Department of Pharmaceutical Sciences, University of Kentucky College of Pharmacy, Lexington, Kentucky 40536-0082, USA.
J Pharm Sci. 2009 Aug;98(8):2611-25. doi: 10.1002/jps.21594.
N-Monoalkyl and N,N-dialkyl carbamate prodrugs of naltrexone (NTX), an opioid antagonist, were synthesized and their in vitro permeation across human skin was determined. Relevant physicochemical properties were also determined. Most prodrugs exhibited lower melting points, lower aqueous solubilities, and higher oil solubilities than NTX. The flux values from N-monoalkyl carbamate prodrugs were significantly higher than those from NTX and N,N-dialkyl carbamates. The melting points of N-monoalkyl carbamate prodrugs were quite low compared to the N,N-dialkyl carbamate prodrugs and NTX. Heats of fusion for the N,N-dialkyl carbamate prodrugs were higher than that for NTX. N-Monoalkyl carbamate prodrugs had higher stratum corneum/vehicle partition coefficients than their N,N-dialkyl counterparts. Higher percent prodrug bioconversion to NTX in skin appeared to be related to increased skin flux. N,N-Dialkyl carbamate prodrugs were more stable in buffer and in plasma than N-monoalkyl carbamate prodrugs. In conclusion, N-monoalkyl carbamate prodrugs of NTX improved the systemic delivery of NTX across human skin in vitro. N,N-Dialkyl substitution in the prodrug moiety decreased skin permeation and plasma hydrolysis to the parent drug. The cross-sectional area of the carbamate head group was the major determinant of flux of the N-monoalkyl and N,N-dialkyl carbamate prodrugs of NTX.
纳曲酮（NTX）的 N-单烷基和 N,N-二烷基氨基甲酸酯前药是一种阿片类拮抗剂，被合成并测定了它们在人体皮肤中的体外渗透情况。还测定了相关的物理化学性质。大多数前药的熔点、水溶解度和油溶解度均低于 NTX。N-单烷基氨基甲酸酯前药的通量值明显高于 NTX 和 N,N-二烷基氨基甲酸酯。与 N,N-二烷基氨基甲酸酯前药和 NTX 相比，N-单烷基氨基甲酸酯前药的熔点相当低。N,N-二烷基氨基甲酸酯前药的熔融热高于 NTX。N-单烷基氨基甲酸酯前药在角质层/载体中的分配系数高于其 N,N-二烷基对应物。皮肤中前药转化为 NTX 的百分比增加似乎与皮肤通量增加有关。N,N-二烷基氨基甲酸酯前药在缓冲液和血浆中的稳定性均高于 N-单烷基氨基甲酸酯前药。总之，NTX 的 N-单烷基氨基甲酸酯前药提高了 NTX 在人体皮肤中的全身递送。前药部分的 N,N-二烷基取代降低了皮肤渗透和母体药物的血浆水解。氨基甲酸酯头部基团的横截面积是 NTX 的 N-单烷基和 N,N-二烷基氨基甲酸酯前药通量的主要决定因素。
