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3 RELATED EXCIPIENT COMPANIES

4EXCIPIENTS BY APPLICATIONS

Chemistry

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Also known as: Clexane, Ardeparin, Bemiparin, Semuloparin, Lovenox, Lmwh
Molecular Formula
C26H42N2O37S5
Molecular Weight
1134.9  g/mol
InChI Key
HTTJABKRGRZYRN-UHFFFAOYSA-N

Enoxaparin Sodium
Tinzaparin is a low molecular weight heparin (LMWH), obtained by controlled enzymatic depolymerization of heparin from porcine intestinal mucosa, with antithrombotic properties. Tinzaparin is a potent inhibitor of several activated coagulation factors, especially Factors Xa and IIa (thrombin); its primary activity is mediated through the plasma protease inhibitor antithrombin. In addition, this agent may inhibit angiogenesis through: 1) competitive binding of the heparin-binding sites on endothelial cells for the proangiogenic cytokines vascular endothelial growth factor (VEGF) and beta-fibroblast growth factor (beta-FGF) and 2) increasing the release of tissue factor pathway inhibitor (TFPI), a negative regulator of angiogenesis.
1 2D Structure

Enoxaparin Sodium

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
6-[6-[6-[5-acetamido-4,6-dihydroxy-2-(sulfooxymethyl)oxan-3-yl]oxy-2-carboxy-4-hydroxy-5-sulfooxyoxan-3-yl]oxy-2-(hydroxymethyl)-5-(sulfoamino)-4-sulfooxyoxan-3-yl]oxy-3,4-dihydroxy-5-sulfooxyoxane-2-carboxylic acid
2.1.2 InChI
InChI=1S/C26H42N2O37S5/c1-4(30)27-7-9(31)13(6(56-23(7)39)3-55-67(43,44)45)58-26-19(65-70(52,53)54)12(34)16(20(62-26)22(37)38)60-24-8(28-66(40,41)42)15(63-68(46,47)48)14(5(2-29)57-24)59-25-18(64-69(49,50)51)11(33)10(32)17(61-25)21(35)36/h5-20,23-26,28-29,31-34,39H,2-3H2,1H3,(H,27,30)(H,35,36)(H,37,38)(H,40,41,42)(H,43,44,45)(H,46,47,48)(H,49,50,51)(H,52,53,54)
2.1.3 InChI Key
HTTJABKRGRZYRN-UHFFFAOYSA-N
2.1.4 Canonical SMILES
CC(=O)NC1C(C(C(OC1O)COS(=O)(=O)O)OC2C(C(C(C(O2)C(=O)O)OC3C(C(C(C(O3)CO)OC4C(C(C(C(O4)C(=O)O)O)O)OS(=O)(=O)O)OS(=O)(=O)O)NS(=O)(=O)O)O)OS(=O)(=O)O)O
2.2 Synonyms
2.2.1 Depositor-Supplied Synonyms

