Preservation of Hirdin Antithrombin Activity in a Low-Water-Activity Solid Premix: Formulation Performance and the Human Pharmacodynamic Context of Direct Thrombin Inhibition

Hirudin is a specific direct thrombin inhibitor, and its use depends on retaining conformational integrity and antithrombin activity. We characterized a dry solid premix developed to stabilize hirudin during powder processing and unit-dose filling. Formulation results were considered alongside published human pharmacodynamic studies of recombinant hirudin. The BCLC® premix used trehalose, mannitol and colloidal silicon dioxide for preadsorptive dispersion; citric acid-sodium citrate for local pH control; microcrystalline cellulose and pregelatinized starch as a low-hygroscopicity matrix; and geometric dilution under low humidity. Water activity was 0.26-0.34 in the three optimized formulations. Activity retention was 90.6-92.1%, activity-distribution RSD was 3.8-4.7%, and capsule fill-weight RSD was 2.9-3.4%. Retained activity fell to 76.4% without protective dispersion and staged dilution, 72.9% during high-humidity processing, and 80.1% without the buffer. Intravenous and subcutaneous studies of recombinant hirudin report dose-related prolongation of thrombin time and activated partial thromboplastin time. These pharmacodynamic findings define biomarkers for later studies of stabilized hirudin systems.