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

• US 20030147943A1
• Filed: 01/22/2003
• Published: 08/07/2003
• Est. Priority Date: 12/16/1999
• Status: Abandoned Application

• Current Assignee: Eric C. Luo, Tsung-Min Hsu
• Original Assignee: Eric C. Luo, Tsung-Min Hsu
• Inventors: Luo, Eric C., Hsu, Tsung-Min
• Application Number:
  US10/349,582
• Publication Number:
  US 20030147943A1
• Time in Patent Office: Days
• US Class Current: 424/449
• 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 composition of matter useful for the delivery of a peptidyl drug through a body surface, comprising:

(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 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; and

wherein the amount of hydroxide-releasing agent in the composition is the total of (a) the amount required to neutralize any acidic species in the composition plus (b) an amount equal to approximately 0.25 wt. % to 25.0 wt. % of the composition; and

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

2. The composition of claim 1, wherein the composition has a pH in the range of approximately 8.0 to 13.

3. The composition of claim 2, wherein the composition has a pH in the range of approximately 8.0 to 11.5.

4. The composition of claim 3, wherein the composition has a pH in the range of approximately 8.5 to 11.5.

5. The composition of claim 1, wherein the carrier is aqueous.

6. The composition of claim 5, comprising a cream, a gel, a lotion, or paste.

7. The composition of claim 6, comprising a cream.

8. The composition of claim 6, comprising a gel.

9. The composition of claim 1, wherein the carrier is nonaqueous.

10. The composition of claim 9, comprising an ointment.

11. The composition of claim 1, wherein the composition is substantially free of additional permeation enhancers.

12. The composition of claim 1, wherein the composition further comprises an additional permeation enhancer.

13. The composition of claim 1, wherein the composition is substantially free of organic solvents.

14. The composition 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.

15. The composition of claim 14, wherein the hydroxide-releasing agent is an inorganic hydroxide.

16. The composition of claim 15, wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures thereof

17. The composition of claim 16, wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide, and mixtures thereof.

18. The composition of claim 17, wherein the inorganic hydroxide is sodium hydroxide.

19. The composition of claim 17, wherein the inorganic hydroxide is potassium hydroxide.

20. The composition of claim 14, wherein the hydroxide-releasing agent is an inorganic oxide.

21. The composition of claim 20, wherein the inorganic oxide is selected from the group consisting of magnesium oxide, calcium oxide and mixtures thereof.

22. The composition of claim 14, wherein the hydroxide-releasing agent is a metal salt of a weak acid.

23. The composition of claim 22, 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.

24. The composition of claim 15, wherein the amount of inorganic hydroxide in the composition is the total of (a) the amount required to neutralize any acidic species in the composition plus (b) an amount equal to approximately 0.25 wt. % to 7.0 wt. % of the composition.

25. The composition of claim 24, wherein the amount of inorganic hydroxide in the composition is the total of (a) the amount required to neutralize any acidic species in the composition plus (b) an amount equal to approximately 0.5 wt. % to 4.0 wt. % of the composition.

26. The composition of claim 25, wherein the amount of inorganic hydroxide in the composition is the total of (a) the amount required to neutralize any acidic species in the composition plus (b) an amount equal to approximately 0.75 wt. % to 2.0 wt. % of the composition.

27. The composition of claim 26, wherein the amount of inorganic hydroxide in the composition is the total of (a) the amount required to neutralize any acidic species in the composition plus (b) an amount equal to approximately 1.0 wt. % of the composition.

28. The composition of claim 1, wherein the peptidyl drug is a peptide.

29. The composition of claim 1, wherein the peptidyl drug is a polypeptide.

30. The composition of claim 1, wherein the peptidyl drug is a protein.

31. The composition 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.

32. The composition of claim 31, wherein the peptidyl drug is a coagulation modulator.

33. The composition of claim 32, wherein the coagulation modulator is selected from the group consisting of α

₁-antitrypsin, a₂-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.

