CN1262627A - 新型组合物 - Google Patents
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- CN1262627A CN1262627A CN98806975A CN98806975A CN1262627A CN 1262627 A CN1262627 A CN 1262627A CN 98806975 A CN98806975 A CN 98806975A CN 98806975 A CN98806975 A CN 98806975A CN 1262627 A CN1262627 A CN 1262627A
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Abstract
一种含有速释形式SSRI和缓释形式β－阻滞剂的药物组合物。
Description
本发明涉及一类选择性5-羟色胺重吸收抑制剂(SSRI)的新型制剂。具体地说，本发明提供了一类提高SSRI的治疗活性，尤其是改善治疗起效作用的制剂。
Artigas等(Arch.Gen Psychiatry，Vol.51，pp 248-251，Mar.1994)曾报道，对于先前使用帕罗西汀治疗无效的病人在用SSRI帕罗西汀(20mg，每日一次)治疗期间，给予吲哚洛尔(2.5mg，每日三次)缓解了患者的抑郁症状。
随后，EP-A-0714663认为SSRI西酞普兰、三氟戊肟胺和帕罗西汀的作用可通过联合施用某些药物，特别是吲哚洛尔、喷布洛文、普萘洛文、特他洛文和其它已知为5-羟色胺IA受体拮抗剂的化合物组合得到增强，但没有包括帕罗西汀-吲哚洛尔的组合。
所有联合用药方案的一个问题是确保患者的顺应性，尤其是在例如Artigas所建议的方案中，它包括每日要给药三次(设想帕罗西汀与第一次吲哚洛尔同时服用)。
本发明的目的在于克服与联合使用SSRI和增强化合物有关的问题。
从广义上说，本发明提供一种含速释形式SSRI和缓释形式β-阻滞剂的SSRI组合物。该组合物可方便地呈片剂或胶囊形式。
本发明中使用的代表性SSRI是帕罗西汀、三氟戊肟胺、西酞普兰和舍曲林。优选SRRI是帕罗西汀。联合使用的β-阻滞剂优选是吲哚洛尔。
SSRI和β-阻滞剂的优选组合是帕罗西汀和吲哚洛尔。片剂和胶囊优选含有20mg速释形式帕罗西汀和7.5mg缓释形式吲哚洛尔。
典型缓释形式的β-阻滞剂可提供相当于每日三次给药持续12-16小时的释放。或者，该药物可在三次间隔期释放。
当SSRI与β-阻滞剂的持续释放制剂合用时，本发明的组合物优选呈双层片剂形式，其中一层含SSRI的常规快速释放制剂，另一层含β-阻滞剂的缓释制剂。
可通过将β-阻滞剂与不与β-阻滞剂或SSRI相互作用的任何常规的缓释赋形剂或赋形剂混合物共同配制来提供缓释。
适宜地，是通过将β-阻滞剂掺入在胃酸中溶胀的赋形剂中，典型地是当片剂通过患者肠道时形成凝胶，凝胶溶解和/或被磨蚀，释放出活性成分，从而提供缓释。按常规方式可通过改变赋形剂的分子量和/或共同配制主要赋形剂与以不同于主要赋形剂的速率溶解或崩解的材料，以使在溶胀或胶凝化的主要赋形剂中形成微孔从而可控制释放速率。
适合的主要赋形剂选自可溶胀的粘合剂，例如甲基纤维素(如在Methocel K4M和E5商品名下销售的)、乙基纤维素、聚丙烯酸(如在Carbopol 974P商品名下销售的)、聚丙烯酸酯(例如在Eudragit L30D和RS30D下销售的)、黄原胶和淀粉。
主要赋形剂的释放曲线可通过掺入填充剂和崩解剂改变，它们是例如乳糖，尤其是乳糖一水合物、微晶纤维素(例如在Avicel pH102商品名下销售的)、硫酸钙、硫酸二钙(例如在Encompress商品名下销售的)、聚乙烯吡咯烷酮(例如在Povidone 30商品名下销售的)、氢化植物油(例如在Lubritab商品名下销售的)。
为了有助于片剂制造，还可能包括常规的片剂赋形剂，例如冲模润滑剂，如硬脂酸镁、榆树酸甘油酯(例如在Compritol 888商品名下销售的)等。
或者，组合物可以包含包衣的β-阻滞剂小丸的胶囊形式，该包衣小丸是具有不同溶解时间的包衣小丸混合物，它们分散在SSRI的粉末制剂中，包衣小丸和粉末制剂均被包装在可溶性胶囊中。
例如，适合的β-阻滞剂小丸包衣材料是耐胃酸，但溶于肠道的材料。可通过改变包衣层的厚度来改变溶解时间。包衣小丸优选是混合的，以提供基本上持续释放的吲哚洛尔，但如果需要，小丸也可以是三种包衣厚度的混合小丸，以致吲哚洛尔可以在例如12-14小时所需的给药时间内，分三个时期释放。SSRI的粉末制剂可通过将SSRI与常规赋形剂混合制备。含有活性成分混合物的可溶性胶囊可由明胶按常规制备。
可在本发明中使用的上述亲水性基质型和肠溶包衣型的代表性缓释制剂，在有关的权威性教科书中均有描述。
我们发现，当这种缓释的β-阻滞剂制剂具有如下的释放分布状态时，可以获得适用于临床使用的释放曲线：在体外酸/缓冲液中测定，具有溶解时间T50％为1.73小时、T90％为8.45小时以及T100％为14小时。
