methylcellulose and sorbitan-monooleate

The goal of this study was to demonstrate that MK-0364 solid dispersions can be developed as a means to increase the solubility and bioavailability of a poorly water-soluble drug, MK-0364. The potential solid dispersions would enable an oral solid dosage form as a monotherapy or combination product of MK-0364. Preliminary screening included sample preparation via a solvent casting method, physical characterization, and in vitro dissolution testing. Lead formulations were subsequently manufactured using hot melt extrusion (HME) and spray-drying (SD). All HME (without polyvinyl pyrrolidone) and SD formulations exhibit characteristics of a single phase glass including an amorphous halo when analyzed with X-ray powder diffraction (XRPD), a single glass transition temperature (Tg) measured with differential scanning calorimetry (DSC), and supersaturation when dissolved in dissolution media. The oral absorption of MK-0364 from selected HME and SD formulations in monkeys results in marginally greater exposure with a consistently longer Tmax relative to a liquid filled capsule reference. Based on the processability, physical characterization, in vitro dissolution, and animal pharmacokinetic results, copovidone- and hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based solid dispersion formulations are viable product concepts. The physical stability of both the solid dispersion formulations was also evaluated for 54 weeks under different conditions. The copovidone-based solid dispersion requires protection from moisture.

Topics: Amides; Animals; Cannabinoid Receptor Agonists; Excipients; Hexoses; Macaca mulatta; Methylcellulose; Polyethylene Glycols; Polysorbates; Pyridines; Pyrrolidines; Solubility; Surface-Active Agents; Vinyl Compounds; Vitamin E; Water