Ophthalmic formulation for the prevention and treatment of adverse ocular conditions, particularly those associated with the aging eye

• US 20040137068A1
• Filed: 12/22/2003
• Published: 07/15/2004
• Est. Priority Date: 12/20/2002
• Status: Abandoned Application

• Current Assignee: Livionex, Inc.
• Original Assignee: Livionex, Inc.
• Inventors: Bhushan, Rajiv
• Application Number:
  US10/744,524
• Publication Number:
  US 20040137068A1
• Time in Patent Office: Days
• US Class Current: 424/486
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/4172 Imidazole-alkanecarboxylic acids, e.g. histidine
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/0051 Ocular inserts, ocular implants
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/08 Mydriatics or cycloplegics
• CPC Class Codes: A61P 27/10 for accommodation disorders, e.g. myopia
• CPC Class Codes: A61P 27/12 for cataracts
• CPC Class Codes: A61P 31/02 Local antiseptics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 39/04 : Chelating agents
• CPC Class Codes: A61P 39/06 : Free radical scavengers or antioxidants
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

An ophthalmic formulation is provided for the prevention and treatment of adverse ocular conditions, including presbyopia, arcus senilis, age-related macular degeneration, and other conditions associated with aging. The formulation is also useful in the prevention and treatment of other adverse ocular conditions such as those associated with oxidative and/or free radical damage within the eye; these conditions can involve a condition, disease, or disorder of the cornea, retina, lens, sclera, anterior segment, or posterior segment of the eye. In one embodiment, the formulation contains at least 0.6 wt. % of a biocompatible chelating agent, an effective permeation enhancing amount of an ophthalmic permeation enhancer such as methylsulfonylmethane (MSM), an anti-AGE agent, i.e., a compound that serves to reduce the presence of advanced glycation endproducts (AGEs) in the eye, and a pharmaceutically acceptable ophthalmic carrier suited to the particular formulation type (e.g., eye drops or ointments). Preferred components of the formulation are multifunctional and naturally occurring.

Claims

1. A sterile ophthalmic formulation, comprising:

a biocompatible chelating agent at a concentration of at least 0.6% by weight;

an effective permeation-enhancing concentration of a permeation enhancer;

an anti-AGE agent selected from AGE breakers, AGE formation inhibitors, and glycation inhibitors; and

a pharmaceutically acceptable ophthalmic carrier.

2. The formulation of claim 1, wherein the carrier is at least partially aqueous.

3. The formulation of claim 2, comprising a solution.

4. The formulation of claim 2, comprising a suspension.

5. The formulation of claim 2, wherein the carrier further includes a water-swellable polymer and the formulation comprises a hydrogel.

6. The formulation of claim 2, wherein the carrier comprises a thermoreversible hydrogel-forming polymer such that the formulation forms a hydrogel in situ following ocular administration.

7. The formulation of claim 1, wherein the carrier is an ointment base, and the formulation comprises an ointment.

8. A sterile ophthalmic delivery system comprising a liposomal dispersion of the formulation of claim 1.

9. The delivery system of claim 1, comprising a colloidal suspension of microspheres, nanospheres, microcapsules, or nanocapsules containing the formulation of claim 1.

10. The formulation of claim 1, wherein the biocompatible chelating agent is selected from ethylenediamine tetraacetic acid (EDTA), cyclohexanediamine tetraacetic acid (CDTA), hydroxyethylethylenediamine triacetic acid (HEDTA), diethylenetriamine pentaacetic acid (DTPA), dimercaptopropane sulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylene phosphonic acid (ATPA), citric acid, ophthalmologically acceptable salts thereof, and combinations of any of the foregoing.

11. The formulation of claim 10, wherein the biocompatible chelating agent is selected from EDTA and ophthalmologically acceptable salts thereof.

12. The formulation of claim 11, wherein the biocompatible chelating agent is EDTA.

13. The formulation of claim 11, wherein the biocompatible chelating agent is an ophthalmologically acceptable EDTA salt.

14. The formulation of claim 13, wherein the ophthalmologically acceptable EDTA salt is selected from diammonium EDTA, disodium EDTA, dipotassium EDTA, triammonium EDTA, trisodium EDTA, tripotassium EDTA, calcium disodium EDTA, and combinations thereof.

15. The formulation of claim 1, wherein the chelating agent is selected from chelating antibiotics, chelating agents containing two or more chelating nitrogen atoms, phosphates, and deferoxamine.

16. The formulation of claim 15, wherein the chelating agent is a chelating antibiotic selected from chloroquine and tetracycline.

17. The formulation of claim 15, wherein the chelating agent is selected from pyrophosphates, tripolyphosphates, hexametaphosphates, and combinations thereof.

