Enhanced bioavailability of sirolimus via preparation of solid dispersion nanoparticles using a supercritical antisolvent process

Abstract

Background

The aim of this study was to improve the physicochemical properties and bioavailability of poorly water-soluble sirolimus via preparation of a solid dispersion of nanoparticles using a supercritical antisolvent (SAS) process.

Methods

First, excipients for enhancing the stability and solubility of sirolimus were screened. Second, using the SAS process, solid dispersions of sirolimus-polyvinylpyrrolidone (PVP) K30 nanoparticles were prepared with or without surfactants such as sodium lauryl sulfate (SLS), tocopheryl propylene glycol succinate, Sucroester 15, Gelucire 50/13, and Myrj 52. A mean particle size of approximately 250 nm was obtained for PVP K30-sirolimus nanoparticles. Solid state characterization, kinetic solubility, powder dissolution, stability, and pharmacokinetics were analyzed in rats.

Results

X-ray diffraction, differential scanning calorimetry, and high-pressure liquid chromatography indicated that sirolimus existed in an anhydrous amorphous form within a solid dispersion of nanoparticles and that no degradation occurred after SAS processing. The improved supersaturation and dissolution of sirolimus as a solid dispersion of nanoparticles appeared to be well correlated with enhanced bioavailability of oral sirolimus in rats. With oral administration of a solid dispersion of PVP K30-SLS-sirolimus nanoparticles, the peak concentration and AUC_0→12h of sirolimus were increased by approximately 18.3-fold and 15.2-fold, respectively.

Conclusion

The results of this study suggest that preparation of PVP K30-sirolimus-surfactant nanoparticles using the SAS process may be a promising approach for improving the bioavailability of sirolimus.

Keywords:

• sirolimus
• solubility
• bioavailability
• supercritical antisolvent
• nanoparticles

Acknowledgments

This work was supported by the Priority Research Centers Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (2009-0093815) and, in part, by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A080470).

Disclosure

The authors report no conflicts of interest in this work.