Pluronic block copolymers and Pluronic poly(acrylic acid) microgels in oral delivery of megestrol acetate.
Several Pluronic-based formulations were studied in-vitro and in a rat model with respect to the release and bioavailability of megestrol acetate (MA) after oral administration. It was demonstrated that an aqueous, micellar formulation comprising a mixture of a hydrophobic (L61) and a hydrophilic (F127) Pluronic copolymer, significantly enhanced the bioavailability of MA administered orally at relatively low doses (1-7 mg kg(-1)). Pluronic-based microgels (spherical gel particles of sub-millimetre size) were introduced as MA vehicles. The microgels comprised a cross-linked network of poly(acrylic acid) onto which the Pluronic chains were covalently attached. Microgels of Pluronic L92 and poly(acrylic acid) fabricated into tablet dosage forms exhibited dramatically lowered MA initial burst release. The MA release was pH-dependent owing to the pH sensitivity of the microgel swelling, with the drug retained by the microgel at pH 1.8 and released slowly at pH 6.8. In the rat model, a significant increase in MA bioavailability was observed when the microgel-formulated MA was administered orally at a high dose of 10 mg kg(-1), owing to the enhanced retention of the microgel. The study of the microgel passage through the gastrointestinal tract demonstrated the microgel retention characteristic of a very high molecular weight polymer and the absence of any systemic absorption of the polymer.
Supratek Pharma, Inc., 215, Boulevard Bouchard, Suite 1315, Dorval, Quebec H9S 1A9, Canada. valery.alakhov@supratek.com
Valery
V
Alakhov
Grzegorz
G
Pietrzynski
Kishore
K
Patel
Alexander
A
Kabanov
Lev
L
Bromberg
T Alan
TA
Hatton
D000179:Acrylates / Q000737:chemistry / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D016503:Drug Delivery Systems; D005260:Female; D005772:Gastrointestinal Transit; D005782:Gels; D006863:Hydrogen-Ion Concentration; D019290:Megestrol Acetate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D020442:Poloxamer / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012996:Solutions; D013501:Surface-Active Agents / Q000737:chemistry
D000179:Acrylates; D005782:Gels; D012996:Solutions; D013501:Surface-Active Agents; C117167:carbopol 974P NF; D020442:Poloxamer; D019290:Megestrol Acetate