Study On The Production Technology And Quality Standard Of Anticoagulant Argatroban

Thrombotic diseases are one of the major diseases that seriously endanger human health.Anticoagulant therapy is an important measure to treat thrombotic diseases.Argatroban,is a small molecule derivative of arginine,direct antithrombin inhibitor,and was developed by Mitsubishi Chemical Company.Argatroban exhibits strong selective inhibition effect on thrombin by reversible binding with the catalytic activity of thrombin.Argatroban has a wide range of clinical applications,now mainly used in clinical peripheral arterial occlusive disease,heparin-induced thrombocytopenia,acute ischemic stroke,acute myocardial infarction,blood purification,percutaneous coronary intervention(PCI)and surgical anticoagulation,etc.The current work was based upon patent EP0008746,US4258192,US4201863,EP0823430 as the main body of argatroban production process optimization and development,which was in accordance with the Chinese Pharmacopoeia(2015 version)of its quality standards for research and achieved the following results:(1)Based on the patent documents,we reproduced herein the literature and optimized the literature process in terms of time,economy and security,the final synthesis route is completed in 4 steps,and passed the small test,pilot test,enlarged production,to establish a stable,controlled,quality guaranteed production process.(2)By comparative study of domestic drug registration standards and standards contained in the Japanese Pharmacopoeia(16 version),we established methods for the detection of substances,isomers,contents and other routine items and conducted the necessary methodological studies.(3)Through the influence factor test,accelerated test and long-term stability test,the feasibility of test methods and product quality controllability were further researched.