CN101980999A - 用于经皮药物递送系统的具有有效稳定性的托特罗定酸式盐 - Google Patents

用于经皮药物递送系统的具有有效稳定性的托特罗定酸式盐 Download PDF

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CN101980999A
CN101980999A CN2009801113470A CN200980111347A CN101980999A CN 101980999 A CN101980999 A CN 101980999A CN 2009801113470 A CN2009801113470 A CN 2009801113470A CN 200980111347 A CN200980111347 A CN 200980111347A CN 101980999 A CN101980999 A CN 101980999A
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黄用渊
金南镐
崔源宰
金容汉
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Abstract

本发明涉及托特罗定酸式盐，其具有更优异的稳定性并用作经皮药物递送系统。更具体地，本发明涉及新的托特罗定酸式盐，其相比常规托特罗定酸式盐具有更优异的稳定性，其用作用于治疗膀胱过度活动症的药物组合物并且能够配制为经皮药物递送系统。

Description

用于经皮药物递送系统的具有有效稳定性的托特罗定酸式盐
技术领域
本发明涉及托特罗定酸式盐，其具有更优异的稳定性并且用作经皮药物递送系统。
背景技术
美国专利号5,382,600公开(经取代的)3，3-二苯基丙胺对治疗膀胱过度活动症有效。特别是，上述专利教导2-[(1R)-3-(二异丙基氨基)-1-苯基丙基)-4-甲基苯酚可用于对膀胱过度活动症的治疗，其具有通用名托特罗定[式1]并且称为N，N-二异丙基-3-(2-羟基-5-甲基苯基)-3-苯基丙胺。托特罗定是美国专利号5,382,600实施例22中公开的化合物。托特罗定优选通过WO公开号98/29402中公开的方法来生产。
H.Postlind等人报告托特罗定是毒蕈碱的受体拮抗剂[DrugMetabolism and Disposition，26(4)：289-293(1998)]。它已作为(Pharmacia)市场化。托特罗定以片剂形式口服给予以治疗膀胱过度活动症。托特罗定的活性代谢物是羟基托特罗定。
美国专利号5,559,269和H.Postlind等人公开羟基托特罗定[Drug Metabolism and Disposition，26(4)：289-293(1998)]。
美国专利号5,559,269教导上述化合物在对膀胱过度活动症的治疗中有效的，并且报告羟基托特罗定具有抗毒蕈碱特性[Pharmacol.Toxicol.，81：169-172(1997)]。
WO公开号98/29402公开甲烷磺酸，盐酸，氢溴酸，硫酸，磷酸，硝酸，苯甲酸，柠檬酸，酒石酸，富马酸，马来酸，CH3-(CH2)n-COOH(此处n是0-4的整数)，HOOC-(CH2)n-COOH(此处n是0-4的整数)的托特罗定盐。
WO公开号02/34245公开托特罗定治疗哮喘、COPD和变态性鼻炎的用途。
托特罗定，用于治疗膀胱过度活动症的商业治疗试剂，以覆膜片剂形式给予以在胃肠道中释放，该片剂包含1mg、2mg或4mg的托特罗定L-酒石酸盐。关于药物，用户总是在要求选择性递送形式以改善其生活品质，比如优秀的效力和/或方便的治疗。
‘膀胱过度活动症’，是新造的医学词汇，它指具有尿频、尿急或紧急尿失禁的症状的身体状况。
‘尿频’是指人排尿多于8次每日并且其可以伴随排尿之后仍有排尿欲望的病症。
‘尿急’是指当不再能忍住排尿并需要紧急排尿时的人的病症。
‘紧急尿失禁’是指当因突然不能忍受的排尿欲望而漏出尿液时的人的病症。
