CA2422059A1 - Methods and products related to low molecular weight heparin - Google Patents

Methods and products related to low molecular weight heparin Download PDF

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Publication number
CA2422059A1
CA2422059A1 CA002422059A CA2422059A CA2422059A1 CA 2422059 A1 CA2422059 A1 CA 2422059A1 CA 002422059 A CA002422059 A CA 002422059A CA 2422059 A CA2422059 A CA 2422059A CA 2422059 A1 CA2422059 A1 CA 2422059A1
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Prior art keywords
sample
polysaccharide
delta
composition
lmwh
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CA002422059A
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French (fr)
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CA2422059C (en
Inventor
Mallikarjun Sundaram
Ganesh Venkataraman
Zachary Shriver
Dongfang Liu
Yiwei Qi
Ram Sasisekharan
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Massachusetts Institute of Technology
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/26—Preparation of nitrogen-containing carbohydrates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/86—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood coagulating time or factors, or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2400/00—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
    • G01N2400/10—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2400/00—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
    • G01N2400/10—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • G01N2400/38—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence, e.g. gluco- or galactomannans, e.g. Konjac gum, Locust bean gum, Guar gum
    • G01N2400/40—Glycosaminoglycans, i.e. GAG or mucopolysaccharides, e.g. chondroitin sulfate, dermatan sulfate, hyaluronic acid, heparin, heparan sulfate, and related sulfated polysaccharides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
    • Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
    • Y10T436/143333—Saccharide [e.g., DNA, etc.]

Abstract

The invention relates to methods and products for characterizing and using polysaccharides. Low molecular weight heparin products and methods of use ar e described. Methods for characterizing purity and activity of polysaccharide preparations including glycosaminoglycans such as heparin are also described .

Claims (101)

