Bioerodible devices for intermittent release of simvastatin acid

Abstract

The association polymer system of cellulose acetate phthalate (CAP) and Pluronic F-127 (PF-127) was used to create intermittent release devices for mimicking the daily injection of simvastatin that has been reported to stimulate bone formation. To enhance solubility in water, prodrug simvastatin was modified by lactone ring opening, which converts the molecule to its hydroxyacid form. CAP/PF-127 microspheres incorporating simvastatin acid were prepared by a water–acetone–oil–water (W/A/O/W) triple emulsion process. Devices were then fabricated by pressure-sintering UV-treated blank and drug-loaded microspheres. Using a multilayered fabrication approach, pulsatile release profiles were obtained. Delivery was varied by changing loading, number of layers, blend ratio, and incubation conditions. To determine the cellular effects of intermittent exposure to simvastatin acid, MC3T3-E1 cells were cultured with either alternating or sustained concentrations of simvastatin acid in the medium, and DNA content, alkaline phosphatase activity, and osteocalcin secretion were measured. For all three cell responses, cultures exposed to simvastatin acid showed higher activity than did control cultures. Furthermore, cell activity was greater for cells cultured with intermittent concentrations of simvastatin acid compared to cells that were constantly treated. These results imply that devices intermittently releasing simvastatin acid warrant further study for locally promoting osteogenesis.