Transdermal drug delivery systems, devices, and methods employing novel pharmaceutical vehicles

• US 20070083186A1
• Filed: 09/27/2006
• Published: 04/12/2007
• Est. Priority Date: 09/30/2005
• Status: Abandoned Application

• Current Assignee: TTI Ellebeau, Inc. (Ease Asset Management Ltd.)
• Original Assignee: TTI Ellebeau, Inc. (Ease Asset Management Ltd.)
• Inventors: Carter, Darrick, Kalamasz, Dale
• Application Number:
  US11/541,383
• Publication Number:
  US 20070083186A1
• Time in Patent Office: Days
• US Class Current: 604/501
• CPC Class Codes: A61N 1/0436 Material of the electrode
• CPC Class Codes: A61N 1/044 Shape of the electrode
• CPC Class Codes: A61N 1/0444 Membrane
• CPC Class Codes: A61N 1/0448 Drug reservoir
• 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
• CPC Class Codes: A61N 1/306 Arrangements where at least part of the apparatus is introduced into the body

Abstract

Systems, devices, and methods for transdermal delivery of one or more therapeutic active agents to a biological interface. An iontophoretic drug delivery system is provided for transdermal delivery of one or more therapeutic active agents to a biological interface of a subject. The iontophoretic drug delivery system includes at least one active agent reservoir. The one or more active agent reservoirs are loadable with a vehicle for transporting, delivering, encapsulating, and/or carrying the one or more active agents

Claims

1. An iontophoretic drug delivery device for providing transdermal delivery of one or more therapeutic active agents to a biological interface, comprising:

an active electrode assembly including at least one active electrode element; and

at least one active agent reservoir, the at least one active agent reservoir including a pharmaceutically acceptable vehicle for transporting one or more active agents, the pharmaceutically acceptable vehicle comprising

at least one surfactant,

at least one nonpolar solvent, and

at least one polar agent;

the at least one active electrode element operable to provide an electromotive force for driving the pharmaceutically acceptable vehicle from the at least one active agent reservoir to the biological interface.

2. The iontophoretic drug delivery device of claim 1 wherein the at least one surfactant comprises at least a glycerol residue moiety, one or more C₁₀-C₂₀ hydrocarbon chain moieties, and a moiety selected from phosphatidic acids, phosphatidylcholines, lyso-phosphatidylcholines, phosphatidylethanol amines, lysol-phosphatidylethanol amines, phosphatidylserines, and phosphatidylinositols.

3. The iontophoretic drug delivery device of claim 1 wherein the at least one surfactant is selected from one or more emulsifying agents, amphoteric surfactants, non-ionic surfactants, ionic surfactants, acetone-insoluble phosphatides, phospholipids, sorbitan esters, sorbitan monoester, and polyoxypropylene-polyoxethylene block copolymers, or combinations thereof.

4. The iontophoretic drug delivery device of claim 1 wherein the at least one surfactant is selected from one or more amphiphiles, biocompatible surfactants, ether lipids, fluoro-lipids, polyhydroxyl lipids, polymerized liposomes, lecithin, hydrogenated lecithin, naturally occurring lecithin, egg lecithin, hydrogenated egg lecithin, soy lecithin, hydrogenated soy lecithin, vegetable lecithin, sorbitan esters, sorbirant monoesters, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monostearate-palmitate, sorbitan sexquioleate, sorbitan tristearate, sorbitan trioleate, diacylglycerols, gangliosides, glycerophospholipids, lysophospholipids, mixed-chain phospholipids, pegylated phospholipids, phosphatidic acids, phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, phosphocholines, phosphoethanolamines, phosphoglycerols, phosphoserines, phytosphingosines, poloxamers, polyoxypropylene-polyoxethylene block copolymers, and sphingosines, or combinations thereof.

5. The iontophoretic drug delivery device of claim 1, wherein the at least one surfactant of the pharmaceutically acceptable vehicle comprises:

at least a first surfactant and a second surfactant;

the first surfactant selected from phosphatidylcholines, and the second surfactants selected from poloxamers and polyoxypropylene-polyoxethylene block copolymers.

6. The iontophoretic drug delivery device of claim 1 wherein the at least one nonpolar solvent is selected from:

organic solvents;

vegetable oils;

saturated or unsaturated, linear or branched, substituted or unsubstituted alkanes;

ethers;

esters;

fatty acids; and

amines.

7. The iontophoretic drug delivery device of claim 1 wherein the at least one nonpolar solvent is selected from ethyl laureate, ethyl myristate, isopropyl myristate, isopropyl palmitate, cyclopentane, cyclooctane, trans-decalin, trans-pinane, n-pentane, n-hexane, n-hexadecane, and tripropylamine.

