Methods and apparatus for improved administration of testosterone pharmaceuticals

• US 6,726,673 B1
• Filed: 05/24/1999
• Issued: 04/27/2004
• Est. Priority Date: 05/24/1999
• Status: Expired due to Fees

• Current Assignee: Nuvo Research AG (Searchlight Pharma, Inc.)
• Original Assignee: Zars, Inc.
• Inventors: Zhang, Hao, Zhang, Jie, Rigby, Larry, Hull, Wade A.
• Primary Examiner(s): Casler, Brian L.
• Assistant Examiner(s): WILLIAMS, CATHERINE SERKE
• Application Number:
  US09/317,313
• Time in Patent Office: 1,800 Days
• Field of Search: 604/20, 604/46, 604/47, 604/48, 604/500, 604/501, 604/289, 604/290, 604/291, 604/304, 604/307, 604/113, 606/27-31, 424/443, 424/444, 424/447, 424/448, 424/449
• US Class Current: 604/500
• CPC Class Codes: A61F 7/032 using oxygen from the air, e.g. pocket-stoves
• 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 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• 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
• CPC Class Codes: A61M 2037/0007 having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
• CPC Class Codes: A61M 31/002 Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time artificial gland structures or devices A61F2/022; intra-uterine contraceptive devices A61F6/14; tampons for introducing into the vagina A61F13/20, A61L15/00; suppositories or bougies for intra-vaginal or intra-uterine application A61K9/02; physical forms of medicinal preparations for sustained or differential drug release A61K9/20, A61K9/50
• 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

Abstract

The present invention relates to a method and apparatus for increasing the delivery rate of an androgen transdermal therapeutic system through the skin. An androgen transdermal therapeutic system can be applied to a patient'"'"'s skin for delivery of the androgen. A temperature modification apparatus which is capable of generating controlled heat is applied approximate to the androgen transdermal therapeutic system. The heating from the temperature modification apparatus raises the temperature of the androgen transdermal therapeutic system and raises the temperature of the patient'"'"'s skin to achieve an increased rate of delivery of androgen through the skin. The controlled heat can also be used to adjust dosage rates of the androgen transdermal therapeutic system and to mimic natural circadian patterns. The controlled heating may also be used to improve or regulate the release of androgen from injected/implanted extended/controlled release systems.

Claims

1. A method of increasing the delivery rate of an androgen transdermal therapeutic system through skin to correspond to a natural circadian pattern, the method comprising:

applying an androgen transdermal therapeutic system to the skin for delivery of androgen;

applying an apparatus capable of generating heat proximate the androgen transdermal therapeutic systems and configured to create heat in a manner that mimics the endogenous circadian androgen production; and

heating the androgen transdermal therapeutic system with the apparatus capable of generating heat at a safe, pre-designed temperature for a safe, pre-designed length of time to achieve an increased rate of delivery of androgen through the skin to simulate to a natural circadian pattern.

2. The method of claim 1, wherein the step of applying the apparatus capable of generating heat proximate to the androgen transdermal therapeutic system comprises applying a temperature modification apparatus to the androgen transdermal therapeutic systems.

3. The method of claim 1, wherein the step of heating the androgen transdermal therapeutic system includes heating said skin to a temperature of between about 38 and 45°

C.

4. The method of claim 1, wherein the step of heating the androgen transdermal therapeutic system includes heating said skin to a temperature of between about 39 and 43°

C.

5. The method of claim 1, wherein the step of heating the androgen transdermal therapeutic system includes heating said skin up to a temperature of about 50°

C.

6. The method of claim 1, wherein the step of heating the androgen transdermal therapeutic system effectuates an increase in the rate of androgen delivery to the human body through increasing skin permeability.

7. The method of claim 1, wherein the step of heating the androgen transdermal therapeutic system effectuates an increase in the rate of androgen delivery through increasing the permeability of blood vessel walls in the skin and subskin tissues.

8. The method of claim 1, wherein the step of heating the androgen transdermal therapeutic system effectuates an increase in the rate of androgen delivery to the human body through increasing circulation of body fluid in the skin and subskin tissues proximate the androgen transdermal therapeutic systems.

9. The method of claim 1, further including the step of reducing heating of the skin under the androgen transdermal therapeutic system with the temperature modification apparatus after a desired concentration of target androgen in the human body is achieved after a predetermined period of time.

10. The method of claim 1, further including the step of removing the temperature modification apparatus when a desired concentration of target androgen in the human body is achieved.

