盐酸坦洛新双层渗透泵控释片的研制
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摘要
目的:盐酸坦洛新是一种新型的α1A肾上腺素受体拮抗剂,1993年首次在日本上市。本品能显著改善前列腺增生引起的排尿困难和夜间尿频、残尿感等症状,可以超选择性地阻断膀胱颈、前列腺受体及被膜的平滑肌α1A受体、降低平滑肌张力、减少下尿路阻力、明显改善排尿症状,从而达到治疗前列腺增生症的目的,在同类药物中毒副作用最小,并对其它部位的α受体阻断影响很小,作用部位更为明确,因此它的α受体阻滞副作用更小。将盐酸坦洛新制成渗透泵型控制片,可有效地降低它的肝首过效应,提高生物利用度,减少服药次数,降低用药成本。
方法:用单冲压片机制备片芯,以醋酸纤维素为包衣材料,PEG4000为致孔剂,丙酮:水(100:3)为溶剂配制包衣液,锅包衣法制备盐酸坦洛新双层渗透泵控释片。在文献和预实验基础上初步确定了包衣过程中的包衣温度、包衣锅转速和喷雾压力。对盐酸坦洛新双层渗透泵控释片的片芯含药层、助推层,衣膜组成,制备工艺,和体外释药条件等因素进行了单因素考察。并以相似因子法评价其体外释药曲线的相似性。在上述实验基础上选择药层中PEO的用量、助推层中促渗剂的用量、增塑剂和致孔剂的用量和包衣膜重量作为4个影响因素,分别选取3个水平,按L9(34)正交实验,采用加权评分法,以4、8、12小时的释放量为3个评分点确定优化处方。按优化处方制备盐酸坦洛新双层渗透泵控释片,进行体外释放度实验,得到累积释放的曲线。
释放度实验依照《中国人民共和国药典》2005年版二部附录X C溶出度测定法第一法装置,以0.1mol/L的盐酸100 ml为释放介质,转速100 rpm,介质温度(37.0±0.5)℃,分别在1、2、4、6、8、10、12小时取液2 ml同时补充等体积同温释放介质,过0.45μm微孔滤膜后,续滤液作为供试溶液。另精密取盐酸坦洛新10 mg置100 ml量瓶中,定容摇匀后精密取1 ml定容于100 ml量瓶中,作为对照溶液。在下述色谱条件下,对对照溶液和供试溶液进行测定,按峰面积计算累积释放度。
在文献和预实验基础上,建立了高效液相分析方法测定盐酸坦洛新。色谱条件:色谱柱为Kromasil C18 (250mm×4.6mm,5μm);流动相为甲醇-乙腈-磷酸溶液(30:20:50);流速为1.0 ml/min;检测波长为223 nm。
对盐酸坦洛新双层渗透泵控释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。加速实验是在60℃下,相对湿度75%条件下分别在0、6个月取样对其外观、含量、释放度进行考察。
体内药代动力学实验:以Beagle犬为实验动物,采用随机分组的方法将Beagle犬分为两组,分别口服给予盐酸坦洛新原料药和自制盐酸坦洛新双层渗透泵控释片,在预定的时间点取血,对血浆处理后进行分析,清洗一周以后进行交叉实验。用高效液相-荧光色谱法测定给药后不同时间点的血药浓度,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7 mm,硬度7～8 kg,片重140mg。包衣工艺为:包衣温度40℃,包衣锅转速35rpm,喷雾压力2 kg/cm2。最佳处方为:渗透压活性物质为氯化钠,包衣液中PEG4000是醋酸纤维素的10%(g/g),包衣膜重量是片芯的8%,醋酸纤维素的浓度为3%(w/v)。
用HPLC法对盐酸坦洛新进行体外含量测定,其保留时间为4.5 min,辅料对测定无干扰,y=20858x-1961.3,r=0.9993,在1-8μg/ml的范围内,线性关系良好。日间精密度RSD为1.04～1.85%,日内精密度RSD为0.25～0.43%,回收率为98.96～100.12%。
影响因素实验中,在92.5%的相对湿度下样品在5天和10天时吸湿严重,而在75%的相对湿度下样品在5天和10天时变化不大,10天后外观、含量和释放不变;在60℃和4500±500 lx强光照射条件下,10天后样品外观、含量和释放都不变。加速实验中,在6个月后样品外观、含量和释放均不变。
药物动力学研究,其主要的药动学参数分别为:双层渗透泵片和原料药的Tmax(h)分别为4.67±0.76和3.33±0.92;Cmax(ng/ml)分别为89.34±4.02和228.99±18.58;MRT(h)分别为5.86±1.79和1.84±1.28。
可见双层渗透泵片与原料药相比,药物达峰浓度的时间和MRT均延长,而峰浓度降低。
结论:盐酸坦洛新双层渗透泵控释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12小时,重现性好,而且温度、湿度、光照不影响制剂的质量。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。体内实验证明药物达峰时间和MRT均比原料药长,且峰浓度降低。
Objectives: tamsulosin hydrochloride is a new type ofα1A adrenergic receptor antagonist which was on sale in Japan for the first time in 1993. This product can significantly improve dysuria caused by benign prostatic hyperplasia and nighttime urinary frequency, residual urine sensation and other symptoms,it also can be super-selective blocking the bladder neck and prostate smooth muscle receptor and envelopeα1A receptors, reduce muscle tension, reduce lower urinary tract resistance, significant improvement in urinary symptoms, so as to achieve the purpose of treatment of benign prostatic hyperplasia,it has the minimal side-effects of similar drugs,and has little effect ofα-adrenergic receptor blocking on other parts,and it makes the site of action more clearly,so it,sα-blocker side effects is smaller.
