POLYMER FORMULATIONS FOR NASOLACRIMAL STIMULATION

• US 20150238754A1
• Filed: 02/24/2015
• Published: 08/27/2015
• Est. Priority Date: 02/25/2014
• Status: Active Grant

• Current Assignee: Oculeve Incorporated (Abbvie Incorporated)
• Original Assignee: Oculeve Incorporated (Abbvie Incorporated)
• Inventors: LOUDIN, James Donald, GUPTA, Amitava, WARDLE, John, STIVERS, Christopher William, DORAISWAMY, Anand, CHRIST, Marie Dvorak, CHRIST, F. Richard
• Granted Patent: US 9,770,583 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61N 1/0456 Specially adapted for transcutaneous electrical nerve stimulation [TENS]
• CPC Class Codes: A61N 1/0496 characterised by using specific chemical compositions, e.g. hydrogel compositions, adhesives
• CPC Class Codes: A61N 1/0546 Nasal electrodes
• CPC Class Codes: A61N 1/36014 External stimulators, e.g. with patch electrodes external pacemakers A61N1/3625
• CPC Class Codes: C08F 220/20 of polyhydric alcohols or phenols , e.g. 2-hydroxyethyl (meth)acrylate or glycerol mono-(meth)acrylate
• CPC Class Codes: C08F 220/54 Amides , e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
• CPC Class Codes: C08F 222/102 of dialcohols, e.g. ethylene glycol di(meth)acrylate or 1,4-butanediol dimethacrylate
• CPC Class Codes: C08F 226/10 N-Vinyl-pyrrolidone
• CPC Class Codes: C08F 230/08 containing silicon
• CPC Class Codes: H01B 1/125 comprising aliphatic main chains, e.g. polyactylenes
• CPC Class Codes: Y10T 29/49826 Assembling or joining
• CPC Class Codes: Y10T 29/49885 with coating before or during assembling

Abstract

Described herein are polymer formulations for facilitating electrical stimulation of nasal or sinus tissue. The polymer formulations may be hydrogels that are prepared by a UV cross-linking process. The hydrogels may be included as a component of nasal stimulator devices that electrically stimulate the lacrimal gland to improve tear production and treat dry eye. Additionally, devices and methods for manufacturing the nasal stimulators, including shaping of the hydrogel, are described herein.

Claims

1. An electrically conductive hydrogel comprising:

a first monomer;

a second monomer; and

a photoinitiator,

wherein the first monomer is an acrylate monomer and the electrically conductive hydrogel has one or more characteristics that adapt it for use with a nasal stimulator device.

2. The electrically conductive hydrogel of claim 1, wherein the first monomer and the second monomer are the same.

3. The electrically conductive hydrogel of claim 1, wherein the acrylate monomer is a monofunctional monomer, a difunctional monomer, a trifunctional monomer, or a precursor or a derivative thereof.

4. The electrically conductive hydrogel of claim 3, wherein the monofunctional monomer is selected from the group consisting of acrylic acid, butyl acrylate, butyl methacrylate, 2-chloroethyl vinyl ether, ethyl acrylate, 2-ethylhexyl acrylate, furfuryl acrylate, glycerol monomethacrylate, hydroxyethyl methacrylate, methacrylic acid, methoxy polyethylene glycol dimethacrylate, and methoxy polyethylene glycol monoacrylate.

5. The electrically conductive hydrogel of claim 3, wherein the difunctional monomer is selected from the group consisting of diethylene glycol diacrylate, ethylene glycol dimethacrylate, neopenyl glycol diacrylate, polyethylene glycol diacrylate, triethylene glycol diacrylate, and N,N′

dimethylene bisacrylamide.

6. The electrically conductive hydrogel of claim 3, wherein the trifunctional monomer is selected from the group consisting of pentaerythritol triacrylate, propxylated glycol triacrylate, trimethylpropane triacrylate, and trimethylol propane trimethacrylate.

7. The electrically conductive hydrogel of claim 1, wherein the second monomer is selected from the group consisting of dimethylacrylamide, glycidyl methacrylate, N-vinylpyrrolidone, and 1,4-butanediol diacrylate.

