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

Int J Nanomedicine. 2011;6:2997-3009. doi: 10.2147/IJN.S26546. Epub 2011 Nov 24.

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: bioavailability; nanoparticles; sirolimus; solubility; supercritical antisolvent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Analysis of Variance
  • Animals
  • Area Under Curve
  • Biological Availability
  • Drug Carriers / administration & dosage
  • Drug Carriers / chemistry
  • Drug Carriers / pharmacokinetics
  • Drug Stability
  • Male
  • Nanoparticles / chemistry*
  • Nanotechnology / methods*
  • Povidone / chemistry
  • Rats
  • Rats, Sprague-Dawley
  • Sirolimus / administration & dosage
  • Sirolimus / chemistry
  • Sirolimus / pharmacokinetics*
  • Solubility
  • Surface-Active Agents / chemistry

Substances

  • Drug Carriers
  • Surface-Active Agents
  • Povidone
  • Sirolimus