Methods: A method for preparation of tamsulosin hydrochloride push-pull osmotic pump release tablets was obtained by coating core tablet compressed by single punch tablet machine. Cellulose acetate, PEG 4000, acetone:wate(r100:3) were respectively used as coating material, channeling agent and solvent. On the basis of pretesting and scientific literatures, the temperature of coating, rotary speed of coating pot and pressure of spraying were determined. Single factor tests were carried out on the formulation of tablet core and coating material,procedure as well as the in vitro release condition,which affect the release behavivor were analyzed by similar factor method. The orthogonal experiment was designed to optimize formula in which the amount of PEO, the amout of NaCl,the amout of PEG 400, and thickness of coating membrane were taken as four influential factors and three different levels were selected to part, each of them was selected refer to the L9(34) orthogonal design table.According to accumulative release percentage at,4h,8h,12h to select optimal formula with the colligation evaluation. The osmotic pump tablet with the optimal formula was prepared and its in vitro cumulative release profile was obtained.
In vitro release test was performed in a dissolution apparatus using the third method according to CHP. The stirring rates in 0.1mol/L HCl was 100rpm. The temperature was maintained at (37±0.5)℃. At the predetermined intervals (1, 2, 4, 6, 8, 10, 12h), 2ml samples were with drawn from each vessel, filtered with a 0.45μm membrane, and analyzed with HPLC method for tamsulosin hydrochloride. The same volume of fresh medium was replaced after sampling.
Concentration of tamsulosin hydrochloride was determined using a HPLC system. Separation was achieved by using a Kromasil column(C18, 4.6mm×250mm,5μm).The mobile phase consisted of methanol–acetonitrile–Phosphate solution at a ratio of 30:20:50(v/v/v). The flow rate was 1.0ml/min, and the injection volume was 20μl. All chromatographic separations were performed at 25℃. The wavelength of detection was set at 223nm.
The chemical and physical stability of optimal formula was investigated under following circumstances: high humidity, high temperature, strong illumination and accelerated condition (60℃/75% RH for 6 months). 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: we selected the Beagle dogs as laboratory animal, which were divided into two groups in random. One group was given push-pull osmotic pump release tablets and the other was given market sustained release tablets. Plasma samples were obtained at different times. Crossover experiment was taken after two weeks. HPLC with Fluorescence detector was adopted in examining concentration of plasma. Then 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 core tablet conditions were as follows: hardness of tablet, 7～8kg; diameter of tablet, 7mm; weight of tablet, 140mg. The coating conditions were as follows: coating temperature, 40℃; rotation rate of pot, 35rpm; spray pressure, 2kg/cm2. The optimal formula were as follows: the type of osmotic agent, NaCl; osmotic agent in the drug of core tablet, 25%(g/g); PEG 4000 in the cellulose acetate, 10%(g/g); coating membrane in core tablet, 3%(g/g). Total coating materials in the coating solution: 3.0%(w/v).
