Tammara V K, Narurkar M M, Crider A M, Khan M A
Division of Pharmaceutics and Medicinal Chemistry, School of Pharmacy, Northeast Louisiana University, Monroe 71209.
J Pharm Sci. 1994 May;83(5):644-8. doi: 10.1002/jps.2600830510.
Morpholinoalkyl esters (HCl salts) of diclofenac (1) were synthesized and evaluated in vitro and in vivo for their potential use as prodrugs for oral delivery. Prodrugs were freely soluble in simulated gastric fluid (SGF) and pH 7.4 phosphate buffer and showed a minimum of a 2000-fold increase in solubility over the parent drug. All prodrugs were more lipophilic than 1 as indicated by n-octanol/pH 7.4 buffer partition coefficients, but less lipophilic than 1 in terms of n-octanol/SGF partition coefficients. Potentiometrically determined ionization constants (pKas) were in the range of 7.52 to 8.40 at 25 degrees C. The chemical and enzymatic hydrolyses of prodrugs were evaluated in SGF/pH 7.4 phosphate buffer and rat plasma, respectively, at 37 degrees C. All prodrugs were quantitatively hydrolyzed to 1 by either chemical and/or enzymatic means. An increase in carbon chain length rendered the prodrugs more stable at pH 7.4, but less stable in SGF. In general, the esters were hydrolyzed rapidly in rat plasma at 37 degrees C, the half-lives of hydrolysis being in the range of 4.85 to 23.49 min. Based on in vitro results, prodrug 2 was chosen to evaluate solid-state stability, bioavailability, and in vivo ulcerogenicity. At elevated temperatures, the solid-state decomposition of 2 followed biphasic kinetics, with rapid decomposition occurring initially. The extent, but not the rate, of absorption was significantly greater in rats for prodrug 2 than 1 following single dose oral administration. Prodrug 2 was significantly less irritating to gastric mucosa than 1 following single and chronic oral administration in rats.
合成了双氯芬酸（1）的吗啉代烷基酯（盐酸盐），并在体外和体内对其作为口服给药前体药物的潜在用途进行了评估。前体药物可自由溶于模拟胃液（SGF）和pH 7.4的磷酸盐缓冲液，其溶解度比母体药物至少增加了2000倍。正辛醇/pH 7.4缓冲液分配系数表明，所有前体药物的亲脂性均高于1，但正辛醇/SGF分配系数表明其亲脂性低于1。在25℃下，电位滴定法测定的电离常数（pKa）在7.52至8.40范围内。分别在37℃下于SGF/pH 7.4磷酸盐缓冲液和大鼠血浆中评估了前体药物的化学和酶促水解。所有前体药物均通过化学和/或酶促方法定量水解为1。碳链长度的增加使前体药物在pH 7.4时更稳定，但在SGF中更不稳定。一般来说，酯在37℃的大鼠血浆中迅速水解，水解半衰期在4.85至23.49分钟范围内。基于体外结果，选择前体药物2来评估固态稳定性、生物利用度和体内致溃疡性。在升高的温度下，2的固态分解遵循双相动力学，最初会快速分解。单次口服给药后，大鼠体内前体药物2的吸收程度（而非速率）明显高于1。在大鼠单次和长期口服给药后，前体药物2对胃黏膜的刺激性明显小于1。
