Method for transdermal iontophoretic delivery of chelated agents

• US 20100272827A1
• Filed: 07/07/2009
• Published: 10/28/2010
• Est. Priority Date: 04/25/2009
• Status: Active Grant

• Current Assignee: FE3 Medical Incorporated
• Original Assignee: FE3 Medical Incorporated
• Inventors: Patel, Sanjay, Berenson, Ronald J., Imran, Mir, Hashim, Mir
• Granted Patent: US 8,821,945 B2
• Time in Patent Office: Days
• US Class Current: 424/604
• CPC Class Codes: A61K 33/26 Iron; Compounds thereof
• CPC Class Codes: A61K 33/42 Phosphorus; Compounds thereof
• CPC Class Codes: A61K 41/00 Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
• CPC Class Codes: A61K 41/0047 Sonopheresis, i.e. ultrasonically-enhanced transdermal delivery, electroporation of a pharmacologically active agent
• CPC Class Codes: A61K 9/0009 involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis microelectromechanical systems A61K9/0097
• CPC Class Codes: A61K 9/703 characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
• CPC Class Codes: A61K 9/7084 Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
• CPC Class Codes: A61N 1/0496 characterised by using specific chemical compositions, e.g. hydrogel compositions, adhesives
• CPC Class Codes: A61N 1/30 Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
• CPC Class Codes: A61N 1/325 for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body electrodes for external use A61N1/0428
• CPC Class Codes: A61P 7/06 Antianaemics

Abstract

Embodiments provide devices, systems and methods for the transdermal delivery of chelated compounds. One embodiment provides a method for the iontophoretic transdermal delivery of a chelated iron complex for the treatment of anemia. A first patch comprising an active electrode and a chelated iron complex is applied to the skin; a second patch containing an electrode is also applied. An electrical current is then delivered to the skin from the active electrode. The chelated complex is transported across the skin via electromotive force from the current, with the iron being substantially chromogenically unreactive with the skin during transport so that there is little or no tattooing of the skin due to the formation of insoluble oxidative products. The complex is then dissociated by phagocytosis or related process to release the iron where it may be bound by transferrin or ferritin and carried to other sites for storage or metabolic use.

Claims

1. A method for the iontophoretic transdermal delivery of a chelated complex comprising a therapeutic agent, the method comprising:

applying a patch to the skin, the patch comprising an electrode and a chelated complex, the chelated complex comprising a therapeutic agent electrostatically bound to a chelating agent;

delivering an electrical current to the skin using the electrode;

utilizing the current to transport the chelated complex across the skin, wherein the therapeutic agent is substantially chromogenically unreactive with the skin during transport; and

dissociating the complex in tissue to release the therapeutic agent.

2. The method of claim 1, wherein the dissociation occurs intracellularly.

3. The method of claim 2, wherein the dissociation occurs in a cell cytoplasm.

4. The method of claim 1, wherein the complex is transported without producing substantial injury or irritation to the skin.

5. The method of claim 4, wherein the injury or irritation is erythema.

6. The method of claim 1, wherein the complex is transported without producing a substantial cosmetic change to the skin.

7. The method of claim 6, wherein the cosmetic change is a tattoo.

8. The method of claim 1, wherein the therapeutic agent is available for metabolic use upon dissociation.

9. The method of claim 1, wherein the therapeutic complex is delivered to a sub-dermal tissue layer.

10. The method of claim 1, wherein the therapeutic complex comprises iron.

11. The method of claim 10, wherein the transported therapeutic complex comprises a therapeutically effective amount of iron for the treatment of iron deficiency.

12. The method of claim 10, wherein the therapeutic complex comprises ferric pyrophosphate.

13. The method of claim 10, wherein the therapeutic complex comprises edetate, ethylenediamineedetate or ethylenediaminesuccinate

14. The method of claim 10, wherein the dissociation of the complex releases iron available for binding with ferritin or transferrin.

15. The method of claim 10, wherein the therapeutic complex is transported without substantial precipitation of iron in the skin.

