Larsen Susan W, Østergaard Jesper, Poulsen Sara V, Schulz Bjørn, Larsen Claus
Department of Pharmaceutics and Analytical Chemistry, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Eur J Pharm Sci. 2007 Jul;31(3-4):172-9. doi: 10.1016/j.ejps.2007.03.005. Epub 2007 Mar 19.
The present work describes the characterization of diflunisal salts of the analgesic agents bupivacaine, lidocaine, and morphine including their solubility behaviour and release characteristics from solutions and selected salt suspensions in vitro using the rotating dialysis cell model. The solubility of the 1:1 salts at pH 7.4 differed by a factor of 9 with the bupivacaine and lidocaine salts representing the poorest and most soluble salt (0.73 and 6.6mM, respectively). Common ion effects were observed for the diflunisal salts of bupivacaine and morphine when various concentrations of the lidocaine-diflunisal salt were present in aqueous buffer (pH 7.4). The most pronounced salting-out effect was observed for the poorest soluble salt. From Setschenow type plots apparent salting-out constants of 265 M(-1) (bupivacaine) and 54.7 M(-1) (morphine) were calculated. After instillation of mixed salt suspensions comprising the diflunisal salts of bupivacaine and lidocaine into the donor cell of the release model, lidocaine appeared rapidly in the acceptor phase. After clearance of lidocaine from the donor cell, equal and constant fluxes of bupivacaine and diflunisal were observed. The residence times of bupivacaine within the donor compartment was prolonged with increasing lidocaine-diflunisal salt load in the mixed suspensions whereas the slopes of the linear part of the bupivacaine release profiles were affected to a minor extent only. The obtained data indicate that local multimodal analgesia, characterized by rapid onset and extended duration of action, can be achieved upon injection of mixed suspensions of salts differing with respect to aqueous solubility comprising a common ion into a small body compartment (such as the joint cavity).
本研究描述了镇痛剂布比卡因、利多卡因和吗啡的双氟尼酸（二氟尼柳）盐的特性，包括它们的溶解行为以及在体外使用旋转透析池模型从溶液和选定的盐悬浮液中的释放特性。在pH 7.4条件下，1:1盐的溶解度相差9倍，布比卡因盐和利多卡因盐分别是溶解度最差和最好的盐（分别为0.73和6.6mM）。当水性缓冲液（pH 7.4）中存在不同浓度的利多卡因 - 双氟尼酸盐时，观察到布比卡因和吗啡的双氟尼酸盐存在同离子效应。对于溶解度最差的盐，观察到最明显的盐析效应。根据Setschenow型图，计算出表观盐析常数分别为265 M⁻¹（布比卡因）和54.7 M⁻¹（吗啡）。将包含布比卡因和利多卡因的双氟尼酸盐的混合盐悬浮液滴入释放模型的供体池中后，利多卡因迅速出现在受体相中。利多卡因从供体池中清除后，观察到布比卡因和双氟尼酸的通量相等且恒定。随着混合悬浮液中利多卡因 - 双氟尼酸盐负载量的增加，布比卡因在供体隔室内的停留时间延长，而布比卡因释放曲线线性部分的斜率仅受到轻微影响。所获得的数据表明，通过将在水溶性方面不同且包含共同离子的盐的混合悬浮液注射到小体腔室（如关节腔）中，可以实现以起效迅速和作用持续时间延长为特征的局部多模式镇痛。
