title: 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 pH-dependent 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, high-performance liquid chromatography, and x-ray powder diffraction. Suspension of the free drug in a solution of hydroxypropylcellulose (reference formulation) and aqueous dispersions of pH-sensitive 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 (AUC0-48h of 6.5 microg x h/mL and coefficient of variation (CV) of 116%) and much higher Tmax, as compared to both pH-sensitive formulations. With respect to exposure and interindividual variability, nanoparticles were superior to microparticles (AUC0-48h of 27.1 microg x h/mL versus 17.7 microg x 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, pH-dependent dissolving particles have a great potential as oral delivery systems for drugs with low water solubility and acceptable permeation properties.
authors.affiliation: School of Pharmacy, University of Geneva, CH 1211, Geneva 4, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: De Jaeghere
authors.forename: E
authors.initials: E
authors.lastname: Allémann
authors.forename: R
authors.initials: R
authors.lastname: Cerny
authors.forename: B
authors.initials: B
authors.lastname: Galli
authors.forename: A F
authors.initials: AF
authors.lastname: Steulet
authors.forename: I
authors.initials: I
authors.lastname: Müller
authors.forename: H
authors.initials: H
authors.lastname: Schütz
authors.forename: E
authors.initials: E
authors.lastname: Doelker
authors.forename: R
authors.initials: R
authors.lastname: Gurny
mesh_terms: D000180:Acrylic Resins; D000284:Administration, Oral; D000818:Animals; D004285:Dogs; D004337:Drug Carriers; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D008297:Male; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry; D010599:Pharmacokinetics; D014961:X-Ray Diffraction
chemical_list: D000180:Acrylic Resins; D004337:Drug Carriers; C446821:Eudragit L100-55; D004364:Pharmaceutical Preparations