1. A method of analyzing a sample comprising:
(A) applying an experimental constraint to a polysaccharide in a sample, to produce a modified polysaccharide, having a signature component, (B) detecting the presence of the signature component, in the sample as an indication that the polysaccharide is present in the sample, and (C) determining the presence or absence of the signature component to analyze the sample.
2. The method of claim 1, wherein the signature component has a known biological activity.
3. The method of claim 1, wherein the signature component is biologically inactive.
4. The method of claim 1, wherein the experimental constraint applied to the sample is capillary electrophoresis.
5. The method of claim 1, wherein the experimental constraint applied to the sample is high pressure liquid chromatography.
6. The method of claim 1, wherein the experimental constraint applied to the sample is gel permeation chromatography.
7. The method of claim 1, wherein the experimental constraint applied to the sample is nuclear magnetic resonance.
8. The method of claim 1, wherein the sample is a batch of polysaccharide and the signature component is used to monitor the purity of the batch by determining the amount of signature component in the batch.
9. The method of claim 2, wherein the method of analysis is a method for monitoring the presence of active components in the sample, wherein the presence of the signature component in the sample is indicative of an active component in the sample.
10. The method of claim 3, wherein the method of analysis is a method for monitoring the presence of active components in the sample, wherein the presence of the signature component in the sample is indicative of a sample lacking a specific activity.
11. The method of claim 2, wherein the method of analysis is a method for determining the amount of active components in the sample by determining the amount of signature component in the sample.
12. The method of claim 2, wherein the method is performed on at least two samples and wherein the relative amounts of signature component in each of the at least two samples is determined, wherein the highest relative level of signature component is indicative of the most active sample.
13. The method of claim 2, further comprising the use of the signature component to identify biologically active molecules.
14. The method of claim 13, wherein the signature component is used to screen a library.
15. The method of claim 1, wherein the signature component is a biologically active portion of a polysaccharide.
16. The method of claim 15, wherein the biologically active portion of polysaccharide is a tetrasaccharide of the AT-III biding domain of heparin.
17. The method of claim 15, wherein the biologically active portion of polysaccharide is a tetrasaccharide of the FGF biding domain of heparin.
18. The method of claim 1, wherein the experimental constraint applied to the sample is digestion with an exoenzyme.
19. The method of claim 1, wherein the experimental constraint applied to the sample is digestion with an endoenzyme.
20. The method of claim 1, wherein the experimental constraint applied to the sample is chemical digestion.
21. The method of claim 1, wherein the experimental constraint applied to the sample is chemical modification.
22. The method of claim 1, wherein the experimental constraint applied to the sample is modification with an enzyme.
23. The method of claim 1, wherein the polysaccharide in the sample is compared to a reference database of polysaccharides of identical size as the polysaccharide, wherein the polysaccharides of the reference database have also been subjected to the same experimental constraints as the polysaccharide in the sample, wherein the comparison provides a compositional analysis of the sample polysaccharide.
24. The method of claim 1, wherein the polysaccharide is a glycosaminoglycan.
25. The method of claim 1, wherein the polysaccharide is low molecular weight heparin.
26. The method of claim 1, wherein the polysaccharide is heparin.
27. The method of claim 1, wherein the polysaccharide is a biotechnologically prepared heparin.
28. The method of claim 1, wherein the polysaccharide is a chemically modified heparin.
29. The method of claim 1, wherein the polysaccharide is a synthetic heparin.
30. The method of claim 1, wherein the polysaccharide is heparan sulfate.
31. The method of claim 1, wherein the sample is a pharmaceutical product.
32. The method of claim 1, wherein the sample is biological sample.
33. The method of claim 1, wherein the sample is a blood sample.
34. The method of claim 1, wherein the signature component is one of the peaks corresponding to any One Of .DELTA.UH NAC,6S GH NS,3S,6S, .DELTA.UH
NS,6SC GH NS,3S,6S;
.DELTA.UH NAC,6S GH NS,3S; or .DELTA.UH NS,6S GH NS,3S.
35. A kit for analyzing a polysaccharide sample comprising:
(A) a control composition for identifying a signature component of a polysaccharide, (B) and instructions for applying an experimental constraint to a polysaccharide sample to produce a modified polysaccharide having a signature component characteristic of the polysaccharide and for comparing the modified polysaccharide to the control composition to identify the presence or absence of the signature component.
36. The kit of claim 35, wherein the polysaccharide is a glycosaminoglycan.
37. The kit of claim 35, wherein the polysaccharide is low molecular weight heparin.
38. The kit of claim 35, wherein the polysaccharide is heparin.
39. The kit of claim 35, wherein the polysaccharide is heparan sulfate.
40. The kit of claim 35, wherein the polysaccharide is biotechnologically prepared heparin.
41. The kit of claim 35, wherein the polysaccharide is a chemically modified heparin.
42. The kit of claim 35, wherein the polysaccharide is a synthetic heparin.
43. The kit of claim 35 further comprising a composition for applying an experimental constraint to the polysaccharide sample.
44. The lit of claim 43, wherein the composition is an exoenzyme.
45. The kit of claim 43, wherein the composition is an endoenzyme.
46. The kit of claim 43, wherein the signature component a tetrasaccharide of the AT-III biding domain of heparin.
47. The kit of claim 43, wherein the signature component a tetrasaccharide of the FGF biding domain of heparin.
48. The kit of claim 43, wherein the signature component is one of the peaks corresponding to any one Of .DELTA.UH NAC,6S GH NS,3S,6S, .DELTA.UH NS,6S GH
NS,3S,6S;
.DELTA.UH NAC,6S GH NS,3S ; or .DELTA.UH NS,6S GH NS,3S.
49. The kit of claim 35, wherein the instructions include the steps for quantifying the signature component of the polysaccharide in the sample.
50. A method for evaluating the quality of a polysaccharide sample comprising the steps of:
identifying a component within the polysaccharide sample, determining a quantitative value of the amount of component, wherein the quantitative value of the component is indicative of the quality of the polysaccharide sample.
