CN100333723C - 用于治疗帕金森病的罗替伐汀离子电渗给药 - Google Patents
用于治疗帕金森病的罗替伐汀离子电渗给药 Download PDFInfo
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Abstract
通过使用位于离子电渗装置中的组合物来治疗帕金森病，其中组合物包含含有罗替伐汀和至少一种浓度为1到140mmol/l的盐酸盐的组合物，组合物的pH为4到6.5，这能获得比以往从常规被动扩散系统中穿过人角质层得到的罗替伐汀流量更高的流量。
Description
技术领域
本发明涉及一种用于治疗或减轻帕金森病症状的有效方法，其使用了多巴胺受体激动剂罗替伐汀(INN)的离子电渗给药。
背景技术
帕金森病被认为主要是由黑质的多巴胺能神经元衰退引起的。实际上，这致使在尾状核中丧失了强直性(tonic)多巴胺分泌和与多巴胺有关的神经活性的调节，因此在特定脑区域中就缺乏多巴胺。神经递质乙酰胆碱和多巴胺的进而失衡最终导致了与疾病相关的症状。虽然帕金森病通常被视为运动系统素乱，但是其现在被认为是包括运动和非运动系统在内的更复杂的紊乱。这种让人虚弱的疾病的特征是其主要临床特征包括震颤、运动徐缓、强直、运动障碍、步态障碍和语言障碍。在一些患者中，还伴有痴呆的症状。自主神经系统可以引起体位性低血压、突发性面红、与热调节有关的问题、便秘和丧失对膀胱和括约肌的控制。帕金森病也可以伴随出现心理上的紊乱例如丧失动力和抑郁。
帕金森病主要是中年人和中年以上人的疾病，它对男人和女人的影响是相同的。帕金森病的最高发生率出现在70岁以上年龄组中，其中这些人里有1.5到2.5％都患有帕金森病。发作的平均年龄在58到62岁之间，大多数患者都在50到79岁之间出现帕金森病。在美国约有800,000人有帕金森病。
帕金森病的早期运动缺陷能描述为黑质多巴胺一释放的细胞的最初退化。该神经元变性引起了连接黑质和纹状体的多巴胺能通路缺损。随着疾病的发展，可以逐步出现顽固性运动、自发和精神异常，这意味着纹状体受体机制进一步退化。
帕金森病的临床诊断根据的是特殊物理体征的存在。已知该疾病在临床表现上为逐渐发作、缓慢发展和反复无常。有证据表明在出现症状前的年龄匹配对照组，发现纹状体多巴胺的含量下降到了20％以下的水平。
已经尝试用尤其是L-多巴(左旋多巴)来治疗帕金森病，它还是治疗帕金森病的金本位(gold standard)。左旋多巳作为多巴胺的前体能通过血脑屏障，然后在脑内转化为多巴胺。L-多巴改善了帕金森病的症状但会引起严重的副作用。此外，该药物在治疗的头两到三年后往往会失去其有效性。五到六年后，只有25％到50％的患者保持改善。
此外，目前对帕金森病应用的治疗的主要缺点在于最终表现为“波动综合征”，这导致了“有或没有”(all-or-none)的状况，其特征是带有运动障碍的活动性“开”周期与带有运动减少或运动不能的“关”周期的交互出现。显示出对口服抗帕金森疗法的不可预知或游走的“开-关”现象的患者对i.v.给予L-多巴和其它多巴胺激动剂具有可预知的有益应答，这暗示血药浓度的波动是造成“开-关”现象的原因。“开-关”现象的频率也已经通过连续输注多巴胺受体激动剂阿朴吗啡和麦角乙脲得以改善。然而，这种给药方式是不方便的。因此，能提供更稳定血药水平的其它给药方式，例如局部给药是有益的，并且在以往也已经被建议。
如上所述，帕金森病的一个治疗方法包括多巴胺受体激动剂。多巴胺受体激动剂(有时也指多巴胺激动剂)是尽管与多巴胺结构不同但能结合不同多巴胺受体亚型并能触发产生可与多巴胺相比拟的效果的物质。由于降低了副作用，因此有利的是这些物质选择性结合到多巴胺受体的亚型例如D2受体上。
已经用于治疗帕金森病症状的一个多巴胺受体激动剂就是罗替伐汀。它大部分都是以其盐酸物的形式进行试验。罗替伐汀的国际非专利名称(INN)为化合物(-)-5，6，7，8-四氢-6-[丙基-[2-(2-噻吩基)乙基]-氨基]-萘酚，其结构如下所示
以往就已知通过被动经皮治疗系统(TTS)给予罗替伐汀。该用于给予罗替伐汀的被动经皮治疗系统已经在例如WO94/07568和WO99/49852中有所描述。然而，由这些被动经皮治疗系统得到的罗替伐汀流量(flux)对所有的患者来说都未必是足够的。
