Controlled generation of nitric oxide

• US 20030064028A1
• Filed: 08/28/2002
• Published: 04/03/2003
• Est. Priority Date: 09/05/2001
• Status: Active Grant

• Current Assignee: Vero Biotech LLC
• Original Assignee: GENO LLC
• Inventors: Wheeler, David, Fine, David H., Jarvis, George, MacDonald, Stephen J., Rolfe, Jonathan L., Rounbehler, David
• Granted Patent: US 8,066,904 B2
• Time in Patent Office: Days
• US Class Current: 424/43
• CPC Class Codes: A61K 33/00 Medicinal preparations containing inorganic active ingredients
• CPC Class Codes: A61K 33/24 Heavy metals; Compounds thereof
• CPC Class Codes: A61K 33/30 Zinc; Compounds thereof
• CPC Class Codes: A61K 33/34 Copper; Compounds thereof
• CPC Class Codes: A61K 9/007 Pulmonary tract; Aromatherapy
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/205 Polysaccharides, e.g. alginate, gums; Cyclodextrin
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61M 16/10 Preparation of respiratory gases or vapours
• CPC Class Codes: A61M 16/12 by mixing different gases
• CPC Class Codes: A61M 2016/1035 the anaesthetic agent concentration
• CPC Class Codes: A61M 2202/0275 Nitric oxide [NO]
• CPC Class Codes: A61M 2209/06 Packaging for specific medical equipment
• CPC Class Codes: C01B 21/24 Nitric oxide (NO) C01B21/203 takes precedence

Abstract

Inhalation of low levels of nitric oxide can rapidly and safely decrease pulmonary hypertension in mammals. Precise delivery of nitric oxide at therapeutic levels of 20 to 100 ppm and inhibition of reaction of nitric oxide with oxygen to form toxic impurities such as nitrogen dioxide can provide effective inhalation therapy for pulmonary hypertension.

Claims

1. A nitric oxide generating composition comprising:

a nitric oxide precursor contained within a matrix, the matrix being non-reactive with the nitric oxide precursor.

2. The composition of claim 1 wherein the matrix includes a hydrogel.

3. The composition of claim 2 wherein the hydrogel includes a polymer selected from a group consisting of a urethane, a polysaccharide, a polyphosphazene, a polyacrylate, a block copolymer, a polyethylene oxide-polypropylene glycol block copolymer, a fibrin, a polyvinylpyrrolidone, a hyaluronic acid, a collagen and a polyethylene glycol.

4. The composition of claim 3 wherein the hydrogel includes a urethane.

5. The composition of claim 1 wherein the nitric oxide precursor includes a precursor salt.

6. The composition of claim 5 wherein the precursor salt includes a nitrite salt.

7. The composition of claim 6 wherein the nitric oxide precursor includes a nitrite salt selected from a group consisting of potassium nitrite, sodium nitrite, rubidium nitrite, strontium nitrite, barium nitrite, calcium nitrite, copper nitrite and zinc nitrite.

8. The composition of claim 6 wherein the nitrite salt is sodium nitrite.

9. The composition of claim 1 wherein the matrix is in a shape selected from a group consisting of sphere, monolith and three-dimensional object.

10. The composition of claim 9 wherein the matrix is a monolith.

11. The composition of claim 9 wherein the three dimensional object includes a cylinder.

13. The composition of claim 1 wherein the matrix is a hydrophilic polymer

14. The composition of claim 13 wherein the hydrophilic polymer includes a polysaccharide.

15. The composition of claim 13 wherein the hydrophilic polymer includes a component selected from a group consisting of guar gum, gum arabic, gum karaya, gum ghatti, locust bean gum, tamarind gum, agar, agarose, carageenan gum, pectin and gluten.

16. The composition of claim 1 wherein the matrix further includes an additive selected from a group consisting of a polymer, a salt, a filler and a solvent.

