Hemostatic compositions and methods for controlling bleeding

• US 20030175327A1
• Filed: 12/31/2002
• Published: 09/18/2003
• Est. Priority Date: 12/31/2001
• Status: Active Grant

• Current Assignee: Craig E. Lighty, International Manufacturing Center
• Original Assignee: Crosslink-D, Inc.
• Inventors: Cochrum, Kent C., Jemtrud, Susan
• Granted Patent: US 7,101,862 B2
• Time in Patent Office: Days
• US Class Current: 424/445
• CPC Class Codes: A61L 15/225 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 15/28 Polysaccharides or their derivatives A61L15/225 takes precedence
• CPC Class Codes: A61L 15/44 Medicaments
• CPC Class Codes: A61L 2300/232 Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
• CPC Class Codes: A61L 2300/418 Agents promoting blood coagulation, blood-clotting agents, embolising agents
• CPC Class Codes: A61L 2400/04 Materials for stopping bleeding
• CPC Class Codes: A61L 33/08 Polysaccharides
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: C08L 1/26 Cellulose ethers
• CPC Class Codes: C08L 5/02 Dextran; Derivatives thereof
• CPC Class Codes: C08L 5/04 Alginic acid; Derivatives thereof

Abstract

The invention provides hemostatic compositions useful to promote hemostasis at active bleeding wound sites. The hemostatic compositions typically include an article containing cellulose, e.g., cotton gauze, and a polysaccharide covalently linked to the cellulose, or a polysaccharide ionically cross-linked and in association with the article. Methods of making and using the hemostatic compositions are also provided.

Claims

1. A method for controlling bleeding at an active bleeding wound site of an animal, said method comprising applying a hemostatic composition to said active bleeding wound site, said hemostatic composition comprising an article comprising cellulose and a polysaccharide covalently linked to said cellulose.

2. The method of claim 1, wherein said polysaccharide is selected from the group consisting of dextran, starch, and alginate.

3. The method of claim 2, wherein said polysaccharide is dextran.

4. The method of claim 3, wherein said dextran is in the form covalently cross-linked beads.

5. The method of claim 3, wherein the molecular weight of said dextran is from about 10,000 to about 2,000,000.

6. The method of claim 5, wherein the molecular weight of said dextran ranges from about 20,000 to about 100,000.

7. The method of claim 1, wherein said covalently linked polysaccharide has a molecular weight exclusion limit greater than about 30,000 Daltons.

8. The method of claim 1, wherein said article comprising cellulose is selected from the group consisting of a bandage, suture, dressing, gauze, gel, foam, web, film, tape, or patch.

9. The method of claim 1, wherein said article comprising cellulose comprises cotton.

10. The method of claim 9, wherein said article comprising cellulose is cotton gauze.

11. The method of claim 1, wherein prior to said application of said hemostatic composition, said active bleeding wound site bleeds at a rate from about 0.5 ml/min to about 1000 ml/min.

12. The method of claim 11, wherein after application of said hemostatic composition, said active bleeding wound site bleeds at a rate of less than 0.03 ml/min.

13. The method of claim 12, wherein said rate of less than 0.03 ml/min is achieved from about 2 to about 20 minutes after application of said bandage.

14. The method of claim 7, wherein said hemostatic composition further comprises a second polysaccharide covalently linked to said cellulose.

15. The method of claim 7, wherein said hemostatic composition further comprises dextran having a molecular weight from about 800,000 to about 2M covalently linked to said cellulose.

26. The method according to claim 1 or claim 16, wherein said hemostatic composition further comprises an agent selected from the group consisting of analgesics, steroids, antihistamines, anesthetics, bactericides, disinfectants, fungicides, vasoconstrictors, hemostatics, chemotherapeutic drugs, antibiotics, keratolytics, cauterizing agents, antiviral drugs, epidermal growth factor, fibroblast growth factors, transforming growth factors, glycoproteins, collagen, fibrinogen, fibrin, humectants, preservatives, lymphokines, cytokines, odor controlling materials, vitamins, and clotting factors.

