title: Novel cyclosporin derivatives featuring enhanced skin penetration despite increased molecular weight.
abstract: Topical cyclosporin A (CsA, 1) is not effective in the treatment of skin diseases, due to its low skin penetration. Following a prodrug strategy, a series of novel derivatives of 1 and of 2-[O-(2-hydroxyethyl)-d-Ser(8)]-CsA (SDZ IMM 125, 5) with potentially enhanced skin penetration properties were synthesized, in order to achieve higher levels of the active parent drugs in the skin. Permeation through skin and prodrug/drug levels in the skin were measured in vitro using rat and human skin. Introduction of a polar side chain, either in the form of a positively charged quaternary amine, a negatively charged phosphate or sulfate, or an amphiphilic phosphocholine moiety, generally increased permeability. Maximal increase in permeability through skin relative to CsA was up to 300-fold with rat skin, and up to 16-fold with human skin. Penetration into skin, as evaluated by measurement of prodrug/drug concentrations in the skin after 48 h, could be enhanced up to 14-fold (rat and human skin). Increases of permeation rates and skin concentrations showed no strict correlation. Using the phosphate 10 as prodrug, a 2.5-fold higher concentration of the active parent compound (5) could be achieved in rat skin as when administering 5 itself. The results demonstrate that in contrast with the '500 Dalton rule', which postulates poor skin penetration of molecules larger than 500 Da, high skin permeation can be achieved also with compounds of a molecular weight in the range between 1200 and 1600 Da. Results also indicate that in principle higher skin levels of active drug can be attained with a prodrug strategy in this class of compounds.
authors.affiliation: Novartis Institutes for BioMedical Research, Brunnerstrasse 59, A-1235 Vienna, Austria. andreas.billich@pharma.novartis.com
authors.forename: Andreas
authors.initials: A
authors.lastname: Billich
authors.forename: Hermann
authors.initials: H
authors.lastname: Vyplel
authors.forename: Maximilian
authors.initials: M
authors.lastname: Grassberger
authors.forename: Fritz P
authors.initials: FP
authors.lastname: Schmook
authors.forename: Andrea
authors.initials: A
authors.lastname: Steck
authors.forename: Anton
authors.initials: A
authors.lastname: Stuetz
mesh_terms: D000287:Administration, Topical; D000818:Animals; D003524:Cyclosporins / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D015194:Diffusion Chambers, Culture; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008968:Molecular Conformation; D008970:Molecular Weight; D010539:Permeability / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D012869:Skin Absorption / Q000187:drug effects*
chemical_list: D003524:Cyclosporins; D011355:Prodrugs; C075935:SDZ IMM 125