title: Enhancement of oral bioavailability of poorly water-soluble drugs by poly(ethylene glycol)-block-poly(alkyl acrylate-co-methacrylic acid) self-assemblies.
abstract: The purpose of the present study was to determine whether pH-sensitive polymeric micelles could improve the oral bioavailability of a poorly water-soluble drug. Poly(ethylene glycol)-block-poly(alkyl acrylate-co-methacrylic acid)s were synthesized by atom transfer radical polymerization and the composition of the ionizable polymer block was varied to maximize drug loading and pH-dependent release. Poorly water-soluble model drugs viz. fenofibrate (FNB) and progesterone (PRG) were incorporated in the self-assemblies by the oil-in-water emulsion or film casting methods. The pH-dependent release of several formulations was studied in vitro and the oral bioavailabilities of FNB-loaded micelles, Lipidil Micro and FNB coarse suspension were assessed in Sprague-Dawley rats at a dose of 7.5 mg/kg. Entrapment efficiency (defined as the ratio of experimental drug loading in self-assemblies to the initial amount of drug added) ranged between 55-75% and was dependent on polymer composition and drug-loading method. Hydrophobic chain composition of the polymer had tremendous impact on in vitro release kinetics, with only poly(ethylene glycol)-block-poly(n-butyl acrylate(17)-co-methacrylic acid(17)) micelles showing the desired pH-dependent drug-release profile. The oral bioavailability of FNB from these self-assemblies revealed 156% and 15% increases vs. FNB coarse suspension and Lipidil Micro, respectively. The results suggest that these pH-sensitive self-assemblies have potential for improving the oral bioavailability of poorly water-soluble drugs.
authors.affiliation: Canada Research Chair in Drug Delivery, Faculty of Pharmacy, University of Montreal, C.P. 6128 Succ. Centre-ville, Montréal, QC, Canada H3C 3J7.
authors.forename: Vinayak P
authors.initials: VP
authors.lastname: Sant
authors.forename: Damon
authors.initials: D
authors.lastname: Smith
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Leroux
mesh_terms: D000179:Acrylates / Q000008:administration & dosage; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D011345:Fenofibrate / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D006863:Hydrogen-Ion Concentration; D008297:Male; D008689:Methacrylates / Q000008:administration & dosage; D008823:Micelles; D011092:Polyethylene Glycols / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
chemical_list: D000179:Acrylates; D008689:Methacrylates; D008823:Micelles; C008384:methacrylic acid; D011092:Polyethylene Glycols; D011345:Fenofibrate