pH-Dependent dissolving nano- and microparticles for improved peroral delivery of a highly lipophilic compound in dogs.
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.
De Jaeghere
F
F
School of Pharmacy, University of Geneva, CH 1211, Geneva 4, Switzerland.
Allémann
E
E
Cerny
R
R
Galli
B
B
Steulet
A F
AF
Müller
I
I
Schütz
H
H
Doelker
E
E
Gurny
R
R
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
D000180:Acrylic Resins; D004337:Drug Carriers; C446821:Eudragit L100-55; D004364:Pharmaceutical Preparations