Potential use of cyclodextrins to enhance the solubility of YM466 in aqueous solution

Various solubilizing agents for YM466, a new Factor Xa inhibitor, were investigated to begin designing the aqueous formulation for subcutaneous administration. The tentative target concentration was 5 mg/mL. First, three kinds of buffer solutions (glycine-HCl, citrate, and lactate) were examined for their solubilizing effects. The dissolution rate of YM466 in lactate buffer was the fastest, as determined by visual examination at room temperature. The dissolution rate of YM466 in lactate buffer was enhanced, without degradation, by heating at 40 degrees C, and YM466 solution at a concentration of 1 mg/mL became transparent 10 min after the start of heating. The solubility of YM466 increased along with lactate concentrations ranging from 50 mM to 200 mM and reached a high of 1.3 mg/mL after increasing lactate concentration to 200 mM at 5 degrees C. The addition of cyclodextrins beta-cyclodextrin (beta-CD), 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and gamma-cyclodextrin (gamma-CD), but not alpha-cyclodextrin (alpha-CD), had remarkable impact on its solubility, and 7-8 mg/mL of YM466 was dissolved by the addition of HP-beta-CD or gamma-CD. These results demonstrated that YM466 was included in cyclodextrins and that the inclusion formations required a cavity size larger than alpha-CD. Based on the calculation from the linear portion of the phase solubility diagrams, apparent stability constants of alpha-CD, beta-CD, HP-beta-CD, and gamma-CD at 5 degrees C were estimated to be 2M(-1), 206M(-1), 143M(-1), and 276M(-1), respectively. Therefore, we found that gamma-CD has the largest inclusion capacity.