Topical and transdermal administration of peptidyl durgs using hydroxide releasing agents as permeation enhancers

• US 20010038862A1
• Filed: 12/14/2000
• Published: 11/08/2001
• Est. Priority Date: 12/16/1999
• Status: Active Grant

• Current Assignee: Technology Recovery Systems, LLC
• Original Assignee: Dermatrends, Inc.
• Inventors: Luo, Eric C., Hsu, Tsung-Min
• Granted Patent: US 6,558,695 B2
• Time in Patent Office: Days
• US Class Current: 424/688
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/7023 Transdermal patches and similar drug-containing composite devices, e.g. cataplasms galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006

Abstract

A method is provided for increasing the permeability of skin or mucosal tissue to a topically or transdermally administered pharmacologically or cosmeceutically active peptide, polypeptide or protein. The method involves use of a specified amount of a hydroxide-releasing agent, the amount optimized to increase the flux of the peptide, polypeptide or protein through a body surface while minimizing the likelihood of skin damage, irritation or sensitization. Formulations and drug delivery devices employing hydroxide-releasing agents as permeation enhancers are provided as well.

Claims

1. A method for enhancing the flux of a peptidyl drug through a body surface, comprising administering the peptidyl drug to a localized region of a human patient'"'"'s body surface in combination with a hydroxide-releasing agent applied to the body surface in a predetermined amount effective to enhance the flux of the drug through the localized region of the body surface without causing damage thereto.

2. A method of

claim 1

, wherein the predetermined amount of the hydroxide-releasing agent is effective to provide a pH in the range of approximately 8.0 to 13 at the localized region of the body surface, during drug administration.

3. The method of

claim 2

, wherein the pH is in the range of approximately 8.0 to 11.5.

4. The method of

claim 3

, wherein the pH is in the range of approximately 8.5 to 11.5.

5. The method of

claim 1

, wherein the body surface is skin.

6. The method of

claim 1

, wherein the body surface is mucosal tissue.

7. The method of

claim 1

, wherein the peptidyl drug and the hydroxide-releasing agent are applied to the body surface simultaneously.

8. The method of

claim 1

, wherein the peptidyl drug and hydroxide-releasing agent are present in a single pharmaceutical formulation.

9. The method of

claim 8

, wherein the formulation is aqueous.

10. The method of

claim 9

, wherein the formulation has a pH in the range of approximately 8.0 to 13.

11. The method of

claim 10

, wherein the pH is in the range of approximately 8.0 to 11.5.

12. The method of

claim 11

, wherein the pH is in the range of approximately 8.5 to 11.5.

13. The method of

claim 9

, wherein the aqueous formulation is selected from the group consisting of a cream, a gel, a lotion, and a paste.

14. The method of

claim 13

, wherein the formulation is a cream.

15. The method of

claim 13

, wherein the formulation is a gel.

16. The method of

claim 8

, wherein the formulation is nonaqueous.

17. The method of

claim 16

, wherein the formulation is an ointment.

18. The method of

claim 1

, wherein the hydroxide-releasing agent is administered to the localized region of the body surface prior to administration of the drug, wherein the hydroxide-releasing agent is in a solution comprised of a protic solvent having a pH in the range of approximately 8.0 to 13.

19. The method of

claim 1

, wherein the hydroxide-releasing agent releases free hydroxide ions in the presence of an aqueous fluid.

20. The method of

claim 1

, wherein the hydroxide-releasing agent is selected from the group consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids, and mixtures thereof.

21. The method of

claim 8

, wherein the hydroxide-releasing agent is selected from the group consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids, and mixtures thereof.

22. The method of

claim 20

, wherein the hydroxide-releasing agent is an inorganic hydroxide.

23. The method of

claim 22

, wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures thereof.

24. The method of

claim 23

, wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide, and mixtures thereof.

25. The method of

claim 24

, wherein the inorganic hydroxide is sodium hydroxide.

26. The method of

claim 24

, wherein the inorganic hydroxide is potassium hydroxide.

27. The method of

claim 20

, wherein the hydroxide-releasing agent is an inorganic oxide.

28. The method of

claim 27

, wherein the inorganic oxide is selected from the group consisting of magnesium oxide, calcium oxide and mixtures thereof.

