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 69698 (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, Transcutol and Labrasol, the bioavailability of 1 was determined to be 11.8%. This represented about 2-fold improvement over 6% bioavailability observed previously with an aqueous suspension of the drug in 0.5% methylcellulose. When the formulation contained only Labrasol, in which 1 was completely solubilized, the bioavailability of 1 was 12.9%. Addition of a surfactant, polysorbate 80, at a strength of 10% to the dispersion with PEG 3350 and Labrasol as carriers increased the bioavailability of 1 from 11.8 to 27.6%. This result was attributed to the ability 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 further increase the bioavailability of 1. DSC and powder XRD data demonstrated that the major fraction of drug was dissolved in the carrier. A possible explanation for the maximum achievable bioavailability of about 25% with solid dispersion preparation may be that once released, a significant fraction of drug may precipitate in the GI tract. Re-solubilization of the precipitated drug for the absorption is likely to be difficult due to its very low aqueous solubility.