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CN1371277A - 药用曲马朵盐 - Google Patents

药用曲马朵盐 Download PDF

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CN1371277A
CN1371277A CN00812159A CN00812159A CN1371277A CN 1371277 A CN1371277 A CN 1371277A CN 00812159 A CN00812159 A CN 00812159A CN 00812159 A CN00812159 A CN 00812159A CN 1371277 A CN1371277 A CN 1371277A
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tramadol
medicament
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salt according
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CN1200700C (zh
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H·库格尔曼
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Gruenenthal GmbH
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Abstract

本发明涉及由活性剂曲马朵和至少一种糖代用品组成的药用盐。本发明还涉及含有这些盐的药物、这些盐在制备药物中的应用和含有这些盐的给药形式。

Description

药用曲马朵盐
本发明涉及活性物质曲马朵和至少一种糖代用品的药用盐、含有这些盐的药物、这些盐在制备药物中的应用，并且涉及含有这些盐的给药形式。
盐酸曲马朵-(1RS，2RS)-2-[(二甲基氨基)甲基]-1-(3-甲氧基苯基)-环己醇盐酸盐—适合用来控制强烈的和中等强度的疼痛，并且可以治疗尿失禁。US-PS-3,652,589和WO98/46216公开了活性物质曲马朵与无机酸(如硫酸、硝酸或磷酸)和有机酸(如苯甲酸、水杨酸或邻苯二甲酸)的其它盐在制备控制疼痛或治疗尿失禁的药物中的应用。
尽管该盐在疼痛控制中功效优异，但活性物质曲马朵及其速溶盐的非常苦的味道使患者无法遵从剂量指导，并且无法接受那些在他们摄取后就立刻释放出这种活性物质的药物。包衣和复合方法，如薄膜包衣的应用，可以改善味道，但却妨碍了该活性物质由药物形式中即时释放。
由于盐酸曲马朵的水溶性非常好，所以缓释药物形式的制备也非常困难，并且导致需要昂贵的阻滞加工，例如缓释包衣的应用或把该活性物质包埋在缓释骨架中。
所以，本发明的目的是提供活性物质曲马朵的药用化合物，其没有曲马朵的苦味，并且与常规、广泛使用的盐(即盐酸曲马朵)相比可以更加有效地缓释曲马朵。
按照本发明，该目的是通过活性物质曲马朵和至少一种糖代用品的药用盐的制备来达到。
这些盐在水和/或含水流体中的溶解度优选≤100mg/ml，特别优选≤30mg/ml且非常特别优选≤10mg/ml。
适用的糖代用品是任何酸性糖代用品，其通过产生一种带有至少一个负电荷的形式，能够与活性物质曲马朵形成盐。该糖代用品优选糖精、环己基氨基磺酸盐(酯)、乙酰舒泛或这些糖代用品的至少两种的混合物。
为了制备本发明的药用盐，使曲马朵和/或至少一种非常易溶于水的曲马朵盐与至少一种糖代用品的至少一种游离酸和/或至少一种水溶性盐反应。所述的曲马朵的盐优选与糖代用品的水溶性盐在中性pH的含水介质内反应。优选用盐酸曲马朵作为所述的曲马朵的盐。所用的糖代用品的盐优选是糖精和/或环已基氨基磺酸盐和/或乙酰舒泛的钠、钾、钙或铵盐；和/或所用糖代用品的游离酸优选是糖精/环己基氨基磺酸盐和/或乙酰舒泛的游离酸。如果曲马朵自身与糖代用品的游离酸反应，他们是在有机溶剂中反应，优选在链烷醇中反应，并且特别优选在乙醇中反应。
本发明还提供药物，其中含有至少一种作为药物活性物质的本发明的曲马朵盐以及任选的其它活性物质和/或辅助物质。所述的药物适合用来控制/治疗疼痛、尿失禁、咳嗽、炎症和变应性反应、抑郁、药物和/或酒精滥用、胃炎、腹泻、心血管疾病、呼吸疾病、精神病和/或癫痫。
本发明还提供至少一种本发明的曲马朵盐在制备用于控制/治疗疼痛、尿失禁、咳嗽、炎症和变应性反应、抑郁、药物和/或酒精滥用、胃炎、腹泻、心血管疾病、呼吸疾病、精神病和/或癫痫的药物中的应用。
