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Novel amide conjugates of the NSAID naproxen (NAP, 1) with short-chain alpha-alkylamino acids (C4 to C6 alkyl chain) were synthesized through a carbodiimide (EDAC)-assisted coupling reaction and evaluated as dermal prodrugs of NAP. The 2-alpha-aminobutyl derivative (2) showed lipophilicity similar to that of NAP, while the higher homologues (3) and (4) were more lipophilic than the parent drug, as assessed by CLogP and HPLC methods. The chemical and enzymatic hydrolysis of these compounds was evaluated in aqueous buffer solution (pH 7.4) and 80% human plasma. All compounds showed a good chemical stability (t1/2 = 88-133 h) but underwent a rapid enzymatic hydrolysis to NAP (t1/2 around 3 h). The bioconversion of prodrugs into NAP was confirmed by an in vivo test, since i.p. administration of compounds 2-4 to mice gave a similar analgesic response than the parent drug. In vitro skin permeation experiments were performed using adult human SCE samples mounted in Franz-type diffusion cells. The butyl derivative 2 that showed an increased aqueous solubility compared to NAP gave a 5-fold improvement of skin permeation compared to NAP. In conclusion, the conjugate 2 could be regarded as a good candidate to improve NAP topical delivery and will be further studied as a prodrug for topical administration of this drug.

The effects of different silicone emulsifiers on the in vitro permeation through human skin of two sunscreens (octylmethoxycinnamate, OMC, and butylmethoxydibenzoylmethane, BMBM) were investigated from cosmetic emulsions. The formulations being tested were prepared using the same oil and aqueous phase ingredients and the following silicone emulsifiers: dimethicone copolyol and cyclomethicone (emulsion 1), cetyldimethicone copolyol (emulsion 2), polyglyceryl-4-isostearate and cetyldimethicone copolyol and hexyllaurate (emulsion 3), lauryldimethicone copolyol (emulsion 4), and cyclomethicone and dimethicone copolyol (emulsion 5). The cumulative amount of OMC that permeated in vitro through human skin after 22 h from emulsions 1-5 decreased in the order 2 approximate, equals 1 > 5 > 4 approximate, equals 3 and was about twofold higher from emulsion 2 compared to emulsion 4. As for BMBM, no significant difference was observed in regard to its skin permeation from the emulsions being tested. In vitro release experiments of OMC and BMBM from emulsions 1-5 were performed through cellulose acetate membranes using Franz diffusion cells. Emulsions 1-3 showed an initial slow release of BMBM followed by a fast release phase, while the release of OMC showed a different pattern since the sunscreen was released very rapidly at the beginning of the experiment and then a plateau was observed followed by a second step of fast release. A pseudo-first-order release rate was observed only for BMBM from emulsion 4, while emulsion 5 released very small amounts of both sunscreens during 22 h. These findings could be attributed both to changes in sunscreen thermodynamic activity in the vehicle and to modified interactions between the active ingredient and the formulation components. The results of this study suggest that the type of silicone emulsifier used to prepare sunscreen emulsions should be carefully chosen in order to prevent the percutaneous absorption of sunscreens from these cosmetic formulations.