PH modulated films for delivery of actives

• US 20070149731A1
• Filed: 12/14/2006
• Published: 06/28/2007
• Est. Priority Date: 10/12/2001
• Status: Active Grant

• Current Assignee: Aquestive Therapeutics, Inc.
• Original Assignee: Monosol Rx LLC (Kuraray Company Limited)
• Inventors: Myers, Garry
• Granted Patent: US 7,910,641 B2
• Time in Patent Office: Days
• US Class Current: 526/154
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 9/0036 Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• 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 9/7015 Drug-containing film-forming compositions, e.g. spray-on

Abstract

The invention relates to pH modulated films and methods of their preparation. The film compositions include at least one component having a non-neutral pH when combined with water; and a pH modulated polymer system selected to reduce or prevent synerisis when combined with the non-neutral component in combination with aqueous media. The films demonstrate a non-self-aggregating uniform heterogeneity. Desirably, the films disintegrate in water and may be formed by a controlled drying process, extrusion process, or other process that maintains the required uniformity of the film.

Claims

1. A composition comprising:

(a) at least one component having a non-neutral pH when combined with water; and

(b) a pH modulated polymer system selected to reduce or prevent synerisis when combined with said non-neutral component in combination with water.

2. The composition of claim 1, wherein the composition is in the form of a film

3. The composition of claim 2, wherein the film includes an active.

4. The composition of claim 3, wherein the active is the non-neutral component.

5. The composition of claim 3, wherein the active is a different component from the non-neutral component.

6. The composition of claim 1, wherein said at least one non-neutral component is acidic, and said polymer system comprises a neutral or acidic polymer.

7. The composition of claim 1, wherein said at least one non-neutral component is acidic, and said polymer system comprises a neutral polymer, a basic polymer and a weak base.

8. The composition of claim 1, wherein said at least one non-neutral component is basic, and said polymer system comprises a neutral polymer, a basic polymer and a weak acid.

9. The composition of claim 1, wherein said at least one non-neutral component is basic, and said polymer system comprises at least one basic polymer.

10. The composition of claim 1, wherein said polymer system comprises a neutral polymer selected from the group consisting of hydroxyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyethylene oxide, gum arabic, xanthan gum, guar gum, locust bean gum, polydextrose, dextrin, dextran, pullulan, tamarine, starch and combinations thereof.

11. The composition of claim 1, wherein said polymer system comprises a neutral polymer selected from the group consisting of polyethylene oxides, cellulosic polymers and combinations thereof.

12. The composition of claim 11, wherein said neutral polymer is a combination of hydroxypropyl methylcellulose and polyethylene oxide.

13. The composition of claim 11, wherein said neutral polymer is polyethylene oxide.

14. The composition of claim 1, wherein said polymer system comprises an acidic polymer selected from the group consisting of poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polyanhydrides, sulfated carrageenan, furcelleran, xanthan and combinations thereof.

15. The composition of claim 1, wherein said polymer system comprises a basic polymer selected from the group consisting of polyamino acids, polyaminocarbonates, polycarbonates, polyamides, carboxymethyl cellulose, alginates, carageenans, pectin and combinations thereof.

16. The composition of claim 1, wherein said polymer system comprises an alginate polymer.

17. The composition of claim 16, wherein said alginate polymer is propylene glycol alginate.

18. The composition of claim 1, wherein said polymer system provides a neutral pH when combined with said non-neutral component in combination with water.

19. The composition of claim 1, wherein said polymer system comprises a buffer system.

20. The composition of claim 19, wherein said buffer system comprises a weak acid, a weak base, or salts thereof.

21. The composition of claim 20, wherein said weak acid is selected from the group consisting of acetic acid, ascorbic acid, benzoic acid, butyric acid, carbonic acid, citric acid, formic acid, lactic acid, malic acid, nitrous acid, oxalic acid, phosphoric acid, propanoic acid, propionic acid, pyrophosphoric acid, pyruvic acid, valeric acid and combinations thereof.

