CN1745061A - 抗炎剂的十六烷基吡啶鎓盐以及含有该盐的药物组合物 - Google Patents

抗炎剂的十六烷基吡啶鎓盐以及含有该盐的药物组合物 Download PDF

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CN1745061A
CN1745061A CNA200480003068XA CN200480003068A CN1745061A CN 1745061 A CN1745061 A CN 1745061A CN A200480003068X A CNA200480003068X A CN A200480003068XA CN 200480003068 A CN200480003068 A CN 200480003068A CN 1745061 A CN1745061 A CN 1745061A
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cetyl pyridinium
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G·皮费里
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Abstract

双氯芬酸的十六烷基吡啶鎓盐。

Description

抗炎剂的十六烷基吡啶鎓盐以及 含有该盐的药物组合物
本发明涉及抗炎剂的十六烷基吡啶鎓盐以及含有该盐的药物组合物。
已知很多芳基乙酸和芳基丙酸及其与可药用有机和无机碱的碱式加成盐广泛用作系统性和局部性的非甾类抗炎药物(NSAIDs)。
大量文献详细记载了NSAIDs的疗效。然而，在具有有用的治疗活性的同时，还已知NSAIDs伴随着各种不良的副作用，特别是当其系统性给药时可能对胃粘膜产生副作用。因此，对于局部病症，优选通过局部给药。
最后，由于NSAIDs的酸形式几乎不溶于水，因此已经开发出很多种与可药用有机和无机碱形成的碱式加成盐。
某些NSAIDs形式，从相对方便的角度而言是指具有水溶性的碱式加成盐适合将其合并入供局部使用的药物剂型中，例如凝胶剂、乳膏剂、香膏剂、眼药水、漱口水、阴道洗液等。
另一方面，对于其它NSAIDs，如果不使用增溶剂例如醇类、表面活性剂等，其碱式加成盐在水中的溶解性并不足以制备得到供局部使用的药物剂型。
这样的一种NSAIDs是双氯芬酸(diclofenac)(2-(2，6-二氯苯胺基)苯基乙酸)。正如现有文献中已知的那样，唯一一种具有足够的水溶性从而可以制备得到其供局部使用的药物剂型的盐是胆碱盐(EP-A-0521393)。然而，这种盐具有胆碱的典型缺陷，表现为具有令人不快的气味和味道。因此，这些影响器官感觉的特性在用于局部治疗口腔疾病的药物剂型中尤其不利，例如漱口水和喷雾剂，其治疗活性相应地越高，那么其滞留在粘膜中的时间就越长。
另外，还已知局部炎症往往是因为细菌感染而持续很长时间或伴随细菌感染同时出现或者还可能随后需要进行手术治疗。对于这两种情形以及抗炎治疗，为了治疗或预防的目的，很有必要服用抗菌剂。
因此，应该制备一种供局部使用的药物剂型，它含有两种不同化合物的联合物：可完全溶于水中的NSAID碱式加成盐、以及同样可完全溶于水中的抗菌剂。然而，寻找到两种除了具有上述理化性质、同时还具有最佳的抗菌活性谱的化合物，并且这两种化合物还可以互相配伍从而获得长时间保持稳定的药物剂型绝非轻而易举的事情。
现在已经发现，双氯芬酸的十六烷基吡啶鎓(1-十六烷基吡啶鎓)盐具有上述特性。
更令人惊喜地发现，虽然该盐不能充分溶解于水中，但是在水存在下，它很容易合并入一定量的空气而膨胀得到具有凝胶状粘度的溶液/混悬液。这种性质在制备供局部用的药物剂型中特别有利，这是因为不再需要加入粘性赋型剂。
另外，这种盐还相对比较可口。
这种盐为具有尖锐的熔点(52-55℃)的稳定结晶固体。
其在水存在下的稳定性实质上无限稳定，因此足以用于药物用途。
因此，本发明一方面涉及式(I)的双氯芬酸的十六烷基吡啶鎓盐
Figure A20048000306800051
本发明另一方面涉及一种方法，它包括根据下述反应路线在适宜溶剂中制备双氯芬酸的十六烷基吡啶鎓盐(I)：
Figure A20048000306800052
(1)+XY
其中
X是H或者无机或有机阳离子，以及
Y是OH或卤素，
然后通过常规方法分离所得到的盐(I)。
优选阳离子的实例是碱金属。
在第一优选实施方案中，将双氯芬酸的钠盐与十六烷基吡啶鎓氯化物反应。
在第二优选实施方案中，将双氯芬酸(X＝H)与十六烷基吡啶鎓氢氧化物反应。
优选的溶剂是水。其它适宜溶剂的实例有脂族烃、芳族烃、酮、以及低分子量的卤代烃。
优选该低分子量的脂族卤代烃含有1-3个碳原子。更优选其选自二氯甲烷、氯仿、四氯化碳、二氯乙烷、三氯乙烷、四氯乙烷、三氯乙烯和三氯丙烷。
通过常规方法例如相分离或溶剂蒸发分离由此形成的本发明的盐(I)。
本发明又一方面涉及药物组合物，它含有有效剂量的双氯芬酸的十六烷基吡啶鎓盐(I)以及至少一种可药用惰性成分。
优选将本发明的可药用组合物制成适宜的剂型形式。
适宜的剂型实例有片剂、胶囊剂、包衣片剂、颗粒剂、溶液剂和口服糖浆剂；供局部给药的霜剂、凝胶剂、软膏剂、香膏剂、加药牙膏、加药硬膏剂、眼药水、漱口水以及阴道洗液；供直肠给药的栓剂、通过注射给药的灭菌溶液剂、以及气雾剂。
优选供局部给药剂型。
该剂型还可以含有本领域熟知的其它常规成分，例如：防腐剂、稳定剂、缓冲剂、用于调节渗透压的盐、甜味剂、乳化剂、着色剂、调味剂等。
特别优选为具有凝胶状粘度的溶液剂或混悬剂。它们可以通过简单地加入水而方便地制备得到。通常，本发明盐和水的重量比例为1∶1至1∶15。有利地，还可以加入防腐剂和调味剂。根据本发明的具有凝胶状粘度的混悬剂的特性之一在于不必加入粘性聚合物，例如聚硅氧烷、泊洛沙姆、羧甲基纤维素、羧乙烯基聚合物等，而为了得到凝胶通常需要加入这些粘性聚合物。
