Development of a continuous hot melt extrusion process for manufacturing solid oral dosage forms containing a BCS II drug.

The purpose of this work was the development of a continuous process for manufacturing solid oral dosage forms containing itraconazole (ITZ), a model poorly soluble drug. In order to improve its bioavailability, its aqueous solubility must be enhanced. One useful method for increasing the solubility of these drugs is the conversion of the crystalline form into its amorphous form to obtain an amorphous solid dispersion (ASD) by hot melt extrusion (HME). Soluplus® (SOL) was chosen as the main polymer matrix due to its ability to interact with ITZ and to stabilize its amorphous form. However, SOL exhibits a “gel effect” in solution which slowed down the release of ITZ. A screening study enabled the selection of gel-breaking excipients that were used in a design of experiment (DoE) to optimize the formulation. In parallel, the limits of the HME process parameters were also determined and included in the DoE. The optimum formulation was the one containing 2.5 wt. % of AcDiSol® produced at 155 °C and 100 rpm. Moreover, the design space around the optimum was determined. The second strategy used during this work for increasing the solubility and dissolution rate of ITZ is the formation of inclusion complexes with cyclodextrins (CD) by HME. Moreover, SOL was added as a ternary component for facilitating the extrusion process since CD are not thermoplastic compounds; and to help stabilizing the complex in solution. Out of the six tested CD, two were discarded after the preformulation study using rheology and extrudability testing. The four remaining CD were processed by HME. Saturation concentration, DSC and ATR-FTIR measurements confirmed that the best formulation was the one containing HP-beta;-CD 0.63. Then the two optimized formulations were tested on rats in the framework of the Three Rs ethical concept. Only 10 µL of blood (about one drop) was withdrawn from the tail of the rats using specific sampling devices for each time point. Regarding the pharmacokinetic parameters of ITZ and its active metabolite (AUC and Cmax) the following ranking was obtained: Sporanox® < SOL/ITZ ASD < SOL/ITZ/CD < SOL/ITZ/AcDiSol®.The best formulation SOL/ITZ/AcDiSol® was produced in a continuous way using an original thermoforming apparatus. When coupled to the extruder, it enabled the production of easily swallowable oral dosages forms containing 100 mg of ITZ with a mass and content variation and of less than 4 % and 2 %, respectively; which is in accordance with the limit set by the Pharmacopeia.