs. With crossover design, HPLC method was employed to detect the concentration in dogs’plasma administerd with single dose. The pharmacokinetics parameters were caculated by non-compartmental model analysis method.
Results: The optimal technology and formula were defined through simple factor test and orthogonal experiments. The tableting technology were as follows:the diameter of tablet, 11mm; the hardness of tablet, 8kg; the weight of tablet, 0.3g.The coating technology were as follows: the coating temperature, 35~40℃; the rotation rate of pot, 60rpm/min; the spray pressure, 2kg/cm2. The optimal formula was as follows: tartaric acid as cosolvent;lactose-mannitol (1:1) 150mg as osmotic agent; the acetone solution of cellulose acetate as the coating solution; PEG400 in cellulose acetate, 100%(g/g); diethyl phthalate in cellulose acetate,20% (g/g); the weight of coating membrane, 3%;the concentraton of coating solution, 3%(w/v).
The content of DOX was determined by HPLC. The blank excipient has no effect on the determinations. The regression equation was A=69126C-777.49(r=0.9999), and the linearity range was 0.25~5.0μg/ml. The average within-day precision was 0.35%, and the average between-day precision was 0.79%. The average recovery was 99.64%.
In the stability experiment,the weight of DOX osmotic pump tablets which was exposed in the 92.5% relative humidity was increased a lot after 5 days and 10 days. But the weight of DOX osmotic pump tablets which was exposed in the 75% relative humidity was increased a bit after 5 days and 10 days, and there was little change in physical appearance, drug content and drug release characteristics. When the DOX osmotic pump tablets were exposed in high temperature (60℃) and strong illumination (4500±500lx), there was no change in physical appearance, drug content and drug release characteristics after 5 days and 10 days.
The pharmacokinetics studies were took in Beagle dogs with the reference tablets Pfizer commercial controlled-release tablets. According to the defined HPLC condition, the main pharmacokinetics parameters were respectively as following: Testing tablets Reference tablets tmax(h) 7.67±1.51 9.67±0.82 Cmax(ng/ml) 55.84±2.69 54.37±1.72 AUC(ng·h/ml) 1208.36±44.54 1175.33±64.66 AUMC 20977.5±2499.5 23647.0±2179.4 MRT 17.33±1.55 20.09±0.77 F (%) 103.03 100
Compared with the commercial release tablets, Cmax and AUC had no significant differences, but the t_(max) is sightly short.
Conclusions: DOX microporous osmotic pump tablets had good effect of controlled release property and repetition in vitro. The quality is independent on temperature, humidity and illumination. The methods of assay and dissolution for DOX microporous osmotic pump tablets were established, which provided a guideline with quality control. The experiment in vivo showed that C_(max) and AUC had no significant differences, but the tmax is sightly short.