施用给患者的活性物质的量根据患者的体重、给药类型、适应症和疾病的严重程度而变化。通常，至少一种本发明的曲马朵盐是以其中活性物质曲马朵的含量相当于1-600mg/天的量给药。
本发明还提供含有至少一种本发明的曲马朵盐的给药形式。
曲马朵和糖代用品在本发明的药物形式或给药形式中的量的选择应使活性物质曲马朵的苦味被糖代用品的味道弥补。本发明的给药形式优选含有等摩尔量的糖代用品和曲马朵，即两种成分事实上完全为盐形式。根据所用糖代用品的甜度和/或对曲马朵的预期释放轮廓(profile)，本发明的给药形式也可以含有不同摩尔量的曲马朵和糖代用品。
本发明的给药形式可以是固体、半固体或液体，优选口服药物制剂，其除了含有活性物质曲马朵与至少一种糖代用品的盐以外，可以任选地含有其它活性物质和常规辅助物质和添加剂。
本发明的固体给药形式优选是多粒子制剂，特别优选是颗粒、微粒、微片或小丸剂的形式且填充或不填充在胶囊中，或者片剂的形式，优选快速崩解片或泡腾片，所述的片剂优选是由小丸剂压制或通过热熔挤出法制成。
如果本发明的固体给药形式用来经肠道释放活性物质，它们必须具有至少一个抵抗胃液的包衣，其溶解为pH依赖性的。由于这种包衣，该形式在通过胃时不溶解而只在肠道内释放出活性物质。
本发明的给药形式还优选配制为凝胶、口香糖、果汁，特别优选含油或含水果汁；或喷雾剂，特别优选舌下喷雾剂。
本发明的给药形式的一个经胃释放曲马朵的优选实施方式是由例如含油或含水果汁组成，其不延迟释放活性物质。
至少一种缓释包衣的应用、活性物质的盐在至少一种缓释骨架中的包埋或者它们的联合可以实现阻滞作用，并还由此进一步改进活性物质曲马朵以及任选其它活性物质的释放。
阻滞作用适宜借助于缓释包衣来完成。适用的缓释包衣包括非水溶性蜡或聚合物，例如丙烯酸树脂，优选聚(甲基)丙烯酸酯；或非水溶性纤维素，优选乙基纤维素。这些物质是现有技术已知的，如Bauer，Lehmann，Osterwald，Rothgang“berzogene Arzneiformen”(“包衣药物形式”)，Wissenschaftliche Verlagsgesellschaft mbHStuttgart，1988，自69起，其在此引入作为参考且由此构成公开内容的一部分。
为了调节活性物质的释放速率，缓释包衣除了含有非水溶性聚合物以外，可以任选地含有：至多30％(重量)的非阻滞性、水溶性的聚合物，如聚乙烯吡咯烷酮，或水溶性纤维素，优选羟丙基甲基纤维素或羟丙基纤维素；和/或亲水性成孔剂，如蔗糖、氯化钠和甘露糖醇；和/或已知的增塑剂。
为了阻滞这种活性物质的盐，本发明的给药形式也可以优选地含有存在于缓释骨架内的所述盐，优选成为均匀分布。
可使用的骨架材料是所属领域技术人员已知的生理相容性、亲水性材料。所用的亲水性骨架材料优选聚合物，并且特别优选纤维素醚、纤维素酯和/或丙烯酸树脂。所用的骨架材料非常特别优选乙基纤维素、羟丙基甲基纤维素、羟丙基纤维素、羟甲基纤维素、聚(甲基)丙烯酸和/或其衍生物，如其盐、酰胺或酯。
同样优选的骨架材料是由疏水性材料组成的那些，如疏水性聚合物、蜡、脂肪、长链脂肪酸、脂肪醇或相应的酯或醚或其混合物。所用的疏水性材料特别优选C12-C30脂肪酸一-或二甘油酯和/或C12-C30脂肪醇和/或蜡，或其混合物。
所用的缓释骨架材料也可以是所述亲水性和疏水性材料的混合物。
本发明的给药形式可以通过所属领域技术人员熟知的那些不同方法制备。这些方法是现有技术已知的，如“PharmaceuticalPelletization Technology”，Drugs and the PharmaceuticalSciences Vol 37，Verlag Marcel Decker或“Remington’sPharmaceutical Sciences”，Mack Publishing Company，Easton，Pennsylvania。将它们在此引入作为参考并由此构成公开内容的一部分。
如果本发明的给药形式如片剂或丸剂具有包衣，它们可以通过常规方法涂布，譬如通过包衣锅法，通过溶液、分散体或混悬液的喷雾，通过热熔法或通过粉末涂布法。
由本发明用来经口腔粘膜释放曲马朵的给药形式，例如由凝胶、口香糖或舌下喷雾剂，在不使用缓释骨架和/或缓释包衣的情况下获得基本上恒定的曲马朵释放。
由本发明用来经肠道释放曲马朵的给药形式，例如由胶囊、片剂、粒剂或丸剂，在不使用缓释骨架和/或缓释包衣，但使用抵抗胃液包衣的情况下同样可获得恒定的曲马朵释放。
此外，本发明的给药形式的优点在于，曲马朵的强烈苦味被同时释放的糖代用品所弥补。这提高了剂量指导的患者依从性，并使含有活性物质曲马朵的药物被更加广泛地接受。本发明的药物还适合糖尿病患者。与盐酸曲马朵相比，由曲马朵和糖代用品和/或辅助物质生成的、在水中和/或含水体液中的溶解度≤100mg/ml的盐利用常规阻滞方法产生更加有效的活性物质曲马朵的阻滞作用。因此，可以更加简便、对成本更有利地制备含有本发明的这些曲马朵盐的缓释药物。这也适合于本发明的药物的其它改变方案，例如具有抵抗胃液包衣的那些方案。
