盐酸左旋沙丁胺醇缓释片的研制
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摘要
目的:将治疗哮喘的手性新药盐酸左旋沙丁胺醇(levalbuterol hydrochloride,L-SBA),制备成一种缓释给药系统——盐酸左旋沙丁胺醇缓释片,以延长药物作用时间和提高治疗顺应性。与普通制剂相比,减小血药浓度波动,降低药物的毒副作用,是较为理想的缓释释药系统。
方法:通过湿法制粒压制片芯,采用骨架缓释技术,结合水性包衣技术制备盐酸左旋沙丁胺醇缓释片。以释放度为筛选指标,在单因素考察的基础上,设计正交实验优化处方,并对处方进行工艺重现性验证。对释放度曲线进行了拟合,探讨了缓释片的释药机理。探讨了缓释片质量标准的适用性,对本品进行质量检查和稳定性试验。
释药机制的研究:对最佳处方体外释放度曲线进行方程拟合,分析释药机理。质量标准的研究:分别采用正相和反相高效液相色谱法(HPLC)对缓释片含量、有关物质、释放度进行检测。评价分析方法的可靠性、准确性及缓释片的质量。对三批最优处方的含量、杂质、释放度进行检测验证工艺可靠性。
制剂稳定性研究:对缓释片进行影响因素实验(高温实验、高湿实验、强光照射实验),加速试验和长期试验。考察缓释片的外观、含量、对映体等有关物质及释放度的影响。结果:最优处方的三批产品平均累积释药量为2h(27.99%),4h(54.64%),8h(82.91%),12h(96.31)。药物释放符合Weibull方程模型,药物以扩散和溶蚀相结合的方式释放;三批处方验证含量、有关物质、释放度均合格;稳定性实验表明,本品密封包装并贮存在干燥处3个月后外观、含量、对映体与有关物质的量、释放度等均无明显变化。
结论:盐酸左旋沙丁胺醇缓释片通过调整片芯及包衣层处方组成能够得到预期释放效果,药物在12小时内释放完全;采用手性固定相,用正相高效液相色谱法可分离盐酸左旋沙丁胺醇及其对映体,适用于本品的质量检查;本品密封包装后贮存在干燥处质量稳定。通过该种剂型的研究能够为水溶性药物制成缓释片提供一定依据。
Objective:The new chiral drug levalbuterol hydrochloride was used for asthma therapy,which was select as the model drug and was prepared the sustained-release tablets including its effective time and bioavailiability. Comparing with the ordinary preparation, the sustained-release tablets diminish fluctuation of blood drug level and degrade the adverse reaction. So this kind of dosage form was a ideal sustained-release system.
Method: The core tablets were prepared by wet granulation compression, combing with matrix-sustained release technique, the levalbuterol hydrochloride sustained-release tablets, which extend the drug release to 12 hours in vitro were prepared by using latex coating technique. The prescription of sustained-release tablet was selected by drug release investigation. Base on single-factor tests about prescription, the optimal prescription was selected by orthogonal design. The optimal formulation was authenticated by in vitro release determination. The drug release profile was analysis by using different equations. The drug release mechanism of sustained-release tablets was investigated by fitting drug release model. The quality standard of preparation was studied. Then the stability of sustained-release tablets was investigated.
Result:The average cumulative release of optimization is 2h(27.99%), 4h(54.64%), 8h(82.91%), 12h(96.31%). The drug release profile in vitro was followed Weibull model equation. The mechanism of drug-release was diffusion and corrosion. The content and limited substance and drug release were qualified. Stability studies of preparation were shown that hight temperature and light have not obvious effect on L-SBA sustained-release tablet, but the humidity has some effect on the appearance and realese rate of L-SBA sustained-release tablet. The preparation should be stocked in cool and dry place.
Conclusion : The sustained-release tablets were prepared by adjusting the prescription of core tablet and coat-layer. The drug release was complete after 12h.The HPLC method was suitable for the quality control of the preparation. The tablet should be packed in moistureproof material and preserved under cool and dry condition.