方法:以酒石酸、乳糖、甘露醇为主要辅料用单冲压片机制备片芯,以醋酸纤维素为包衣材料,PEG400为致孔剂,邻苯二甲酸二乙酯为增塑剂,丙酮为溶剂配制包衣液,锅包衣法制备甲磺酸多沙唑嗪微孔渗透泵片。在文献和预实验的基础上,对片芯中的助溶剂种类及用量、粘合剂种类、渗透压活性物质种类及用量、包衣液浓度、致孔剂的用量、增塑剂的用量和包衣膜重量进行考察,并以相似因子法评价其体外释药曲线的相似性。在上述单因素实验基础上选择渗透压促进剂的用量、致孔剂的用量和包衣膜重量作为3个影响因素,分别选取3个水平,按L_9(3~4)正交实验,采用加权评分法,以2、12、24h的累积释放度及0~24小时药物累积释放度与时间t的释放曲线进行直线拟合得到的相关系数r为评分点优化处方。
在文献和预实验基础上,建立了高效液相色谱分析方法测定甲磺酸多沙唑嗪。色谱条件:色谱柱为Hypersil OSD2 (4.6mm×150mm,5μm);流动相为甲醇-醋酸缓冲液(冰醋酸15ml,三乙胺1ml,加水至500ml)(52:48);流速为1.0 ml/min;柱温为30℃;检测波长为246nm。
对甲磺酸多沙唑嗪微孔渗透泵片进行了初步稳定性考察,影响因素实验包括高温、高湿、强光照射3个影响因素实验,分别在0、5、10天取样对其外观、含量、释放度进行考察,并用上述色谱方法进行测定。
体内药代动力学实验:以市售控释片(辉瑞)为对照,对甲磺酸多沙唑嗪微孔渗透泵片进行了Begael犬体内药物动力学研究。采用双周期自身交叉实验设计,以高效液相色谱法对6只健康Baegle犬体内血药浓度进行测定。采用非隔室模型方法计算各种药动学参数。
结果:通过单因素考察和正交实验,筛选出压片工艺为片芯直径9mm,硬度8kg,采用深弧度冲压片,片重0.3g/片。包衣工艺为:包衣温度35~40℃,包衣锅转速60rpm,喷雾压力2kg/cm2。最佳处方为:酒石酸作助溶剂,渗透压活性物质选用乳糖-甘露醇(1:1)150mg,包衣液为醋酸纤维素的丙酮溶液,其中PEG400为醋酸纤维素的100%(g/g),邻苯二甲酸二乙酯为醋酸纤维素的20%(g/g),包衣膜增重为片芯重量的3%,醋酸纤维素的浓度为3%(w/v)。
用HPLC法对甲磺酸多沙唑嗪进行体外含量测定,其保留时间约为7min,辅料对测定无干扰,线性回归方程为A=69126C-777.49(r=0.9999),线性范围为0.25~5.0μg/ml,日内精密度的平均RSD值为0.35%,日间精密度的平均RSD值为0.79%,平均回收率为99.64%。
影响因素实验中,在92.5%的相对湿度下样品在5天和10天时增重较大,而在75%的相对湿度下样品在5天后外观和含量均无明显变化,释放行为也无明显差异;10天后有轻度吸湿现象,外观和释放行为无明显差异,含量有少许下降;在60℃和4500Lx强光照射条件下,10天后样品外观、含量和释放都不变。
以辉瑞市售控释片为参比制剂进行Beagle犬体内的药物动力学研究,根据所选液相条件进行实验,其主要的药动学参数分别为:受试制剂参比制剂tmax(h) 7.67±1.51 9.67±0.82 Cmax(ng/ml) 55.84±2.69 54.37±1.72 AUC(ng·h/ml) 1208.36±44.54 1175.33±64.66 AUMC 20977.5±2499.5 23647.0±2179.4 MRT 17.33±1.55 20.09±0.77 F (%) 103.03 100
与市售控释片相比,药物达峰浓度和药时曲线下面积均无明显差异,药物的达峰时间稍有提前。
结论:甲磺酸多沙唑嗪微孔渗透泵片具有显著控释制剂的释药特征,符合零级释放动力学模型,能够恒速释药24h,重现性好,温度、光照不影响制剂的质量,湿度对制剂有影响,应注意防潮保存。同时建立了含量测定、释放度测定的方法,为考察质量提供了可靠方法。体内实验表明,与市售控释片相比,药物达峰浓度和药时曲线下面积均无明显差异,药物的达峰时间稍有提前。
Objectives: Mesylate doxazosin (DOX) for quinoline derivatives, are selective postsynapticα1-adrenergic receptors blockers. By blocking theα1-recepters to expand blood vessels, reduce vascular resistance,in order to decrease the blood pressure. It has little effect on cardiac output which is applicable to primary mild to moderate hypertension and accompanied by high blood pressure in patients with benign prostatic hyperplasia. As otherα1-recepter blockers, DOX has great impacts on orthostatic blood pressure and heart rate. In the application of ordinary tablets, if take the therapeutic doses directly,it may cause a sharp fall in blood pressure which led to syncope, orthostatic hypotension and other adverse reactions due to a sudden increase in blood concentration. Therefore we must adjust the dosage from the beginning small dose, taking a lot of inconvenience in applications. As a typical representative of controlled-release formulations, osmotic pump controlled-release formulations with zero-order release characteristic, independ on the media environment, pH, gastric motility, food and other factors in drug release process, which have a good correlation as well as in vivo and in vitro drug release. The study prepared DOX porous osmotic pump tablets. By controlling the release rate to make the plasma concentration placidity, not only improved the patient's tolerance but also simplifies the process of dose adjustment, showing the more good clinical superiority.