另一种已经用于治疗帕金森病的多巳胺激动剂是R-阿朴吗啡。R-阿朴吗啡的国际非专利名称(INN)为化合物(R)-5，6，6a，7-四氢-6-甲基-4H-二苯并喹啉-11，12-二醇，其结构如下所示
先前已经记载了一些用于生成通过离子电渗给予R-阿朴吗啡的系统的方法(参见例如R.van der Geest，M.Danhof，H.E.Boddé″阿朴吗啡的离子电渗疗法给药：体外优化及验证″，Pharm.Res.(1997)，14，1797-1802；M.Danhof， R. van der Geest，T.van Laar，H.E.Boddé，″在帕金森病中优化R-阿朴吗啡给药的完整药物动力学-药效学方法″，Advanced Drug Delivery Reviews(1998)，33，253-263)。然而，尽管作出了这些努力，但是仅得到了位于1.4到10.7ng/ml治疗浓度范围较低端值的浓度。
另一个多巴胺拮抗剂是罗平尼咯盐酸盐。罗平尼咯(INN)是(4-[2-二丙胺]乙基)-1，3-二氢-2H-吲哚-2-酮，其结构如下所示
虽然通过离子电渗给予罗平尼咯被认为是可行的，但是其仅能获得位于治疗范围较低端值的流量(参见A.Luzardo-Alvarez，M.B.Delgado-Charro，J.Blanco-Méndez，″通过离子电渗给予罗平尼咯盐酸盐：电流密度和载体形成的影响″，Pharmaceutical Research(2001)，18(12)，1714-1720)。
许多患者都需要比用离子电渗给予阿朴吗啡或罗平尼咯要明显高的浓度。
考虑到帕金森病的症状范围广以及严重程度的不同，所以强烈需要一种能调节罗替伐汀通过皮肤的流量并同时能对帕金森患者多巴胺受体进行持续受体刺激的方法。优选的是，这种系统也应该能比被动经皮给药系统得到的罗替伐汀的流量高。
考虑到通过离子电渗疗法给予阿朴吗啡令人沮丧的经历，所以令人惊奇的是通过离子电渗给予罗替伐汀能提供不仅比常规被动扩散系统要高的血药浓度，而且还能实质上达到给予药学有效药物剂量范围的浓度。使用本发明的方法得到的结果能达到合理的期望，那就是能提供帕金森病的有效治疗。我们应该能明白的是，本申请上下文中的术语“治疗”指的是治疗或减轻帕金森病的症状，而不是致使完全治愈的真正的病因(causative)治疗。
发明内容
本发明提供了一种包含罗替伐汀和至少一种浓度为1到140mmol/l的盐酸盐的组合物用于制备治疗帕金森病的离子电渗装置的用途，其中组合物的pH为4到6.5。
离子电渗是借助电流将不同的离子导入皮肤中。如果与被动经皮给药相比，离子电渗能提供在帕金森病的治疗中有用的几个优点：
-它能通过调节电流来设计达到所需治疗速率的流量，以及
-如果需要的话，它能通过简单地开启或关闭离子电渗给药系统而达到快速的开始或终止给药。
由于离子电渗的流量受一些参数影响，因此分别最优化(optimise)这些参数以达到最佳的流量是至关重要的。
令人惊奇的是，已经发现使用pH为4到6.5的组合物能达到在治疗范围内的良好流量，其中组合物包含位于离子电渗装置原料槽(donor chamber)中的罗替伐汀和至少一种浓度为1到140mmol/l的盐酸盐。
通过降低原料槽的电解质浓度，能在较低电流密度下达到目标离子电渗流量或提高每面积单位的经皮剂量。
在进行研究以评价通过离子电渗给予罗替伐汀的可行性期间，我们发现当pH升高时，罗替伐汀的溶解度降低。然而，令人惊奇的是，我们发现在4到6.5的pH间隔中，在非常低的罗替伐汀浓度下，能达到相应的治疗速率。
为了提供穿过人角质层的最佳流量，也需要在原料相中提供用于电极反应的足量Cl-离子浓度。然而，当继续进行电极反应时，增加的盐酸盐降低了罗替伐汀的溶解度。因此，经证实盐酸盐的最佳浓度是1到140mmol/l，优选50到100mmol/l，更优选60到80mmol/l。
为了在帕金森病的治疗中获得治疗效果，罗替伐汀的浓度可以根据患者的需要和流量需求而不同。然而，就最佳操作来说，优选至少0.5mg/ml，更优选0.5mg/ml到3mg/ml。