全世界约超过50百万人罹患‘膀胱过度活动症’。40岁或以上的成人的约22％患有膀胱过度活动症症状。实际上，它在全部年龄群体的男性和女性中都有发展，但是在女性中更频发。它由逼尿肌(过度活动膀胱的平滑肌)的极端频繁收缩引起。也就是说，膀胱肌肉收缩频度超过正常情况，或当不需要时发生收缩，并因此发出排尿的突然信号。大多数情况下的主要原因并未确认，但是在某些患者中其原因显得是神经传递的缺陷或手术或分娩婴儿造成的神经元损伤。对于男性，同时患有前列腺肥大和膀胱过度活动症是很普遍的。
‘膀胱过度活动症’是通常伴随缺少睡眠、工作效率降低、回避性生活、抑郁和对疾病缺乏认识并感到羞耻引起的社交恐怖症的疾病，并因此使生活质量大幅下降。调查了包括膀胱过度活动症的疾病与生活质量的相关性而结果(SF-36问卷)显示膀胱过度活动症与其它成人疾病比如糖尿病和高血压相比更强烈地降低生活质量。所以，迫切需要发展新的药物化合物以恢复膀胱过度活动症患者的生活质量。
从药理学角度来看，托特罗定(式1)优选呈游离碱形式。然而，其在生产过程期间非常难以处理，原因是其是高粘度液体形式，这使收率下降并且具有不良的贮藏稳定性，因此它一般以药学上可接受的酸的酸式盐形式给予。
目前用于治疗膀胱过度活动症的托特罗定酸式盐是托特罗定酒石酸盐(式2)
[式1]
Figure BPA00001232377200031
[式2]
Figure BPA00001232377200032
韩国专利号90,479公开药学上可接受的盐应符合下述四种物理化学要求：(1)优秀的溶解度(2)优秀的贮藏稳定性(3)非吸湿性(4)可处理为片剂的特性。然而，药学上可接受的盐不容易符合上面列出的全部条件。实际上，甚至当置于溶液中时托特罗定酒石酸盐本身也在数周内分解，这又提出了稳定性问题。此外，它的经皮吸收速率与托特罗定游离碱形式相比要低很多。
发明公开
技术问题
本发明的发明人已研究了制备自液体无定形托特罗定游离碱的各种新托特罗定酸式盐，以及通过各种配制方法经皮递送这些新的药物化合物的方法。作为结果，他们有效率且成本效益高地成功生产了各种托特罗定酸式盐。另外，对于上述某些新的药物化合物，发明人通过运用药学技术已开发出用于经皮递送新药物化合物的新方法，在药物递送方面发现其与常规托特罗定酒石酸盐相比更加有用。
所以，本发明的目标是提供制备自液体无定形托特罗定游离碱的各种托特罗定酸式盐。
本发明的又一目标是提供用于运用药学技术经皮递送上述新药物化合物的方法。
本发明的又一目标是提供用于治疗膀胱过度活动症的包含上述新药物化合物作为活性成分的药物组合物。
技术方案
本发明涉及新托特罗定酸式盐，其与常规托特罗定酒石酸盐相比具有改善贮藏稳定性并且还能够配制为经皮药物递送系统。
实施本发明的最佳模式
如下文所述进一步描述本发明。
出于各种托特罗定酸式盐的关键要求，注意到常规托特罗定酒石酸盐的经皮吸收与托特罗定游离碱相比低很多，本发明作为结果选择了马尿酸，己二酸，龙胆酸，苯磺酸，p-甲苯磺酸，L-焦谷氨酸，苯甲酸，萘-1，5-二磺酸，1-羟基-2-萘甲酸，羟乙酸，视黄酸，并通过使用上述11种不同酸来制备各种托特罗定酸式盐。
取决于酸式盐制备方法存在少许差异。
各种托特罗定酸式盐能够这样制备：将托特罗定游离碱与酸以1.0∶0.1～2.0的当量比例混合，在极性有机溶剂(乙酸乙酯，丙酮，甲醇，乙醇，异丙醇，叔丁醇，二氯甲烷，氯仿，甲苯，四氢呋喃，等)存在下搅拌混合物1-24小时；或对其加入非极性有机溶剂(己烷，庚烷，辛烷，二乙基醚，等)并搅拌；或减压蒸发有机溶剂(乙酸乙酯，丙酮，甲醇，乙醇，异丙醇，叔丁醇，二氯甲烷，氯仿，甲苯，四氢呋喃，己烷，庚烷，辛烷，二乙基醚，等。)。这些方法对本领域技术人员已是熟知的。
[式3：托特罗定尿酸盐]
[式4：托特罗定半己二酸盐]
[式5：托特罗定龙胆酸盐]
Figure BPA00001232377200053
[式6：托特罗定苯磺酸盐]
Figure BPA00001232377200054