The results of the system serve experiment of the HPLC method to determine the content of tamsulosin hydrochloride: the reserve time of tamsulosin hydrochloride were about 4.5min, the recoveries were 98.96~100.12%, the within-day precision was 0.25~0.43%, the between-day precision was 1.04~1.85%. Regression equation was y=20858x-1961.3, (r=0.9993). The linearity range of tamsulosin hydrochloride was 1μg/ml~8μg/ml. Excipients had no interference with the results.
Stability experiment: the result of high humidity test showed that 10 days after osmotic pump release tablets being placed in humidity(RH 92.5%), the weight highly increased. But in humidity(RH 75%), the weight hardly increased. There was no change in physical appearance, drug content and drug release characteristics after being stored at high humidity(RH 75%), high temperature(60℃) and strong illumination (4500±500 lx) for 10 days. The result of accelerated experiment showed that the data were not significantly different from before.
Pharmacokinetic study: The main pharmacokinetics parameters were respectively as following: Tmax(h), Cmax(μg/ml) and MRT of osmotic pump tablet were 4.67±0.76, 3.33±0.92 and 17.09±2.284 respectively. Tmax(h), Cmax(μg/ml) and MRT of conventional capsule were 89.34±4.02, 5.86±1.79 and 1.84±1.28 respectively.
Compared with tamsulosin hydrochloride, both peak time and MRT of osmotic pump tablet was extended and concentration of osmotic pump tablet was decreased.
Conclusions: Tamsulosin hydrochloride push-pull 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 tamsulosin hydrochloride osmotic pump tablets were established, which provided a guideline with quality control. The experiment in vivo showed that both peak time and MRT of osmotic pump tablet was extended and plasma concentration of osmotic pump tablet was decreased.
方法:用单冲压片机制备片芯,以醋酸纤维素为包衣材料,PEG4000为致孔剂,丙酮:水(100:3)为溶剂配制包衣液,锅包衣法制备盐酸坦洛新双层渗透泵控释片。在文献和预实验基础上初步确定了包衣过程中的包衣温度、包衣锅转速和喷雾压力。对盐酸坦洛新双层渗透泵控释片的片芯含药层、助推层,衣膜组成,制备工艺,和体外释药条件等因素进行了单因素考察。并以相似因子法评价其体外释药曲线的相似性。在上述实验基础上选择药层中PEO的用量、助推层中促渗剂的用量、增塑剂和致孔剂的用量和包衣膜重量作为4个影响因素,分别选取3个水平,按L9(34)正交实验,采用加权评分法,以4、8、12小时的释放量为3个评分点确定优化处方。按优化处方制备盐酸坦洛新双层渗透泵控释片,进行体外释放度实验,得到累积释放的曲线。
释放度实验依照《中国人民共和国药典》2005年版二部附录X C溶出度测定法第一法装置,以0.1mol/L的盐酸100 ml为释放介质,转速100 rpm,介质温度(37.0±0.5)℃,分别在1、2、4、6、8、10、12小时取液2 ml同时补充等体积同温释放介质,过0.45μm微孔滤膜后,续滤液作为供试溶液。另精密取盐酸坦洛新10 mg置100 ml量瓶中,定容摇匀后精密取1 ml定容于100 ml量瓶中,作为对照溶液。在下述色谱条件下,对对照溶液和供试溶液进行测定,按峰面积计算累积释放度。
在文献和预实验基础上,建立了高效液相分析方法测定盐酸坦洛新。色谱条件:色谱柱为Kromasil C18 (250mm×4.6mm,5μm);流动相为甲醇-乙腈-磷酸溶液(30:20:50);流速为1.0 ml/min;检测波长为223 nm。
对盐酸坦洛新双层渗透泵控释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。加速实验是在60℃下,相对湿度75%条件下分别在0、6个月取样对其外观、含量、释放度进行考察。
体内药代动力学实验:以Beagle犬为实验动物,采用随机分组的方法将Beagle犬分为两组,分别口服给予盐酸坦洛新原料药和自制盐酸坦洛新双层渗透泵控释片,在预定的时间点取血,对血浆处理后进行分析,清洗一周以后进行交叉实验。用高效液相-荧光色谱法测定给药后不同时间点的血药浓度,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7 mm,硬度7～8 kg,片重140mg。包衣工艺为:包衣温度40℃,包衣锅转速35rpm,喷雾压力2 kg/cm2。最佳处方为:渗透压活性物质为氯化钠,包衣液中PEG4000是醋酸纤维素的10%(g/g),包衣膜重量是片芯的8%,醋酸纤维素的浓度为3%(w/v)。
用HPLC法对盐酸坦洛新进行体外含量测定,其保留时间为4.5 min,辅料对测定无干扰,y=20858x-1961.3,r=0.9993,在1-8μg/ml的范围内,线性关系良好。日间精密度RSD为1.04～1.85%,日内精密度RSD为0.25～0.43%,回收率为98.96～100.12%。
影响因素实验中,在92.5%的相对湿度下样品在5天和10天时吸湿严重,而在75%的相对湿度下样品在5天和10天时变化不大,10天后外观、含量和释放不变;在60℃和4500±500 lx强光照射条件下,10天后样品外观、含量和释放都不变。加速实验中,在6个月后样品外观、含量和释放均不变。
