EP0081853A1
Expired / Lapsed
EP
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Conjugates of anticoagulant and protein
Assignee: Cordis Europa NV
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Filing: 1982-12-15
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Granted: —
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Expires: 2002-12-15
Abstract
Abstract Conjugates are provided which are covalently bonded conjugates of an anticoagulant and protein that are prepared in the presence of a coupling agent that forms amide linkages between the anticoagulant and the protein. Such amide linking coupling agents exclude highly toxic coupling agents such as CNBr. These conjugates are useful for enhancing the blood compatibility of certain surfaces of a prosthetic device, a surgical apparatus, or an extra-corporeal medical device.
Inventors
- 👤 Jan Feijen
- 👤 Wilhelmus E. Hennink
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-23 07:01
CPC Classifications
C; C08; C08B; C08B37/00; C08B37/006; C08B37/0063; C08B37/0075; A; A61; A61L; A61L33/00; A61L33/0005; A61L33/0011; C08H; C08H1/00
Claims Analysis
Total Claims: 30
Claim 1
Independent Claim
70 words
A process for the preparation of a conjugate of an anticoagulant and a water soluble protein, wherein the process includes coupling said anticoagulant to said protein within an aqueous medium and in the presence of a coupling agent and wherein the improvement comprises providing an anticoagulant-protein conjugate by using a coupling agent that is an amide bond forming agent to form an amide linkage between said anticoagulant and said protein.
Claim 2
Dependent Claim
70 words
A process for the preparation of a conjugate of an anticoagulant and a water soluble protein, wherein the process includes coupling said anticoagulant to said protein within an aqueous medium and in the presence of a coupling agent and wherein the improvement comprises providing an anticoagulant-protein conjugate by using a coupling agent that is an amide bond forming agent to form an amide linkage between said anticoagulant and said protein.
Claim 3
Dependent Claim
15 words
The process according to claim 1, wherein said anticoagulant-protein conjugate is formed by covalent bonding.
Claim 4
Dependent Claim
32 words
The process according to claims 1-2, wherein said amide bond forming agent is 1-ethyl-3-dimethylaminopropyl carbodiimide or a homolog thereof, N-hydroxy succinimide ester or a homolog thereof, or N-ethyl-5-phenyl-isoxazolium-3-sulfonate or a homolog thereof.
Claim 5
Dependent Claim
14 words
The process according to any of the preceding claims, wherein said anticoagulant is heparin.
Claim 6
Dependent Claim
81 words
The process according to any of the preceding claims, wherein the process includes dissolving said anti- coagulant and said protein in water to form a solution, adjusting the pH of the solution to a value not greater than 5.5; adding an aqueous solution of said coupling agent to said solution, said adding step being in incremental batches while maintaining the pH value at not greater than 5.5; agitating the solution while said coupling is proceeding; and recovering the anticoagulant protein conjugate.
Claim 7
Dependent Claim
16 words
The process according to claim 5, wherein the pH value is between about 5.0 and 5.5.
Claim 8
Dependent Claim
43 words
The process according to any of the preceding claims, further including adjusting the mol ratio of said anticoagulant to said protein by varying the weight of anticoagulant added during the process with respect to the weight of said protein added during the process.
Claim 9
Dependent Claim
22 words
The process according to any of the preceding claims, further including adding an aldehyde to crosslink said protein of the anticoagulant-protein conjugate.
Claim 10
Dependent Claim
11 words
The process according to claim 8, wherein said aldehyde is glutaraldehyde.
Claim 11
Dependent Claim
43 words
The process according to any of the preceding claims, wherein said anticoagulant is heparin, and further including fractionating said heparin into heparin fractions by separating same on the basis of differing molecular weights and/or on the basis of differing affinity to anti-thrombin III.
Claim 12
Dependent Claim
17 words
The process according to any of the preceding claims, wherein said water soluble protein is human albumin.
Claim 13
Dependent Claim
100 words
The process according to claims 5-11, wherein said recovering step includes passing a mixture including the anticoagulant-protein conjugate, free protein and free anticoagulant over a first sorption agent to thereby sorb the anticoagulant-protein conjugate, free protein and free anticoagulant to the first sorption agent; utilizing an element of increasing ionic strength in order to first elute the free protein and form an anticoagulant-containing eluate including the anticoagulant-protein conjugate and the free anticoagulant; passing said anticoagulant-containing eluate over a second sorption agent from which the anticoagulant-protein conjugate and the free anticoagulant are separately desorbed in order to isolate the anticoagulant-protein conjugate.
