title: Development of amorphous solid dispersion formulations of a poorly water-soluble drug, MK-0364.
abstract: 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.
authors: Department of Product Value Enhancement, Merck & Company, Inc., West Point, PA 19486, USA. sutthilug_sotthivirat@merck.com
authors: S
authors: S
authors: Sotthivirat
authors: C
authors: C
authors: McKelvey
authors: J
authors: J
authors: Moser
authors: B
authors: B
authors: Rege
authors: W
authors: W
authors: Xu
authors: D
authors: D
authors: Zhang
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000737:chemistry* / Q000493:pharmacokinetics; D005079:Excipients / Q000737:chemistry; D006601:Hexoses / Q000737:chemistry; D008253:Macaca mulatta; D008747:Methylcellulose / Q000031:analogs & derivatives / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011136:Polysorbates / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics; D011759:Pyrrolidines / Q000737:chemistry; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry; D014753:Vinyl Compounds / Q000737:chemistry; D014810:Vitamin E / Q000031:analogs & derivatives / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D000577:Amides; D063386:Cannabinoid Receptor Agonists; D005079:Excipients; D006601:Hexoses; D011136:Polysorbates; D011725:Pyridines; D011759:Pyrrolidines; D013501:Surface-Active Agents; D014753:Vinyl Compounds; C402301:poly(vinylpyrrolidone-co-vinyl-acetate); D014867:Water; C018665:sorbitan monooleate; D014810:Vitamin E; D011092:Polyethylene Glycols; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose; C014225:tocophersolan; C521311:N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide