Method and compositions for enhancing white blood cell functioning on a mucosal or cutaneous surface

• US 5,466,680 A
• Filed: 03/26/1992
• Issued: 11/14/1995
• Est. Priority Date: 03/26/1992
• Status: Expired due to Term

• Current Assignee: Cytologic Incorporated
• Original Assignee: Cytologic Incorporated
• Inventors: Rudy, Michael A.
• Primary Examiner(s): GRIFFIN, RONALD
• Application Number:
  US07/858,290
• Time in Patent Office: 1,328 Days
• Field of Search: 514/57, 514/781, 514/885, 514/887, 514/866, 514/917, 514/921, 514/928, 514/925, 514/926, 514/927, 514/931, 514/932, 514/933, 514/934
• US Class Current: 514/57
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• CPC Class Codes: A61K 33/00 Medicinal preparations containing inorganic active ingredients
• CPC Class Codes: A61K 33/06 Aluminium, calcium or magnesium; Compounds thereof , e.g. clay
• CPC Class Codes: A61K 33/14 Alkali metal chlorides; Alkaline earth metal chlorides
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14

Abstract

The present invention relates to a method for enhancing white blood cell functioning and metabolism on a mucosal surface of a mammal. The present invention also relates to a method for treating or preventing a condition in a mammal caused by the presence of a disease-causing agent on a mucosal surface or a cutaneous surface wherein the disease-causing agent can be diminished by the actions of the white blood cells. The present invention yet also relates to a method for healing a wound of a mucosal or cutaneous surface. The present invention also relates to compositions for use in such methods.

Claims

1. A method for treating or preventing a condition in a mammal caused by the presence of a disease causing agent on a mucosal surface or a cutaneous surface wherein said disease causing agent can be diminished by the actions of the white blood cells of a mammal comprising contacting the mucosal surface or the cutaneous surface of said mammal in need of said treatment or prevention with an effective amount to treat or prevent said condition of a composition comprising:

(a) an energy source for white blood cells;

(b) a source of cations to provide a cation selected from the group consisting of sodium, potassium, magnesium, calcium and mixtures thereof; and

(c) a source of anions to provide an anion selected from the group consisting of chloride, sulfate, phosphate, bicarbonate, and mixtures thereof;

wherein the pH of said composition is from about 4 to about 10 and the osmolality of said composition is from about 140 mOsm/kg to about 2,000 mOsm/kg;

with the proviso that said mucosal surface is not the oral cavity.

2. The method of claim 1 wherein said mammal is a human.

3. The method of claim 2 wherein said mucosal surface is selected from the group consisting of conjunctiva, the mucosa of the inner surface of an eyelid, nasal mucosa, paranasal sinus mucosa, vaginal mucosa, urinary bladder mucosa, urethral mucosa, ano-rectal mucosa, cervical mucosa, tracheal mucosa and bronchial mucosa.

4. The method of claim 3 wherein said mucosal surface is the conjunctiva and said condition is selected from the group consisting of allergic conjunctivitis, nonspecific conjunctival irritation and inflammation and dry eye syndromes.

5. The method of claim 3 wherein said mucosal surface is the mucosa of the inner surface of the eyelid and said condition is selected from the group consisting of allergic conjunctivitis, nonspecific conjunctival irritation and inflammation and dry eye syndromes.

6. The method of claim 3 wherein said mucosal surface is the nasal mucosa and said condition is selected from the group consisting of irritation and inflammation due to a common cold, influenza, upper respiratory infections, hayfever, respiratory allergies and environmental irritants.

7. The method of claim 3 wherein said mucosal surface is the paranasal mucosal surface and said condition is selected from the group consisting of acute and chronic sinusitis, irritation and inflammation due to a common cold, influenza, upper respiratory infections, hayfever, respiratory allergies and environmental irritants.

