CN1290506C - 药物组合物 - Google Patents
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Abstract
一种含有N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒，以及硫代丁基醚β-环糊精或其盐两者中任一项的药物组合物。硫代丁基醚β-环糊精可增加N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒的溶解度。因此，该药物组合物可在长期稳定性以及热和光照稳定性上得到改善。
Description
技术领域
本发明涉及一种含有以高浓度溶解的N-(3-氯-4吗啉-4基)苯基-N′-羟基亚氨甲脒的药物组合物，该组合物具有改进了的药物稳定性以及恒定的品质。
背景技术
N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒是公开于WO01/32164的一种化合物，并被认为能够选择性地抑制20-HETE-生产酶以控制肾脏疾病、心血管疾病、脑血管疾病(特别是脑梗塞)。
公知的改善微溶于水的药物的水溶性以获得可注射的溶液等的方法有：使其成盐、胶束、助溶剂以及脂质乳液制剂，以及β-环糊精包合法。对于通过β-环糊精包合的微水溶性药物的增溶情况，WO85/02767公开了通过羟丙基β-环糊精包合的微水溶性药物的增溶情况，USP 5134127公开了通过硫代丁基醚β-环糊精包合的微水溶性药物的增溶情况。
然而，由于各种药物之间特性的差异，获得适宜的增溶方法是非常困难的。进而，即使可以增溶，在长时间的溶解度和安全性上也会产生各种问题。
尽管N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒优选通过静脉途径给药，然而它在水中的溶解度非常低，而由于其在酸性溶液中不稳定的特性，它也不适于制成酸式盐的形式增溶，而且在溶液状态将其暴露在光线下也是不稳定的。因此，需要某些特殊的方法以制备诸如注射溶液之类的药物组合物。此外，对于脑梗塞的预防性疗法，由于需要考虑到延长的静脉输注，因此有必要在药物制剂的生产操作中考虑到生物体的安全性。
发明公开
本发明的目的是提供一种含有以高浓度溶解的N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒的药物组合物。该药物组合物不仅具有优良的经时、热及光照稳定性，而且对于生物体是安全的。
由于为了实现上述目的的重复试验的结果，本发明发明人发现，通过向N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒加入硫代丁基醚β-环糊精或其盐，可以得到含有以高浓度溶解的该药物的制剂，并且在热及光暴露下具有改进的稳定性同时不会在给药时对生物体造成伤害。本发明以此发现为基础而完成。本发明涉及一种含有药学有效量的N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒和硫代丁基醚β-环糊精或其盐的药物组合物。在本发明的药物组合物之中，其进一步的经时稳定性可以通过将其制成冻干制剂来保证。
发明的最佳实施方式
本发明在下文中进行更为详细的描述。
本发明涉及一种含有药学有效量的N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒，以及硫代丁基醚β-环糊精或其盐的药物组合物。
在本发明之中，N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒可以通过，例如，WO01/32164(化合物302)中所记载的方法合成，剂量则根据疾病和给药形式的不同而不同，其通常剂量为0.1-3000mg每天，优选1-300mg每天。
硫代丁基醚β-环糊精或其盐可作为商业产品得到(例如，CyDex.Inc.制造的Captisol)，或者根据USP 5134127所述的方法，可以通过将硫代丁基基团引入到β-环糊精的OH基团上合成。单个β-环糊精分子的OH上取代的硫代丁基基团的数量称为“取代度”。所有β-环糊精分子取代度的平均值称为“平均取代度”。平均取代度优选为约5-8，更优选的约为6-7，最优选约为7。硫代丁基醚β-环糊精的优选的盐是药学可接受的盐，诸如碱金属盐。特别优选的是钠盐。
每摩尔N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒中通常含有1.18-35.45摩尔，优选5.91-17.7摩尔的硫代丁基醚β-环糊精或其盐。
例如，以一份N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒重量计，通常含有10-300重量份，优选50-150重量份的Captisol。
此外，如有需要，还可含有药物可接受的载体或其它添加剂诸如等渗剂(例如，甘油或葡萄糖)以及pH调节剂。
本发明药物组合物可以配制成各种药物形式诸如注射溶液、冻干可注射制剂、片剂、颗粒、粉末、胶囊、内用溶液或干糖浆。特别地，优选可注射溶液和冻干可注射溶液。这些可注射溶液以及冻干可注射制剂可以单次给药或者通过静脉输注给药。
本发明药物组合物可以通过常规制备方法配制。例如，制备可注射溶液的通常方法，包括将N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒、硫代丁基醚β-环糊精或其盐、注射用水搅拌混合并溶解该混合物。特别地，有一种方法包括将注射用水加入到N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒、硫代丁基醚β-环糊精或其盐的粉末之中，并溶解该混合物；还有一种方法包括先将硫代丁基醚β-环糊精或其盐溶解于注射用水中，再向所得溶液中加入N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒，并溶解该混合物。搅拌通常是通过搅拌器来实施，然而，为了诸如缩短溶解时间等目的，也可以使用具有剪切力或研磨力的乳化器或匀化器。
常规的高压蒸汽灭菌法和过滤除菌法是可注射溶液制备中的灭菌方法，然而，在本发明的药物组合物的情况下，高压蒸汽灭菌法有降低药物含量的可能，因此优选的是过滤除菌法。通常，过滤除菌可以通过使用孔径约为0.2μm的滤器实施。除了诸如吸附等问题之外，滤器的材料没有特别的限制。
