Transdermal delivery system for zidovudine: in vitro, ex vivo and in vivo evaluation

• Published in: Biopharmaceutics & drug disposition Vol. 25; no. 1; pp. 9 - 20
• Main Authors: Narishetty, Sunil Thomas Kumar, Panchagnula, Ramesh
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.01.2004; Wiley
• Subjects: Adjuvants, Pharmaceutic - chemistry; Adjuvants, Pharmaceutic - pharmacokinetics; Administration, Cutaneous; Animals; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - pharmacokinetics; Area Under Curve; Biological and medical sciences; combination strategy; Drug Delivery Systems - methods; Drug Evaluation, Preclinical - methods; Gels; Hypromellose Derivatives; in vivo study; Injections, Intravenous; Male; Medical sciences; Menthol - chemistry; Menthol - pharmacokinetics; Menthol - therapeutic use; Methylcellulose - analogs & derivatives; Methylcellulose - chemistry; Methylcellulose - pharmacokinetics; Oleic Acid - chemistry; Oleic Acid - pharmacokinetics; Oleic Acid - therapeutic use; penetration enhancer; Permeability - drug effects; Pharmaceutical Vehicles - chemistry; Pharmaceutical Vehicles - pharmacokinetics; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; single and multiple transdermal applications; Skin - drug effects; Skin - ultrastructure; Skin Absorption - drug effects; Skin Absorption - physiology; skin irritation; Time Factors; zidovudine; Zidovudine - administration & dosage; Zidovudine - blood; Zidovudine - pharmacokinetics; Delivery system; penetration enhancer; RNA-directed DNA polymerase; Transdermal system; Enzyme; Toxicity; Transferases; Enzyme inhibitor; in vivo study; In vitro; Percutaneous route; In vivo; single and multiple transdermal applications; Nucleotidyltransferases; combination strategy; Dideoxynucleoside; Reverse transcriptase inhibitor; Antiviral; Skin; Nucleosidic analog; Pyrimidine nucleoside; Zidovudine; skin irritation
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.381

The objective of this study was to prepare a transdermal delivery system (TDS) for zidovudine (AZT) with a combination of menthol and oleic acid as penetration enhancers incorporated in hydroxypropyl methylcellulose, and to evaluate ex vivo as well as in vivo permeation across rat skin. It was found that AZT in gel formulation was stable in both refrigerated as well as accelerated stability conditions for 3 months and further, the gel did not significantly retard the permeability of AZT across the skin in comparison with solution formulation. Ex vivo steady state flux of AZT across rat skin from gel was 2.26 mg cm−2 h−1, which is sufficient to achieve therapeutic plasma concentrations. Intravenous pharmacokinetic parameters of AZT in rats were determined and used together with ex vivo flux data to generate theoretical plasma profiles of AZT and compared with plasma concentrations achieved after application of TDS. Further, steady state plasma concentrations of drug following multiple applications of TDS were determined and good correlations between ex vivo and in vivo data were observed. In addition, the combination of penetration enhancers used at 2.5% w/w in this study proved efficient in achieving sufficient enhancement in the transdermal permeability of AZT across rat skin with reduced skin irritation potential when compared with individual penetration enhancers at higher concentrations. Copyright © 2004 John Wiley & Sons, Ltd.