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1. WO2020223177 - MEK INHIBITORS FOR CORNEAL SCARRING AND NEOVASCULARIZATION

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[ EN ]

WHAT IS CLAIMED:

1 . An ophthalmic composition comprising a MAPK/ERK kinase (MEK) inhibitor and

phosphate buffered saline (PBS).

2. The ophthalmic composition of claim 1 , further comprising about 0.1 % to 20% DMSO and about 1% to about 20% HPMC and the at MAPK/ERK kinase (MEK) inhibitor is a concentration of about 0.1 to about 10 mM or about 10% to 50% poloxamer 407 and about 1% to about 20% MEK inhibitor.

3. The ophthalmic composition of claim 1 or 2, further comprising a pharmaceutically

acceptable ophthalmic excipient.

4. The ophthalmic composition of claim 3, wherein the ophthalmic excipient is polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, polyols, Carbopol, pluronics, carbomers, carboxymethyl cellulose, hydroxyethyl cellulose, cyclodextrins, phosphate buffer, citrate buffer, Tris buffer, sodium chloride, potassium chloride, polysorbate 80, vegetable oil, preservative or a combination thereof.

5. The ophthalmic composition of any one of claims 1 -4 provided in a suitable carrier, or formulated for topical administration.

6. The ophthalmic composition of any one of claims 1 -5, wherein the MAPK/ERK kinase (MEK) inhibitor is a MEK1 or MEK2 inhibitor.

7. The ophthalmic composition of claim 6, wherein the MEK1 or MEK2 inhibitor is

PD098059, PD0325901/Mirdametnib, Trametinib, Cobimetinib, MEK 1/2 inhibitor AS703988, MEK inhibitor AZD8330, MEK inhibitor CS3006, MEK inhibitor R04987655, MEK inhibitor SHR 7390, MEK inhibitor TAK-733, MEK/Aurora kinase dual inhibitor Bl 847325, MEK-1/MEKK-1 inhibitor E6201 , refametinib, selumetinib, binimetinib, CI-1040, AZD6244, GDC-0973, GSK1 120212, AS703026, BS203580, MEK162, GDC-0623, R05126766, WX-554, HL-085, or U0126.

8. The ophthalmic composition of any one of claims 1 -5, wherein the MAPK/ERK kinase (MEK) inhibitor is an ERK inhibitor.

9. The ophthalmic composition of claim 8, wherein the ERK inhibitor is FRI-20, ON-01060, VTX-1 1 e, 25-OH-D3-3-BE, B3CD, bromoacetoxycalcidiol, 180204 AEZ-131 , AEZS-131 , AEZS-136, SCH-772984, AZ-13767370, BL-EI-001 , LY-3214996, LTT-462, KO-947 CC- 90003, GDC-0994, RG-7842, MK-8353, SCH900353, BVD-523, or Ulixertinib.

10. The ophthalmic composition of any one of claims 1 -5, wherein the MAPK/ERK kinase (MEK) inhibitor is PD0325901 .

1 1. A method of reducing or preventing scarring, opacification, or neovascularization on the surface of the eye of a subject comprising administering to the subject an ophthalmic composition of any one of claims 1 -10.

12. A method of improving vision or reducing limitations on vision in a subject in need,

wherein the method comprises administering to the subject an ophthalmic composition of any one of claims 1 -10.

13. The method of claim 1 1 or 12, wherein the subject is suffering from Aniridia, corneal scarring, corneal opacification, corneal neovascularization, ocular surface inflammation, severe ocular surface injuries, limbal stem cell deficiency, infections, auto-immune disease, inflammatory diseases or congenital diseases associated with reduced expression of PAX6.

14. A method of treating an ocular disease or condition in a subject in need, wherein the method comprises administering to the subject an ophthalmic composition of any one of claims 1 -10.

15. The method of claim 14 wherein the ocular disease or condition is Aniridia, corneal scarring, corneal opacification, corneal neovascularization, ocular surface inflammation, severe ocular surface injuries, limbal stem cell deficiency, infections, auto-immune disease, inflammatory diseases or congenital diseases associated with reduced expression of PAX6.

