CN107095844A - 一种用于制备难溶性药物口服固体制剂的药用组合物 - Google Patents

一种用于制备难溶性药物口服固体制剂的药用组合物 Download PDF

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CN107095844A
CN107095844A CN201710269058.XA CN201710269058A CN107095844A CN 107095844 A CN107095844 A CN 107095844A CN 201710269058 A CN201710269058 A CN 201710269058A CN 107095844 A CN107095844 A CN 107095844A
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陈再新
葛育红
王勇军
王淑娟
朱峰
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JIANGSU YABANG AIPUSEN PHARMACEUTICAL CO Ltd
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Abstract

本发明公开了一种用于制备难溶性药物口服固体制剂的药用组合物，其中难溶性药物包括替米沙坦、氯雷他定、盐酸小檗碱、呋塞米。本发明通过将难溶性药物与一定比例的稳定剂混合后，采用热熔挤出、熔融制粒或喷雾干燥后来制备难溶性药物的固体颗粒。采用该技术方案，制备的颗粒粒径减小、药物颗粒聚集减小、易浸润和分散从而提高了替米沙坦、氯雷他定、盐酸小檗碱、呋塞米在溶出介质中的溶出速率及溶出度，同时不会降低其化学稳定性，产品质量好。

Description

一种用于制备难溶性药物口服固体制剂的药用组合物
技术领域
本发明涉及一种用于制备难溶性药物口服固体制剂的药用组合物，尤其涉及一种以替米沙坦、氯雷他定、盐酸小檗碱、呋塞米作为有效成分的固体颗粒组合物。
背景技术
生物利用度是指药物吸收进入血液循环的程度和速度。在新药研究中，提高难溶性有效成分的生物利用度是一项很重要的工作。据报道，《美国药典》中有三分之一以上的药物为水难溶性药物，另目前大约40％的药物因存在溶解度问题而限制使用。
药物进入体内一般需要经过吸收、分布、代谢和排泄四个环节，药物的生物利用度受多方面影响，主要包括药物的水溶性、渗透性和首过效应等。大多数药物的吸收靠被动扩散，在通过胃黏膜吸收前需先溶解到胃肠道消化液中，因此药物须有合适的亲水/亲脂性才能较好地透过消化道黏膜被吸收。通过选择合适的载体和制剂技术可改善药物的理化性质、提高药物与胃肠道黏膜的亲和性，由此药物的吸收利用与药物的理化性质、辅料、剂型、制剂工艺等因素密切相关。
根据药物药剂学分类系统药物可分为四类。Ⅰ类：高溶解性高透膜性；Ⅱ类：低溶解性高透膜性；Ⅲ类：高溶解性低透膜性；Ⅳ类：低溶解性低透膜性，可见除第Ⅰ类药物外，其他三类的药物制剂均存在不同程度的生物利用度问题。Ⅱ类和Ⅳ类药都属于水难溶性药物，Ⅳ类药最难吸收，通常考虑采用静脉给药途径，但据文献[3]报道，设计前体药物可提高此类药物的生物利用度。对于Ⅱ类药物低溶解性和强的疏水性不仅导致药物很难在黏膜黏液层和不流动水层中的扩散，影响跨膜转运，最重要的是使药物难以溶解于胃肠道消化液中。因此，提高溶解度和溶出速度以及延长在吸收部位的滞留时间是改善此类难溶性药物生物利用度的首要方法。对于体内半衰期短的药物，过快的消除速率不仅增加了药物的给药次数，也降低了生物利用度。一般而言药物的消除速率与药物浓度成正比，将此种药物制备成缓释制剂，使血药浓度维持在相对稳定的水平，可以提高药物的生物利用度。