药物动力学研究,其主要的药动学参数分别为:双层渗透泵片和原料药的Tmax(h)分别为4.67±0.76和3.33±0.92;Cmax(ng/ml)分别为89.34±4.02和228.99±18.58;MRT(h)分别为5.86±1.79和1.84±1.28。
可见双层渗透泵片与原料药相比,药物达峰浓度的时间和MRT均延长,而峰浓度降低。
结论:盐酸坦洛新双层渗透泵控释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12小时,重现性好,而且温度、湿度、光照不影响制剂的质量。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。体内实验证明药物达峰时间和MRT均比原料药长,且峰浓度降低。
Objectives: tamsulosin hydrochloride is a new type ofα1A adrenergic receptor antagonist which was on sale in Japan for the first time in 1993. This product can significantly improve dysuria caused by benign prostatic hyperplasia and nighttime urinary frequency, residual urine sensation and other symptoms,it also can be super-selective blocking the bladder neck and prostate smooth muscle receptor and envelopeα1A receptors, reduce muscle tension, reduce lower urinary tract resistance, significant improvement in urinary symptoms, so as to achieve the purpose of treatment of benign prostatic hyperplasia,it has the minimal side-effects of similar drugs,and has little effect ofα-adrenergic receptor blocking on other parts,and it makes the site of action more clearly,so it,sα-blocker side effects is smaller.
Methods: A method for preparation of tamsulosin hydrochloride push-pull osmotic pump release tablets was obtained by coating core tablet compressed by single punch tablet machine. Cellulose acetate, PEG 4000, acetone:wate(r100:3) were respectively used as coating material, channeling agent and solvent. On the basis of pretesting and scientific literatures, the temperature of coating, rotary speed of coating pot and pressure of spraying were determined. Single factor tests were carried out on the formulation of tablet core and coating material,procedure as well as the in vitro release condition,which affect the release behavivor were analyzed by similar factor method. The orthogonal experiment was designed to optimize formula in which the amount of PEO, the amout of NaCl,the amout of PEG 400, and thickness of coating membrane were taken as four influential factors and three different levels were selected to part, each of them was selected refer to the L9(34) orthogonal design table.According to accumulative release percentage at,4h,8h,12h to select optimal formula with the colligation evaluation. The osmotic pump tablet with the optimal formula was prepared and its in vitro cumulative release profile was obtained.
In vitro release test was performed in a dissolution apparatus using the third method according to CHP. The stirring rates in 0.1mol/L HCl was 100rpm. The temperature was maintained at (37±0.5)℃. At the predetermined intervals (1, 2, 4, 6, 8, 10, 12h), 2ml samples were with drawn from each vessel, filtered with a 0.45μm membrane, and analyzed with HPLC method for tamsulosin hydrochloride. The same volume of fresh medium was replaced after sampling.
Concentration of tamsulosin hydrochloride was determined using a HPLC system. Separation was achieved by using a Kromasil column(C18, 4.6mm×250mm,5μm).The mobile phase consisted of methanol–acetonitrile–Phosphate solution at a ratio of 30:20:50(v/v/v). The flow rate was 1.0ml/min, and the injection volume was 20μl. All chromatographic separations were performed at 25℃. The wavelength of detection was set at 223nm.
