Bioavailability Enhancement and Polymorphic Stabilization of One BCS Class IV Metastable Drug Through Novel...

This study aims to enhance the bioavailability and polymorphic stability of Ticagrelor, a metastable, low-soluble and low-permeable Biopharmaceutics Classification System Class IV drug, by exploring different formulation approaches.

Ticagrelor was taken as a model drug for the enhancement of bioavailability and polymorphic stability. Initially, various techniques, such as micronization, amorphous solid dispersion (ASD), and Self-Microemulsifying Drug Delivery System, were evaluated for dissolution enhancement. Based on the improvement in dissolution rate, polymorphic stability, and process viability, an ASD technique was selected for dissolution enhancement of Ticagrelor. Co-povidone VA 64 and vitamin E TPGS were used as carriers for the preparation of Ticagrelor solid dispersion (SD) by the solvent evaporation technique. The formulation was optimized and further evaluated for dissolution performance in biorelevant media fasted state simulated gastric fluid and fasted state simulated intestinal fluid. The bioavailability of the Ticagrelor SD tablet formulation was compared with a conventional immediate release tablet formulation prepared by wet granulation process in line with reference product Brilinta^® (AstraZeneca LP). In vivo pharmacokinetic (PK) studies were carried out in Wistar rats with due approval from ethics committees such as CPCSEA and IAEC (CPCSEA/DIPS/02/23/61). Patients are not involved in this study, hence informed consent not applicable.

The relative bioavailability and peak plasma concentration (C_max) of Ticagrelor SD formulation compared to conventional immediate release tablet formulation in line with Brilinta^® (AstraZeneca LP) were found to be 141.61±2.29% and 137.0±0.59%, respectively. Further, based on a doseadjusted PKs study of Ticagrelor SD, a 70 mg Ticagrelor tablet formulated with the SD technique was found to be equivalent to a 90 mg dose of Ticagrelor conventional immediate release tablet formulation with a comparable C_max, area under the curve (AUC)_0-24, and AUC_0-∞. Visual observation of the dissected gastric organ through a stereomicroscope revealed no redness or bleeding post-administration of Ticagrelor SD formulations.

The SD technique with carrier co-povidone VA 64 and vitamin E TPGS prepared by the solvent evaporation process could yield a Ticagrelor formulation with improved bioavailability and polymorphic stability.