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

Abstract

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.

Evaluation of Cell Tolerability of a Series of Lipoamino Acids Using Biological Membranes and a Biomembrane Model.

“…(1) and Table 1. Short-chain LAAs (C-6 to C-8) were also included in the study: these promoieties have been more recently used to obtain drug conjugates with amphiphilic properties but a residual solubility on aqueous and biological media [14][15][16], in respect to the lower solubility shown by conjugates with LAA bearing longer alkyl chains. We first of all tested by differential scanning calorimetry (DSC) the thermotropic effects exerted by different molar fractions of each LAA upon a biomembrane model consisting of pure dimyristoylphosphatidylcholine (DMPC) multilamellar liposomes (MLVs).…”

A calorimetric evaluation of the interaction of amphiphilic prodrugs of idebenone with a biomembrane model

“…LAA have been conjugated to many drugs, including antitumor and anti-inflammatory agents [9][10][11][12]. Shorter-chain LAA have more recently been used by us instead of the originally proposed long-chain ones [7].…”