IngentaConnect Synthesis and In Vitro Skin Permeation of Naproxen Conjugates wit...

Authors: Pignatello, Rosario¹; Montenegro, Lucia¹; Stancampiano, Annalisa H.S.¹; Puleo, Antonina¹; Puglisi, Giovanni¹

Source: Current Drug Delivery, Volume 2, Number 2, April 2005 , pp. 185-189(5)

Publisher: Bentham Science Publishers

Abstract:

Novel amide conjugates of the NSAID naproxen (NAP, 1) with short-chain agr

-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- agr

-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.

Keywords: naproxen; prodrugs; 2-alkylamino acids; lipophilicity; dermal delivery

Document Type: Review article

DOI: 10.2174/1567201053585976

Affiliations: 1: Dipartimento di Scienze Farmaceutiche, Universita degli Studi di Catania; Viale A. Doria, 6, I-95125 Catania, Italy.

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Synthesis and In Vitro Skin Permeation of Naproxen Conjugates with - Alkylamino Acids