FORMULATION ASSESSMENT OF MK-886, A POORLY WATER-SOLUBLE DRUG, IN THEBEAGLE DOG

MK-886 is an orally active leukotriene biosynthesis inhibitor which ma y have therapeutic benefits in inflammatory diseases. The compound is the sodium salt of an organic acid with low aqueous equilibrium solubi lity and potentially poor oral absorption characteristics. Since there is no adequate in vitro method of predicting oral bioavailability for such poorly water-soluble compounds, assessment of formulations was c onducted in vivo. The beagle dog was chosen as an animal model to sele ct a suitable dosage form with good absorption characteristics. Dosage form performance was evaluated by comparing the following pharmacokin etic parameters: area under the plasma concentration vs time curve (AU C), peak plasma concentration (C-max) and the time required to reach t his peak (T-max). Since no intravenous formulation was available, oral absorption from the different solid and liquid soft gelatin capsule f ormulations was evaluated relative to the absorption from a reference oral solution of MK-886 in PEG 400. Oral absorption of MK-886 in PEG 4 00 solutions was independent of solution concentration within the 15-f old range of concentration tested and was not affected by encapsulatin g the solutions in a soft gelatin shell. Food or co-administration of an alkalizing agent had no effect on the absorption of MK-886 from the soft gelatin capsules. Solid oral dosage forms, both capsules and tab lets, had similar absorption characteristics to those of the PEG 400 s olutions when the drug was granulated with an aqueous solution of poly vinylpyrrolidone (PVP), a hydrophilic polymer. PVP-granulated solid or al dosage forms had superior absorption characteristics when compared with a dry filled capsule of ungranulated drug.