11. The method of claim 1, wherein the delivery system androgen is testosterone.

12. The method of claim 1, wherein the delivery system androgen is a testosterone derivative.

13. The method of claim 1, wherein the temperature modification apparatus comprises a chamber containing a medium capable of generating heat when exposed to oxygen.

14. The method of claim 1, wherein the temperature modification apparatus comprises a chamber containing reactants capable of undergoing exothermic oxidation when exposed to oxygen.

15. The method of claim 13, wherein the medium capable of generating heat when exposed to oxygen comprises iron powder and activated carbon.

16. The method of claim 13, wherein the chamber is comprised of parts being substantially impermeable to oxygen and a structure which allows a predetermined flow rate of ambient oxygen into said medium capable of generating heat inside said chamber.

17. The method of claim 16, wherein said structure comprises a cover substantially impermeable to oxygen, said cover having holes, the holes being covered by a membrane with selected oxygen permeability.

18. The method of claim 1, wherein the increased rate of delivery of the delivery system androgen through the skin is sufficient to provide a desired increased concentration of the target androgen in the systemic circulation.

19. The method of claim 1, wherein the increased rate of delivery of androgen through the skin is used to facilitate the establishment of target androgen concentration vs. time relationship that mimics the natural human circadian pattern.

20. The method of claim 19, including the step of discontinuing the heating when the desired concentration of androgen in the systemic circulation in the body is achieved.

21. The method of claim 20, the step of heating the androgen transdermal therapeutic system continues for a predetermined time, the predetermined time of heating being a time sufficient to obtain desired increased concentration levels of androgen within a patient'"'"'s systemic circulation.

22. The method of claim 20, wherein the predetermined time is between one and five hours following the initiation of the heating step.

23. A method of reducing the time it takes to achieve a desired, increased concentration of a target androgen in a systemic circulation of a human body comprising:

applying an androgen transdermal therapeutic system to the skin of the human body for delivery of therapeutic androgen to the systemic circulation of the human body;

applying a temperature control apparatus capable of generating heat proximate the androgen transdermal therapeutic system and configured to create heat in a manner that mimics the endogenous circadian androgen production; and

heating the skin under the androgen transdermal therapeutic systems with the temperature control apparatus to reduce the time it takes to achieve a desired increased concentration of the target androgen in the systemic circulation of the human body.

24. The method of claim 23, wherein the step of applying the temperature control apparatus capable of generating heat proximate the androgen transdermal therapeutic system further comprises applying the temperature control apparatus directly to the androgen transdermal therapeutic systems.

25. The method of claim 23, wherein the step of heating the androgen transdermal therapeutic system includes heating the skin to a temperature of between about 38 and 45°

C.

26. The method of claim 23, wherein the step of heating the skin under the androgen transdermal therapeutic system includes heating the skin to a temperature of between about 39 and 43°

C.

27. The method of claim 23, wherein the step of heating the skin under the androgen transdermal therapeutic system includes heating the skin up to a temperature of about 50°

C.

28. The method of claim 23, wherein the step of heating the skin under the androgen transdermal therapeutic system effectuates reducing the time it takes to achieve a desired, increase concentration of the target androgen in said systemic circulation of said human body through increasing skin permeability by heating.

29. The method of claim 23, wherein the step of heating the skin under said androgen transdermal therapeutic system effectuates reducing the time it takes to achieve a desired, increase concentration of the target androgen in the systemic circulation of the human body through increasing the permeability of blood vessel walls in sub-skin tissues by the heating.

30. The method of claim 23, wherein the step of heating the skin under the androgen transdermal therapeutic system effectuates reducing the time it takes to achieve a desired, increase concentration of the target androgen in the systemic circulation of the human body through increasing circulation of body fluid proximate the transdermal androgen deliver system by heating.

31. The method of claim 23, further comprising the step of reducing said heating of the skin under the androgen transdermal therapeutic system with the temperature control apparatus after a desired increase in concentration of target androgen in the systemic circulation in the human body is achieved.

32. The method of claim 23, wherein the desired increase in concentration of the target androgen in the systemic circulation in the human body is a concentration which facilitates the mimicking of natural human circadian patterns.

33. The method of claim 23, wherein the desired increase in concentration of the target androgen is achieved between the range of about one to about five hours after the step of applying the temperature control apparatus.

34. The method of claim 33, wherein the desired increased concentration of the target androgen in the systemic circulation in the human body is a concentration which facilitates the mimicking of natural human circadian patterns.

35. The method of claim 34, wherein the concentration peaks in the morning.

36. The method of claim 35, wherein the target androgen is testosterone.

37. The method of claim 23, wherein the temperature control apparatus comprises a chamber containing a medium capable of generating heat when exposed to oxygen.