[式7：托特罗定p-甲苯磺酸盐]
Figure BPA00001232377200061
[式8：托特罗定L-焦谷氨酸盐]
Figure BPA00001232377200062
[式9：托特罗定苯甲酸盐]
Figure BPA00001232377200063
[式10：托特罗定半萘-1，5-二磺酸盐]
Figure BPA00001232377200064
[式11：托特罗定1-羟基-2-萘甲酸盐]
Figure BPA00001232377200071
[式12：托特罗定羟乙酸盐]
[式13：托特罗定视黄酸盐]
Figure BPA00001232377200073
本发明的各种新酸式盐都符合全部下述作为药学上可接受的盐的五种物理化学要求。
(1)低吸湿性
(2)合适的溶解度
(3)优秀的贮藏稳定性
(4)便于大量生产
所以，本发明涉及用于治疗膀胱过度活动症的包含前文提及的各种新托特罗定酸式盐作为活性成分的药物组合物。
本发明的药物组合物能够口服地或胃肠外地给予用于临床试验并可以一般的药物配制剂形式使用。也即，它能够通过使用稀释剂比如填充剂、粘接剂、润湿剂、崩解剂、表面活性剂或赋形剂配制为用于口服或胃肠外给药的各种制剂。
固体制剂的实例包括片剂，丸剂，粉末，颗粒剂，胶囊剂，等。
用于口服给药的液体制剂的实例包括悬浮液、口服液剂、乳剂、糖浆等，并且其除了一般所用的稀释剂比如水、液体烷烃还可以包含各种赋形剂比如润湿剂、增甜剂、芳香剂、防腐剂。
用于胃肠外给药的制剂的实例包括已灭菌的含水溶液、悬浮液、乳剂、冻干剂、栓剂和贴剂。
非水溶剂或悬浮液溶剂的实例包括丙二醇、聚乙烯二醇、植物油比如橄榄油、可注射的酯比如油酸乙酯。
用于栓剂的基本物质是Witepsol，Macrogol，Tween 61，可可油，甘油明胶，等。
用于贴剂的基本物质包括各种赋形剂和帮助其粘合至皮肤的粘合剂。
给予患者的本发明药物组合物的剂量可以取决于患者年龄，体量，给药途径，健康条件，和疾病严重性而变化。
对于治疗膀胱过度活动症比如尿频、尿急和紧急尿失禁口服给予托特罗定酒石酸盐两次每日，每次给药2mg。
用下述实施例来进一步详细描述本发明但是这不应理解为对本发明范围的限制。
实施例1：制备托特罗定尿酸盐
于室温(25℃)将溶于50mL丙酮的3.25g托特罗定与1.79g马尿酸混合，将其悬浮与50mL丙酮，然后搅拌。通过氮回流设备除去上述混合物中的丙酮，和当除去约10-20mL丙酮时开始出现固体沉淀。于室温(25℃)搅拌混合物1小时之后，过滤固体沉淀，然后用己烷洗涤。于室温(25℃)干燥反应产物24小时，获得4.66g(理论收率：92.3％)终产物，为白色固体。
实施例2：制备托特罗定半己二酸盐
于室温(25℃)将溶于50mL丙酮的3.25g托特罗定与0.73g己二酸混合，将其悬浮50mL丙酮中，然后搅拌。在10分钟内，开始出现固体沉淀。对其加入100mL丙酮并于室温(25℃)搅拌混合物1小时。过滤所得固体沉淀，然后用丙酮洗涤。于室温(25℃)干燥反应产物24小时，获得2.96g(理论收率：74.3％)的终产物，是白色固体。
实施例3：制备托特罗定龙胆酸盐
于室温(25℃)将溶于50mL丙酮的3.25g托特罗定与4.80g龙胆酸混合，将其悬浮50mL丙酮中，然后搅拌。通过氮回流设备除去上述混合物中的丙酮，当除去约10-20mL丙酮时开始出现固体沉淀。于室温(25℃)搅拌混合物1小时之后，过滤固体沉淀，然后用己烷洗涤。于室温(25℃)干燥反应产物24小时，获得2.04g(理论收率：42.5％)的终产物，是白色固体。
实施例4：制备托特罗定苯磺酸盐
于室温(25℃)将溶于50mL丙酮的3.25g托特罗定与1.58g苯磺酸混合，将其悬浮50mL丙酮中，然后搅拌。通过氮回流设备除去上述混合物中的丙酮。当除去约70-80mL丙酮时对其加入二乙基醚和己烷的混合溶液并搅拌，开始出现固体沉淀。于室温(25℃)搅拌所得混合物1小时之后，过滤固体沉淀，然后用己烷洗涤。于室温(25℃)干燥反应产物24小时，获得4.35g(理论收率：89.9％)的终产物，是白色固体。