曲马朵和糖代用品的盐的溶解度测定如下：
将(1RS，2RS)-2-[(二甲基氨基)甲基]-1-(3-甲氧基苯基)-环己醇和相应的糖代用品的盐置于25℃的去离子水中，使其用量(例如约1g的曲马朵糖精盐在10ml去离子水中)能够在此温度下形成饱和溶液，其在25℃下搅拌20小时后仍然饱和。任选通过预备试验可以测得曲马朵和适当糖代用品的盐的所需量。当曲马朵和适当糖代用品的未溶解盐业已沉降后，吸出澄清的上清液且以至少3000rpm的速度离心5分钟。将如此所得澄清上清液的一部分转移至HPLC样品瓶中并以盐酸曲马朵作为标准测定曲马朵和适当糖代用品的盐的浓度。
本发明借助于下列实施例进行说明。说明的作用只是举例而不限定本发明的广义实质。
实施例1
为了制备曲马朵糖精盐，在加热下，将30.0g(0.1mol)盐酸曲马朵和20.53g(0.1mol)糖精钠或24.13g糖精钠二水合物(0.1mol)分别完全溶于尽可能少量的水中。随后搅拌下将两种溶液混合。冷却后，只需短时间后水溶液中就可结晶出曲马朵糖精盐，通过常规方法分离且用乙醇纯化。
按照上述方法测定了如此得到的曲马朵糖精盐在水中的溶解度，结果为22.5mg/ml。
实施例2
将30.0g(0.1mol)盐酸曲马朵溶于20g水，并且在搅拌下与20.13g(0.1mol)环己基氨基磺酸钠在36g水中的溶液缓慢混合。随后将所得溶液在5℃的温度下保存16小时。得到结晶形式的曲马朵环己基氨基磺酸盐，通过常规方法分离且用乙醇纯化。
实施例3
将30.0g(0.1mol)盐酸曲马溶于13g水中，并且在搅拌下与20.13g(0.1mol)乙酰舒泛钾在53g水的溶液缓慢混合。随后将所得溶液在5℃的温度下保存过夜。得到结晶形式的曲马朵乙酰舒泛盐，通过常规方法分离且用乙醇纯化。
实施例4
口服凝胶的制备通过，首先在80℃下把0.33g对羟基苯甲酸甲酯、0.05g对羟基苯甲酸丙酯和75.0g木糖醇溶于197.63g净化水，随后将该混合物冷却至40℃。此后搅拌下加入0.75g曲马朵糖精盐，随后加入2g黄原胶，将该混合物进一步搅拌1小时并且补充因蒸发损失的水。冷却至室温后，在搅拌下将该混合物用0.625g柑橘矫味剂(Orange-Mandarine Flavor)10888-56(Givaudan Roure FlavorsLtd.CH 8600 Dübendorf)矫味。
实施例5
将5g粉碎口香糖物块(Popeye Amural Confections，Yorkville，Illinois，USA)在Fanta盘中加热至30-40℃。用捣棒将150mg曲马朵糖精盐掺混在该粘的口香糖物块中。在聚四氟乙烯涂层的模子中将均化的物块分为1g的部分。鉴于对比味道试验，通过相同的方法用等化学计量量的曲马朵(相当于100mg盐酸曲马朵)制备口香糖。
味道试验的结果是，含有盐酸曲马朵的口香糖只在短时间后就具有难以忍受的苦味并且不再能够咀嚼。含有曲马朵糖精盐的口香糖在开始时具有良好的味道并且在长时间咀嚼后仍然宜人。
实施例6
为了制备含水果汁，首先在80℃下把0.33g对羟基苯甲酸甲酯、0.05g对羟基苯甲酸丙酯和75.0g木糖醇溶于198.37g净化水，随后使该混合物冷却至40℃，搅拌下加入0.75g曲马朵糖精盐。随后加入0.25g黄原胶，将该混合物进一步搅拌1小时并补充因蒸发损失的水。冷却至室温后，搅拌下，该混合物用0.075g Tutti Frutti9/008897(Dragoco Gerberding & Co.AG，37603 Holzminden)矫味。
实施例7
为了制备含油果汁，在80℃下将0.33g对羟基苯甲酸甲酯和0.05g对羟基苯甲酸丙酯溶于209.88g的用饱和C8-10脂肪酸酯酯化的甘油。使该混合物冷却至25℃，在搅拌下将37.5g粉碎的木糖醇、1.25g高分散二氧化硅和0.75g曲马朵糖精盐悬浮在其中。在搅拌下，该混合物用0.0125g血橙9/028658(Dragoco Gerberding & Co.AG，37603 Holzminden)矫味。
实施例8
舌下喷雾剂的制备是通过，首先在80℃下把0.33g对羟基苯甲酸甲酯、0.05g对羟基苯甲酸丙酯和75.0g木糖醇溶于197.37g蒸馏水。随后使该溶液冷却至40℃且加入0.75g曲马朵糖精盐。随后加入0.15g黄原胶，将该混合物进一步搅拌1小时，并且补充因蒸发损失的水。将该溶液冷却至25℃且用0.75g的葡萄柚14391786(IFF，International Flavors & Fragrances GmbH，46446 Emmerich)矫味。

