CN1110135A - 控制释放的药物组合物 - Google Patents
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Abstract
一种提供极好零级控制释放曲线的易受侵蚀的
药物组合物，它包含于25℃在水中溶解度不大于
80mg/ml的治疗活性物质，羟丙基甲基纤维素和依
赖于药物溶解度和药物负载的侵蚀改良剂如乳糖和
丙二醇的聚氧基亚烷基衍生物以及其它惰性物质如
粘合剂和润滑剂。
Description
本发明涉及具有极好的零级控制释放曲线的易受侵蚀的药物组合物。易受侵蚀的组合物含有溶解度不大于80mg/ml的治疗活性物质，羟丙基甲基纤维素衍生物和依赖于药物溶解度和药物负载的侵蚀改良剂和乳糖和丙二醇的聚氧亚烷基衍生物以及其它惰性物质如粘合剂和润滑剂。组合物在所需的时间内侵蚀恒定的侵蚀体积，当被摄取时，基质形成两层，正在侵蚀的水化基质外层和未改变的基质内核。该组合物提供零级释放曲线，部分由于药物扩散出基质的速率可以忽略或它与基质的侵蚀速率相当，所以水化层内药物浓度保持恒定。
零级释放意味着在组合物的整个有效期内单位时间释放的活性物质速率基本保持恒定。例如，每小时释放10%活性成分的组合物在10小时内将释放约100%的活性成分。
更详细地说，本发明涉及成形和压成固体剂型的易受侵蚀的药物组合物，它提供治疗活性物质的零级控制释放，易受侵蚀的组合物含有于25℃在水中溶解度不大于80mg/mL的约5%到60%w/w的治疗活性物质和约5%到约50%w/w的低粘度羟丙基甲基纤维素和由惰性载体组成的易受侵蚀组合物的其它物质。
按照本发明，制备口服给药的具有零级释放的易受侵蚀药物组合物的配方制备如下。活性成份与纤维素醚衍生物如MethocelRK100LV和侵蚀改良剂如乳糖或非离子表面活性剂如丙二醇的聚氧亚烷基衍生物（以商品名Pluronic F-68出售）一起混合物，直接混合或与适当的粘合剂如聚乙烯基吡咯烷酮或羟丙基纤维素湿粒化。聚乙烯吡咯烷酮可以商品名Povidone买到。Klucel LF是市售的羟丙基纤维素。湿粒在50℃下干燥，并通过＃30目筛子筛分。润滑剂如硬脂酸镁与干粒混合。使用适当的片剂压机，把粒压成指定重量的片剂。存在于组合物中的活性成份量为组合物的5%到60%w/w。
通过组合治疗活性物质，纤维素醚衍生物和当需要时，侵蚀改良剂如乳糖或Pluronic F-68制成易受侵蚀的组合物。存在于基质中纤维素醚衍生物量为5%到50%w/w。优选的组合物含纤维素醚衍生物量为10%到25%w/w。
可适用于本发明的纤维素醚衍生物的实施例包括羟丙基甲基纤维素或羟丙基纤维素或其混合物。最优选的易受侵蚀基质为甲氧基含量约为19-30%，羟丙基含量约为7-12%，甲氧基取代度为1.1到2.0和分子量约为20，000到26，000道尔顿的羟丙基甲基纤维素。一种2%w/w聚合物溶液表现出凝胶点为62°-90℃，于25℃粘度为50到100cps。
本发明的零级释放药物转运系统适用于药物如硝苯啶，（E）-4-〔〔3-（2-（4-环丁基-2-噻唑基）乙烯基〕苯基〕氨基〕-2，2-二乙基-4-氧代丁酸，（+）-顺-3-（2酰基氧基）-2，3-二氢-2-（4-甲氧基苯基）-5-〔2-二甲基氨基）乙基〕萘并（1，2-b）-1，4-噻氮杂草-4（5H）-酮，琥珀酸西苯唑啉（CibenzolineSuccinate），地尔硫卓，8-氟-5，6-二氢-5-甲基-6-氧代-4H-咪唑并〔1，5-a〕〔1，4〕苯并二氮杂草-3-羧酸乙酯（Flumazenil），氯苯丙胺，4-（2，2-二苯基乙烯基）-1-〔1-氧代-9-（3-吡啶基）壬基〕哌啶，7-氯-N-甲基-5-（1H-吡咯-2-基）-3H-1，4-苯并二氮杂草-2-胺和5-〔3-〔4-（2-氯苯基）-9-甲基-6H-噻吩并〔3，2-f〕〔1，2，4〕三唑并〔4，3-a〕〔1，4〕二氮杂草-2-基〕-2-丙炔基〕-菲啶-6（5H）-酮。