方法:通过湿法制粒压制片芯,采用骨架缓释技术,结合水性包衣技术制备盐酸左旋沙丁胺醇缓释片。以释放度为筛选指标,在单因素考察的基础上,设计正交实验优化处方,并对处方进行工艺重现性验证。对释放度曲线进行了拟合,探讨了缓释片的释药机理。探讨了缓释片质量标准的适用性,对本品进行质量检查和稳定性试验。
释药机制的研究:对最佳处方体外释放度曲线进行方程拟合,分析释药机理。质量标准的研究:分别采用正相和反相高效液相色谱法(HPLC)对缓释片含量、有关物质、释放度进行检测。评价分析方法的可靠性、准确性及缓释片的质量。对三批最优处方的含量、杂质、释放度进行检测验证工艺可靠性。
制剂稳定性研究:对缓释片进行影响因素实验(高温实验、高湿实验、强光照射实验),加速试验和长期试验。考察缓释片的外观、含量、对映体等有关物质及释放度的影响。结果:最优处方的三批产品平均累积释药量为2h(27.99%),4h(54.64%),8h(82.91%),12h(96.31)。药物释放符合Weibull方程模型,药物以扩散和溶蚀相结合的方式释放;三批处方验证含量、有关物质、释放度均合格;稳定性实验表明,本品密封包装并贮存在干燥处3个月后外观、含量、对映体与有关物质的量、释放度等均无明显变化。
结论:盐酸左旋沙丁胺醇缓释片通过调整片芯及包衣层处方组成能够得到预期释放效果,药物在12小时内释放完全;采用手性固定相,用正相高效液相色谱法可分离盐酸左旋沙丁胺醇及其对映体,适用于本品的质量检查;本品密封包装后贮存在干燥处质量稳定。通过该种剂型的研究能够为水溶性药物制成缓释片提供一定依据。
Objective:The new chiral drug levalbuterol hydrochloride was used for asthma therapy,which was select as the model drug and was prepared the sustained-release tablets including its effective time and bioavailiability. Comparing with the ordinary preparation, the sustained-release tablets diminish fluctuation of blood drug level and degrade the adverse reaction. So this kind of dosage form was a ideal sustained-release system.
Method: The core tablets were prepared by wet granulation compression, combing with matrix-sustained release technique, the levalbuterol hydrochloride sustained-release tablets, which extend the drug release to 12 hours in vitro were prepared by using latex coating technique. The prescription of sustained-release tablet was selected by drug release investigation. Base on single-factor tests about prescription, the optimal prescription was selected by orthogonal design. The optimal formulation was authenticated by in vitro release determination. The drug release profile was analysis by using different equations. The drug release mechanism of sustained-release tablets was investigated by fitting drug release model. The quality standard of preparation was studied. Then the stability of sustained-release tablets was investigated.
Result:The average cumulative release of optimization is 2h(27.99%), 4h(54.64%), 8h(82.91%), 12h(96.31%). The drug release profile in vitro was followed Weibull model equation. The mechanism of drug-release was diffusion and corrosion. The content and limited substance and drug release were qualified. Stability studies of preparation were shown that hight temperature and light have not obvious effect on L-SBA sustained-release tablet, but the humidity has some effect on the appearance and realese rate of L-SBA sustained-release tablet. The preparation should be stocked in cool and dry place.
Conclusion : The sustained-release tablets were prepared by adjusting the prescription of core tablet and coat-layer. The drug release was complete after 12h.The HPLC method was suitable for the quality control of the preparation. The tablet should be packed in moistureproof material and preserved under cool and dry condition.
引文
[1]殷凯生.我国支气管哮喘防治中值得重视的几个问题.现代医学,2005.33(2)71～73.
[2]钟南山.支气管哮喘-基础与临床.人民卫生出版社,2006.607～608.
[3]Monica Thompson, Suzanne Wise, Howard Rodenberg etc. A preliminary comparison of Levalbuterol and Alburerol in prehospital care. The Journal of Emergency Medicine. 2004.26(3):271～277.
