Treatment of ocular surface pain

Abstract

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 and ocular congestion by administering 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 806,682, which is incorporated herein in its entirety. Technical Field

[0003] The present disclosure relates to methods of using 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Compound I) to treat ocular surface diseases or disorders. Background Art

[0004] The ocular surface, especially the cornea, is densely innervated by sensory nerves. The activity of the corneal nerves can be modified by inflammation caused by a variety of factors, such as osmotic stress and tissue damage, as well as ocular surface nerve damage. Ocular surface symptoms are an alarm system for indicating an unbalanced ocular surface homeostasis, which leads to chronic ocular surface pain due to ocular surface pressure and ocular surface sensitization caused by persistent stimulation.

[0005] Patients with ocular surface pain, particularly chronic ocular surface pain, have a significantly reduced quality of life. To date, in pragmatic studies, the burden of severe chronic ocular surface pain has been compared to moderate to severe angina, dialysis, or disabling hip fracture. Severe chronic ocular surface pain is also associated with depression and suicidal thoughts. In many patients, ocular surface pain is not resolved despite treatment of the underlying pathological condition (e.g., recent trauma or surgery, infection, or inflammation). Moreover, treatments used for the short-term management of ocular pain (e.g., nonsteroidal anti-inflammatory drugs, steroids) cannot be used for long-term treatment. Therefore, there is a long-standing and unmet need for safe and effective treatments for ocular surface pain, particularly chronic ocular surface pain, when there are no other options that can improve patients' quality of life or complement current treatments. Summary of the invention

[0006] In one embodiment, the present disclosure provides a method of treating ocular surface pain in a subject in need thereof, the method comprising ocularly administering an effective amount of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Formula I) having the following structure:

[0007]

[0008] or a salt, solvate, polymorph, or cocrystal thereof to the subject.

[0009] In some embodiments, the ocular surface pain is episodic or acute pain. In some embodiments, the ocular surface pain is chronic ocular surface pain (COSP) that persists for at least about three months.

[0010] In some embodiments, the compound of formula I is administered to the cornea of ​​a subject. In some embodiments, the compound of formula I is administered to a subject 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. In specific embodiments, the compound of formula I is administered 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. In some embodiments, the compound of Formula I is administered to a subject at a concentration of about 5 mg / ml to about 35 mg / ml, about 5 mg / ml to about 25 mg / ml, or about 5 mg / ml to about 15 mg / ml, about 5 mg / ml to about 30 mg / ml, about 10 mg / ml to about 25 mg / ml, about 15 mg / ml to about 30 mg / ml, or about 5 mg / ml to about 25 mg / ml. In specific embodiments, the compound of Formula I is administered at a concentration of about 5 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, or about 35 mg / ml.

[0011] In some embodiments of the methods of treating ocular surface pain described herein, COSP is associated with dry eye. In some embodiments, administration results in a reduction in symptoms of dry eye. In specific embodiments, administration results in a reduction in eye pain associated with dry eye. In some embodiments, administration results in a reduction in the incidence of one or more of dry eyes, eye discomfort, eye congestion, eye burning or stinging, grittiness or foreign body sensation, or photophobia by at least about 10%.

[0012] In some embodiments of the methods of treating ocular surface pain described herein, the subject suffers from one or more of the following: dry eye disease, Sjögren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), Map-Dot-fingerprint dystrophy, Acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including complex The invention relates to a patient suffering from corneal dystrophy, epithelial basement membrane dystrophy, corneal erosion or abrasion (including recurrent corneal erosion or abrasion), ocular surface disease, blepharitis, graft-versus-host disease, tarsal gland inflammation, glaucoma, conjunctivochalasis, corneal lesions (including herpetic keratopathy, filamentous keratopathy, band or bullous keratopathy, exposure keratopathy), keratitis (including herpes simplex keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, dry eye, or patients recovering from neurotrophic keratitis. In some embodiments of the methods described herein, the subject suffers from eye pain that lasts for at least three months after photorefractive keratectomy (PRK) surgery or laser-assisted in situ keratomileusis (LASIK) surgery.

[0013] In some embodiments, the methods of treating ocular surface pain described herein comprise administering to the subject an additional therapeutic agent.

[0014] In some embodiments of the methods of treating ocular surface pain described herein, administration of Compound 1 to a subject results in a reduction in pain score of at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, or at least about 10, as measured by a visual analog scale (VAS) compared to placebo. In further embodiments, administration of Compound 1 to a subject results in a reduction in pain score of at least about 6, at least about 7, at least about 8, at least about 9, or at least about 10, as measured by VAS, compared to placebo.