18. The formulation of claim 1, wherein the permeation enhancer is selected from methylsulfonylmethane, dimethyl sulfoxide, and combinations thereof.

19. The formulation of claim 20, wherein the permeation enhancer is methylsulfonylmethane.

20. The formulation of claim 18, comprising methylsulfonylmethane and dimethyl sulfoxide at a weight ratio of approximately 1:

1 to about 50;

1.

21. The formulation of claim 1, wherein the anti-AGE agent is an AGE breaker.

22. The formulation of claim 17, wherein the AGE breaker is selected from L-carnosine, 3-phenacyl-4,5-dimethylthiazolium chloride, N-phenacylthiazolium bromide, 4,5-dimethylthiazolium bromide, and combinations thereof.

23. The formulation of claim 22, wherein the AGE breaker is L-carnosine.

24. The formulation of claim 1, wherein the anti-AGE agent is selected from glycation inhibitors and AGE formation inhibitors.

25. The formulation of claim 24, wherein the anti-AGE agent is selected from aminoguanidine, 4-(2,4,6-trichlorophenylureido)phenoxyisobutyric acid, 4-[(3,4-dichlorophenylmethyl)₂-chlorophenylureido]phenoxyisobutyric acid, N,N′

-bis(2-chloro-4-carboxyphenyl)formamidine, and combinations thereof.

26. The formulation of claim 1, further comprising a microcirculatory enhancer.

27. The formulation of claim 26, wherein the microcirculatory enhancer is phosphodiesterase inhibitor.

28. The formulation of claim 27, wherein the phosphodiesterase inhibitor is a Type (I) phosphodiesterase inhibitor.

29. The formulation of claim 28, wherein the phosphodiesterase inhibitor is vinpocetine.

30. The formulation of claim 1, further including at least one additive selected from thickeners, isotonic agents, and buffering agents.

31. The formulation of claim 1, having a pH in the range of about 6.5 to about 8.0.

50. A sterile ocular insert for delivery of an ophthalmic formulation to the eye, comprising a controlled release implant housing the formulation of any one of claims 1, 33, and 43 and suitable for implantation into the conjunctiva, sclera, pars plana, anterior segment or the posterior segment of the eye.

51. The ocular insert of claim 50, wherein the implant is comprised of a polymeric matrix that gradually releases the formulation to the eye through diffusion and/or matrix degradation.

52. The ocular insert of claim 51, wherein the polymeric matrix is completely biodegradable.

53. The ocular insert of claim 50, wherein the implant is comprised of a laminated structure in which an inner core housing the formulation is contained between outer layers of a permeable polymer through which the formulation gradually diffuses.

54. A sterile ocular insert for delivery of an ophthalmic formulation to the eye, comprising a controlled release implant housing the formulation of any one of claims 1, 33, and 43 and suitable for implantation into the conjunctiva, sclera, pars plana, anterior segment, or posterior segment of the eye.

55. The ocular insert of claim 54, wherein the implant is comprised of a polymeric matrix that gradually releases the formulation to the eye through dissolution of the matrix and/or diffusion.

56. The ocular insert of claim 55, wherein the polymeric matrix is completely soluble and/or biodegradable in the eye.

57. The ocular insert of claim 56, wherein the implant is comprised of a reservoir housing the formulation and enclosed in a polymeric membrane through which the formulation gradually diffuses.

58. The ocular insert of claim 55, wherein the implant is comprised of an osmotic system from which the formulation is gradually released as a result of increased osmotic pressure within the system following implantation in the eye.

59. A method for preventing or treating a mammalian individual susceptible to or afflicted with an adverse ocular condition, comprising topically administering the formulation of any one of claims 1, 33, and 43 to an eye of the individual.

60. The method of claim 59, wherein the adverse ocular condition is associated with oxidative and/or free radical damage to the eye.

61. The method of claim 59, wherein the adverse ocular condition is a condition, disease, or disorder of the cornea, retina, lens, sclera, anterior segment, or posterior segment of the eye.

62. The method of claim 59, wherein the adverse ocular condition is associated with aging.

63. The method of claim 62, wherein the adverse ocular condition is opacification.

64. The method of claim 62, wherein the adverse ocular condition is decreased lens accommodation.

65. The method of claim 62, wherein the adverse ocular condition involves the formation of lipid deposits.

66. The method of claim 62, wherein the adverse ocular condition is visual acuity impairment.

67. The method of claim 62, wherein the adverse ocular condition is decreased contrast sensitivity.

68. The method of claim 62, wherein the adverse ocular condition is photophobia.

69. The method of claim 62, wherein the adverse ocular condition involves a decreased amount of light reaching the retina.

