Journal
JOURNAL OF CONTROLLED RELEASE
Volume 104, Issue 2, Pages 289-300Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2005.02.010
Keywords
polymeric micelles; pH-sensitive; drug solubilization; oral bioavailability; fenofibrate; atom transfer radical polymerization
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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 (R) 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 co-methacrylic acid) 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 (R), respectively. The results suggest that these pH-sensitive self-assemblies have potential for improving the oral bioavailability of poorly water-soluble drugs. (c) 2005 Elsevier B.V. All rights reserved.
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