Wang Jhi-Joung, Sung K C, Huang Jeng-Fen, Yeh Chih-Hui, Fang Jia-You
Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan.
J Pharm Pharmacol. 2007 Jul;59(7):917-25. doi: 10.1211/jpp.59.7.0002.
Two alkyl esters of morphine, morphine propionate (MPR) and morphine enanthate (MEN), were synthesized as potential prodrugs for transdermal delivery. The ester prodrugs could enhance transdermal morphine delivery. The mechanisms of this enhancing effect were elucidated in this study. Both prodrugs were more lipophilic than their parent drug as evaluated by the skin/vehicle partition coefficient (log P) and capacity factor (log K'). The in-vitro skin permeation of morphine and its prodrugs from pH 6 buffer was in the order of MEN > MPR > morphine. MPR and MEN respectively enhanced the transdermal delivery of morphine by 2- and 5-fold. A contrary result was observed when using sesame oil as the vehicle. The prodrugs were stable against chemical hydrolysis in an aqueous solution, but were readily hydrolysed to the parent drug when exposed to skin homogenate and esterase. Approximately 98% MPR and approximately 75% MEN were converted to morphine in an in-vitro permeation experiment. The viable epidermis/dermis contributed to a significant resistance to the permeation of ester prodrugs. According to the data of skin permeation across ethanol-, alpha-terpineol-, and oleic acid-pretreated skin, MEN was predominantly transported via lipid bilayer lamellae in the stratum corneum. The intercellular pathway was not important for either morphine or MPR permeation.
合成了两种吗啡的烷基酯，即吗啡丙酸酯（MPR）和吗啡庚酸酯（MEN），作为经皮给药的潜在前药。酯类前药可增强吗啡的经皮递送。本研究阐明了这种增强作用的机制。通过皮肤/载体分配系数（log P）和容量因子（log K'）评估，两种前药均比其母体药物更具亲脂性。吗啡及其前药在pH 6缓冲液中的体外皮肤渗透顺序为MEN > MPR > 吗啡。MPR和MEN分别将吗啡的经皮递送提高了2倍和5倍。当使用芝麻油作为载体时，观察到相反的结果。前药在水溶液中对化学水解稳定，但暴露于皮肤匀浆和酯酶时很容易水解为母体药物。在体外渗透实验中，约98%的MPR和约75%的MEN转化为吗啡。有活力的表皮/真皮对酯类前药的渗透有显著阻力。根据乙醇、α-松油醇和油酸预处理皮肤的皮肤渗透数据，MEN主要通过角质层中的脂质双分子层薄片转运。细胞间途径对吗啡或MPR的渗透并不重要。
