HEMOACTIVE COMPOSITIONS AND METHODS FOR THEIR MANUFACTURE AND USE

• US 20020042378A1
• Filed: 06/10/1999
• Published: 04/11/2002
• Est. Priority Date: 06/10/1999
• Status: Active Grant

• Current Assignee: Baxter Healthcare SA (Baxter International Inc.), Baxter International Inc.
• Original Assignee: Baxter Healthcare Corporation (Baxter International Inc.)
• Inventors: REICH, CARY J., OSAWA, A. EDWARD, TRAN, HELEN
• Granted Patent: US 6,706,690 B2
• Time in Patent Office: Days
• US Class Current: 514/21
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1658 Proteins, e.g. albumin, gelatin
• CPC Class Codes: A61L 2400/04 Materials for stopping bleeding
• CPC Class Codes: A61L 26/008 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids
• CPC Class Codes: C07K 14/4732 Casein in foodstuffs A23J
• CPC Class Codes: C07K 14/4741 Keratin; Cytokeratin
• CPC Class Codes: C07K 14/75 Fibrinogen
• CPC Class Codes: C07K 14/76 Albumins
• CPC Class Codes: C07K 14/78 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
• CPC Class Codes: C07K 14/805 Haemoglobins; Myoglobins
• CPC Class Codes: Y10S 435/81 Packaged device or kit

Abstract

Dried hemoactive materials comprise both a cross-linked biologically compatible polymer and a non-cross-linked biologically compatible polymer. The cross-linked polymer is selected to form a hydrogel when exposed to blood. The non-cross-linked polymer is chosen to solubilize relatively rapidly when exposed to blood. The non-cross-linked polymer serves as a binder for holding the materials in desired geometries, such as sheets, pellets, plugs, or the like. Usually, the cross-linked polymer will be present in a particulate or fragmented form. The materials are particularly suitable for hemostasis and drug delivery.

Claims

1. A dried hemoactive material comprising:

a cross-linked biologically compatible polymer which forms a hydrogel when exposed to blood; and

a non-cross-linked biologically compatible polymer which solubilizes when exposed to blood;

wherein the cross-linked polymer is dispersed in a dried matrix of the non-cross-linked polymer.

3. A material as in claim 1 or 2, wherein the cross-linked polymer has a degradation time of at least one day.

4. A material as in claim 1 or 2, wherein the non-cross-linked polymer solubilizes in 15 minutes or less when exposed to blood.

5. A material as in claim 1 or 2, wherein the cross-linked polymer is fragmented so that, upon hydration in blood, the polymer will form a gel with a sub-unit size in the range from 0.01 mm to 5 mm.

6. A material as in claim 5, wherein the cross-linked polymer has an equilibrium swell in the range from 400% to 5,000%.

7. A material as in claim 1 or 2, wherein the cross-linked polymer is present at from 50 weight % to 95 weight % of the material and the non-cross-linked material is present at from 50 weight % to 1 weight % of the material.

8. A material as in claim 7, further comprising a plasticizer present at from 1 weight % to 20 weight % of the material.

9. A material as in claim 8, wherein the plasticizer is present in at least the non-cross-linked polymer.

10. A material as in claim 9, wherein the plasticizer is selected from the group consisting of polyethylene glycol, sorbitol, and glycerol.

11. A material as in claim 1, wherein the cross-linked polymer is a protein selected from the group comprising gelatin, collagen, albumin, hemoglobin, fibrinogen, fibrin, fibronectin, elastin, keratin, laminin, and casein.

12. A material as in claim 1, wherein the cross-linked polymer is a carbohydrate or carbohydrate derivative selected from the group consisting of glycosaminglycans, starches, celluloses, hemicelluloses, xylan, agarose, alginate, and chitosan.

13. A method as in claim 1, wherein the cross-linked polymer is a non-biologic hydrogel-forming polymer or copolymer selected from the group consisting of polyacrylates, polymethacrylates, polyacrylamides, polyvinyl polymers, polylactides-glycolides, polycaprolactones, polyoxyethelenes, and copolymers thereof.

14. A material as in claim 1, wherein the non-cross-linked biologically compatible polymer is a protein selected from the group consisting of gelatin, collagen, albumin, elastin, and keratin.

15. A material as in claim 1, wherein the non-cross-linked biologically compatible polymer is a carbohydrate or carbohydrate derivative selected from the group consisting of glycosaminoglycans, alginate, starch, cellulose, and derivatives thereof.

16. A material as in claim 1 or 2, further comprising an active agent.

17. A material as in claim 16, wherein the active agent is present in at least the non-cross-linked polymer.

18. A material as in claim 16, wherein the active agent is present in at least the cross-linked polymer.

19. A material as in claim 16, wherein the active agent is present in both the non-cross-linked polymer and the cross-linked polymer.

20. A material as in claim 16, wherein the active agent is selected from the group consisting of antibiotics, anti-neoplastic agents, bacteriostatic agents, bactericidal agents, antiviral agents, anesthetics, anti-inflammatory agents, hormones, anti-angiogenic agents, antibodies, enzymes, enzyme inhibitors, and neurotransmitters.

21. A material as in claim 16, wherein the active agent is a hemostatic substance.

22. A material as in claim 21, wherein the hemostatic substance is a clotting factor.

23. A material as in claim 22, wherein the clotting factor is thrombin.

24. A material as in claim 1 or 2, in the form of a sheet having a thickness in the range from 1 mm to 25 mm.

25. A material as in claim 24, wherein the sheet is packed in a sterile pack.

26. A kit comprising:

a sterile pack;

a sterile sheet of material as in claim 24, packaged in the sterile pack; and

instructions for use setting forth a method for inhibiting bleeding by placing the sterilized sheet of material over bleeding tissue.

27. A method for inhibiting bleeding, said method comprising:

applying the material of claim 21 to a wound site.

28. A method for delivering an active agent to a patient, said method comprising:

exposing the material of claim 16 to patient blood.

2. A dried hemoactive material comprising:

a non-cross-linked polymer comprising a dry gelatin matrix; and

dry, cross-linked gelatin polymer particles dispersed in the dry non-cross-linked gelatin matris.

29. A method for making a hemoactive material, said method comprising:

dissolving a non-cross-linked biologically compatible polymer which solubilizes when exposed to blood in an aqueous medium;

suspending particles of a cross-linked biologically compatible polymer which forms a hydrogel when exposed to blood in the aqueous medium; and

drying the aqueous medium to form a solid phase comprising the dried polymeric particles in a dry matrix of the non-cross-linked polymer.