51. The method of claim 50, wherein the method involves identifying at least two components within the polysaccharide sample and determining a quantitative value of the amount of each of the at least two components to evaluate the quality of the polysaccharide sample.
52. The method of claim 51, wherein the quantitative value is calculated as the area under the curve when the sample is processed by capillary electrophoresis.
53. The method of claim 51, wherein the quantitative value is calculated as the response factor.
54. The method of claim 51, wherein the quantitative value is calculated as the percent relative amount of each fraction present in the sample.
55. The method of claim 51, wherein the step of calculating the percent relative amount of each fraction present in the sample is determined according to the below equation:
PRA = RF x AUC%R
wherein PRA = percent relative amount of each fraction RF = response factor AUC%R = percent relative AUC [(100 x AUC C)/AUC T)]
AUC C = Area under the curve for one component AUC T = the sum of the Area under the curve for all components.
56. A computer-implemented method for generating a data structure, tangibly embodied in a computer-readable medium, representing a quantitative value of a component of a polysaccharide, the method comprising an act of performing the calculation of claim 55.
57. The method of claim 50, wherein the component is signature component is one of the peaks corresponding to any one of .DELTA.UH NAC,6S GH NS,3S,6S, .DELTA.UH NS,6S GH NS,3S,6S ; .DELTA.UH NAC,6S GH NS,3S ; or .DELTA.UH NS,6S
GH NS,3S.
58. Method of producing a composition of glycosaminoglycans comprising;
(A) performing a salt precipitation of a glycosaminoglycan-containing sample in a solvent to produce a first higher molecular weight fraction, and a second lower molecular weight fraction of isolated LMWH, and (B) processing the second fraction of isolated LMWH to produce a concentrated LMWH preparation.
59. The method of claim 58, wherein the salt used in the precipitation step is a salt of divalent cations and weak anions.
60. The method of claim 58, wherein the salt is selected from elements from among the group comprising: barium calcium, magnesium, strontium, copper, silver, gold, nickel, cadmium, zinc, mercury, beryllium, palladium, platinum, iron, or tin.
61. The method of claim 59, wherein the salt of divalent cations and weak anions are acetates of cations of elements of the periodic table having divalent valence.
62. The method of claim 58, wherein the salt of the divalent cations and weak anions is selected from among the group comprising; barium acetate, calcium acetate, magnesium acetate, strontium acetate, copper acetate, nickel acetate, cadmium acetate, or calcium chloride.
63. The method of claim 58, wherein the salt of the divalent cations and weak anions is barium acetate.
64. The method of claim 58, wherein the salt of the divalent cations and weak anions is calcium acetate.
65. The method of claim 58, wherein the precipitation is performed at a temperature in a range of 0°C to 70°C.
66. The method of claim 58, wherein the precipitation is performed at a temperature of 4°C.
67. The method of claim 58, wherein the solvent is a polar solvent.
68. The method of claim 67 wherein the polar solvent is H2O, H2O mixed with ethanol, H2O mixed with acetone, or a combination of H2O, ethanol, and acetone.
69. The method of claim 67, wherein the polar solvent is a mixture of H2O, ethanol, and acetone.
70. The method of claim 58, wherein the processing of the second fraction to yield the concentrated LMWH preparation is an enzymatic digestion.
71. The method of claim 70, wherein the enzyme used for the enzymatic digestion is Heparinase III.
72. The method of claim 58 wherein the processing of the second fraction to yield the concentrated LMWH preparation is chemical degradation.
73. The method of claim 72 wherein the chemical degradation methods comprise: oxidative depolymerization with H2O2 or CU+ and H2O2; deaminative cleavage with isoamyl nitrite, or nitrous acid; .beta.-eliminative cleavage with benzyl ester of heparin by alkaline treatment or by heparinase.
74. The method of claim 58, wherein the glycosaminoglycan is selected from the group consisting of heparin, heparin analogs, LMWH, biotechnological heparin, chemically modified heparin, or synthetic heparin.
75. The method of claim 58, wherein the processing of the first fraction to yield the concentrated LMWH preparation is a purification step to produce a purified LMWH preparation.
76. The method of claim 75, further comprising formulating the purified LMWH preparation in a pharmaceutical carrier.
77. The method of claim 58, wherein the concentrated LMWH preparation is a LMWH preparation containing intact AT-binding domain.
78. The method of claim 58, further comprising the step of subjecting the second fraction to ion exchange chromatography prior to processing.
79. A composition comprising a LMWH preparation having an anti-Xa activity of at least 150 IU/mg.
80. The composition of claim 79, wherein the LMWH preparation has an anti-factor Xa:anti-factor IIa activity ratio of greater than 1.
81. The composition of claim 79, wherein the LMWH preparation has an anti-factor Xa:anti-factor IIa activity ratio of greater than 3.
82. The composition of claim 79, wherein the LMWH preparation has an anti-factor Xa:anti-factor IIa activity ratio of greater than 4.
83. The composition of claim 79, wherein the LMWH preparation has an anti-factor Xa:anti-factor IIa activity ratio of greater than 5.
84. The composition of claim 79, wherein the LMWH preparation is isolated.
85. The composition of claim 79, wherein the LMWH preparation is synthetic.
86. The composition of claim 79, wherein the LMWH preparation is formulated for subcutaneous delivery.
87. The composition of claim 79, wherein the LMWH preparation is formulated for intravenous delivery.
88. The composition of claim 79, wherein the LMWH preparation is formulated for aerosol delivery.
89. The composition of claim 79, wherein the LMWH preparation is formulated for oral delivery.
90. The composition of claim 79, wherein the LMWH preparation includes at least 3.5% .DELTA.UH NAC,6S GH NS,3S,6S, .DELTA.UH NS,6S GH NS,3S,6S;
.DELTA.UH NAC,6S GH NS,3S; or .DELTA.UH NS,6S GH NS,3S.
91. The composition of claim 79, wherein the LMWH preparation includes at least 4.0% of one of the peaks corresponding to .DELTA.UH NAC,6S GH NS,3S,6S, .DELTA.UH NS,6S GH NS,3S,6S; .DELTA.UH NAC,6S GH NS,3S; or .DELTA.UH NS,6S GH
NS,3S.
92. The composition of claim 79, wherein the LMWH preparation includes at least 5.0% of one of the peaks corresponding to .DELTA.UH NAC,6S GH NS,3S,6S, .DELTA.UH NS,6S GH NS,3S,6S; .DELTA.UN NAC,6S GH NS,3S; or .DELTA.UH NS,6S GH
NS,3S.
93. A composition comprising a LMWH preparation having an anti-factor Xa:anti-factor IIa activity ratio of greater than 5.
94. A method for treating a subject having a condition, comprising;