药学上可接受的所有盐酸盐都可以用于本发明的组合物中。在本发明的一个优选实施方案中，盐酸盐选自NaCl、三乙铵氯化物和三丁铵氯化物。尤其优选三乙铵氯化物和三丁铵氯化物，因为它们能导致较高的罗替伐汀流量。
在本发明的一个尤其优选的实施方案中，用作离子电渗装置原料相的组合物包含浓度为0.5到3mg/ml的罗替伐汀和至少一个浓度为60到80mmol/l的三乙铵氯化物和三丁铵氯化物，原料相的pH为4.5到5.5。
另一方面，本发明提供了一种治疗帕金森病的方法，其中将离子电渗装置用于需要治疗的患者皮肤上，装置中包含含有罗替伐汀和至少一种浓度为1到140mmol/l的盐酸盐的组合物，组合物的pH为4到6.5。
任何一种常规离子电渗装置都可以用在本发明中。这样的离子电渗装置记载于例如V.Nair，O.Pillai，R.Poduri，R.Panchagnula，″经皮离子电渗疗法，第I部分：基本原理和考虑事项″Methods Find.Exp.Clin.Pharmacol.(1999)，21(2)，139-151中。
离子电渗期间使用的电流密度可以根据患者的需求而不同，这将取决于离子电渗装置和使用的组合物。可以通过随从医生确定适宜的电流。通常，适宜的电流密度优选在200到500μA/cm2的范围内。
实施例1
用R.van der Geest等人(R.van der Geest，M.Danhof，H.E.Boddé，″新型离子电渗连续流通转运细胞的验证及测试″，J.Control.Release(1998)，51，85-19)描述的三槽流通扩散细胞(three-chamberflow-through diffusion cells)进行体外给予罗伐他丁的离子电渗研究。置于接受槽(acceptor chamber)人角质层(SC)的两侧。具有5.000Dacut-off的透析膜被用作支持膜。外槽(outer chamber)的体积约为2ml，而接受槽的体积则为0.54ml。两个外槽包含银器(阳极)或银/氯化银(阴极)驱动电子。原料相包括用5mM柠檬酸盐缓冲液(2.1mM柠檬酸盐二水合物和2.9mM柠檬酸)缓冲的罗替伐汀溶液。
在使用这个装置时，在原料槽的pH为5，电流密度为500μA/cm2，接受槽的pH为7.4，温度为20℃，原料槽的NaCl浓度为70mmol/l下，测定原料相中不同药物浓度的罗替伐汀流量。
| 罗替伐汀浓度(mg/ml)(供试液)(donor solution) | 罗替伐汀浓度(mM)(供试液) | 罗替伐汀流量(nmol/cm2/h) |
| 0.5 | 1.4 | 22.9 |
| 1.0 | 2.8 | 30.2 |
| 1.4 | 3.98 | 53.2 |
实施例2：
使用与实施例1同样的步骤，罗替伐汀的浓度为1.4mg/ml(3.98mM)，原料槽的pH为5，电流密度为500μA/cm2，接受槽的pH为7.4，温度为20℃，但用三乙铵氯化物(TEACl)或三丁铵氯化物(TBACl)代替NaCl，评价不同阳离子对流量的影响。供试液中盐酸盐的浓度为70mmol/l。
| 联合-离子源(Co-Ions source) | 罗替伐汀流量(nmol/cm2/h) |
| NaCl | 53.2 |
| TEACl | 72.8 |
| TBACl | 62.0 |
实施例3：
使用与实施例2同样的步骤和同样的参数，评价不同盐酸盐对接受槽中从7.4到6.2下降的pH的影响。供试液中盐酸盐的浓度为70mmol/l。
| 联合-离子源 | 罗替伐汀流量(nmol/cm2/h) |
| NaCl | 58.9 |
| TEACl | 43.2 |
| TBACl | 76.5 |
Claims (8)
1.包含罗替伐汀和至少一种浓度为1到140mmol/l的盐酸盐的组合物用于制备治疗帕金森病的离子电渗装置的用途，其中组合物的pH为4到6.5.
2.根据权利要求1的用途，其中罗替伐汀的浓度至少为0.5mg/ml。
3.根据权利要求1或2任意之一的用途，其中罗替伐汀的浓度为0.5到3mg/ml.
4.根据权利要求1的用途，其中盐酸盐选自NaCl、三乙铵氯化物和三丁铵氯化物.
5.根据权利要求4的用途，其中盐酸盐是三乙铵氯化物或三丁铵氯化物。
6.根据权利要求4或5的用途，其中盐酸盐的浓度为60到80mmol/l.
