This invention relates to formulations of c-Met kinase inhibitors.
A variety of c-Met kinase inhibitors have been disclosed for the treatment of various disorders related to c-Met kinase functioning, including the treatment of cellular proliferative disorders. Such disorders include, but are not limited to, cancer, hyperplasias, restenosis, cardiac hypertrophy immune disorders and inflammation. Representative examples of c-Met kinase inhibitors include those disclosed International Publication WO2008/008310, which published on Jan. 17, 2008, to Merck & Co., Inc., which is hereby incorporated by reference in its entirety.
C-Met kinase inhibitors can be formulated for oral dosing as tablets, by using a direct compression, wet granulation, hot melt extrusion, spray drying and/or roller compaction method. Similarly, c-Met kinase inhibitors can be formulated for oral dosing as gelatin capsules, being a liquid in a soft capsule, or dry powder or semi-solid in a hard capsule. In addition, c-Met kinase inhibitors can be formulated for intravenous dosing.
The formulations of the instant invention have advantages over other formulations of c-Met kinase inhibitors. Many c-Met kinase inhibitors exhibit pH-dependent solubility through the pH range 1-7, having higher solubility in acidic pH. Based upon the sharp dependence of solubility on pH, it can be postulated that the performance of these formulations can vary based on variability in gastric pH. For example, recent data from clinical studies with Compound A indicated high variability in Compound A exposure among patients, with lower exposures in some patients who were concomitantly taking antacids (i.e. with high gastric pH). Exposure can vary due to many factors, including whether the inhibitor is taken with or without food. The formulations of the instant invention give in vivo exposures to the drug that are less sensitive to changes in gastric pH than other formulations. Hence while the formulations of the instant invention give a similarly high exposure to the drug at low gastric pH as other formulations, the formulations of the instant invention give a higher exposure to the drug at higher gastric pH than other formulations.
The use of acidulant as described in the instant invention is more efficacious than extemporaneous use of acidulant. For example, with the baseline of a simple formulation absent of acidulant, the improvement in drug solubilisation at high pH from the use of the instant invention is much greater than from coadministering an acidic beverage (e.g. cola).