17. The composition of claim 1 further comprising a reaction solution.

18. The composition of claim 17 wherein the reaction solution includes a pH buffer combination selected from a group consisting of acetic acid/acetate, hydrochloric acid/chloride, hydrochloric acid/citrate, citric acid-phosphate, phosphoric acid/phosphate and citric acid/citrate systems.

19. The composition of claim 17 wherein the reaction solution includes a ferrous salt.

12. The composition of 9 wherein the three dimensional object includes a film.

20. A method of administering nitric oxide to a mammal comprising:

generating a therapeutic gas including nitric oxide from a nitric oxide precursor contained in a matrix that is non-reactive with the precursor; and

transporting the therapeutic gas in a transport gas stream to the mammal.

21. The method of claim 20 wherein generating the therapeutic gas includes contacting the nitric oxide precursor with a reaction solution to form a mixture.

22. The method of claim 21 wherein the reaction solution includes a pH buffer combination.

23. The method of claim 21 wherein the reaction solution includes a pH buffer combination selected from a group consisting of acetic acid/acetate, hydrochloric acid/chloride, hydrochloric acid/citrate, citric acid-phosphate, phosphoric acid/phosphate and citric acid/citrate.

24. The method of claim 21 wherein the reaction solution maintains a pH of the mixture in the range of 4 to 7.

25. The method of claim 21 wherein the reaction solution maintains a pH of the mixture in the range of 6.5-6.9.

26. The method of claim 20 wherein generating the therapeutic gas includes contacting the nitric oxide precursor with a nitric oxide releasing salt.

27. The method of claim 26 wherein the nitric oxide releasing salt includes a ferrous salt.

28. The method of claim 20 wherein transporting the therapeutic gas includes delivering at least 1 ppm of nitric oxide to the mammal.

29. The method of claim 20 wherein transporting the therapeutic gas includes delivering less than 100 ppm of nitric oxide to the mammal.

30. The method of claim 20, wherein transporting the therapeutic gas includes controlling the flow rate of the transport gas stream in the range of 1 to 20 liters per minute.

31. The method of claim 30, wherein transporting the therapeutic gas includes controlling the flow rate of the transport gas stream in the range of 1 to 5 liters per minute.

32. The method of claim 20, wherein the transport gas stream includes oxygen.

33. The method of claim 20 wherein the transport gas stream includes ambient air.

34. The method of claim 20 wherein the transport gas includes a mixture of air and oxygen.

35. The method of claim 20 wherein generating the therapeutic gas includes releasing nitric oxide over a period of time from one hour to seven days.

36. The method of claim 20 wherein generating the therapeutic gas includes releasing nitric oxide over a period of time from two hours to 24 hours.

37. The method of claim 20 wherein transporting the therapeutic gas includes releasing nitric oxide for at least one hour.

38. The method of claim 20 wherein the therapeutic gas is substantially devoid of nitrogen dioxide.

39. The method of claim 20 wherein transporting the therapeutic gas includes sweeping a transport gas over the mixture.

40. A unitary structure comprising a mixture of a matrix and a plurality of nitric oxide precursor particles contained in the matrix.

41. The structure of claim 40 wherein the matrix includes a hydrophilic polymer.

42. The structure of claim 40 wherein the matrix includes a polysaccharide.

43. The structure of claim 40 wherein the matrix includes a polymer selected from the group consisting of guar gum, gum arabic, gum karaya, gum ghatti, locust bean gum, tamarind gum, agar, agarose, carageenan gum, pectin and gluten.

44. The structure of claim 43 wherein the matrix includes an agar polymer.

45. The structure of claim 40 wherein the matrix further includes an additive selected from a group consisting of a polymer, a buffer, a salt, a filler and a solvent.

46. The structure of claim 45 wherein the buffer includes a pH buffer combination selected from a group consisting of a acetic acid/acetate buffer, a hydrochloric/chloride, a hydrochloric acid/citrate buffer, a hydrochloric acid/citrate buffer, a citric acid-phosphate buffer, a phosphoric acid/phosphate buffer and a citric acid/citrate buffer.

