pH-Dependent dissolving nano- and microparticles for improved peroral delivery of a highly lipophilic compound in dogs

Abstract

RR01, a new highly lipophilic drug showing extremely low water solubility and poor oral bioavailability, has been incorporated into pHdependent dissolving particles made of a poly(methacrylic acid-co-ethylacrylate) copolymer. The physicochemical properties of the particles were determined using laser-light-scattering techniques, scanning electron microscopy, highperformance liquid chromatography, and x-ray powder diffraction. Suspension of the free drug in a solution of hydroxypropylcellulose (reference formulation) and aqueous dispersions of pHsensitive RR01-loaded nanoparticles or microparticles were administered orally to Beagle dogs according to a 2-block Latin square design (n = 6). Plasma samples were obtained over the course of 48 hours and analyzed by gas chromatography/mass spectrometry. The administration of the reference formulation resulted in a particularly high interindividual variability of pharmacokinetic parameters, with low exposure to compound RR01 (AUC 0-48h of 6.5 μg.h/mL and coefficient of variation (CV) of 116%) and much higher T max , as compared to both pH-sensitive formulations. With respect to exposure and interindividual variability, nanoparticles were superior to microparticles (AUC 0-48h of 27.1 μg.h/mL versus 17.7 μg.h/mL with CV of 19% and 40%, respectively), indicating that the particle size may play an important role in the absorption of compound RR01. The performance of pH-sensitive particles is attributed to their ability to release the drug selectively in the upper part of the intestine in a molecular or amorphous form. In conclusion, pHdependent dissolving particles have a great potential as oral delivery systems for drugs with low water solubility and acceptable permeation properties.

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