The chemical and physical stability of optimal formula was investigated under following circumstances: high humidity, high temperature, strong illumination and accelerated condition (60℃/75% RH for 6 months). 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: we selected the Beagle dogs as laboratory animal, which were divided into two groups in random. One group was given push-pull osmotic pump release tablets and the other was given market sustained release tablets. Plasma samples were obtained at different times. Crossover experiment was taken after two weeks. HPLC with Fluorescence detector was adopted in examining concentration of plasma. Then 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 core tablet conditions were as follows: hardness of tablet, 7～8kg; diameter of tablet, 7mm; weight of tablet, 140mg. The coating conditions were as follows: coating temperature, 40℃; rotation rate of pot, 35rpm; spray pressure, 2kg/cm2. The optimal formula were as follows: the type of osmotic agent, NaCl; osmotic agent in the drug of core tablet, 25%(g/g); PEG 4000 in the cellulose acetate, 10%(g/g); coating membrane in core tablet, 3%(g/g). Total coating materials in the coating solution: 3.0%(w/v).
The results of the system serve experiment of the HPLC method to determine the content of tamsulosin hydrochloride: the reserve time of tamsulosin hydrochloride were about 4.5min, the recoveries were 98.96~100.12%, the within-day precision was 0.25~0.43%, the between-day precision was 1.04~1.85%. Regression equation was y=20858x-1961.3, (r=0.9993). The linearity range of tamsulosin hydrochloride was 1μg/ml~8μg/ml. Excipients had no interference with the results.
Stability experiment: the result of high humidity test showed that 10 days after osmotic pump release tablets being placed in humidity(RH 92.5%), the weight highly increased. But in humidity(RH 75%), the weight hardly increased. There was no change in physical appearance, drug content and drug release characteristics after being stored at high humidity(RH 75%), high temperature(60℃) and strong illumination (4500±500 lx) for 10 days. The result of accelerated experiment showed that the data were not significantly different from before.
Pharmacokinetic study: The main pharmacokinetics parameters were respectively as following: Tmax(h), Cmax(μg/ml) and MRT of osmotic pump tablet were 4.67±0.76, 3.33±0.92 and 17.09±2.284 respectively. Tmax(h), Cmax(μg/ml) and MRT of conventional capsule were 89.34±4.02, 5.86±1.79 and 1.84±1.28 respectively.
Compared with tamsulosin hydrochloride, both peak time and MRT of osmotic pump tablet was extended and concentration of osmotic pump tablet was decreased.
Conclusions: Tamsulosin hydrochloride push-pull 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 tamsulosin hydrochloride osmotic pump tablets were established, which provided a guideline with quality control. The experiment in vivo showed that both peak time and MRT of osmotic pump tablet was extended and plasma concentration of osmotic pump tablet was decreased.
