Transdermal drug delivery using an osmolyte and vasoactive agent
A formulation and method for delivery of bioactive substances when applied to, or within, the skin or other exterior region of a mammal. for example, a patient, includes a vasoactive agent; an osmolyte; and an active ingredient. The formulation is sufficiently hygroscopic so as to create a condition of hypertonicity when absorbed by the skin. When the formulation is applied to the skin, the vasoactive agent can be delivered to the dermis so as to contact the vasculature of a patient.
1. A formulation for topical delivery of an active ingredient to a mammal, said mammal having a body surface and the body surface having a topical application site comprising skin, the formulation comprising:
a vasodilator, an osmolyte, and an active ingredient,
wherein:
a) the vasodilator is selected from the group consisting of arginine, methyl nicotinate, naftidrofuryl oxalate, papaverine, tolazoline, and combinations of the foregoing,
b) the osmolyte is a sugar;
c) the vasodilator and the osmolyte are present in amounts effective to work together in a synergistic manner to enable penetration of the active ingredient into or through the skin;
d) the vasodilator, the osmolyte, and the active ingredient are non-identical; and
e) the formulation has an osmolarity that is greater than 350 milliOsmol/L.
2. The formulation of claim 1 , further comprising a component selected from the group consisting of a transpiration barrier, a penetration enhancer, and a drug administration patch.
3. The formulation of claim 1 , further comprising a transpiration barrier, wherein the transpiration barrier includes at least one of a chemical barrier or a physical barrier.
4. The formulation of claim 1 , wherein said formulation is packaged in a water-resistant delivery system.
5. The formulation of claim 1 , wherein the active ingredient is a sirtuin inhibitor.
6. The formulation of claim 1 , wherein the active ingredient is a sirtuin activator.
7. The formulation of claim 1 , wherein the vasodilator is methyl nicotinate.
8. A method for enhancing the penetration of an active ingredient into or through a body surface comprising skin, the method comprising administering to the skin a formulation according to claim 1 .
9. The method of claim 8 , wherein the active ingredient penetrates to at least one of the epidermis, a dermis, or a systemic circulatory vessel.
10. The method of claim 8 , wherein the active ingredient is a sirtuin inhibitor or sirtuin activator and the region of the body surface is skin.
11. A method for topical delivery of an active ingredient to a mammal, said mammal having a body surface and said body surface comprising a dermis and a topical application site comprising skin, the method comprising:
administering a vasodilator to the topical application site, said vasodilator being deliverable to a region of said dermis and said vasodilator being selected from the group consisting of arginine, methyl nicotinate, naftidrofuryl oxalate, papaverine, tolazoline, and combinations of the foregoing;
administering an osmolyte to the topical application site, wherein the osmolyte is a sugar; and
administering the active ingredient to the topical application site, wherein the vasodilator and the osmolyte are present in amounts effective to work together in a synergistic manner to enable penetration of the active ingredient into or through the skin, wherein the vasodilator, the osmolyte, and the active ingredient are non-identical and wherein the vasodilator, the osmolyte, and the active ingredient have an osmolarity that is greater than 350 milliOsmol/L.
12. The method of claim 11 , wherein the vasodilator and osmolyte are applied sequentially.
13. The method of claim 11 , wherein the vasodilator and osmolyte are applied together.
14. The method of claim 11 , further comprising applying an occlusive barrier to the topical application site.
15. A kit for topical delivery of an active ingredient to a mammal, said kit comprising:
i) a formulation including:
a) a vasodilator selected from the group consisting of arginine, methyl nicotinate, naftidrofuryl oxalate, papaverine, tolazoline, and combinations of the foregoing;
b) an osmolyte, wherein the osmolyte is a sugar;
c) an active ingredient;
wherein the vasodilator and the osmolyte are present in amounts effective to work together in a synergistic manner to enable penetration of the active ingredient into or through the skin,
wherein the vasodilator, the osmolyte, and the active ingredient are non-identical and wherein the vasoactive agent, the osmolyte, and the active ingredient have an osmolarity that is greater than 350 milliOsmol/L; and
(ii) a set of written instructions for use, by or on said mammal, of said vasodilator, said osmolyte, and said active ingredient according to the method of claim 11 .
16. The formulation of claim 1 , wherein the osmolarity is greater than 600 milliosmol/L.
17. The method of claim 8 , wherein the osmolarity is greater than 600 milliosmol/L.
18. The method of claim 11 , wherein the osmolarity is greater than 600 milliosmol/L.
19. The kit of claim 15 , wherein the osmolarity is greater than 600 milliosmol/L.
20. The method of claim 11 , wherein the vasodilator induces an increased blood flow in the body surface.
21. The method of claim 20 , wherein the increase in blood flow is greater than 1% as measured by laser-Doppler velocimetry.