如果特殊治疗需要的话，本发明的药物组合物可以含有同时服用是有用的其它药理活性成分。
在本发明的药物组合物中，双氯芬酸的十六烷基吡啶鎓盐(I)的剂量可以在较宽范围内变化，这取决于各种已知的因素，例如被治疗疾病的类型、疾病的严重程度、患者体重、剂型、给药方法以及每日服药的次数。
当然，根据双氯芬酸和十六烷基吡啶鎓在治疗功能方面所具有的已知活性，本领域技术人员可以按照常识方便地确定该最佳剂量。
本发明药物组合物的剂型可以根据药剂师所熟知的各种方法制备，这些方法包括混合、制粒、压制、溶出、灭菌等。
有利的是，本发明的药物组合物可用于创伤学、静脉学、牙口腔学、喉科学、耳科学、鼻科学、眼科学、泌尿学、妇科学、直肠病学、皮肤病学等领域。
下面的实例用于对本发明进行示例说明，而不是对其构成限制。
实施例1
制备双氯芬酸的十六烷基吡啶鎓盐(方法A)
将预热至60℃的十六烷基吡啶鎓氯化物单水合物(5.35g；14.94mmol)的水(60mL)溶液迅速逐滴加入至双氯芬酸钠(5.0g；15.72mmol)的水(50mL)溶液中，同时在60℃下搅拌。
在60℃下搅拌3小时候，冷却溶液。形成两相。收集下层的油相，同时水相用二氯甲烷(70mL)萃取。
将油相溶解于二氯甲烷(20mL)中，从而分离水相，将其弃去。
合并上述两份有机相，用无水硫酸钠干燥，真空蒸发至干。油性残余物(8.87g)通过在冷异丙基醚(25mL)中研制凝固，得到熔点为52-55℃的结晶状白色固体。
H2O(K.F.)；3.1％：1H-NMR(CDCl3)δ0.88(t，3H，J＝6.4Hz)，1.10-1.40(m，26H)，1.79-1.97(m，2H)，3.05(s，2H，H2O)，3.66(s，2H)，4.69(t，2H，J＝7.2Hz)，6.44(d，1H，J＝7.4Hz)，6.74-7.01(m，3H)，7.18(d，1H，J＝6.2Hz)，7.29(d，2H，J＝9.0Hz)，7.78-7.87(m，2H)，8.12-8.22(m，1H)，8.96(d，2H，J＝5.6Hz)，9.62(bs，1H)。
实施例2
制备双氯芬酸的十六烷基吡啶鎓盐(方法B)
将双氯芬酸钠(3.18g；10mmol)和十六烷基吡啶鎓氯化物(3.40g；10mmol)一起在室温下于二氯甲烷(40mL)中搅拌反应，直到交换反应基本上完全(大约30分钟)。
通过减压过滤除去所形成的氯化钠之后，有机溶液用水(5mL)洗涤。从乳液中分离除去水，有机相用无水硫酸钠干燥。除去溶剂，残余物溶解于异丙基米中，在冷冻条件下静置过夜。
通过过滤收集所形成的固体产物，并减压干燥。
从而得到白色固体(5.4g)；m.p.52-55℃，波谱特征与实施例1中报道的相同。
实施例3
供局部用的凝胶剂/混悬剂
双氯芬酸的十六烷基吡啶鎓盐           ：1.00g
纯化水                               ：4.00g
实施例4
漱口水
根据常规方法制备得到具有下述组成的溶液剂：
双氯芬酸的十六烷基吡啶鎓盐            ：0.20g
木糖醇                                ：10.0g
苯甲酸钠                              ：1.00g
天然香精                              ：0.30g
着色剂E114                            ：0.20g
纯化水适量至                          ：100g
实施例5
加药牙膏
根据常规方法制备得到具有下述组成的牙膏：
双氯芬酸的十六烷基吡啶鎓盐            ：0.10g
木糖醇                                ：5.00g
单氟硼酸钠                            ：0.15g
天然香精                              ：0.45g
十二烷基硫酸钠                        ：0.10g
黄原胶                                ：10.0g
着色剂E131                            ：0.20g
纯化水适量至                          ：100g
实施例6
牙用凝胶剂
根据常规方法制备得到具有下述组成的凝胶剂：
双氯芬酸的十六烷基吡啶鎓盐            ：1.00g
KathomTM                             ：0.65g
乙二胺四乙酸二钠                      ：0.10g
聚乙氧化的氢化蓖麻油                  ：6.00g
泊洛沙姆TM407                        ：22.0g
聚山梨醇酯                            ：6.00g
氯化钠                                ：0.50g
灭菌纯化水适量至                   ：100g
实施例7
直肠用香膏剂
根据常规方法制备得到具有下述组成的花香膏：
双氯芬酸的十六烷基吡啶鎓盐         ：0.50g
苯佐卡因                           ：1.00g
液体石蜡                           ：3.00g
聚乙二醇(混合物)                   ：50.0g
白色凡士林油                       ：10.0g
丙二醇                             ：10.0g
滑石                               ：5.00g
灭菌纯化水适量至                   ：100g

Claims (11)

1.式(I)的双氯芬酸的十六烷基吡啶鎓盐
Figure A2004800030680002C1
2.根据权利要求1的双氯芬酸的十六烷基吡啶鎓盐(I)，其特征在于：其在52-55℃熔化。
3.一种方法，它包括根据下述反应路线在适宜溶剂中制备双氯芬酸的十六烷基吡啶鎓盐(I)：
Figure A2004800030680002C2
其中
X是H或者无机或有机阳离子，以及
Y是OH或卤素，
然后通过常规方法分离所得到的盐(I)。
4.根据权利要求3的方法，其特征在于：X是碱金属。
5.根据权利要求3的方法，其特征在于：Y是Cl。
6.根据权利要求3的方法，其特征在于：所述溶剂是水。
7.根据权利要求3的方法，其特征在于：所述溶剂是低分子量的卤代烃。
8.根据权利要求7的方法，其特征在于：所述卤代烃含有1-3个碳原子。
9.根据权利要求8的方法，其特征在于：所述卤代烃选自二氯甲烷、氯仿、四氯化碳、二氯乙烷、三氯乙烷、四氯乙烷、三氯乙烯和三氯丙烷。
10.药物组合物，其特征在于：它含有有效剂量的双氯芬酸的十六烷基吡啶鎓盐(I)以及至少一种可药用惰性成分。
11.根据权利要求10的药物组合物，其特征在于：所述双氯芬酸的十六烷基吡啶鎓盐(I)在52-55℃熔化。
CNB200480003068XA 2003-02-14 2004-02-12 抗炎剂的十六烷基吡啶鎓盐以及含有该盐的药物组合物 Expired - Fee Related CN1318389C (zh)

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