Method for transdermal iontophoretic delivery of chelated agents

• US 9,402,904 B2
• Filed: 08/29/2014
• Issued: 08/02/2016
• Est. Priority Date: 04/25/2009
• Status: Active Grant

• Current Assignee: FE3 Medical Incorporated
• Original Assignee: FE3 Medical Incorporated
• Inventors: Imran, Mir, Hashim, Mir, Patel, Sanjay, Berenson, Ronald J.
• Primary Examiner(s): Parad, Dennis J
• Application Number:
  US14/474,027
• Publication Number:
  US 20150045721A1
• Time in Patent Office: 704 Days
• Field of Search: 424/646, 424/604, 604/20
• US Class Current: 1/1
• 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 iron complex, the method comprising:

applying an iontophoretic transdermal delivery device to the skin of a subject, the device comprising an electrode and iron comprising a chelated iron complex comprising ferric pyrophosphate;

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

thus transporting the chelated iron complex across the skin, wherein the complex is transported across the skin without precipitation of iron in the skin, thereby reducing chromogenic reactions with the skin relative to the transport of non-chelated iron.

2. The method of claim 1, wherein the iontophoretic transdermal delivery device comprises a patch.

3. The method of claim 1, wherein the complex releases iron available for heme synthesis.

4. The method of claim 1, wherein the complex is transported without producing 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 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 iron complex is dissociated by phagocytosis.

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

10. The method of claim 1, wherein the iontophoretic transdermal delivery device comprises a therapeutically effective amount of iron for the treatment of iron deficiency.

11. The method of claim 1, wherein the complex is transported without an increase in the electrical impedance in the skin from precipitation of iron in the skin.

12. The method of claim 1, wherein the complex is transported without a temperature increase in the skin from ohmic heating resulting from precipitation of iron in the skin.

13. The method of claim 1, wherein up to about 10 mg of elemental iron is transported across the skin.

14. The method of claim 1, wherein up to about 20 mg of elemental iron is transported across the skin.

15. The method of claim 1, wherein up to about 30 mg of elemental iron is transported across the skin.

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

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

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

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

20. The method of claim 19, wherein the current is modulated in frequency.

21. The method of claim 19, wherein the current is modulated by a controller.

22. The method of claim 19, wherein the current is modulated to minimize pain perception.

23. The method of claim 19, wherein the current is modulated to minimize thermal injury to the skin.

24. The method of claim 19, wherein the current is modulated to reduce discoloration of the skin.

25. The method of claim 19, wherein the current is modulated to enhance transport of the chelated iron complex across the skin.

26. The method of claim 19, wherein the current is modulated to titrate delivery of the chelated iron complex across the skin.

27. A method for treating iron deficiency in a patient, the method comprising:

applying an iontophoretic transdermal delivery device to the skin of the patient, the device comprising an electrode and iron comprising a chelated iron complex comprising ferric pyrophosphate;

delivering an electrical current to the skin using the electrode;

thus transporting a therapeutically effective amount of the chelated iron complex across the skin, wherein the complex is transported across the skin without precipitation of iron in the skin, thereby reducing chromogenic reactions with the skin relative to the transport of non-chelated iron; and

dissociating the complex in tissue to release the iron, thus treating the iron deficiency.

28. The method of claim 27, wherein the complex is transported without an increase in the electrical impedance in the skin from precipitation of iron in the skin.

29. The method of claim 27, wherein the complex is transported without a temperature increase in the skin from ohmic heating from precipitation of iron in the skin.

30. A method for treating iron deficiency in a patient, the method comprising:

applying an iontophoretic transdermal delivery device to the skin of the patient, the device comprising an electrode and iron comprising a chelated iron complex comprising ferric pyrophosphate;

delivering an electrical current to the skin using the electrode;

thus transporting a therapeutically effective amount of the chelated iron complex across the skin, wherein the iron is sufficiently electrostatically bound by the chelating agent so that the iron is not available to form insoluble salts within the skin during transport, thereby reducing chromogenic reactions with the skin relative to the transport of non-chelated iron; and

dissociating the complex in tissue to release the iron, thus treating the iron deficiency.

31. The method of claim 30, wherein the dissociation of the complex releases iron available for heme synthesis.

32. The method of claim 30, further comprising:

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

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

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

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

36. The method of claim 30, further comprising:

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

37. The method of claim 36, wherein the biomarker of iron status is a serum concentration of iron, ferritin or a transferrin iron saturation.

38. The method of claim 36, wherein the transport rate or total amount of chelated iron complex transported is titrated.