Oral bioavailability of a poorly water soluble HIV-1 protease inhibitor incorporated into pH-sensitive particles: effect of the particle size and nutritional state

The new chemical entity CGP 70726, a very poorly water-soluble HIV-1 protea se inhibitor, was incorporated into pH-sensitive nanoparticles and micropar ticles made of the poly(methacrylic acid-co-ethylacrylate) copolymer Eudrag it(R) L100-55. The particles were characterized in terms of morphology, siz e distribution, drug loading, production yield and dispersion state of the drug inside the polymeric matrices. Aqueous dispersions of the particles we re administered orally to Beagle dogs against a suspension of free drug (co ntrol formulation) all at a dose of 100 mg/kg. Oral administration was cond ucted in the absence and presence of food. Plasma concentrations and pharma cokinetic parameters were determined within 8 h post-dose. While no measura ble absorption of the drug resulted after administration of the control for mulation, substantial systemic exposure to the compound was obtained with b oth kinds of pH-sensitive formulations. The selective release of CGP 70726 in a highly dispersed/amorphous state and creation of high concentrations c lose to its absorption site was thought to account for this positive result . The largest areas under the plasma concentration-time curve (AUC) were ob tained in the fasted state, with slightly better performance of the micropa rticles over the nanoparticles, in both nutritional states (7.8+/-1.5 versu s 5.8+/-0.8 mu mol.h/l in the fasted state; 4.4+/-1.4 versus 2.00+/-0.5 mu mol.h/l in the fed state). With these results, the potential of pH-sensitiv e particles for the oral delivery of HIV-1 protease inhibitors with low wat er solubility was confirmed. (C) 2000 Elsevier Science B.V. All rights rese rved.