IONTOPHORETIC DEVICE AND METHOD OF DELIVERY OF ACTIVE AGENTS TO BIOLOGICAL INTERFACE

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IONTOPHORETIC DEVICE AND METHOD OF DELIVERY OF ACTIVE AGENTS TO BIOLOGICAL INTERFACE
World Intellectual Property Organization
WO/2007/038555

CLAIMS

claim:

1. An iontophoresis device to delivery active agents to a biological interface, the iontophoresis device comprising an active electrode assembly and a counter electrode assembly, the active electrode assembly further including: an active electrode element operable to provide an electrical potential; an electrolyte reservoir comprising an electrolyte composition; and an inner active agent reservoir including a gel matrix and distributed in said gel matrix, a first positively charged active agent, the gel matrix comprising a hydrophilic polycarboxylated polymer having net negative charges.

2. The iontophoresis device of claim 1 wherein the polycarboxylated polymer comprises linear primary polymer particles having a plurality of carboxylate groups, the primary polymer particles being chemically bonded and interconnected via cross-linkers.

3. The iontophoresis device of claim 2 wherein the linear primary polymer is represented by the following formula:

wherein, n is an integer of at least 10;

Ri. R2, R3 and R4 are the same or different and independently hydrogen, alkyl, alkenyl, -COOR Or -CH2COOR, provided at least one of R1, R2, R3 and R4 is -COOR or -CH2COOR, and

R is hydrogen, lower alkyl, aryl, aralkyl, amino (including mono- or di-substituted aminos), or a counter ion.

4. The iontophoresis device of claim 2 wherein the cross- linker is a molecule comprising at least two olefinic bonds.

5. The iontophoresis device of claim 4 wherein the cross- linker is allyl ethers of sucrose, pentaerythritol, polyalkenyl ethers, divinyl glycol, divinylbenzene, N,N-diallylacrylamide, 3,4-dihydroxy-1 ,5-hexadiene, 2,5- dimethyl-1 ,5-hexadiene and similar agents.

6. The iontophoresis device of claim 2 wherein the polycarboxylated polymer is a CarbopolŮ.

7. The iontophoresis device of claim 1 wherein the electrolyte composition comprises water, physiological ions and an anti-oxidant.

8. The iontophoresis device of claim 7 wherein the electrolyte composition includes a hydrogel.

9. The iontophoresis device of claim 7 wherein the antioxidant is ascorbic acid, tocopherol, sodium citrate or a combination thereof.

10. The iontophoresis device of claim 2 wherein the positively charged active agents bind to the negatively charged polycarboxylated polymer gel matrix via ionic interaction at pH in the range of about 3 - 6.8.

11. The iontophoresis device of claim 10 wherein the positively charged active agents dissociate from polycarboxylated polymer gel matrix at pH below 3.


12. The iontophoresis device of claim 2 wherein the positively charged active agents bind to the negatively charged polycarboxylated polymer gel matrix via ionic interaction at pH in the range of about 5.5 - 6.5.

13. The iontophoresis device of claim 12 wherein the positively charged active agents dissociate from polycarboxylated polymer gel matrix at pH below 5.5.

14. The iontophoresis device of claim 1 further comprising an inner ion selective membrane positioned between said electrolyte reservoir and said inner active agent reservoir,

15. The iontophoresis device of claim 14 wherein the inner ion selective membrane substantially passes anions and substantially blocks cations.

16. The iontophoresis device of claim 14 further comprising an outermost ion selective membrane having an outer surface, the outer surface being proximate the biological interface when in use.

17. The iontophoresis device of claim 16 the outer ion selective membrane substantially passes cations and substantially blocks anion.

18. The iontophoresis device of claim 16 further comprising a second positively charged active agent cached in the outermost ion selective membrane.

19. The iontophoresis device of claim 16 further comprising a third positively charged active agent deposited on the outer surface of the outermost ion selective membrane.


20. The iontophoresis device of claim 16 further comprising an outer release liner underlying said outer surface, said outer release liner being proximate the biological interface when in use.

21. The iontophoresis device of claim 1 further comprising a microneedle array contacting an outer surface of the iontophoresis device.

22. The iontophoresis device of claim 1 wherein the active electrode element is an inert electrode.

23. The iontophoresis device of claim 22 wherein the electrolyte composition comprising water and protons are produced when in use.

24. The iontophoresis device of claim 1 wherein the positively charged active agents are 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, 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, marcaine, chloroprocaine, etidocaine, prilocaine, lignocaine, benzocaine, zolamine, ropivacaine, and dibucaine, or combinations thereof.


25. The iontophoresis device of claim 1 wherein the first positively charged active agent is Lidocaine? .

26. An article of manufacture for transdermal administration of medication by iontophoresis, comprising: an active electrode assembly includig an active electrode element operable to provide an electrical potential; an electrolyte reservoir comprising an electrolyte composition; and an inner active agent reservoir including a gel matrix, the gel matrix being a hydrophilic polycarboxylated polymer having net negative charges; and at least one dosage form comprising one or more active agents loaded in the inner active agent reservoir.

27. The article of manufacture of claim 26 wherein the one or more active agents are positively charged.

28. The article of manufacture of claim 26 wherein the one or more active agents include analgesic or anesthetic agents.

29. The article of manufacture of claim 28 wherein the one or more active agents are 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, marcaine, chloroprocaine, etidocaine, prilocaine, lignocaine, benzocaine, zolamine, ropivacaine, and dibucaine, or combinations thereof.

30. The article of manufacture of claim 28 wherein the one or more active agents include Lidocaine?.

31. The article of manufacture of claim 27 wherein the iontophoresis device further comprises an inner ion selective membrane positioned between the electrolyte reservoir and the inner active agent reservoir.

32. The article of manufacture of claim 31 wherein the inner ion selective membrane passes anions and substantially blocks cations.

33. The article of manufacture of claim 31 wherein the iontophoresis device further comprises an outer ion selective membrane, wherein the outer ion selective membrane passes cations and substantially blocks anions.

34. The article of manufacture of claim 26 further comprising a counter electrode assembly.

35. A method for transdermal administration of an active agent by iontophoresis, comprising: positioning an active electrode assembly and a counter electrode assembly of an iontophoresis device on a biological interface of a subject, the active electrode assembly including an active electrode element operable to provide an electrical potential; an electrolyte reservoir comprising an electrolyte

composition; and an inner active agent reservoir comprising a gel matrix and distributed in said gel matrix, a positively charged active agent, the gel matrix comprising a hydrophilic polycarboxylated polymer having net negative charges; wherein the positively charged active agent is bound to the gel matrix; and applying a sufficient amount of current to release the active agent from the gel matrix and transport the active agent to the biological interface of the subject, and to administer a therapeutically effective amount of the positively charged active agent in the subject for a limited period of time.

36. The method of claim 35 wherein applying the sufficient amount of current include electrochemically oxidizing water in the electrolyte composition and producing protons.

37. The method of claim 36 wherein the protons neutralize the negative charge of the gel matrix and cause the positively charged active agent to be released.