Transdermal and topical administration of drugs using basic permeation enhancers

• US 20030104041A1
• Filed: 06/20/2002
• Published: 06/05/2003
• Est. Priority Date: 12/16/1999
• Status: Abandoned Application

• Current Assignee: Dematrends, Inc., Dermatrends, Inc.
• Original Assignee: Dematrends, Inc.
• Inventors: Luo, Eric C., Gricenko, Nicole T., Hsu, Tsung-Min, Obara, Jane, Jacobson, Eric C., LoBello, Rose C., Hickey, Alan T. J.
• Application Number:
  US10/177,436
• Publication Number:
  US 20030104041A1
• Time in Patent Office: Days
• US Class Current: 424/449
• CPC Class Codes: A61K 31/04 Nitro compounds
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/20 having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• CPC Class Codes: A61K 31/343 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• CPC Class Codes: A61K 31/365 Lactones
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/60 Salicylic acid; Derivatives thereof
• CPC Class Codes: A61K 31/662 Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• CPC Class Codes: A61K 31/7004 Monosaccharides having only carbon, hydrogen and oxygen atoms
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/737 Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate A61K31/727 takes precedence
• CPC Class Codes: A61K 31/795 Polymers containing sulfur
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 8/0208 Tissues; Wipes; Patches
• CPC Class Codes: A61K 8/19 containing inorganic ingredients
• CPC Class Codes: A61K 8/347 : Phenols
• CPC Class Codes: A61K 8/41 : Amines
• CPC Class Codes: A61K 8/92 : Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
• CPC Class Codes: A61K 9/0014 : Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/06 : Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/7038 : Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
• CPC Class Codes: A61K 9/7053 : obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
• CPC Class Codes: A61Q 19/02 : for chemically bleaching or whitening the skin

Abstract

Methods are provided for enhancing the permeability of skin or mucosal tissue to topical or transdermal application of pharmacologically or cosmeceutically active agents. The methods entail the use of a base in order to increase the flux of the active agent through a body surface while minimizing the likelihood of skin damage, irritation or sensitization. The permeation enhancer can be an inorganic or organic base. Compositions and transdermal systems are also described.

Claims

1. A method for enhancing the flux of an analgesic agent through a body surface, comprising:

(a) administering the analgesic agent to a localized region of a human patient'"'"'s body surface; and

(b) administering a basic permeation enhancer to the localized region, the enhancer comprising a pharmaceutically acceptable inorganic base and being present in an amount effective to provide a pH within the range of about 8.0-13.0 at the localized region of the body surface during administration of the analgesic agent and to enhance the flux of the analgesic agent through the body surface without causing damage thereto.

2. The method of claim 1 wherein the pH is within the range of about 8.0-11.5.

3. The method of claim 2 wherein the pH is within the range of about 8.5-10.5.

4. The method of claim 1 wherein the base is selected from the group consisting of ammonium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium oxide, sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, potassium phosphate, ammonium phosphate, and combinations thereof.

5. The method of claim 1 wherein the base is selected from the group consisting of inorganic hydroxides, inorganic oxides, inorganic salts of weak acids, and combinations thereof.

6. The method of claim 5 wherein the base is an inorganic hydroxide.

7. The method of claim 6 wherein the inorganic hydroxide is selected from the group consisting of ammonium hydroxide, alkali metal hydroxides, and alkaline earth metal hydroxides.

8. The method of claim 7 wherein the inorganic hydroxide is ammonium hydroxide.

9. The method of claim 7 wherein the inorganic hydroxide is an alkali metal hydroxide selected from the group consisting of sodium hydroxide and potassium hydroxide.

10. The method of claim 7 wherein the inorganic hydroxide is an alkaline earth metal hydroxide selected from the group consisting of calcium hydroxide and magnesium hydroxide.

11. The method of claim 5 wherein the base is an inorganic oxide.

12. The method of claim 11 wherein the inorganic oxide is selected from the group consisting of magnesium oxide and calcium oxide.

13. The method of claim 5 wherein the base is an inorganic salt of a weak acid.

14. The method of claim 13 wherein the inorganic salt of a weak acid is selected from the group consisting of ammonium phosphate, alkali metal salts of weak acids, and alkaline earth metal salts of weak acids.

15. The method of claim 14 wherein the inorganic salt of a weak acid is ammonium phosphate.

16. The method of claim 14 wherein the inorganic salt of a weak acid is an alkali metal salt of a weak acid selected from the group consisting of sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, and potassium phosphate.

