Transdermal delivery of levonorgestrel

Abstract

This review of the research and development of transdermal delivery systems for levonorgestrel and combinations of levonorgestrel and estrogens also contains explanatory material on skin structure and absorption of drugs by diffusion and partition, permeability and use of enhancers to facilitate absorption, use of pro-drugs and derivatives, and cutaneous side effects. Drug absorption entails diffusion through the lipophilic stratum corneum and the hydrophilic epidermis, and between the two layers. Diffusion of levonorgestrel is driven by the saturated solution in the medium, such as ethanol, but the rate was insufficient. The target delivery rate for levonorgestrel used alone as a contraceptive is 35 mcg/day for transdermal use, which would require a delivery rate of 0.3 mcg/sq.cm. Ethyl acetate was found to be the best "penetration enhancer," speeding absorption 17-fold in rat skin. Levonorgestrel in ethyl acetate diffused through human cadaver skin at a rate requiring a patch of 7.5 sq. cm. Use of pro-drugs and derivatives is based on the theory that even though the derivative may diffuse more slowly because of its larger size, it is more soluble in both lipophilic and hydrophilic media. The best pro-drug was levonorgestrel-glycidol, with a 32-fold increase in penetration. Pro-drugs have the drawback of requiring complete FDA approval. They are hydrolyzed in skin to the native steroid, however. The type of transdermal delivery system needed for levonorgestrel is a membrane-based patch with a reservoir. Ethylene vinyl acetate copolymer systems have been tested or rabbits and in Phase I clinical trials. The micro-reservoir systems has been marketed for estradiol in a 3.5-day patch. A similar system has been developed experimentally using levonorgestrel and estradiol combined. Most transdermal systems cause mild skin irritation in a high proportion of users, but the likelihood of contact allergy or urticaria with levonorgestrel is minimal. Development of a transderm system with levonorgestrel and ethyl acetate, which is generally recognized as safe (GRAS), would be feasible as soon as the stability of levonorgestrel in ethyl acetate is defined.