[0015] In some embodiments of the methods of treating ocular surface pain described herein, administration of Compound I to a subject results in a reduction in pain in the subject of at least about 10%, at least about 15%, at least about 20%, or at least about 25%, compared to placebo. In some embodiments, the reduction in pain score is the difference between the pain score before and after administration of Compound I to the subject. In some embodiments of the methods described herein, Compound I is administered to the subject, and the reduction in pain score occurs within about half an hour after administration of Compound I to the subject.

[0016] In some embodiments of the methods of treating ocular surface pain described herein, administering Compound 1 to a subject results in a decrease in hyperemia in the subject of 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).

[0017] In some embodiments of the methods of treating ocular surface pain described herein, administration of Compound 1 to a subject does not result in a change in one or more of best corrected visual acuity, slit lamp biomicroscopy, dilated pupil examination, blink rate, tear production, intraocular pressure, compared to placebo.

[0018] In some embodiments of the methods of treating ocular surface pain described herein, the compound of Formula I is administered for at least about one month, at least about two months, or at least about three months. In some embodiments, the compound of Formula I is administered for greater than 3 months. In some embodiments, the compound of Formula I is administered one to four times per day. In specific embodiments, the compound of Formula I is administered once or twice per day.

[0019] In some embodiments, the present disclosure relates to compounds having Formula I

[0020]

[0021] or a salt, solvate, polymorph or cocrystal thereof,

[0022] Used to treat or relieve ocular surface pain.

[0023] In some embodiments, the ocular surface pain is acute or episodic ocular surface pain. In some embodiments, the ocular surface pain is chronic ocular surface pain that lasts for at least 1 month, at least 2 months, or at least 3 months.

[0024] In some embodiments of the uses described herein, 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.

[0025] In some embodiments of the uses described herein, the compound having Formula I is administered 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.

[0026] In some embodiments, the present disclosure relates to a drug for treating or alleviating ocular surface pain, the drug comprising as an active ingredient a compound having formula I

[0027]

[0028] or a salt, solvate, polymorph or co-crystal thereof.

[0029] In some embodiments, the ocular surface pain is acute or episodic ocular surface pain. In some embodiments, the ocular surface pain is chronic ocular surface pain that lasts for at least 1 month, at least 2 months. In some embodiments, the ocular surface pain is chronic ocular surface pain that lasts for at least 3 months. In some embodiments, 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. In some embodiments, the compound having Formula I is administered 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.

[0030] In some embodiments, the present disclosure relates to compounds having Formula I

[0031]

[0032] Or use of a salt, solvate, polymorph or co-crystal thereof in the manufacture of a medicament for treating or alleviating ocular surface pain.

[0033] In some embodiments, the use of Compound I is for acute or episodic ocular surface pain. In some embodiments, the use of Compound I is for chronic ocular surface pain that lasts for at least 1 month, at least 2 months, or at least 3 months.

[0034] In some embodiments of the uses described herein, 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.

[0035] In some embodiments of the uses described herein, the compound having Formula I is administered 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.

[0036] In some embodiments, the disclosure relates to a method of reducing ocular surface pain in a subject in need thereof, the method comprising ocularly administering 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Formula I) having the following structure:

[0037]

[0038] or a salt, solvate, polymorph, or cocrystal thereof to the subject; 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.

[0039] In some embodiments, the ocular surface pain is acute or episodic ocular surface pain. In some embodiments, the ocular surface pain is chronic ocular surface pain that lasts for at least 1 month, at least 2 months, or at least 3 months.

[0040] In some embodiments of the methods of reducing ocular pain described herein, the COSP is associated with dry eye disease.

[0041] In some embodiments of the methods of reducing ocular surface pain described herein, administering Compound 1 to a subject results in reduction of dry eye symptoms.

[0042] In some embodiments of the methods described herein for reducing ocular surface pain, administration of Compound I to a subject results in a reduction in ocular pain associated with dry eye disease. In some embodiments of the methods described herein, administration of Compound I to a subject results in a reduction in the incidence of one or more of ocular dryness, ocular discomfort, ocular congestion, ocular burning or stinging, grittiness or foreign body sensation, or photophobia by at least about 10%.