7.根据权利要求1的用途，其中组合物用在离子电渗装置的原料相中。
8.根据权利要求1的用途，其中离子电渗装置原料相中的组合物包含浓度为0.5到3mg/ml的罗替伐汀和至少一种浓度为60到80mmol/l的三乙铵氯化物和三丁铵氯化物，其中原料相的pH为4.5到5.5。
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| EP02026871A EP1426049B1 (en) | 2002-12-02 | 2002-12-02 | Iontophoretic delivery of rotigotine for the treatment of Parkinson's disease |
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Families Citing this family (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19814084B4 (de) | 1998-03-30 | 2005-12-22 | Lts Lohmann Therapie-Systeme Ag | D2-Agonist enthaltendes transdermales therapeutisches System zur Behandlung des Parkinson-Syndroms und Verfahren zu seiner Herstellung |
| DE10041478A1 (de) * | 2000-08-24 | 2002-03-14 | Sanol Arznei Schwarz Gmbh | Neue pharmazeutische Zusammensetzung |
| DE10041479A1 (de) * | 2000-08-24 | 2002-03-14 | Sanol Arznei Schwarz Gmbh | Neue pharmazeutische Zusammensetzung zur Verabreichung von N-0923 |
| US20030026830A1 (en) * | 2001-05-08 | 2003-02-06 | Thomas Lauterback | Transdermal therapeutic system for parkinson's disease inducing high plasma levels of rotigotine |
| US20030027793A1 (en) * | 2001-05-08 | 2003-02-06 | Thomas Lauterback | Transdermal treatment of parkinson's disease |
| US20040048779A1 (en) * | 2002-05-06 | 2004-03-11 | Erwin Schollmayer | Use of rotigotine for treating the restless leg syndrome |
| US8246979B2 (en) | 2002-07-30 | 2012-08-21 | Ucb Pharma Gmbh | Transdermal delivery system for the administration of rotigotine |
| DE10234673B4 (de) * | 2002-07-30 | 2007-08-16 | Schwarz Pharma Ag | Heißschmelz-TTS zur Verabreichung von Rotigotin und Verfahren zu seiner Herstellung sowie Verwendung von Rotigotin bei der Herstellung eines TTS im Heißschmelzverfahren |
| US8211462B2 (en) * | 2002-07-30 | 2012-07-03 | Ucb Pharma Gmbh | Hot-melt TTS for administering rotigotine |
| US8246980B2 (en) * | 2002-07-30 | 2012-08-21 | Ucb Pharma Gmbh | Transdermal delivery system |
| DE10261696A1 (de) * | 2002-12-30 | 2004-07-15 | Schwarz Pharma Ag | Vorrichtung zur transdermalen Verabreichung von Rotigotin-Base |
| DE10334188B4 (de) * | 2003-07-26 | 2007-07-05 | Schwarz Pharma Ag | Verwendung von Rotigotin zur Behandlung von Depressionen |
| DE10359528A1 (de) | 2003-12-18 | 2005-07-28 | Schwarz Pharma Ag | (S)-2-N-Propylamino-5-hydroxytetralin als D3-agonistisches Therapeutikum |
| DE10361258A1 (de) * | 2003-12-24 | 2005-07-28 | Schwarz Pharma Ag | Verwendung von substituierten 2-Aminotetralinen zur vorbeugenden Behandlung von Morbus Parkinson |
| US20050197385A1 (en) * | 2004-02-20 | 2005-09-08 | Schwarz Pharma Ag | Use of rotigotine for treatment or prevention of dopaminergic neuron loss |
| DE102004014841B4 (de) * | 2004-03-24 | 2006-07-06 | Schwarz Pharma Ag | Verwendung von Rotigotin zur Behandlung und Prävention des Parkinson-Plus-Syndroms |
| TWI392670B (zh) * | 2006-06-22 | 2013-04-11 | Ucb Pharma Gmbh | 經取代的２-胺基萘滿之於製造用於預防、減緩及／或治療各種類型疼痛之藥物上的用途 |
| EP1987815A1 (en) * | 2007-05-04 | 2008-11-05 | Schwarz Pharma Ag | Oronasopharyngeally deliverable pharmaceutical compositions of dopamine agonists for the prevention and/or treatment of restless limb disorders |
| US8592477B2 (en) * | 2007-11-28 | 2013-11-26 | Ucb Pharma Gmbh | Polymorphic form of rotigotine and process for production |
| DE102008010223A1 (de) | 2008-02-20 | 2009-08-27 | Wash Tec Holding Gmbh | Reinigungsvorrichtung |
| DE202008002377U1 (de) | 2008-02-20 | 2009-06-25 | Washtec Holding Gmbh | Reinigungsvorrichtung |
| EP2281559A1 (en) | 2009-06-26 | 2011-02-09 | UCB Pharma GmbH | Pharmaceutical composition comprising rotigotine salts (acid or Na), especially for iontophoresis |
| DK2515887T3 (en) | 2009-12-22 | 2018-09-17 | Ucb Biopharma Sprl | Polyvinylpyrrolidone to stabilize a solid dispersion of the non-crystalline form of rotigotine |