34. The composition of claim 31, wherein the peptidyl drug is a cytokine.

35. The composition of claim 34, wherein the cytokine 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.

36. The composition of claim 31, wherein the peptidyl drug is an endorphin.

37. The composition of claim 36, wherein the endorphin is selected from the group consisting of dermorphin, dynorphin, α

-endorphin, β

-endorphin, γ

-endorphin, α

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

38. The composition of claim 31, wherein the peptidyl drug is a kinin.

39. The composition of claim 38, wherein the kinin is selected from the group consisting of bradykinin, potentiator B, bradykinin potentiator C, kallidin and combinations thereof.

40. The composition of claim 31, wherein the peptidyl drug is a peptidyl hormone.

41. The composition of claim 40, wherein the peptidyl hormone 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.

42. The composition of claim 41, wherein the peptidyl hormone is oxytocin.

43. The composition of claim 31, wherein the peptidyl drug is an LHRH analog.

44. The composition of claim 43, wherein the LHRH analog is selected from the group consisting of buserelin, deslorelin, fertirelin, goserelin, histrelin, leuprolide, lutrelin, nafarelin, tryptorelin and combinations thereof.

45. The composition of claim 44, wherein the LHRH analog is leuprolide.

46. The composition 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.

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

(a) at least one drug reservoir containing the peptidyl 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 and 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; and

wherein the amount of hydroxide-releasing agent in the reservoir is the total of (a) the amount required to neutralize any acidic species in the reservoir plus (b) an amount equal to approximately 0.25 wt. % to 25.0 wt. % of the reservoir;

(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.

48. The system of claim 47, wherein the backing layer is occlusive.

49. The system of claim 48, wherein the drug reservoir is comprised of a polymeric adhesive.

50. The system of claim 49, wherein the polymeric adhesive serves as the means for maintaining the system in drug and enhancer transmitting relationship to the body service.

51. The system of claim 47, wherein the drug reservoir is comprised of a hydrogel.

52. The system of claim 47, wherein the drug reservoir is comprised of a sealed pouch containing the drug and hydroxide-releasing agent in a liquid or semi-solid formulation.

53. The system of claim 47, wherein the hydroxide-releasing agent is selected from the group consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids, and mixtures thereof.

54. The system of claim 53, wherein the hydroxide-releasing agent is an inorganic hydroxide selected from the group consisting of ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, and mixtures thereof.

55. The system of claim 54, wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, sodium hydroxide, calcium hydroxide, potassium hydroxide, magnesium hydroxide, and mixtures thereof.

56. The system of claim 53, wherein the hydroxide-releasing agent is an inorganic oxide selected from the group consisting of magnesium oxide, calcium oxide and mixtures thereof.

57. The system of claim 53, wherein the hydroxide-releasing agent is a metal salt of a weak acid 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.

58. The system of claim 47, wherein the peptidyl drug is a peptide.

59. The system of claim 47, wherein the peptidyl drug is a polypeptide.

60. The system of claim 47, wherein the peptidyl drug is a protein.

61. The system of claim 47, wherein the peptidyl drug is selected from the group consisting of coagulation modulators, cytokines, endorphins, kinins, peptidyl hormones, LHRH analogs and combinations thereof.

62. The system of claim 61, wherein the peptidyl drug is a coagulation modulator selected from the group consisting of α

₁-antitrypsin, a₂-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.

63. The system of claim 61, wherein the peptidyl drug is a cytokine 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-1 0, interleukin-1 1, interleukin-1 2, 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.

64. The system of claim 61, wherein the peptidyl drug is an endorphin 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.

65. The system of claim 61, wherein the peptidyl drug is a kinin selected from the group consisting of bradykinin, potentiator B, bradykinin potentiator C, kallidin and combinations thereof.

66. The system of claim 61, wherein the peptidyl drug is a peptidyl hormone 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.

67. The system of claim 61, wherein the peptidyl drug is an LHRH analog selected from the group consisting of buserelin, deslorelin, fertirelin, goserelin, histrelin, leuprolide, lutrelin, nafarelin, tryptorelin and combinations thereof.

68. The system of claim 47, 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, domase-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

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