Method for facilitating absorption of pharmaceutically active compounds

• US 6,465,006 B1
• Filed: 04/07/2000
• Issued: 10/15/2002
• Est. Priority Date: 07/28/1995
• Status: Expired due to Term

• Current Assignee: Nuvo Research AG (Searchlight Pharma, Inc.)
• Original Assignee: Zars, Inc.
• Inventors: Zhang, Hao, Zhang, Jie
• Primary Examiner(s): Williamson, Michael A.
• Application Number:
  US09/545,496
• Time in Patent Office: 921 Days
• Field of Search: 424/449, 424/448, 424/447, 424/443, 424/402, 602/41, 602/46
• US Class Current: 424/449
• CPC Class Codes: A61F 2013/00187 insulating; warmth or cold applying
• CPC Class Codes: A61F 2013/00204 insulating
• CPC Class Codes: A61F 2013/00906 for transcutaneous or transdermal drugs application
• CPC Class Codes: A61F 2013/0091 with disinfecting or anaesthetics means, e.g. anti-mycrobic
• CPC Class Codes: A61F 7/032 using oxygen from the air, e.g. pocket-stoves
• CPC Class Codes: A61F 7/034 Flameless
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/4535 containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
• 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: A61M 37/00 Other apparatus for introducing media into the body for reproduction or fertilisation A61B17/425; apparatus for iontophoresis or cataphoresis A61N1/30; Percutany, i.e. introducing medicines into the body by diffusion through the skin salt baths A61H33/04
• 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

Methods and apparatus for improving administration of drugs through the use of heat and other physical means. The present invention relates to the use of heat and other physical means in conjunction with specially designed dermal drug delivery systems, conventional commercial dermal drug delivery systems, or drugs delivered into a sub-skin depot site via injection and other methods to alter, mainly increase, the drug release rate from the dermal drug delivery systems or the depot sites to accommodate certain clinical needs.

Claims

1. A method for facilitating the absorption of a pharmaceutical through human skin comprising the steps of:

administering said pharmaceutical through a portion of said skin, and

placing an exothermic heating means proximate said portion of skin to increase the temperature on and around said portion of skin by heating to within a safe, pre-designed narrow temperature range for a safe, pre-designed length of time, said exothermic heating means comprising a pre-determined amount of iron powder and water disposed in a chamber.

2. A method as in claim 1, wherein said step of placing an exothermic heating means proximate said portion of skin increases the permeability of the human skin to said pharmaceutical.

3. A method as in claim 1, wherein said step of placing an exothermic heating means proximate said portion of skin increases the solubility of an active ingredient in a pharmaceutical formulation to increase transdermal absorption of said active ingredient.

4. The method as in claim 3, wherein said formulation is delivered by a dermal drug delivery system.

5. The method of claim 1, wherein the step of placing heating means proximate to said portion of skin minimizes variation in transdermal absorption of said pharmaceutical.

6. The method of claim 1, wherein said pharmaceutical is delivered by a dermal drug delivery system.

7. The method of claim 1, wherein the step of placing an exothermic heating means proximate said portion of skin increases the speed of drug transport from storage sites under human skin to a targeted area.

8. The method of claim 1, wherein said step of placing an exothermic heating means proximate said portion of skin increases the speed of drug transport from a dermal drug delivery system to systemic circulation.

9. The method of claim 1, wherein said step of placing an exothermic heating means proximate said portion of skin boosts the absorption of an active ingredient in said pharmaceutical from a dermal drug delivery system.

10. The method of claim 1, wherein said step of placing an exothermic heating means proximate said portion of skin increases the speed of release of an active ingredient from a dermal drug delivery system.

11. The method of claim 1, wherein said step of placing an exothermic heating means proximate to said portion of skin shortens the onset time of said pharmaceutical.

12. The method of claim 1, wherein said safe, pre-designed length of time is sufficient to cause an increase in the quantity of active ingredient transported from the dermal drug delivery system into a targeted site in a patient'"'"'s body within the first four hours of heating.

13. The method of claim 1, wherein said safe, pre-designed length of time is sufficient because less than about a 90% increase in the transport of an active ingredient from pharmaceutical.

14. The method of claim 1, wherein said safe, pre-designed length of time is based on the effect of the drug on the patient.

15. The method of claim 1, wherein said heating means is disposed on a dermal drug delivery system.

16. The method of claim 1, wherein said heating means increases the temperature of a formulation containing said pharmaceutical.

