A dual-functional nanosuspension-in-matrix mini-tablet system for enhancing oral bioavailability and prolonging antiplatelet response of ticagrelor.

Ticagrelor (TCG) is an oral P2Y12 receptor antagonist with limited aqueous solubility, which can restrict its dissolution and oral absorption. In this study, a ticagrelor nanosuspension-loaded sustained-release mini-tablet (TCG-NSP@SMT) was developed to combine nanosuspension-based dissolution enhancement with matrix-mediated release control. TCG nanosuspension (TCG-NSP) was prepared by antisolvent precipitation using D-α-tocopheryl polyethylene glycol 1000 succinate and polyvinyl alcohol as stabilizers, followed by spray drying. The resulting TCG-NSP exhibited a mean particle size of 188.8 ± 2.4 nm and a polydispersity index of 0.136 ± 0.003, and retained acceptable redispersibility after spray drying. Solid-state analyses indicated reduced crystallinity of TCG in the nanosuspension formulation. A D-optimal experimental design was applied to optimize the type and amount of matrix-forming polymer, and Metolose 4000 at 12.7% was selected as the optimal sustained-release polymer system. The optimized TCG-NSP@SMT showed pH-independent sustained release over 12 h, while TCG-NSP powder exhibited rapid dissolution. In rats, TCG-NSP@SMT at 10 mg/kg markedly increased systemic exposure, with a Cmax of 170.7 ± 28.8 ng/mL and an AUC0-24 of 2066.9 ± 1027.8 ng·h/mL, corresponding to a relative bioavailability of 795.6% compared with raw TCG. CT imaging supported prolonged gastrointestinal integrity of the matrix tablet, and PK/PD simulation predicted enhanced and sustained antiplatelet activity. These results suggest that TCG-NSP@SMT is a promising oral formulation strategy for improving the pharmacokinetic and predicted pharmacodynamic performance of poorly water-soluble antiplatelet drugs.