8. The method of claim 3 wherein said mucosal surface is the vaginal mucosa and said condition is selected from the group consisting of fungal infections, viral infections, bacterial infections, protozoal infections, chlamydial infections, radiation vaginitis, dryness secondary to systemic chemotherapy for cancer, irritation secondary to systemic chemotherapy for cancer, inflammation secondary to systemic chemotherapy for cancer, dryness secondary to use of antidepressant medication, irritation secondary to use of antidepressant medication and inflammation secondary to use of antidepressant medication.

9. The method of claim 8 wherein said condition is selected from the group consisting of Candida vulvovaginitis, herpes simplex virus infections, herpes zoster virus infections and human papillomavirus infections.

10. The method of claim 9 wherein said condition Candida vulvovaginitis.

11. The method of claim 3 wherein said mucosal surface is the urethral mucosa and said condition is radiation urethritis.

12. The method of claim 3 wherein said mucosal surface is the ano-rectal mucosa and said condition is selected from the group consisting of viral infections, fungal infections, inflammations of hemorrhoids, anal pruritis and radiation proctitis.

13. The method of claim 3 wherein said mucosal surface is the cervical mucosa and said condition is selected from the group consisting of viral infections, fungal infections, protozal infections, chlamydial infections, nonspecific cervicitis and hemorrhagic infections.

14. The method of claim 13 wherein said condition is selected from the group consisting of human papillomavirus infections and herpes simplex virus infections.

15. The method of claim 3 wherein said mucosal surface is the urinary bladder mucosa and said condition is radiation cystitis.

16. The method of claim 3 wherein said mucosal surface is the bronchial mucosa or tracheal mucosa and said condition is selected from the group consisting of irritation or inflammation secondary to chronic tracheo-bronchitis, asthmatic tracheo-bronchitis and chronic obstructive pulmonary disease.

17. The method of claim 1 wherein said energy source is selected from the group consisting of metabolic intermediates involved in energy production, monosaccharides, oligosaccharides, polysaccharides, metabolizable lipids, amino acids, oligopeptides and metabolizable proteins.

18. The method of claim 1 wherein said energy source is selected from the group consisting of D-glucose, glucose-6-phosphate, fructose-6-phosphate, D-mannose, D-galactose, D-fructose, maltose, lactose, sucrose, glycogen, starch, fatty acids, neutral fats, pyruvic acid, lactic acid, citric acid and pharmaceutically acceptable salts thereof, and mixtures thereof.

19. The method of claim 18 wherein said energy source is D-glucose.

20. The method of claim 17 wherein said energy source is present in an amount of energy equivalent to D-glucose of from about 0.10 to about 10 weight percent D-glucose of the composition.

21. The method of claim 1 wherein said source of cations is selected from the group consisting of sodium chloride, potassium chloride, magnesium sulfate, calcium chloride and mixtures thereof.

22. The method of claim 1 wherein the source of anions is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, potassium phosphates, sodium bicarbonate, magnesium sulfate heptahydrate and mixtures thereof.

23. The method of claim 1 wherein the source of cations is present in an amount of from about 0.35 to about 33 percent by weight of the composition and the source of anions is present in an amount of from about 0.25 to about 25 percent by weight of the composition.

24. The method of claim 1 wherein said source of cations provides the cations sodium, potassium, magnesium and calcium and said source of anions provides the anions chloride, sulfate, phosphate and bicarbonate.

25. The method of claim 24 wherein said source of anions and said source of cations provide from about 0.45 to about 0.85 percent by weight sodium chloride, from about 0.01 to about 0.03 percent by weight of potassium chloride, from about 0.009 to about 0.02 percent by weight of calcium chloride dihydrate, from about 0.009 to about 0.02 percent by weight magnesium sulfate heptahydrate, from about 1.5 to about 3 percent by weight sodium bicarbonate and from about 0.005 to about 0.01 percent by weight potassium phosphate.

