FORMULATION STUDIES OF A POORLY WATER-SOLUBLE DRUG IN SOLID DISPERSIONS TO IMPROVE BIOAVAILABILITY

To improve the bioavailability of a poorly water-soluble drug, RP 6969 8 (1), solid dispersion formulations were investigated in beagle dogs. The formulations were prepared by a melting method with water-soluble carriers in which 1 is highly soluble. When incorporated into a solid dispersion formulation composed of polyethylene glycol (PEG) 3350, Tr anscutol and Labrasol, the bioavailability of 1 was determined to be 1 1.8%. This represented about 2-fold improvement over 6% bioavailabilit y observed previously with an aqueous suspension of the drug in 0.5% m ethylcellulose. When the formulation contained only Labrasol, in which 1 was completely solubilized, the bioavailability of 1 was 12.9%. Add ition of a surfactant, polysorbate 80, at a strength of 10% to the dis persion with PEG 3350 and Labrasol as carriers increased the bioavaila bility of 1 from 11.8 to 27.6%. This result was attributed to the abil ity of the surfactant to increase the wettability and spreadability of the drug in a solubilized state once released in the gastrointestinal medium. Increase in the concentration of the surfactant did not furth er increase the bioavailability of 1. DSC and powder XRD data demonstr ated that the major fraction of drug was dissolved in the carrier. A p ossible explanation for the maximum achievable bioavailability of abou t 25% with solid dispersion preparation may be that once released, a s ignificant fraction of drug may precipitate in the GI tract. Re-solubi lization of the precipitated drug for the absorption is likely to be d ifficult due to its very low aqueous solubility.