1. Clexane

2. Ardeparin

3. Bemiparin

4. Semuloparin

5. Lovenox

6. Lmwh

7. Certoparin

8. Dalteparin

9. Fraxiparin

10. Nadroparin

11. Nadroparine

12. Clivarin

13. Clivarine

14. Liquaemin

15. Reviparin

16. Alpha-heparin

17. Heparinic Acid

18. Adomiparin

19. Heparinate

20. Multiparin

21. Novoheparin

22. Parnaparin

23. Parvoparin

24. Sandoparin

25. Sublingula

26. Thromboliquine

27. Tinzaparin

28. Arteven

29. Eparina

30. Heparina

31. Heparine

32. Heparinum

33. Hepathrom

34. Liquemin

35. Octaparin

36. Pabyrin

37. Pk-10169

38. Pularin

39. Subeparin

40. Triofiban

41. Fluxum

42. Vetren

43. Heparin Sulfate

44. Hed-heparin

45. Depo-heparin

46. Lipo-hepin

47. Fragmin A

48. Fragmin B

49. Vitrum Ab

50. Eparina [dcit]

51. Heparin [ban]

52. Adomiparin [usan]

53. Cy 216

54. Fr 860

55. Heparin Cy 216

56. Heparine [inn-french]

57. Heparinum [inn-latin]

58. Heparina [inn-spanish]

59. Semuloparin [usan:inn]

60. Unii-1k5kdi46kz

61. Unii-4qw4an84nq

62. Unii-e47c0nf7lv

63. Unii-vl0l558gcb

64. 1k5kdi46kz

65. 4qw4an84nq

66. E47c0nf7lv

67. Unii-p776jq4r2f

68. Unii-v72ot3k19i

69. Vl0l558gcb

70. 2-o-sulfohexopyranuronosyl-(1->4)-2-deoxy-3-o-sulfo-2-(sulfoamino)hexopyranosyl-(1->4)-2-o-sulfohexopyranuronosyl-(1->4)-2-acetamido-2-deoxy-6-o-sulfohexopyranose

71. Schembl543122

72. Unii-5r0l1d739e

73. Unii-7uq7x4y489

74. Unii-m316wt19d8

75. Unii-s79o08v79f

76. Unii-t2410km04a

77. Gtpl6811

78. M 118reh

79. P776jq4r2f

80. V72ot3k19i

81. Cy 222

82. Hsdb 3094

83. Dtxsid80872762

84. 5r0l1d739e

85. 7uq7x4y489

86. M316wt19d8

87. S79o08v79f

88. T2410km04a

89. Unii-9816xa9004

90. Ave-5026

91. Bcp13334

92. Einecs 232-681-7

93. Kb 101

94. Op 386

95. Op 622

96. M118

97. Rp-54563

98. 9816xa9004

99. M 118

100. Q416516

101. 6-[5-acetamido-4,6-dihydroxy-2-(sulfooxymethyl)oxan-3-yl]oxy-3-[5-(6-carboxy-4,5-dihydroxy-3-sulfooxyoxan-2-yl)oxy-6-(hydroxymethyl)-3-(sulfoamino)-4-sulfooxyoxan-2-yl]oxy-4-hydroxy-5-sulfooxyoxane-2-carboxylic Acid

102. 6-[6-[6-[5-acetamido-4,6-dihydroxy-2-(sulfooxymethyl)tetrahydropyran-3-yl]oxy-2-carboxy-4-hydroxy-5-sulfooxy-tetrahydropyran-3-yl]oxy-2-(hydroxymethyl)-5-(sulfoamino)-4-sulfooxy-tetrahydropyran-3-yl]oxy-3,4-dihydroxy-5-sulfooxy-tetrahydropyran-2-carboxylic Acid

2.3 Create Date
2005-06-23
3 Chemical and Physical Properties
Molecular Weight 1134.9 g/mol
Molecular Formula C26H42N2O37S5
XLogP3-10.8
Hydrogen Bond Donor Count15
Hydrogen Bond Acceptor Count38
Rotatable Bond Count21
Exact Mass1134.0069961 g/mol
Monoisotopic Mass1134.0069961 g/mol
Topological Polar Surface Area652 Ų
Heavy Atom Count70
Formal Charge0
Complexity2410
Isotope Atom Count0
Defined Atom Stereocenter Count0
Undefined Atom Stereocenter Count20
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Information
1 of 2  
Drug NameLovenox
PubMed HealthEnoxaparin (Injection)
Drug ClassesAnticoagulant
Active IngredientEnoxaparin sodium
Dosage FormInjectable
RouteIntravenous, subcutaneous; injection
Strength300mg/3ml (100mg/ml); 100mg/ml
Market StatusPrescription
CompanySanofi Aventis Us

2 of 2  
Drug NameLovenox
PubMed HealthEnoxaparin (Injection)
Drug ClassesAnticoagulant
Active IngredientEnoxaparin sodium
Dosage FormInjectable
RouteIntravenous, subcutaneous; injection
Strength300mg/3ml (100mg/ml); 100mg/ml
Market StatusPrescription
CompanySanofi Aventis Us

4.2 Drug Indication

For prevention of deep vein thrombosis, which may result in pulmonary embolism, following knee surgery.


Enoxaparin is indicated for the prevention of ischemic complications in unstable angina and in non Q-wave myocardial infarction; it is indicated in conjunction with percutaneous intervention and/or other treatment for the management of acute ST elevation myocardial infarction. Enoxaparin is also indicated in the prophylaxis of DVT in abdominal surgery, hip replacement, knee replacement, or medical patients with severely restricted mobility during acute illness. Additionally, enoxaparin is indicated for the inpatient treatment of DVT with or without pulmonary embolism and the treatment of outpatient DVT without pulmonary embolism.


Investigated for use/treatment in cardiovascular disorders and coronary artery disease.


Dalteparin is used as a prophylaxis for deep-vein thrombosis and pulmonary embolisms in patients undergoing general surgery (e.g., abdominal, gynecologic, urologic), and in patients with acute medical conditions (e.g. cancer, bed rest, heart failure, severe lung disease). It is also used in patients who have severely restricted mobility, which poses a risk for thromboembolic complications. Dalteparin is also used concomitantly with aspirin and/or other therapy (e.g., nitrates, -adrenergic blockers, clopidogrel, platelet glycoprotein [GP] IIb/IIIa-receptor inhibitors) to reduce the risk of acute cardiac ischemic events. The patients who undergo this treatment combination have unstable angina or non-ST-segment elevation/non-Q-wave myocardial infarction (i.e., non-ST-segment elevation acute coronary syndromes). It is also used in the prevention of clotting during hemodialysis and hemofiltration in connection with acute renal failure or chronic renal insufficiency.


Tinzaparin is used for the prevention of postoperative venous thromboembolism in patients undergoing orthopedic surgery and in patients undergoing general surgery who are at high risk of developing postoperative venous thromboembolism. It is also used for the treatment of deep vein thrombosis and/or pulmonary embolism. It is indicated for use in preventing clot formation in indwelling intravenous lines for hemodialysis.


Nadroparin is used for prophylaxis of thromboembolic disorders and general surgery in orthopedic surgery, treatment of deep vein thrombosis, prevention of clotting during hemodialysis and treatment of unstable angina and non-Q wave myocardial infarction.


Bemiparin is indicated in the following cases: To prevent blood clots in the veins after general abdominal surgery in patients with a moderate risk of venous thromboembolism; in the prevention of the thromboembolic disease in non-surgical patients; prevention of clotting in the extracorporeal circuit during hemodialysis; to prevent blood clots in the veins after a major orthopedic surgery in patients with high risk of venous thromboembolism; secondary prevention of venous thromboembolism; recurrence in patients with deep vein thrombosis; transient prevention and treatment of deep vein thrombosis (DVT).


By the FDA, reviparin is indicated for the treatment of deep vein which may lead to pulmonary embolism in pediatric patients. It is also indicated for the long-term treatment of acute deep vein thrombosis with or without pulmonary embolism in pregnant patients.


Used in the prevention and treatment of venous thromboembolism (deep vein thrombosis and pulmonary embolism) and in the treatment of myocardial infarction.


Used in the prevention and treatment of venous thromboembolism (deep vein thrombosis and pulmonary embolism) and in the treatment of myocardial infarction.


Investigated for use/treatment in thrombosis.


5 Pharmacology and Biochemistry
5.1 Pharmacology

Ardeparin, an anticoagulant, is a fractionated heparin. It acts at multiple sites in the normal coagulation system to inhibit reactions that lead to the clotting of blood and the formation of fibrin clots both in vitro and in vivo.


This drug has an immediate onset of action. Enoxaparin increases Thrombin Time (TT) and activated partial thromboplastin time (aPTT), preventing and reducing thromboembolic complications such as DVT, pulmonary embolism, and ischemic cardiac complications. Administered at 1.5 mg/kg subcutaneously in a pharmacodynamic study, enoxaparin led to a higher ratio of anti-Factor Xa to anti-Factor IIa activity (mean SD, 14.03.1) (based on areas under anti-Factor activity versus time curves) when compared to that of heparin (mean SD, 1.220.13). Increases in the TT and aPTT were 1.8 times those of the control group. Enoxaparin at 1 mg/kg subcutaneously every 12 hours led to aPTT values of 45 seconds or less in most patients. Average aPTT prolongation time on Day 1 was approximately 16% higher than on Day 4 of enoxaparin therapy. Caution is advised during treatment with enoxaparin - the risk of hemorrhage and thrombocytopenia is increased. In pregnant women with prosthetic mechanic heart valves, the risk of thromboembolism is increased.


