Human Skin Permeation of 3-O-Alkyl Carbamate Prodrugs of Naltrexone
Human Skin Permeation of 3-O-Alkyl Carbamate Prodrugs of Naltrexone
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DOI：
10.1002/jps.21594
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发表时间：
2009-08-01
影响因子：
3.8
通讯作者：
Stinchcomb, Audra L.
中科院分区：
文献类型：
--
作者：
Vaddi, Haranath K.;Banks, Stan L.;Stinchcomb, Audra L.
合成了阿片拮抗剂纳曲酮 (NTX) 的 N-单烷基和 N,N-二烷基氨基甲酸酯前药，并测定了它们在体外对人体皮肤的渗透性。还测定了相关的物理化学性质。大多数前药表现出比 NTX 更低的熔点、更低的水溶解度和更高的油溶解度。 N-单烷基氨基甲酸酯前药的通量值显着高于来自NTX和N,N-二烷基氨基甲酸酯的通量值。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化热高于NTX。 N-单烷基氨基甲酸酯前药比其 N,N-二烷基对应物具有更高的角质层/载体分配系数。皮肤中较高百分比的前药生物转化为 NTX 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比N-单烷基氨基甲酸酯前药更稳定。总之，NTX 的 N-单烷基氨基甲酸酯前药改善了 NTX 体外跨人体皮肤的全身递送。前药部分中的 N,N-二烷基取代降低了母体药物的皮肤渗透和血浆水解。氨基甲酸酯头基的横截面积是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。 (C) 2008 Wiley-Liss, Inc. 和美国药剂师协会 J Pharm Sci 98:2611-2625, 2009
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. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2611-2625, 2009