Methods and apparatus for improved administration of pharmaceutically active compounds

• US 6,245,347 B1
• Filed: 09/29/1998
• Issued: 06/12/2001
• 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): Dodson, Shelley A.
• Assistant Examiner(s): Williamson, Michael A.
• Application Number:
  US09/162,890
• Time in Patent Office: 987 Days
• Field of Search: 424/402, 424/443, 424/447, 424/448, 424/449, 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 of controlling the rate of absorption of a drug in a target area of a human body comprising:

initiating the transdermal administration of a drug to a portion of the body;

activating a controlled temperature modification apparatus proximate the drug being administered by exposing to oxygen an oxygen-activated exothermic medium disposed within the controlled temperature modification apparatus; and

varying the amount of oxygen to which the exothermic medium is exposed to vary a rate of reaction of the exothermic medium and thereby adjusting the temperature of said target area of the body with said controlled temperature modification apparatus.

2. The method of claim 1, wherein said target area of the body comprises a systemic bloodstream.

3. The method of claim 1, wherein said target area of the body comprises an area of the body which can be reached by a systemic bloodstream of the body.

4. The method of claim 1, wherein said target area of the body comprises the brain of the body.

5. The method of claim 1, wherein said target area of the body comprises a body tissue region proximate a location of said administering of said drug.

6. The method of claim 1, wherein said administration of said drug to said portion of the body includes applying said drug transdermally.

7. The method of claim 6, wherein said applying said drug transdermally is effectuated by applying a dermal drug delivery system to the skin of said portion of the body.

8. The method of claim 7, wherein said applying said controlled temperature modification apparatus proximate said administered drug comprises applying said controlled temperature modification apparatus to said dermal drug delivery system.

9. The method of claim 1, wherein said administration of said drug to said portion of the body includes depositing said drug into the skin of the body.

10. The method of claim 9, wherein said depositing said drug into the skin of the body comprises a delivery method selected from the group consisting of:

injection, implantation, iontophoresis, electroportion, hitting said drug into portion of said patient'"'"'s body with supersonic speed, ultrasound assist transdermal permeation, and embedding said drug.

11. The method of claim 9, wherein said depositing said drug into the skin of the body comprises depositing a sustained release drug into the skin of the body.

12. The method of claim 9, wherein said depositing said sustained release drug into the skin of the body comprises depositing said drug incorporated in a biodegradable, biocompatible polymer.

13. The method of claim 12, wherein said biodegradable, biocompatible polymer is a polymer of lactic and glycolic acid.

14. The method of claim 12, wherein said biodegradable, biocompatible polymer is selected from the group consisting of poly(DL-lactide), poly(DL-lactide-co-glycolide), poly(DL-lactide-co-ε

-caprolactone), polycaprolactone, and combinations thereof.

15. The method of claim 1, wherein said administration of said drug to said portion of the body includes depositing said drug into tissues under the skin of the body.

16. The method of claim 15, wherein said depositing said drug into tissues under the skin of the body comprises a delivery method selected from the group consisting of:

injection, implantation, iontophoresis, electroportion, hitting said drug into portion of said patient'"'"'s body with supersonic speed, ultrasound assist transdermal permeation, and embedding said drug.

17. The method of claim 15, wherein said depositing said drug into tissues under the skin of the body comprises depositing a sustained release drug into tissues under the skin of the body.

18. The method of claim 17, wherein said depositing said sustained release drug under the skin of the body comprises depositing said drug incorporated in a biodegradable, biocompatible polymer.

19. The method of claim 18, wherein said biodegradable, biocompatible polymer is a polymer of lactic and glycolic acid.

20. The method of claim 18, wherein said biodegradable, biocompatible polymer is selected from the group consisting of poly(DL-lactide), poly (DL-lactide-co-glycolide), poly(DL-lactide-co-ε

-caprolactone), polycaprolactone, and combinations thereof.

21. The method of claim 1, wherein said administration of said drug to said portion of said patient'"'"'s body includes depositing said drug intramuscularly.

22. The method of claim 21, wherein said depositing said drug intramuscularly comprises a delivery method selected from the group consisting of:

injection and implantation.

23. The method of claim 21, wherein said depositing said drug intramuscularly comprises depositing a sustained release drug intramuscularly.

24. The method of claim 23, wherein depositing said sustained release drug intramuscularly comprises depositing said drug incorporated in a biodegradable, biocompatible polymer.

