Transdermal delivery system for anti-emetic medication

• US 7,415,306 B2
• Filed: 04/27/2005
• Issued: 08/19/2008
• Est. Priority Date: 10/31/2002
• Status: Expired due to Fees

• Current Assignee: Syneron Medical Limited (Syneron Incorporated)
• Original Assignee: TransPharma Medical Ltd. (Syneron Incorporated)
• Inventors: Levin, Galit, Daniel, Dorit
• Primary Examiner(s): Kennedy; Sharon E.
• Application Number:
  US11/116,065
• Publication Number:
  US 20050260252A1
• Time in Patent Office: 1,210 Days
• Field of Search: 604/21, 604/20, 604/501, 607/2, 607/3, 600/391, 600/372
• US Class Current: 604/20
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• CPC Class Codes: A61K 9/7053 obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
• CPC Class Codes: A61K 9/7061 Polyacrylates
• CPC Class Codes: A61N 1/0476 Array electrodes (including any electrode arrangement with more than one electrode for at least one of the polarities)
• CPC Class Codes: A61N 1/0496 characterised by using specific chemical compositions, e.g. hydrogel compositions, adhesives
• CPC Class Codes: A61N 1/325 for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body electrodes for external use A61N1/0428
• CPC Class Codes: A61N 1/327 for enhancing the absorption properties of tissue, e.g. by electroporation
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides a transdermal delivery system for hydrophilic anti-emetic agents and methods of using thereof. The system includes an anti-emetic hydrophilic adhesive composition of a hydrophilic polymer and hydrophilic anti-emetic agent, a patch containing at least one hydrophilic layer of the composition, and an apparatus that generates hydrophilic micro-channels in skin of a subject using the patch or composition. The system preferably avoids the use of penetration enhancers and is particularly useful for transdermal delivery of hydrophilic anti-emetic agents.

Claims

1. A system for transdermal delivery of a hydrophilic anti-emetic agent from a pharmaceutical composition comprising:

an apparatus for facilitating transdermal delivery of a hydrophilic anti-emetic agent through skin of a subject, said apparatus comprises;

(a) an electrode cartridge comprising at least one electrode; and

(b) a main unit comprising a control unit which is adapted to apply electrical energy to the electrode when the electrode is in vicinity of the skin, enabling ablation of stratum corneum in an area beneath the electrode, thereby generating at least one micro-channel in an area on the skin of the subject;

and a separate patch that does not receive electrical energy from the apparatus, the patch is adapted to be applied to the area on the skin after the at least one microchannel is generated, said patch comprising at least one hydrophilic layer comprising a hydrophilic polymer and a therapeutically effective amount of the hydrophilic anti-emetic agent in a pharmaceutical composition, devoid of permeation enhancers.

2. The system according to claim 1, wherein the patch further comprises at least one layer selected from a backing layer, an adhesive, and a release liner.

3. The system according to claim 1, wherein the hydrophilic polymer is selected from the group consisting of cellulose, hydroxy cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polysaccharides, chitin, chitosan, diacylated chitin, gum acacia, agarose, carrageenan, gelatin, gum tragacanth, alginate, karaya gum, veegum, pectin, hyaluronic acid, pluronic acid, maltodextrin, polyvinylpyrrolidone, polyglycolic acid, polyoxyethylene, polyoxypropylene, colloidal silicon dioxide, polyvinyl alcohol, polyacrylamide, polyacrylic acid, polyacrylates, methacrylate polymers, and fumed silica.

4. The system according to claim 1, wherein the electrode cartridge is removable.

5. The system according to claim 1, wherein the electrode cartridge comprises a plurality of electrodes capable of generating a plurality of micro-channels of uniform shape and dimensions.

6. The system according to claim 1, wherein the electrical energy is of radio frequency.

7. The system according to claim 1, wherein the anti-emetic agent is selected from the group consisting of dopamine antagonists, acetylcholine receptor antagonists, 5-hydroxytryptamine receptor antagonists, and pharmaceutically acceptable salts, and hydrates thereof.

8. The system according to claim 7, wherein the 5-hydroxytryptamine receptor antagonist is selected from the group consisting of hydrophilic derivatives of granisetron, ondansetron, lerisetron, dolasetron, tropisetron, itasetron, and ramosetron.

9. The system according to claim 8, wherein the 5-hydroxytryptamine receptor antagonist is granisetron hydrochloride.

10. The system according to claim 1, wherein the pharmaceutical composition further comprises at least one component selected from the group consisting of a plasticizer, a cross-linker, a buffering agent, a stabilizer, and an anti-oxidant.

11. A method for transdermal administration of a hydrophilic anti-emetic agent comprising:

generating at least one micro-channel in an area of skin of a subject; and

affixing a patch to the area of skin where the at least one micro-channel is present, the patch comprises at least one hydrophilic layer comprising a hydrophilic polymer and a therapeutically effective amount of a hydrophilic anti-emetic agent in a pharmaceutical composition, devoid of permeation enhancers.

