Microsponge-derived mini tablets loaded with immunosuppressive agents: Pharmacokinetic investigation in human volunteers, cell viability and IVIVC correlation

Abstract

Sirolimus, a potent immunosuppressant, has been demonstrated to have remarkable activity in inhibiting allograft rejection in transplantation. The objective of the study was to fabricate microsponge mini tablets with enhanced solubility and bioavailability. β-Cyclodextrin and NEOCEL C91 were selected to prepare the microsponges (SLM-M) to improve the stability and solubility of sirolimus. The current study involved the quasi emulsion-solvent diffusion technique to design sirolimus-loaded microsponges that were further compressed into mini tablets 4 mm in diameter. Solid-state characterization, dissolution at different pH values, stability, and pharmacokinetic profiles with IVIVC data were analyzed in humans. Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD) were used to characterize the formulations, and high-performance liquid chromatography (HPLC) was used to assess the drug stability of the compressed microsponge minitablets. The API changed from the crystalline state to an amorphous state, as shown by XRD and DSC. The compressed mini tablets showed a 4-fold enhancement in the drug dissolution profile. A toxicology investigation suggested that mini tablets were safe. In humans, the bioavailability of sirolimus compressed mini tablets from SLM-M was significantly improved. The results suggest that mini tablets prepared with β-cyclodextrin and NEOCEL C91 by a quasi emulsion-solvent diffusion process might be an alternative way to improve the bioavailability of sirolimus. In addition, the manufacturing process is easily scalable for the commercialization of drugs to market.

Keywords

• Sirolimus
• Solubility
• Solid dispersions
• Bioavailability
• IVIVC