METHOD FOR EMBOLIZATION USING LIQUID EMBOLIC MATERIALS

• US 20090054535A1
• Filed: 08/20/2008
• Published: 02/26/2009
• Est. Priority Date: 08/24/2007
• Status: Active Grant

• Current Assignee: E. I. du Pont de Nemours and Company (Corteva, Inc.)
• Original Assignee: E. I. du Pont de Nemours and Company (Corteva, Inc.)
• Inventors: Richardson, Llewellyn Bentley III, Figuly, Garret D.
• Granted Patent: US 8,241,609 B2
• Time in Patent Office: Days
• US Class Current: 514/772.700
• CPC Class Codes: A61L 24/043 Mixtures of macromolecular materials
• CPC Class Codes: A61L 2430/36 for embolization or occlusion, e.g. vaso-occlusive compositions or devices artificial blood vessels A61L27/507
• CPC Class Codes: C08L 5/02 Dextran; Derivatives thereof

Abstract

A method for embolization using liquid embolic materials is described. The method comprises the use of two liquid components. The first liquid component is an aqueous solution or dispersion comprising at least one oxidized polysaccharide. The second liquid component is either an aqueous solution or dispersion comprising at least one water-dispersible, multi-arm amine, or a water-dispersible multi-arm amine in the form of a neat liquid. The two components crosslink in situ to form a hydrogel that should act as an effective embolic agent.

Claims

1. A method for embolization in a mammal comprising the steps of:

a) premixing

(i) a first aqueous solution or dispersion comprising at least one oxidized polysaccharide containing aldehyde groups, having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons, said at least one oxidized polysaccharide having an equivalent weight per aldehyde group of about 90 to about 1500 Daltons, said solution or dispersion containing about 5% to about 40% by weight of said at least one oxidized polysaccharide; and

ii) a second aqueous solution or dispersion comprising at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by a primary amine group, wherein said at least one multi-arm amine has a number-average molecular weight of about 450 to about 200,000 Daltons, said solution or dispersion containing about 5% to about 70% by weight of said at least one multi-arm amine;

or

(iii) a water-dispersible, multi-arm amine in the form of a neat liquid wherein at least three of the arms are terminated by a primary amine group, wherein said at least one multi-arm amine has a number-average molecular weight of about 450 to about 200,000 Daltons;

to form a mixture; and

b) introducing said mixture into the vasculature of the mammal before said mixture completely cures.

2. The method according to claim 1 wherein the at least one oxidized polysaccharide has a weight-average molecular weight from about 3,000 to about 250,000 Daltons.

3. The method according to claim 1 wherein the water dispersible, multi-arm amine has a number-average molecular weight from about 2,000 to about 40,000 Daltons.

4. The method according to claim 1 wherein the at least one oxidized polysaccharide is selected from the group consisting of oxidized dextran, oxidized starch, oxidized agar, oxidized cellulose, and oxidized hyaluronic acid.

5. The method according to claim 4 wherein the at least one oxidized polysaccharide is oxidized dextran.

6. The method according to claim 5 wherein the oxidized dextran has a weight-average molecular weight of 8,500 to 11,500 Daltons and an equivalent weight per aldehyde group of about 146 Daltons.

7. The method according to claim 5 wherein the oxidized dextran has a weight-average molecular weight of 60,000 to 90,000 Daltons and an equivalent weight per aldehyde group of about 322 Daltons.

8. The method according to claim 1 wherein at least one of the first aqueous solution or dispersion or the second aqueous solution or dispersion further comprises an additive selected from the group consisting of pH modifiers, viscosity modifiers, antimicrobials, colorants, surfactants, pharmaceutical drugs, therapeutic agents, and radio-opaque compounds.

9. The method according to claim 8 wherein at least one of the first aqueous solution or dispersion or the second aqueous solution or dispersion further comprises a pharmaceutical drug or therapeutic agent.

10. The method according to claim 1 wherein the first aqueous solution or dispersion contains about 15% to about 30% by weight of the at least one oxidized polysaccharide.

11. The method according to claim 1 wherein the water-dispersible, multi-arm amine is selected from the group consisting of a water dispersible multi-arm polyether amine, an amino-terminated dendritic polyamidoamine, and a multi-arm branched end amine.

12. The method according to claim 11 wherein the water-dispersible multi-arm polyether amine is selected from the group consisting of amino-terminated star polyethylene oxides, amino-terminated dendritic polyethylene oxides, amino-terminated comb polyethylene oxides, amino-terminated star polypropylene oxides, amino-terminated dendritic polypropylene oxides, amino-terminated comb polypropylene oxides, amino-terminated star polyethylene oxide-polypropylene oxide copolymers, amino-terminated dendritic polyethylene oxide-polypropylene oxide copolymers, amino-terminated comb polyethylene oxide-polypropylene oxide copolymers, polyoxyalkylene triamines, and multi-arm branched end polyether amines.

