COADMINISTRATION OF A WATER-SOLUBLE POLYMER INCREASES THE USEFULNESS OF CYCLODEXTRINS IN SOLID ORAL DOSAGE FORMS

Purpose. The aim of this study was to investigate the effect of cyclod extrins (beta-CD, HP-beta-CD and (SBE)(7m)-beta-CD), and co-administra tion of a water-soluble polymer (HPMC) and cyclodextrins, on the oral bioavailability of glibenclamide in dogs. Methods. Effects of cyclodex trins on the aqueous solubility of glibenclamide, with and without hyd roxypropylmethylcellulose (HPMC), were determined by a phase-solubilit y method. Solid inclusion complexes were prepared by freeze-drying. Gl ibenclamide was administered orally and intravenously to beagle dogs. Results. Aqueous solubility of glibenclamide increased as a function o f cyclodextrin concentration, showing an AL-type diagram for P-CD and an A(p)-type diagrams for both of the beta-CD derivatives studied. HPM C enhanced the solubilising effect of cyclodextrins, but did not affec t the type of phase-solubility diagram. Orally administered glibenclam ide and its physical mixture with HP-beta-CD showed poor absolute bioa vailability, while orally administered glibenclamide/cyclodextrin-comp lexes significantly enhanced the absolute bioavailability of glibencla mide. Orally administered glibenclamide/beta-CD/HPMC and glibenclamide /(SBE)(7m)-beta-CD/HPMC complexes showed similar absolute bioavailabil ity compared to formulations not containing HPMC, even though 80% (in the case of (SBE)(7m)-beta-CD) or 40% (in the case of beta-CD) less cy clodextrin was used. Conclusions. The oral bioavailability of glibencl amide was significantly increased by cyclodextrin complexation. HPMC i ncreased the solubilising effect of cyclodextrins and, therefore, the amount of cyclodextrin needed in the solid dosage form was significant ly reduced by their co-administration. In conclusion, the pharmaceutic al usefulness of cyclodextrins in oral administration may be substanti ally improved by co-administration of a water-soluble polymer.