因此，本发明的一个优选实施方案是提供一种SSRI和β-阻滞剂制剂，其中的β-阻滞剂是缓释形式的，其体外释放分布T50％为1.73小时±20％，T90％为8.45小时±20％以及T100％为14小时±20％。
SSRI优选是盐酸帕罗西汀，其最优选的剂量为20mg，β-阻滞剂优选是吲哚洛尔，其最优选的剂量为7.5mg。
一般使用的吲哚洛尔是市售的外消旋体。但是，也可使用其活性异构体，其剂量应调整至与其一规定剂量的外消旋体的生物等效。
本发明的组合物，尤其是盐酸帕罗西汀与吲哚洛尔的组合物的治疗用途包括治疗酒精中毒、焦虑、抑郁、强迫观念性疾病(OCD)、恐慌、慢性疼痛、肥胖、老年性痴呆、偏头痛、食欲过盛、食欲缺乏、社会恐怖症、经前期综合征(PMS)、青春期抑郁、拔毛发癖、心理沮丧和滥用药物毒物(本文中统称为“疾病”)。
因此，本发明还提供
将SSRI和缓释形式的β-阻滞剂用来制备片剂或胶囊剂，用于对人和动物治疗和预防这些疾病，
一种用于治疗或预防这些疾病的方法，包括对需此治疗的人或动物给予含SSRI和缓释形式的β-阻滞剂的片剂或胶囊。
在本发明的用途和方法中，片剂或胶囊是优选的本发明组合物，它们具有如上所示的优选的用途。
本发明通过下列实施例加以说明：
实施例1
按如下制备帕罗西汀和缓释吲哚洛尔的双层片剂。
吲哚洛尔成分
通过对如下混合物采用高剪切湿制粒法，制备了缓释形式的吲哚洛尔，它是基于同可溶性填充剂/崩解剂的亲水性混合，以便在水合时增加基质的多孔性：
吲哚洛尔碱 7.5重量份
甲基纤维素(Methocel K4M) 35重量份
乳糖一水合物 25重量份
微晶纤维素(Acicel pH102) 32重量份
干燥过筛后，将0.5重量份的榆树酸甘油酯(Compritol 888)作为润滑剂，通过滚动混合掺入。
帕罗西汀成分
将20重量份的盐酸帕罗西汀和80重量份的常规赋形剂混合，制备速释形式的帕罗西汀。
制片
在第一个装料台，将100mg缓释吲哚洛尔制剂装入旋转制片机压盘的片模中。经过预轻压固定片模中的粉末制剂后，将压盘送入第二装料台，在此将152mg帕罗西汀制剂加到缓释制剂的表面。然后将片模中的两层混合物给予足够的压力，制备出在缓释基质中含20mg盐酸帕罗西汀和7.5mg吲哚洛尔的252mg片剂，每种活性成分是位于两层片剂的不同层中。
Claims (13)
1、一种药物组合物，含有速释形式的SSRI和缓释形式的β-阻滞剂。
2、权利要求1的药物组合物，它采取双层片剂形式，其中的一层含有SSRI的速释制剂，另一层含有β-阻滞剂的缓释制剂。
3、权利要求1的药物组合物，它采取胶囊形式，其中含有SSRI速释制剂和β-阻滞剂缓解制剂的混合物。
4、权利要求1～3任一项的药物组合物，其中β-阻滞剂是缓释形式，具有在体外的释放分布T50％为1.73小时±20％，T90％为8.45小时±20％以及T100％为14小时±20％。
5、权利要求1～4任一项的药物组合物，其中的SSRI是帕罗西汀或其可药用衍生物。
6、权利要求5的药物组合物，其中的帕罗西汀是盐酸盐的形式。
7、权利要求1～6任一项的药物组合物，其中的β-阻滞剂是吲哚洛尔。
8、权利要求7的药物组合物，其中的吲哚洛尔是外消旋体形式。
9、权利要求8的药物组合物，其中含有20mg盐酸帕罗西汀和7.5mg吲哚洛尔外消旋体。
10、权利要求7的药物组合物，其中吲哚洛尔是以活性异构体的形式存在。
11、一种治疗疾病的方法，包括对需此治疗的患者施用有效量或预防量的根据权利要求1～10任一项所定义的药物组合物，所述疾病是酒精中毒、焦虑、抑郁、强迫观念性疾病(OCD)、恐慌、慢性疼痛、肥胖、老年性痴呆、偏头痛、食欲过盛、食欲缺乏、社会恐怖症、经前期综合征(PMS)、青春期抑郁、拔毛发癖、心理沮丧和滥用药物毒物。
12、权利要求1～10定义的药物组合物在制备用于治疗或预防下述疾病的药物中的应用，所述疾病为酒精中毒、焦虑、抑郁、强迫观念性疾病(OCD)、恐慌、慢性疼痛、肥胖、老年性痴呆、偏头痛、食欲过盛、食欲缺乏、社会恐怖症、经前期综合征(PMS)、青春期抑郁、拔毛发癖、心理沮丧和滥用药物毒物。
13、权利要求1～10定义的药物组合物，用于治疗或预防酒精中毒、焦虑、抑郁、强迫观念性疾病(OCD)、恐慌、慢性疼痛、肥胖、老年性痴呆、偏头痛、食欲过盛、食欲缺乏、社会恐怖症、经前期综合征(PMS)、青春期抑郁、拔毛发癖、心理沮丧和滥用药物毒物。
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| NZ511442A (en) | 1998-11-02 | 2003-02-28 | Elan Corp Plc | Multiparticulate modified release composition for multiple dosing of ADD patients with methylphenidate HCl |
| US10179130B2 (en) | 1999-10-29 | 2019-01-15 | Purdue Pharma L.P. | Controlled release hydrocodone formulations |
