Films based on copolymers, their applications in transdermal systems and their processes of preparation

• US 5,556,635 A
• Filed: 10/27/1994
• Issued: 09/17/1996
• Est. Priority Date: 12/21/1992
• Status: Expired due to Fees

• Current Assignee: Bio Holding, Inc.
• Original Assignee: Spi-Bio
• Inventors: Grognet, Jean-Marc, Darnez, Charles, Istin, Michel
• Primary Examiner(s): BROUILLETTE, D GABRIELLE
• Application Number:
  US08/284,669
• Time in Patent Office: 691 Days
• Field of Search: 424/448, 424/449
• US Class Current: 424/448
• 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

Abstract

Films based on copolymers, their applications in transdermal systems and their processes of preparation. The said films consist of a hydrophobic polymer of ethylene/vinyl acetate (EVA) type containing at least one active principle and composed of 15 to 50% of hydrophilic inclusions formed from at least one hydrophilic monomer chosen from the group which comprises acrylamide, methylolacrylamide, diacetone acrylamide, maleic acid, acrylic acid, fumaric acid, itaconic acid, propylene glycol acrylate, ethylene glycol methacrylate, methacrylamide, methacrylic acid, propylene glycol methacrylate, hydroxyethyl methacrylate, dimethylaminoethyl methacrylate, N-vinylpyrrolidone, vinylacetic acid or vinylsulphonic acids.

Claims

1. A film, capable of being used as an active principle matrix in a transdermal system, comprising:

a hydrophobic ethylene/vinyl acetate polymer containing at least one active principle and composed of 10-50 wt. % of hydrophilic inclusions consisting of a hydrophilic polymer formed from at least one hydrophilic monomer selected from the group consisting of acrylamide, methylolacrylamide, diacetone acrylamide, maleic acid, acrylic acid, fumaric acid, itaconic acid, propylene glycol acrylate, ethylene glycol methacrylate, methacrylamide, methacrylic acid, propylene glycol methacrylate, hydroxyethyl methacrylate, dimethylaminoethyl methacrylate, N-vinylpyrrolidone, vinylacetic acid and vinylsulfonic acids.

2. The film of claim 1, wherein said ethylene/vinyl acetate polymer comprises up to 40 wt. % vinyl acetate.

3. The film of claim 2, wherein said ethylene/vinyl acetate polymer comprises 14-22 wt. % vinyl acetate.

4. The film of claim 1, wherein said hydrophilic monomer comprises acrylic acid.

5. The film of claim 4, wherein said ethylene/vinyl acetate polymer comprises 22-33 wt. % acrylic acid.

6. The film of claim 5, wherein said ethylene/vinyl acetate polymer is an ethylene/vinyl acetate graft copolymer comprising 14-33 wt. % vinyl acetate and having 22-30 wt. % acrylic acid grafted thereto.

7. The film of claim 6, wherein said graft copolymer comprises 14-22 wt. % vinyl acetate and has 26 wt. % acrylic acid grafted thereto.

8. The film of claim 4, wherein said ethylene/vinyl acetate polymer is an ethylene/vinyl acetate graft copolymer containing 30-36 wt. % vinyl acetate and having 26 wt. % acrylic acid grafted thereto.

9. The film of claim 1, wherein said hydrophilic inclusions consist of a hydrophilic polymer formed from a mixture of acrylic acid/N-vinylpyrrolidone or acrylamide/N-vinylpyrrolidone.

10. The film of claim 1, wherein said inclusions consist of a hydrophilic polymer formed from acrylamide.

11. The film of claim 1, having a thickness of 50-500 microns.

12. The film of claim 1, comprising up to 40 wt. % of said active principle.

13. The film of claim 12, wherein said active principle is selected from the group consisting of non-steroidal anti-inflammatory agents, 17β

-oestradiol, progestogen, anticholinesterases, trinitrin, nicotine, morphine, dihydroergotamine, physostigmine, bromocriptine and salicylic acid.

14. The film of claim 13, wherein said active principle is 17β

-oestradiol.

