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

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.

Improved dissolution behavior of lipophilic drugs by solid dispersions: the production process as starting point for formulation considerations.

INTRODUCTION: Many new drug substances have low aqueous solubility which can cause poor bioavailability after oral administration. The application of solid dispersions is a useful method to increase the dissolution rate of these drugs and thereby improve their bioavailability. So far, several methods have been developed to prepare solid dispersions. To obtain a product with the desired attributes, both the formulation and production processes should be considered. AREAS COVERED: The most currently used methods to produce solid dispersions, such as the fusion method, hot melt extrusion, spray drying, freeze drying and supercritical fluid precipitation, are reviewed in this paper. In addition, the physicochemical characteristics of the obtained solid dispersions are discussed. EXPERT OPINION: Solid dispersions can be successfully prepared by simple fusion, hot melt extrusion, spray drying, freeze drying and supercritical fluid precipitation. Hot melt extrusion, spray drying and freeze drying are processes that can be applied for large scale production. The simple fusion method is not very suitable for large scale production, but is particularly suitable for screening formulations. The most recent method to produce sold dispersions is supercritical fluid precipitation. The process conditions of this method need extensive investigation, in particular in relationship with the selection of the type of carrier and/or solvent. Both processes and formulation aspects strongly affect the characteristics of solid dispersion products. Furthermore, application of crystalline solid dispersions is gaining increasing interest because they are thermodynamically more stable than amorphous solid dispersions.

Surface-active derivative of inulin (Inutec® SP1) is a superior carrier for solid dispersions with a high drug load.

The aim of this study was to compare the applicability of inulin, its surface-active derivative (Inutec® SP1), and polyvinylpyrrolidone (PVP) as carriers in high drug load solid dispersions (SDs) for improving the dissolution rate of a range of lipophilic drugs (diazepam, fenofibrate, ritonavir, and efavirenz). The SDs were prepared by spray freeze-drying. Scanning electron microscopy showed that the obtained samples were highly porous spherical particles. Modulated differential scanning calorimetry showed that the drugs incorporated in these carriers were fully or partially amorphous. The solubility of the drugs in solutions of the different carriers was increased in an order: inulin 2.3 kDa < PVP K30 ≪ Inutec® SP1. The dissolution behavior of SD tablets was evaluated. Inutec® SP1-based SD tablets showed the best performance followed by PVP- and inulin-based SD tablets. The superior dissolution behavior of the drugs from Inutec® SP1-based SDs could be ascribed to its surface-active nature. In addition, Inutec® SP1-based SD tablets gave good physical stability at 20 °C/45% relative humidity (RH) and 40 °C/75% RH for 3 months.

Effect of drug-carrier interaction on the dissolution behavior of solid dispersion tablets.

The objective of this study was to compare the dissolution behavior of tablets prepared from solid dispersions with and without drug-carrier interactions. Diazepam and nifedipine were used as model drugs. Two types of carriers were used; polyvinylpyrrolidone (PVP K12, K30 and K60) and saccharides (inulin 1.8 kDa, 4 kDa and 6.5 kDa). Solid dispersions with various drug loads were prepared by lyophilization. It was found that the drug solubility in aqueous PVP solutions was significantly increased indicating the presence of drug-carrier interaction while the drug solubility was not affected by the saccharides indicating absence of drug-carrier interaction. X-ray powder diffraction and modulated differential scanning calorimetry revealed that all solid dispersions were fully amorphous. Dissolution behavior of solid dispersion tablets based on either the PVPs or saccharides was governed by both dissolution of the carrier and drug load. It was shown that a fast drug dissolution of solid dispersions with a high drug load could be obtained with carrier that showed interaction with the drug.