8. The electrically conductive hydrogel of claim 1, wherein the photoinitiator is selected from the group consisting of acylphosphine oxides, bisacylphosphine oxides, 2,2-dimethoxy-1,2-diphenylethan-1-one (Igracure®

photoinitiator), benzoin ethers, benzyl ketals, alpha-dialkoxyacetophenones, alpha-hydroxyalkylphenones, alpha-amino alkylphenones, benzophenones, thioxanthones, and combinations and derivatives thereof.

9. The electrically conductive hydrogel of claim 8, wherein the acylphosphine oxide is selected from the group consisting of 2,4,6-trimethylbenzoyl-diphenylphospine oxide;

benzoyl-diphenylphosphine oxide;

2,4,6-trimethylbenzoyl-methoxy-phenylphosphine oxide;

phthaloyl-bis(diphenylphosphine oxide);

tetrafluoroterephthanoyl-bis(diphenylphosphine oxide);

2,6-difluoro benzoyl-diphenylphospine oxide;

(1-naphthoyl)diphenylphosphine oxide; and

combinations thereof.

10. The electrically conductive hydrogel of claim 9, wherein the photoinitiator is 2,4,6-trimethylbenzoyl-diphenylphospine oxide.

11. The electrically conductive hydrogel of claim 8, wherein the bisacylphospine oxide is selected from the group consisting of bis(2,4,6-trimethylbenzoyl)-phenylphosphine oxide;

bis(2,6-dimethoxybenzoyl)-2,4,4-trimethyl-pentylphosphine oxide;

1-hydroxy-cyclohexyl-phenyl-ketone; and

combinations thereof.

12. The electrically conductive hydrogel of claim 1, wherein the one or more characteristics that adapt it for use with a nasal stimulator device are selected from the group consisting of electrical resistivity, maximum hydration level, tensile strength, Young'"'"'s modulus, glass transition temperature, and cross-link density.

13. The electrically conductive hydrogel of claim 12, wherein the electrical resistivity ranges from about 150 to about 800 Ohms·

cm.

14. The electrically conductive hydrogel of claim 12, wherein the electrical resistivity ranges from about 400 to about 800 Ohms·

cm.

15. The electrically conductive hydrogel of claim 12, wherein the electrical resistivity ranges from about 200 to about 600 Ohms·

cm.

16. The electrically conductive hydrogel of claim 12, wherein the electrical resistivity ranges from about 150 to about 500 Ohms·

cm.

17. The electrically conductive hydrogel of claim 12, wherein the electrical resistivity ranges from about 550 to about 600 Ohms·

cm.

18. The electrically conductive hydrogel of claim 12, wherein the maximum hydration level ranges from about 35% to about 80% by weight.

19. The electrically conductive hydrogel of claim 12, wherein the tensile strength ranges from about 35% and 150% at 30% relative humidity.

20. The electrically conductive hydrogel of claim 12, wherein the tensile strength ranges from about 35% to about 100% at 30% relative humidity.

21. The electrically conductive hydrogel of claim 12, wherein Young'"'"'s modulus ranges from about 0.1 to about 1.5 MPa.

22. The electrically conductive hydrogel of claim 12, wherein Young'"'"'s modulus ranges from about 0.1 to about 1.0 MPa.

23. The electrically conductive hydrogel of claim 12, wherein the glass transition temperature ranges from about 5 to about 25 degrees Celsius.

24. The electrically conductive hydrogel of claim 12, wherein the cross-link density ranges from about 0.01 to about 0.10 moles/mole.

25. The electrically conductive hydrogel of claim 1, further comprising a diluent.

26. The electrically conductive hydrogel of claim 25, wherein the diluent is selected from the group consisting of glycerin, isopropanol, methanol, polyethylene glycol, water, and combinations thereof.

27. The electrically conductive hydrogel of claim 1, wherein the acrylate monomer is an acrylic terminated silane monomer or an acrylic terminated siloxane monomer.

