Preparation Of Low Molecular Weight Heparins From Different Species Using Nitrous Acid Degradation

Heparin is a class of linear glycosaminoglycans(GAGs)that are commonly found on the cell surface the extracellular matrix of mammals.Heparin is composed of repeating disaccharide units composed of uronic acid and glucosamine(-HexA?/?1,4-GlcN?1,4-).Due to the occurrence of carboxyl groups on uronic acid and Sulfation modification,heparin with a large number of negative charges.Since heparin was discovered in 1916,it has been used in clinical anticoagulant therapy.In the 1980s,low molecular weight heparin(LMWH)prepared from unfractionated heparin,including Enoxaparin sodium,Dalteparin Sodium,etc.,are also widely used as injection drugs to prevent and treat thrombotic diseases.Currently,more than 60%of heparin raw materials on the market are used to prepare low molecular weight heparin preparations.At present,the ageing phenomenon in the world is intensifying,and the over-60-year old population is rapidly increasing.Cardiovascular and cerebrovascular diseases,which are generally high in elderly people,are a major threat to the life and health of the elderly.The growth of the aging population will inevitably lead to an increase in the number of patients suffering from diseases such as cardiovascular and cerebrovascular diseases,leading to the drug of treating cardiovascular and cerebrovascular diseases increasing.Although anticoagulant small molecule drugs are currently available in the market,LMWH prepared from naturally heparin still play an irreplaceable role in the prevention and treatment of thrombotic diseases.Dalteparin sodium is an important type of low molecular weight heparin(LMWH)and widely used in clinic as anticoagulant drug.It is produced by nitrous acid depolymerization of unfractionated heparin from porcine intestine mucosa.Because of the foreseeable shortage and other potential risks rising from sole species resource,reintroduction of bovine lung heparin as well as expansion of other animal tissue heparins,such as ovine intestine heparin,are being actively investigated by a number of laboratories.Heparins from different tissues are known to differ in structure and bioactivity potency,and these variations may be carried over to the LMWH products.To elucidate the effects of starting materials from different animal tissues and corresponding process conditions on the properties of final dalteparin products,sophisticated analytical techniques have been applied to compare various versions of dalteparins produced from porcine intestine heparin,bovine lung heparin and ovine intestine heparin.With adjusted depolymerization conditions,dalteparins that qualify the European Pharmacopeia(EP)specifications on the aspects of characteristic structures,molecular weight(MW)and anti-factor ?a/?a activities have been manufactured using non-porcine heparins.Dissimilarities among three interspecies animal tissue heparin-derived dalteparins on fine structure have also been disclosed,and their origins haven been discussed.