Synthesis and vasorelaxant and platelet antiaggregatory activities of a new series of 6-halo-3-phenylcoumarins.

A series of 6-halo-3-hydroxyphenylcoumarins (resveratrol-coumarins hybrid derivatives) was synthesized in good yields by a Perkin reaction followed by hydrolysis. The new compounds were evaluated for their vasorelaxant activity in intact rat aorta rings pre-contracted with phenylephrine (PE), as well as for their inhibitory effects on platelet aggregation induced by thrombin in washed human platelets. These compounds concentration-dependently relaxed vascular smooth muscle and some of them showed a platelet antiaggregatory activity that was up to thirty times higher than that shown by trans-resveratrol and some other previously synthesized derivatives.

Enhancement of availability of cloricromene at brain level by a lipophilic prodrug.

The pharmacokinetics of a lipophilic alkylamino acid (LAA) prodrug of cloricromene (AD6), name CLOR-C4, was studied in rat plasma and brain. In particular, we observed that the intraperitoneal administration of CLOR-C4 to rats was able to provide a slight but statistically significant higher concentration of the active drug metabolite (cloricromene acid) in the brain compared with the parent drug administered by the same way. The correlation between pharmacokinetic data and calculated partition (LogP) and brain distribution coefficients (LogBB) supported the hypothesis that the amphiphilic nature of the LAA promoiety could be responsible for a better penetration into the brain, more than the simple increase of lipophilicity gained with respect to the parent drug.

Preparation and characterization of eudragit retard nanosuspensions for the ocular delivery of cloricromene.

The purpose of this study was to improve the stability of cloricromene (AD6) in ophthalmic formulations and its drug availability at the ocular level. To this end, AD6-loaded polymeric nanoparticle suspensions were made using inert polymer resins (Eudragit RS100 and RL100). We modified the quasi-emulsion solvent diffusion technique by varying some formulation parameters (the drug-to-polymer ratio, the total drug and polymer amount, and the stirring speed). The chemical stability of AD6 in the nanosuspensions was assessed by preparing some formulations using (unbuffered) isotonic saline or a pH 7 phosphate buffer solution as the dispersing medium. The formulations were stored at 4 degrees C, and the rate of degradation of AD6 was followed by high performance liquid chromatography (HPLC). The obtained nanosuspensions showed mean sizes and a positive surface charge (zeta-potential) that make them suitable for an ophthalmic application; these properties were maintained upon storage at 4 degrees C for several months. In vitro dissolution tests confirmed a modified release of the drug from the polymer matrixes. Nanosuspensions prepared with saline solution and no or lower amounts of surfactant (Tween 80) showed an enhanced stability of the ester drug for several months, with respect to an AD6 aqueous solution. Based on the technological results, AD6-loaded Eudragit Retard nanoparticle suspensions appear to offer promise as a means to improving the shelf life and bioavailability of this drug after ophthalmic application.

Eudragit RL100 nanoparticle system for the ophthalmic delivery of cloricromene.

A Eudragit RL100 polymer nanoparticle system loaded with cloricromene was prepared and characterized on the basis of physicochemical properties, stability and drug release features. To investigate the ocular bioavailability of cloricromene after inclusion in the polymer matrix, the new nanoparticle system was topically administered in the rabbit eye and compared with an aqueous solution of the same drug. The nanoparticle system showed interesting size distribution and surface charge values, suitable for ophthalmic application. The results indicated that the dispersion of cloricromene within Eudragit RL100 polymer nanoparticles increased its ocular bioavailability and enhanced the biopharmaceutical profile. The new cloricromene-loaded nanoparticle system described here may be useful in clinical practice.

In vitro evaluation of PLA nanoparticles containing a lipophilic drug in water-soluble or insoluble form.

Cloricromene (AD6), an anti-ischemic drug, is rapidly metabolised into a stable and active metabolite (cloricromene acid, AD6-acid) poorly soluble in water and less lipophilic than cloricromene. The aim of this study was to evaluate which of the two forms has more possibility to be efficiently encapsulated in nanoparticles based on poly(D,L-lactide) and prepared using the nanoprecipitation method. Increasing the theoretical loading of AD6, an increase in drug actual loading and in the mean particle size occurred, while no formation of nanoparticles was observed when the highest theoretical loading (50 mg) was employed. Changing the pH of the aqueous phase the drug content dramatically increased. However, at a pH value of 11 a more rapid hydrolysis of AD6 occurred. When AD6-acid was embedded in the nanoparticles, suitable results concerning both drug content and encapsulation efficiency were achieved. A good control in the release of AD6 from the AD6-loaded nanoparticles was observed while the liberation of AD6-acid from the AD6-acid-loaded nanoparticles was faster than the dissolution of the AD6-acid free. These results confirm that the most easy encapsulable form in nanoparticles is AD6-acid probably owing to its poor water solubility. Further studies will be carried out in order to evaluate if the increase in the liberation of AD6-acid by nanoencapsulation may have outcomes in its bioavaibility in vivo.