16. The method of claim 10, wherein the complex is transported without a substantial increase in the electrical impedance in the skin from precipitation of iron in the skin.

17. The method of claim 10, wherein the complex is transported without a substantial temperature increase in the skin from ohmic heating from precipitation of iron in the skin.

18. The method of claim 10, wherein up to about 10 mg of elemental iron is transported across the skin.

19. The method of claim 10, wherein up to about 20 mg of elemental iron is transported across the skin.

20. The method of claim 10, wherein up to about 30 mg of elemental iron is transported across the skin.

21. The method of claim 10, wherein the dissociation of the iron occurs intracellularly.

22. The method of claim 1, wherein the chelating agent has a negative charge and therapeutic agent has a positive charge.

23. The method of claim 1, wherein the current comprises an alternating current.

24. The method of claim 1, wherein the current has a waveform having a square wave, sine wave, saw tooth or trapezoidal shape.

25. The method of claim 1, wherein the current comprises an alternating current component and a direct current component.

26. The method of claim 25, wherein the alternating current component is configured to break down capacitive charge build up in the skin.

27. The method of claim 25, wherein the alternating current component is configured to oscillate the chelated complex during transport through the skin.

28. The method of claim 1, wherein the current is modulated.

29. The method of claim 28, wherein the current is modulated in frequency.

30. The method of claim 28, wherein the current is modulated by a controller.

31. The method of claim 28, wherein the current is modulated to minimize pain perception.

32. The method of claim 28, wherein the current is modulated to minimize thermal injury to the skin.

33. The method of claim 28, wherein the current is modulated to reduce discoloration of the skin.

34. The method of claim 28, wherein the current is modulated to enhance transport of the chelated complex across the skin.

35. The method of claim 28, wherein the current is modulated to titrate delivery of the chelated complex across the skin.

36. A method for treating iron deficiency, the method comprising:

applying a patch to the skin, the patch comprising an electrode and a chelated iron complex, the chelated complex comprising iron electrostatically bound to a chelating agent;

delivering an electrical current to the skin using the electrode; and

utilizing the current to transport a therapeutically effective amount of the chelated iron complex across the skin, wherein the complex is transported across the skin without substantial precipitation of iron in the skin; and

dissociating the complex in tissue to release the iron.

37. The method of claim 36, wherein the iron complex comprises ferric pyrophosphate.

38. The method of claim 36, wherein the complex is transported without a substantial increase in the electrical impedance in the skin from precipitation of iron in the skin.

39. The method of claim 36, wherein the complex is transported without a substantial temperature increase in the skin from ohmic heating from precipitation of iron in the skin.

40. A method for treating iron deficiency, the method comprising:

applying a patch to the skin, the patch comprising an electrode and a chelated iron complex, the chelated complex comprising iron electrostatically bound to a chelating agent;

delivering an electrical current to the skin using the electrode; and

utilizing the current to transport a therapeutically effective amount of the chelated iron complex across the skin, wherein the iron is substantially chromogenically unreactive with the skin during transport; and

dissociating the complex in tissue to release the iron.

41. The method of claim 40, wherein the iron complex comprises ferric pyrophosphate.

42. The method of claim 40, wherein the dissociation of the complex releases iron available for heme synthesis.

43. The method of claim 40, further comprising:

enhancing one of an amount of heme synthesis or blood hemoglobin utilizing the released iron.

44. The method of claim 40, wherein up to about 10 mg of elemental iron is transported across the skin.

45. The method of claim 40, wherein up to about 20 mg of elemental iron is transported across the skin.

46. The method of claim 40, wherein up to about 30 mg of elemental iron is transported across the skin.

47. The method of claim 40, further comprising:

titrating the transport of the chelated iron complex in response to a biomarker of iron status.

48. The method of claim 47, wherein the biomarker of iron status is a serum concentration of iron, ferritin or a transferrin iron saturation.

49. The method of claim 47, wherein the transport rate or total amount of chelated iron complex transported is titrated.