17. The method of claim 1, wherein said heating means increases the temperature of a component of said heating means.

18. The method of claim 1, wherein said heating means heats a rate limiting membrane for said pharmaceutical.

19. The method of claim 18, wherein said heating said membrane increases the absorption of an active ingredient of said pharmaceutical.

20. The method of claim 1, wherein said heating increases the temperature of storage sites.

21. The method of claim 1, wherein said heating means heats storage sites and surrounding tissues.

22. The method of claim 1, wherein said heating means heat a formulation within a dermal drug delivery system.

23. The method of claim 1, wherein said heating apparatus heats an area of skin under which a pharmaceutical has been implanted.

24. The method of claim 23, wherein said skin and surroundina tissues are heated to a temperature range between about 37°

to 50°

centigrade.

25. The method of claim 1, wherein step of administering said pharmaceutical comprises using a delivery method to deliver a formulation containing a pharmaceutically active ingredient into a site in a human body that is within about 5 centimeters from a patient'"'"'s skin surface.

26. The method of claim 1, wherein the step of administering said pharmaceutical comprises administering a formulation containing an active ingedient whose solubility in said formulation can be increased by increasing the temperature of said formulation to within a range of about 37°

to about 50°

centigrade.

27. The method of claim 1, wherein the method of administering said pharmaceutical comprises administering a formulation containing an active ingredient, said active ingredient'"'"'s absorption into a patient'"'"'s skin being limited by a rate limiting membrane in a dermal drug delivery system.

28. The method of claim 1, wherein the step of administering a pharmaceutical comprises applying a dermal drug delivery system on human skin to deliver an active inoredient to a storage site within the skin and surrounding tissues for subsequent delivery of the active ingredients from the storage site into systemic circulation.

29. The method of claim 1, further comprising the step of terminating said heating.

30. The method of claim 1, wherein said step of terminating the heating comprises terminating the heating when a need for an increased rate of absorption of an active ingredient ceases to exist.

31. The method of claim 1, wherein the step of placing an exothermic heating means proximate said portion of skin is carried out when there is a need to increase the speed of transport of said pharmaceutical from a storage site to a patient'"'"'s systemic circulation.

32. The method of claim 1, wherein the step of placing an exothermic heating means proximate said portion of skin occurs when there is a need to increase the absorption of an active ingredient.

33. The method of claim 32, wherein said need to increase absorption of active ingredients is a perceived need based upon previous clinical experience of more than one patient.

34. The method of claim 32, wherein the need to increase the absorption of an active ingredient is determined baa the experience of the patient using said heating means.

35. The method of claim 32, wherein the need to increase the absorption of an active ingredient is based upon a lower than desirable affect of said active ingedient.

36. The method of claim 32, wherein the need to increase the absorption of an active ingredient is based on a sensation of the patient to whom the pharmaceutical was administered.

37. The method of claim 32, wherein the need to increase the absorption of the active ingredient is based on physiological parameters of a specific patient.

38. The method of claim 1, wherein said step of administering said pharmaceutical comprises disposing said pharmaceutical within at least one storage site in a patient'"'"'s skin and said heating controls the need of transport of said pharmaceutical from said storage.

39. The method of claim 38, wherein said step of administering said pharmaceutical comprises injecting said pharmaceutical into a patient.

40. The method of claim 38, wherein said administering of said pharmaceutical comprises implanting said pharmaceutical into a patient.

41. The method of claim 38, wherein said step of administering said pharmaceutical comprises using ionospheres to deliver said pharmaceutical.

42. The method of claim 38, wherein said step of administering said pharmaceutical further comprises using an electroporation to deliver said pharmaceutical.

43. The method of claim 38, wherein the step for administering said pharmaceutical comprises hitting a formulation containing a pharmaceutically active ingredient onto human skin.

44. The method of claim 43, wherein formulation is hit onto human skin at a speed of at least about 10 meters per second.

45. The method of claim 1, wherein said heat generating means comprises an exothermic phase transition to generate heat.

46. The method of claim 1, wherein said narrow temperature range is below about 60°

centigrade.

47. The method of claim 1, wherein said temperature range is between about 38°

centigrade to about 45°

centigrade.

48. The method of claim 1, wherein said temperature range is between about 39°

to about 43°

centigrade.

