Chirality and its implications in transdermal drug development.
Today more than 50% of marketed drugs are chiral. It has been well recognized that the stereochemistry of chiral drugs has a major influence on their pharmacological, pharmacokinetic, and toxicological actions. Studies on enantiomeric differences in the percutaneous permeation of chiral compounds have been actively pursued in recent years. Stratum corneum, the rate-limiting barrier in transdermal permeation, is made up of keratin and ceramide, which could potentially provide chiral environment. Transdermal delivery is often facilitated by the presence of penetration enhancers, which act primarily by altering the diffusion by disrupting the highly ordered membrane structure or by affecting the partitioning behavior of the diffusant molecules. Enantioselective permeation was observed with some chiral excipients including terpene enhancers. While studies on crystalline structures of pure enantiomers and racemates are helpful in understanding the basis for differentiation of physicochemical properties, prediction and control of permeability of enantiomers and racemates based on the physicochemical characteristics would be highly beneficial. The flux characteristics of enantiomers and racemates appear to be dependent upon their thermodynamic properties. Such analyses have a predictive value and are useful in the transdermal drug product development of chiral molecules. While the decision to market either an individual enantiomer or racemate lies strictly under the control of the sponsors, the 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 enhancers. Regulatory perspectives on chiral drug product development are also discussed.
Reddy
I K
IK
Department of Pharmaceutical Sciences, Texas Tech School of Pharmacy, Amarillo 79106, USA.
Kommuru
T R
TR
Zaghloul
A A
AA
Khan
M A
MA
D000279:Administration, Cutaneous; D000818:Animals; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D006801:Humans; D013237:Stereoisomerism