Synthesis and in vitro skin permeation of naproxen conjugates with alpha-alkylamino acids.

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.

Enhancement of drug affinity for cell membranes by conjugation with lipoamino acids. I. Synthesis and biological evaluation of lipophilic conjugates of tranylcypromine.

Conjugation with lipoamino acids (LAAs) increases the lipophilicity of drug molecules. Because of their amphipatic nature, they also provide the conjugated drugs a 'membrane-like character', capable to facilitate their interaction with and penetration through cell membranes and biological barriers. To study such a feature, our aim is to collect experimental and computational data using a novel series of lipophilic conjugates between a model drug (tranylcypromine (TCP)) and LAA residues containing a short, a medium or a long alkyl side chain (C-4 to C-16), to provide a wide range of lipophilicity. For comparison, a corresponding set of amides of TCP with alkanoic or fatty acids was prepared and characterized. Their in vitro monoamine oxidase inhibitory activity also tested.

Effect of liposomal delivery on in vitro antitumor activity of lipophilic conjugates of methotrexate with lipoamino acids.

Some selected lipophilic conjugates of the antifolate drug methotrexate (MTX) with lipoamino acids (LAA), previously described, were incorporated in liposomes with a different composition and charge (neutral, positive, or negative). The properties of the liposomal systems were determined. The inhibitory activity of the conjugates after incorporation in the vesicles was determined in a preliminary assessment against a human erythroleukemic cell line (K562 cells) and compared with the activity of the parent drug and of free conjugates. The influence of liposome surface charge and of the type of conjugate (i.e., in the carboxylic or ester form) on the biological effect is discussed.

Eudragit RS100 nanosuspensions for the ophthalmic controlled delivery of ibuprofen.

Topical application of non-steroidal anti-inflammatory drugs on the eye is a common treatment used to contrast the miosis induced by surgical traumas, such as cataract extraction. With the aim of improving the availability of sodium ibuprofen (IBU) at the intraocular level, IBU-loaded polymeric nanoparticle suspensions were made from inert polymer resins (Eudragit RS100). The nanosuspensions were prepared by a modification of the quasi-emulsion solvent diffusion technique using variable formulation parameters (drug-to-polymer ratio, total drug and polymer amount, stirring speed). Nanosuspensions had mean sizes around 100 nm and a positive charge (zeta-potential of +40/+60 mV), this makes them suitable for ophthalmic applications. Stability tests (up to 24 months storage at 4 degrees C or at room temperature) or freeze-drying were carried out to optimize a suitable pharmaceutical preparation. In vitro dissolution tests indicated a controlled release profile of IBU from nanoparticles. In vivo efficacy was assessed on the rabbit eye after induction of an ocular trauma (paracentesis). An inhibition of the miotic response to the surgical trauma was achieved, comparable to a control aqueous eye-drop formulation, even though a lower concentration of free drug in the conjunctival sac was reached from the nanoparticle system. Drug levels in the aqueous humour were also higher after application of the nanosuspensions; moreover, IBU-loaded nanosuspensions did not show toxicity on ocular tissues.