Chirality and its implications in transdermal drug development

Today more than 50% of marketed drugs are chiral. It has been well recogniz ed that the stereochemistry of chiral drugs has a major influence on their pharmacological, pharmacokinetic, and toxicological actions. Studies on ena ntiomeric differences in the percutaneous permeation of chiral compounds ha ve been actively pursued in recent years. Stratum corneum, the rate-limitin g barrier in transdermal permeation, is made up of keratin and ceramide, wh ich could potentially provide chiral environment. Transdermal delivery is o ften facilitated by the presence of penetration enhancers, which act primar ily by altering the diffusion by disrupting the highly ordered membrane str ucture or by affecting the partitioning behavior of die diffusant molecules . Enantioselective permeation was observed with some chiral excipients incl uding terpene enhancers. While studies on crystalline structures of pure en antiomers and racemates are helpful in understanding the basis for differen tiation of physicochemical properties, prediction and control of permeabili ty of enantiomers and racemates based on the physicochemical characteristic s would be highly beneficial. The flux characteristics of enantiomers and r acemates appear to be dependent upon their thermodynamic properties. Such a nalyses have a predictive value and are useful in the transdermal drug prod uct development of chiral molecules. While the decision to market either an individual enantiomer or racemate lies strictly under the control of the s ponsors, die guidance of the Food and Drug Administration is very helpful. This review presents an overview of the skin structure and transport and a concise review of enantioselective permeation with or without chiral enhanc ers. Regulatory perspectives on chiral drug product development are also di scussed.