或用转篮法或用浆法采用USP溶解试验步骤以指定速度评价药物从易受侵蚀基质中的释放。转篮法和浆法记载于美国药典（USP）XXII1578页上和国家药方集（NF）XVII（美国药典委员会，Inc.，Rockville，MD，1990）。简单地说，在两种方法中片剂放在下述的含有指定量溶解介质的适当仪器中，开始搅拌。用现有技术中UV光谱测量法测定溶解的药量。用于转篮法的设备由下面组成：标称容量为1000mL的带盖玻璃容器，发动器，金属驱动轴，和圆柱形蓝。含900mL指定溶解介质（即：水，1%非离子表面活性剂Emulphor ON-87磷酸缓冲液，pH7.5，或3%十二烷基硫酸钠，pH9.0的容器部分浸入适当水浴中，平衡到37°±0.5℃。可用密封盖以阻止蒸发。安装轴使其轴线任何点距容器垂直轴线不超过2mm，并且轴平稳旋转而无明显摆动。使用调速装置，它可选择轴旋轴速度并保持在指定速率。建议的转篮速度为100rpm。在试验过程中容器内底与转篮之间的距离保持在25±2mm。
用于浆法的装置与用于转蓝法的设备相同，只是浆由叶片形成且轴用作搅拌元件。安置轴使得它的轴线任何点距容器的垂直轴线不超过2mm，轴平稳转动而无明显摆动。建议的浆速为50rpm。在试验期间保持容器内底与叶片之间的距离为25±2mm。溶解介质按规定使用（即900ml模拟胃液或1%非离子表面活性剂EmulphorON-870的磷酸盐缓冲液，于37℃pH7.5）。用紫外光谱仪测定药物。
用USP设备1测定片剂的侵蚀曲线（转篮法）。步骤与上述评价药物释放的方法相似。片剂放在USP转蓝内，浸在900ml纯化水中，速度为100rpm。在指定的时间间隔，具有残留片剂的篮子从介质中移开，于50℃在炉内干燥片剂至少18小时和/或直到得到恒定的重量。基于片剂的重量损失计算侵蚀百分数。
图1示意描述转运系统的释放机制。图1描述有侵蚀的外水化层和不改变的内核的基质。在本发明的组合物中，药物扩散出基质的速率可以忽略或与基质的侵蚀速率相匹配，所以在水化层内的药物浓度保持恒定。基质的恒定侵蚀体积控制药物释放。在时间t释放的药量（Vt）由下面等式描述：
Mt＝VtC（等式1）
dVtdt＝k0（等式2）
其中Vt为在时间t侵蚀的水化层体积;C为水化层的药物浓度;dVtdt为侵蚀速率（K0），它为常数。
当水化层药物浓度C保持恒定时，药物释放速率dMt/dt为零级。随着HPMC的水化，基质本身的溶解或侵蚀导致分散在基质中的活性成份的释放。
如图2-7和9-16所示，本发明药物组合物在给定的溶解介质内产生零级释放曲线。在含本发明聚合物的药物组合物中使用高溶性药物如马来酸氯化非尼拉敏在溶解介质中由于活性物质的附加扩散不产生如图8所示的零级释放曲线。
图4表明治疗活性物质从药物组合物的释放速度与组合物的侵蚀速率紧密相关。
本发明的控制释放（CR）基质组合物进一步由下面实施例举例说明，但不限于实施例。
实施例1
组份 mg/片剂
(E)-4-[[3-[2-(4-环丁基-2-噻唑
基)乙烯基]苯基]氨基]-2,2-二乙
基-4-氧代丁酸) 100.0
Pluroric F68 100.0
Methocel K100LK 135.0
水合乳糖 135.0
Povidone K30 28.5
硬脂酸镁 1.5
100mg CR片剂的释放曲线表示在图2和3中。100mg（E）-4-〔〔3-〔2-（4-环丁基-2-噻唑基）乙烯基〕苯基〕氨基〕-2，2-二乙基-4-氧代丁酸CR片剂的释放和侵蚀曲线的比较表示在图4中。
实施例2
组份 mg/片剂
(E)-4-[[3-[2-(4-环丁基-2-噻唑
基)乙烯基]苯基]氨基]-2,2-二乙
基-4-氧代丁酸) 100.0
Methocel K100LK 31.2
无水乳糖 46.8
Povidone K30 20.0
硬脂酸镁 2.0
（E）-4-〔〔3-〔2-（4-环丁基-2-噻唑基）乙烯基〕苯基〕氨基〕-2，2-二乙基-4-氧代丁酸CR片剂的释放曲线表示在图5中。
实施例3
组份 mg/片剂
(+)-顺-3-(乙酰基氧基)-2,3-二氢-2-
(4-甲氧基苯基)-5-[2-(二甲基氨基)
乙基]萘并[1,2-b]-1,4-噻氮杂
-4
(5H)-酮 54.0
无水乳糖 200.0
Methocel K100LV 125.0
Povidone K30 20.0
硬脂酸镁 3.0
54mg（+）-顺-3-（乙酰基氧基）-2，3-二氢-2-（4-甲氧基苯基）-5-〔2-（二甲基氨基）乙基〕萘并〔1，2-b〕-1，4-噻氮杂草-4（5H）-酮CR片剂的释放曲线表示在图6中。
实施例4
组份 mg/片剂
琥珀酸西苯唑啉 232.2
Methocel K100LK 200.0
Povidone K30 50.0
硬脂酸 5.0
Syloid 244 5.0
硬脂酸镁 10.0
琥珀酸西苯唑啉（R片剂的释放曲线表示在图7中。
实施例5
组份 mg/片剂