Methods: With tartaric acid, lactose, mannitol as the main excipients prepared the core tablets by the sigle-punch machine. Cellulose acetate, PEG400, diethyl phthalate and acetone were respectively used as coating material, channeling agent, plasticizer and solvent. DOX porous osmotic pump tablets were coat by pan coating method. On the basis of pretesting and scientific literatures, the type and amount of consolvent, the type of adhesive, the type and amount of osmotic agent, the concentration of coating solution, the amount of porogen and plasticizer, the thickness of coating membrane were investigated and evaluated by similarity (f2). The orthogonal experiment was designed to optimize formula in which the amount of osmotic agent, PEG400 and the thickness of coating membrane were taken as three influential factors and three different levels were selected. Each of them was selected refer to the L_9(3~4) orthogonal design table. According to accumulative release percentage at 2h, 12h, 24h and the correlation coefficient (r) of the 0~24h drug release profile to select optimal formula with the colligation evaluation.
The concertration of DOX was determined using a HPLC system on the basis of pretesting and scientific literatures. Separation was achieved by using a Hypersil OSD2 column (4.6mm×150mm, 5μm). The mobile phase was methanol- acetic acid buffer(glacial acetic acid 15ml, triethylamine 1ml, add water to 500ml)(52:48)(v/v).The flow rate was 1.0ml/min. All chromatographic separations were performed at 30℃. The wavelength of detectionwas set at 246nm.
The chemical and physical stability of optimal formula was investigated under following circumstances: high humidity, high temperature, and strong illumination. At the end of the study period, the formula was observed for change in physical appearance, drug content and drug release characteristics.
Pharmacokinetics study in vivo: With the commercial DOX tablet as the reference, the pharmacokinetic study of self-prepared DOX porous osmotic pump controlled-release tablets was performed in six Beagle dogs. With crossover design, HPLC method was employed to detect the concentration in dogs’plasma administerd with single dose. The pharmacokinetics parameters were caculated by non-compartmental model analysis method.
Results: The optimal technology and formula were defined through simple factor test and orthogonal experiments. The tableting technology were as follows:the diameter of tablet, 11mm; the hardness of tablet, 8kg; the weight of tablet, 0.3g.The coating technology were as follows: the coating temperature, 35~40℃; the rotation rate of pot, 60rpm/min; the spray pressure, 2kg/cm2. The optimal formula was as follows: tartaric acid as cosolvent;lactose-mannitol (1:1) 150mg as osmotic agent; the acetone solution of cellulose acetate as the coating solution; PEG400 in cellulose acetate, 100%(g/g); diethyl phthalate in cellulose acetate,20% (g/g); the weight of coating membrane, 3%;the concentraton of coating solution, 3%(w/v).
The content of DOX was determined by HPLC. The blank excipient has no effect on the determinations. The regression equation was A=69126C-777.49(r=0.9999), and the linearity range was 0.25~5.0μg/ml. The average within-day precision was 0.35%, and the average between-day precision was 0.79%. The average recovery was 99.64%.
In the stability experiment,the weight of DOX osmotic pump tablets which was exposed in the 92.5% relative humidity was increased a lot after 5 days and 10 days. But the weight of DOX osmotic pump tablets which was exposed in the 75% relative humidity was increased a bit after 5 days and 10 days, and there was little change in physical appearance, drug content and drug release characteristics. When the DOX osmotic pump tablets were exposed in high temperature (60℃) and strong illumination (4500±500lx), there was no change in physical appearance, drug content and drug release characteristics after 5 days and 10 days.
