# US 2021/0275529 A1 · Methods for treating ocular surface pain

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- Number: US 2021/0275529 A1
- Document ID: US20210275529A1
- Status: Published application
- Kind: A1
- Application number: 17/225,290
- Filed: 2021-04-08
- Published: 2021-09-09
- Earliest claimed: 2019-02-15
- Assignees: Novartis AG
- Applicants: Novartis AG
- Inventors: Quintus MEDLEY; Muneto MOGI; Michela MONTECCHI-PALMER; Kalliopi STASI
- Web page: https://patentgrep.com/patent/US20210275529A1

## CPC

- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 9/10: Dispersions; Emulsions
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 27/02: Ophthalmic agents
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides methods 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 methods for treating dry eye disease and ocular hyperemia by administering 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile.

## Claims

### Claim at position 1

-52. (canceled)

### Claim 53

A method of treating chronic ocular surface pain in a subject in need thereof, comprising ocularly administering an effective amount of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Formula I) having structure:
or a salt, solvate, polymorph, or co-crystal thereof to the subject.

### Claim 54 (depends on 53)

The method of claim 53, comprising administering the compound of formula I in a formulation at a concentration of about 0.5% w/v, about 1.0% w/v, about 1.5% w/v, about 2.0% w/v, about 2.5% w/v, about 3.0% w/v, or about 3.5% w/v.

### Claim 55 (depends on 53)

The method of claim 53, comprising administering the compound of formula I at a total daily dose per eye of about 0.5 to about 3.5 mg, or about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, or about 3.5 mg.

### Claim 56 (depends on 53)

The method according to claim 53, wherein the subject suffers from one or more of dry eye disease, Sjogren's Syndrome, conjunctivitis (including keratoconjuctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), Map-Dot-Fingerprint Dystrophy, acanthamoeba, fibromyalgia, Meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Steven-Johnson's syndrome, corneal epitheliopathies, corneal neuropathies (including LASIK induced corneal neuropathies), corneal dystrophies (including recurrent corneal dystrophies), epithelial basement membrane dystrophy, corneal erosions or abrasions (including recurrent corneal erosions or abrasions), ocular surface diseases, blepharitis, graft vs host disease, meibomitis, glaucoma, conjunctivochalasis, keratopathis (including herpetic keratopathy, filamentary keratopathy, band or bullous keratopathy, exposure keratopathy), keratitis (including herpes simplex virus keratitis), iritis, episclentis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, patients recovering from neurotrophic keratitis, or ocular pain persisting for at least three months after photorefractive keratectomy (PRK) surgery or laser-assisted in situ keratomileusis (LASIK) surgery.

### Claim 57 (depends on 53)

The method according to claim 53, wherein the administration results in a reduction in the subject's pain of at least about 10%, at least about 15%, at least about 20%, or at least about 25%, compared to a placebo, wherein the reduction in the pain score arises from the difference in pain scores prior to and after administration of compound I to the subject.

### Claim 58 (depends on 57)

The method according to claim 57, wherein the reduction in pain score occurs within about half hour after administration of compound I to the subject.

### Claim 59 (depends on 53)

The method according to claim 53, wherein the compound of formula I is administered for at least about one, at least about two, or at least about three months.

### Claim 60 (depends on 59)

The method according to claim 59, wherein the compound of formula I is administered to the subject one to four times daily.

### Claim 61 (depends on 53)

The method according to claim 53, wherein the subject suffers from dry eye disease, and the administration results in a decrease in the ocular pain associated with dry eye disease.

### Claim 62 (depends on 61)

The method according to claim 61, wherein the administration results in reduced incidence of at least about 10% in one or more of ocular dryness, ocular discomfort, ocular hyperemia, ocular burning or stinging, grittiness or foreign body sensation, or photophobia.