22. The method of claim 21 , wherein the increase in blood flow is greater than 5%.
23. The method of claim 20 , wherein the osmolyte is absorbed by the body surface and the increased blood flow works in synergy with the osmolyte to enhance penetration of the active ingredient.
24. The method of claim 11 , wherein administration of the vasodilator, the osmolyte, and the active ingredient results in passage of the vasodilator through a basement membrane of the body surface.
25. The method of claim 11 , wherein the administered vasodilator and the osmolyte exert a physiological change in the body surface of the mammal to thereby allow transport of the administered active agent through the body surface.
26. The method of claim 25 , wherein the administered vasodilator and the osmolyte exert a physiological change in the body surface of the mammal to thereby allow transport of the administered active agent into at least one of an epidermal tissue of the body surface, a dermal tissue of the body surface, or a portion of a systemic circulatory system of the mammal.
27. The formulation of claim 1 , wherein the vasodilator is tolazoline.
28. The formulation of claim 1 , wherein the vasodilator is papaverine.
29. The formulation of claim 1 , wherein the vasodilator is naftidrofuryl oxalate.
30. The formulation of claim 1 , wherein the vasodilator is arginine.
31. The formulation of claim 8 , wherein the vasodilator is methyl nicotinate.
32. The formulation of claim 8 , wherein the vasodilator is tolazoline.
33. The formulation of claim 8 , wherein the vasodilator is papaverine.
34. The formulation of claim 8 , wherein the vasodilator is naftidrofuryl oxalate.
35. The formulation of claim 8 , wherein the vasodilator is arginine.
36. The formulation of claim 11 , wherein the vasodilator is methyl nicotinate.
37. The formulation of claim 11 , wherein the vasodilator is tolazoline.
38. The formulation of claim 11 , wherein the vasodilator is papaverine.
39. The formulation of claim 11 , wherein the vasodilator is naftidrofuryl oxalate.
40. The formulation of claim 11 , wherein the vasodilator is arginine.
41. The kit of claim 15 , wherein the vasodilator is methyl nicotinate.
42. The kit of claim 15 , wherein the vasodilator is tolazoline.
43. The kit of claim 15 , wherein the vasodilator is papaverine.
44. The kit of claim 15 , wherein the vasodilator is naftidrofuryl oxalate.
45. The kit of claim 15 , wherein the vasodilator is arginine.
46. The formulation of claim 1 , wherein the osmolyte is xylobiose.
47. The formulation of claim 1 , wherein the osmolyte is galactose.
48. The formulation of claim 1 , wherein the osmolyte is lactose.
49. The formulation of claim 1 , wherein the osmolyte is glucose.
50. The method of claim 8 , wherein the osmolyte is xylobiose.
51. The method of claim 8 , wherein the osmolyte is galactose.
52. The method of claim 8 , wherein the osmolyte is lactose.
53. The method of claim 8 , wherein the osmolyte is glucose.
54. The method of claim 11 , wherein the osmolyte is xylobiose.
55. The method of claim 11 , wherein the osmolyte is galactose.
56. The method of claim 11 , wherein the osmolyte is lactose.
57. The method of claim 11 , wherein the osmolyte is glucose.
58. The kit of claim 15 , wherein the osmolyte is xylobiose.
59. The kit of claim 15 , wherein the osmolyte is galactose.
60. The kit of claim 15 , wherein the osmolyte is lactose.
61. The kit of claim 15 , wherein the osmolyte is glucose.
62. The formulation of claim 1 , wherein the active ingredient is ibuprofen.
63. The formulation of claim 1 , wherein the active ingredient is acetaminophen.
64. The formulation of claim 1 , wherein the active ingredient is benfotiamine.
65. The method of claim 8 , wherein the active ingredient is ibuprofen.
66. The method of claim 8 , wherein the active ingredient is acetaminophen.
67. The method of claim 8 , wherein the active ingredient is benfotiamine.
68. The method of claim 11 , wherein the active ingredient is ibuprofen.
69. The method of claim 11 , wherein the active ingredient is acetaminophen.
70. The method of claim 11 , wherein the active ingredient is benfotiamine.
71. The kit of claim 15 , wherein the active ingredient is ibuprofen.
72. The kit of claim 15 , wherein the active ingredient is acetaminophen.
73. The kit of claim 15 , wherein the active ingredient is benfotiamine.