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

Authors: Pignatello, Rosario; Montenegro, Lucia; Stancampiano, Annalisa H.S.; Puleo, Antonina; Puglisi, Giovanni

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

Publisher: Bentham Science Publishers

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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: http://dx.doi.org/10.2174/1567201053585976

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

Publication date: 2005-04-01

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The aim of Current Drug Delivery is to publish peer-reviewed articles, short communications, short and in-depth reviews in the rapidly developing field of drug delivery. Modern drug research aims to build in delivery properties of a drug at the design phase, however in many cases this ideal cannot be met and the development of delivery systems becomes as important as the development as the drugs themselves.

The journal aims to cover the latest outstanding developments in drug and vaccine delivery employing physical, physico-chemical and chemical methods. The drugs include a wide range of bioactive compounds from simple pharmaceuticals to peptides, proteins, nucleotides, nucleosides and sugars. The journal will also report progress in the fields of transport routes and mechanisms including efflux proteins and multi-drug resistance.

The journal is essential for all pharmaceutical scientists involved in drug design, development and delivery.

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

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