29. The method of

claim 20

, wherein the hydroxide-releasing agent is a metal salt of a weak acid.

30. The method of

claim 29

, wherein the hydroxide-releasing agent is selected from the group consisting of sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, tribasic sodium phosphate, dibasic sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, dibasic potassium phosphate, tribasic potassium phosphate, dibasic ammonium phosphate, and mixtures thereof.

31. The method of

claim 22

, wherein the amount of inorganic hydroxide in the formulation is the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 0.25 wt. % to 7.0 wt. % of the formulation.

32. The method of

claim 31

, wherein the amount of inorganic hydroxide in the formulation is the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 0.5 wt. % to 4.0 wt. % of the formulation.

33. The method of

claim 32

, wherein the amount of inorganic hydroxide in the formulation is the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 0.75 wt. % to 2.0 wt. % of the formulation.

34. The method of

claim 33

, wherein the amount of inorganic hydroxide in the formulation is the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 1.0 wt. % of the formulation.

35. The method of

claim 27

, wherein the formulation contains up to approximately 25 wt. % of the hydroxide-releasing agent.

36. The method of

claim 35

, wherein the formulation contains up to approximately 20 wt. % of the hydroxide-releasing agent.

37. The method of

claim 1

, wherein the peptidyl drug and hydroxide-releasing agent are administered by applying a drug delivery device to the localized region of the patient'"'"'s body surface thereby forming a body surface-delivery device interface, the device comprising the peptidyl drug and the hydroxide-releasing agent, and having an outer backing layer that serves as the outer surface of the device during use.

38. The method of

claim 37

, wherein the peptidyl drug and hydroxide-releasing agent are present in an adhesive, gel or liquid formulation contained within the device.

39. The method of

claim 37

, wherein the outer backing layer is occlusive.

40. The method of

claim 37

, wherein the pH at the interface is in the range of approximately 8.0 to 13.

41. The method of

claim 40

, wherein the pH at the interface is in the range of approximately 8.0 to 11.5.

42. The method of

claim 41

, wherein the pH at the interface is in the range of approximately 8.5 to 11.5.

43. The method of

claim 1

, wherein the peptidyl drug is administered in combination with an additional permeation enhancer.

44. The method of

claim 1

, wherein the peptidyl drug is administered in combination with an additional permeation enhancer.

45. The method of

claim 1

, wherein the peptidyl drug is systemically acting and administration is transdermal.

46. The method of

claim 1

, wherein the peptidyl drug and hydroxide-releasing agent are administered without any additional permeation enhancer.

47. The method of

claim 1

, wherein the peptidyl drug is a peptide.

48. The method of

claim 1

, wherein the peptidyl drug is a polypeptide.

49. The method of

claim 1

, wherein the peptidyl drug is a protein.

50. The method of

claim 1

, wherein the peptidyl drug is selected from the group consisting of coagulation modulators, cytokines, endorphins, kinins, peptidyl hormones, LHRH analogs and combinations thereof.

51. The method of

claim 50

, wherein the peptidyl drug is a coagulation modulator.

52. The method of

claim 51

, wherein the peptidyl drug is selected from the group consisting of α

₁-antitrypsin, α

₂-macroglobulin, antithrombin III, factor I, factor II, factor III, factor V, factor VII, factor VIII, factor IX, factor X, factor XI, factor XII, heparin cofactor II, kallikrein, plasmin, plasminogen, prekallikrein, protein C, protein S, thrombomodulin and combinations thereof.

53. The method of

claim 50

, wherein the peptidyl drug is a cytokine.

54. The method of

claim 53

, wherein the peptidyl drug is selected from the group consisting of colony stimulating factor 4, heparin binding neurotrophic factor, interferon-α

, interferon α

-2a, interferon α

-2b, interferon α

-n3, interferon-β

, interferon-γ

, interleukin-1, interleukin-2, interleukin-3, interleukin-4, interleukin-5, interleukin-6, interleukin-7, interleukin-8, interleukin-9, interleukin-10, interleukin- 11, interleukin-12, interleukin-13, interleukin-14, interleukin-15, interleukin-16, interleukin-17, tumor necrosis factor, tumor necrosis factor-α

, granuloycte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, midkine, thymopoietin and combinations thereof.