26. The method of claim 1 wherein said pH is from about 5 to about 8.

27. The method of claim 1 wherein said composition further comprises a buffer system comprising from about 0.4 to about 4.7 percent by weight of a bicarbonate, from about 0.5 to about 9 percent by weight of a phosphate, from about 0.05 to about 0.1 percent by weight of citric acid and from about 1.0 to about 2.0 percent by weight of acetic acid.

28. The method of claim 27 wherein said bicarbonate is sodium bicarbonate and said phosphate is monopotassium dihydrogen phosphate.

29. The method of claim 1 wherein said composition further comprises from about 0.5 to about 5.0 percent by weight of acetic acid or an equivalent amount of a salt thereof.

30. The method of claim 1 wherein said osmolality is from about 675 mOsm/kg to about 825 mOsm/kg.

31. The method of claim 1 wherein said composition has a viscosity of at least about 30 centipoise.

32. The method of claim 31 wherein said viscosity is from about 35 to about 500,000 centipoise.

33. The method of claim 1 wherein said composition further comprises a water-soluble polymer having a molecular weight of from about 2,000 to about 4,000,000 daltons.

34. The method of claim 33 wherein said water-soluble polymer is a cellulose ether polymer.

35. The method of claim 34 wherein the cellulose ether polymer is carboxymethylcellulose.

36. The method of claim 2 wherein said cutaneous surface is selected from the group consisting of skin and vulva.

37. The method of claim 36 wherein said cutaneous surface is skin and said condition is selected from the group consisting of herpes zoster virus infections, varicella zoster virus infections, cutaneous Candidiasis and human papillomavirus infections.

38. The method of claim 36 wherein said cutaneous surface is the vulva and said condition is selected from the group consisting of chronic vulvovestibulitis, herpes simplex virus infections, herpes zoster virus infections, varicella zoster virus infections and human papillomavirus infections.

39. The method of claim 1 wherein said composition is in a form selected from the group consisting of a solution, suspension and emulsion.

40. The method of claim 39 wherein said form is a solution and the solvent in said solution is water.

92. The method of claim 1 wherein said osmolality is between about 675 mOsm/Kg and 1460 mOsm/Kg.

41. A method for healing a wound of a mucosal surface or cutaneous surface of a mammal comprising contacting the mucosal surface or the cutaneous surface of a mammal in need of said healing with a therapeutically effective amount of a composition comprising:

(a) an energy source for white blood cells;

(b) a source of cations to provide a cation selected from the group consisting of sodium, potassium, magnesium, calcium and mixtures thereof; and

(c) a source of anions to provide an anion selected from the group consisting of chloride, sulfate, phosphate, bicarbonate and mixtures thereof;

wherein the pH of said composition is from about 4 to about 10 and the osmolality of said composition is from about 140 mOsm/kg to about 2,000 mOsm/kg.

42. The method of claim 41 wherein said mammal is a human.

43. The method of claim 42 wherein said mucosal surface is selected from the group consisting of conjunctiva, the mucosa of the inner surface of the eyelid, nasal mucosa, paranasal sinus mucosa, vaginal mucosa, urinary bladder mucosa, urethral mucosa, ano-rectal mucosa, cervical mucosa, tracheal mucosa, bronchial mucosa, oral mucosa and gingival mucosa.

44. The method of claim 43 wherein said mucosal surface is selected from the group consisting of the mucosa of the inner surface of the eyelid, nasal mucosa, paranasal sinus mucosa, uretheral mucosa, ano-rectal mucosa, tracheal mucosa, oral mucosa, gingival mucosa and bronchial mucosa and said wound is selected from the group consisting of surgical wounds, traumatic wounds and burns.

45. The method of claim 43 wherein the mucosal surface is the conjunctiva and said wound is selected from the group consisting of surgical wounds, traumatic wounds, burns and wounds associated with corneal grafting procedures.

46. The method of claim 43 wherein said mucosal surface is the vaginal mucosa and said wound is selected from the group consisting of surgical wounds, traumatic wounds, burns, wounds associated with childbirth and wounds associated with topical chemotherapy.