[0043] In some embodiments, the subject in need of relief of ocular surface pain suffers from one or more of the following: dry eye disease, Sjögren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), Map-Dot-fingerprint dystrophy, Acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy Patients with ocular dystrophy, epithelial basement membrane dystrophy, corneal erosion or abrasion (including recurrent corneal erosion or abrasion), ocular surface disease, blepharitis, graft-versus-host disease, tarsal adenitis, glaucoma, conjunctivochalasis, corneal disease (including herpetic keratopathy, filamentous keratopathy, band or bullous keratopathy, exposure keratopathy), keratitis (including herpes simplex keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or recovering from neurotrophic keratitis.

[0044] In some embodiments, the methods of reducing ocular surface pain described herein comprise administering an additional therapeutic agent to the subject.

[0045] In some embodiments of the methods described herein for reducing ocular surface pain, administration of the compound to a subject results in a decrease in the subject's pain score of at least about 3, as measured on a visual analog scale (VAS), compared to the pain score prior to administration of the compound 1. In some embodiments of the methods described herein, administration of compound 1 to a subject results in a decrease in pain score of at least about 3, at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, or at least about 10, as measured on a visual analog scale (VAS), compared to placebo. In some embodiments of the methods described herein, administration of compound 1 to a subject results in a decrease in the subject's pain score of at least about 6, at least about 7, at least about 8, at least about 9, or at least about 10, as measured on a VAS, compared to placebo.

[0046] In some embodiments of the methods described herein for reducing ocular surface pain, administration of Compound I to a subject results in a reduction in pain in the subject of at least about 10%, at least about 15%, at least about 20%, or at least about 25%, compared to placebo. In some embodiments of the methods described herein, the reduction in pain score is the difference in pain score before and after administration of Compound I to the subject.

[0047] In some embodiments of the methods of reducing ocular surface pain described herein, administering Compound 1 to a subject results in a decrease in hyperemia in the subject of 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).

[0048] In some embodiments, the disclosure relates to a method of reducing ocular congestion in a subject in need thereof, the method comprising ocularly administering 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Formula I) having the following structure:

[0049]

[0050] or a salt, solvate, polymorph, or cocrystal thereof to the subject; 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.

[0051] In some embodiments of the methods described herein, administration of Compound 1 to a subject results in a reduction in ocular hyperemia of 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). In some embodiments of the methods described herein, administration of Compound 1 to a subject results in a reduction in the incidence of one or more of dry eyes, ocular discomfort, ocular burning or stinging, grittiness or foreign body sensation, or photophobia of at least about 10%.

[0052] In some embodiments of the method of reducing ocular congestion, the subject suffers from one or more of the following: dry eye disease, Sjögren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), Map-Dot-fingerprint dystrophy, Acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), Patients with ocular dystrophy, epithelial basement membrane dystrophy, corneal erosion or abrasion (including recurrent corneal erosion or abrasion), ocular surface disease, blepharitis, graft-versus-host disease, tarsal adenitis, glaucoma, conjunctivochalasis, corneal disease (including herpetic keratopathy, filamentous keratopathy, band or bullous keratopathy, exposure keratopathy), keratitis (including herpes simplex keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or recovering from neurotrophic keratitis.

[0053] Some embodiments of the methods of reducing ocular congestion described herein further comprise administering to the subject an additional therapeutic agent.

[0054] Specific preferred embodiments of the present invention will become apparent from the following more detailed description of certain preferred embodiments and the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1 Model estimated means (+ / - SE) for visual analogue scale (VAS) pain assessments (primary PD analysis set) over time are shown.

[0056] Figure 2 A histogram of the incidence of oral rescue medication use (number of patients who did not use oral rescue medication) (Secondary PD Analysis Set) is shown. For each time period, the right column represents subjects who were administered Compound I, while the left column represents subjects who were administered vehicle. The y-axis shows the percentage of patients who did not use oral rescue medication (ORM). n / N represents the count / total number of patients at each treatment.

[0057] Figure 3 provides the arithmetic means (+ / - SD) of the Ocular Pain Assessment Survey (OPAS) over time for questions 4, 5, and 6 (secondary PD analysis set). Figure 3A Provide the results of Question 4: 24-hour eye pain at its most painful (pain level), Figure 3B Provide the results of Question 5: 24-hour eye pain at the lowest level of distress (pain level), Figure 3C Provide the results of Question 6: Average (pain level) 24hr eye pain. Figure 3A , 3B In each of 3C and 3D, the dashed line with "×" represents the vehicle, and the solid line with a circle (o) represents Compound I.