47. The structure of claim 45 wherein the salt is a ferrous salt.

48. The structure of claim 40 wherein the nitric oxide precursor includes a precursor salt.

49. The structure of claim 48 wherein the precursor salt includes a nitrite salt.

50. The structure of claim 40 wherein the nitric oxide precursor includes a nitrite salt selected from a group consisting of potassium nitrite, sodium nitrite, rubidium nitrite, strontium nitrite, barium nitrite, calcium nitrite, copper nitrite and zinc nitrite.

51. The structure of claim 50 wherein the nitrite salt is sodium nitrite.

52. A method of manufacturing a unitary structure for delivering nitric oxide comprising:

combining a matrix and a plurality of nitric oxide precursor particles to form a mixture; and

shaping the mixture to form a unitary structure.

53. The method of claim 52 wherein the matrix is in a shape selected from a group consisting of a sphere, a monolith and a three dimensional object.

54. The method of claim 53 wherein the matrix includes a monolith.

55. The method of claim 53 wherein the three dimensional object includes a cylinder.

56. The method of 53 wherein the three dimensional object includes a film.

57. A process for preparing a formulation for delivering nitric oxide comprising:

combining a plurality of the nitric oxide precursor particles within a hydrophilic matrix.

58. The process of claim 57 wherein the hydrophilic matrix is a polysaccharide.

59. The process of claim 57 wherein the hydrophilic matrix includes a polymer selected from a group consisting of guar gum, gum arabic, gum karaya, gum ghatti, locust bean gum, tamarind gum, agar, agarose, carageenan gum, pectin and gluten.

60. An electrophoresis apparatus for delivering nitric oxide to a patient comprising:

a delivery portion;

a reaction chamber in fluid communication with the delivery portion; and

a nitric oxide precursor receiving portion comprising an electrophoresis region bounded by a first electrode and a second electrode arranged to migrate a nitric oxide precursor to the reaction chamber when a voltage is applied across the first electrode and the second electrode.

61. The apparatus of claim 60 wherein the nitric oxide precursor includes a precursor salt.

62. The apparatus of claim 61 wherein the precursor salt includes a nitrite salt.

63. The apparatus of claim 62 wherein the nitrite salt is sodium nitrite.

64. A method of producing nitric oxide comprising:

applying a voltage across a cavity including an electrophoresis region bound by a first electrode and a second electrode arranged to migrate a nitric oxide precursor in the electrophoresis region to a reaction chamber; and

contacting the nitric oxide precursor with a reaction solution in the reaction chamber to generate a therapeutic gas including nitric oxide.

65. The method of claim 64 further comprising varying voltage between the electrodes.

66. The method of claim 64 wherein contacting the nitric oxide precursor includes varying concentration of the nitric oxide precursor.

67. The method of claim 64 wherein the nitric oxide precursor includes a precursor salt.

68. The method of claim 67 wherein the precursor salt includes a nitrite salt.

69. The method of claim 68 wherein the nitrite salt is sodium nitrite.

70. A kit comprising a nitric oxide precursor and an instructional material describing a method of generating a therapeutic gas and transporting the therapeutic gas, the therapeutic gas comprising nitric oxide and being substantially devoid of nitrogen dioxide.

71. The kit of claim 70 wherein the nitric oxide precursor includes a precursor salt.

72. The kit of claim 71 wherein the precursor salt includes a nitrite salt.

73. The kit of claim 70 wherein the nitric oxide precursor includes a nitrite salt selected from a group consisting of potassium nitrite, sodium nitrite, rubidium nitrite, strontium nitrite, barium nitrite, calcium nitrite, copper nitrite and zinc nitrite.

74. The kit of claim 72 wherein the nitrite salt includes sodium nitrite.

75. The kit of claim 70 wherein generating the therapeutic gas includes releasing nitric oxide from the precursor over a period of time from one hour to seven days.

76. The kit of claim 75 wherein generating the therapeutic gas includes releasing nitric oxide from the precursor over a period of time from two hours to 24 hours.