| EP2559435A1 (en) | 2011-08-19 | 2013-02-20 | UCB Pharma GmbH | Rotigotine in the treatment of hemispatial neglect, stroke and deficits following stroke |
| TW201431570A (zh) | 2012-11-22 | 2014-08-16 | Ucb Pharma Gmbh | 用於經皮投服羅替戈汀（Ｒｏｔｉｇｏｔｉｎｅ）之多天式貼片 |
| CA2916183C (en) | 2013-07-03 | 2022-03-29 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system with electronic component |
| CN106456567A (zh) | 2014-05-20 | 2017-02-22 | Lts勒曼治疗系统股份公司 | 在经皮递送系统中调节活性剂释放的方法 |
| CN106456566B (zh) | 2014-05-20 | 2020-06-16 | Lts勒曼治疗系统股份公司 | 含罗替戈汀的经皮递送系统 |
| CA2948221C (en) | 2014-05-20 | 2022-11-22 | Lts Lohmann Therapie-Systeme Ag | Transdermal delivery system including an interface mediator |
| US9956201B2 (en) | 2014-07-21 | 2018-05-01 | Spriaso Llc | Compositions comprising bioreversible derivatives of hydroxy N-substituted-2-aminotetralins, and related dosage forms |
| CA3030043C (en) * | 2016-07-21 | 2021-01-19 | Shandong Luye Pharmaceutical Co., Ltd. | Rotigotine behenate, preparation method and use thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4996226A (en) * | 1984-08-13 | 1991-02-26 | Whitby Research, Inc. | Method and compositions for treatment of parkinsonism syndrome in mammels |
| CN1295470A (zh) * | 1998-03-30 | 2001-05-16 | Lts洛曼医疗系统有限责任公司 | 一种含有d2促进素的经由皮肤治疗帕金森氏症的体系及其制备方法 |
| WO2002015903A2 (de) * | 2000-08-24 | 2002-02-28 | Schwarz Pharma Ag | Neue pharmazeutische zusammensetzung zur verabreichung von n-0923 |
Family Cites Families (92)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5108991A (en) * | 1975-06-19 | 1992-04-28 | Whitby Research, Inc. | Vehicle composition containing 1-substituted azacycloalkan-2-ones |
| US5204339A (en) * | 1986-01-31 | 1993-04-20 | Whitby Research, Inc. | Penetration enhancers for transdermal delivery of systemic agents |
| JPS63502282A (ja) * | 1986-01-31 | 1988-09-01 | ホイットビ−・リサ−チ・インコ−ポレ−テッド | １−置換アザシクロアルカン類より成る組成物とその用法 |
| US4801586A (en) * | 1986-04-23 | 1989-01-31 | Nelson Research & Development Co. | Penetration enhancers for transdermal delivery of systemic agents |
| US5142044A (en) * | 1986-04-23 | 1992-08-25 | Whitby Research, Inc. | Penetration enhancers for transdermal delivery of systemic agents |
| US5073544A (en) * | 1986-08-15 | 1991-12-17 | Whitby, Inc. | Transdermal compositions of 1-oxohydrocarbyl-substituted azacyclohexanes |
| US4917896A (en) * | 1986-08-15 | 1990-04-17 | Nelson Research & Development Co. | Penetration enhancers for transdermal delivery of systemic agents |
| US4808414A (en) * | 1986-09-29 | 1989-02-28 | Nelson Research & Development Co. | Amide penetration enhancers for transdermal delivery of systemic agents |
| US5118845A (en) * | 1986-09-29 | 1992-06-02 | Whitby Research, Inc. | Penetration enhancer for transdermal delivery of systemic agents |
| US5273757A (en) * | 1987-09-01 | 1993-12-28 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Apparatus for the delivery of substances, processes for the production thereof and use thereof |
| US5071645A (en) * | 1987-10-19 | 1991-12-10 | Ppg Industries, Inc. | Process of producing an active agent delivery device |
| EP0317269B1 (en) * | 1987-11-20 | 1992-03-04 | FARMITALIA CARLO ERBA S.r.l. | Antiparkinson ergoline derivatives |
| US4915950A (en) * | 1988-02-12 | 1990-04-10 | Cygnus Research Corporation | Printed transdermal drug delivery device |
| US5656286A (en) * | 1988-03-04 | 1997-08-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
| US5472946A (en) | 1988-04-08 | 1995-12-05 | Peck; James V. | Transdermal penetration enhancers |
| DE3827561C1 (zh) * | 1988-08-13 | 1989-12-28 | Lts Lohmann Therapie-Systeme Gmbh & Co Kg, 5450 Neuwied, De | |
| US4973468A (en) * | 1989-03-22 | 1990-11-27 | Cygnus Research Corporation | Skin permeation enhancer compositions |
| US5234945A (en) * | 1989-05-09 | 1993-08-10 | Whitby Research, Inc. | Method of producing body weight and food intake using a dopamine D2 receptor agonist |