[4]FDA, Chirality 4 (1992) 338～340.
[5]Xopenex? (levalbuterol HCl) Inhalation Solution*, 0.63 mg, 1.25 mg Potency expressed as levalbuterol.NDA 20-837:4～22.
[6]左旋沙丁胺醇.中国医药技术与市场 2004.4(1):38.
[7]Diana Pancu , Michelle LaFlamme, Elizabeth Evans etc. Levalbuterol is as effective as racemic albuterol in lowering serum potassium. The Journal of Emergency Medicine, 2003.25(1): 13～16.
[8]Biswas, Fruedenthal. Levalbuterol toxicity: no reason to be jittery. European Respiratory Journal, 2003.12(2): 0903～1936.
[9]曹廷兴,朱悟淳. 沙丁胺醇的给药方式. 医药导报,1998.10(17):287.
[10]张彦 ,张志荣.硫酸沙丁胺醇脉冲控释片的研制.中国医院药学杂.
[11]王建华,陈慧云,杨永,等.口服缓释药物制剂技术研究进展,药学专论,2000.14(8):14～15.
[12]王汝兴,马超,刘喜纲.新型口服缓释、控释制剂的研究及发展. 承德医学院学报,2002.19(2):146～148.
[13] 王璐璐,郑稳生,孙慧芬.盐酸左旋沙丁胺醇的HPLC测定[J].中国药学杂志,2004(9):695～696.
[14]国家药典委员会 中国药典[S]. 2005 版.二部.
[15]徐冬羽,屠锡德.口服亲水凝胶骨架片的研究进展.药学进展, 2002. 26(1):10～15.
[16]吕丹,裴元英.羟丙基甲基纤维素-卡波普缓释亲水凝胶骨架片的研制和释药影响因素的考察.中国药学杂志,2001. 36(9):603～606.
[17]肖秋生,蒋永培. 羟丙甲基纤维素控释、缓释骨架片研究进展.西北药学杂志, 2000.15(3):15～17.
[18]董志超,蒋雪涛.羟丙基甲基纤维素在凝胶骨架中的含量与水溶性药物释放机制的关系.药学学报,1996.31(1):43.
[19]陈挺,陈子晟,包泳初,等. 国产 HPMC 作为盐酸普萘洛尔缓释骨架片基质的研究.中国医药工业杂志,1998.29(1):10.
[20]林晓,陈济民. 水溶性药物骨架片释放达零级的几种方法. 中国药学杂志.2002. 37(3):192～195.
[21]高生彬,赵华,康文通.药物包衣技术进展.河北工业科技.2006.23(6):367～369.
[22]容永欢.高效液相色谱法测定复方吲哚美辛栓中硫酸沙丁胺醇的含量. 时珍国医国药,2005.16(1):15～16.
[23]冯 波,何仲责,赵临襄,等。沙丁胺醇包合物缓释片在家犬体内药动学研究.中国医药工业杂志,2002,33(1O):41～42.
[24]郭涛,隋因,周俭平,等.沙丁胺醇在家犬体内药代动力学研究.中国药理学通报2001,17(2):239～40.
[25]李铜铃,许小红,李 莉,等.硫酸沙丁胺醇缓释胶囊人体生物利用度.四川大学学报医学版,2003,34(4):750～751.
[26]吕万良,屠锡德,蒋曙光,等.硫酸沙丁胺醇缓释片的制备及其在健康人体内的药动学研究.中国药科大学学报,1997,28(5):278～281.
[27]段京莉,黄竞,吴晨,等.国产硫酸沙丁胺醇控释片的人体药代动力学与相对生物利用度.中国新药杂志,2003,12(4):281～284.
[28]郭涛,隋因,周俭平,等.沙丁胺醇在家犬体内药代动力学研究.中国药理学通报,2001,17(2):239～240.
[2]钟南山.支气管哮喘-基础与临床.人民卫生出版社,2006.607～608.
