Transdermal Delivery of Zidovudine: Effect of Terpenes and Their Mechanism of Action

J Control Release. 2004 Mar 24;95(3):367-79. doi: 10.1016/j.jconrel.2003.11.022.

Abstract

The effect of various oxygen-containing monoterpenes such as cineole, menthol, alpha-terpineol, menthone, pulegone and carvone was investigated on ex vivo permeation of zidovudine (AZT) across rat skin. Furthermore, saturation solubility of AZT, its stratum corneum (SC)/vehicle partition coefficient and activation energy for diffusion across skin with or without terpene(s) in vehicle (66.6% ethanol in water) were determined to understand their mechanism of action. All the terpenes studied significantly increased transdermal flux of AZT in comparison to vehicle (p<0.05) and their enhancement activities are in the following decreasing order: cineole>menthol>menthone approximately pulegone approximately alpha-terpineol>carvone>vehiclewater. On the other hand, saturation solubility and SC/vehicle partition coefficient of AZT were not significantly altered (p>0.05) by terpenes. Activation energies of AZT permeation across rat skin from water, vehicle and cineole in vehicle were measured to be 20.4, 18.6 and 10.6 kcal/mol, respectively. Interactions between terpenes and SC lipids were studied with molecular modeling and found that terpenes form hydrogen bonds (bond lengths<2 A) with lipid head groups. The mechanism of permeation enhancement of AZT by terpenes was explained with thermodynamic activity, SC/vehicle partition coefficient, activation energy and molecular modeling studies.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Pharmaceutic / chemistry
  • Adjuvants, Pharmaceutic / pharmacokinetics
  • Adjuvants, Pharmaceutic / standards
  • Administration, Cutaneous*
  • Algorithms
  • Animals
  • Chemistry, Pharmaceutical / methods
  • Diffusion
  • Drug Carriers / chemistry
  • Drug Carriers / pharmacokinetics
  • Drug Carriers / standards
  • Drug Evaluation, Preclinical / methods
  • Ethanol / chemistry
  • Ethanol / pharmacokinetics
  • Excipients / chemistry
  • India
  • Male
  • Models, Biological
  • Monoterpenes / chemistry
  • Monoterpenes / pharmacokinetics
  • Monoterpenes / standards
  • Permeability / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Skin Absorption / drug effects
  • Skin Absorption / physiology
  • Thermodynamics
  • Zidovudine / administration & dosage*
  • Zidovudine / chemistry
  • Zidovudine / therapeutic use

Substances

  • Adjuvants, Pharmaceutic
  • Drug Carriers
  • Excipients
  • Monoterpenes
  • Ethanol
  • Zidovudine