17. The method of claim 1 wherein the body surface is skin.

18. The method of claim 1 wherein the body surface is mucosal tissue.

19. The method of claim 1 wherein the analgesic agent and basic permeation enhancer are present in a single pharmaceutical formulation.

20. The method of claim 1 wherein the analgesic agent and basic permeation enhancer are present in separate pharmaceutical formulations.

21. The method of claim 20 wherein steps (a) and (b) are done simultaneously.

22. The method of claim 20 wherein step (a) is done prior to step (b).

23. The method of claim 20 wherein step (b) is done prior to step (a).

24. The method of claim 1 wherein the analgesic agent and basic permeation enhancer are administered by applying a drug delivery device to the localized region of the patient'"'"'s body surface thereby forming a body surface-delivery device interface, the device comprising the analgesic agent and basic permeation enhancer, and having an outer backing layer that serves as the outer surface of the device during use.

25. The method of claim 1 wherein the basic permeation enhancer is contained within an aqueous formulation.

26. The method of claim 25 wherein the aqueous formulation has a pH within the range of about 8.0-13.0

27. The method of claim 26 wherein the pH is within the range of about 8.0-11.5.

28. The method of claim 27 wherein the pH is within the range of about 8.5-10.5.

29. The method of claim 25 wherein the aqueous formulation is selected from the group consisting of a cream, a gel, a lotion, and a paste.

30. The method of claim 1 wherein the analgesic agent is selected from the group consisting of capsaicin, clonidine, tramadol, indomethacin, pharmaceutically acceptable derivatives thereof, and combinations thereof.

31. The method of claim 1 wherein the analgesic drug is a narcotic analgesic.

32. The method of claim 31 wherein the analgesic agent is selected from the group consisting of alfentanil, buprenorphine, butorphanol, codeine, enkephalin, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, nicomorphine, opium, oxycodone, oxymorphone, pentazocine, propoxyphene, sufentanil, pharmaceutically acceptable derivatives thereof, and combinations thereof.

33. The method of claim 32 wherein the analgesic agent is selected from the group consisting of buprenorphine, butorphanol, fentanyl, hydrocodone, hydromorphone, levorphanol, methadone, morphine, oxycodone, oxymorphone, pharmaceutically acceptable derivatives thereof, and combinations thereof.

34. The method of claim 1 wherein the flux of the analgesic agent is enhanced by at least about 3-fold.

35. The method of claim 34 wherein the flux of the analgesic agent is enhanced by at least about 6-fold.

36. A composition for the enhanced delivery of an analgesic agent through a body surface, comprising an aqueous formulation of:

(a) a therapeutically effective amount of the analgesic agent;

(b) a pharmaceutically acceptable inorganic base in an amount effective to provide a pH within the range of about 8.0-13.0 at the body surface during administration of the analgesic agent and to enhance the flux of the analgesic agent through the body surface without causing damage thereto; and

(c) a pharmaceutically acceptable carrier suitable for topical or transdermal drug administration, wherein the composition provides for at least about 3-fold enhanced delivery.

37. The composition of claim 36 wherein the analgesic agent is an acidic species.

38. The composition of claim 37 wherein the base is present in an amount that is the total of (a) the amount required to neutralize the acidic species plus (b) an amount equal to about 0.3-7.0 wt % of the composition.

39. The composition of claim 36 wherein the analgesic agent is a non-acidic species.

40. The composition of claim 39 wherein the base is present in an amount equal to about 0.3-7.0 wt % of the composition.

41. The composition of claim 36 comprising a cream, a gel, a lotion, or a paste.

42. The composition of claim 36 wherein the composition provides for at least about 6-fold enhanced delivery.

43. The composition of claim 36 wherein the base is selected from the group consisting of inorganic hydroxides, inorganic oxides, inorganic salts of weak acids, and combinations thereof.

44. The composition of claim 43 wherein the base is an inorganic hydroxide selected from the group consisting of ammonium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide.

45. The composition of claim 43 wherein the base is an inorganic oxide selected from the group consisting of magnesium oxide and calcium oxide.

46. The composition of claim 43 wherein the base is an inorganic salt of a weak acid selected from the group consisting of ammonium phosphate, sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, and potassium phosphate.

47. The composition of claim 36 wherein the base is effective to provide a pH within the range of about 8.5-10.5 at the localized region of the body surface during administration of the analgesic agent.

