A method for improving drug stability of bivalirudin

Abstract

The invention discloses a method for improving stability of a Bivalirudin medicine. The method comprises the following steps of preparing the Bivalirudin raw medicine into a freeze-drying liquid; then, adopting a superlow-temperature vacuum freeze-drying method to prepare a Bivalirudin freeze-drying powder injection, wherein before drying, the pH (potential of hydrogen) value of the freeze-drying liquid is regulated to 5.0 to 6.0 by a sodium carbonate solution; in the superlow-temperature vacuum freeze-drying process, the pre-freezing temperature is -188 to -55 DEG C, the sublimation drying temperature is -40 to 10 DEG C, and the desorption drying temperature is 10 to 60 DEG C. The method has the advantages that sodium carbonate is used as a pH regulator, a more moderate effect is realized, and the degrading capability is effectively decreased; the dissolving speed of a product is improved by the superlow-temperature vacuum freeze-drying, the water content of the product is reduced, and the stability of the product is improved; verified by experiments, an injection Bivalirudin preparation is formed after freeze-drying, the quality and stability of the preparation are obviously improved, the uniformity of the product is improved, and the usage risk of the medicine is decreased.

Description

technical field [0001] The invention relates to the technical field of preparation of bivalirudin pharmaceutical preparations, in particular to a method for improving the stability of bivalirudin pharmaceuticals. Background technique [0002] Bivalirudin is a direct thrombin inhibitor that has been used clinically in recent years. Its effective anticoagulant component is a hirudin derivative fragment, which exerts an anticoagulant effect by directly and specifically inhibiting thrombin activity. Reversible and short-lived. Early clinical studies have shown that anticoagulant therapy with bivalirudin is effective and has a lower incidence of bleeding events, and it is safer to use than traditional heparin anticoagulant therapy. Bivalirudin can be used as an alternative to heparin in patients undergoing percutaneous coronary intervention (PCI). [0003] Bivalirudin formulation was approved for marketing in the United States in 2000. The listed variety is AngiomaxTM, and ther...

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Problems solved by technology

In the published patent document CN100586422C, sodium carbonate of 0.5 mol / L is used to adjust the pH, which needs to add a large amount of pH regulator, which is not easy to control; in the published patent document CN104146969A, it is reported that sodium hydroxide is used as the pH regulator. Alkali sensitive, easy to produce Asp during adjustment 9 Bivalirudin impurities and fragment impurities; the lyophilization method used in the open patent document CN104338117A has a prefreezing temperature of -30°C, slow prefreezing, and slow product dissolution; the open patent document CN102813908A uses an annealing method to improve the stability of the preparation Although there is some improvement, the operation is complicated and the improvement is not obvious

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