Study Of Two Low Molecular Weight Heparin (lmwh) Production Technology And Quality Standards

Low-molecular-weight heparin (LMWH) is a series of antithrombotic drugs derived from heparin in the last two decades. LMWH has a higher antithrombotic effect, but a lower anticoagulant effect than unfractionated heparin. In addition, there are various advantages of LMWH when it is clinically used in prophylaxis and treatment of thrombosis, including delightful subcutaneous absorption, high bioactivity, limited hemorrhage, free of clinical monitoring, and so on.China is one of the biggest heparin consuming country, however, the domestic LMWH products just take a market share lower than 20%. The gap between domestic and international advanced manufacturing technique and quality standard, decrease their competitive strength in domestic market. Our national standard of LMWH was established in 2005, the requirement of which was similar to the profile of LMWH in British Pharmacopoeia. In 2008, the event of over sulfated chondroitin sulfate accelerates the revise of heparin quality standard in many countries. This event suggested that LMWH probably also exists such contamination risks. In this consideration, The US, EU, Japan, Australia, and a number of developing countries subsequently revised the quality standard of heparin and all kinds of LMWHs.In this work, we choose Enoxaparin and Dalteparin Sodium, two of the most representative LMWH products in our country, to optimize the manufacturing technique, and to determine the key parameters, so as to make our own standard get close to advanced international quality standard.1. Optimization of the manufacturing technique of Enoxaparin and Dalteparin SodiumManufacturing technique and key parameters, especially controlling the quantity of Chondrotin sulfate/Dermatan sulfate, were optimized through experiments. A new method was established for online manufactruring control, as well as elevated the industry product quality level. As a result, these measures enhanced the quality of domestic LMWHs and increased their competing strength. 2. Quality standard and detecting method of Enoxaparin and Dalteparin SodiumThe LMWH quality standard in China is comparatively simple than western countries, especially there is no classification over molecular weight and distribution of LMWH manufactured through different techniques. Molecular weight, a main quality index for LMWH, greatly affects the product quality. Molecular weight detecting method and condition apparently affects the final result, therefore, after referring the detecting results obtained by foreign institutions, the detecting condition and method were optimized in this work.3. Establishment of the impurity detecting methodAfter the event of over sulfated chondroitin sulfate, each country applied a much stricter quality standard to control heparin product on their impurity limits. Though similar events did not occur on LMWH, yet there are also latent risks in these products. In the mean while, the impurities brought into and generated in the product during manufacturing process are the main factor that decreases drug security. In consequence, it is necessary to establish a set of detecting method to control impurity contamination.