16. A method of inducing PAX6 expression in a cell comprising administering to the cell an effective amount of a MAPK/ERK kinase (MEK) inhibitor.

17. The method of clam 16, wherein the cell is an epithelial cell of the surface of the eye or a fibroblast cell on the surface of the eye.

18. A method of reducing or preventing scarring, opacification, or neovascularization on the surface of the eye of a subject comprising administering to the subject an effective amount of a MAPK/ERK kinase (MEK) inhibitor.

19. A method of improving vision or reducing limitations on vision in a subject in need,

wherein the method comprises administering to the subject an effective amount of a MAPK/ERK kinase (MEK) inhibitor.

20. The method of claim 18 or 19, wherein the subject is suffering from Aniridia, corneal scarring, corneal opacification, corneal neovascularization, ocular surface inflammation, severe ocular surface injuries, limbal stem cell deficiency, cancer, infections, auto immune disease, inflammatory diseases or congenital diseases associated with reduced expression of PAX6.

21. A method of treating an ocular disease or condition in a subject in need, wherein the method comprises administering to neovascularization the subject an effective amount of a MAPK/ERK kinase (MEK) inhibitor.

22. The method of claim 21 wherein the ocular disease or condition is Aniridia, scarring on the surface of the eye, opacification of the surface of the eye, neovascularization on the surface of the eye, ocular surface inflammation, severe ocular surface injuries, limbal stem cell deficiency, cancer, infections, auto-immune disease, inflammatory diseases or congenital diseases associated with reduced expression of PAX6.

23. The method of any one of claims 16-22, wherein the MAPK/ERK kinase (MEK) inhibitor is a MEKI or MEK2 inhibitor.

24. The method of claim 23, wherein the MEK1 or MEK2 inhibitor is PD098059, PD0325901 , Tratetinib, Cobimetinib, MEK 1/2 inhibitor AS703988, MEK inhibitor PD325089, MEK inhibitor AZD8330, MEK inhibitor CS3006, MEK inhibitor R04987655, MEK inhibitor SHR 7390, MEK inhibitor TAK-733, MEK/Aurora kinase dual inhibitor Bl 847325, MEK- 1/MEKK-1 inhibitor E6201 , refametinib, selumetinib, CI-1040, AZD6244, GDC-0973, GSK1 120212, AZD8330, R051267655, R04987655, AS703026, BS203580, MEK162, GDC-0623, R05126766, WX-554, HL-085, or U0126.

25. The method of any one of clams 16-22, wherein the MAPK/ERK kinase (MEK) inhibitor is an ERK inhibitor.

26. The method of claim 25, wherein the ERK inhibitor is FRI-20, ON-01060, VTX-1 1 e, 25- OH-D3-3-BE, B3CD, bromoacetoxycalcidiol, 180204 AEZ-131 , AEZS-131 , AEZS-136, SCH-772984, AZ-13767370, BL-EI-001 , LY-3214996, LTT-462, KO-947 CC-90003, GDC-0994, RG-7842, MK-8353, SCH900353, BVD-523, or Ulixertinib.

27. The method of any one of claims 16-22, wherein the MAPK/ERK kinase (MEK) inhibitor is PD0325901 , at a concentration of about 0.1 to about 10 pm.

28. The method of any one of claims 16-27, wherein the MAPK/ERK kinase (MEK) inhibitor is administered as an ophthalmic composition, and the composition comprises the MAPK/ERK kinase (MEK) inhibitor and PBS.

29. The method of claim 28, wherein the ophthalmic composition further comprises about 1 % to about 20% DMSO and about 1% to about 20% HPMC.

30. The method of claim 28, where the ophthalmic composition further comprises about 10% to 50% poloxamer 407.

31. The method of any one of claims 28-30, wherein the MAPK/ERK kinase (MEK) inhibitor is at a concentration of about 0.1 to about 10 mM.

32. The method of any one of claims 16-31 , wherein the MAPK/ERK kinase (MEK) inhibitor is administered by topical route or oral route.