13. The method according to claim 12 wherein the water-dispersible multi-arm polyether amine is a polyethylene glycol comprising eight arms, each arm being terminated by a primary amine group, and having a number-average molecular weight of about 10,000 Daltons.

14. The method according to claim 12 wherein the water-dispersible multi-arm polyether amine is a polyethylene glycol comprising four arms, each arm being terminated by a primary amine group, and having a number-average molecular weight of about 2,000 Daltons.

15. The method according to claim 1 wherein the second aqueous solution or dispersion contains about 20% to about 50% by weight of the water dispersible, multi-arm amine.

16. A method for embolization in a mammal comprising the step of:

introducing into the vasculature of said mammal;

i) a first aqueous solution or dispersion comprising at least one oxidized polysaccharide containing aldehyde groups, having a weight-average molecular weight of about 1,000 to about 1,000,000 Daltons, said at least one oxidized polysaccharide having an equivalent weight per aldehyde group of about 90 to about 1500 Daltons, said solution or dispersion containing about 5% to about 40% by weight of said at least one oxidized polysaccharide; and

(ii) a second aqueous solution or dispersion comprising at least one water-dispersible, multi-arm amine wherein at least three of the arms are terminated by a primary amine group, wherein said at least one multi-arm amine has a number-average molecular weight of about 450 to about 200,000 Daltons, said solution or dispersion containing about 5% to about 70% by weight of said at least one multi-arm amine;

or

(iii) a water-dispersible, multi-arm amine in the form of a neat liquid wherein at least three of the arms are terminated by a primary amine group, wherein said at least one multi-arm amine has a number-average molecular weight of about 450 to about 200,000 Daltons;

wherein (i) and (ii) or (iii) react to form a hydrogel

17. The method according to claim 16 wherein the at least one oxidized polysaccharide has a weight-average molecular weight from about 3,000 to about 250,000 Daltons.

18. The method according to claim 16 wherein the water dispersible, multi-arm amine has a number-average molecular weight from about 2,000 to about 40,000 Daltons.

19. The method according to claim 16 wherein the at least one oxidized polysaccharide is selected from the group consisting of oxidized dextran, oxidized starch, oxidized agar, oxidized cellulose, and oxidized hyaluronic acid.

20. The method according to claim 19 wherein the at least one oxidized polysaccharide is oxidized dextran.

21. The method according to claim 20 wherein the oxidized dextran has a weight-average molecular weight of 8,500 to 11,500 Daltons and an equivalent weight per aldehyde group of about 146 Daltons.

22. The method according to claim 20 wherein the oxidized dextran has a weight-average molecular weight of 60,000 to 90,000 Daltons and an equivalent weight per aldehyde group of about 322 Daltons.

23. The method according to claim 16 wherein at least one of the first aqueous solution or dispersion or the second aqueous solution or dispersion further comprises an additive selected from the group consisting of pH modifiers, viscosity modifiers, antimicrobials, colorants, surfactants, pharmaceutical drugs, therapeutic agents, and radio-opaque compounds.

24. The method according to claim 23 wherein at least one of the first aqueous solution or dispersion or the second aqueous solution or dispersion further comprises a pharmaceutical drug or therapeutic agent.

25. The method according to claim 16 wherein the first aqueous solution or dispersion contains about 15% to about 30% by weight of the at least one oxidized polysaccharide.

26. The method according to claim 16 wherein the water-dispersible multi-arm amine is selected from the group consisting of a water dispersible multi-arm polyether amine, an amino-terminated dendritic polyamidoamine, and a multi-arm branched end amine.

27. The method according to claim 26 wherein the water-dispersible multi-arm polyether amine is selected from the group consisting of amino-terminated star polyethylene oxides, amino-terminated dendritic polyethylene oxides, amino-terminated comb polyethylene oxides, amino-terminated star polypropylene oxides, amino-terminated dendritic polypropylene oxides, amino-terminated comb polypropylene oxides, amino-terminated star polyethylene oxide-polypropylene oxide copolymers, amino-terminated dendritic polyethylene oxide-polypropylene oxide copolymers, amino-terminated comb polyethylene oxide-polypropylene oxide copolymers, polyoxyalkylene triamines, and multi-arm branched end polyether amines.

28. The method according to claim 27 wherein the water-dispersible multi-arm polyether amine is a polyethylene glycol comprising eight arms, each of said arms being terminated by a primary amine group, and having a number-average molecular weight of about 10,000 Daltons.

29. The method according to claim 27 wherein the water-dispersible multi-arm polyether amine is a polyethylene glycol comprising four arms, each of said arms being terminated by a primary amine group, and having a number-average molecular weight of about 2,000 Daltons.

30. The method according to claim 16 wherein the second aqueous solution or dispersion contains about 20% to about 50% by weight of the water dispersible, multi-arm amine.