马来酸氯代苯丙胺 54
无水乳糖 200
Methocel L100LV 125
Povidone K30 20
硬脂酸镁 6
马来酸氯代苯丙胺片剂的释放曲线表示在图8中。
实施例6
组份 mg/片剂
(E)-4-[[3-[2-(4-环丁基
-2-噻唑基)乙烯基]苯基]氨基]
-2,2-二乙基-4-氧代丁酸) 300.0
Methocel K100LK 52.9
片剂的释放曲线表示在图9中。
实施例7
组份 mg/片剂
(E)-4-[[3-[2-(4-环丁基
-2-噻唑基)乙烯基]苯基]氨基]
-2,2-二乙基-4-氧代丁酸) 300
Klucel LF 18
Methocel K100LV 60
无水乳糖 216
硬脂酸镁 6
片剂的释放曲线表示在图10中
实施例8
组份 mg/片剂
(E)-4-[[3-[2-(4-环丁基
-2-噻唑基)乙烯基]苯基]氨基]
-2,2-二乙基-4-氧代丁酸) 300
Klucel LF 18
Methocel K100LV 30
无水乳糖 246
硬脂酸镁 6
片剂的释放曲线表示在图11中
实施例9
组份 mg/片剂
(E)-4-[[3-[2-(4-环丁基
-2-噻唑基)乙烯基]苯基]氨基]
-2,2-二乙基-4-氧代丁酸) 300
Methocel K100LV 90
Klucel LF 18
无水乳糖 186
硬脂酸镁 6
片剂的释放曲线表示在图12中
实施例10
组份 mg/片剂
4-(2,2-二苯基乙烯基)-1-
(1-氧代-9-(3-吡啶基)壬基]
哌啶,微粒 300
Klucel LF 18
无水乳糖 150
Methocel K100LK 126
硬脂酸镁 6
片剂的侵蚀曲线表示在图13中
实施例11
组份 mg/片剂
7-氯-N-甲基-5-(1H-吡咯-2-
基)-3H-1,4-苯并二氮杂
-2-胺,
微粉 300
Klucel LF 18
无水乳糖 150
Methocel K100LK 126
硬脂酸镁 6
片剂的侵蚀曲线表示在图14中
实施例12
组份 mg/片剂
5-(3-[4-(2-氯代苯基)-9-甲基-6H
-噻吩并["3,2-f)[1,2,4]三唑并
[4,3-a][1,4]二氮杂
-2-基]
-2-丙炔基]菲啶-6(5H)-酮,
-微粒 75
Klucel LF 9
无水乳糖 113
Methocel K100LV 100
硬脂酸镁 3
片剂的侵蚀曲线表示在图15中
实施例13
组份 mg/片剂
Flumazenil 100
Methocel K100LV 250
无水乳糖 60
Povidone K30 36
硬脂酸镁 4
片剂的侵蚀曲线表示在图16中
图1示意描述本发明药物组合物的剂型。
图2表示实施例1的药物组合物的释放曲线，用转篮法以100rpm速度于37℃在900mL1%Emulphor ON-870的磷酸盐缓冲液（pH7.5）中进行。
图3表示使用浆法以50rpm的速度在900mL1% Emulphor ON-870的磷酸盐缓冲液（pH7.5）中于37℃下进行的实施例1的药物组合物的释放曲线。
图4表示于37℃在900ml1%Emulphor ON-870的磷酸盐缓冲液（pH7.5）中用转篮法以100rpm进行的实施例1药物组合物的释放和侵蚀曲线。
图5表示于37℃在900ml1%Emulphor ON-870的磷酸盐缓冲溶液（pH7.5）中用浆法经50rpm的速度进行的实施例2药物组合物的释放曲线。
图6表示于37℃在900ml模拟胃液中用浆法以50rpm的速度进行的实施例3药物组合物的释放曲线。
图7表示于37℃在900ml水中转篮法以100rpm的速度进行的实施例4药物组合物的释放曲线。
图8表示于37℃在900ml水中转篮法以100rpm的速度进行的实施例5药物组合物的释放曲线。
图9表示于37℃在900ml含3%十二烷基硫酸钠的水（pH9.0）用转篮法以100rpm的速度进行的实施例6药物组合物的释放曲线。
图10表示于37℃在900ml含3%十二烷基硫酸钠的水（pH9.0）中用转篮法以100rpm的速度进行的实施例7药物组合物的释放曲线。
图11表示于37℃在900ml含3%十二烷基硫酸钠的水（pH9.0）中用转篮法以100rpm的速度进行的实施例8药物组合物的释放曲线。
图12表示于37℃在900ml含3%十二烷基硫酸钠的水（pH9.0）中用转篮法以100rpm的速度进行的实施例9药物组合物的释放曲线。