33. Use of an effective amount of a MAPK/ERK kinase (MEK) inhibitor for the preparation of a medicament for inducing PAX6 expression in a cell comprising administering to the cell an effective amount of a MAPK/ERK kinase (MEK) inhibitor.

34. The use of clam 33, wherein the cell is an epithelial cell of the surface of the eye or a fibroblast cell on the surface of the eye corneal epithelial cell.

35. Use of an effective amount of a MAPK/ERK kinase (MEK) inhibitor for the preparation of a medicament for the reducing or preventing scarring, opacification, or

neovascularization on the surface of the eye of a subject.

36. Use of an effective amount of a MAPK/ERK kinase (MEK) inhibitor for the preparation of a medicament for improving vision or reducing limitations on vision in a subject in need, wherein the method comprises administering to the subject.

37. The use of claim 35 or 36, wherein the subject is suffering from Aniridia, scarring on the surface of the eye, corneal opacification, neovascularization on the surface on the eye, ocular surface inflammation, severe ocular surface injuries, limbal stem cell deficiency, cancer, infections, auto-immune disease, inflammatory diseases or congenital diseases associated with reduced expression of PAX6.

38. Use of an effective amount of a MAPK/ERK kinase (MEK) inhibitor for the preparation of a medicament for treating an ocular disease or condition in a subject in need.

39. The use of claim 38 wherein the ocular disease or condition is Aniridia, scarring on the surface of the eye, corneal opacification, neovascularization on the surface of the eye, ocular surface inflammation, severe ocular surface injuries, limbal stem cell deficiency, cancer, infections, auto-immune disease, inflammatory diseases or congenital diseases associated with reduced expression of PAX6.

40. The use of any one of claims 33-39, wherein the MAPK/ERK kinase (MEK) inhibitor is a MEK1 or MEK2 inhibitor.

41. The use of claim 40, wherein the MEK1 or MEK2 is PD098059, PD0325901 , Tratetinib, Cobimetinib, MEK 1/2 inhibitor AS703988, MEK inhibitor PD325089, MEK inhibitor AZD8330, MEK inhibitor CS3006, MEK inhibitor R04987655, MEK inhibitor SHR 7390, MEK inhibitor TAK-733, MEK/Aurora kinase dual inhibitor Bl 847325, MEK-1/MEKK-1 inhibitor E6201 , refametinib, selumetinib, CI-1040, AZD6244, GDC-0973, GSK1 120212, AZD8330, R051267655, R04987655, AS703026, BS203580, MEK162, GDC-0623, R05126766, WX-554, HL-085, or U0126.

42. The use of any one of clams 33-39, wherein the MAPK/ERK kinase (MEK) inhibitor is an ERK inhibitor.

43. The use of claim 42, wherein the ERK inhibitor is FRI-20, ON-01060, VTX-1 1 e, 25-OH- D3-3-BE, B3CD, bromoacetoxycalcidiol, 180204 AEZ-131 , AEZS-131 , AEZS-136, SCH- 772984, AZ-13767370, BL-EI-001 , LY-3214996, LTT-462, KO-947 CC-90003, GDC- 0994, RG-7842, MK-8353, SCH900353, BVD-523, or Ulixertinib.

44. The use of any one of claims 33-39, wherein the MAPK/ERK kinase (MEK) inhibitor is PD0325901 at a concentration of about 0.1 to about 10 pm.

45. The use of any one of claims 33-44, wherein the medicament is administered as an ophthalmic composition, and the composition comprises the MAPK/ERK kinase (MEK) inhibitor and PBS.

46. The use of claim 45, wherein the ophthalmic composition further comprises about 1 % to about 20% DMSO and about 1% to about 20% HPMC.

47. The use of claim 46, where the ophthalmic composition further comprises about 10% to 50% poloxamer 407.

48. The use of any one of claims 45-47, wherein the MAPK/ERK kinase (MEK) inhibitor is at a concentration of about 0.1 to about 10 mM.