8. The iontophoretic drug delivery device of claim 1 wherein the at least one polar agent is selected from water, alcohols, polyalcohols, glycerols, polyglycerols, glycols, polyglycols, ethylene glycol, and formamide.

9. The iontophoretic drug delivery device of claim 1 wherein the pharmaceutically acceptable vehicle takes the form of a colloidal dispersion having an aqueous phase and a lipid phase.

10. The iontophoretic drug delivery device of claim 1 wherein the pharmaceutically acceptable vehicle takes the form of a gel.

11. The iontophoretic drug delivery device of claim 1 wherein the pharmaceutically acceptable vehicle takes the form of an organogel.

12. The iontophoretic drug delivery device of claim 1 wherein the pharmaceutically acceptable vehicle has an organic phase and an aqueous phase.

13. The iontophoretic drug delivery device of claim 1 wherein the pharmaceutically acceptable vehicle has a dispersed phase and a continuous phase.

14. The iontophoretic drug delivery device of claim 1, wherein the at least one surfactant of the pharmaceutically acceptable vehicle comprises:

at least a first surfactant and a second surfactant;

wherein the first surfactant is selected from lecithin, hydrogenated lecithin, naturally occurring lecithin, egg lecithin, hydrogenated egg lecithin, soy lecithin, hydrogenated soy lecithin, and vegetable lecithin;

the second surfactant is selected from poloxamers and polyoxypropylene-polyoxethylene block copolymers;

the at least one nonpolar solvent is selected from ethyl laureate, ethyl myristate, isopropyl myristate, isopropyl palmitate, cyclopentane, cyclooctane, trans-decalin, trans-pinane, n-pentane, n-hexane, n-hexadecane, and tripropylamine; and

the at least one polar agent is selected from water, alcohols, polyalcohols, glycerol, glycerols, polyglycerols, ethylene glycol, polyglycols, and formamide.

15. The iontophoretic drug delivery device of claim 14 wherein the pharmaceutically acceptable vehicle takes the form of a lecithin organogel.

16. The iontophoretic drug delivery device of claim 14 wherein the pharmaceutically acceptable vehicle takes the form of a pluronic lecithin organogel.

17. The iontophoretic drug delivery device of claim 1 wherein the pharmaceutically acceptable vehicle is formulated as a controlled-release formulation.

18. The iontophoretic drug delivery device of claim 1, further comprising:

a therapeutically effective amount of one or more active agents stored in the at least one active agent reservoir.

19. The iontophoretic drug delivery device of claim 18 wherein the one or more active agents are selected from immuno-adjuvants, immuno-modulators, immuno-response agents, immuno-stimulators, specific immuno-stimulators, non-specific immuno-stimulators, and immuno-suppressants, or combinations thereof.

20. The iontophoretic drug delivery device of claim 18 wherein the one or more active agents are selected from vaccines, agonists, antagonist, opioid agonist, opioid antagonist, antigens, adjuvants, immunological adjuvants, immunogens, tolerogens, allergens, toll-like receptor agonists, and toll-like receptor antagonists, or combinations thereof.

21. The iontophoretic drug delivery device of claim 18 wherein the one or more active agents are selected from analgesics, anesthetics, or combinations thereof.

22. The iontophoretic drug delivery device of claim 18, further comprising:

at least a therapeutically effective amount of a first active agent and a therapeutically effective amount of a second active agent, the second active agent different than the first active agent, the first and the second active agents stored in the at least one active agent reservoir.

23. The iontophoretic drug delivery device of claim 22 wherein the first active agent is selected from an analgesic and the second active agent is selected from an antihistamine drug.

24. The iontophoretic drug delivery device of claim 22 wherein the first active agent is selected from an analgesic and the second active agent is selected from a steroid.

25. The iontophoretic drug delivery device of claim 22 wherein the first active agent is selected from an analgesic and the second active agent is selected from a vasoconstrictor drug.

26. The iontophoretic drug delivery device of claim 1, further comprising:

at least a first active agent and a second active, the second active agent different than the first active agent, the first and the second active agents stored in the at least one active agent reservoir;

wherein the pharmaceutically acceptable vehicle includes an organic phase for storing the first active agent, and an aqueous phase for storing the second active agent.

27. The iontophoretic drug delivery device of claim 1, wherein the pharmaceutically acceptable vehicle further comprises:

a complex of a cyclodextrin with at least one active agent.

