Cyanoacrylate solutions containing preservatives

• US 6,579,469 B1
• Filed: 10/29/1999
• Issued: 06/17/2003
• Est. Priority Date: 10/29/1999
• Status: Expired due to Term

• Current Assignee: Ethicon Incorporated (Johnson & Johnson)
• Original Assignee: Closure Medical Corporation (Johnson & Johnson)
• Inventors: Badejo, Ibraheem T., Stewart, Ubonwan A., Narang, Upvan, Hedgpeth, Daniel L., Nicholson, William S. C., Mainwaring, Lawrence H.
• Primary Examiner(s): MEDLEY, MARGARET B
• Application Number:
  US09/430,180
• Time in Patent Office: 1,327 Days
• Field of Search: 252/182.11, 252/182.18, 252/182.29, 524/310, 524/295, 524/296, 524/297, 524/315, 524/317, 524/486, 524/470, 524/375, 524/369, 524/259, 524/81, 521/71, 521/74, 521/77, 521/173, 422/1, 422/22, 523/111, 523/118, 522/152
• US Class Current: 252/182.11
• CPC Class Codes: A61L 24/001 Use of materials characterised by their function or physical properties
• CPC Class Codes: A61L 24/06 obtained by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043, A61L24/046 take precedence
• CPC Class Codes: C08F 22/32 Alpha-cyano-acrylic acid; Esters thereof
• CPC Class Codes: C08F 222/326 Alpha-cyano-acrylic acid longer chain ester
• CPC Class Codes: C08L 35/04 Homopolymers or copolymers of nitriles C08L35/06, C08L35/08 take precedence
• CPC Class Codes: C09J 4/00 Adhesives based on organic non-macromolecular compounds having at least one polymerisable carbon-to-carbon unsaturated bond ; adhesives, based on monomers of macromolecular compounds of groups C09J183/00 - C09J183/16

Abstract

An adhesive composition that contains a preservative is particularly useful as a medical adhesive and can include alkyl cyanoacrylate monomers. The preservative is preferably soluble in the monomer. The composition may optionally be sterilized by placing a mixture of a polymerizable adhesive monomer and a preservative in a container, sealing the container, and sterilizing the mixture and the container.

Claims

1. A monomeric adhesive composition comprising a polymerizable alkyl cyanoacrylate monomer and an antimicrobial preservative agent, wherein said agent is soluble in said monomer at room temperature and substantially all of said monomer remains stable for at least five minutes after forming the composition,

wherein said agent is selected from the group consisting of parabens, cresols, pyrocatechol, resorcinol, 4-n-hexyl resorcinol, 3a,4,7,7a-tetrahydro-2-((trichloromethyl)thio)-1H-isoindole-1,3(2H)-dione, benzyl alcohol, chlorobutanol, dehydroacetic acid, methylparaben sodium, o-phenylphenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium benzoate, potassium sorbate, propylparaben sodium, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal, 4-chloro-1-butanol, methyl-4-hydroxy benzoate, elemental metals and metal compounds, and a non-polymer stabilized material that is soluble or insoluble in the monomer.

2. The composition of claim 1, wherein said composition remains stable for at least one hour after forming the composition.

3. The composition of claim 1, wherein said composition remains stable for at least twenty-four hours after forming the composition.

4. The composition of claim 1, wherein said composition remains stable for at least eighteen months after forming the composition.

5. The composition of claim 1, wherein said composition remains stable for at least twenty-four months after forming the composition.

6. The composition of claim 1, wherein a concentration of said agent is substantially uniform throughout said composition.

7. The composition of claim 1, wherein said monomer is at least one member selected from the group consisting of n-butyl cyanoacrylate, 2-octyl cyanoacrylate, and ethyl cyanoacrylate.

8. The composition of claim 1, wherein said agent is selected from the group consisting of parabens and cresols.

9. The composition of claim 1, wherein said agent is selected from the group consisting of alkyl parabens having an alkyl group of from 1-4 carbon atoms.

10. The composition of claim 1, wherein said agent is methylparaben.

11. The composition of claim 1, wherein said agent is selected from the group consisting of pyrocatechol, resorcinol, 4-n-hexyl resorcinol, 3a,4,7,7a-tetrahydro-2-((trichloromethyl)thio)-1H-isoindole-1,3(2H)-dione, benzyl alcohol, butylparaben, chlorobutanol, chlorocresol, cresol, dehydroacetic acid, ethylparaben, methylparaben, methylparaben sodium, o-phenylphenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium benzoate, potassium sorbate, propylparaben, propylparaben sodium, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, and thimerosal.

13. The composition of claim 1, wherein said agent is 4-chloro-1-butanol.

16. The composition of claim 1, wherein said agent is methyl-4-hydroxy benzoate.

17. The composition of claim 1, wherein said agent is selected from the group consisting of elemental metals and metal compounds.

18. The composition of claim 1, wherein said agent is an elemental metal selected from the group consisting of silver and copper.

19. The composition of claim 1, wherein said agent is a metal compound selected from the group consisting of mercurial compounds, copper chloride, copper sulfate, copper peptides, zinc chloride, zinc sulfate, silver nitrate, silver iodide, silver acetate, silver benzoate, silver carbonate, silver chloride, silver citrate, silver oxide, silver sulfate, and tincture of iodine.

20. The composition of claim 1, wherein said agent is a mercurial compound selected from the group consisting of phenolmercuric chloride, phenolmercuric acetate, acetomeroctol, nitromersol, thimerosal, mercurochrome, mercuric chloride, and mercuric iodide.

21. The composition of claim 1, wherein said agent is provided by a non-polymer stabilized material that is soluble or insoluble in the monomer.