49. The use of any one of claims 33-48, wherein the medicament is formulated for

administration by topical route or oral route.

50. A composition for inducing PAX6 expression in a cell, wherein the composition

comprises an effective amount of a MAPK/ERK kinase (MEK) inhibitor.

51. The composition of clam 50, wherein the cell is an epithelial cell of the surface of the eye or a fibroblast cell on the surface of the eye corneal epithelial cell corneal epithelial cell.

52. A composition for reducing or preventing scarring on the surface of the eye,

opacification, or neovascularization on the surface of the eye of a subject, wherein the composition comprises an effective amount of a MAPK/ERK kinase (MEK) inhibitor.

53. A composition for improving vision or reducing limitations on vision in a subject in need, wherein the composition comprises an effective amount of a MAPK/ERK kinase (MEK) inhibitor.

54. The composition of claim 52 or 53, wherein the subject is suffering from Aniridia,

scarring on the surface of the eye, corneal opacification, neovascularization on the surface of the eye, ocular surface inflammation, severe ocular surface injuries, cancer, limbal stem cell deficiency infections, auto-immune disease, inflammatory diseases or congenital diseases associated with reduced expression of PAX6.

55. A composition for of treating an ocular disease or condition in a subject in need, wherein the composition comprises an effective amount of a MAPK/ERK kinase (MEK) inhibitor.

56. The composition of claim 55 wherein the ocular disease or condition is Aniridia, scarring on the surface of the eye, corneal opacification, neovascularization on the surface of the eye, ocular surface inflammation, severe ocular surface injuries, limbal stem cell deficiency, cancer, infections, auto-immune disease, inflammatory diseases or congenital diseases associated with reduced expression of PAX6.

57. The composition of any one of claims 50-56, wherein the MAPK/ERK kinase (MEK) inhibitor is a MEK1 or MEK2 inhibitor.

58. The composition of claim 57, wherein the MEK1 or MEK2 inhibitor is PD098059,

PD0325901 , Tratetinib, Cobimetinib, MEK 1/2 inhibitor AS703988, MEK inhibitor PD325089, MEK inhibitor AZD8330, MEK inhibitor CS3006, MEK inhibitor R04987655, MEK inhibitor SHR 7390, MEK inhibitor TAK-733, MEK/Aurora kinase dual inhibitor Bl 847325, MEK-1/MEKK-1 inhibitor E6201 , refametinib, selumetinib, CI-1040, AZD6244, GDC-0973, GSK1 120212, AZD8330, R051267655, R04987655, AS703026,

BS203580, MEK162, GDC-0623, R05126766, WX-554, HL-085, or U0126.

59. The composition of any one of clams 50-56, wherein the MAPK/ERK kinase (MEK)

inhibitor is an ERK inhibitor.

60. The composition of claim 59, wherein the ERK inhibitor is FRI-20, ON-01060, VTX-1 1 e, 25-OH-D3-3-BE, B3CD, bromoacetoxycalcidiol, 180204 AEZ-131 , AEZS-131 , AEZS- 136, SCH-772984, AZ-13767370, BL-EI-001 , LY-3214996, LTT-462, KO-947 CC-90003, GDC-0994, RG-7842, MK-8353, SCH900353, BVD-523, or Ulixertinib.

61. The composition of any one of claims 50-60, wherein the MAPK/ERK kinase (MEK) inhibitor is PD0325901 at a concentration of about 0.1 to about 10 pm.

62. The composition of any one of claims 50-61 , is an ophthalmic composition, and the composition comprises the MAPK/ERK kinase (MEK) inhibitor and PBS.

63. The composition of claim 62, wherein the ophthalmic composition further comprises about 1% to about 20% DMSO and about 1% to about 20% HPMC.

64. The method of claim 62, where the ophthalmic composition further comprises about 10% to 50% poloxamer 407.

65. The composition of any one of claims 62-64, the MAPK/ERK kinase (MEK) inhibitor is at a concentration of about 0.1 to about 10 mM.

66. The composition of any one of claims 50-65, wherein the composition is formulated for the administration by topical route or oral route.