Methods for treating ocular surface pain

Abstract

To provide safe and effective therapeutic agents and methods for the treatment of ocular surface pain, particularly chronic ocular surface pain. [Solution] The present invention provides a method for treating ocular surface pain by administering 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I). The present invention also provides a method for treating dry eye disease and ocular conjunctivitis by administering 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile.

Claims

1. A method for treating ocular surface pain in a person in need of it, comprising an effective amount of... Construction: 【Chemistry 1】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3) -I-benzonitrile (formula I) or its salts, solvates, polymorphs or cocrystals The method, which includes instilling eye drops into the subject.

2. The method according to claim 1, wherein the ocular surface pain is chronic ocular surface pain (COSP).

3. The method according to claim 1, wherein the compound of formula I is administered to the cornea of ​​the subject.

4. Approximately 0.5% w / v to approximately 3.5% w / v, approximately 0.5% w / v to approximately 2.5% w / v, or approximately 0 .. 5% w / v to about 1.5 w / v, about 0.5% to about 3.0% w / v, about 1.0% to about 2.5 % w / v, at concentrations of approximately 1.5% to 3.0% w / v or approximately 0.5% to 2.5% w / v The method according to any one of claims 1 to 3, comprising administering a compound of formula I.

5. About 0.5% w / v, about 1.0% w / v, about 1.5% w / v, about 2.0% w / v, about 2. The compound of formula I is administered at concentrations of 5% w / v, approximately 3.0% w / v, or approximately 3.5% w / v. The method according to claim 4, which includes the action of

6. The COSP is associated with a dry eye disease, as described in any one of claims 1 to 5. Method of loading.

7. The method according to claim 6, wherein the administration results in a reduction of the symptoms of dry eye disease.

8. The administration results in a reduction of the ocular pain associated with dry eye disease, as described in claim 6. method.

9. The above administration may cause dryness of the eyes, discomfort of the eyes, redness of the eyes, burning or stinging sensation of the eyes, roughness, or This results in a reduction in the incidence of at least approximately 10% in one or more of the following: foreign body sensation or photophobia. The method according to claim 7.

10. The aforementioned conditions include dry eye disease, Sjögren's syndrome, and conjunctivitis (keratoconjunctivitis, vernal keratoconjunctivitis). (including allergic conjunctivitis), corneal epithelial basement membrane dystrophy, Acanthamoeba, line Vistiligo, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome Group, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (LASIK-induced) Corneal neuropathy (including corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), epithelium Basement membrane dystrophy, corneal erosion or corneal abrasion (recurrent corneal erosion or corneal abrasion) (Including abrasions), ocular surface diseases, blepharitis, graft-versus-host disease, meibomian gland inflammation, glaucoma, conjunctiva Keratosis, keratopathy (herpes zoster keratopathy, filamentous keratopathy, zoan or bullous keratopathy, lagophthalmos) (including), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, Recovering from multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmos, and neurotrophic keratitis. Patients who have undergone laser refractive keratotomy (PRK) or laser corneal reshaping surgery. One or more eye pains that have persisted for three months, even if not following LASIK surgery. The method according to any one of claims 1 to 5, for a person suffering from the disease.

11. Any one of claims 1 to 10 further comprises administering an additional therapeutic agent to the subject. Methods used.

12. The aforementioned dose, when measured using a visual analog scale (VAS), compared to placebo. so at least about 3, at least about 4, at least about 5, at least about 6, at least about 7. A reduction in pain score of at least approximately 8, at least approximately 9, or at least approximately 10. The method according to any one of claims 1 to 11.

13. The aforementioned dose, when measured by VAS, was at least approximately 6 less than placebo. Approximately 7, at least 8, at least 9, or at least 10 of the pain levels of the subject The method according to any one of claims 1 to 12, which results in a reduction of core size.

14. The aforementioned administration was at least about 10%, at least about 15%, less than placebo. Claims 1 to 1 result in a reduction of approximately 20% or at least approximately 25% of the pain in the subject. The method described in any one of the 11 items.

15. The reduction in the pain score is the difference in pain scores before and after administration of compound I to the subject. The method according to claim 12 or 13, arising from the above.

16. The reduction in the VAS score occurs within approximately half an hour after administration of compound I to the subject. The method according to any one of claims 12 to 15.

17. The aforementioned dose corresponds to at least about 1, at least about 2, and at least about 1 on the McMoney's scale.

3. A reduction in congestion in the subject by at least about 4 or at least about 5. The method described in any one of the requests 1 to 16.

18. The aforementioned administration, compared to placebo, showed the following results: best corrected visual acuity, slit-lamp biomicroscopy, pupil dilation, The following claims 1 to 17 do not result in one or more changes in blinking speed, tear production, or intraocular pressure. The method described in either of the above terms.

19. The compound of formula I is used for at least about one month, at least about two months, or at least about The method according to any one of claims 1 to 18, administered over a period of three months.

20. The compound of formula I is administered over a period of more than three months, as per any one of claims 1 to 19. The method described in section [section number].