55. The method of

claim 50

, wherein the peptidyl drug is an endorphin.

56. The method of

claim 55

, wherein the peptidyl drug is selected from the group consisting of dermorphin, dynorphin, α

-endorphin, β

-endorphin, γ

-endorphin, σ

-endorphin [Leu⁵]enkephalin, [Met⁵]enkephalin, substance P, and combinations thereof.

57. The method of

claim 50

, wherein the peptidyl drug is a kinin.

58. The method of

claim 57

, wherein the peptidyl drug is selected from the group consisting of bradykinin, potentiator B, bradykinin potentiator C, kallidin and combinations thereof.

59. The method of

claim 50

, wherein the peptidyl drug is a peptidyl hormone.

60. The method of

claim 59

, wherein the peptidyl drug is selected from the group consisting of activin, amylin, angiotensin, atrial natriuretic peptide, calcitonin, calcitonin gene-related peptide, calcitonin N-terminal flanking peptide, cholecystokinin, ciliary neurotrophic factor, corticotropin, corticotropin-releasing factor, epidermal growth factor, follicle-stimulating hormone, gastrin, gastrin inhibitory peptide, gastrin-releasing peptide, ghrelin, glucogon, gonadotropin-releasing factor, growth hormone releasing factor, human chorionic gonadotropin, inhibin A, inhibin B, insulin, leptin, lipotropin, luteinizing hormone, luteinizing hormone-releasing hormone, α

-melanocyte-stimulating hormone, β

-melanocyte-stimulating hormone, γ

-melanocyte-stimulating hormone, melatonin, motilin, oxytocin, pancreatic polypeptide, parathyroid hormone, placental lactogen, prolactin, prolactin-release inhibiting factor, prolactin-releasing factor, secretin, somatotropin, somatostatin, thyrotropin, thyrotropin-releasing factor, thyroxine, triiodothyronine, vasoactive intestinal peptide, vasopressin and combinations thereof.

61. The method of

claim 60

, wherein the peptidyl drug is oxytocin.

62. The method of

claim 50

, wherein the peptidyl drug is an LHRH analog.

63. The method of

claim 62

, wherein the peptidyl drug is selected from the group consisting of buserelin, deslorelin, fertirelin, goserelin, histrelin, leuprolide, lutrelin, nafarelin, tryptorelin and combinations thereof.

64. The method of

claim 63

, wherein the peptidyl drug is leuprolide.

65. The method of

claim 1

, wherein the peptidyl drug is selected from the group consisting of abarelix, adenosine deaminase, anakinra, ancestim, alteplase, alglucerase, asparaginase, bivalirudin, bleomycin, bombesin, desmopressin acetate, des-Q14-ghrelin, dornase-α

, enterostatin, erythropoeitin, exendin-4, fibroblast growth factor-2, filgrastim, β

-glucocerebrosidase, gonadorelin, hyaluronidase, insulinotropin, lepirudin, magainin I, magainin II, nerve growth factor, pentigetide, thrombopoietin, thymosin α

-1, thymidin kinase, tissue plasminogen activator, tryptophan hydroxylase, urokinase, urotensin II and combinations thereof.

66. A composition of matter useful for the delivery of a peptidyl drug through a body surface, comprising an aqueous formulation of:

(a) a therapeutically effective amount of a peptidyl drug;

(b) a hydroxide-releasing agent in an amount effective to enhance the flux of the peptidyl drug through the body surface without causing damage thereto; and

(c) a pharmaceutically acceptable carrier suitable for topical or transdermal peptidyl drug administration.

67. The composition of

claim 66

, having a pH in the range of approximately 8.0 to 13.

68. The composition of

claim 67

, having a pH in the range of approximately 8.0 to 11.5.

69. The composition of

claim 68

, having a pH in the range of approximately 8.5 to 11.5.

70. The composition of

claim 66

, wherein the carrier is aqueous.

71. The composition of

claim 70

, comprising a cream, a gel, a lotion, or paste.

72. The composition of

claim 71

, comprising a cream.

73. The composition of

claim 71

, comprising a gel.