提高难溶性药物溶解度或溶出速度的方式包括：（1）合成水溶性前体；（2）加助溶剂或表面活性剂；（3）药物微粉化技术；（4）包合技术；（5）制备固体分散体技术；（6）纳米结晶；（7）自（微）乳化技术；（8）共晶技术等。
替米沙坦、氯雷他定、盐酸小檗碱、呋塞米均为难溶性药物，其在体内溶出是其药物吸收的限速，提高这些难溶性药物的溶出度能够提高这些难溶性药物在人体内生物利用度。
发明内容
本发明的目的是提供一种以替米沙坦、氯雷他定、盐酸小檗碱、呋塞米作为有效成分的固体颗粒组合物。
为实现上述发明目的，本发明采用了如下的技术方案。
一种用于制备难溶性药物口服固体制剂的药用组合物，其特征在于，包括通过热熔挤出、熔融制粒或喷雾干燥后获得的替米沙坦、氯雷他定、盐酸小檗碱、呋塞米固体颗粒。
以上所述的药用组合物，其特征是所述的颗粒还包括与替米沙坦、氯雷他定、盐酸小檗碱、呋塞米一起进行热熔挤出、熔融制粒或喷雾干燥的不同比例的稳定剂，其中稳定剂的量的范围是：药物/稳定剂=20/1～2/1。
如上所述的一种制备难溶性药物口服固体制剂药用组合物的方法，依次对替米沙坦、氯雷他定、盐酸小檗碱、呋塞米和稳定剂、溶剂执行如下操作步骤：
（a）混合，将难溶性药物与稳定剂、溶剂充分混合均匀；
（b）加热，为下一步的热熔制粒、减压干燥或喷雾干燥制备颗粒做准备；
（c）干燥，在此过程中将键合于固体物质的残留溶剂被除去，从而留下干燥的固体颗粒。
上述制备的固体颗粒可与填充剂、崩解剂、润滑剂一起混合或单独灌胶囊、或压制成片剂、或制成颗粒剂。
以上所述的制备难溶性药物口服固体制剂的药用组合物的方法，其中所述的混合步骤方法还包括湿法研磨或配成原料液的步骤。
由于采用上述的技术方案，制备的颗粒药物粒径减小、药物颗粒聚集减小、易浸润和分散从而提高了替米沙坦、氯雷他定、盐酸小檗碱、呋塞米在溶出介质中的溶出速率及溶出度，同时不会降低化学稳定性，产品质量好。
具体实施方式
为更进一步阐明本发明为达成预定目的所采取的技术手段及效果，请参阅以下有关本发明的详细说明，应理解这些实施例仅用于说明本发明而不用于限制本发明的范围，在阅读了本发明之后，本领域技术人员对本发明的各种等价形式的修改均落于本申请所附权利要求所限定的范围。
本发明采用热熔制粒制备的含有替米沙坦、氯雷他定、盐酸小檗碱、呋塞米作为有效成分的药用组合物及制备方法如下：将原料与稳定剂聚乙二醇3350、乳糖置制粒锅中开启搅拌，低速混合5min，加热通过高速剪切热熔制粒、流化热熔制粒、热熔挤出制粒、喷雾冷凝制粒得到固体颗粒组合物。
本发明采用湿法研磨制备的含有替米沙坦、氯雷他定、盐酸小檗碱、呋塞米作为有效成分的药用组合物及制备方法如下：将原料与稳定剂羟丙甲基纤维素、甘露醇的水溶液混合于超细粉碎机研磨或于高压匀浆机，低压研磨初步减小粒径，然后高压匀浆制成纳米混悬液，通过干燥得到固体颗粒组合物。
本发明采用配成原料液的含有替米沙坦、氯雷他定、盐酸小檗碱、呋塞米作为有效成分的药用组合物及制备方法如下：将原料于PVPK25溶于溶剂乙醇、丙酮、水等溶剂或混合溶剂中通过干燥得到固体颗粒组合物。
将上述制备的固体颗粒可与填充剂、崩解剂、润滑剂一起混合或单独灌胶囊、压制成片剂、制成颗粒剂。
本发明解决了难溶性药物生物利用度低的缺点，相助提高药物的吸收和药效，消除食物影响，加速起效时间。
由技术常识可知，本发明可以通过其他的不脱离其精神实质或必要特征的实施方案来实现。因此，上述公开的实施方案，就各方面而言，都是举例说明，并不是仅有的。所有在本发明范围内或在等同于本发明的范围内的改变均被本发明包含。