28. The electrically conductive hydrogel of claim 27, wherein the acrylate monomer is trimethyl silyl methacrylate, 2 (trimethylsilyloxy) ethyl methacrylate, 3-(trimethyoxysilyl)propyl methacrylate, or (3-methacryloyloxypropyl) tris (trimethylsiloxy)silane.

29. The electrically conductive hydrogel of claim 1, further comprising a hydrating medium.

30. The electrically conductive hydrogel of claim 29, wherein the hydrating medium comprises propylene glycol.

31. The electrically conductive hydrogel of claim 30, wherein the hydrating medium comprises about 5 to about 85 percent by volume propylene glycol.

32. The electrically conductive hydrogel of claim 31, wherein the hydrating medium comprises about 35 percent by volume propylene glycol.

33. The electrically conductive hydrogel of claim 31, wherein the hydrating medium comprises about 40 percent by volume propylene glycol.

34. The electrically conductive hydrogel of claim 31, wherein the hydrating medium comprises about 45 percent by volume propylene glycol.

35. The electrically conductive hydrogel of claim 31, wherein the hydrating medium comprises about 50 percent by volume propylene glycol.

99. The electrically conductive hydrogel of claim 1, wherein the hydrogel further comprises a hydrophilic additive.

100. The electrically conductive hydrogel of claim 99, wherein the hydrophilic additive comprises a polysaccharide.

101. The electrically conductive hydrogel of claim 100, wherein the polysaccharide is selected from the group consisting of dextran sulfate, hyaluronic acid, sodium hyaluronate, hydroxymethyl cellulose, chitosan, sodium alginate, and combinations thereof.

36. A process for producing an electrically conductive hydrogel comprising the steps of:

mixing a first monomer, a second monomer, and a photoinitiator to prepare a formulation, wherein the first monomer is an acrylate monomer; and

irradiating the formulation with UV radiation to cross-link the formulation.

37. The process of claim 36, wherein the step of irradiating the formulation with UV radiation is performed at a wavelength ranging from about 350 to about 450 nm.

38. The process of claim 36, wherein the first monomer and the second monomer are the same.

39. The process of claim 36, wherein the acrylate monomer is a monofunctional monomer, a difunctional monomer, a trifunctional monomer, or a precursor or a derivative thereof.

40. The process of claim 36, wherein the monofunctional monomer is selected from the group consisting of acrylic acid, butyl acrylate, butyl methacrylate, 2-chloroethyl vinyl ether, ethyl acrylate, 2-ethylhexyl acrylate, furfuryl acrylate, glycerol monomethacrylate, hydroxyethyl methacrylate, methacrylic acid, methoxy polyethylene glycol dimethacrylate, and methoxy polyethylene glycol monoacrylate.

41. The process of claim 39, wherein the difunctional monomer is selected from the group consisting of diethylene glycol diacrylate, ethylene glycol dimethacrylate, neopenyl glycol diacrylate, polyethylene glycol diacrylate, triethylene glycol diacrylate, and N,N′

dimethylene bisacrylamide.

42. The process of claim 39, wherein the trifunctional monomer is selected from the group consisting of pentaerythritol triacrylate, propxylated glycol triacrylate, trimethylpropane triacrylate, and trimethylol propane trimethacrylate.

43. The process of claim 36, wherein the second monomer is selected from the group consisting of dimethylacrylamide, glycidyl methacrylate, N-vinylpyrrolidone, and 1,4-butanediol diacrylate.

44. The process of claim 36, wherein the acrylate monomer is an acrylic terminated silane monomer or an acrylic terminated siloxane monomer.

45. The process of claim 44, wherein the acrylate monomer is trimethyl silyl methacrylate, 2 (trimethylsilyloxy) ethyl methacrylate, 3-(trimethyoxysilyl)propyl methacrylate, or (3-methacryloyloxypropyl) tris (trimethylsiloxy)silane.