The pharmacokinetics studies were took in Beagle dogs with the reference tablets Pfizer commercial controlled-release tablets. According to the defined HPLC condition, the main pharmacokinetics parameters were respectively as following: Testing tablets Reference tablets tmax(h) 7.67±1.51 9.67±0.82 Cmax(ng/ml) 55.84±2.69 54.37±1.72 AUC(ng·h/ml) 1208.36±44.54 1175.33±64.66 AUMC 20977.5±2499.5 23647.0±2179.4 MRT 17.33±1.55 20.09±0.77 F (%) 103.03 100
Compared with the commercial release tablets, Cmax and AUC had no significant differences, but the t_(max) is sightly short.
Conclusions: DOX microporous osmotic pump tablets had good effect of controlled release property and repetition in vitro. The quality is independent on temperature, humidity and illumination. The methods of assay and dissolution for DOX microporous osmotic pump tablets were established, which provided a guideline with quality control. The experiment in vivo showed that C_(max) and AUC had no significant differences, but the tmax is sightly short.
引文
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7 Sapna N. Makhija,Pradeep R. Vavia. Controlled porosity osmotic pump-based controlled release systems of pseudoephedrine I. Cellulose acetate as a semipermeable membrane[J]. Journal of Controlled Release,2003, 89:5~18
8高申主编.现代药物新剂型新技术.北京:人民军医出版社.200:258
9郎轶咏.尼莫地平渗透泵型控释片的研究[硕士学位论文].沈阳:沈阳药科大学,2001
10钟玲.人参总皂昔微孔渗透泵控释片的药学初步研究[硕士学位论文].成都:成都中医药大学,2006
1刘振,郑璐侠,郑艳斌等.甲磺酸多沙唑嗪胶囊的HPLC测定[J].中国医药工业杂志, 2004,35(5):298~299
2国家药品标准.国家食品药品监督管理局.WS1-(X-044)- 2003Z
3 Longxiao Liu,Binjie Che.Preparation of monolithic osmotic pump system by coating the indented core tablet[J]. European Journal of Pharmaceutics and Biopharmaceutics, 2006, 64: 180 ~184
4赵颖.甲磺酸多沙唑嗪控释制剂的研究[硕士学位论文].沈阳:沈阳药科大学,2004
5钟玲.人参总皂昔微孔渗透泵控释片的药学初步研究[硕士学位论文].成都:成都中医药大学,2006
1 Ning Ma,Wenying Liu,Huande Li,et al. LC–MS determination and relative bioavailability of doxazosin mesylate tablets in healthy Chinese male volunteers[J]. Journal of Pharmaceutical and Biomedical Analysis, 2007,43,:1049~1056
2梁文权主编.生物药剂学与药物动力学[M].第二版,北京:人民卫生出版社,2003:328~344
1 Javad Shokri,Parinaz Ahmadi,Parisa Rashidi et al.Swellable elementary osmotic pump (SEOP):An effective device for delivery of poorly water-soluble drugs[J].European Journal of Pharmaceutics and Biopharmaceutics,2008,68:289~297
2曲昌海,汤韧,高永良.不同溶解性药物口服渗透泵片片芯的处方设计[J].中国医院药学杂志,2005,25(12):1164~1165
3陆彬.药物新剂型与新技术[M].北京:人民卫生出版社,1998,282~283
4赵丽华,邹若飞,徐学君.口服渗透泵型药物制剂的研究进展[J].安徽医药,2006,10(5):373~375
5 D Prabakaran,Paramjit Singh,ParijatKanaujia et al. Effect of hydrophilic polymers on the release of diltiazem hydrochloride from elementary osmotic pumps[J]. International Journal of Pharmaceutics, 2003,259:173~179
6 Longxiao Liu,Xiagning Xu.Preparation of bilayer-core osmotic pump tablet by coating the indented core tablet[J]. International Jounal of Pharmaceutics, 2008,352:225~230