Claim 14
Dependent Claim
37 words
The process according to claim 12, wherein said first sorption agent is an anion exchange material, and said first sorption agent is a material having a varying affinity for said anticoagulant-protein conjugate and for said free anticoagulant.
Claim 15
Dependent Claim
60 words
A process for the improvement of compatibility between blood and a substrate, the process including coating the substrate with an anticoagulant-containing material, wherein the process comprises adsorbing a protein-anticoagulant conjugate to said substrate, said substrate being a hydrophobic material or a hydrophilic material, and said protein- heparin conjugate is prepared according to the process of any of the preceding claims.
Claim 16
Dependent Claim
30 words
The process according to claim 14, wherein the protein of said protein-anticoagulant conjugate is non-crosslinked when adsorbed to said substrate, and the process further includes intermolecular cross-linking of the protein.
Claim 17
Dependent Claim
47 words
A process for the improvement of compatibility between blood and a substrate, the process including coating the substrate with an anticoagulant-containing material, wherein the process comprises chemically attaching a protein-anticoagulant conjugate to said substrate, said protein-anticoagulant conjugate having been prepared according to the process of claims 1-13.
Claim 18
Dependent Claim
31 words
The process according to claim 16, wherein the protein of said protein-anticoagulant conjugate is non-crosslinked when chemically attached to said substrate, and the process further includes intermolecular cross-linking of the protein.
Claim 19
Dependent Claim
58 words
A process for the improvement of compatibility between blood and a substrate, the process including coating the substrate with anticoagulant material, wherein the process comprises coating the substrate with a protein component, said protein component being a non-crosslinked protein or a crosslinked protein, wherein said protein component is coupled with anticoagulants by a process according to claims 1-13.
Claim 20
Dependent Claim
62 words
An article including a surface having an enhanced blood compatibility coating, wherein the coating is effected from a conjugate of anticoagulant and a water soluble protein, said protein being a non-crosslinked protein or a crosslinked protein, said conjugate having been formed by coupling a protein component and an anticoagulant with an amide bond forming agent by the process according to claims 1-13.
Claim 21
Dependent Claim
51 words
A conjugate for coating a surface of a medical device to enhance blood compatibility of the surface, said conjugate comprising a protein moiety and an anti- coagulant moiety, which protein moiety and anti- coagulant moiety are covalently bonded by an amide bond forming agent by the process according to claims 1-13.
Claim 22
Dependent Claim
31 words
The conjugate of claim 20, wherein said anti- coagulant moiety and said protein moiety are present in the conjugate at a mol ratio of no greater than 3 to 1, respectively.
Claim 23
Dependent Claim
28 words
A process for the fractionation of conjugates of heparin and a water soluble protein into fractions by separating same on the basis of differing affinity to anti-thrombin III.
Claim 24
Dependent Claim
28 words
A process for the fractionation of conjugates of heparin and a water soluble protein into fractions by separating same on the basis of differing affinity to anti-thrombin III.
Claim 25
Dependent Claim
58 words
A process for the improvement of compatibility between blood and a substrate, the process including coating the substrate with heparinous material, wherein the process comprises covalently linking a protein component being a non crosslinked protein or a crosslinked protein, wherein said protein component is coupled with heparin by a procedure utilizing 1-ethyl-3-dime tylaminopropyl carbodiimide as a coupling agent.
Claim 26
Dependent Claim
58 words
A process for the improvement of compatibility between blood and a substrate, the process including coating the substrate with heparinous material, wherein the process comprises covalently linking a protein component being a non crosslinked protein or a crosslinked protein, wherein said protein component is coupled with heparin by a procedure utilizing 1-ethyl-3-dime tylaminopropyl carbodiimide as a coupling agent.
Claim 27
Dependent Claim
11 words
The process according to claim 23 wherein said-protein component is albumin.
Claim 28
Dependent Claim
66 words
A process for the improvement of compatibility between blood and a substrate, the process including coating the substrate with anticoagulant material, wherein the process comprises covalently linking a protein component to a substrate, said protein component being a non crosslinked protein or a crosslinked protein, wherein said protein component is coupled with anticoagulant by a procedure utilizing an amide bond forming agent as a coupling reagent.
Claim 29
Dependent Claim
66 words
A process for the improvement of compatibility between blood and a substrate, the process including coating the substrate with anticoagulant material, wherein the process comprises covalently linking a protein component to a substrate, said protein component being a non crosslinked protein or a crosslinked protein, wherein said protein component is coupled with anticoagulant by a procedure utilizing an amide bond forming agent as a coupling reagent.
Claim 30
Dependent Claim
19 words
The process according to claim 25 wherein said protein component is albumin and the anticoagulant is a heparinous material.
References Cited (Backward Citations)
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