HEPARIN (LOW MOLECULAR WEIGHT) FRAGMENTS CENTAXARIN® [FH-0309] (ML-009723) is the sodium salt of heparin fragments of an average molecular weight of about 6,000. It is obtained by oxidative-depolymerization of heparin sodium of porcine intestinal mucosa and meets the compendial quality of the European Pharmacopoeia for low molecular weight heparins (LMWH). LMWH chains consist of derivatives of D-glucosamine (N-sulfated, N-acetylated, and/or O-sulfated) and hexuronic acid (L-iduronic or D-glucuronic acid, including O-sulfated derivatives).As compared to unfractionated heparin, LMWH exhibit a reduced anticoagulant effect because heparin fragments of less than 5400 Daltons do not effectively catalyze thrombin-antithrombin interaction. However, LMWH have an enhanced capacity to inhibit Factor Xa associated with the surface-bound prothrombinase complex thereby contributing to an improved antithrombotic effect.
 
The plasma concentration of Centaxarin® is easily predicted since there is a direct relationship between the administered dose and the anti-Factor Xa activity in plasma measured as area under the curve (AUC). The half-life of Centaxarin® is twice that of unfractionated heparin and is less dose-dependent. One mg of protamine sulfate neutralizes approximately 100 anti-Factor Xa Units of administered Centaxarin®. The effect on APTT is almost immediately and completely neutralized. The effect on anti- Factor Xa is antagonized by 78%, based on AUC evaluation. The chemistry of Centaxarin® corresponds to that of the active ingredient of the listed drug ARDEPARIN SODIUM INJECTION. Since there are no exclusivity impediments, Centaxarin® can be made available to an appropriate sponsor of an ANDA for a generic LMWH. References
European Pharmacopoeia 1997; 0828; 934-937.
References
Sawicki E, Hauser TR, Stanley TW. Elbert W. The 3-methyl-2-benzothiazolone hydrazone test.
Anal Chem 1961; 33:93-96. HEPARIN SODIUM, NITROUS ACID DEAMINATED [DH-0325] is obtained by deaminative hydrolysis of heparin sodium of porcine intestinal mucosa. Nitrous acid selectively cleaves the glycosidic bonds of the N-sulfated glucosamine residues with formation of di, tetra, hexa and higher saccharides terminated with 2,5-anhydro-D-mannose (AM) residues as reducing terminal groups. The terminal AM residues may be stabilized with sodium borohydride or coupled to an aminated surface by reductive amination. The formation of AM may be determined using the Indole reaction which is quite specific for anhydrosugars. References
Braswell E. Heparin: Molecular weight and degradation studies. Biochim Biophys Acta 1968;
158:103-116. HEPARIN SODIUM, PARTIALLY DE-N-SULFATED [PD-0324] is produced by selective de-N-sulfation of heparin sodium of porcine intestinal mucosa. Residual amino groups are determined by the trinitrobenzenesulfonate method before and after de-N-sulfation. The Nsulfate content may be directly determined by turbidimetry of the inorganic sulfate liberated after treatment of the sample with nitrous acid. References
Inoue Y, Nagasawa K. Selective N-desulfation of heparin with dimethyl sulfoxide containing
water or methanol. Carbohydr Res 1976; 46:87-95. HEPARIN SODIUM, PERIODATE-OXIDIZED [RH-0326] is manufactured pursuant to FDA Drug Master File # 11641 by controlled periodate-oxidation of heparin sodium of porcine intestinal mucosa. Periodate-oxidation causes cleavage of carbon-carbon bonds if the adjacent carbons bear hydroxyl groups or a hydroxyl and an amino group. Thus, unsulfated uronic acid residues in heparin are susceptible to periodate or Smith degradation with formation of polysaccharides having aldehydes as reducing terminal groups. Heparin containing aldehyde moieties will undergo reversible Schiff-base reactions with organic amines, and if treated with sodium cyanoborohydride the Schiff base intermediate is reduced to its corresponding amine forming an irreversible bond. References
Fransson LA, Lewis W. Relationship between anticoagulant activity of heparin and
susceptibility to periodate oxidation. FEBS 1979; 97:119-23.
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