47. The method of claim 43 wherein said mucosal surface is the cervical mucosa and said wound is selected from the group consisting of surgical wounds, traumatic wounds, burns, wounds associated with childbirth and wounds associated with topical chemotherapy.

48. The method of claim 43 wherein said mucosal surface is the urinary bladder mucosa and said wound is selected from the group consisting of surgical wounds and traumatic wounds.

49. The method of claim 41 wherein said energy source is selected from the group consisting of metabolic intermediates involved in energy production, monosaccharides, oligosaccharides, polysaccharides, metabolizable lipids, amino acids, oligopeptides and metabolizable proteins.

50. The method of claim 41 wherein said energy source is selected from the group consisting of D-glucose, glucose-6-phosphate, fructose-6-phosphate, D-mannose, D-galactose, D-fructose, maltose, lactose, sucrose, glycogen, starch, fatty acids, neutral fats, pyruvic acid, lactic acid, citric acid and pharmaceutically acceptable salts thereof, and mixtures thereof.

51. The method of claim 50 wherein said energy source is D-glucose.

52. The method of claim 49 wherein said energy source is present in an amount of energy equivalent to D-glucose of from about 0.10 to about 10 weight percent D-glucose of the composition.

53. The method of claim 41 wherein said source of cations is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, magnesium sulfate and mixtures thereof.

54. The method of claim 41 wherein said source of anions is selected form the group consisting of sodium chloride, potassium chloride, calcium chloride, potassium phosphates, sodium bicarbonate, magnesium sulfate heptahydrate and mixtures thereof.

55. The method of claim 41 wherein said source of cations provides the cations sodium, potassium, magnesium and calcium and said source of anions provides the anions chloride, sulfate, phosphate and bicarbonate.

56. The method of claim 55 wherein said source of anions and said source of cations provide from about 0.45 to about 0.85 percent by weight sodium chloride, from about 0.01 to about 0.03 percent by weight of potassium chloride, from about 0.009 to about 0.02 percent by weight of calcium chloride dihydrate, from about 0.009 to about 0.02 percent by weight magnesium sulfate heptahydrate, from about 1.5 to about 3 percent by weight sodium bicarbonate and from about 0.005 to about 0.01 percent by weight potassium phosphate.

57. The method of claim 41 wherein the source of cations is present in an amount of from about 0.35 to about 33 percent by weight of the composition and the source of anions is present in an amount of from about 0.25 to about 25 percent by weight of the composition.

58. The method of claim 41 wherein said pH is from about 5 to about 8.

59. The method of claim 41 wherein said composition further comprises a buffer system comprising from about 0.4 to about 4.7 percent by weight of a bicarbonate, from about 0.5 to about 9 percent by weight of a phosphate, from about 0.05 to about 0.1 percent by weight of citric acid and from about 1.0 to about 2.0 percent by weight of acetic acid.

60. The method of claim 59 wherein said bicarbonate is sodium bicarbonate and said phosphate is monopotassium dihydrogen phosphate.

61. The method of claim 41 wherein said composition further comprises from about 0.5 to about 5.0 percent by weight of acetic acid or an equivalent amount of a salt thereof.

62. The method of claim 41 wherein said osmolality is from about 675 mOsm/kg to about 825 mOsm/kg.

63. The method of claim 41 wherein said composition has a viscosity of at least about 30 centipoise.

64. The method of claim 63 wherein said viscosity is from about 35 to about 500,000 centipoise.

65. The method of claim 41 wherein said composition further comprises a water-soluble polymer having a molecular weight of from about 2,000 to about 4,000,000 daltons.

66. The method of claim 65 wherein said water-soluble polymer is a cellulose ether polymer.

67. The method of claim 66 wherein said cellulose ether polymer is carboxymethylcellulose.

68. The method of claim 42 wherein said cutaneous surface is selected from the group consisting of skin and vulva.

69. The method of claim 68 wherein said cutaneous surface is skin and said wound is selected from the group consisting of surgical wounds, traumatic wounds, burns and wounds associated with skin grafting procedures.