49. The method of claim 1, wherein said length of time is between about 3 minutes to about 7 days.

50. The method of claim 1, wherein said length of time is about 10 minutes to about 72 hours.

51. The method of claim 1, wherein said length of time is between about 20 minutes to about 24 hours.

52. The method of claim 1, Wherein said length of time is based solely upon the effect of the drug.

53. The method of claim 1, wherein said exothermic heating means further comprises activated carbon.

54. The method of claim 1, wherein said pharmaceutical is nicotine, testosterone, estradiol, nitroglycerin, clonidine, dexamethasone, tetracaine, lidocaine, fentanyl, sufentanil, progesterone, insulin, vitamin A, vitamin C, vitamin E, prilocaine, or bupivacaine.

55. The method of claim 1, wherein said pharmaceutical is an androgen, an estrogen, a non-steroidal anti-inflammatory agent an anti-hypertensive agent, an analgesic agent, an anti-depressant, an antibiotic, an anti-cancer agent, a local anesthetic, an anti-emetics, an anti-infectant, a contraceptive an anti-diabetic agent a steroid an anti-allergy agent, an anti-migraine agent, an anti-obesity agent, or an agent for smoke cessation.

56. An apparatus for facilitating the absorption of pharmaceuticals through human skin comprising the steps of:

a chamber comprising air-impermeable walls and having pre-determined number of holes with pre-determined size in at least one wall to allow the passage of air into said chamber;

determined amount of a heat generating medium comprising iron powder and water disposed in said chamber said amount of said heat generating medium being so selected that the heat generation by said heat generating medium in said chamber lasts a pre-determined length of time.

57. The apparatus of claim 56, further comprising a means to affix to skin.

58. The apparatus of claim 56, further comprising a means to affix to skin under which a storage site exists.

59. The apparatus of claim 56, wherein said heat heats human skin.

60. The apparatus of claim 56, wherein said heat heats a rate limiting membrane and a formulation containing active pharmaceutical ingredients disposed in a dermal drug delivery system.

61. The apparatus of claim 56, wherein said heat heats storage sites.

62. The apparatus of claim 56, wherein said heat heats a pharmaceutical formulation.

63. The apparatus of claim 56, wherein said heating facilitates transdermal absorption of a pharmaceutical.

64. The apparatus of claim 56, wherein said heating shortens the onset time of a dermal drug delivery system.

65. The apparatus of claim 56, wherein said heating facilitates the absorption of an active ingredient from a dermal drug delivery system on healing skin.

66. The apparatus of claim 56, wherein said heating increases the speed of drug transport from a storage site to a patient'"'"'s systemic circulation.

67. The apparatus of claim 56, wherein said heating increases the speed of drug transport from a dermal drug delivery system to a patient'"'"'s systemic circulation.

68. The apparatus of claim 56, wherein said heating increases solubility of active ingredients in a formulation of the dermal drug delivery system to increase transdermal absorption of said active ingredient.

69. The apparatus of claim 56, wherein said heat controls the speed of transport of a pharmaceutically active ingredient from a storage site in a human body.

70. The apparatus of claim 69, wherein said storage site is within about 5 centimeters from a patient'"'"'s skin surface.

71. A method for making a heat generating apparatus comprising:

selecting pre-determined amounts of iron powder, activated carbon and water,

mixing iron powder and activated carbon with a liquid in such a ratio that the mixture is semi-solid,

placing said mixture into a chamber with air impermeable walls, said chamber having at least one opening,

evaporating said liquid to form an intermediate mixture,

adding pre-determined amounts of water into said intermediate mixture, to form an exothermic heat generating medium that generates heat at a safe, pre-designed temperature for a safe, pre-designed length of time and

covering said at least one opening with a cover having a desired air permeability.

72. The method as in claim 71, wherein said liquid is selected from the group of ethyl alcohol, methyl alcohol, and propel alcohol.

73. The method of making a heat generating apparatus comprising:

mixing iron powder and an amount of water together, said amount of water being sufficient to prevent a heat generating reaction,

placing said mixture into a chamber having an air impermeable wall and at least one opening,

evaporating a portion of said amount of water until a pre-determined amount of water is left in said mixture, covering said at least one opening with a cover having a safe, pre-designed air permeability.

74. The method of claim 73, wherein said step of evaporating a portion of said amount of water is conducted into an oxygen-less environment.