Amphiphilic vehicles improve the oral bioavailability of a poorly soluble HIV protease inhibitor at high doses

Abstract

DMP 323 is the first clinical candidate from a novel series of HIV protease inhibitors having a cyclic urea structural backbone. In dogs dosed with glycol-based vehicles, DMP 323 was approximately 50% orally bioavailable after a 100 mg dose, but bioavailability was almost 10-fold lower when a 350 mg dose was administered. Since DMP 323 has very low water solubility, it was expected that this loss of bioavailability at a high dose was due to drug precipitation in the aqueous fluids of the gastrointestinal tract. Clinically, high doses were desired so as to maximize antiviral effects. Therefore, formulation strategies to improve bioavailability at high doses were examined. Bioavailability of 350 mg doses in dogs was not improved using formulations consisting of glycols with low concentrations of added surfactants, or with solid dispersions of DMP 323 in PEG or PEG/PVP matrices. An alternative approach was to use formulations comprised primarily of an amphiphilic material such as Gelucire 44/14 (a mixture of glycerides and PEG esters). Bioavailability was increased to 50% using a semi-solid Gelucire 44/14 formulation, compared with the 6% or lower value observed at this dose with glycol vehicles. Gelucire 44/14 increased DMP 323 aqueous solubility and dissolution rate, as did other amphiphilic materials with high HLB values. Oral bioavailability of DMP 323 is determined by the DMP 323 dose, the solubilization afforded by the vehicle when diluted into an aqueous environment, and the vehicle dose. Amphiphilic vehicles such as Gelucire 44/14 could be used to administer high doses of DMP 323 without compromising oral bioavailability. A limitation of this approach is the volume of vehicle required.