28. A method of making an active agent laminate for an iontophoretic drug delivery device that provides transdermal delivery of one or more therapeutic active agents to a biological interface, comprising:

preparing a lipophilic composition comprising a first surfactant and a nonpolar solvent;

preparing a hydrophilic composition comprising a second surfactant and a polar agent;

mixing the lipophilic composition and the hydrophilic composition using a high-shear mixer to form a pharmaceutically acceptable vehicle having a lipophilic phase and a hydrophilic phase;

impregnating at least one substrate with the pharmaceutically acceptable vehicle;

forming a multi-layer active agent laminate including the at least one substrate with the pharmaceutically acceptable vehicle and at least one delivery rate controlling membrane; and

physically coupling the multi-layer active agent laminate to an active electrode assembly of an iontophoretic drug delivery device, the active electrode assembly including at least one active electrode element operable to provide an electromotive force to drive at least some of the pharmaceutically acceptable vehicle from the multi-layer active agent laminate to a biological interface.

29. The method of claim 28, wherein the lipophilic composition further comprises one or more lipophilic active agents.

30. The method of claim 29, wherein preparing a lipophilic composition further comprises:

combining the first surfactant, the nonpolar solvent, and the one or more lipophilic active agents.

31. The method of claim 28, wherein the hydrophilic composition further comprises one or more hydrophilic active agents.

32. The method of claim 31, wherein preparing a hydrophilic composition further comprises:

combining the second surfactant, the nonpolar agent, and the one or more hydrophilic active agents.

33. The method of claim 28, wherein forming at least one multi-layer active agent laminate comprises:

physically coupling the at least one delivery rate controlling membrane to the at least one active agent reservoir wherein the delivery rate controlling membrane controls the rate of delivery of the pharmaceutically acceptable vehicle.

34. An article of manufacture for transdermal administration of medication by iontophoresis, comprising:

an iontophoretic drug delivery device comprising an active electrode assembly comprising at least one active electrode element and at least one active agent reservoir, the at least one active agent reservoir including a pharmaceutically acceptable vehicle comprising at least one surfactant, at least one nonpolar solvent, and at least one polar agent, the at least one active electrode element operable to provide an electromotive force to drive one or more active agents from the at least one active agent reservoir;

at least one dosage form comprising one or more active agents selected from analgesics, anesthetics, or combinations thereof, the at least one dosage form loaded in the pharmaceutically acceptable vehicle; and

a package insert providing instructions for transdermally administering, to a subject in need of pain therapy, a therapeutically effective amount of the at least one dosage form.

35. The article of manufacture of claim 34, wherein the package insert further comprises:

a table of current dose settings in mA-minutes for delivering a therapeutically effective amount of the at least one dosage form.

36. A method for transdermal administration of at least one analgesic or anesthetic by iontophoresis, comprising:

positioning an active electrode assembly and a counter electrode assembly of an iontophoretic delivery device on a biological interface of a subject, the active electrode including an active agent reservoir comprising at least one analgesic or anesthetic active agent carried by a pharmaceutically acceptable vehicle comprising at least one surfactant, at least one nonpolar solvent, and at least one polar agent; and

applying a sufficient amount of current to transport the at least one analgesic or anesthetic active agent from the active agent reservoir, to the biological interface of the subject, and to administer a therapeutically effective amount of the at least one analgesic or anesthetic active agent to produce analgesic or anesthetic therapy in the subject for a limited period of time.

37. The method of claim 36 wherein the at least one analgesic or anesthetic active agent is selected from alfentanil, codeine, COX-2 inhibitors, opiates, opioid agonist, opioid antagonist, diamorphine, fentanyl, meperidine, methadone, morphine morphinomimetics, naloxone, nonsteroidal anti-inflammatory drugs (NSAIDs), oxycodone, remifentanil, sufentanil, and tricyclic antidepressants, or combinations thereof.

38. The method of claim 36, wherein the at least one analgesic or anesthetic active agent, further comprises:

one or more active agents selected from immuno-adjuvants, immuno-modulators, immuno-response agents, immuno-stimulators, specific immuno-stimulators, non-specific immuno-stimulators, and immuno-suppressants vaccines, agonist, antagonist, opioid agonist, opioid antagonist, antigens, adjuvants, immunological adjuvants, immunogens, tolerogens, allergens, toll-like receptor agonists, and toll-like receptor antagonists, or combinations thereof.

39. The method of claim 36 wherein applying a sufficient amount of current to transport the at least one analgesic or anesthetic active agent comprises:

providing sufficient voltage and current to deliver a therapeutically effective amount of the at least one analgesic or anesthetic active agent carried by the pharmaceutically acceptable vehicle comprising the at least one surfactant, the at least one nonpolar solvent, and the at least one polar agent;

from the active agent reservoir to the biological interface of the subject.

40. The method of claim 36 wherein applying a sufficient amount of current to transport the at least one analgesic or anesthetic active agent comprises:

providing a sufficient voltage and current to the active electrode assembly to substantially achieve sustained-delivery or controlled-delivery of a therapeutically effective amount of the at least one analgesic or anesthetic active agent carried by the pharmaceutically acceptable vehicle comprising the at least one surfactant, the at least one nonpolar solvent, and the at least one polar agent;

from the active agent reservoir to the biological interface of the subject.