48. The composition of claim 36 wherein the analgesic agent is selected from the group consisting of capsaicin, clonidine, tramadol, indomethacin, pharmaceutically acceptable derivatives thereof, and combinations thereof.

49. The composition of claim 36 wherein the analgesic drug is a narcotic analgesic.

50. The composition of claim 49 wherein the analgesic agent is selected from the group consisting of alfentanil, buprenorphine, butorphanol, codeine, enkephalin, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, nicomorphine, opium, oxycodone, oxymorphone, pentazocine, propoxyphene, sufentanil, pharmaceutically acceptable derivatives thereof, and combinations thereof.

51. The composition of claim 50 wherein the analgesic agent is selected from the group consisting of buprenorphine, butorphanol, fentanyl, hydrocodone, hydromorphone, levorphanol, methadone, morphine, oxycodone, oxymorphone, pharmaceutically acceptable derivatives thereof, and combinations thereof.

52. The composition of claim 36 which further comprises at least one irritation-mitigating additive.

53. A system for the enhanced topical or transdermal administration of an analgesic agent, comprising:

(a) at least one drug reservoir containing the analgesic agent and a pharmaceutically acceptable inorganic base, in an amount effective to enhance the flux of the analgesic agent through the body surface without causing damage thereto;

(b) a means for maintaining the system in agent and base transmitting relationship to the body surface and forming a body surface-system interface; and

(c) a backing layer that serves as the outer surface of the device during use, wherein the base is effective to provide a pH within the range of about 8.5-10.5 at the body surface-system interface during administration of the analgesic agent, and wherein the system provides for at least about 3-fold enhanced delivery.

54. The system of claim 53 wherein the backing layer is occlusive.

55. The system of claim 53 wherein the drug reservoir is comprised of a polymeric adhesive.

56. The system of claim 55 wherein the polymeric adhesive serves as the means for maintaining the system in agent and base transmitting relationship to the body service.

57. The system of claim 53 wherein the drug reservoir is comprised of a hydrogel.

58. The system of claim 53 wherein the drug reservoir is comprised of a sealed pouch containing the analgesic agent and inorganic base in a liquid or semi-solid formulation.

59. The system of claim 53 wherein the analgesic agent is an acidic species.

60. The system of claim 59 wherein the base is present in an amount that is the total of (a) the amount required to neutralize the acidic species plus (b) an amount equal to about 0.3-7.0 wt % of the drug reservoir.

61. The system of claim 53 wherein the analgesic agent is a non-acidic species.

62. The system of claim 61 wherein the base is present in an amount equal to about 0.3-7.0 wt % of the drug reservoir.

63. The system of claim 53 wherein the composition provides for at least about 6-fold enhanced delivery.

64. The system of claim 53 wherein the base is selected from the group consisting of inorganic hydroxides, inorganic oxides, inorganic salts of weak acids, and combinations thereof.

65. The system of claim 64 wherein the base is an inorganic hydroxide selected from the group consisting of ammonium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide.

66. The system of claim 64 wherein the base is an inorganic oxide selected from the group consisting of magnesium oxide and calcium oxide.

67. The system of claim 64 wherein the base is an inorganic salt of a weak acid selected from the group consisting of ammonium phosphate, sodium acetate, sodium borate, sodium metaborate, sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium citrate, potassium acetate, and potassium phosphate.

68. The system of claim 53 wherein the analgesic agent is selected from the group consisting of capsaicin, clonidine, tramadol, indomethacin, pharmaceutically acceptable derivatives thereof, and combinations thereof.

69. The system of claim 53 wherein the analgesic drug is a narcotic analgesic.

70. The system of claim 69 wherein the analgesic agent is selected from the group consisting of alfentanil, buprenorphine, butorphanol, codeine, enkephalin, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, nicomorphine, opium, oxycodone, oxymorphone, pentazocine, propoxyphene, sufentanil, pharmaceutically acceptable derivatives thereof, and combinations thereof.

71. The system of claim 70 wherein the analgesic agent is selected from the group consisting of buprenorphine, butorphanol, fentanyl, hydrocodone, hydromorphone, levorphanol, methadone, morphine, oxycodone, oxymorphone, pharmaceutically acceptable derivatives thereof, and combinations thereof.

72. The system of claim 53 which further comprises at least one irritation-mitigating additive.