Dalteparin has an antithrombin binding site that is essential for high affinity binding to the plasma protein antithrombin (ATIII). Anti-Xa activity of plasma is used as both as an estimate of clotting activity, and as a basis to determine dosage. Its use should be avoided in patients with a creatinine clearance less than 20mL/min. In these patients, unfractionated heparin should only be used. As for monitoring, active partial thromboplastin time (aPTT) will only increase at high doses of low molecular weight heparins (LMWH). Therefore, monitoring aPTT is not recommended. However, anti-Xa activity can be measured to monitor the efficacy of the LMWH.


Tinzaparin, like other LMWHs, have a higher anti-Xa activity than anti-IIa activity. The anti-Xa activity of tinzaparin is 2.0 +/- 0.5 times greater than its to anti-IIa activity. Heparin exhibits approximately equal inhibitory activity against Xa and IIa. Tinzaparin is an anticoagulant that blocks the formation of thrombi. Like all LMWHs, tinzaparin only causes activated partial thromboplastin time (aPTT) prolongation at higher doses and routine monitoring is not recommended. However, anti-factor Xa levels may be monitored in some conditions such as pregnancy and renal dysfunction. Its use should be avoided in patients with a creatinine clearance less than 20 mL/min. In these patients, unfractionated heparin should be used. Tinzaparin can be used in patients who have a creatinine clearance between 20-30 mL/min, giving it the highest safety threshold for use in renal failure patients compared to all the LMWHs.


Nadroparin is a low molecular weight heparin that is composed of a heterogeneous mixture of sulfated polysaccaride glycosaminoglycan chains. Th mean molecular weight is approximately 4300 daltons. The ratio of anti-Xa activity to anti-IIa is 3.5:1 whereas it is about 1:1 for heparin. Its use should be avoided in patients with a creatinine clearance less than 40mL/min. In these patients, unfractionated heparin should only be used. As for monitoring, active partial thromboplastin time (aPTT) will only increase at high doses of low molecular weight heparins (LMWH). Therefore, monitoring aPTT is not recommended. However, anti-Xa activity can be measured to monitor the efficacy of the LMWH.


Bemiparin is an anticoagulant classified under the broad category of low molecular weight heparins. In humans, bemiparin has been proven to possess antithrombotic activity and, at therapeutic doses, does not significantly prolong global clotting laboratory tests.


Reviparin is been shown to present significant inhibition of smooth muscle cell migration and proliferation in human cell cultures without affecting endothelial cell growth.


5.2 ATC Code

B - Blood and blood forming organs

B01 - Antithrombotic agents

B01A - Antithrombotic agents

B01AB - Heparin group

B01AB04 - Dalteparin


B - Blood and blood forming organs

B01 - Antithrombotic agents

B01A - Antithrombotic agents

B01AB - Heparin group

B01AB05 - Enoxaparin


B - Blood and blood forming organs

B01 - Antithrombotic agents

B01A - Antithrombotic agents

B01AB - Heparin group

B01AB06 - Nadroparin


B - Blood and blood forming organs

B01 - Antithrombotic agents

B01A - Antithrombotic agents

B01AB - Heparin group

B01AB07 - Parnaparin


B - Blood and blood forming organs

B01 - Antithrombotic agents

B01A - Antithrombotic agents

B01AB - Heparin group

B01AB08 - Reviparin


B - Blood and blood forming organs

B01 - Antithrombotic agents

B01A - Antithrombotic agents

B01AB - Heparin group

B01AB10 - Tinzaparin


B - Blood and blood forming organs

B01 - Antithrombotic agents

B01A - Antithrombotic agents

B01AB - Heparin group

B01AB12 - Bemiparin


5.3 Absorption, Distribution and Excretion

Absorption

Well absorbed following subcutaneous administration, with a mean bioavailability of 92% (based on anti-factor Xa activity).