### Claim 63

A method of reducing ocular hyperemia in a subject in need thereof, comprising ocularly administering 4 to the subject -(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Formula I) having structure:
or a salt, solvate, polymorph, or co-crystal thereof; wherein the compound of formula I is administered at a concentration of about 0.5% w/v to about 3.5% w/v, about 0.5% w/v to about 2.5% w/v, or about 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, about 1.5% to about 3.0% w/v, or about 0.5% to about 2.5% w/v.

### Claim 64 (depends on 63)

The method according to claim 63, wherein the reduction in ocular hyperemia is at least about 1, at least about 2, at least about 3, at least about 4, or at least about 5, on the McMonnies scale.

### Claim 65 (depends on 63)

The method of claim 63, comprising administering the compound of formula I at a total daily dose per eye of about 0.5 to about 3.5 mg, or about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, or about 3.5 mg.

### Claim 66 (depends on 63)

The method of claim 63, wherein the ocular hyperemia is associated with one or more of dry eye disease, Sjogren's Syndrome, conjunctivitis (including keratoconjuctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), Map-Dot-Fingerprint Dystrophy, acanthamoeba, fibromyalgia, Meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Steven-Johnson's syndrome, corneal epitheliopathies, corneal neuropathies (including LASIK induced corneal neuropathies), corneal dystrophies (including recurrent corneal dystrophies), epithelial basement membrane dystrophy, corneal erosions or abrasions (including recurrent corneal erosions or abrasions), ocular surface diseases, blepharitis, graft vs host disease, meibomitis, glaucoma, conjunctivochalasis, keratopathis (including herpetic keratopathy, filamentary keratopathy, band or bullous keratopathy, exposure keratopathy), keratitis (including herpes simplex virus keratitis), iritis, episclentis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, patients recovering from neurotrophic keratitis, or ocular pain persisting for at least three months after photorefractive keratectomy (PRK) surgery or laser-assisted in situ keratomileusis (LASIK) surgery.

### Claim 67

A method of reducing chronic ocular surface pain in a subject in need thereof, comprising ocularly administering an effective amount of 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Formula I) having structure:
or a salt, solvate, polymorph, or co-crystal thereof to the subject.

### Claim 68 (depends on 67)

The method of claim 67, comprising administering the compound of formula I in a formulation at a concentration of about 0.5% w/v, about 1.0% w/v, about 1.5% w/v, about 2.0% w/v, about 2.5% w/v, about 3.0% w/v, or about 3.5% w/v.

### Claim 69 (depends on 67)

The method of claim 67, comprising administering the compound of formula I at a total daily dose per eye of about 0.5 to about 3.5 mg, or about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, or about 3.5 mg.

### Claim 70 (depends on 67)

The method according to claim 67, wherein the subject suffers from one or more of dry eye disease, Sjogren's Syndrome, conjunctivitis (including keratoconjuctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), Map-Dot-Fingerprint Dystrophy, acanthamoeba, fibromyalgia, Meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Steven-Johnson's syndrome, corneal epitheliopathies, corneal neuropathies (including LASIK induced corneal neuropathies), corneal dystrophies (including recurrent corneal dystrophies), epithelial basement membrane dystrophy, corneal erosions or abrasions (including recurrent corneal erosions or abrasions), ocular surface diseases, blepharitis, graft vs host disease, meibomitis, glaucoma, conjunctivochalasis, keratopathis (including herpetic keratopathy, filamentary keratopathy, band or bullous keratopathy, exposure keratopathy), keratitis (including herpes simplex virus keratitis), iritis, episclentis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, patients recovering from neurotrophic keratitis, or ocular pain persisting for at least three months after photorefractive keratectomy (PRK) surgery or laser-assisted in situ keratomileusis (LASIK) surgery.

### Claim 71 (depends on 67)

The method according to claim 67, wherein the administration results in a reduction in the subject's pain of at least about 10%, at least about 15%, at least about 20%, or at least about 25%, compared to a placebo, wherein the reduction in the pain score arises from the difference in pain scores prior to and after administration of compound I to the subject.

### Claim 72 (depends on 71)

The method according to claim 71, wherein the reduction in pain score occurs within about half hour after administration of compound I to the subject.