41. An iontophoretic drug delivery device for providing transdermal delivery of one or more therapeutic active agents to a biological interface, comprising:

an active electrode assembly including at least one active electrode element; and

at least one active agent reservoir, the at least one active agent reservoir including a pharmaceutically acceptable vehicle comprising a plurality of first vesicles;

wherein the plurality of first vesicles are selected from liposomes, nisomes, ethasomes, transfersomes, virosomes, cyclic oligosaccharides, non ionic surfactant vesicles, and phospholipid surfactant vesicles;

at least some of the first vesicles including one or more therapeutic active agents; and

the at least one active electrode element operable to provide an electromotive force to drive at least some of the pharmaceutically acceptable vehicle comprising the plurality of first vesicles;

from the at least one active agent reservoir to the biological interface.

42. The iontophoretic drug delivery device of claim 41 wherein the one or more therapeutic active agents are selected from immuno-adjuvants, immuno-modulators, immuno-response agents, immuno-stimulators, specific immuno-stimulators, non-specific immuno-stimulators, and immuno-suppressants, or combinations thereof.

43. The iontophoretic drug delivery device of claim 41 wherein the one or more therapeutic active agents are selected from vaccines, agonist, antagonist, opioid agonist, opioid antagonist, antigens, adjuvants, immunological adjuvants, immunogens, tolerogens, allergens, toll-like receptor agonists, and toll-like receptor antagonists, or combinations thereof.

44. The iontophoresis device of claim 41 wherein the one or more therapeutic active agent are selected from centbucridine, tetracaine, Novocaine®

(procaine), ambucaine, amolanone, amylcaine, benoxinate, betoxycaine, carticaine, chloroprocaine, cocaethylene, cyclomethycaine, butethamine, butoxycaine, carticaine, dibucaine, dimethisoquin, dimethocaine, diperodon, dyclonine, ecogonidine, ecognine, euprocin, fenalcomine, formocaine, hexylcaine, hydroxyteteracaine, leucinocaine, levoxadrol, metabutoxycaine, methyl chloride, myrtecaine, butamben, bupivicaine, mepivacaine, beta-adrenoceptor antagonists, opioid analgesics, butanilicaine, ethyl aminobenzoate, fomocine, hydroxyprocaine, isobutyl p-aminobenzoate, naepaine, octacaine, orthocaine, oxethazaine, parenthoxycaine, phenacine, phenol, piperocaine, polidocanol, pramoxine, prilocalne, propanocaine, proparacaine, propipocaine, pseudococaine, pyrrocaine, salicyl alcohol, parethyoxycaine, piridocaine, risocaine, tolycaine, trimecaine, tetracaine, anticonvulsants, antihistamines, articaine, cocaine, procaine, amethocaine, chloroprocaine, Lidocaine®

(xylocaine), marcaine, chloroprocaine, etidocaine, prilocaine, lignocaine, benzocaine, zolamine, ropivacaine, and dibucaine, or combinations thereof.

45. The iontophoretic drug delivery device of claim 41 wherein the pharmaceutically acceptable vehicle comprising a plurality of first vesicles is formulated as a controlled-release formulation.

46. The iontophoresis device of claim 41 wherein a substantial portion of the plurality of first vesicles takes the form of liposomes.

47. The iontophoresis device of claim 41 wherein a substantial portion of the plurality of first vesicles includes one or more therapeutic active agents selected from amphiphilic active agents, lipophilic active agents, hydrophilic active agents, and charged hydrophilic active agents, or combinations thereof.

48. The iontophoresis device of claim 41 wherein a substantial portion of the plurality of first vesicles takes the form of unilamella or multilamellar vesicles

49. The iontophoresis device of claim 41 wherein a substantial portion of the plurality of first vesicles includes at least one vesicle bilayer and an encapsulated aqueous compartment.

50. The iontophoresis device of claim 49 wherein a substantial portion of the plurality of first vesicles includes at least a first therapeutic active agent in the encapsulated aqueous compartment, and a second therapeutic active agent associated with the at least on vesicle bilayer;

the first active agent selected from one or more hydrophilic active agents and charged hydrophilic active agents, the second therapeutic active agent selected from amphiphilic active agents, and lipophilic active agents.

51. The iontophoresis device of claim 41 wherein at least 10% of the plurality of first vesicles includes a first active agent.

52. The iontophoresis device of claim 41 wherein at least 30% of the plurality of first vesicles includes a first active agent.

53. The iontophoresis device of claim 41 wherein at least 60% of the plurality of first vesicles includes a first active agent.