Claims (5)

1.一种用于制备难溶性药物口服固体制剂的药用组合物，其特征在于通过热熔挤出、熔融制粒或喷雾干燥后来制备难溶性药物的固体颗粒。
2.如权利要求1所述的一种用于制备难溶性药物口服固体制剂的药用组合物，其中所述的颗粒还包括与难溶性药物一起进行热熔挤出、熔融制粒或喷雾干燥的不同比例的稳定剂。
3.如权利要求1~2所述的一种用于制备难溶性药物口服固体制剂的药用组合物，其中难溶性药物包括替米沙坦、氯雷他定、盐酸小檗碱和呋塞米。
4.如权利要求1~3所述的一种用于制备难溶性药物口服固体制剂的药用组合物，其制备方法包括以下步骤：
（a）混合，将难溶性药物与稳定剂充分混合均匀，加入溶剂润湿；
（b）加热，为下一步的热熔挤出、熔融制粒或喷雾干燥制备颗粒做准备；
（c）干燥，将键合于固体物质的残留溶剂被除去，得到干燥的固体颗粒。
5.如根据权利要求4所述的所制备的固体颗粒可与填充剂、崩解剂、润滑剂一起混合或单独灌胶囊、或压制成片剂、或制成颗粒剂。
CN201710269058.XA 2017-04-24 2017-04-24 一种用于制备难溶性药物口服固体制剂的药用组合物 Pending CN107095844A (zh)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108570051A (zh) * 2018-07-20 2018-09-25 中国科学院上海药物研究所 呋塞米-氨苯蝶啶盐、晶型i及其制备方法和应用
WO2019038430A1 (en) * 2017-08-25 2019-02-28 Eleonor Sprl COMPOSITION COMPRISING AT LEAST ONE PROTOBERBERIN ALKALOID AND METHOD FOR PRODUCING THE SAME
WO2021209623A1 (fr) * 2020-04-17 2021-10-21 Eleonor Sprl Composition comprenant au moins un alcaloïde de protoberbérine et son procédé de fabrication

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Publication number Priority date Publication date Assignee Title
CN101219120A (zh) * 2007-12-27 2008-07-16 江苏万邦生化医药股份有限公司 替米沙坦分散片及其制备方法
WO2016135175A1 (en) * 2015-02-27 2016-09-01 Boehringer Ingelheim International Gmbh Immeadiate release oral tablet

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Publication number Priority date Publication date Assignee Title
CN101219120A (zh) * 2007-12-27 2008-07-16 江苏万邦生化医药股份有限公司 替米沙坦分散片及其制备方法
WO2016135175A1 (en) * 2015-02-27 2016-09-01 Boehringer Ingelheim International Gmbh Immeadiate release oral tablet

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019038430A1 (en) * 2017-08-25 2019-02-28 Eleonor Sprl COMPOSITION COMPRISING AT LEAST ONE PROTOBERBERIN ALKALOID AND METHOD FOR PRODUCING THE SAME
BE1025649B1 (fr) * 2017-08-25 2019-05-20 Eleonor Sprl Composition comprenant au moins un alcaloïde de protoberbérine et son procédé de fabrication
CN108570051A (zh) * 2018-07-20 2018-09-25 中国科学院上海药物研究所 呋塞米-氨苯蝶啶盐、晶型i及其制备方法和应用
CN108570051B (zh) * 2018-07-20 2021-02-02 中国科学院上海药物研究所 呋塞米-氨苯蝶啶盐、晶型i及其制备方法和应用
WO2021209623A1 (fr) * 2020-04-17 2021-10-21 Eleonor Sprl Composition comprenant au moins un alcaloïde de protoberbérine et son procédé de fabrication
BE1028182B1 (fr) * 2020-04-17 2022-03-28 Eleonor Composition comprenant au moins un alcaloïde de protoberbérine et son procédé de fabrication

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Application publication date: 20170829