| US5252335A (en) * | 1989-07-12 | 1993-10-12 | Cygnus Therapeutic Systems | Transdermal administration of lisuride |
| US5091186A (en) * | 1989-08-15 | 1992-02-25 | Cygnus Therapeutic Systems | Biphasic transdermal drug delivery device |
| US5124157A (en) * | 1989-08-18 | 1992-06-23 | Cygnus Therapeutic Systems | Method and device for administering dexmedetomidine transdermally |
| US5252334A (en) * | 1989-09-08 | 1993-10-12 | Cygnus Therapeutic Systems | Solid matrix system for transdermal drug delivery |
| US5271940A (en) * | 1989-09-14 | 1993-12-21 | Cygnus Therapeutic Systems | Transdermal delivery device having delayed onset |
| US5071875A (en) * | 1989-09-25 | 1991-12-10 | Northwestern University | Substituted 2-amidotetralins as melatonin agonists and antagonists |
| US5151446A (en) * | 1989-09-25 | 1992-09-29 | Northwestern University | Substituted 2-amidotetralins as melatonin agonists and antagonists |
| DE3933460A1 (de) * | 1989-10-06 | 1991-04-18 | Lohmann Therapie Syst Lts | Oestrogenhaltiges wirkstoffpflaster |
| EP0507863A4 (en) * | 1989-12-28 | 1993-07-07 | Virginia Commonwealth University | Sigma receptor ligands and the use thereof |
| IL92952A (en) * | 1990-01-03 | 1994-06-24 | Teva Pharma | R-enantiomers of n-propargyl-1-aminoindan compounds, their preparation and pharmaceutical compositions containing them |
| US5147916A (en) * | 1990-02-21 | 1992-09-15 | Dow Corning Corporation | Hot-melt silicone pressure sensitive adhesive composition and related methods and articles |
| US5246997A (en) * | 1990-02-21 | 1993-09-21 | Dow Corning Corporation | Method of making a hot-melt silicone pressure sensitive adhesive-coated substrate |
| US5069909A (en) * | 1990-06-20 | 1991-12-03 | Cygnus Therapeutic Systems | Transdermal administration of buprenorphine |
| US6086905A (en) * | 1991-03-21 | 2000-07-11 | Peck; James V. | Topical compositions useful as skin penetration barriers |
| US5273755A (en) * | 1991-08-23 | 1993-12-28 | Cygnus Therapeutic Systems | Transdermal drug delivery device using a polymer-filled microporous membrane to achieve delayed onset |
| US5234690A (en) * | 1991-08-23 | 1993-08-10 | Cygnus Therapeutic Systems | Transdermal drug delivery device using an unfilled microporous membrane to achieve delayed onset |
| US5273756A (en) * | 1991-08-23 | 1993-12-28 | Cygnus Therapeutic Systems | Transdermal drug delivery device using a membrane-protected microporous membrane to achieve delayed onset |
| US5225198A (en) * | 1991-08-27 | 1993-07-06 | Cygnus Therapeutic Systems | Transdermal administration of short or intermediate half-life benzodiazepines |
| AU2514292A (en) * | 1991-08-27 | 1993-03-16 | Cygnus Therapeutic Systems | Transdermal formulations for administering prazosin |
| GB9127306D0 (en) * | 1991-12-23 | 1992-02-19 | Boots Co Plc | Therapeutic agents |
| US5308625A (en) * | 1992-09-02 | 1994-05-03 | Cygnus Therapeutic Systems | Enhancement of transdermal drug delivery using monoalkyl phosphates and other absorption promoters |
| US5989586A (en) * | 1992-10-05 | 1999-11-23 | Cygnus, Inc. | Two-phase matrix for sustained release drug delivery device |
| DE4301781C2 (de) * | 1993-01-23 | 1995-07-20 | Lohmann Therapie Syst Lts | Nitroglycerinhaltiges Pflaster, Verfahren zu seiner Herstellung und Verwendung |
| JPH09503997A (ja) * | 1993-07-08 | 1997-04-22 | シグナス，インコーポレイテッド | モノリシックなマトリックス経皮送達システム |
| US5382596A (en) * | 1993-08-05 | 1995-01-17 | Whitby Research, Inc. | Substituted 2-aminotetralins |
| US5554381A (en) * | 1993-08-09 | 1996-09-10 | Cygnus, Inc. | Low flux matrix system for delivering potent drugs transdermally |
| EP0643981B1 (en) * | 1993-09-22 | 2002-01-09 | Hisamitsu Pharmaceutical Co., Inc. | A matrix for iontophoreses |
| US5771890A (en) * | 1994-06-24 | 1998-06-30 | Cygnus, Inc. | Device and method for sampling of substances using alternating polarity |