引文
1 Ning Wu, Li-Shan Wang, Darren. Mathematical modeling and in vitro study of controlled drug release via a highly swellable and dissoluble polymer matrix: polyethylene oxide with high molecular weights [J].Journal of Controlled Release,2005,102:569-581
2 Development of a controlled release low dose class II drug-Glipizide [J]. International Journal of Pharmaceutics,2006,312:24-32
3 Longxiao Liu, Gilson Khang, John M. Rhee, Hai Bang ,Lee.Monolithic osmotic tablet system for nifedipine delivery [J].Journal of controlled release, 2000,67: 309-322
4 Longxiao Liu,Xiaocui Wang.Solubility-modulated monolithic osmotic pump tablet for atenolol delivery[J].European Journal of Pharmaceutics and Biopharmaceutics, 2008,68:298-302
5 D.Prabakaran, Paramjit Singh, Parijat Kanaujia. Modified push–pull osmotic system for simultaneous delivery of theophylline and salbutamol:development and in vitro characterization [J]. International Journal of Pharmaceutics, 2004,284 :95-108
6曹国良,谭建国,张志宏.长春西汀双层渗透泵控释片的制备及体外释放度考察[J].沈阳药科大学学报,2007,24(9):524-527
7陆彬.药物新剂型与新技术[M].第2版,北京:人民卫生出版社,2005:436-447
8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):192-194
9孙光美,杨星钢,聂淑芳.非诺贝特双层渗透泵制剂的处方优化[J].中国药剂学杂志, 2009,4(7):212-217
10崔福德.药剂学实验[M].第1版,北京:人民卫生出版社,2005:180-187
11吴学明,聂淑芳,张宁.尼索地平双层渗透泵片的制备及其体外释放度的考察[J].中国药学杂志,2004,39(1):46-48
12李伟,张志宏,杜玍妮.格列齐特推拉式渗透泵的制备[J].中国新药杂志2006,3(17):233-236
13甘勇,周新腾,胡建平.格列吡嗪双层渗透泵控释片的制备及体外释放度考察[J].沈阳药科大学学报, 2006,3(16):224-228
14薛梅.盐酸坦洛新口崩片的制备工艺研究[J].中国药房, 2008,31(19):2445-2446
15彭光平,汪蕾,梁丽平.盐酸坦洛新治疗慢性前列腺炎临床研究[J].中国男科学杂志,2008,3(22):42-44
1李宁,徐文进,高崇凯. HPLC法测定丹参酚酸渗透泵片中丹酚酸B的含量[J].广东药学院学报, 2008, 10(5):469-471
2国家药典委员会.中华人民共和国药典[S].2000版第二部,北京:化学工业出版社, 2000:856~866
3夏志国,马忠朝,陈文波.盐酸坦洛新渗透泵片的研制及释药影响因素考察[J].浙江海洋学院学报,2007,27(4):435-438
4樊慧蓉,谷元,司端运.高灵敏度LC-MS/MS法测定犬血浆中的坦洛新[J].药学学报,2007,42(8):872-876
1 Min-SooKim,Jeong-SooKim,Yeon-HeeYou. Development and optimization of a novel oral controlled delivery system for tamsulosin hydrochloride using response surface methodology[J]. International Journal of Pharmaceutics,2007,341:97-104
2李好枝.体内药物分析[M].第1版,北京:中国医药科技出版社,2003:120-131
3胡季强,王如伟,刘广余.盐酸坦洛新缓释胶囊生物利用度研究[J].医学导报,2009,26(6):705-707
4梁文权.生物药剂学与药物动力学[M].第2版,北京:人民卫生出版社,2006:226-271
5刘丽鹤,王鹏,李好枝.盐酸坦洛新血药浓度测定方法及其药动学研究进展[J].中国药学杂志,2003,38(7):884-984
6宫爱申,佘高红,王丹.盐酸坦洛新及其缓释微丸犬药代动力学研究[J].中国临床药学杂志,2004,7:1358-1364
7杨劲,丁黎,郝歆愚.盐酸坦洛新缓释胶囊在人体内的药动学和生物等效性[J].中国临床药学杂志,2005,14:339-342
8吴学明.尼索地平渗透泵控释制剂的研制[D].沈阳:沈阳药科大学硕士学位论文,2003
1张丽,欧阳静.口服渗透泵制剂研究进展[J].中国药业,2006.15:65-68
2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,2006,5(18):192-195
3刘海洲,刘爱云,高峰.渗透泵型控释片制备工艺研究进展[J].齐鲁药事,2008,8:486-489
4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,2001,6(3):235-240
5曹高忠,傅红兴,张福志.盐酸沙格雷酯渗透泵控释片的研制[J].中国医院药学杂志,2008,28(13):1055-1058
6凌静,王华,李士敏.酒石酸托特罗定渗透泵片的制备及释放度测定[J].中国现代应用药学杂志,2006,23(5):372-374