16. A method for controlling bleeding at an active bleeding wound site of an animal, said method comprising applying a hemostatic composition to said active bleeding wound site, said hemostatic composition comprising an article comprising cellulose in association with an ionically cross-linked polysaccharide.

17. The method according to claim 16, wherein said ionically cross-linked polysaccharide is alginate.

18. The method according to claim 17, wherein said alginate is ionically cross-linked with a cation selected from the group consisting of:

Mg2+;

Ni2+;

Ca2+;

Sr2+;

Ba2+;

Zn2+;

Cd2+;

Cu2+;

Pb2+;

Fe3+; and

Al3+.

19. The method according to claim 18, wherein said cation is Ca2+.

20. The method according to claim 17, further comprising a second polysaccharide physically trapped in a network formed by said ionically-cross-linked polysaccharide.

21. The method according to claim 20, wherein said second polysaccharide is dextran.

22. The method according to claim 21, wherein said dextran is in the form of covalently cross-linked beads.

23. The method according to claim 20, wherein said polysaccharide is further covalently linked to said cellulose.

24. The method according to claim 17, wherein said alginate is further covalently linked to dextran.

25. The method according to claim 24, wherein said dextran is in the form of covalently cross-linked beads.

27. A method for manufacturing a composition, said method comprising incubating a linking agent, a polysaccharide, and an article comprising cellulose to form a hemostatic composition comprising said polysaccharide covalently linked to said cellulose.

28. The method according to claim 27, wherein said linking agent is epichlorohydrin.

29. The method according to claim 27, wherein said incubating occurs in an aqueous alkaline solution.

30. The method according to claim 27, wherein said incubating occurs at a temperature of from about 40°

C. to about 70°

C.

31. The method according to claim 30, wherein said incubating occurs at a temperature of about 50°

C.

32. The method according to claim 27, wherein said incubating is allowed to occur for from about 1 to about 24 hours.

33. The method according to claim 29, further comprising performing said incubating step in the presence of a stabilizing solution.

34. The method according to claim 33, wherein said stabilizing solution comprises cellulose acetate butyrate.

35. The method according to claim 27, wherein said polysaccharide is dextran.

36. The method of claim 35, wherein said dextran is in the form of covalently cross-linked beads.

37. The method of claim 35, wherein the molecular weight of said dextran is from about 10,000 to about 2,000,000.

38. The method of claim 37, wherein the molecular weight of said dextran is from about 20,000 to about 100,000.

39. The method of claim 29, wherein said incubating is carried out in an aqueous alkaline solution having about 12% to about 75% dextran.

40. The method of claim 27, wherein said covalently linked polysaccharide has a molecular weight exclusion limit greater than about 30,000 Daltons.

41. The method of claim 27, wherein said article comprising cellulose comprises cotton.

42. The method of claim 41, wherein said article comprising cellulose is cotton gauze.

43. A method for manufacturing a composition, said method comprising incubating an article comprising cellulose in a solution of a polysaccharide and a cation to form a hemostatic composition wherein said polysaccharide is ionically cross-linked and associated with said article.

44. The method according to claim 43, wherein said polysaccharide is alginate.

45. The method according to claim 43, wherein said cation is Ca2+ ion.

46. The method according to claim 45, wherein said Ca2+ is derived from Ca2+-ion-loaded porous, cross-linked, dextran beads.

47. The method according to claim 43, wherein said solution further comprises a second polysaccharide.

48. The method according to claim 47, wherein said second polysaccharide is dextran.

49. The method according to claim 48, wherein said dextran is in the form of covalently cross-linked beads.

50. The method according to claim 47, wherein said second polysaccharide is physically trapped by a network formed by said ionically cross-linked polysaccharide.

51. The method according to claim 43, further comprising incubating a second polysaccharide and a linking agent with said article comprising cellulose to form a hemostatic composition comprising said second polysaccharide covalently linked to said cellulose.