| ATE526950T1 (de) | 1999-10-29 | 2011-10-15 | Euro Celtique Sa | Hydrocodon-formulierungen mit gesteuerter freisetzung |
| GB0004003D0 (en) * | 2000-02-22 | 2000-04-12 | Knoll Ag | Therapeutic agents |
| EP2263658A1 (en) | 2000-10-30 | 2010-12-22 | Euro-Celtique S.A. | Controlled release hydrocodone formulations |
| EP1793818A2 (en) * | 2004-09-17 | 2007-06-13 | Neurocure Ltd. | Pindolol for treating premenstrual syndrome and premenstrual dysphoric disorder |
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| CA2134038C (en) * | 1994-06-16 | 1997-06-03 | David Taiwai Wong | Potentiation of drug response |
| EP0714663A3 (en) * | 1994-11-28 | 1997-01-15 | Lilly Co Eli | Potentiation of drug responses by serotonin 1A receptor antagonists |
| ES2145977T3 (es) * | 1995-08-16 | 2000-07-16 | Lilly Co Eli | Potenciacion de la respuesta de la serotonina. |
| EP0792649A1 (en) * | 1996-02-29 | 1997-09-03 | Eli Lilly And Company | Treatment of sleep disorders |
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| Publication number | Publication date |
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| GB9714675D0 (en) | 1997-09-17 |
| NO20000107L (no) | 2000-01-10 |
| JP2002508003A (ja) | 2002-03-12 |
| CA2295822A1 (en) | 1999-01-21 |
| OA11276A (en) | 2003-07-31 |
| AU9340198A (en) | 1999-02-08 |
| WO1999002142A2 (en) | 1999-01-21 |
| ID24191A (id) | 2000-07-13 |
| CO4950552A1 (es) | 2000-09-01 |
| HUP0003074A2 (hu) | 2001-01-29 |
| IL133869A0 (en) | 2001-04-30 |
| MA24604A1 (fr) | 1999-04-01 |
| WO1999002142A3 (en) | 1999-04-15 |
| HUP0003074A3 (en) | 2001-12-28 |
| BR9810996A (pt) | 2000-08-08 |
| AR016128A1 (es) | 2001-06-20 |
| PE99699A1 (es) | 1999-12-21 |
| KR20010021644A (ko) | 2001-03-15 |
| NO20000107D0 (no) | 2000-01-10 |
| DZ2556A1 (fr) | 2003-02-15 |
| AP2000001728A0 (en) | 2000-03-31 |
| EA200000112A1 (ru) | 2000-10-30 |
| BG104119A (en) | 2000-12-29 |
| PL338017A1 (en) | 2000-09-25 |
| SK72000A3 (en) | 2000-12-11 |
| ZA986138B (en) | 2000-01-10 |
| TR200000074T2 (tr) | 2000-05-22 |
| EP0996466A2 (en) | 2000-05-03 |
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