Medical device comprising glycosaminoglycan-antithrombin III/heparin cofactor II conjugates
First Claim
1. A material for use in a medical or prosthetic device, said material comprising a polymer covalently attached to a covalent comjugate composition, said covalent conjugate composition comprising glycosaminoglycans linked to a species by covalent linkage, wherein the species comprises at least one primary amino group, and wherein the species is directly covalently linked via said amino group to a terminal aldose residue of the glycosaminoglycans, said covalent linkages comprising an α
- -carbonyl amine formed by a substantial amount of subsequent Amadori rearrangement of an imine resulting from reaction between said amino group and said terminal aldose residue of said glycosaminoglycans,wherein said glycosaminoglycans are heparin (H) and said amino-containing species is antithrombin III (AT).
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Accused Products
Abstract
Novel conjugates of glycosaminoglycans, particularly heparin and dermatan sulfate, and amine containing species and therapeutic uses thereof are described. In particular, mild methods of conjugating heparins to proteins, such as antithrombin III and heparin cofactor II, which provide covalent conjugates which retain maximal biological activity are described. Uses of these conjugates to prevent thrombogenesis, in particular in lung airways, such as found in infant and adult respiratory distress syndrome, and on surfaces in contact with blood are also described.
133 Citations
59 Claims
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1. A material for use in a medical or prosthetic device, said material comprising a polymer covalently attached to a covalent comjugate composition, said covalent conjugate composition comprising glycosaminoglycans linked to a species by covalent linkage, wherein the species comprises at least one primary amino group, and wherein the species is directly covalently linked via said amino group to a terminal aldose residue of the glycosaminoglycans, said covalent linkages comprising an α
- -carbonyl amine formed by a substantial amount of subsequent Amadori rearrangement of an imine resulting from reaction between said amino group and said terminal aldose residue of said glycosaminoglycans,
wherein said glycosaminoglycans are heparin (H) and said amino-containing species is antithrombin III (AT). - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 13, 17, 18, 27, 32, 35, 36, 40, 48)
- -carbonyl amine formed by a substantial amount of subsequent Amadori rearrangement of an imine resulting from reaction between said amino group and said terminal aldose residue of said glycosaminoglycans,
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9. A material for use in a medical or prosthetic device, said material comprising a polymer in contact with a covalent conjugate composition, said covalent conjugate composition comprising glycosaminoglycans linked to a species by covalent linkages, wherein the species comprises at least one primary amino group, wherein the glycosaminoglycans are heparins, the species is antithrombin III, and the covalent conjugate composition comprises antithrombin III-heparin (ATH), said ATH being covalently attached to the polymer, and wherein the species is directly covalently linked via said amino group to a terminal aldose residue of the glycosaminoglycans to a substantial degree by an α
- -carbonyl linkage.
- View Dependent Claims (10, 21, 22, 28, 33, 37, 39, 41, 43, 49)
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11. A material for use in a medical or prosthetic device, said material comprising a polymer covalently attached to a covalent conjugate composition comprising a substantial amount of glycosaminoglycans covalently bonded to an amino-group containing species by, CO—
- CH2—
NH, said CO CH2—
portion being derived from said glycosaminoglycans and said —
NH—
portion from an amino group of said species,wherein said glycosaminoglycans are heparin (H) and said amino-containing species is antithrombin III (AT). - View Dependent Claims (14, 23, 25, 29, 34, 38, 42, 46, 51, 52, 53, 54, 55, 56, 57, 58)
- CH2—
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12. A material for use in a medical or prosthetic device, said material comprising a polymer covalently attached to a covalent conjugate composition comprising a substantial amount of a complex of the formula:
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glycosaminoglycan CO—
CH2—
NH-protein,wherein said glycosaminoglycan is heparin (H) and said protein is antithrombin III (AT). - View Dependent Claims (15, 24, 26, 30, 47)
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16. A material for use in a medical or prosthetic device, said material comprising a polymer covalently attached to a covalent conjugate, said covalent conjugate comprising a glycosaminoglycan linked to a species by a covalent linkage, wherein the species comprises at least one primary amino group, and wherein the species is directly convalently linked via said amino group to a terminal aldose residue of the glycosaminoglycan, said covalent linkage comprising an α
- -carbonyl amine formed by (a) substantial subsequent Amadori rearrangement of an imine resulting from reaction between said amino group and said terminal aldose residue of said glycosaminoglycan and (b) isolation of the rearrangement product,
wherein said glycosaminoglycan are heparin (H) and said amino-containing species is antithrombin III (AT). - View Dependent Claims (19, 20, 31, 50)
- -carbonyl amine formed by (a) substantial subsequent Amadori rearrangement of an imine resulting from reaction between said amino group and said terminal aldose residue of said glycosaminoglycan and (b) isolation of the rearrangement product,
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44. A material for use in a medical or prosthetic device, said material comprising a polymer covalently attached to a covalent conjugate composition comprising glycosyaminoglycans and molecules comprising at least one amino group, wherein said amino group is directly linked to said glycosaminoglycans by covalent linkages, wherein said conjugate composition is made by the process comprising:
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(a) incubating said glycosaminoglycans with said molecules at a pH and for a time sufficient for imine formation between said amino group and a terminal aldose residue of said glycosaminoglycans, and at a time and temperature sufficient for said imines to undergo a substantial amount of subsequent Amadori rearrangement to an α
-carbonyl amine forming said covalent linkages;
(b) isolating said conjugate composition, or a pharmaceutically acceptable salt of said covalent conjugate composition, wherein said glycosaminoglycans are heparin (II) and said amino-containing species is antithrombin III (AT). - View Dependent Claims (45)
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59. A material for use in medical or prosthetic device, saod material comprising a polymer covalently attached to a covalent conjugate composition, said covalent conjugate composition comprising glycosaminoglycans linked to a species by covalent linkages, wherein the species comprises at least one primary amino group, and wherein the species is directly covalently linked via amino group to terminal aldose residue of the glycosaminoglycans, said covalent linkages comprising an α
- -carbonyl amine formed by a substantial amount of subsquent Arnadori rearragement of an imine resulting from reaction between said amino group and said terminal aldose residue of said glycosaminoglycans.
Specification