| US5670501A (en) * | 1994-09-01 | 1997-09-23 | Discovery Therapeutics, Inc. | N-substituted 9-alkyladenines |
| US6024974A (en) * | 1995-01-06 | 2000-02-15 | Noven Pharmaceuticals, Inc. | Composition and methods for transdermal delivery of acid labile drugs |
| US5677346A (en) * | 1995-01-31 | 1997-10-14 | Sepracor, Inc. | Treating urinary incontinence using (S)-desethyloxybutynin |
| US5532278A (en) * | 1995-01-31 | 1996-07-02 | Sepracor, Inc. | Methods and compositions for treating urinary incontinence using optically pure (S)-oxybutynin |
| FR2732223B1 (fr) * | 1995-03-30 | 1997-06-13 | Sanofi Sa | Composition pharmaceutique pour administration transdermique |
| US5601839A (en) * | 1995-04-26 | 1997-02-11 | Theratech, Inc. | Triacetin as a penetration enhancer for transdermal delivery of a basic drug |
| ES2190472T5 (es) * | 1995-06-07 | 2012-03-09 | Ortho-Mcneil Pharmaceutical, Inc. | Parche transdérmico para la administración de 17-deacetil norgestimato, en combinación con un estrógeno. |
| US6316022B1 (en) * | 1995-06-07 | 2001-11-13 | Noven Pharmaceuticals, Inc. | Transdermal compositions containing low molecular weight drugs which are liquid at room temperatures |
| US5906830A (en) * | 1995-09-08 | 1999-05-25 | Cygnus, Inc. | Supersaturated transdermal drug delivery systems, and methods for manufacturing the same |
| US5902603A (en) * | 1995-09-14 | 1999-05-11 | Cygnus, Inc. | Polyurethane hydrogel drug reservoirs for use in transdermal drug delivery systems, and associated methods of manufacture and use |
| US5891461A (en) * | 1995-09-14 | 1999-04-06 | Cygnus, Inc. | Transdermal administration of olanzapine |
| US6063398A (en) * | 1995-09-20 | 2000-05-16 | L'oreal | Cosmetic or dermopharmaceutical patch containing, in an anhydrous polymeric matrix, at least one active compound which is, in particular, unstable in oxidizing mediums, and at least one water-absorbing agent |
| US5807570A (en) * | 1995-09-29 | 1998-09-15 | Cygnus, Inc. | Transdermal administration of ropinirole and analogs thereof |
| US5733571A (en) * | 1995-12-08 | 1998-03-31 | Euro-Celtique, S.A. | Transdermal patch for comparative evaluations |
| AUPN814496A0 (en) * | 1996-02-19 | 1996-03-14 | Monash University | Dermal penetration enhancer |
| US6221627B1 (en) * | 1997-02-24 | 2001-04-24 | Smithkline Beecham Corporation | cDNA clone HDPB130 that encodes a novel human 7-transmembrane receptor |
| US5879701A (en) * | 1997-02-28 | 1999-03-09 | Cygnus, Inc. | Transdermal delivery of basic drugs using nonpolar adhesive systems and acidic solubilizing agents |
| US6242572B1 (en) * | 1997-05-13 | 2001-06-05 | Smithkline Beecham Corporation | Human G protein coupled lysophosphatidic acid receptor |
| US6514530B2 (en) * | 1997-09-09 | 2003-02-04 | Alza Corporation | Dosage form comprising means for changing drug delivery shape |
| DE19814083C2 (de) * | 1998-03-30 | 2002-02-07 | Lohmann Therapie Syst Lts | Verfahren zur Herstellung von transdermalen therapeutischen Systemen unter Verwendung von basischen Alkalimetallsalzen zur Umwandlung von Wirkstoffsalzen in die freien Basen |
| PT1053043E (pt) * | 1998-05-13 | 2002-11-29 | Cygnus Therapeutic Systems | Montagens de recolha para sistemas de amostragem transdermica |
| DE19828273B4 (de) * | 1998-06-25 | 2005-02-24 | Lts Lohmann Therapie-Systeme Ag | Transdermales therapeutisches System, enthaltend Hormone und Kristallisationsinhibitoren |
| WO2000015108A1 (en) * | 1998-09-17 | 2000-03-23 | Cygnus, Inc. | Press device for a gel/sensor assembly |
| FR2792529B1 (fr) * | 1999-04-26 | 2001-09-28 | Sod Conseils Rech Applic | Nouvelles compositions pharmaceutiques comprenant des derives de 2-isoxazole-8-aminotetralines |
| AU5325000A (en) * | 1999-06-05 | 2000-12-28 | David Houze | Solubility enhancement of drugs in transdermal drug delivery systems and methodsof use |