46. The process of claim 36, wherein the photoinitiator is selected from the group consisting of acylphosphine oxides, bisacylphosphine oxides, 2,2-dimethoxy-1,2-diphenylethan-1-one (Igracure®

photoinitiator), benzoin ethers, benzyl ketals, alpha-dialkoxyacetophenones, alpha-hydroxyalkylphenones, alpha-amino alkylphenones, benzophenones, thioxanthones, and combinations thereof.

47. The process of claim 46, wherein the acylphosphine oxide is selected from the group consisting of 2,4,6-trimethylbenzoyl-diphenylphospine oxide;

benzoyl-diphenylphosphine oxide;

2,4,6-trimethylbenzoyl-methoxy-phenylphosphine oxide;

phthaloyl-bis(diphenylphosphine oxide);

tetrafluoroterephthanoyl-bis(diphenylphosphine oxide);

2,6-difluoro benzoyl-diphenylphospine oxide;

(1-naphthoyl)diphenylphosphine oxide; and

combinations thereof.

48. The process of claim 47, wherein the photoinitiator is 2,4,6-trimethylbenzoyl-diphenylphospine oxide.

49. The process of claim 46, wherein the bisacylphospine oxide is selected from the group consisting of bis(2,4,6-trimethylbenzoyl)-phenylphosphine oxide;

bis(2,6-dimethoxybenzoyl)-2,4,4-trimethyl-pentylphosphine oxide;

1-hydroxy-cyclohexyl-phenyl-ketone; and

combinations thereof.

50. The process of claim 36, wherein the formulation is cross-linked by covalent bonds.

51. The process of claim 36, wherein the formulation is cross-linked by ionic bonds.

52. The process of claim 36, wherein the formulation further comprises a hydrating medium.

53. The process of claim 52, wherein the hydrating medium comprises propylene glycol.

54. The process of claim 53, wherein the hydrating medium comprises about 5 to about 85 percent by volume propylene glycol.

55. The process of claim 54, wherein the hydrating medium comprises about 35 percent by volume propylene glycol.

56. The process of claim 54, wherein the hydrating medium comprises about 40 percent by volume propylene glycol.

57. The process of claim 54, wherein the hydrating medium comprises about 45 percent by volume propylene glycol.

58. The process of claim 54, wherein the hydrating medium comprises about 50 percent by volume propylene glycol.

59. A cross-linked, electrically conductive hydrogel produced by mixing a first monomer, a second monomer, and a photoinitiator to prepare a formulation, wherein the first monomer is an acrylate monomer;

molding or shaping the formulation; and

irradiating the formulation with UV radiation to cross-link the formulation.

60. The cross-linked, electrically conductive hydrogel of claim 59, comprising a hydrophilic cross-linked network having hydrophobic segments.

61. A method for stimulating a lacrimal gland comprising:

placing an arm of a nasal stimulator device against a nasal or a sinus tissue, the arm having a distal end and an electrically conductive hydrogel disposed at the distal end; and

activating the nasal stimulator device to provide electrical stimulation to the nasal or the sinus tissue,

wherein the electrically conductive hydrogel is used to facilitate an electrical connection between the nasal stimulator device and the nasal or the sinus tissue.

62. The method of claim 61, wherein the electrically conductive hydrogel comprises:

a first monomer;

a second monomer; and

a photoinitiator,

wherein the first monomer is an acrylate monomer and the electrically conductive hydrogel has one or more characteristics that adapt it for use with a nasal stimulator device.

63. The method of claim 62, wherein the acrylate monomer is an acrylic terminated silane monomer or an acrylic terminated siloxane monomer.

64. The method of claim 61, wherein the electrical stimulation is used to treat dry eye.

65. The method of claim 61, wherein the electrically conductive hydrogel is formulated to be non-abrasive to nasal tissue.

66. The method of claim 65, wherein the electrically conductive hydrogel has a Young'"'"'s modulus ranging from 0.1 to 1.5 MPa.

67. The method of claim 62, wherein the electrically conductive hydrogel further comprises a hydrating medium.

68. The method of claim 67, wherein the hydrating medium comprises propylene glycol.

69. The method of claim 68, wherein the hydrating medium comprises about 5 to about 85 percent by volume propylene glycol.