为了制备冷冻干燥可注射制剂，可以使用普通的冷冻干燥器。进而，为了防止药物分解，不管组合物的溶液状况或冷冻状况如何，可以优选将小瓶或安瓿的顶端空间用氮气替代。
正如随后的试验实施例中所显示的，本发明的药物组合物可含有以非常高的浓度溶解的N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒。也就是说，在硫代丁基醚β-环糊精钠盐的10w/v％的水溶液的情况下，N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒在硫代丁基醚β-环糊精或其盐水溶液中的溶解度为25℃下3.57mg/mL；而在20w/v％水溶液的情况下，该药物的溶解度为25℃下7.67mg/mL。相反，上述药物在用于将其制备成胶束、共溶剂及脂质乳胶制剂的5％Tween 80、10％聚乙二醇、大豆油和橄榄油的之中的溶解度不高于25℃下0.5mg/mL。由此，本发明药物组合物与常规制剂相比，可含有以显著更高的浓度溶解的上述药物。
进而，在硫代丁基醚β-环糊精溶液中，N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒在热和光照下也是非常稳定的，因此，其便于实际的应用。
本发明将通过以下实施例和试验实施例进行更为详细的阐述，这些实施例并非用于限制本发明的范围。根据这些详细的描述，各种改变和修饰对于本领域技术人员来说都是显而易见的，而所述改变和修饰仍然属于本发明范围之内。
实施例
实施例1
称取N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒(1g)和硫代丁基醚β-环糊精钠盐(Captisol；平均取代度约为7)(110g)，加入注射用蒸馏水(1L)；通过搅拌器分散后，使用匀化器溶解混合物。然后，使用滤器(孔径0.22μm)过滤对溶液除菌。将溶液(10mL)填充入20mL的琥珀色小瓶中。每一小瓶顶端空间用氮气替代；封堵小瓶得到含1mg/mL药物的可注射溶液。
实施例2
称取N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒(1g)和硫代丁基醚β-环糊精钠盐(Captisol；平均取代度约为7)(110g)，加入注射用蒸馏水(1L)；通过搅拌器分散之后，使用匀化器将混合物溶解。然后，使用滤器(孔径0.22μl)对溶液过滤除菌。溶液(10mL)填充入20mL-琥珀色小瓶中，进行冷冻干燥，冷冻架温度设为-10℃。每一小瓶的顶端用氮气代替；将小瓶封堵，得到每瓶含10mg药物的冻干可注射制剂。
对比实施例1
按照实施例1的相同方法得到N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒的饱和水溶液，除了没有使用硫代丁基醚β-环糊精钠盐。
对比实施例2
按照实施例2的相同的方法得到N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒的冻干可注射溶液，除了用等渗剂100g羟丙基β-环糊精和30g右旋甘露糖醇替代110g硫代丁基醚β-环糊精钠盐。
测试实施例1[增溶测试]
将过量N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒分别加入到10w/v％和20w/v％硫代丁基醚β-环糊精钠盐(Captisol；平均取代度约为7)的水溶液以及作为空白对照的纯净水之中。在调节到25℃的水浴中摇晃一天，测定药物的溶解度。
结果是，N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒在纯净水中的空白对照溶解度为0.08mg/mL，并发现在向溶液加入了硫代丁基醚β-环糊精钠盐后，溶解度增加，结果示于表1之中。。
相应地，结果显示了硫代丁基醚β-环糊精可用于溶解N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒。
表1
| 硫代丁基醚β-环糊精的浓度 | 溶解度 |
| 10w/v％20w/v％ | 3.57mg/mL7.67mg/mL |
测试实施例2[光稳定性测试]
实施例1的溶液和对比实施例1的溶液分别置于无色透明的有盖玻璃管之中，并在3000lux的荧光条件下保存，测定N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒的剩余率。结果是，如表2所示，在实施例1的溶液中的N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒比在对比实施例1的溶液中更稳定。相应地，结果显示，硫代丁基醚β-环糊精非常有用于使N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒稳定。
表2
| 实施例1 | 对比实施例1 | |
| 保存时间(hrs)剩余率％ | 4897.8 | 2438.7 |
测试实施例3[冻干可注射制剂的稳定性测试]
将实施例2的冻干可注射制剂和比较实施例2的冻干可注射制剂在60℃下保存7天之后，测定其药物的剩余率。
结果如表3所示，在实施例2的冻干可注射制剂中的N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒比在对比实施例2的冻干可注射剂中的要稳定得多。相应地，结果显示硫代丁基醚β-环糊精很有效地使N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒稳定。作为结果，本发明的药物组合物的冻干可注射制剂被证明在实际保存和使用中具有杰出的热稳定性和良好的便利度。
表3
| 实施例2 | 对比实施例2 | |
| 保存时间(天) | 7 | 7 |
| 剩余率(％) | 99.4 | 97.8 |
工业实用性
由于本发明药物组合物可含有以高浓度溶解的N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒，并可使药物在一段时间内和在热和光暴露下保持稳定，因此该药物对于实际应用是十分便利的。
Claims (3)
1.一种药物组合物，含有N-(3-氯-4-吗啉-4-基)苯基-N′-羟基亚氨甲脒和硫代丁基醚β-环糊精或其盐。
2.权利要求1的药物组合物，它是冷冻干燥的。
3.权利要求1或2的药物组合物，它是可注射溶液。
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| JP154624/2002 | 2002-05-28 | ||