70. The method of claim 68 wherein said cutaneous surface is the vulva and said wound is selected from the group consisting of surgical wounds, traumatic wounds, burns and wounds associated with skin grafting procedures.

71. The method of claim 41 wherein said composition is in a form selected from the group consisting of a solution, suspension and emulsion.

72. The method of claim 71 wherein said form is a solution and the solvent in said solution is water.

93. The method of claim 41 wherein said osmolality is between about 675 mOsm/Kg and 1460 mOsm/Kg.

73. A composition comprising:

(a) a source of cations to provide a cation selected from the group consisting of magnesium, calcium and mixtures thereof;

(b) a source of anions to provide an anion selected from the group consisting of phosphate, bicarbonate and mixtures thereof;

(c) a chelating agent capable of contributing to the stabilization of said composition; and

(d) a cellulose ether polymer;

wherein the molar ratio of said chelating agent to the total numbers of moles of said calcium cations plus said magnesium cations is such that said composition results in no greater than about a 10% by weight decrease in the calcium plus magnesium concentration in said composition after four weeks of storage at 42°

C. when the composition is formulated as an aqueous solution to have a pH of about 4 and an osmolality of about 140 mOsm/kg to about 2,000 mOsm/kg.

74. The composition of claim 73 wherein said composition is formulated to have a pH of about 7 and an osmolality of about 750 mOsm/kg.

75. The composition of claim 73 wherein said composition has a pH of from about 4 to about 10 and has an osmolality of from about 140 mOsm/kg to about 2,000 mOsm/kg.

76. The composition of claim 73 which further comprises an energy source for white blood cells.

77. The composition of claim 76 wherein said energy source is selected from the group consisting of metabolic intermediates involved in energy production, monosaccharides, oligosaccharides, polysaccharides, metabolizable lipids, amino acids, oligopeptides and metabolizable proteins.

78. The composition of claim 73 wherein said energy source is selected from the group consisting of D-glucose, glucose-6-phosphate, fructose-6-phosphate, D-mannose, D-galactose, D-fructose, maltose, lactose, sucrose, glycogen, starch, fatty acids, neutral fats, pyruvic acid, lactic acid, citric acid and pharmaceutically acceptable salts thereof and mixtures thereof.

79. The composition of claim 78 wherein said energy source is D-glucose.

80. The composition of claim 73 wherein said source of cations provides the cations sodium, potassium, magnesium and calcium and the source of anions provides the anions chloride, sulfate, phosphate and bicarbonate.

81. The composition of claim 73 wherein said composition further comprises from about 0.5 to about 5.0 percent by weight acetic acid or a salt thereof.

82. The composition of claim 73 wherein said cellulose ether polymer is carboxymethylcellulose that has a molecular weight of from about 50,000 to about 1,000,000 daltons.

83. The composition of claim 73 wherein said chelating agent is selected from the group consisting of citric acid, EDTA, saccharic acid, NTA, HEEOTA, EDDHA, EGTA, DTPA, DCTA, N, N-bishydroxyethylglycine, HIMDA and salts thereof.

84. The composition of claim 83 wherein said chelator is citric acid or a salt thereof and said molar ratio is about 2.

94. The composition of claim 73 wherein said osmolality is between about 675 mOsm/Kg and 1460 mOsm/Kg.

85. A method for treating or preventing a condition in a mammal caused by the presence of a disease causing agent on a mucosal surface or a cutaneous surface wherein said disease causing agent can be diminished by the actions of the white blood cells of a mammal comprising contacting the mucosal surface or the cutaneous surface of said mammal in need of said treatment or prevention with an effective amount to treat or prevent said condition of a composition comprising:

(a) a source of cations to provide a cation selected from the group consisting of magnesium, calcium and mixtures thereof;

(b) a source of anions to provide an anion selected from the group consisting of phosphate, bicarbonate and mixtures thereof;

(c) a chelating agent capable of contributing to the stabilization of said composition;

(d) a cellulose ether polymer; and

(e) an energy source for white blood cells;

wherein the molar ratio of said chelating agent to the total numbers of moles of said calcium cations plus said magnesium cations is such that said composition results in no greater than about a 10% by weight decrease in the calcium plus magnesium concentration in said composition and the pH of said composition is from about 4 to about 10 and the osmolality of said composition is from about 140 mOsm/kg to about 2,000 mOsm/kg.