22. The composition of claim 20, wherein said weak base is selected from the group consisting of alanine, ammonia, dimethylamine, ethylamine, glycine, hydrazine, methylamine, trimethylamine and combinations thereof.

23. The composition of claim 20, wherein said buffer system comprises a salt of an organic acid.

24. The composition of claim 23, wherein said organic acid salt is citrate.

25. A composition comprising:

(a) a component having an acidic pH when combined with water; and

(b) a polymer system comprising at least one neutral or acidic polymer.

26. The composition of claim 25, wherein the composition is in the form of a film.

27. The composition of claim 26, wherein the film includes an active.

28. The composition of claim 27, wherein the active is the acidic component.

29. The composition of claim 27, wherein the active is a different component from the acidic component.

30. The composition of claim 25, wherein said at least one neutral polymer is selected from the group consisting of polyethylene oxide, hydroxypropyl methyl cellulose and combinations thereof.

31. The composition of claim 25, wherein said at least one neutral polymer is polyethylene oxide.

32. The composition of claim 25, wherein said acidic polymer is selected from the group consisting of poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polyanhydrides and combinations thereof.

33. The composition of claim 25, wherein said polymer system comprises said neutral polymer, and a weak base.

34. The composition of claim 33, wherein said polymer system further comprises a basic polymer.

35. The composition of claim 34, wherein said basic polymer is an alginate polymer.

36. The composition of claim 33, wherein said weak base comprises a salt of an organic acid.

37. The composition of claim 36, wherein said salt is of an organic acid selected from the group consisting of acetic acid, benzoic acid, butyric acid, citric acid, formic acid, lactic acid, malic acid, propionic acid, pyruvic acid, valeric acid and combinations thereof.

38. A composition comprising:

(a) a component having a basic pH when combined with water; and

(b) a polymer system comprising at least one basic polymer.

39. The composition of claim 38, wherein the composition is in the form of a film.

40. The composition of claim 39, wherein the film includes an active.

41. The composition of claim 40, wherein the active is the basic component.

42. The composition of claim 40, wherein the active is a different component from the basic component.

43. The composition of claim 38, wherein said basic polymer is selected from the group consisting of polyamino acids, polyaminocarbonates, polycarbonates, polyamides, carboxymethyl cellulose, alginates, carageenans, pectin, tragacanth, karaya and combinations thereof.

44. A device comprising:

(a) a film composition comprising

(i) at least one component having a non-neutral pH when combined with water; and

(ii) a pH modulated polymer system selected to reduce or prevent synerisis when combined with said non-neutral component in combination with water; and

(b) a delivery substrate.

45. The composition of claim 44, wherein the film composition includes an active.

46. The composition of claim 45, wherein the active is the non-neutral component.

47. The composition of claim 45, wherein the active is a different component from the non-neutral component.

48. The device of claim 44, wherein said delivery substrate is a tampon or bandage.

49. A method of preparing a film comprising:

(a) providing a component having a non-neutral pH when combined with water;

(b) providing a pH modulated polymer system selected to reduce or prevent synerisis when combined with said non-neutral component in combination with an aqueous solvent;

(c) combining said non-neutral component and said polymer system with an aqueous solvent to produce a film-forming composition; and

(d) forming said film-forming composition into a film.

50. The method of claim 49, wherein the non-neutral component is an active.

51. The method of claim 49, further comprising combining the film components with an active prior to the forming step.

52. The method of claim 49, wherein said polymer system comprises a buffer system.

53. The method of claim 49, wherein said buffer system comprises a weak acid, a weak base, or salts thereof.

54. The method of claim 49, wherein said non-neutral component is acidic, and said polymer system comprises a neutral or acidic polymer.

55. The method of claim 49, wherein said non-neutral component is acidic, and said polymer system comprises a neutral polymer, a weak base, and a basic polymer.

56. The method of claim 49, wherein said non-neutral component is basic, and said polymer system comprises at least one basic polymer.

