Microparticle and liquid formulation of a novel HIV protease inhibitor.

The purpose of this study was to develop an improved dosage form of a novel protease inhibitor, LB71350. To overcome the dissolution rate-limiting step in oral absorption, amorphous LB71350 formulation was developed by spray drying ethanol solution of LB71350 and lecithin. Spray drying resulted in free flowing spherical microparticles with diameter < or = 5 microns. Powder X-ray diffraction confirmed that LB71350 in spray-dried microparticles and its aqueous dispersion was amorphous. In contrast to the aqueous suspension of crystalline LB71350, dispersion prepared from spray-dried microparticles showed significantly higher oral bioavailability in rat. Aqueous dispersion of spray-dried microparticles was more palatable than that of co-solvent solution formulation. Stability of dispersions depended on the concentration of dispersion and storage temperature. Dispersion containing 50 mg LB71350/mL was stable at 4 degrees C for 6 weeks without any significant physical or chemical changes. However, massive aggregation and crystallization of LB71350 occurred after 3 weeks at 25 degrees C. Dispersion containing 25 mg LB71350/mL showed sedimentation, which was re-dispersible by gentle shaking. When dispersion stored for 4 weeks at 4 degrees C was given orally to rat, plasma concentration profiles were similar to those obtained after administration of fresh sample. On the basis of these results, the dispersion can be stored at least for 4 weeks at 4 degrees C. Spray-dried microparticles have been stable for 1 year at 4 degrees C without drug crystallization and further study is in progress to establish long-term storage stability. The present study establishes the feasibility of LB71350 liquid dosage formulation that is composed of free flowing spray-dried microparticles and aqueous vehicle to be reconstituted at the time of dispensing.