12. The method according to claim 11, wherein generating the at least one micro-channel is performed by an apparatus comprising:

an electrode cartridge comprising at least one electrode; and

a main unit comprising a control unit which is adapted to apply electrical energy to the electrode when the electrode is in vicinity of the skin, enabling ablation of stratum corneum in an area beneath the electrode, thereby generating at least one micro-channel.

13. The method according to claim 12, wherein the electrode cartridge is removable.

14. The method according to claim 12, wherein the electrode cartridge comprises a plurality of electrodes capable of generating a plurality of micro-channels of uniform shape and dimensions.

15. The method according to claim 12, wherein the electrical energy is of radio frequency.

16. The method according to claim 11, wherein the anti-emetic agent is selected from the group consisting of dopamine antagonists, acetylcholine receptor antagonists, 5-hydroxytryptamine receptor antagonists, and pharmaceutically acceptable salts, and hydrates thereof.

17. The method according to claim 16, wherein the 5-hydroxytryptamine receptor antagonist is selected from the group consisting of hydrophilic derivatives of granisetron, ondansetron, lerisetron, dolasetron, tropisetron, itasetron, and ramosetron.

18. The method according to claim 17, wherein the 5-hydroxytryptamine receptor antagonist is granisetron hydrochloride.

19. The method according to claim 11, wherein the pharmaceutical composition further comprises at least one component selected from the group consisting of a plasticizer, a cross-linker, a buffering agent, a stabilizer, and an anti-oxidant.

20. The method according to claim 11, wherein the patch further comprises at least one layer selected from the group consisting of a backing layer, an adhesive, and a release liner.

21. The method according to claim 11, wherein the hydrophilic polymer is selected from the group consisting of cellulose, hydroxy cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polysaccharides, chitin, chitosan, diacylated chitin, gum acacia, agarose, carrageenan, gelatin, gum tragacanth, alginate, karaya gum, veegum, pectin, hyaluronic acid, pluronic acid, maltodextrin, polyvinylpyrrolidone, polyglycolic acid, polyoxyethylene, polyoxypropylene, colloidal silicon dioxide, polyvinyl alcohol, polyacrylamide, polyacrylic acid, polyacrylates, methacrylate polymers, and fumed silica.

22. A method of transdermal administration of a hydrophilic anti-emetic agent comprising:

generating at least one micro-channel in an area of the skin of a subject; and

thereafter affixing a patch to the area of skin of the subject where the at least one micro-channel is present, wherein the patch comprises at least one hydrophilic layer comprising a hydrophilic polymer and a therapeutically effective amount of a hydrophilic anti-emetic agent in a pharmaceutical composition, devoid of permeation enhancers, the hydrophilic anti-emetic agent capable of diffusing through the at least one micro-channel to achieve a therapeutically effective serum concentration of at least 1 ng/ml in the subject.

23. The method according to claim 22 wherein the therapeutically effective serum concentration of the anti-emetic agent of at least 1 ng/ml is maintained for at least 24 to 48 hours.

24. The method according to claim 22, wherein generating the at least one micro-channel is performed by an apparatus comprising:

an electrode cartridge comprising at least one electrode; and

a main unit comprising a control unit which is adapted to apply electrical energy to the electrode when the electrode is in vicinity of the skin, enabling ablation of stratum corneum in an area beneath the electrode, thereby generating at least one micro-channel.

25. The method according to claim 24, wherein the electrode cartridge is removable.

26. The method according to claim 24, wherein the electrode cartridge comprises a plurality of electrodes capable of generating a plurality of micro-channels of uniform shape and dimensions.

27. The method according to claim 24, wherein the electrical energy is of radio frequency.

28. The method according to claim 22, wherein the anti-emetic agent is selected from the group consisting of dopamine antagonists, acetylcholine receptor antagonists, 5-hydroxytryptamine receptor antagonists, and pharmaceutically acceptable salts, and hydrates thereof.

29. The method according to claim 28, wherein the 5-hydroxytryptamine receptor antagonist is selected from the group consisting of hydrophilic derivatives of granisetron, ondansetron, lerisetron, dolasetron, tropisetron, itasetron, and ramosetron.

30. The method according to claim 29, wherein the 5-hydroxytryptamine receptor antagonist is granisetron hydrochloride.

31. The method according to claim 22, wherein the pharmaceutical composition further comprises at least one component selected from the group consisting of a plasticizer, a cross-linker, a buffering agent, a stabilizer, and an anti-oxidant.

32. The method according to claim 22, wherein the patch further comprises at least one layer selected from the group consisting of a backing layer, an adhesive, and a release liner.

33. The method according to claim 22, wherein the hydrophilic polymer is selected from the group consisting of cellulose, hydroxy cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polysaccharides, chitin, chitosan, diacylated chitin, gum acacia, agarose, carrageenan, gelatin, gum tragacanth, alginate, karaya gum, veegum, pectin, hyaluronic acid, pluronic acid, maltodextrin, polyvinylpyrrolidone, polyglycolic acid, polyoxyethylene, polyoxypropylene, colloidal silicon dioxide, polyvinyl alcohol, polyacrylamide, polyacrylic acid, polyacrylates, methacrylate polymers, and fumed silica.