7 Kazuto Okimoto, Yuji Tokunaga, Rinta Ibuki.Applicability of (SBE)7m-β-CD in controlled-porosity osmotic pump tablets (OPTs) [J]. International Journal of Pharmaceutics,2004(286):81-88
8 Vincent Malaterrea, Joerg Ogorka, Nicoletta Loggia. Approach to design push-pull osmotic pumps[J]. International Journal of Pharmaceutics,2009
9吴涛,潘卫三,庄殿友.口服渗透泵制剂的研究进展[J].中国药学杂志,1999,34(2):76-78
10潘卫三,甘勇.双室型渗透泵控释制剂的研究进展[J].沈阳药科大学学报,2003.3:147-151
11 Dorottya Kiss, Karoly Suvegh, Romána Zelk.The effect of storage and active ingredient properties on the drug release profile of poly(ethylene oxide) matrix tablets[J]. Carbohydrate Polymers,2008,74:930-933
12 Zhi-hong Zhang,Wei Li a, Shu-fang Nie.Overcome side identification in PPOP by making orifices on both layers[J].International Journal of Pharmaceutics,2009,1(7):1-7
13 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
14 Longxiao Liu, Xiangning Xu. Preparation of bilayer-core osmotic pump tablet by coating the indented core tablet[J]. International Journal of Pharmaceutics,2008,352:225-230
15 Rajan K. Verma, Divi Murali Krishna, Sanjay Garg. Formulation aspects in the development of osmotically controlled oral drug delivery systems[J]. Journal of Controlled Release,2002,27(7):8-27
16 Shajahan Abdul, S.S. Poddar. A flexible technology for modified release of drugs:multilayered tablets[J]. Journal of Controlled Release,2004,97:393-405
17刘龙孝,徐清,姜吉善.夹芯渗透泵片用于水不溶性药物的控制释放[J].药学学报, 2003,38 (12):966-967
18刘辉,漆正林,刘宏.盐酸文拉法新微孔型渗透泵控释片的制备工艺研究[J].医学导报,2009,10(10):1331-1334
19宋金春,以盛,吕烨.磷酸川穹嗪微孔渗透泵片的研制及释药机制研究[J].中国药方,2008,.19(6):420-423
2 Development of a controlled release low dose class II drug-Glipizide [J]. International Journal of Pharmaceutics,2006,312:24-32
3 Longxiao Liu, Gilson Khang, John M. Rhee, Hai Bang ,Lee.Monolithic osmotic tablet system for nifedipine delivery [J].Journal of controlled release, 2000,67: 309-322
4 Longxiao Liu,Xiaocui Wang.Solubility-modulated monolithic osmotic pump tablet for atenolol delivery[J].European Journal of Pharmaceutics and Biopharmaceutics, 2008,68:298-302
5 D.Prabakaran, Paramjit Singh, Parijat Kanaujia. Modified push–pull osmotic system for simultaneous delivery of theophylline and salbutamol:development and in vitro characterization [J]. International Journal of Pharmaceutics, 2004,284 :95-108
6曹国良,谭建国,张志宏.长春西汀双层渗透泵控释片的制备及体外释放度考察[J].沈阳药科大学学报,2007,24(9):524-527
7陆彬.药物新剂型与新技术[M].第2版,北京:人民卫生出版社,2005:436-447
8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):192-194
9孙光美,杨星钢,聂淑芳.非诺贝特双层渗透泵制剂的处方优化[J].中国药剂学杂志, 2009,4(7):212-217
10崔福德.药剂学实验[M].第1版,北京:人民卫生出版社,2005:180-187
11吴学明,聂淑芳,张宁.尼索地平双层渗透泵片的制备及其体外释放度的考察[J].中国药学杂志,2004,39(1):46-48
12李伟,张志宏,杜玍妮.格列齐特推拉式渗透泵的制备[J].中国新药杂志2006,3(17):233-236
13甘勇,周新腾,胡建平.格列吡嗪双层渗透泵控释片的制备及体外释放度考察[J].沈阳药科大学学报, 2006,3(16):224-228
14薛梅.盐酸坦洛新口崩片的制备工艺研究[J].中国药房, 2008,31(19):2445-2446
15彭光平,汪蕾,梁丽平.盐酸坦洛新治疗慢性前列腺炎临床研究[J].中国男科学杂志,2008,3(22):42-44