实施例5：制备托特罗定甲苯磺酸盐
于室温(25℃)将溶于50mL丙酮的3.25g托特罗定与1.72g的p-甲苯磺酸混合，将其悬浮50mL丙酮中，然后搅拌。通过氮回流设备除去上述混合物中的丙酮，当除去约70-80mL丙酮时开始出现固体沉淀。于室温(25℃)搅拌混合物1小时之后，过滤固体沉淀，然后用己烷洗涤。于室温(25℃)干燥反应产物24小时，获得4.13g(理论收率：83.0％)的终产物，是白色固体。
实施例6：制备托特罗定L-焦谷氨酸盐
于室温(25℃)将溶于50mL丙酮的3.25g托特罗定与1.29g的L-焦谷氨酸混合，将其悬浮50mL丙酮中，然后搅拌。在10分钟内，开始出现固体沉淀。对其加入50mL丙酮，并于室温(25℃)搅拌混合物1小时。过滤所得固体沉淀，然后用丙酮洗涤。于室温(25℃)干燥反应产物24小时，获得3.74g(理论收率：82.3％)的终产物，是白色固体。
实施例7：制备托特罗定苯甲酸盐
于室温(25℃)将溶于50mL丙酮的3.25g托特罗定与1.22g苯甲酸混合，将其悬浮50mL丙酮中，然后搅拌。在10分钟内，开始出现固体沉淀。对其加入50mL丙酮并于室温(25℃)搅拌混合物1小时。所得固体沉淀温度(25℃)for 24小时，获得3.27g(理论收率：73.1％)的终产物，是白色固体。
实施例8：制备托特罗定半萘-1，5-二磺酸盐
于室温(25℃)将溶于50mL丙酮的3.25g托特罗定与1.44g萘-1，5-二磺酸混合，将其悬浮50mL丙酮中，然后搅拌。在10分钟内，开始出现固体沉淀。对其加入50mL丙酮并于室温(25℃)搅拌混合物1小时。过滤所得固体沉淀，然后用丙酮洗涤。于室温(25℃)干燥反应产物24小时，获得3.68g(理论收率：78.4％)的终产物，是白色固体。
实施例9：制备托特罗定1-羟基-2-萘甲酸盐
于室温(25℃)将溶于50mL丙酮的3.25g托特罗定与1.88g的1-羟基-2-萘甲酸混合，将其悬浮50mL丙酮中，然后搅拌for 30分钟。通过氮回流设备除去上述混合物中的丙酮，当除去约10-20mL丙酮时开始出现固体沉淀。于室温(25℃)搅拌混合物1小时之后，过滤固体沉淀，然后用己烷洗涤。于室温(25℃)干燥反应产物24小时，获得4.32g(理论收率：84.1％)终产物，是浅褐色固体。
实施例10：制备托特罗定羟乙酸盐
于室温(25℃)将溶于50mL丙酮的3.25g托特罗定与0.76g羟乙酸混合，将其悬浮50mL丙酮中，然后搅拌。在10分钟内，开始出现固体沉淀。对其加入50mL丙酮并于室温(25℃)搅拌混合物1小时。过滤所得固体沉淀，然后用丙酮洗涤。于室温(25℃)干燥反应产物24小时，获得2.78g(理论收率：69.2％)的终产物，是白色固体。
实施例11：制备托特罗定视黄酸盐
于室温(25℃)将溶于15mL丙酮的3.25g托特罗定与3.0g视黄酸混合，将其悬浮于15mL丙酮中，然后搅拌。在10分钟内，对其加入30mL乙醇以完全溶解混合物。在1小时内开始出现固体沉淀)，于室温(25℃)搅拌混合物12小时。过滤所得固体沉淀，然后用丙酮洗涤。于室温(25℃)干燥反应产物24小时，获得1.40g(理论收率：22.4％)终产物，是黄色固体。
实施例12：配制包含托特罗定酸式盐的经皮贴剂
将上述实例5中制备的0.5g托特罗定甲苯磺酸盐溶于7mL乙醇，加入3mL丙二醇和3mL棕榈酸异丙酯，然后加入25g Durotak87-2287(National Starch)作为丙烯酸类粘合剂，于室温放置大约24小时以除去泡沫。通过使用自动涂布机将反应产物以厚度的600μm涂布于硅涂布的PET释放薄膜，允许在80℃干燥20分钟，通过用其覆盖使PET支撑薄膜分层。用长方形的切割器切割所得产物以最终制得经皮贴剂。
实施例13：配制包含托特罗定酸式盐的胶囊剂