70. The method of claim 62, wherein the adverse ocular condition involves decreased pupil dilation.

71. The method of claim 62, wherein the adverse ocular condition is presbyopia.

72. The method of claim 62, wherein the adverse ocular condition is cataract formation.

73. The method of claim 72, wherein the adverse ocular condition is secondary cataract formation.

74. The method of claim 62, wherein the adverse ocular condition is age-related macular degeneration.

75. The method of claim 62, wherein the adverse ocular condition is elevated intraocular pressure.

76. The method of claim 62, wherein the adverse ocular condition is macular edema or macular scarring.

77. The method of claim 62, wherein the adverse ocular condition is band keratopathy.

78. The method of claim 62, wherein the adverse ocular condition comprises the presence of floaters in the vitreous humor.

79. The method of claim 62, wherein the adverse ocular condition is arcus senilis.

80. The method of claim 62, wherein the adverse ocular condition is dry eye syndrome.

81. The method of claim 59, wherein the adverse ocular condition comprises an ocular surface growth.

82. The method of claim 81, wherein the ocular surface growth is selected from pingueculae and pterygia.

83. The method of claim 59, wherein the adverse ocular condition is keratoconus.

84. A method for improving the visual acuity of a mammalian individual, comprising administering the formulation of any one of claims 1, 33, and 43 to the eye of the individual.

89. The ocular insert of any one of claims 84, 85, 86, or 87, wherein the implant is comprised of a polymeric matrix that gradually releases the formulation to the eye through dissolution of the matrix and/or diffusion.

90. The ocular insert of claim 89, wherein the polymeric matrix is completely soluble and/or biodegradable in the eye.

91. The ocular insert of any one of claims 84, 85, 86, and 87, wherein the implant is comprised of a reservoir housing the formulation and enclosed in a polymeric membrane through which the formulation gradually diffuses.

92. The ocular insert of claim 91, wherein the implant is comprised of an osmotic system from which the formulation is gradually released as a result of increased osmotic pressure within the system following implantation in the eye.

32. The formulation of claim 32, having a pH in the range of about 6.8 to about 7.8.

33. A sterile ophthalmic formulation, comprising:

a biocompatible chelating agent at a concentration of at least 0.6% by weight;

an effective permeation-enhancing amount of methylsulfonylmethane; and

a pharmaceutically acceptable ophthalmic carrier.

34. The formulation of claim 33, wherein the carrier is distilled or deionized water.

35. The formulation of claim 34, wherein the biocompatible chelating agent is selected from EDTA and ophthalmologically acceptable salts thereof.

36. The formulation of claim 35, wherein the biocompatible chelating agent represents up to 10 wt. % of the formulation.

37. The formulation of claim 33, wherein the methylsulfonylmethane represents approximately 1.0 wt. % to 33 wt. % of the formulation.

38. The formulation of claim 37, further comprising approximately 0.5 wt. % to 30 wt. % L-carnosine.

39. The formulation of claim 37, further comprising approximately 0.1 wt. % to 0.5 wt. % 3-phenacyl-4,5-dimethylthiazolium chloride.

40. The formulation of claim 37, further comprising approximately 1.0 wt. % to 2.0 wt. % dimethyl sulfoxide.

41. The formulation of claim 37, further comprising approximately 0.01 wt. % to 0.2 wt. % vinpocetine.

42. The formulation of claim 33, further including at least one additive selected from thickeners, isotonic agents, and buffering agents.

43. A sterile ophthalmic formulation, comprising:

a biocompatible chelating agent at a concentration of at least 0.6% by weight;

an effective AGE-reducing concentration of L-carnosine; and

a pharmaceutically acceptable ophthalmic carrier.

44. The formulation of claim 43, wherein the carrier is distilled or deionized water.

45. The formulation of claim 44, wherein the biocompatible chelating agent is selected from EDTA and ophthalmologically acceptable salts thereof.

46. The formulation of claim 45, wherein the biocompatible chelating agent represents up to 10 wt. % of the formulation.

47. The formulation of claim 46, wherein the effective AGE-reducing concentration of L-carnosine is in the range of approximately 0.5% to 30% by weight.

48. The formulation of claim 43, further comprising approximately 0.01 wt. % to 0.2 wt. % vinpocetine.

49. The formulation of claim 43, further including at least one additive selected from thickeners, isotonic agents, and buffering agents.

85. A sterile ocular insert for administration of a biocompatible chelating agent to the eye, comprising a controlled release implant housing a formulation consisting essentially of the biocompatible chelating agent and a pharmaceutically acceptable carrier.

86. The insert of claim 85, wherein the biocompatible chelating agent is selected from EDTA and ophthalmologically acceptable salts thereof.

87. A sterile ocular insert for administration of an anti-AGE agent to the eye, comprising a controlled release implant housing a formulation consisting essentially of the anti-AGE agent and a pharmaceutically acceptable carrier.

88. The insert of claim 87, wherein the anti-AGE agent is L-carnosine.