[0058] Figure 4 provides the arithmetic means (+ / - SD) of the Ocular Pain Assessment Survey (OPAS) over time for questions 22, 23, 24, and 25 (secondary PD analysis set). Figure 4A Provide the results of Question 22: Frequency (%) of painful eyes with redness. Figure 4B Provide the results of Question 23: Frequency (%) of eye pain with burning. Figure 4C Provide the results of Question 24: Frequency of eye pain with sensitivity (%). Figure 4D Provide the results of Question 25: Frequency of eye pain with tearing (%). Figure 4A , 4B , 4C and 4D, the dashed line with an "x" represents the vehicle, and the solid line with a circle (o) represents Compound I.

[0059] Figure 5A The arithmetic mean (SD) plasma concentrations of Compound I following topical ocular administration of 2.5% Compound I on Day 1 (PK analysis set) are presented. Figure 5BThe arithmetic mean (SD) plasma concentrations of Compound I following topical ocular administration of 2.5% Compound I on Day 4 (PK analysis set) are presented.

[0060] Fig. 6A Provides a bar graph of ocular hyperemia over time for Compound I, Figure 6B A bar graph of ocular hyperemia over time for vehicle is provided. The quadrants are S: superior, N: nasal, I: inferior, T: temporal.

[0061] Figure 7 The arithmetic mean (+ / -SD) of epithelial defect size over time (safety analysis set) parameters (units) are provided: epithelial wound size (mm), subcategory: area (mm2). Dashed lines with "×" represent vehicle, solid lines with circles (o) represent Compound I. DETAILED DESCRIPTION

[0062] "TRPV1 receptor" refers to transient receptor potential vanilloid 1 which has been characterized by molecular cloning and pharmacology. See, e.g., Caterina MJ, et al., Nature 1997; 389: 816-824. TRPV1 receptor activity was measured as described in WO 2005 / 120510, which is incorporated herein by reference in its entirety.

[0063] The language "effective amount" of a compound described herein refers to the amount of a therapeutic compound necessary or sufficient to achieve its intended function in a mammal. The effective amount of a therapeutic compound may vary depending on factors such as the amount of pathogen already present in the mammal, the age, sex, and weight of the mammal, and the ability of the disclosed therapeutic compound to treat an ocular surface disorder and / or its symptoms in a mammal.

[0064] The term "ophthalmologically compatible" refers to formulations, polymers and other materials and / or dosage forms that are suitable for use in contact with ocular tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0065] As used herein, with respect to a disease or disorder, the term "treat, treating or treatment" in some embodiments refers to alleviating a disease or disorder (i.e., slowing down or preventing or reducing the development of a disease or at least one clinical symptom thereof). In another embodiment, "treat, treating or treatment" refers to alleviating or improving at least one physical parameter, including those that cannot be discerned by the patient. In still another embodiment, "treat, treating or treatment" refers to regulating a disease or disorder physically (e.g., stabilization of discernible symptoms) or physiologically (e.g., stabilization of physical parameters) or both. In yet another embodiment, "treat, treating or treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder or its symptoms.

[0066] As used herein, the term "subject" or "patient" refers to human and non-human mammals, including but not limited to primates, rabbits, pigs, horses, dogs, cats, sheep and cattle. In a specific embodiment, the subject or patient is a human. In some embodiments, the term "patient" or "subject" refers to a person suffering from a condition (i.e., a disease or disorder) described herein and who will benefit from treatment. As used herein, if such a subject (patient) will benefit from such treatment biologically, medically or in terms of quality of life, then the subject is "in need" of treatment. In a specific embodiment, the subject is an adult of at least 18 years old. In a specific embodiment, the subject is an adult of about 18 to about 75 years old. In some embodiments, the subject is a human child of up to about 18 years old.

[0067] As used herein, "ocular surface" refers to the outer surface of the eye, which anatomically includes the cornea (with epithelium, bowman layer, stroma, descement membrane, endothelium), conjunctiva, conjunctival sac, and corneal-scleral junction (i.e., limbus).

[0068] As used herein, ocular administration includes administration to all parts of the eye, including all parts of the ocular surface, such as the cornea, conjunctiva, conjunctival sac, and corneal-scleral junction (ie, limbus).

[0069] As used herein, "pain" refers to a constant or intermittent sensation of actual pain described as, but not limited to, tingling, dull pain, sharp pain, or agony. Pain may also refer to similar related descriptors such as, but not limited to, burning, stinging, gritty, foreign body sensation, dryness, sandy sensation, tiredness, itching, irritation, sensitivity to light.