25. The method of claim 24, wherein said biodegradable, biocompatible polymer is a polymer of lactic and glycolic acid.

26. The method of claim 24, wherein said biodegradable, biocompatible polymer is selected from the group consisting of poly(DL-lactide), poly (DL-lactide-co-glycolide), poly(DL-lactide-co-ε

-caprolactone), polycaprolactone, and combinations thereof.

27. The method of claim 1, wherein said adjusting the temperature of skin proximate said portion of the body with said controlled temperature modification apparatus comprises heating said skin proximate said portion of the body.

28. The method of claim 27, wherein said heating said skin proximate said portion of the body includes heating said skin up to a temperature of about 60°

C.

29. The method of claim 28, wherein said heating said skin proximate said portion of the body includes heating said skin to a temperature of between about 36 and 46°

C.

30. The method of claim 29, wherein said heating said skin proximate said portion of the body includes heating said skin to a temperature of between about 37 and 44°

C.

31. The method of claim 27, wherein said heating said portion of the body effectuates an increase in concentration of said drug in said target area of the body through increasing skin permeability for said drug being applied transdermally.

32. The method of claim 31, wherein applying said drug transdermally is effectuated by applying a dermal drug delivery system to the skin of said portion of the body.

33. The method of claim 27, wherein said heating said portion of the body is effectuated by applying said controlled temperature modification apparatus to a dermal drug system, including a rate limiting membrane, which is applied to the skin of said portion of the body;

and wherein said heating said portion of the body effectuates an increase in concentration of said drug in said target area of the body by heating said rate limiting membrane which increases the permeability of said drug through said rate limiting membrane.

34. The method of claim 27, wherein said heating said portion of the body effectuates an increase in concentration of said drug in said target area of the body through increasing the permeability of blood vessel walls in sub-skin tissues.

35. The method of claim 27, wherein said heating said portion of the body effectuates an increase in concentration of said drug in said target area of the body through increasing the solubility of said drug in a formulation containing said drug.

36. The method of claim 27, wherein said heating said portion of the body effectuates an increase in concentration of said drug in said target area through increasing circulation of body fluid in tissues proximate said drug.

37. The method of claim 1, wherein said applying said controlled temperature modification apparatus proximate said administered drug comprises applying said controlled temperature modification apparatus proximate said administered drug when a clinical need for adjustment of said concentration of said drug in said target area is detected.

38. The method of claim 1, wherein said adjusting said temperature of said portion of the body with said controlled temperature modification apparatus to achieve a desired concentration of said drug in said target area comprises adjusting said temperature of said portion of the body with said controlled temperature modification apparatus proximate said administered drug when a clinical need for adjustment of said concentration of said drug in said target area is detected to achieve a desired concentration of said drug in said target area.

39. The method of claim 1, further including removing said controlled temperature modification apparatus when said desired concentration of said drug in said target area is achieved.

40. The method of claim 1, further including discontinuing said adjustment of said temperature of said portion of the body with said controlled temperature modification apparatus when said desired concentration of said drug in said target area is achieved.

41. A method of controlling the rate of absorption of a drug in a target area of a human body comprising:

initiating the transdermal administration of a drug to a portion of the body activating an apparatus capable of generating heat by exposing oxygen-activated exothermic medium disposed within the apparatus to oxygen proximate said drug being administered; and

varying the amount of oxygen to which the exothermic medium are exposed to vary a rate of reaction of the exothermic medium thereby heating skin proximate said portion of the body to a temperature of between about 38 and 45°

C. with said apparatus to achieve a desired concentration of said drug in said target area.

42. A method of adjusting the concentration of insulin in a human body comprising:

injecting insulin in a sustained release form into a portion of said human body;

applying a temperature modification apparatus proximate said injected, sustained release insulin prior to the intake of food; and

increasing the temperature of skin proximate said portion of said human body with said temperature modification apparatus by exposing oxygen-activated exothermic medium disposed within the apparatus to oxygen and varying the amount of oxygen to which the exothermic medium are exposed to oxygen and rate of reaction of the exothermic medium to achieve a desired increased concentration of said insulin in said human body.

43. The method of claim 42, wherein said adjusting said temperature of said portion of said human body is effected for a duration of time between about 5 minutes and 3 hours.

44. The method of claim 42, wherein said adjusting said temperature of said portion of said human body is effected for a duration of time between about 15 minutes and 2 hours.

45. The method of claim 42, wherein said insulin in said sustained release form is said insulin in a crystalline form.

46. The method of claim 42, wherein said sustained release insulin comprises said insulin incorporated in a biodegradable, biocompatible polymer.