74. The composition of

claim 66

, wherein the carrier is nonaqueous.

75. The composition of

claim 74

, comprising an ointment.

76. The composition of

claim 66

, wherein the composition is substantially free of additional permeation enhancers.

77. The composition of

claim 66

, wherein the composition is substantially free of organic solvents.

78. The composition of

claim 76

, wherein the composition is substantially free of organic solvents.

79. The composition of

claim 66

, wherein the hydroxide-releasing agent is selected from the group consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids, and mixtures thereof.

80. The composition of

claim 79

, wherein the hydroxide-releasing agent is an inorganic hydroxide.

81. The composition of

claim 80

, wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures thereof.

82. The composition of

claim 81

, wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide, and mixtures thereof.

83. The composition of

claim 82

, wherein the inorganic hydroxide is sodium hydroxide.

84. The composition of

claim 82

, wherein the inorganic hydroxide is potassium hydroxide.

85. The composition of

claim 79

, wherein the hydroxide-releasing agent is an inorganic oxide.

86. The composition of

claim 85

, wherein the inorganic oxide is selected from the group consisting of magnesium oxide, calcium oxide and mixtures thereof.

87. The composition of

claim 79

, wherein the hydroxide-releasing agent is a metal salt of a weak acid.

88. The composition of

claim 87

, wherein the hydroxide-releasing agent is selected from the group consisting of sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, tribasic sodium phosphate, dibasic sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, dibasic potassium phosphate, tribasic potassium phosphate, dibasic ammonium phosphate, and mixtures thereof.

89. The composition of

claim 80

, wherein the amount of inorganic hydroxide in the formulation is the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 0.25 wt. % to 7.0 wt. % of the formulation.

90. The composition of

claim 89

, wherein the amount of inorganic hydroxide in the formulation is the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 0.5 wt. % to 4.0 wt. % of the formulation.

91. The composition of

claim 90

, wherein the amount of inorganic hydroxide in the formulation is the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 0.75 wt. % to 2.0 wt. % of the formulation.

92. The composition of

claim 91

, wherein the amount of inorganic hydroxide in the formulation is the total of (a) the amount required to neutralize any acidic species in the formulation plus (b) an amount equal to approximately 1.0 wt. % of the formulation.

93. The composition of

claim 66

, wherein the peptidyl drug is a peptide.

94. The composition of

claim 66

, wherein the peptidyl drug is a polypeptide.

95. The composition of

claim 66

, wherein the peptidyl drug is a protein.

96. The composition of

claim 66

, wherein the peptidyl drug is selected from thegroup consisting of coagulation modulators, cytokines, endorphins, kinins, peptidylhormones, LHRH analogs and combinations thereof.

97. The composition of

claim 96

, wherein the peptidyl drug is a coagulation modulator.

98. The composition of

claim 97

, wherein the peptidyl drug is selected from the group consisting of α

₁-antitrypsin, α

₂-macroglobulin, antithrombin III, factor I, factor II, factor III, factor V, factor VII, factor VIII, factor IX, factor X, factor XI, factor XII, heparin cofactor II, kallikrein, plasmin, plasminogen, prekallikrein, protein C, protein S, thrombomodulin and combinations thereof.

99. The composition of

claim 96

, wherein the peptidyl drug is a cytokine.

100. The composition of

claim 99

, wherein the peptidyl drug is selected from the group consisting of colony stimulating factor 4, heparin binding neurotrophic factor, interferon-α

, interferon α

-2a, interferon α

-2b, interferon α

-n3, interferon-β

, interferon-γ

, interleukin-1, interleukin-2, interleukin-3, interleukin-4, interleukin-5, interleukin-6, interleukin-7, interleukin-8, interleukin-9, interleukin-10, interleukin- 11, interleukin-12, interleukin-13, interleukin-14, interleukin-15, interleukin-16, interleukin-17, tumor necrosis factor, tumor necrosis factor-α

, granuloycte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, midkine, thymopoietin and combinations thereof.

101. The composition of

claim 96

, wherein the peptidyl drug is an endorphin.

102. The composition of

claim 101

, wherein the peptidyl drug is selected from the group consisting of dermorphin, dynorphin, α

-endorphin, β

-endorphin, γ

-endorphin, σ

-endorphin [Leu⁵]enkephalin, [Met⁵]enkephalin, substance P, and combinations thereof.