| US6218421B1 (en) * | 1999-07-01 | 2001-04-17 | Smithkline Beecham P.L.C. | Method of promoting smoking cessation |
| DE19938823A1 (de) | 1999-08-19 | 2001-02-22 | Boehringer Ingelheim Pharma | Medikamentöse Behandlung des Restless Leg Syndroms |
| DE19938825A1 (de) * | 1999-08-19 | 2001-04-26 | Boehringer Ingelheim Pharma | Wirkstoffkombination mit Clonidin |
| DE19940238A1 (de) * | 1999-08-25 | 2001-03-01 | Lohmann Therapie Syst Lts | Wirkstoffhaltiges therapeutisches System zur Applikation auf der Haut mit mindestens zwei polymerhaltigen Schichten |
| ATE245972T1 (de) * | 1999-11-29 | 2003-08-15 | Lohmann Therapie Syst Lts | Transdermale therapeutische systeme mit verbesserter stabilität und ein verfahren zu ihrer herstellung |
| US20020110585A1 (en) * | 1999-11-30 | 2002-08-15 | Godbey Kristin J. | Patch therapeutic agent delivery device having texturized backing |
| US6277875B1 (en) * | 2000-07-17 | 2001-08-21 | Andrew J. Holman | Use of dopamine D2/D3 receptor agonists to treat fibromyalgia |
| US20020119187A1 (en) * | 2000-09-29 | 2002-08-29 | Cantor Adam S. | Composition for the transdermal delivery of fentanyl |
| DE10060550C1 (de) * | 2000-12-06 | 2002-04-18 | Lohmann Therapie Syst Lts | Transdermales therapeutisches System mit dem Wirkstoff Oxybutynin und Verfahren zur Herstellung Oxybutynin enthaltender Wirkstoffschichten |
| US20030027793A1 (en) * | 2001-05-08 | 2003-02-06 | Thomas Lauterback | Transdermal treatment of parkinson's disease |
| HU227543B1 (en) * | 2001-09-28 | 2011-08-29 | Richter Gedeon Nyrt | N-[4-(2-piperazin- and 2-piperidin-1-yl-ethyl)-cyclohexyl]-sulfon- and sulfamides, process for their preparation, their use and pharmaceutical compositions containing them |
| NZ537360A (en) * | 2002-06-25 | 2006-09-29 | Acrux Dds Pty Ltd | Transdermal delivery rate control using amorphous pharmaceutical compositions |
| US8211462B2 (en) * | 2002-07-30 | 2012-07-03 | Ucb Pharma Gmbh | Hot-melt TTS for administering rotigotine |
| US8246979B2 (en) | 2002-07-30 | 2012-08-21 | Ucb Pharma Gmbh | Transdermal delivery system for the administration of rotigotine |
| US8246980B2 (en) * | 2002-07-30 | 2012-08-21 | Ucb Pharma Gmbh | Transdermal delivery system |
| AU2003284342B2 (en) * | 2002-10-25 | 2009-03-05 | Collegium Pharmaceutical, Inc. | Stereoisomers of p-hydroxy-milnacipran, and methods of use thereof |
| US9102726B2 (en) * | 2002-12-04 | 2015-08-11 | Argos Therapeutics, Inc. | Nucleic acid of recombination expression vector encoding soluble forms of CD83, host cells transformed/transfected therewith and pharmaceutical compositions containing same |
| DE10261696A1 (de) * | 2002-12-30 | 2004-07-15 | Schwarz Pharma Ag | Vorrichtung zur transdermalen Verabreichung von Rotigotin-Base |
| US20050032873A1 (en) * | 2003-07-30 | 2005-02-10 | Wyeth | 3-Amino chroman and 2-amino tetralin derivatives |
| CA2554616A1 (en) * | 2004-01-22 | 2005-08-04 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition comprising a monoamine neurotransmitter re-uptake inhibitor and a dopamine agonist |
| US20050197385A1 (en) * | 2004-02-20 | 2005-09-08 | Schwarz Pharma Ag | Use of rotigotine for treatment or prevention of dopaminergic neuron loss |
-
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4996226A (en) * | 1984-08-13 | 1991-02-26 | Whitby Research, Inc. | Method and compositions for treatment of parkinsonism syndrome in mammels |
| CN1295470A (zh) * | 1998-03-30 | 2001-05-16 | Lts洛曼医疗系统有限责任公司 | 一种含有d2促进素的经由皮肤治疗帕金森氏症的体系及其制备方法 |
| WO2002015903A2 (de) * | 2000-08-24 | 2002-02-28 | Schwarz Pharma Ag | Neue pharmazeutische zusammensetzung zur verabreichung von n-0923 |
| WO2002015903A3 (de) * | 2000-08-24 | 2002-05-23 | Sanol Arznei Schwarz Gmbh | Neue pharmazeutische zusammensetzung zur verabreichung von n-0923 |
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