预先混合微晶纤维素(525g，90μm)和干燥玉米淀粉。然后，将预先混合物的一部分加至选自下式1-13化合物的托特罗定酸式盐(70g)，混合物过筛。然后，对其加入剩余的预先混合物并混合10分钟，过筛和然后再混合5分钟。将反应产物填充入合适尺寸的胶囊中以获得胶囊制剂。
实施例14：配制包含托特罗定酸式盐注射剂
将溶于注射用无菌水的氯化钠与丙二醇混合。将选自下式1-13化合物的托特罗定酸式盐加至混合物。溶解之后，对其加入注射用无菌水以制备具有目标浓度的溶液。通过无菌滤器过滤溶液，然后填充入用于注射容器的无菌安瓿。
试验实施例1：稳定性试验
设计该实验以证实各种托特罗定酸式盐的贮藏稳定性。
将药物处理为某些配制剂的关键是提供足够的贮藏稳定性。例如，对于片剂或胶囊剂需要它们在大气条件下具有稳定性，对于注射剂需要水分(水)中的稳定性，而对于贴剂，需要在大气条件下和水分(水)中的稳定性。
下表1显示在氧化条件下可比较的稳定性试验结果，其中托特罗定酒石酸盐和新的托特罗定酸式盐溶于0.3％过氧化氢溶液，于室温放置24小时，用HPLC定量全部有关物质的面积比。
另外，表1显示碱稳定性的可比较的试验结果，其中托特罗定酒石酸盐和新的托特罗定酸式盐溶于1M氢氧化钠溶液，于室温放置24小时，用HPLC定量全部有关物质的面积比。
[表1]托特罗定酸式盐的稳定性试验
[全部杂质：％面积]
Figure BPA00001232377200131
如上表1所示，各种新的托特罗定酸式盐，与常规游离碱或托特罗定酒石酸盐比较下，显示具有氧化条件下以及在酸和碱存在下的优秀贮藏稳定性。
试验实施例2：体外穿透试验之后的累积量测量
将常规托特罗定酒石酸盐和新的托特罗定酸式盐溶解或分散于丙二醇以获得10mg/mL的最终浓度。将1mL托特罗定盐加至装于无毛发小鼠皮肤上的Frantz池上。然后，于32℃定量穿透皮肤的托特罗定的量并测量其累积量。
[表2]
Figure BPA00001232377200141
如上所述，根据本发明的各种新托特罗定酸式盐显示它们是与常规托特罗定酒石酸盐的酸式盐比较更适于制备经皮药物递送系统的酸式盐，并且预期用于治疗膀胱过度活动症的药物组合物。
工业可应用性
本发明提供通过运用各种配制方法来有效率地经皮递送药物比如制备自液体无定形托特罗定游离碱的各种托特罗定酸式盐和自其获得的新药物化合物的方法。

Claims (13)

1.由下式3代表的托特罗定尿酸盐。
[式3]
Figure FPA00001232377100011
2.由下式4代表的托特罗定半己二酸盐。
[式4]
Figure FPA00001232377100012
3.由下式5代表的托特罗定龙胆酸盐。
[式5]
Figure FPA00001232377100013
4.由下式6代表的托特罗定苯磺酸盐。
[式6]
5.由下式7代表的托特罗定p-甲苯磺酸盐。
[式7]
Figure FPA00001232377100022
6.由下式8代表的托特罗定L-焦谷氨酸盐。
[式8]
Figure FPA00001232377100023
7.由下式9代表的托特罗定苯甲酸盐。
[式9]
Figure FPA00001232377100031
8.由下式10代表的托特罗定半萘-1，5-二磺酸盐。
[式10]
Figure FPA00001232377100032
9.由下式11代表的托特罗定1-羟基-2-萘甲酸盐。
Figure FPA00001232377100033
10.由下式12代表的托特罗定羟乙酸盐。
[式12]
Figure FPA00001232377100034
11.由下式13代表的托特罗定视黄酸盐。
[式13]
Figure FPA00001232377100041
12.用于治疗膀胱过度活动症的包含选自权利要求1至11中任一项的酸加成盐作为活性成分的药物组合物。
13.用于治疗膀胱过度活动症的包含选自权利要求1至11中任一项的酸加成盐作为活性成分的经皮药物递送系统组合物。
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