[3]Monica Thompson, Suzanne Wise, Howard Rodenberg etc. A preliminary comparison of Levalbuterol and Alburerol in prehospital care. The Journal of Emergency Medicine. 2004.26(3):271～277.
[4]FDA, Chirality 4 (1992) 338～340.
[5]Xopenex? (levalbuterol HCl) Inhalation Solution*, 0.63 mg, 1.25 mg Potency expressed as levalbuterol.NDA 20-837:4～22.
[6]左旋沙丁胺醇.中国医药技术与市场 2004.4(1):38.
[7]Diana Pancu , Michelle LaFlamme, Elizabeth Evans etc. Levalbuterol is as effective as racemic albuterol in lowering serum potassium. The Journal of Emergency Medicine, 2003.25(1): 13～16.
[8]Biswas, Fruedenthal. Levalbuterol toxicity: no reason to be jittery. European Respiratory Journal, 2003.12(2): 0903～1936.
[9]曹廷兴,朱悟淳. 沙丁胺醇的给药方式. 医药导报,1998.10(17):287.
[10]张彦 ,张志荣.硫酸沙丁胺醇脉冲控释片的研制.中国医院药学杂.
[11]王建华,陈慧云,杨永,等.口服缓释药物制剂技术研究进展,药学专论,2000.14(8):14～15.
[12]王汝兴,马超,刘喜纲.新型口服缓释、控释制剂的研究及发展. 承德医学院学报,2002.19(2):146～148.
[13] 王璐璐,郑稳生,孙慧芬.盐酸左旋沙丁胺醇的HPLC测定[J].中国药学杂志,2004(9):695～696.
[14]国家药典委员会 中国药典[S]. 2005 版.二部.
[15]徐冬羽,屠锡德.口服亲水凝胶骨架片的研究进展.药学进展, 2002. 26(1):10～15.
[16]吕丹,裴元英.羟丙基甲基纤维素-卡波普缓释亲水凝胶骨架片的研制和释药影响因素的考察.中国药学杂志,2001. 36(9):603～606.
[17]肖秋生,蒋永培. 羟丙甲基纤维素控释、缓释骨架片研究进展.西北药学杂志, 2000.15(3):15～17.
[18]董志超,蒋雪涛.羟丙基甲基纤维素在凝胶骨架中的含量与水溶性药物释放机制的关系.药学学报,1996.31(1):43.
[19]陈挺,陈子晟,包泳初,等. 国产 HPMC 作为盐酸普萘洛尔缓释骨架片基质的研究.中国医药工业杂志,1998.29(1):10.
[20]林晓,陈济民. 水溶性药物骨架片释放达零级的几种方法. 中国药学杂志.2002. 37(3):192～195.
[21]高生彬,赵华,康文通.药物包衣技术进展.河北工业科技.2006.23(6):367～369.
[22]容永欢.高效液相色谱法测定复方吲哚美辛栓中硫酸沙丁胺醇的含量. 时珍国医国药,2005.16(1):15～16.
[23]冯 波,何仲责,赵临襄,等。沙丁胺醇包合物缓释片在家犬体内药动学研究.中国医药工业杂志,2002,33(1O):41～42.
[24]郭涛,隋因,周俭平,等.沙丁胺醇在家犬体内药代动力学研究.中国药理学通报2001,17(2):239～40.
[25]李铜铃,许小红,李 莉,等.硫酸沙丁胺醇缓释胶囊人体生物利用度.四川大学学报医学版,2003,34(4):750～751.
[26]吕万良,屠锡德,蒋曙光,等.硫酸沙丁胺醇缓释片的制备及其在健康人体内的药动学研究.中国药科大学学报,1997,28(5):278～281.
[27]段京莉,黄竞,吴晨,等.国产硫酸沙丁胺醇控释片的人体药代动力学与相对生物利用度.中国新药杂志,2003,12(4):281～284.
[28]郭涛,隋因,周俭平,等.沙丁胺醇在家犬体内药代动力学研究.中国药理学通报,2001,17(2):239～240.