38. The method of claim 23, wherein the temperature control apparatus comprises a chamber containing reactants capable of undergoing exothermic oxidation when exposed to oxygen.

39. The method of claim 37, wherein the medium capable of generating heat when exposed to oxygen comprises an iron powder and activated carbon formulation.

40. The method of claim 37, wherein the chamber is comprised of parts being substantially impermeable to oxygen and a structure which allows a predetermined flow rate of ambient oxygen into the medium capable of generating heat inside the chamber.

41. The method of claim 40, wherein said structure comprises a cover substantially impermeable to oxygen, the cover defining holes, the holes being covered by a membrane with selected oxygen permeability.

42. The method of claim 23, wherein the increased rate of delivery of androgen through the skin is sufficient to provide a desired increased concentration of the target androgen in the systemic circulation, the desired concentration being a concentration which facilitates the mimicking of natural human circadian patterns.

43. The method of claim 42, including the step of discontinuing the heating when the desired increased concentration of the target androgen in the systemic circulation in the body is achieved.

44. The method of claim 43, wherein the step of heating the skin under the androgen transdermal therapeutic system continues for a predetermined time.

45. The method of claim 44, wherein the predetermined time of heating is a time sufficient to obtain a desired increased concentration of the target androgen within a patient'"'"'s systemic circulation.

46. The method of claim 45, wherein the predetermined time is between the range of about one and five hours following the initiation of the heating step.

47. A method for adjusting a rate of androgen delivery from an androgen transdermal therapeutic system through the skin to mimic a natural circadian pattern, the method comprising:

placing an androgen transdermal therapeutic system on the skin applying a temperature control apparatus configured to create heat in a manner that mimics the endogenous circadian androgen production;

heating the skin under said androgen transdermal therapeutic system to a safe, predetermined temperature range for a safe, predesigned length of time; and

terminating said heating after the predesigned length of time to mimic the natural circadian pattern.

48. The method as claimed in claim 47, wherein the androgen is testosterone.

49. The method as claimed in claim 47 wherein the androgen is a derivative of testosterone.

50. The method of claim 47 further comprising the step of reducing said heating.

51. The method of claim 50 further comprising the steps of repeating the steps of heating the skin and reducing said heating.

52. A method for obtaining varying serum androgen release rates into the systemic circulation of the human body that correspond to a natural circadian pattern from otherwise substantially constant release delivery systems injected or implanted in said human body, the method comprising:

administering a controlled/extended release androgen therapeutic system in a target site within 3 cm from the skin surface, applying a control heating apparatus on the skin proximate to the target site configured to create heat in a manner that mimics the endogenous circadian androgen production; and

heating the androgen therapeutic system to a safe, predesigned temperature for a safe, predesigned length of time to correspond to the natural circadian pattern.

53. The method as claimed in claim 52, wherein the step of administering controlled release androgen therapeutic system comprises injecting an extended release androgen formulation.

54. The method as claimed in claim 53, wherein the step of applying a controlled heating apparatus on the skin proximate to the target site comprises placing a CHADD patch on the skin above the implanted formulation in the morning to mimic the natural circadian pattern of testosterone concentrations in the systemic circulation of a human body.

55. The method of claim 54 wherein the CHADD patch comprises

a chamber defined by a bottom wall, a top wall and side walls, the bottom wall, top wall and side walls of the chamber being made of flexible substantially air impermeable material, the air impermeable material defining at least one hole through material, and

a temperature regulating mechanism disposed within the chamber, the temperature regulating mechanism comprising reactants capable of creating an exothermic oxidation reaction when exposed to oxygen.

56. The apparatus as in claim 55, wherein the temperature regulating mechanism comprises a mixture of activated carbon, iron powder, and water.

58. The method of claim 55, where in the desired period of time is in the range of about 1-10 hours and the step of administering the patch is done in the morning to properly mimic the patient'"'"'s natural circadian pattern.

57. A method of mimicking a variation of testosterone concentrations in the blood of the human body according to a natural circadian pattern, the method comprising the steps of:

administrating an integrated patch capable of delivering androgen and capable of delivering controlled heat in a manner that mimics the endogenous circadian androgen production to the skin of a patient;

elevating the patient'"'"'s skin temperature proximate to the integrated patch to a safe, predesigned temperature for a safe, predesigned length of time using controlled heat, thereby allowing increased absorption of androgen that human body according to the natural circadian pattern; and

maintaining said increased absorption by said controlled heat for the predesigned length of time.