Improvement of Bioavailability of Menaquinone-4 by Dimethyl-β-cyclodextrin Complexation Following Oral Administration

Aqueous solubility of menaquinone-4 (MK-4), a potent antihemorrhagic vitamin K2, largely increased with heptakis(2, 6-di-O-methyl)-β-cyclodextrin (DM-β-CyD), forming the higher-order complexes. By the analysis of phase solubility diagram, the stoichiometric ratio of the main complex was estimated to be 1 : 3 (MK-4/DM-β-CyD) with the stability constant of 46400M-1. Then, the 1 : 3 solid complex was prepared by the kneading method, and its dissolution, absorption, and pharmacological characteristics were compared with those of MK-4. The plasma levels of MK-4 after the oral administration to dogs and rats in the form of complex were significantly higher than the MK-4 alone, particularly in the cases of the fasted state and the lack of bile. When the complex was administered orally to rats under bile duct cannulation, MK-4 was absorbed through both portal and lymphatic routes. The oral administration of DM-β-CyD complex also attained the shortening of the blood-clotting time of MK-4 for warfarin-induced hypoprothrombinemic dogs. The enhanced bioavailability seemed to be mainly ascribable to the increase in dissolution of MK-4 by DM-β-CyD complexation.