Characterization of excipients to improve pharmaceutical properties of sirolimus in the supercritical anti-solvent fluidized process

Enhanced drug release and bioavailability of poorly soluble active pharmaceutical ingredient (API) can be achieved via a fluidized bed coating integrated with supercritical anti-solvent (SAS-FB) - a process of precipitating drug particles onto carrier granules. However, in the absence of excipients, SAS-FB often results in crystalline of the API on the surface of carriers, limiting the improvement of pharmaceutical properties. Co-processing with excipients is considered an effective approach to improve drug release in the SAS-FB process. Our study used sirolimus, an immune suppressive agent, as the model API to characterize excipients for their effect on pharmaceutical properties in the SAS-FB process. We show that co-precipitation of excipients and sirolumus impacts on carrier specific surface area and drug yield. Among the tested excipients, formulation containing polyvinylpyrrolidone K30 achieved the highest drug yield. Importantly, compared with Rapamune® tablet, our optimized formulation displayed a superior in vivo oral bioavailability by 3.05-fold in Sprague-Dawley rats and 3.99-fold in beagle dogs. A series of characterization of the processed API was performed to understand the mechanism by which excipients contributed to drug dissolution properties. Our study provides a useful guidance for the use of excipients in the SAS-FB technology to improve pharmaceutical properties of sirolimus and other poorly soluble drugs.