103. The composition of

claim 96

, wherein the peptidyl drug is a kinin.

104. The composition of

claim 103

, wherein the peptidyl drug is selected from the group consisting of bradykinin, potentiator B, bradykinin potentiator C, kallidin and combinations thereof.

105. The composition of

claim 96

, wherein the peptidyl drug is a peptidyl hormone.

106. The composition of

claim 105

, wherein the peptidyl drug is selected from the group consisting of activin, amylin, angiotensin, atrial natriuretic peptide, calcitonin, calcitonin gene-related peptide, calcitonin N-terminal flanking peptide, cholecystokinin, ciliary neurotrophic factor, corticotropin, corticotropin-releasing factor, epidermal growth factor, follicle-stimulating hormone, gastrin, gastrin inhibitory peptide, gastrin-releasing peptide, ghrelin, glucogon, gonadotropin-releasing factor, growth hormone releasing factor, human chorionic gonadotropin, inhibin A, inhibin B, insulin, leptin, lipotropin, luteinizing hormone, luteinizing hormone-releasing hormone, α

-melanocyte-stimulating hormone, β

-melanocyte-stimulating hormone, γ

-melanocyte-stimulating hormone, melatonin, motilin, oxytocin, pancreatic polypeptide, parathyroid hormone, placental lactogen, prolactin, prolactin-release inhibiting factor, prolactin-releasing factor, secretin, somatotropin, somatostatin, thyrotropin, thyrotropin-releasing factor, thyroxine, triiodothyronine, vasoactive intestinal peptide, vasopressin and combinations thereof.

107. The composition of

claim 106

, wherein the peptidyl drug is oxytocin.

108. The composition of

claim 96

, wherein the peptidyl drug is an LHRH analog.

109. The composition of

claim 108

, wherein the peptidyl drug is selected from the group consisting of buserelin, deslorelin, fertirelin, goserelin, histrelin, leuprolide, lutrelin, nafarelin, tryptorelin and combinations thereof.

110. The composition of

claim 109

, wherein the drug is leuprolide.

111. The composition of

claim 66

, wherein the peptidyl drug is selected from the group consisting of abarelix, adenosine deaminase, anakinra, ancestim, alteplase, alglucerase, asparaginase, bivalirudin, bleomycin, bombesin, desmopressin acetate, des-Q14-ghrelin, dornase-α

, enterostatin, erythropoeitin, exendin-4, fibroblast growth factor-2, filgrastim, β

-glucocerebrosidase, gonadorelin, hyaluronidase, insulinotropin, lepirudin, magainin I, magainin II, nerve growth factor, pentigetide, thrombopoietin, thymosin α

-1, thymidin kinase, tissue plasminogen activator, tryptophan hydroxylase, urokinase, urotensin II and combinations thereof.

112. A system for the topical or transdermal administration of a peptidyl drug, comprising:

(a) at least one peptidyl drug reservoir containing the drug and a hydroxide-releasing agent in an amount effective to enhance the flux of the drug through the body surface without causing damage thereto;

(b) a means for maintaining the system in drug and enhancer transmitting relationship to the body surface; and

(c) a backing layer that serves as the outer surface of the device during use.

113. The system of

claim 112

, wherein the backing layer is occlusive.

114. The system of

claim 113

, wherein the drug reservoir is comprised of a polymeric adhesive.

115. The system of

claim 114

, wherein the polymeric adhesive serves as the means for maintaining the system in drug and enhancer transmitting relationship to the body service.

116. The system of

claim 112

, wherein the drug reservoir is comprised of a hydrogel.

117. The system of

claim 112

, wherein the drug reservoir is comprised of a sealed pouch containing the drug and hydroxide-releasing agent in a liquid or semi-solid formulation.

118. A method for treating an individual with a peptidyl drug-responsive condition or disease comprising the administration of the peptidyl drug to a localized region of individual'"'"'s body surface in combination with a hydroxide-releasing agent applied to the body surface in a predetermined amount effective to enhance the flux of the peptidyl drug through the predetermined area of the body surface without causing damage thereto.