15. The film of claim 13, wherein said active principle is a mixture of oestradiol and progestogen.

16. The film of claim 13, wherein said active principle is physostigmine.

17. The film of claim 13, wherein said active principle is trinitrin.

18. The film of claim 13, wherein said active principle is nicotine.

19. The film of claim 13, wherein said active principle is dihydroergotamine.

20. The film of claim 13, wherein said active principle is bromocriptine.

21. The film of claim 13, wherein said active principle is salicylic acid.

22. The film of claim 13, wherein said active principle is a non-steroidal anti-inflammatory agent selected from the group consisting of ketoprofen and ibuprofen.

23. The film of claim 12, further comprising a permeability stimulator selected from the group consisting of alcohols and polyols.

24. A transdermal system, comprising:

an occlusive support,

the active principle-containing film of claim 1 in contact with said support,

an adhesive interface in contact with said active principle-containing film, and

a protective film in contact with said adhesive interface.

26. The transdermal system of claim 24 or 25, wherein said occlusive film is selected from the group consisting of polyvinylidene dichlorides, polyethylenes, ethylene/polyvinyl alcohols, polypropylenes, polyesters, polychlorotrifluoroethylenes and combinations thereof with a metal sheet, and

said adhesive interface is chemically inert with respect to said active principle-containing film and is selected from the group consisting of acrylic polymers, polyurethanes, silicones and ethylene/vinyl acetate polymers.

27. The transdermal system of claim 24 or 25, wherein said active principle-containing film is an ethylene/vinyl acetate-acrylic acid graft copolymer.

28. The transdermal system of claim 27, wherein said ethylene/vinyl acetate-acrylic acid graft copolymer comprises 18 wt. % vinyl acetate and 26 wt. % acrylic acid.

29. The transdermal system of claim 24 or 25, wherein said active principle-containing film is an ethylene/vinyl acetate-acrylamide graft copolymer.

30. The transdermal system of claim 24 or 25, wherein said active principle-containing film further comprises a permeability stimulator selected from the group consisting of alcohols and polyols.

31. The transdermal system of claim 24 or 25, wherein said active principle-containing film comprises at least two active principles.

32. The transdermal system of claim 24 or 25, wherein said active principle is distributed throughout said active principle-containing film.

33. The transdermal system of claim 31, wherein said active principle-containing film has at least two regions and said at least two active principles are separately distributed in said at least two regions.

34. A process for the preparation of the film of claim 1, comprising the steps of:

(a) contacting a hydrophobic ethylene/vinyl acetate polymer with at least one hydrophilic monomer selected from the group consisting of acrylamide, methylolacrylamide, diacetone acrylamide, maleic acid, acrylic acid, fumaric acid, itaconic acid, propylene glycol acrylate, ethylene glycol methacrylate, methacrylamide, methacrylic acid, propylene glycol methacrylate, hydroxyethyl methacrylate, dimethylaminoethyl methacrylate, N-vinylpyrrolidone, vinylacetic acid and vinylsulfonic acids to form a mixture,

(b) irradiating said mixture for simultaneously polymerizing said hydrophilic monomers to form hydrophilic polymer and grafting said hydrophilic polymer onto said hydrophobic ethylene/vinyl acetate polymer to form an ethylene/vinyl acetate copolymer having grafted thereto said hydrophilic polymer, to obtain an ethylene/vinyl acetate graft copolymer having a degree of grafting of said hydrophilic polymer of 10-50% to form a copolymer matrix,

(c) charging said ethylene/vinyl acetate polymer or said copolymer matrix with an active principle, and

(d) shaping said copolymer matrix or said charged copolymer matrix to form a film.

35. The process of claim 34, wherein said irradiating and polymerizing step (b) is carried out in a liquid medium in the presence of an inhibitor of homopolymerization of said hydrophilic monomer.

36. The process of claim 34, wherein said irradiating and polymerizing step (b) is carried out in a liquid medium in the presence of a copolymerizable crosslinking agent.

37. The process of claim 35, wherein said copolymerizable crosslinking agent is selected from the group consisting of methylenebisacrylamide, divinylbenzene, triallyl cyanurate, ethylene, butylene glycol acrylates, butylene glycol methacrylates, tetraethylene glycol acrylates, tetraethylene glycol methacrylates and triallyl orthophosphate.