Claims (23)

1.曲马朵和至少一种糖代用品的药用盐。
2.按照权利要求1的药用盐，其特征在于该盐在水和/或含水多的体液中的溶解度≤100mg/ml，优选≤30mg/ml且特别优选≤10mg/ml。
3.按照权利要求1或2的药用盐，其特征在于所述的糖代用品是糖精、环己基氨基磺酸盐或乙酰舒泛。
4.含有权利要求1-3任一项的至少一种所述的曲马朵盐以及任选的其它活性物质和/或辅助物质的药物。
5.按照权利要求4的药物用于治疗/控制疼痛、尿失禁、咳嗽、炎症和变应性反应、抑郁、药物和/或酒精滥用、胃炎、腹泻、心血管疾病、呼吸疾病、精神病和/或癫痫。
6.按照权利要求1-3任一项的至少一种曲马朵盐在制备控制疼痛的药物中的应用。
7.按照权利要求1-3任一项的至少一种曲马朵盐在制备治疗尿失禁的药物中的应用。
8.按照权利要求1-3任一项的至少一种曲马朵盐在制备治疗咳嗽的药物中的应用。
9.按照权利要求1-3任一项的至少一种曲马朵盐在制备治疗炎症和变应性反应的药物中的应用。
10.按照权利要求1-3任一项的至少一种曲马朵盐在制备治疗抑郁的药物中的应用。
11.按照权利要求1-3任一项的至少一种曲马朵盐在制备治疗药品和/或酒精滥用的药物中的应用。
12.按照权利要求1-3任一项的至少一种曲马朵盐在制备治疗胃炎的药物中的应用。
13.按照权利要求1-3任一项的至少一种曲马朵盐在制备治疗腹泻的药物中的应用。
14.按照权利要求1-3任一项的至少一种曲马朵盐在制备治疗心血管疾病的药物中的应用。
15.按照权利要求1-3任一项的至少一种曲马朵盐在制备治疗呼吸性疾病的药物中的应用。
16.按照权利要求1-3任一项的至少一种曲马朵盐在制备治疗精神病的药物中的应用。
17.按照权利要求1-3任一项的至少一种曲马朵盐在制备治疗癫痫的药物中的应用。
18.按照权利要求1-3任一项的含有至少一种曲马朵盐以及任选的其它活性物质和/或辅助物质的给药形式。
19.按照权利要求18的给药形式，其特征在于它们是多粒子制剂，优选是颗粒、微粒、微片或丸剂的形式且填充或未填充在胶囊中；或是片剂、快速崩解片或泡腾片的形式；或是压缩为片剂的丸剂的形式。
20.按照权利要求19的给药形式，其特征在于它们具有至少一层抵抗胃液包衣。
21.按照权利要求18的给药形式，其特征在于它们配制为凝胶、口香糖、果汁，优选含油或含水果汁，或喷雾剂，优选舌下喷雾剂。
22.按照权利要求18-20任一项的或多项的给药形式，其特征在于它们具有至少一种缓释骨架。
23.按照权利要求18-20或22的一项或多项的给药形式，其特征在于它们具有至少一层缓释包衣。
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