Thing Mette, Ågårdh Li, Larsen Susan, Rasmussen Rune, Pallesen Jakob, Mertz Nina, Kristensen Jesper, Hansen Martin, Østergaard Jesper, Larsen Claus Selch
Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
J Pharm Sci. 2014 Dec;103(12):4021-4029. doi: 10.1002/jps.24221. Epub 2014 Oct 29.
Long-acting nonsteroidal anti-inflammatory drug formulations for intra-articular injection might be effective in the management of joint pain and inflammation associated sports injuries and osteoarthritis. In this study, a prodrug-based delivery system was evaluated. The synthesized diclofenac ester prodrug, a weak base (pKa 7.52), has relatively high solubility at low pH (6.5 mg mL(-1) at pH 4) and much lower solubility at physiological pH (4.5 μg mL(-1) at pH 7.4) at 37°C. In biological media including 80% (v/v) human synovial fluid (SF), the prodrug was cleaved to diclofenac mediated by esterases. In situ precipitation of the prodrug was observed upon addition of a concentrated slightly acidic prodrug solution to phosphate buffer or SF at pH 7.4. The degree of supersaturation accompanying the precipitation process was more pronounced in SF than in phosphate buffer. In the rotating dialysis cell model, a slightly acidic prodrug solution was added to the donor cell containing 80% SF resulting in a continuous appearance of diclofenac in the acceptor phase for more than 43 h after an initial lag period of 8 h. Detectable amounts of prodrug were found in the rat joint up to 8 days after knee injection of the acidic prodrug solution.
用于关节内注射的长效非甾体抗炎药制剂可能对治疗与运动损伤和骨关节炎相关的关节疼痛和炎症有效。在本研究中，对一种基于前药的递送系统进行了评估。合成的双氯芬酸酯前药是一种弱碱（pKa 7.52），在低pH值（pH 4时为6.5 mg mL(-1)）下具有相对较高的溶解度，而在生理pH值（pH 7.4时为4.5 μg mL(-1)）下于37°C时溶解度低得多。在包括80%（v/v）人滑液（SF）的生物介质中，前药在酯酶的介导下裂解成双氯芬酸。将浓的微酸性前药溶液添加到pH 7.4的磷酸盐缓冲液或SF中时，观察到前药的原位沉淀。沉淀过程中伴随的过饱和度在SF中比在磷酸盐缓冲液中更明显。在旋转透析池模型中，将微酸性前药溶液添加到含有80% SF的供体细胞中，在最初8小时的延迟期后，在受体相中持续出现双氯芬酸超过43小时。在大鼠膝关节注射酸性前药溶液后长达8天，在大鼠关节中发现了可检测量的前药。