Absorption

Mean absolute bioavailability of enoxaparin, after 1-2 mg/kg given subcutaneously is approximately 100% in healthy volunteers. The absorption of enoxaparin is proportional to the dose, demonstrating linear absorption. The average maximum plasma anti-Xa activity is reached 3 to 5 hours after a subcutaneous injection. A 30 mg IV bolus preceding an immediate 1 mg/kg SC every twice a day led to maximum anti-Factor Xa levels of 1.16 IU/mL. Steady-state is reached within 3-4 days of treatment with a Cmax of 1.2 IU/mL. The AUC under the thrombin generation curve was 305 +/- 48.


Route of Elimination

Enoxaparin is mainly excreted by the kidneys. Renal clearance of active fragments represents about 10% of the administered dose and total renal excretion of active and non-active fragments 40% of the dose.


Volume of Distribution

The volume of distribution of enoxaparin is approximately 4-5L, similar to normal blood volume.


Clearance

The mean clearance of enoxaparin is 0.74 L/h after a 1.5 mg/kg intravenous infusion over 6 hours; clearance of enoxaparin is significantly decreased in patients with severe renal impairment.


Absorption

Almost completely absorbed after subcutaneous (sc) doses, with a bioavialability of about 87%.


Route of Elimination

After 4 hours, about 20% is seen in urine. Most of the remainder is found in the liver, gastrointestinal tract and kidney. The kidneys are the major site of dalteparin excretion (approximately 70% based on animal studies).


Volume of Distribution

3 litres


Clearance

Excreted via kidneys. The plasma clearance rate is 33 mL/min.


Absorption

Subcutaneous injection - about 90% when measured as anti-Xa activity versus 67% for anti-IIa activity.


Route of Elimination

Linear elimination through kidneys


Volume of Distribution

Anti-Xa activity is 4 L. Anti-IIa activity is 10.9 L


Clearance

Clearance is dose-dependant. The clearance of tinzaparin based on anti-Xa activity ranged from 1.14 to 2.04 L/hr


Absorption

Absorption is linear. The bioavailability of nadroparin after subcutaneous administration is about 89%.


Route of Elimination

Nadroparin is eliminated via the kidneys through non-saturable mechanisms.


Volume of Distribution

3.59L


Clearance

The clearance of nadroparin is 21.4 +/- 7.0mL/min


Absorption

Hemiparin sodium is rapidly absorbed following its subcutaneous dose of injection, and the bioavailability is estimated to be 96%.


Route of Elimination

This drug is eliminated by the renal and hepatic routes. Elimination is prolonged in those with renal or hepatic impairment.


Volume of Distribution

5.1 L.


Clearance

Elimination occurs in a linear fashion, with a mean clearance time of over 7 h and total clearance of 0.9 L/h.


5.4 Metabolism/Metabolites

Liver and the reticulo-endothelial system are the sites of biotransformation.


Enoxaparin is mainly metabolized by the liver via desulfation and/or depolymerization to lower and less potent molecular weight metabolites.


Liver and the reticulo-endothelial system are the sites of biotransformation. They are partially metabolized by desulphatation and depolymerization.


Sulfation and polymerization occurs in the liver.


Nadroparin is metabolized in the liver.


In a study of healthy volunteers, bemiparin 3500 IU achieved more anti-Xa activity than enoxaparin 4000 IU, measured by the area under the curve. The peak of anti-Xa activity was reached at 3h post-administration, and there were anti-Xa measurable levels up to 16 h after subcutaneous injection.


5.5 Biological Half-Life

Elimination half-life for anti-factor Xa activity averages 3.3 hours following a single intravenous dose, while elimination half-life for anti-factor IIa activity averages 1.2 hours following a single intravenous dose.


The half-life of enoxaparin is about 4 hours after a single dose administered subcutaneously and about 7 hours after several doses. One source mentions a half-life ranging from 1 hour to 4.5 hours.


Terminal Half life: Intravenous - 2 hours. Subcutaneous - 3-5hours


Anti-Xa activity is 82 minutes. Anti-IIa activity is 71 minutes.


In healthy patients, the half life is between 3.5hrs to 11.2hrs following subcutaneous administration.