[0070] As used herein, "ocular surface pain" refers to pain on the surface of the eye (e.g., cornea). Eye pain can be nociceptive pain, which is usually caused by external physical or chemical damaging stimuli (e.g., corneal surgery, inflammation, or other damage to the corneal surface). Eye pain may also be caused by neuropathic pain, which may occur due to direct damage to the body's neurons, causing pain information to be sent to the central nervous system and brain, regardless of whether there is a harmful stimulus. As used herein, "ocular surface pain" includes nociceptive pain and neuropathic pain.

[0071] As used herein, the term "visual analog scale" (VAS) is a measure of pain intensity, wherein a subject typically marks a position on the scale that is consistent with their pain level. Pain is marked in the range of "no pain" (scored as 0) and "pain as severe as possible" or "worst imaginable pain" (scored as 100). See, for example, Hawker, et al., Arthritis Care & Research 63 (11), pages S240-S252 (November 2011). There are also several other well-designed pain scales that can be used to help assess pain levels. Numerical rating scales (NRS) are often used, in which subjects use numerical values ​​to assess pain. The numerical range can be from 1-10 or 1-100. The Wong-BakerFACES pain scale combines pictures and numerical values ​​for pain assessment. It can be used for children and adults over 3 years old. Six faces depict different expressions, which vary from happy to extremely depressed. Each is assigned a numerical rating between 0 (smile) and 10 (cry). The Verbal Pain Intensity Scale rates pain intensity using words on a scale: No pain / Mild pain / Moderate pain / Severe pain Very severe pain / Worst possible pain.

[0072] The Ocular Sensation Scale is a specific pain scale developed to measure the severity of eye pain. See Caudle LE et al., Optom Vis Sci. 2007 Aug;84(8):752-62. On this scale, pain, discomfort, or light sensitivity is typically measured with 5 category labels, which are "extreme," "severe," "moderate," "mild," or "none."

[0073] The Ocular Pain Assessment Survey (OPAS) is a quantitative, multidimensional questionnaire specifically designed to assess corneal and ocular surface pain and quality of life (QoL) changes. The OPAS assesses pain intensity, frequency of ocular and non-ocular pain, QoL changes, exacerbating factors, associated factors, and quantification of symptomatic relief, thereby allowing monitoring of treatment response. See Qazi et al., Ophthalmology July 123(7): 1458-1468 (2016).

[0074] As used herein, the term "visual task questionnaire" refers to a questionnaire that asks subjects to subjectively rate the degree of difficulty they have in performing certain activities that require fixed or prolonged staring, which may exacerbate eye pain. The questionnaire also asks about coping mechanisms related to the difficulties they encounter in visual task activities.

[0075] As used herein, ocular hyperemia refers to redness of the ocular surface. Ocular hyperemia may be a clinical sign of inflammation and / or ocular irritation. Ocular hyperemia can be measured using the McMonnies scale with a value from 0 to 5 based on standard photographs.

[0076] As used herein, "placebo" refers to an ophthalmic formulation that includes all components of an administered pharmaceutical composition without the drug.

[0077] As used herein, the term "about" refers to a range of values ​​that is + 10% of the specified value.

[0078] As used herein, a pharmaceutical composition is a composition suitable for pharmaceutical use. Compositions suitable for pharmaceutical use can be sterile, homogeneous and / or isotonic. In certain embodiments, the pharmaceutical composition can be prepared in an aqueous form, such as in a pre-filled syringe or other single-dose or multi-dose container. In certain embodiments of the present invention, the pharmaceutical composition is ophthalmologically compatible and suitable for ophthalmic administration to human subjects by, for example, topical or other known delivery methods.

[0079] As used herein, "compounds of formula I," "compound I," "Formula I," and "Compound I" are used interchangeably and refer to a compound named 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile, whose structure is shown below, and which can be synthesized using methods known in the art and described in WO 2005 / 120510 to Chen et al. and U.S. Pat. No. 8,349,852 ("Quinazolinone derivatives useful as vanilloid antagonists") (both of which are hereby incorporated by reference in their entireties).

[0080]

[0081] Additionally or alternatively, various crystalline and polymorphic forms of Compound 1 may be used.

