Ionic complex of risedronate with positively charged deoxycholic acid derivative: evaluation of physicochemical properties and enhancement of intestinal absorption in rats

Risedronate is widely used clinically to treatosteoporosis, Paget’s disease, hypercalcemia, bone metastasis,and multiple myeloma. However, its oral efficacy isrestricted due to its low bioavailability and severe gastrointestinaladverse effects. This study was designed toevaluate the effect of deoxycholic acid derivatives on thepermeability and oral bioavailability of risedronate byincreasing its lipophilicity and affinity to bile transporters. We synthesized two bile acid derivatives, Na-deoxycholyl-L-lysyl-methylester (DCK) and Na-deoxycholyl-L-lysylhydroxide(HDCK) as oral absorption enhancers. Afterionic complex formation with the bile acid derivatives, thecomplexes were characterized by powder X-ray diffraction. Their artificial membrane permeabilities and bioavailabilitiesin rats were investigated in comparison with purerisedronate. Complex formation with DCK or HDCKdemonstrated that risedronate existed in an amorphousform in the complex. A physical complex of risedronatewith DCK enhanced the apparent membrane permeability of risedronate significantly but pure risedronate was notpermeable. An in vivo study revealed that the Cmax andAUClast of risedronate/DCK (1:2) complex were 1.92- and2.64-fold higher than those of pure risedronate, respectively. Thus, the risedronate/DCK complex can improvethe oral absorption of risedronate and patient complianceby reducing dose frequency and adverse reactions.