Studies On Enantioselectivity And The Implication Of Formulation Factors With Respect To Precutaneous Permeation Of Chiral Drugs

Stratum corneum, the percutaneous absorption barrier, which principally made up of chiral material keratin and ceramides, potentially provides a chiral environment, may give rise to differences in the permeation profiles of the enantiomers. Except the components of the stratum corneum, chiral excipients combined in a formulation may also serve as sources for chiral discrimination, and could result in differential diffusion rates. When the biological activity of a chiral molecule is largely associated with one enantiomer, in such cases, any enantioselective skin permeation favoring the active antipode would affect the pharmacological and toxicological spectrum of the transdermal drug products of chiral molecules. To date, however, the effects of stereoisomerism on percutaneous absorption of chiral drugs are not well studied.The aims of this study were to investigate the possible enantioseletive permeation of model drugs, norgestrel (NG), ketoprofen (KP) and flurbiprofen (FP), across excised different skin species, and to explore the potential enantioseletive effects of formulation factors on skin permeation. The selected formulation factors include common enhancers (ethanol, azone and 1,2-propylene glycol), chiral enhancers (linalool and menthol), and chiral pharmaceutical excipients [hydroxypropyl-β-cyclodextrin(HP-β-CD) and Hydroxypropyl methyl cellulose(HPMC)]. Additionly, the enantioselective pharmacokinetics of the FP transdermal paths across rabbit skin was also studied to evaluate the correlation between in vitro skin permeation and in vivo skin absorption. In vitro skin permeation studies of model drugs across the excised skins were performed with Valia-Chien glass diffusion cells.In this study, no enantioselective skin permeation was observed when donor solutions containing racemates of model chiral drugs. But great differences in skin permeation rate between racemate and enantiomer of KP (or NG) were observed, which may be mainly attributed to the melting point discrepancy between enantiomer and racemate. The flux of S-KP across excised rat skin was 50% higher than that of RS-KP, the melting point difference was 22℃. Rac-HG with lower melting point also has significantly higher permeation flux than that of l-NG. For FP, the enantioselective permeation was studied using individual enantiomers and racemate as donor drug, but no intrinsic enantioselectivity attributed to the skin chiral environment was observed in the permeation process.Ethanol, as a widely used transdermal enhancer, may also have enantioselective effect on chiral drugs. The significant difference of permeation flux between S-KP and RS-KP was overwhelmed when donor solutions in presence of ethanol. The enantioselective permeation of FP across excised rat and rabbit skin was aroused when ethanol was presented in the donor solutions containing either enantiomer of FP.Two factors may get involved in chiral enhancer. One is the possible different enhancing effect between enantiomers and racemate of chiral enhancer due to their physicochemical difference such as melting point discrepancy, and another is the possible different enhancing effect on enantiomers of chiral drug attributed to the stereospecific interaction among chiral enhacer, chiral drug or chiral material in stratum corneum. In this study, the enhancing effect of dl-linalool on RS-KP and NG was greater than that of l-linalool, and dl-menthol had greater enhancing effect on RS-FP than l-menthol. Above all, the enantioselective enhancing effects of dl-linalool on KP and NG were observed, Rac-linalool resulted in significantly higher permeation enhancing effect on RS-KP than on S-KP, and greatly higher permeation enhancing effect on l-NG than on d-NG when donor solutions containing dl-HG. The enantioselective enhancing effect of dl-linalool on KP and NG may be attributed to the stereospecific interactions among chiral drug, linalool or keratin or ceramides in stratum corneum.For chiral excipients, HP-β-CD and HPMC, their enantioselective effects on skin permeation of NG and KP were observed. HP-β-CD greatly decreased solubility difference between S-KP and RS-KP, the main way to influence the permeation profiles of enantiomers. Due to the enantioselective release of enantiomer from dl-NG/HP-β-CD inclusion, the enantioselective permeation of dl-NG was observed The enantioselective permeation of KP was aroused when donor solutions containing HPMC, which may be resulted from two factors, one is the decreased solubility difference between S-KP and RS-KP by presence of HPMC, and another is the possible differential adsorption onto HPMC, whereby S-KP is preferentially bound relative to R-KP.The pharmacokinetic study showed that chiral inversion from R-FP to S-FP was observed in rabbit when FP was administered either transdermally or by intravenous injection. The blood concentration ratio of S-FP/R-FP increased with time, indicating enantioselective metabolic behavior of RS-FP. Half-life of the R-enantiomer was significantly lower than that of S-FP reflecting the greater clearance of R-FP. However, the blood concentration ratio of S-FP/R-FP was significantly lower by transdermal administration than by intravenous injection, which may be attributed to the enantioselective metabolic behavior of RS-FP and the continued drug absorption characteristic of transdermal administration.In this study, many valuable enantioselective skin permeation phenomena were observed, which will provide guidance for the development of chiral drug transdermal products. This is the first report on chiral excipients (HP-β-CD and HPMC) effect on enantioselective skin permeation of chiral drug. In summary, except the chiral environment of skin stratum corneum, formulation factors such as enhancer, chiral excipient etc. potentially implicate in stereoselective skin permeation. So, an enantiospecific assay method is necessary for permeation evaluation in transdermal drug products development of chiral molecule in vitro and in vivo, and eutomer oriented formulation screening will be better, particularly when pharmacological and toxicological differences exist between enantiomers of the chiral drug. Additionally, when chiral drug is administered transdermally, enantioselective pharmacokinetics may occur or be different from that of other administration route. In such cases, special focus should be paid to the pharmacological and toxicological effects of enantioselective pharmacokinetics.