肝素製劑品質監測研究   全文下載

Quality Inspection of Heparin in Taiwan

肝素（Heparin）為常用抗血栓藥物，可與凝血級聯反應（Blood clotting cascade）中多種凝血因子結合，具抗凝血活性，除作為採血管之抗凝劑外，常用於治療栓塞疾病。然其來源為家畜腸黏膜或其他適當的組織萃取，可能含有少量的天然不純物質，如硫酸皮膚素（Dermatan sulfate, DS）及硫酸軟骨素（Chondroitin sulfate, CS），因此監測肝素品質狀況至為重要。2008年全球發生使用肝素導致過敏而有多人因而不幸死亡情形，經調查發現原因係過硫酸化硫酸軟骨素（Oversulfated chondroitin sulfate, OSCS）化學物污染造成。有鑒於肝素製劑可能含有污染之雜質危害國人健康，另肝素製劑若活性不足，將導致凝血效能不全，因此於107年度進行肝素製劑及原料藥之品質全面監測調查，並利用陰離子交換高效液相層析法與氫核磁共振儀鑑別肝素及檢測肝素原料藥不純物質（如OSCS與DS等），並使用比色法（Chromogenic assay）分析肝素原料藥及注射劑抗凝血因子Xa與IIa之活性。共抽樣45件檢體，包含傳統肝素注射液、低分子量肝素注射液及肝素原料藥，經分析，結果皆符合中華藥典第八版之規範，可確保國人用藥安全。

Heparin, a kind of the sulfated glycosaminoglycan (GAG), which is the most widely used anticoagulant drug in the world. In vivo, heparin exerts anticoagulant activity by binding to coagulation factors in the blood clotting cascade. It is either used as an anticoagulant for evacuated blood collection tube or to treat blood clot symptoms, for instance, thrombophilia, pulmonary embolism, et al. In addition, heparin is also used to prevent postoperative embolization. Because the main source of heparin is from the intestinal mucosa or other suitable tissues of domestic mammals, formulations of the processed heparin can contain low level of natural contaminants, such as dermatan sulfate (DS) or chondroitin sulfate (CS). DS could induce allergic reactions in human. In 2008, many people died due to the allergy to heparin contaminated with over-sulfated chondroitin sulfate (OSCS) in the United States. OSCS is a substance hard to differentiate from heparin by traditional analytical process (e.g., sheep plasma assay), owing to their similar structure. Therefore, new analytical methods, such as high performance liquid chromatography (HPLC) and Nuclear Magnetic Resonance Spectroscopy (NMR), could help to detect OSCS. In view of heparin containing active pharmaceutical ingredients which do harm human health, we established the SAX-HPLC, 1 H-NMR, size-exclusion chromatography (SEC) analytical methods and anti - coagulation factor Xa and IIa activity assays to identify and to measure the potency of heparin by referring to heparin sodium and injection monographs of the national pharmacopoeias and other relevant references. Forty-five samples (including 41 injections and 4 drug substances) were collected and analyzed; all of them were in compliance with the specification of Chinese Pharmacopeia. Overall, these established methods can be employed in the post-market surveillance for quality control of heparin preparation and for identification of heparin of the unknown sample to ensure the public health.