STEREOSELECTIVE PERCUTANEOUS ABSORPTION AND TRANSDERMAL DELIVERY OF CHIRAL DRUGS

The selection of the enantiomeric or racemate form of a drug is a critical issue in the development of transdermal dosage forms. Indeed, the stratum corneum, the rate-limiting barrier to percutaneous absorption, is mainly composed by keratin and ceramides, which could potentially provide a chiral environment. Therefore, the different binding of enantiomers to keratin or the interactions with ceramides may give rise to differences in the permeation profiles of the enantiomers of chiral molecules. Whereas the implication of different physicochemical properties between enantiomers and racemate in the in vitro skin permeation profiles have been studied, other aspects such as the effect of different counter-ions of ionisable chiral drug and different enantiomer of chiral permeation enhancers on skin permeability have not yet been extensively investigated. This work was therefore focused on these two topics to deep actual understanding and to obtain information useful to rationalize the development of transdermal patches. Among the chiral drugs, propranolol (PR) and ibuprofen (IB) were selected. PR is a good candidate as its biological activity is largely associated to a single enantiomer. In humans, S-PR is about 100 times more potent than the R-enantiomer as β-blocker and the information reported in literature about the in vitro skin permeability suggest that it can be a suitable candidate to transdermal delivery. In the case of IB, largely used in the treatment of musculoskeletal injuries, only the S-enantiomer (S-IB) is therapeutically active, and extensive unidirectional chiral enantiomeric inversion of R to S occurs in vivo. Studies indicates that there aren’t any evidences for the metabolic inversion after topical administration. Till now, although the biological activity of IB resides with the S-enantiomer, the topical preparations available on the market contain the racemate. This work aimed to determinate the skin permeability profiles of the selected drugs and in some case of the their salts, in order to evaluate the enantio-selectivity in the diffusion process. The salts were obtained salifing the drug, either as racemate and pure enantiomer, with different counter-ions, selected on the bases of their physico-chemical characteristics. The experiments were performed by the modified Franz cell method, using human skin epidermis as a membrane and selecting the donor phase on the bases of the drug solubility. Suitable analytical methods for the quantitative determination of the drugs were developed. As a first step the skin permeability test was conducted by using saturated or diluted solutions. On the bases of the preliminary permeability data, the formulation study of monolayer transdermal patches containing the drug in its most appropriate form , and, if necessary, the suitable promotion enhancer, was carried out.