7 Kazuto Okimotoa,Yuji Tokunagaa,Rinta Ibukia,et al. Applicability of (SBE)7m-β-CD in controlled-porosity osmotic pump tablets (OPTs)[J].International Journal of Pharmaceutics, 2004,286:81~88
8 Kazuto Okimoto,Masatoshi Miyake,Norio Ohnishi,et al. Design and Evaluation of an Osmotic Pump Tablet (OPT) for Prednisolone,a Poorly Water Soluble Drug,Using (SBE)7m-β-CD[J].Pharmaceutical Research, 1998,15:1562~1568
9 Longxiao Liu,Xiaocui Wang.Solubility-modulated monolithic osmotic pump tablet for atenolol delivery[J]. European Journal of Pharmaceutics and Biopharmaceutics,2008,68:298~302
10 Ayer A,Theeuwes F,Wong PS.Process for increasing solubility of drug[P].US Patent:4732915,1986-03-22
11 Ozdemir N,Sahin J.Design of a controlled release osmotic pump system of ibuprofen[J].International Journal of Pharmaceutics,1997,158(1):91~97
12 En-Xian Lu,Zhi-Qiang Jiang,Qi-Zhi Zhang,et al.A water-insoluble drug monolithic osmotic tablet system utilizing gum Arabic as a osmotic, suspending and expanding agent[J]. Journal of Control Release,2003,92(3):375~382
13 Xiao-dong Lia,Wei-san Pana,Shu-fang Nie,et al.Studies on controlled release effervescent osmotic pump tablets from Traditional Chinese Medicine Compound Recipe[J].Journal of Control Release,2004,96(3):359~367
14卢恩先,江志强.难溶性药物口服渗透泵片工艺的研究进展[J].药学学报,2001,36(3):235~240
15 US 93-5256440 (CA 1994; 120:14926q)
16 Eur Pat Appl EP 89-339811 (CA1990; 113:46283z)
17 Makhija SN,Vavia PR.Controlled porosity osmotic pump based controlled release systems of pseudoephedrine I. Cellulose acetate as a semipermeable membrane[J]. Journal of Control Release,2003,89(1):5~18
18周伟利,寇翔.口服渗透泵控释制剂的工艺研究发展[J].海峡药学,2006,18(5):192~195
2赵颖.甲磺酸多沙唑嗪控释制剂的研究[硕士学位论文].沈阳:沈阳药科大学,2004
3 S.M. Herbig,J.R. Cardinal,R.W. Korsmeyer,K.L. Smith. Asymmetric-membrane tablet coatings for osmotic drug delivery[J]. Journal of Controlled Release, 1995,35:127~136
4隋红.盐酸万乃洛韦微孔渗透泵控释片的研究[硕士学位论文].沈阳:沈阳药科大学,2003
5潘卫三主编.新药制剂技术[M].第一版,北京:化学工业出版社,2004:170
6 Bengt L,Gert R,Johan H.Osmotic Pumping as a release mechanism for membrane-coated drug formulations[J].Int J Pharm,1989,56:261
7 Sapna N. Makhija,Pradeep R. Vavia. Controlled porosity osmotic pump-based controlled release systems of pseudoephedrine I. Cellulose acetate as a semipermeable membrane[J]. Journal of Controlled Release,2003, 89:5~18
8高申主编.现代药物新剂型新技术.北京:人民军医出版社.200:258
9郎轶咏.尼莫地平渗透泵型控释片的研究[硕士学位论文].沈阳:沈阳药科大学,2001
10钟玲.人参总皂昔微孔渗透泵控释片的药学初步研究[硕士学位论文].成都:成都中医药大学,2006
1刘振,郑璐侠,郑艳斌等.甲磺酸多沙唑嗪胶囊的HPLC测定[J].中国医药工业杂志, 2004,35(5):298~299
2国家药品标准.国家食品药品监督管理局.WS1-(X-044)- 2003Z
3 Longxiao Liu,Binjie Che.Preparation of monolithic osmotic pump system by coating the indented core tablet[J]. European Journal of Pharmaceutics and Biopharmaceutics, 2006, 64: 180 ~184