| JP2002154624 | 2002-05-28 |
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| US (1) | US6818662B2 (zh) |
| EP (1) | EP1508332A4 (zh) |
| JP (1) | JP4475405B2 (zh) |
| CN (1) | CN1290506C (zh) |
| AU (1) | AU2003241800B2 (zh) |
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| JP2008230968A (ja) * | 2005-06-30 | 2008-10-02 | Taisho Pharmaceutical Co Ltd | 脳梗塞治療用の医薬 |
| US7744904B1 (en) * | 2005-09-26 | 2010-06-29 | B.B. Scientific L.L.C. | Stabilization of Clostridium botulinum neurotoxin complex |
| WO2008034011A2 (en) | 2006-09-13 | 2008-03-20 | Mcw Research Foundation, Inc. | Methods of modulating cell proliferation and cyst formation in polycystic kidney and liver diseases |
| BRPI0916689A2 (pt) | 2008-07-28 | 2015-11-17 | Takeda Pharmaceutical | composição farmacêutica estabilizada, preparação sólida, e, métodos para estabilizar uma composição farmacêutica, e para estabilizar uma preparação sólida. |
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| US3502720A (en) * | 1963-12-20 | 1970-03-24 | Schering Ag | N-(2-methyl-4-chlorophenyl)-formamidines |
| US4237168A (en) * | 1979-06-11 | 1980-12-02 | The Dow Chemical Company | N-(4-Chloro-2-methylphenyl)-N-hydroxy methanimidamide and its pesticidal use |
| DE3346123A1 (de) | 1983-12-21 | 1985-06-27 | Janssen Pharmaceutica, N.V., Beerse | Pharmazeutische praeparate von in wasser schwerloeslichen oder instabilen arzneistoffen und verfahren zu ihrer herstellung |
| US5376645A (en) | 1990-01-23 | 1994-12-27 | University Of Kansas | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof |
| KR0166088B1 (ko) * | 1990-01-23 | 1999-01-15 | . | 수용해도가 증가된 시클로덱스트린 유도체 및 이의 용도 |
| JPH092977A (ja) | 1995-06-21 | 1997-01-07 | Dai Ichi Seiyaku Co Ltd | 経口投与用医薬組成物 |
| US6395781B1 (en) * | 1998-02-26 | 2002-05-28 | Mcw Research Foundation | 20-HETE antagonists and agonists |
| US6864254B1 (en) | 1999-11-01 | 2005-03-08 | Taisho Pharmaceutical Co., Ltd. | Inhibitor for 20-hete-yielding enzyme |
| US7214714B2 (en) | 2001-04-26 | 2007-05-08 | Taisho Pharmaceutical Co. Ltd. | 20-hydroxyeicosatetraenoic acid production inhibitors |
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| AU2003241800B2 (en) | 2007-04-19 |
| EP1508332A1 (en) | 2005-02-23 |
| JPWO2003099288A1 (ja) | 2005-09-22 |
| US6818662B2 (en) | 2004-11-16 |
| JP4475405B2 (ja) | 2010-06-09 |
| CA2486571A1 (en) | 2003-12-04 |
| CA2486571C (en) | 2010-04-27 |
| HK1081451A1 (en) | 2006-05-19 |
| RU2313346C2 (ru) | 2007-12-27 |
| EP1508332A4 (en) | 2010-01-13 |
| WO2003099288A1 (fr) | 2003-12-04 |
| MXPA04011777A (es) | 2005-03-31 |
| US20030225032A1 (en) | 2003-12-04 |
| AU2003241800A1 (en) | 2003-12-12 |
| CN1655790A (zh) | 2005-08-17 |
| RU2004138299A (ru) | 2005-06-10 |
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