21. The compound of formula I is administered once to four times a day, as described in any one of claims 1 to 20. The method.

22. Formula I for use in the treatment or reduction of ocular surface pain 【Chemistry 2】 Compounds of the same, or their salts, solvates, polymorphs, or cocrystals.

23. The aforementioned ocular surface pain lasts for at least one month, at least two months, or at least three months. The use according to claim 22, which is chronic ocular surface pain that persists over a period of time.

24. The compound of formula I is present in concentrations of approximately 0.5% w / v to approximately 3.5% w / v, and approximately 0.5% w / v to approximately 2% w / v. 5% w / v or approximately 0.5% w / v to approximately 1.5 w / v, approximately 0.5% to approximately 3.0% w / v, Approximately 1.0% to approximately 2.5% w / v, approximately 1.5% to approximately 3.0% w / v, or approximately 0.5% to approximately 2. The use according to claim 22 or 23, administered at a concentration of 5% w / v.

25. The compound of formula I is found to be approximately 0.5% w / v, approximately 1.0% w / v, approximately 1.5% w / v, and approximately 2% w / v. 0% w / v, approximately 2.5% w / v, w / v, approximately 3.0% w / v, or approximately 3.5% w / v concentration The use according to any one of claims 22 to 24, administered at a dose.

26. Equation I 【Transformation 3】 The eye surface contains an active ingredient which is a compound or a salt, solvate, polymorph or cocrystal thereof. A medicine used to treat or reduce facial pain.

27. The aforementioned ocular surface pain lasts for at least one month, at least two months, or at least three months. The pharmaceutical product according to claim 26, which is chronic ocular surface pain that persists over a period of time.

28. The compound of formula I is present in concentrations of approximately 0.5% w / v to approximately 3.5% w / v, and approximately 0.5% w / v to approximately 2% w / v. 5% w / v or approximately 0.5% w / v to approximately 1.5 w / v, approximately 0.5% to approximately 3.0% w / v, Approximately 1.0% to approximately 2.5% w / v, approximately 1.5% to approximately 3.0% w / v, or approximately 0.5% to approximately 2. The pharmaceutical product according to claim 26 or 27, administered at a concentration of 5% w / v.

29. The compound of formula I is found to be approximately 0.5% w / v, approximately 1.0% w / v, approximately 1.5% w / v, and approximately 2% w / v. Administer at concentrations of 0% w / v, approximately 2.5% w / v, approximately 3.0% w / v, or approximately 3.5% w / v. A pharmaceutical product according to any one of claims 26 to 28.

30. In the manufacture of a pharmaceutical product for the treatment or reduction of ocular surface pain, Formula I 【Chemistry 4】 Use of the compound or its salts, solvates, polymorphs, or cocrystals.

31. The aforementioned ocular surface pain lasts for at least one month, at least two months, or at least three months. The use according to claim 30, which is chronic ocular surface pain that persists over a period of time.

32. The compound of formula I is present in concentrations of approximately 0.5% w / v to approximately 3.5% w / v, and approximately 0.5% w / v to approximately 2% w / v. 5% w / v or approximately 0.5% w / v to approximately 1.5 w / v, approximately 0.5% to approximately 3.0% w / v, Approximately 1.0% to approximately 2.5% w / v, approximately 1.5% to approximately 3.0% w / v, or approximately 0.5% to approximately 2. The use according to claim 30 or 31, administered at a concentration of 5% w / v.

33. The compound of formula I is found to be approximately 0.5% w / v, approximately 1.0% w / v, approximately 1.5% w / v, and approximately 2% w / v. 0% w / v, approximately 2.5% w / v, w / v, approximately 3.0% w / v, or approximately 3.5% w / v concentration The use according to any one of claims 30 to 32, administered at a dose.

34. A method for reducing ocular surface pain in subjects requiring it, comprising: 【Transformation 5】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3) -I-benzonitrile (formula I) or its salts, solvates, polymorphs or cocrystals The method includes instilling the compound of formula I into the eye, and the concentration of the compound is approximately 0.5% w / v to approximately 3.5% w / v. Approximately 0.5% w / v to approximately 2.5% w / v or approximately 0.5% w / v to approximately 1.5 w / v, approximately 0. 5% to about 3.0% w / v, about 1.0% to about 2.5% w / v, about 1.5% to about 3.0% w / v The method described above, wherein the dose is administered at a concentration of v or approximately 0.5% to approximately 2.5% w / v.

35. The method according to claim 34, wherein the ocular surface pain is chronic ocular surface pain (COSP).

36. The COSP is associated with a dry eye disease, according to the method of claim 34 or 35. 。

37. The method according to claim 34, wherein the administration results in a reduction of the symptoms of dry eye disease.

38. The administration results in a reduction of the eye pain associated with dry eye disease, as described in claim 36. The method.