1李宁,徐文进,高崇凯. HPLC法测定丹参酚酸渗透泵片中丹酚酸B的含量[J].广东药学院学报, 2008, 10(5):469-471
2国家药典委员会.中华人民共和国药典[S].2000版第二部,北京:化学工业出版社, 2000:856~866
3夏志国,马忠朝,陈文波.盐酸坦洛新渗透泵片的研制及释药影响因素考察[J].浙江海洋学院学报,2007,27(4):435-438
4樊慧蓉,谷元,司端运.高灵敏度LC-MS/MS法测定犬血浆中的坦洛新[J].药学学报,2007,42(8):872-876
1 Min-SooKim,Jeong-SooKim,Yeon-HeeYou. Development and optimization of a novel oral controlled delivery system for tamsulosin hydrochloride using response surface methodology[J]. International Journal of Pharmaceutics,2007,341:97-104
2李好枝.体内药物分析[M].第1版,北京:中国医药科技出版社,2003:120-131
3胡季强,王如伟,刘广余.盐酸坦洛新缓释胶囊生物利用度研究[J].医学导报,2009,26(6):705-707
4梁文权.生物药剂学与药物动力学[M].第2版,北京:人民卫生出版社,2006:226-271
5刘丽鹤,王鹏,李好枝.盐酸坦洛新血药浓度测定方法及其药动学研究进展[J].中国药学杂志,2003,38(7):884-984
6宫爱申,佘高红,王丹.盐酸坦洛新及其缓释微丸犬药代动力学研究[J].中国临床药学杂志,2004,7:1358-1364
7杨劲,丁黎,郝歆愚.盐酸坦洛新缓释胶囊在人体内的药动学和生物等效性[J].中国临床药学杂志,2005,14:339-342
8吴学明.尼索地平渗透泵控释制剂的研制[D].沈阳:沈阳药科大学硕士学位论文,2003
1张丽,欧阳静.口服渗透泵制剂研究进展[J].中国药业,2006.15:65-68
2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,2006,5(18):192-195
3刘海洲,刘爱云,高峰.渗透泵型控释片制备工艺研究进展[J].齐鲁药事,2008,8:486-489
4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,2001,6(3):235-240
5曹高忠,傅红兴,张福志.盐酸沙格雷酯渗透泵控释片的研制[J].中国医院药学杂志,2008,28(13):1055-1058
6凌静,王华,李士敏.酒石酸托特罗定渗透泵片的制备及释放度测定[J].中国现代应用药学杂志,2006,23(5):372-374
7 Kazuto Okimoto, Yuji Tokunaga, Rinta Ibuki.Applicability of (SBE)7m-β-CD in controlled-porosity osmotic pump tablets (OPTs) [J]. International Journal of Pharmaceutics,2004(286):81-88
8 Vincent Malaterrea, Joerg Ogorka, Nicoletta Loggia. Approach to design push-pull osmotic pumps[J]. International Journal of Pharmaceutics,2009
9吴涛,潘卫三,庄殿友.口服渗透泵制剂的研究进展[J].中国药学杂志,1999,34(2):76-78
10潘卫三,甘勇.双室型渗透泵控释制剂的研究进展[J].沈阳药科大学学报,2003.3:147-151
11 Dorottya Kiss, Karoly Suvegh, Romána Zelk.The effect of storage and active ingredient properties on the drug release profile of poly(ethylene oxide) matrix tablets[J]. Carbohydrate Polymers,2008,74:930-933
12 Zhi-hong Zhang,Wei Li a, Shu-fang Nie.Overcome side identification in PPOP by making orifices on both layers[J].International Journal of Pharmaceutics,2009,1(7):1-7
13 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
14 Longxiao Liu, Xiangning Xu. Preparation of bilayer-core osmotic pump tablet by coating the indented core tablet[J]. International Journal of Pharmaceutics,2008,352:225-230
15 Rajan K. Verma, Divi Murali Krishna, Sanjay Garg. Formulation aspects in the development of osmotically controlled oral drug delivery systems[J]. Journal of Controlled Release,2002,27(7):8-27
16 Shajahan Abdul, S.S. Poddar. A flexible technology for modified release of drugs:multilayered tablets[J]. Journal of Controlled Release,2004,97:393-405
17刘龙孝,徐清,姜吉善.夹芯渗透泵片用于水不溶性药物的控制释放[J].药学学报, 2003,38 (12):966-967
18刘辉,漆正林,刘宏.盐酸文拉法新微孔型渗透泵控释片的制备工艺研究[J].医学导报,2009,10(10):1331-1334
19宋金春,以盛,吕烨.磷酸川穹嗪微孔渗透泵片的研制及释药机制研究[J].中国药方,2008,.19(6):420-423