52. The method according to claim 51, wherein said linking agent is epichlorohydrin.

53. The method according to claim 51, wherein said second polysaccharide is dextran.

54. A method for manufacturing a hemostatic composition, said method comprising:

(a) mixing an aqueous phase alkaline polysaccharide solution with an organic phase stabilizing agent solution to form a mixture comprising polysaccharide spheres;

(b) incubating a cross-linking agent with said mixture to cross-link said polysaccharide spheres;

(c) isolating said cross-linked polysaccharide spheres; and

(d) coating an article comprising a sodium alginate solution with said cross-linked polysaccharide spheres.

55. The method of claim 54, wherein said isolating step comprises removing the organic phase stabilizing agent from said mixture.

56. The method of claim 54, further comprising exposing said cross-linked polysaccharide spheres to a solution comprising Ca2+ ions.

57. The method of claim 54, wherein said polysaccharide comprises dextran.

58. The method of claim 54, wherein said organic phase stabilizing agent solution comprises cellulose acetate butyrate.

59. The method of claim 54, wherein said polysaccharide spheres are between about 30 to about 500 μ

m in size.

60. The method of claim 54, wherein said mixing and said incubating steps occur at a temperature of from about 40°

C. to about 70°

C.

61. The method of claim 54, wherein said coating step occurs by spraying said article with said cross-linked polysaccharide spheres.

62. A hemostatic composition manufactured according to the method of claim 54.

63. A method for manufacturing a hemostatic composition, said method comprising:

(a) providing an aqueous phase alkaline solution comprising dextran and sodium alginate;

(b) preparing dextran-alginate spheres from said aqueous phase alkaline solution; and

(c) incubating said dextran-alginate spheres with a linking agent to link said dextran-alginate spheres.

64. The method of claim 63, wherein said dextran-alginate spheres are prepared with a mechanical droplet generator.

65. The method of claim 63, wherein said linking agent is epichlorohydrin.

66. The method of claim 63, wherein said linking agent is Ca2+ linking agent.

67. The method of claim 63, wherein said dextran-alginate spheres are incubated with a Ca2+ linking agent and an epichlorohydrin linking agent.

68. The method of claim 63, further comprising coating an article with said linked dextran-alginate spheres.

69. The method of claim 68, wherein said coating is performed by spraying said linked dextran-alginate spheres on said article.

70. The method of claim 68, wherein said article comprises a sodium alginate solution.

71. A hemostatic composition manufactured according to the method of claim 63.

72. A hemostatic composition comprising an article comprising cellulose having a polysaccharide covalently linked to said cellulose.

73. The hemostatic composition of claim 72, wherein said polysaccharide is selected from the group consisting of dextran, starch, and alginate.

74. The hemostatic composition of claim 73, wherein said polysaccharide is dextran.

75. The hemostatic composition of claim 74, wherein said dextran linked to said cellulose is in the form of covalently cross-linked beads.

76. The hemostatic composition of claim 73, wherein the molecular weight of said dextran ranges from about 10,000 to about 2,000,000.

77. The hemostatic composition of claim 76, wherein the molecular weight of said dextran ranges from about 20,000 to about 100,000.

78. The hemostatic composition of claim 72, wherein said covalently linked polysaccharide has a molecular weight exclusion limit greater than about 30,000 Daltons.

79. The hemostatic composition of claim 73, wherein said article comprising cellulose comprises cotton.

80. The hemostatic composition of claim 79, wherein said article comprising cellulose is cotton gauze.

81. A hemostatic composition comprising an article comprising cellulose in association with cross-linked alginate and dextran.

82. The hemostatic composition of claim 81, wherein said alginate is covalently linked to said cellulose.

83. The hemostatic composition of claim 81, wherein said dextran is in the form of covalently cross-linked beads.

84. The hemostatic composition of claim 83, wherein said covalently cross-linked dextran beads comprise Ca2+.

85. A hemostatic composition comprising ionically linked dextran-alginate spheres.

86. The hemostatic composition of claim 85, wherein said ionically linked dextran-alginate spheres are linked ionically with Ca2+.

87. The hemostatic composition of claim 86, wherein said ionically linked dextran-alginate spheres are further cross-linked covalently.