22. The composition of claim 21, wherein said agent comprises ions released by said material.

23. The composition of claim 21, wherein said material is insoluble in the monomer.

24. The composition of claim 21, wherein said material is in a form selected from the group consisting of a hollow sphere, a solid ball, a cube, and a flat sheet.

25. The composition of claim 1, wherein said agent is a zinc compound.

26. The composition of claim 1, wherein said agent is selected from the group consisting of methylparaben, ethylparaben, propylparaben, butylparaben, and mixtures thereof.

27. The composition of claim 25, wherein said zinc compound is selected from the group consisting of zinc salts of cyanoacrylic acid, zinc salts of cyanoacetic acid, zinc salts of dicyanoglutaric acid, zinc salts of rosin, zinc oxide, zinc salts of polycyanoacrylic acid, zinc salts of polyacrylic acid, zinc bacitracin, zinc salicylate, zinc stearate, zinc citrate, zinc lactate, and mixtures thereof.

28. The composition of claim 1, wherein said composition has a viscosity of about 1-5000 centipoise at 25°

C.

29. The composition of claim 1, wherein said composition has a viscosity of about 3-600 centipoise at 25°

C.

30. The composition of claim 1, wherein said composition has a viscosity of about 4-50 or 100-250 centipoise at 25°

C.

31. The composition of claim 1, wherein said composition is a gel.

32. The composition of claim 1, wherein said composition further comprises a plasticizing agent.

33. The composition of claim 1, wherein said composition is sterile.

34. The composition of claim 1, wherein said composition is packaged in a single-use container.

35. The composition of claim 1, wherein said composition is packaged in a multi-use container.

12. A method of making a sterile, antimicrobial adhesive composition comprising:

placing a mixture of a polymerizable alkyl cyanoacrylate monomer and an antimicrobial preservative agent in a container,

sealing said container, and

sterilizing the mixture in the container,

wherein said mixture remains stable for at least five minutes after forming the mixture, and

wherein said agent is selected from the group consisting of parabens, cresols, pyrocatechol, resorcinol, 4-n-hexyl resorcinol, 3a,4,7,7a-tetrahydro-2-((trichloromethyl)thio)-1H-isoindole-1,3(2H)-dione, benzyl alcohol, chlorobutanol, dehydroacetic acid, methylparaben sodium, o-phenylphenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium benzoate, potassium sorbate, propylparaben sodium, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal, 4-chloro-1-butanol, methyl-4-hydroxy benzoate, elemental metals and metal compounds, and a non-polymer stabilized material that is soluble or insoluble in the monomer.

14. The method of claim 12, wherein said agent is selected from the group consisting of methylparaben, ethylparaben, propylparaben, butylparaben, and mixtures thereof.

15. The method of claim 12, wherein said mixture further comprises at least one stabilizer.

47. The method of claim 12, wherein said mixture remains stable for at least one hour after forming the composition.

48. The method of claim 12, wherein said mixture remains stable for at least twenty-four hours after forming the composition.

49. The method of claim 12, wherein said composition remains stable for at least eighteen months after forming the composition.

50. The method of claim 12, wherein said composition remains stable for at least twenty-four months after forming the composition.

51. The method of claim 12, wherein said agent is soluble in said monomer at room temperature and said mixture is a solution.

52. The method of claim 51, wherein a concentration of said agent is substantially uniform throughout said solution.

53. The method of claim 12, wherein said sterilizing is performed by dry heat, moist heat, gamma irradiation, electron beam irradiation, microwave irradiation, or retort canning.

54. The method of claim 12, wherein said sterilizing is performed by dry heat.

55. The method of claim 12, wherein said sterilizing is performed by gamma irradiation.

56. The method of claim 12, wherein said sterilizing is performed by electron beam irradiation.

57. The method of claim 12, wherein said sterilizing is performed by retort canning.

58. The method of claim 12, wherein said container is made from at least one material selected from the group consisting of glass, plastic, and metal.

59. The method of claim 12, wherein said container is made from plastic.

60. The method of claim 12, wherein said container is made from glass.

36. A method of making a monomeric adhesive composition, comprising dissolving an antimicrobial preservative agent in a polymerizable alkyl cyanoacrylate monomer, wherein said agent is soluble in the monomer at room temperature and said composition remains stable for at least five minutes after forming the composition,

wherein said agent is selected from the group consisting of parabens, cresols, pyrocatechol, resorcinol, 4-n-hexyl resorcinol, 3a,4,7,7a-tetrahydro-2-((trichloromethyl)thio)-1H-isoindole-1,3(2H)-dione, benzyl alcohol, chlorobutanol, dehydroacetic acid, methylparaben sodium, o-phenylphenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium benzoate, potassium sorbate, propylparaben sodium, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal, 4-chloro-1-butanol, methyl-4-hydroxy benzoate, elemental metals and metal compounds, and a non-polymer stabilized material that is soluble or insoluble in the monomer.

37. The method of claim 36, wherein said composition remains stable for at least one hour after forming the composition.

38. The method of claim 36, wherein said composition remains stable for at least twenty-four hours after forming the composition.

39. The method of claim 36, wherein said composition remains stable for at least eighteen months after forming the composition.

40. The method of claim 36, wherein said composition remains stable for at least twenty-four months after forming the composition.

41. The method of claim 36, wherein a concentration of said agent is substantially uniform throughout said composition.

42. The method of claim 36, wherein said agent is provided by a non-polymer stabilized material that is soluble or insoluble in the monomer.

43. The method of claim 42, wherein said agent comprises ions released by said material.

44. The method of claim 42, wherein said material is insoluble in the monomer.

45. The method of claim 36, further comprising sterilizing said mixture.

46. The method of claim 36, wherein said agent is selected from the group consisting of methylparaben, ethylparaben, propylparaben, butylparaben, and mixtures thereof.