39. The above administration may cause dryness of the eyes, discomfort of the eyes, redness of the eyes, burning or stinging sensation of the eyes, roughness, or This results in a reduction in the incidence of at least approximately 10% in one or more of the following: foreign body sensation or photophobia. The method according to claim 38.

40. The aforementioned conditions include dry eye disease, Sjögren's syndrome, and conjunctivitis (keratoconjunctivitis, vernal keratoconjunctivitis). (including allergic conjunctivitis), corneal epithelial basement membrane dystrophy, Acanthamoeba, line Vistiligo, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome Group, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (LASIK-induced) Corneal neuropathy (including corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), epithelium Basement membrane dystrophy, corneal erosion or corneal abrasion (recurrent corneal erosion or corneal abrasion) (Including abrasions), ocular surface diseases, blepharitis, graft-versus-host disease, meibomian gland inflammation, glaucoma, conjunctiva Keratosis, keratopathy (herpes zoster keratopathy, filamentous keratopathy, zoan or bullous keratopathy, lagophthalmos) (including), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, Recovering from multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmos, and neurotrophic keratitis. Patients who have undergone laser refractive keratotomy (PRK) or laser corneal reshaping surgery. One or more eye pains that persist for at least three months after LASIK surgery. The method according to any one of claims 34 to 39, wherein the person is suffering from the disease.

41. Any one of claims 34 to 40 further comprises administering an additional therapeutic agent to the subject. The method described in section [section number].

42. The aforementioned dose, when measured using a visual analog scale (VAS), represents the dose of the compound. This results in a reduction of at least approximately 3 in the subject's pain score compared to the previous pain score. or the method according to any one of claims 34 to 41.

43. The aforementioned dose, when measured using a visual analog scale (VAS), compared to placebo. so at least about 3, at least about 4, at least about 5, at least about 6, at least about 7. A reduction in pain score of at least approximately 8, at least approximately 9, or at least approximately 10. The method according to any one of claims 34 to 41.

44. The aforementioned dose, when measured by VAS, was at least approximately 6 less than placebo. Approximately 7, at least 8, at least 9, or at least 10 of the pain levels of the subject The method according to any one of claims 34 to 42, which results in a reduction of core size.

45. The aforementioned administration was at least about 10%, at least about 15%, less than placebo. Claim 34, which results in a reduction of approximately 20% or at least approximately 25% of the pain in the subject. The method described in any one of items ~44.

46. The reduction in the pain score is the difference in pain scores before and after administration of compound I to the subject. The method according to any one of claims 42 to 45, arising from the above.

47. The aforementioned dose corresponds to at least about 1, at least about 2, and at least about 1 on the McMoney's scale.

3. A reduction in congestion in the subject by at least about 4 or at least about 5. The method described in any one of the requests 34 to 46.

48. A method for reducing ocular congestion in a person in need, comprising: 【Transformation 6】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3) -I-benzonitrile (formula I) or its salts, solvates, polymorphs or cocrystals The method includes instilling the compound of formula I into the eye, and the concentration of the compound is approximately 0.5% w / v to approximately 3.5% w / v. Approximately 0.5% w / v to approximately 2.5% w / v or approximately 0.5% w / v to approximately 1.5 w / v, approximately 0. 5% to about 3.0% w / v, about 1.0% to about 2.5% w / v, about 1.5% to about 3.0% w / v The method described above, wherein the dose is administered at a concentration of v or approximately 0.5% to approximately 2.5% w / v.

49. The reduction in ocular redness is at least about 1 on the McMonese scale, at least about 2 on the McMonese scale, and less. The method according to claim 48, wherein the number is at least about 3, at least about 4, or at least about 5.

50. The aforementioned administration may cause dryness of the eyes, discomfort of the eyes, burning or stinging sensations in the eyes, roughness or foreign body sensations. A claim that results in a reduced incidence of at least about 10% in one or more cases of photophobia or photophobia. The method described in 48 or 49.

51. The aforementioned conditions include dry eye disease, Sjögren's syndrome, and conjunctivitis (keratoconjunctivitis, vernal keratoconjunctivitis). (including allergic conjunctivitis), corneal epithelial basement membrane dystrophy, Acanthamoeba, line Vistiligo, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome Group, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (LASIK-induced) Corneal neuropathy (including corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), epithelium Basement membrane dystrophy, corneal erosion or corneal abrasion (recurrent corneal erosion or corneal abrasion) (Including abrasions), ocular surface diseases, blepharitis, graft-versus-host disease, meibomian gland inflammation, glaucoma, conjunctiva Keratosis, keratopathy (herpes zoster keratopathy, filamentous keratopathy, zoan or bullous keratopathy, lagophthalmos) (including), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, Recovering from multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmos, and neurotrophic keratitis. Patients who have undergone laser refractive keratotomy (PRK) or laser corneal reshaping surgery. One or more eye pains that persist for at least three months after LASIK surgery. The method according to any one of claims 48 to 50, wherein the person is suffering from the disease.

52. Any one of claims 48 to 51 further comprises administering an additional therapeutic agent to the subject. The method described in section [section number].

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