Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
Int J Pharm. 2012 Dec 15;439(1-2):246-53. doi: 10.1016/j.ijpharm.2012.09.033. Epub 2012 Sep 23.
Intra-articular injection of two drugs in a sustained drug delivery system combining the use of lipophilic solution with the prodrug approach may provide efficient and prolonged postoperative pain treatment after arthroscopic procedures. In the present study, the concomitant release of N,N-diethyl glycolamide ester of naproxen and ropivacaine from an oil vehicle consisting of medium-chain triglycerides were investigated in vitro. The release into both phosphate buffer and 80% (v/v) synovial fluid at pH 7.4 was examined in two dialysis membrane-based release models. The ester prodrug exhibited high solubility in medium-chain triglyceride, a high partition coefficient and was rapidly converted to naproxen in synovial fluid. Compared to naproxen, the release of the prodrug from the oil was sustained. In synovial fluid, the reconversion to naproxen resulted in faster release compared to that observed using buffer. In both release models, the use of ropivacaine-prodrug combination provided concomitant release from the oil into synovial fluid with ropivacaine being released faster than naproxen. The use of lipophilic prodrugs that are converted fast to the parent drug in synovial fluid seems to be a feasible approach to obtain prolonged joint residence time.
在联合使用亲脂性溶液和前药方法的持续药物递送系统中，向关节内注射两种药物可能为关节镜手术后提供有效且持久的术后疼痛治疗。在本研究中，考察了由中链甘油三酯组成的油载体中萘普生的 N,N-二乙基甘醇酰胺酯和罗哌卡因的共同释放。在两种基于透析膜的释放模型中，考察了在磷酸盐缓冲液和 pH7.4 的 80%（v/v）滑液中的释放情况。酯前药在中链甘油三酯中具有高溶解度、高分配系数，并且在滑液中迅速转化为萘普生。与萘普生相比，前药从油中的释放更持久。与缓冲液相比，在滑液中，前药的再转化导致释放更快。在两种释放模型中，使用罗哌卡因-前药组合从油中向滑液中提供了共同释放，罗哌卡因的释放速度快于萘普生。在滑液中快速转化为母体药物的亲脂性前药的使用似乎是获得延长的关节驻留时间的可行方法。