(A) selecting a composition of LMWH having an identified level of AT-binding sequence, the level of AT-binding sequence selected depending on the condition to be treated in the subject, and (B) administering to a subject an effective amount of the composition of LMWH having an identified level of AT-binding sequence.
95. The method of claim 94, wherein the subject has or is at risk of developing venous or arterial thromboembolic disease.
96. The method of claim 95, wherein the composition of LMWH is a LMWH
preparation including at least 3.5% of one of the peaks corresponding to .DELTA.UH NAC,6S GH NS,3S,6S, .DELTA.UN NS,6S GH NS,3S,6S; .DELTA.UH NAC,6S GH
NS,3S; or .DELTA.UH NS,6S GH NS,3S.
97. The method of claim 95, wherein the composition of LMWH is a LMWH
preparation including at least 4.0% of one of the peaks corresponding to .DELTA.UH NAC,6S GH NS,3S,6S, .DELTA.UH NS,6S GH NS,3S,6S; .DELTA.UH NAC,6S, GH NS,3S; or .DELTA.UH NS,6S GH NS,3S.
98. The method of claim 95, wherein the composition of LMWH is a LMWH
preparation including at least 5.0% of one of the peaks corresponding to .DELTA.UH NAC,6S GH NS,3S,6S, .DELTA.UH NS,6S GH NS,3S,6S; .DELTA.UH NAC,6S GH
NS,3S or .DELTA.UH NS,6S GH NS,3S.
99. The method of claim 95, wherein the composition of LMWH is a LMWH
preparation having an anti-Xa activity of at least 150 IU/mg.
100. The method of claim 95, wherein the composition of LMWH is a LMWH
preparation having an anti-factor Xa:anti-factor IIa activity ratio of greater than 5.
101. A composition comprising a LMWH preparation having at least 15%
disulfated disaccharides, less than 75% trisulfated disaccharides, 3-5%
monosulfated disaccharides, and at least 2% 4-7 tetrasaccharide.
CA2422059A 2000-09-12 2001-09-12 Methods and products related to low molecular weight heparin Expired - Lifetime CA2422059C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US23199400P 2000-09-12 2000-09-12
US60/231,994 2000-09-12
PCT/US2001/028457 WO2002023190A2 (en) 2000-09-12 2001-09-12 Methods and products related to low molecular weight heparin

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CA2422059C CA2422059C (en) 2012-05-15

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EP (2) EP1319183B1 (en)
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AT (1) ATE426805T1 (en)
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CA (1) CA2422059C (en)
CY (1) CY1110323T1 (en)
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