86. The method of claim 85 wherein said mucosal surface is the gingival mucosa and said condition is selected from the group consisting of gingivitis and dental plaque.

95. The method of claim 85 wherein said osmolality is between about 675 mOsm/Kg and 1460 mOsm/Kg.

87. A method for healing a wound of a mucosal surface or cutaneous surface of a mammal comprising contacting the mucosal surface or the cutaneous surface of a mammal in need of said healing with a therapeutically effective amount of a composition comprising:

(a) a source of cations to provide a cation

selected from the group consisting of magnesium, calcium and mixtures thereof;

(b) a source of anions to provide an anion selected from the group consisting of phosphate, bicarbonate and mixtures thereof;

(c) a chelating agent capable of contributing to the stabilization of said composition;

(d) a cellulose ether polymer; and

(e) an energy source for white blood cells;

wherein the molar ratio of said chelating agent to the total numbers of moles of said calcium cations plus said magnesium cations is such that said composition results in no greater than about a 10% by weight decrease in the calcium plus magnesium concentration in said composition after four weeks of storage at 42°

C. and the pH of said composition is from about 4 to about 10 and the osmolality of said composition is from about 140 mOsm/kg to about 2,000 mOsm/kg.

96. The method of claim 87 wherein said osmolality is between about 675 mOsm/Kg and 1460 mOsm/Kg.

88. A method for healing a wound of a mucosal surface or cutaneous surface of a mammal comprising contacting the mucosal surface or the cutaneous surface of a mammal in need of said healing with a therapeutically effective amount of a composition comprising:

(a) an energy source for white blood cells;

(b) a source of cations to provide a cation selected from the group consisting of sodium, potassium, magnesium, calcium and mixtures thereof;

(c) a source of anions to provide an anion selected from the group consisting of chloride, sulfate, phosphate, bicarbonate and mixtures thereof; and

(d) acetic acid or a salt thereof;

wherein the pH of said composition is from about 4 to about 10 and the osmolality of said composition is from about 140 mOsm/kg to about 2,000 mOsm/kg.

97. The method of claim 88 wherein said osmolality is between about 675 mOsm/Kg and 1460 mOsm/Kg.

89. A method for treating or preventing in a mammal a condition selected from the group consisting of oral viral infections, oral fungal infections, oral radiation mucositis, the effects of radiation or antidepressant induced salivary dysfunction and the effects on oral soft tissues resulting from Xerostomia, which comprises contacting the oral mucosa or gingival mucosa of a mammal in need of said treatment or prevention with an effective amount to treat or prevent said condition of a composition comprising:

(a) an energy source for white blood cells;

(b) a source of cations to provide a cation selected from the group consisting of sodium, potassium, magnesium, calcium and mixtures thereof; and

(c) a source of anions to provide an anion selected from the group consisting of chloride, sulfate, phosphate, bicarbonate and mixtures thereof;

wherein the pH of said composition is from about 4 to about 10 and the osmolality of said composition is from about 140 mOsm/kg to about 2,000 mOsm/kg.

90. The method of claim 89 wherein said fungal infection is oral Candidiasis.

91. The method of claim 89 wherein said viral infection is selected from the group consisting of herpes simplex virus infections, varicella virus infections and varicella zoster virus infections.

98. The method of claim 89 wherein said osmolality is between about 675 mOsm/Kg and 1460 mOsm/Kg.