Human skin permeation of 3-O-alkyl carbamate prodrugs of naltrexone

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 solubilitie...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 2009-08, Vol.98 (8), p.2611-2625
Main Authors: Vaddi, Haranath K., Banks, Stan L., Chen, Jianhong, Hammell, Dana C., Crooks, Peter A., Stinchcomb, Audra L.
Format: Article
Language:English
Subjects:
bioconversion
Biological and medical sciences
carbamates
cross-sectional area
General pharmacology
Humans
Medical sciences
Naltrexone
Naltrexone - chemistry
Naltrexone - metabolism
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
prodrugs
Prodrugs - chemistry
Prodrugs - metabolism
Skin Absorption - drug effects
Skin Absorption - physiology
skin permeation
Urethane - analogs & derivatives
Urethane - metabolism
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Summary: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. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2611–2625, 2009
ISSN:0022-3549
1520-6017
DOI:10.1002/jps.21594