Bemiparin, when administered in the dose range of 2,500 IU to 12,500 (therapeutic dosing), it has an approximate half-life of 5-6 hours.


5.6 Mechanism of Action

Ardeparin binds to antithrombin III, accelerating its activity in inactivating factor Xa and thrombin, thereby inhibiting thrombosis. Ardeparin also binds to heparin cofactor II, inhibiting thrombin. Ardeparin does not effect prothrombin time (PT) assays and may prolong activated partial thromboplastin time (APTT). Ardeparin has double the anti-factor Xa activity versus anti-factor IIa activity, compared to unfractionated heparin which has approximately equal anti-factor Xa activity and anti-factor IIa activity.


Enoxaparin binds to antithrombin III, a serine protease inhibitor, forming a complex that irreversibly inactivates factor Xa, which is frequently used to monitor anticoagulation in the clinical setting. Following factor Xa inactivation, enoxaparin is released and binds to other anti-thrombin molecules. Factor IIa (thrombin) is directly inhibited by enoxaparin, however with less potency than unfractionated heparin (UFH). Due to the cascade of effects resulting from enoxaparin binding, thrombin is unable to convert fibrinogen to fibrin and form a clot, preventing thromboembolic events.


M118 is a novel drug candidate that has been, through Momenta's proprietary technology, rationally engineered with attributes of monitorability, reversibility, flexible administration (intravenous and subcutaneous), and both potent and predictable anti-Xa (aXa) and anti-IIa (aIIa) activity to provide anticoagulant therapy to patients with ACS. M118 is designed to interact at multiple points in the coagulation cascade by selectively binding to anti-thrombin III and thrombin, two critical factors in the formation of clots.


Dalteparin potentiates the activity of ATIII, inhibiting the formation of both factor Xa and thrombin. The main difference between dalteparin and unfractionated heparin (UH) is that dalteparin preferentially inactivates factor Xa. As a result, only a slight increase in clotting time [(i.e. activated partial thomboplastin time (APTT)] is observed relative to UH. For this same reason, APTT is not used to monitor the effects of dalteparin except as an indicator for overdosage.


Tinzaparin binds to the plasma protein antithrombin III, forming a complex with then accelerates the inhibition of factor Xa. Its affinity for factor Xa is 2-4 times greater than that of unbound ATIII. The inactivation of factor Xa in turn will exponentially generation of thrombin (factor IIa) molecules, which is needed to activate fibrinogen to fibrin. The coagulation cascade is inhibited because fibrin cannot be formed in the presence of tinzaparin. Like all LMWH, it cannot be given intramuscularly due to increased risk of hematoma.


The mechanism of action for nadroparin is similar to all other LMWHs. Like all LMWHs, nadroparin has a pentasaccharide sequence which binds to ATIII, which potentiates the action of ATIII. This complex greatly accelerates the inactivation of factor Xa and factor IIa. As a result, the coagulation cascade is inhibited.


This drug is a second-generation low molecular weight heparin (LMWH). It has a very low mean molecular weight (3600 Dalton), a long half-life (5.3 hrs) and a large anti-Xa: anti-IIa ratio (8:1). The mechanism of action of bemiparin is inhibition of factor Xa, which is a necessary step in the clotting cascade. Factor-Xa is necessary for the propagation of a thrombus. Combined with various co-factors that bind to activated platelets, Factor-Xa increases coagulation by converting prothrombin to thrombin. Activated Factor-X, bound as part of the prothrombinase complex on the external surface of activated platelets, converts significant amounts of prothrombin to thrombin, promoting the so-called thrombin burst, referring to a burst of thrombin release. A secondary but less potent mechanism of action of this drug is binding to antithrombin III and activated factor II (Factor IIa), which further prevents the propagation of thrombi. Due to its excellent pharmacological profile-the second-generation LMWH with the lowest molecular weight, the longest half-life and the highest anti-Factor Xa/anti-Factor IIa activity ratio-it can be safely used in special categories of patients (children, elderly, patients with renal impairment and congestive heart failure). Several studies demonstrated its safety and efficacy, while cost analyses show the economic benefits of bemiparin treatment as compared to other heparins.