70. The method of claim 69, wherein the hydrating medium comprises about 35 percent by volume propylene glycol.

71. The method of claim 69, wherein the hydrating medium comprises about 40 percent by volume propylene glycol.

72. The method of claim 69, wherein the hydrating medium comprises about 45 percent by volume propylene glycol.

73. The method of claim 69, wherein the hydrating medium comprises about 50 percent by volume propylene glycol.

74. A nasal stimulator device comprising:

a reusable housing;

a disposable component removably attached to the reusable housing and comprising an arm having a distal end that extends from the reusable housing when attached thereto;

an electrode disposed within the arm; and

an electrically conductive hydrogel at the distal end of the arm

wherein the electrically conductive hydrogel comprises a first monomer;

a second monomer; and

a photoinitiator, and wherein the first monomer is an acrylate monomer and the electrically conductive hydrogel has one or more characteristics that adapt it for use with a nasal stimulator device.

75. A method of manufacturing a nasal stimulator device comprising shaping a hydrogel in a tip assembly of the device and attaching the tip assembly to a base unit of the device.

76. The method of claim 75, wherein the hydrogel comprises a first monomer;

a second monomer; and

a photoinitiator, wherein the first monomer is an acrylate monomer.

77. The method of claim 75, wherein the step of shaping the hydrogel comprises dipping the tip assembly into the hydrogel.

78. The method of claim 77, wherein the step of dipping is repeated.

79. The method of claim 75, wherein the step of shaping the hydrogel comprises placing the hydrogel into a mold.

80. The method of claim 79, wherein the mold comprises a plurality of cavities, each cavity capable of forming a hydrogel preform.

81. The method of claim 80, wherein the method further comprises the step of cutting the hydrogel into a hydrogel preform.

82. The method of claim 81, wherein the step of cutting is accomplished using a laser, a die, or a blade.

83. The method of claim 75, wherein the hydrogel comprises a plurality of cured or uncured monomers.

84. The method of claim 75, wherein the step of shaping the hydrogel comprises forming a bulge in the hydrogel.

85. The method of claim 75, wherein the step of shaping the hydrogel comprises dispensing the hydrogel through a window in the tip assembly.

86. The method of claim 85, wherein the step of shaping the hydrogel comprises forming a bulge by dispensing curing multiple layers of hydrogel.

87. The method of claim 85, wherein the method further comprises tilting the tip assembly.

88. The method of claim 75, wherein the step of shaping the hydrogel comprises forming a bulge with a casting fixture.

89. The method of claim 75, wherein the tip assembly comprises a hinge.

90. The method of claim 75, wherein the tip assembly is stored in a dispensing cassette.

91. The method of claim 90, wherein the base unit is introduced into the dispensing cassette to attach the tip assembly to the base unit.

92. A method of manufacturing a hydrogel for use as an electrical contact in a nasal stimulator device comprising creating a hydrophilic surface on the hydrogel.

93. The method of claim 92, wherein the hydrophilic surface is created by treating the hydrogel with a low pressure plasma.

94. The method of claim 92, wherein the hydrophilic surface is created by depositing a hydrophilic polymer on the hydrogel using plasma polymerization.

95. The method of claim 92, wherein the hydrophilic surface is created by subjecting the hydrogel to a chemical modification process.

96. The method of claim 95, wherein the chemical modification process comprises subjecting the hydrogel to aqueous sodium hydroxide.

97. The method of claim 92, wherein the hydrophilic surface is created by adding a surfactant to the hydrogel during its formulation.

98. A method of improving electrical contact between an electrode of a nasal stimulator device and a nasal or sinus tissue comprising manufacturing a hydrogel and creating a hydrophilic surface on the hydrogel, wherein the hydrophilic surface is created by treating the hydrogel with a low pressure plasma, depositing a hydrophilic polymer on the hydrogel using plasma polymerization, subjecting the hydrogel to acqueous sodium hydroxide, or adding a surfactant to the hydrogel during its formulation.