图13表示于37℃在900ml含3%十二烷基硫酸钠的水（pH9.0）中用转篮法以100rpm的速度进行的实施例10药物组合物的释放曲线。
图14表示于37℃在900ml水中用转篮法以100rpm的速度进行的实施例11药物组合物的侵蚀曲线。
图15表示于37℃在900ml水中用转篮法以100rpm的速度进行的实施例12药物组合物的侵蚀曲线。
图16表示于37℃在900ml磷酸盐缓冲液（pH7.4）中用转篮法以100rpm的速度进行的实施例13药物组合物的侵蚀曲线。
Claims (8)
1、一种易受侵蚀的药物组合物，整形和压制成固体剂型，它提供治疗活性物质的零级控制释放，该组合物包括于25℃在水中溶解度不大于80mg/ml的约5%到60%w/w的治疗活性物质和约5%到约50%w/w的低粘度羟丙基甲基纤维素和由惰性载体组成的组合物的其它物质。
2、权利要求1的易受侵蚀的药物组合物，其中羟丙基甲基纤维素中甲氧基含量约为19-30%，羟丙基含量为7-12%，甲氧基取代度为1.1到2.0，分子量约为20，000到26，000道尔顿且聚合物的2%w/w溶液于25℃粘度在50到100cps范围内。
3、权利要求1的易受侵蚀的药物组合物，其中羟丙基甲基纤维素在基质中的存在量为10%到25%。
4、权利要求1的易受侵蚀的药物组合物，其中另外存在约10%到约60%w/w的侵蚀改良剂。
5、权利要求1到4中任一个易受侵蚀的药物组合物，其中侵蚀改良剂为乳糖。
6、权利要求1到4中任一个的易受侵蚀的药物组合物，其中侵蚀改良剂为非离子表面活性剂。
7、权利要求1到4中任一个的易受侵蚀的药物组合物，其中治疗活性物质为（E）-4-〔〔3-〔2-（4-环丁基-2-噻唑基）乙烯基〕苯基〕-2，2-二乙基-4-氧代丁酸。
8、权利要求1到4中任一个的易受侵蚀的药物组合物，其中治疗活性物质为Flumazenil。
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-
1993
- 1993-12-13 US US08/166,123 patent/US5393765A/en not_active Expired - Fee Related
-
1994
- 1994-11-17 TW TW083110673A patent/TW438597B/zh not_active IP Right Cessation
- 1994-11-18 CA CA002136118A patent/CA2136118A1/en not_active Abandoned
- 1994-12-05 DE DE69430237T patent/DE69430237T2/de not_active Expired - Fee Related
- 1994-12-05 AT AT94119113T patent/ATE214919T1/de not_active IP Right Cessation
- 1994-12-05 NZ NZ270058A patent/NZ270058A/xx unknown
- 1994-12-05 EP EP94119113A patent/EP0662322B1/en not_active Expired - Lifetime
- 1994-12-05 ES ES94119113T patent/ES2171431T3/es not_active Expired - Lifetime
- 1994-12-06 AU AU80232/94A patent/AU688807B2/en not_active Ceased
- 1994-12-06 ZA ZA949711A patent/ZA949711B/xx unknown
- 1994-12-07 IL IL11192094A patent/IL111920A/xx not_active IP Right Cessation
- 1994-12-07 HU HU9403496A patent/HU219227B/hu not_active IP Right Cessation
- 1994-12-08 JP JP6330524A patent/JP2966745B2/ja not_active Expired - Fee Related
- 1994-12-12 CO CO94056072A patent/CO4340618A1/es unknown
