Preparation and physicochemical evaluation of a new tacrolimus tablet formulation for sublingual administration

Abstract

The aim of this study was to develop a new fast-disintegrating tablet formulation containing 1 mg tacrolimus for sublingual application. First, solid dispersions containing tacrolimus (2.5%, 5% and 10% w/w) incorporated in Ac-Di-Sol^® and carriers (inulin 1.8 kDa and 4 kDa, and polyvinylpyrrolidone (PVP) K30) were prepared by freeze drying. Subsequently, a tablet formulation composed of a mixture of the solid dispersions, Ac-Di-Sol^®, mannitol, Avicel^® PH-101 and sodium stearyl fumarate was optimized concerning drug load in the solid dispersions and the type of carrier. Tablet weight was kept constant at 75 mg by adjusting the amount of Avicel^® PH-101. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) results indicated the absence of the drug in the crystalline state, which was confirmed by the scanning electron microscopy (SEM). These results suggest that tacrolimus incorporated in all of the solid dispersions was fully amorphous. Dissolution of the tablets containing solid dispersions with a low drug load highly depends on the type of carrier and increased in the order: PVP K30 < inulin 4 kDa < inulin 1.8 kDa. Solid dispersions with a drug load of 10% w/w incorporated in the carriers yielded optimal formulations. In addition, the physicochemical characteristics and the dissolution behavior of the tablet formulation containing inulin 1.8 kDa-based solid dispersions with a drug load of 10% w/w did not change after storage at 20°C/45%RH for 6 months indicating excellent storage stability.

Keywords::

• Tacrolimus
• disintegration
• dissolution
• amorphous
• solid dispersions
• freeze drying
• inulin
• polyvinylpyrrolidone

Acknowledgments

This research was performed within the framework of project T5-105 of the Dutch Top Institute Pharma. The authors would like to acknowledge Anko C. Eissens for his assistance on SEM pictures, Natasja Kranenborg for procuring tacrolimus, Renella Herder for performing the GC analysis, and the Government Pharmaceutical Organization (Thailand) for the scholarship of P. Srinarong.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.