4赵颖.甲磺酸多沙唑嗪控释制剂的研究[硕士学位论文].沈阳:沈阳药科大学,2004
5钟玲.人参总皂昔微孔渗透泵控释片的药学初步研究[硕士学位论文].成都:成都中医药大学,2006
1 Ning Ma,Wenying Liu,Huande Li,et al. LC–MS determination and relative bioavailability of doxazosin mesylate tablets in healthy Chinese male volunteers[J]. Journal of Pharmaceutical and Biomedical Analysis, 2007,43,:1049~1056
2梁文权主编.生物药剂学与药物动力学[M].第二版,北京:人民卫生出版社,2003:328~344
1 Javad Shokri,Parinaz Ahmadi,Parisa Rashidi et al.Swellable elementary osmotic pump (SEOP):An effective device for delivery of poorly water-soluble drugs[J].European Journal of Pharmaceutics and Biopharmaceutics,2008,68:289~297
2曲昌海,汤韧,高永良.不同溶解性药物口服渗透泵片片芯的处方设计[J].中国医院药学杂志,2005,25(12):1164~1165
3陆彬.药物新剂型与新技术[M].北京:人民卫生出版社,1998,282~283
4赵丽华,邹若飞,徐学君.口服渗透泵型药物制剂的研究进展[J].安徽医药,2006,10(5):373~375
5 D Prabakaran,Paramjit Singh,ParijatKanaujia et al. Effect of hydrophilic polymers on the release of diltiazem hydrochloride from elementary osmotic pumps[J]. International Journal of Pharmaceutics, 2003,259:173~179
6 Longxiao Liu,Xiagning Xu.Preparation of bilayer-core osmotic pump tablet by coating the indented core tablet[J]. International Jounal of Pharmaceutics, 2008,352:225~230
7 Kazuto Okimotoa,Yuji Tokunagaa,Rinta Ibukia,et al. Applicability of (SBE)7m-β-CD in controlled-porosity osmotic pump tablets (OPTs)[J].International Journal of Pharmaceutics, 2004,286:81~88
8 Kazuto Okimoto,Masatoshi Miyake,Norio Ohnishi,et al. Design and Evaluation of an Osmotic Pump Tablet (OPT) for Prednisolone,a Poorly Water Soluble Drug,Using (SBE)7m-β-CD[J].Pharmaceutical Research, 1998,15:1562~1568
9 Longxiao Liu,Xiaocui Wang.Solubility-modulated monolithic osmotic pump tablet for atenolol delivery[J]. European Journal of Pharmaceutics and Biopharmaceutics,2008,68:298~302
10 Ayer A,Theeuwes F,Wong PS.Process for increasing solubility of drug[P].US Patent:4732915,1986-03-22
11 Ozdemir N,Sahin J.Design of a controlled release osmotic pump system of ibuprofen[J].International Journal of Pharmaceutics,1997,158(1):91~97
12 En-Xian Lu,Zhi-Qiang Jiang,Qi-Zhi Zhang,et al.A water-insoluble drug monolithic osmotic tablet system utilizing gum Arabic as a osmotic, suspending and expanding agent[J]. Journal of Control Release,2003,92(3):375~382
13 Xiao-dong Lia,Wei-san Pana,Shu-fang Nie,et al.Studies on controlled release effervescent osmotic pump tablets from Traditional Chinese Medicine Compound Recipe[J].Journal of Control Release,2004,96(3):359~367
14卢恩先,江志强.难溶性药物口服渗透泵片工艺的研究进展[J].药学学报,2001,36(3):235~240
15 US 93-5256440 (CA 1994; 120:14926q)
16 Eur Pat Appl EP 89-339811 (CA1990; 113:46283z)
17 Makhija SN,Vavia PR.Controlled porosity osmotic pump based controlled release systems of pseudoephedrine I. Cellulose acetate as a semipermeable membrane[J]. Journal of Control Release,2003,89(1):5~18
18周伟利,寇翔.口服渗透泵控释制剂的工艺研究发展[J].海峡药学,2006,18(5):192~195