47. The method of claim 46, wherein said biodegradable, biocompatible polymer is a polymer of lactic and glycolic acid.

48. The method of claim 46, wherein said biodegradable, biocompatible polymer is a copolymer of lactic and glycolic acid.

49. The method of claim 46, wherein said biodegradable, biocompatible polymer is selected from the group consisting of poly(DL-lactide), poly (DL-lactide-co-glycolide), poly(DL-lactide-co-ε

-caprolactone), polycaprolactone, and combinations thereof.

50. A method of adjusting the concentration of testosterone in a human body comprising:

administering testosterone in a sustained release formulation into a portion of said human body within about 3 centimeters from a skin surface;

applying a temperature modification apparatus proximate said injected, sustained release testosterone; and

increasing the temperature of skin proximate said portion of said human body with said temperature modification apparatus by exposing oxygen-activated exothermic medium disposed within the apparatus to oxygen and varying the amount of oxygen to which the exothermic medium are exposed to vary a rate of reaction of the exothermic medium to achieve a desired increased concentration of said testosterone in said human body.

51. The method of claim 50, wherein said applying a temperature modification apparatus proximate said injected, sustained release testosterone formulation comprises applying a temperature modification apparatus proximate said injected, sustained release testosterone each morning to mimic natural circadian pattern concentrations of testosterone.

52. The method of claim 50, wherein said applying a temperature modification apparatus proximate said injected, sustained release testosterone formulation is effected for a duration of time between about 2 hours and 14 hours.

53. The method of claim 52, wherein said applying a temperature modification apparatus proximate said injected, sustained release testosterone formulation is effected for a duration of time between about 4 hours and 10 hours.

54. The method of claim 50, wherein said sustained release formulation is selection form the group of formulations consisting of testosterone enanthate, testosterone cypionate, testosterone incorporated into a biodegradable, biocompatible polymer, and a testosterone ester incorporated into a biodegradable, biocompatible polymer.

55. The method of claim 54, wherein said biodegradable, biocompatible polymer is a polymer of lactic and glycolic acid.

56. The method of claim 54, wherein said biodegradable, biocompatible polymer is a copolymer of lactic and glycolic acid.

57. A method of controlling the rate of absorption of a drug in a target area of the human body comprising:

initiating the transdermal administration of a drug to a portion of the body activating a controlled temperature apparatus capable of generating heat by exposing oxygen-activated exothermic medium disposed within the apparatus to oxygen and varying the amount of oxygen to which the exothermic medium is exposed to vary a rate of reaction of the exothermic medium and thereby adjusting the temperature the portion of the body proximate said drug being administered to provide a predetermined temperature for a predetermined time.

58. The method of claim 57, further comprising titrating the amount of drug delivered by varying the amount of oxygen to which the exothermic medium are exposed.

59. The method of claim 57, further comprising titrating the rate of delivery by varying the amount of oxygen to which the exothermic medium are exposed.

60. The method of claim 57, wherein said exothermic medium are exposed to oxygen through a membrane having limited permeability to oxygen.

61. The method of claim 57, wherein said exothermic medium are exposed to oxygen through selectively uncoverable holes in air impermeable membrane.

62. The method of claim 57, wherein said exothermic medium are exposed to oxygen through a selectively uncoverable air permeable membrane.

63. A method of controlling the rate of absorption of a drug in a target area of a human body comprising:

initiating the transdermal administration of a drug to a portion of the body;

activating a controlled temperature modification apparatus proximate the drug being administered to a provide steady rate of drug delivery by exposing oxygen-activated exothermic medium disposed within the controlled temperature modification apparatus to oxygen; and

increasing the amount of oxygen to which the exothermic medium are exposed to increase a rate of reaction of the exothermic medium and thereby increase the temperature of said portion of the body with said controlled temperature modification apparatus to provide a therapeutic dose of said drug to treat a breakthrough pain episode.

64. The method of claim 63, further comprising titrating the amount of drug delivered by varying the amount of oxygen to which the exothermic medium are exposed.

65. The method of claim 63, further comprising titrating the rate of drug delivery by varying the amount of oxygen to which the exothermic medium are exposed.

66. The method of claim 63, wherein said exothermic medium are exposed to oxygen through a membrane having limited permeability to oxygen.

67. The method of claim 63, wherein said exothermic medium are exposed to oxygen through selectively uncoverable holes in air impermeable membrane.

68. The method of claim 63, wherein said exothermic medium are exposed to oxygen through a selectively uncoverable air permeable membrane.