38. The process of claim 34, wherein said irradiating and polymerizing step (b) is carried out by irradiating with ionizing radiation to provide a total irradiation dose of between 0.5-50 kGy.

39. The process of claim 34, wherein said charging step (c) is carried out before said shaping step (d).

40. The process of claim 34, wherein said charging step (c) is carried out after said shaping step (d).

41. The process of claim 34, wherein said charging step (c) comprises steeping said active principle into said ethylene/vinyl acetate polymer or said copolymer matrix, dispersing said active principle into said ethylene/vinyl acetate polymer or said copolymer matrix, diffusing said active principle into said ethylene/vinyl acetate polymer or said copolymer matrix from a support impregnated with said active principle, or immersing said ethylene/vinyl acetate polymer or said copolymer matrix in a saturated vapor atmosphere of said active principle.

42. The process of claim 34, wherein said shaping step (d) is carried out by extrusion.

43. A process for the preparation of the film of claim 1, comprising the steps of:

(a) irradiating a hydrophobic ethylene/vinyl acetate polymer in the powder, granule, or film form, at a dose between 10-80 kGy,

(b) storing the irradiated ethylene/vinyl acetate polymer,

(c) contacting said stored irradiated ethylene/vinyl acetate polymer with at least one hydrophilic monomer selected from the group consisting of acrylamide, methylolacrylamide, diacetone acrylamide, maleic acid, acrylic acid, fumaric acid, itaconic acid, propylene glycol acrylate, ethylene glycol methacrylate, methacrylamide, methacrylic acid, propylene glycol methacrylate, hydroxyethyl methacrylate, dimethylaminoethyl methacrylate, N-vinylpyrrolidone, vinylacetic acid, and vinylsulfonic acids to form an ethylene/vinyl acetate copolymer having grafted thereto said hydrophilic monomer in the form of a hydrophilic polymer, to obtain an ethylene/vinyl acetate graft copolymer having a degree of grafting of said hydrophilic polymer of 10-50%, to form a copolymer matrix,

(c) charging said ethylene/vinyl acetate polymer or said copolymer matrix with an active principle, and

(d) shaping said copolymer matrix or said charged copolymer matrix to form a film.

25. A transdermal system comprising:

an occlusion support,

an active principle-containing film comprising a hydrophobic ethylene/vinyl acetate polymer containing at least one active principle and composed of 10-50 wt. % of hydrophilic inclusions consisting of a hydrophilic polymer formed from at least one hydrophilic monomer selected from the group consisting of acrylamide, ethylene glycol acrylate, methylolacrylamide, diacetone acrylamide, maleic acid, acrylic acid, fumaric acid, itaconic acid, propylene glycol acrylate, ethylene glycol methacrylate, methacrylamide, methacrylic acid, propylene glycol methacrylate, hydroxyethyl methacrylate, dimethylaminoethyl methacrylate, N-vinylpyrrolidone, vinylacetic acid and vinyl sulfonic acids, in contact with said support,

an adhesive interface in contact with said active principle-containing film, and

a protective film in contact with said adhesive interface.

44. A process for the preparation of an ethylene/vinyl acetate graft copolymer having grafted thereto hydrophilic monomers in the form of a hydrophilic polymer, comprising the steps of:

(a) irradiating a hydrophobic ethylene/vinyl acetate polymer in the powder, granule, or film form, at a dose between 10-80 kGy,

(b) storing the irradiated ethylene/vinyl acetate polymer,

(c) contacting said stored irradiated ethylene/vinyl acetate polymer with at least one hydrophilic monomer selected from the group consisting of acrylamide, methylolacrylamide, diacetone acrylamide, maleic acid, acrylic acid, fumaric acid, itaconic acid, propylene glycol acrylate, ethylene glycol methacrylate, methacrylamide, methacrylic acid, propylene glycol methacrylate, hydroxyethyl methacrylate, dimethylaminoethyl methacrylate, N-vinylpyrrolidone, vinylacetic acid, and vinylsulfonic acids to form an ethylene/vinyl acetate copolymer having grafted thereto said hydrophilic monomer in the form of a hydrophilic polymer, to obtain an ethylene/vinyl acetate graft copolymer having a degree of grafting of said hydrophilic polymer of 10-50%, to form a copolymer matrix.