- 1994-12-12 PL PL94306245A patent/PL306245A1/xx unknown
- 1994-12-12 CZ CZ19943127A patent/CZ287718B6/cs not_active IP Right Cessation
- 1994-12-12 BR BR9404953A patent/BR9404953A/pt not_active Application Discontinuation
- 1994-12-12 CN CN94119315A patent/CN1110135A/zh active Pending
- 1994-12-12 KR KR1019940033656A patent/KR950016783A/ko active IP Right Grant
- 1994-12-12 UA UA94129170A patent/UA41887C2/uk unknown
- 1994-12-12 NO NO944803A patent/NO944803L/no not_active Application Discontinuation
- 1994-12-13 RU RU94043809/14A patent/RU2174832C2/ru not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100408044C (zh) * | 1997-04-11 | 2008-08-06 | 艾博特公司 | 红霉素衍生物的缓释制剂 |
Also Published As
| Publication number | Publication date |
|---|---|
| TW438597B (en) | 2001-06-07 |
| DE69430237T2 (de) | 2002-07-18 |
| EP0662322A3 (en) | 1997-01-29 |
| PL306245A1 (en) | 1995-06-26 |
| ES2171431T3 (es) | 2002-09-16 |
| IL111920A (en) | 1999-08-17 |
| NO944803L (no) | 1995-06-14 |
| NZ270058A (en) | 1996-07-26 |
| DE69430237D1 (de) | 2002-05-02 |
| HU219227B (en) | 2001-03-28 |
| JP2966745B2 (ja) | 1999-10-25 |
| IL111920A0 (en) | 1995-03-15 |
| ATE214919T1 (de) | 2002-04-15 |
| RU94043809A (ru) | 1996-11-10 |
| JPH07196535A (ja) | 1995-08-01 |
| AU688807B2 (en) | 1998-03-19 |
| US5393765A (en) | 1995-02-28 |
| KR950016783A (ko) | 1995-07-20 |
| ZA949711B (en) | 1995-08-21 |
| HUT75456A (en) | 1997-05-28 |
| CO4340618A1 (es) | 1996-07-30 |
| CA2136118A1 (en) | 1995-06-14 |
| HU9403496D0 (en) | 1995-02-28 |
| CZ287718B6 (en) | 2001-01-17 |
| CZ312794A3 (en) | 1995-09-13 |
| EP0662322B1 (en) | 2002-03-27 |
| UA41887C2 (uk) | 2001-10-15 |
| EP0662322A2 (en) | 1995-07-12 |
| RU2174832C2 (ru) | 2001-10-20 |
| NO944803D0 (no) | 1994-12-12 |
| AU8023294A (en) | 1995-06-22 |
| BR9404953A (pt) | 1995-08-08 |
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