57. The method of claim 49, wherein said non-neutral component is basic, and said polymer system comprises a neutral polymer, a basic polymer and a weak acid.

58. The method of claim 55, wherein said basic polymer is an alginate polymer, which reduces synerisis in said film-forming composition in the presence of said acidic component and said weak base.

59. A method of topical administration of an active comprising:

(a) providing a pH modulated film composition comprising

(i) a component having a non-neutral pH when combined with water; and

(ii) a pH modulated polymer system selected to reduce or prevent synerisis when combined with said non-neutral component in combination with water; and

(b) applying said pH modulated film composition to a body surface in the presence of an active.

60. The method of claim 59, wherein the active is present in the pH modulated film composition.

61. The method of claim 60, wherein the active is said non-neutral component.

62. The method of claim 60, wherein the active is a different component from said non-neutral component.

63. The method of claim 59, wherein the active is present in a second film composition used in conjunction with the pH modulated film composition.

64. The method of claim 59, wherein the body surface is a mucosal membrane.

65. The method of claim 59, wherein the body surface is a wound.

66. The method of claim 59, further comprising applying said pH modulated film composition to a delivery substrate before said applying step.

67. The method of claim 66, wherein the delivery substrate is a tampon.

68. The method of claim 66, wherein the delivery substrate is a bandage.

69. The method of claim 59, wherein said non-neutral component is acidic, and said polymer system comprises a neutral or acidic polymer.

70. The method of claim 59, wherein said non-neutral component is acidic, and said polymer system comprises a neutral polymer, a weak base, and a basic polymer.

71. The method of claim 59, wherein said non-neutral component is basic, and said polymer system comprises at least one basic polymer.

72. The method of claim 59, wherein said non-neutral component is basic and said polymer system comprises a neutral polymer, a basic polymer and a weak acid.

73. The method of claim 70, wherein said basic polymer is an alginate polymer, which reduces synerisis in said pH modulated film composition in the presence of said acidic component and said weak base.

74. A system for applying an active, comprising:

(a) a water soluble composition in the form of a first film, said composition comprising (i) at least one component having a non-neutral pH when combined with water; and

(ii) a pH modulated polymer system selected to reduce or prevent synerisis when combined with said non-neutral component in combination with aqueous media; and

(b) an aqueous solvent for dissolving said water soluble first film, said solvent being provided for direct contact with said first film to cause said non-neutral component to be dissolved or dispersed out of said first film in the presence of an active, whereby said active can be delivered to a surface area in need thereof.

75. The system of claim 74, wherein said active is present in the first water soluble film.

76. The system of claim 74, further comprising a second water soluble film that includes said active.

77. The system of claim 74, further comprising an applicator for applying said active to said surface area in need thereof.

78. The system of claim 77, wherein said applicator is a sponge.

79. The system of claim 77, wherein said film is deposited on top of a sponge applicator wetted with said solvent.

80. The system of claim 77, wherein said film is deposited on top of a dry sponge applicator, which when subsequently wetted with said solvent, is for applying said active.

81. The system of claim 74, wherein said solvent is in a container.

82. The system of claim 81, wherein said container is separate from said film.

83. The system of claim 81, wherein said container is affixed to said film.

84. The system of claim 74, wherein said film is interposed between a container including said solvent and an area of skin.

85. The system of claim 77, wherein said film is interposed between a container including said solvent, and a sponge applicator.

86. The system of claim 74, wherein said at least one non-neutral component is acidic, and said polymer system comprises a neutral or acidic polymer.

87. The system of claim 74, wherein said at least one non-neutral component is acidic, and said polymer system comprises a neutral polymer, a basic polymer and a weak base.

88. The system of claim 74, wherein said at least one non-neutral component is basic and said polymer system comprises a neutral polymer, a basic polymer and a weak acid.

89. The system of claim 74, wherein said at least one non-neutral component is basic, and said polymer system comprises at least one basic polymer.