[0082] In some embodiments, Compound I is in polymorph Form B as described in U.S. Pat. No. 8,349,852, which is incorporated herein by reference. In some embodiments, polymorph B is characterized by an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from 9.3, 10.6, and 14.4 +-.0.2° 2θ. In some embodiments, polymorph B is characterized by an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from 9.3, 10.6, 14.4, 15.5, 17.9, 19.9, 23.4. +-.0.2° 2θ.

[0083] Any chemical formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures represented by the formulas given herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of the present disclosure include, for example, isotopes of hydrogen, carbon, nitrogen, and oxygen, such as 3 H. 11 C. 13 C. 14 C and 15 N. Thus, it will be appreciated that the methods of the invention can or may involve the incorporation of one or more of any of the above isotopes (including, for example, radioisotopes (such as 3 H and 14 C)) or the presence of non-radioactive isotopes (such as 2 H and 13 C) of the substance. This isotope-labeled compound can be used for metabolic studies (using 14 C) reaction kinetics studies (e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution determinations, or for radiotherapy of patients. Isotope-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, such as using appropriate isotope-labeled reagents to replace unlabeled previously used reagents.

[0084] The present invention encompasses the following embodiments, which include all pharmaceutically acceptable salts of compounds useful according to the present invention provided herein. As used herein, "pharmaceutically acceptable salts" refer to derivatives of disclosed compounds in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or in an organic solvent or in a mixture of the two; typically, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. For example, preferred pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines. For example, the salt may be a hydrochloride. Other examples of suitable salts may be found in U.S. Pat. No. 8,349,852, the contents of which are incorporated herein by reference in their entirety.

[0085] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0086] Compound (I) or a pharmaceutically acceptable salt thereof can be incorporated into formulations for delivery in various ways. For example, a topical formulation can be used and can include an ophthalmologically acceptable preservative, surfactant, viscosity enhancer, buffer, sodium chloride and water to form an aqueous ophthalmologically compatible solution and suspension.

[0087] The compound of formula I is typically included in these formulations in an amount of about 0.1% to about 5.0% w / v. In some embodiments, the concentration range of Compound I for topical administration is about 0.5% to about 1.5% w / v, about 0.5% to about 2.5% w / v, about 0.5% to about 3.5% 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, about 0.5% to about 2.5% w / v. In some embodiments, the concentration of the compound of formula I in the formulation for topical use is at least about 0.5% w / v, at least about 1.0% w / v, at least about 1.5% w / v, at least about 2.0% w / v, or at least about 2.5% w / v. In some embodiments, the concentration of the compound of Formula I in the formulation for topical use is no more than about 5.0% w / v, no more than about 4.5% w / v, no more than about 4.0% w / v, no more than about 3.5% w / v, or no more than about 3.0% w / v. In specific embodiments, the concentration of the compound of Formula I in the formulation for topical use is 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. It is well known that equivalent concentrations can be expressed in different units. For example, a concentration of 0.1% w / v can also be expressed as 1 mg / ml solution. In some embodiments, expressed in mg / ml, the compound of formula I is administered to a subject at a concentration of about 5 mg / ml to about 35 mg / ml, about 5 mg / ml to about 25 mg / ml, or about 5 mg / ml to about 15 mg / ml, about 5 mg / ml to about 30 mg / ml, about 10 mg / ml to about 25 mg / ml, about 15 mg / ml to about 30 mg / ml, or about 5 mg / ml to about 25 mg / ml. In some embodiments, the concentration of the compound of formula I in the formulation for topical use is at least about 5 mg / ml, at least about 10 mg / ml, at least about 15 mg / ml, at least about 20 mg / ml, or at least about 25 mg / ml. In some embodiments, the concentration of the compound of formula I in the formulation for topical use is no more than about 50 mg / ml, no more than about 45 mg / ml, no more than about 40 mg / ml, no more than about 35 mg / ml, or no more than about 30 mg / ml. In specific embodiments, the compound having Formula I is administered at a concentration of about 5 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, or about 35 mg / ml.

[0088] In some embodiments, the formulation is delivered to the ocular surface one to six times per day (depending on the routine judgment of a skilled clinician). In some embodiments, the formulation is administered once, twice, three times, or four times per day.

[0089] Unless otherwise indicated, the weight or dosage referred to herein for a compound of Formula I is the weight or dosage of the compound itself (rather than its salt or its prodrug), which may be different for achieving the desired therapeutic effect. For example, the weight or dosage of the corresponding salt of a compound suitable for the methods, compositions or combinations disclosed herein may be calculated based on the ratio of the molecular weight of the salt to the compound itself.

[0090] Compound (I) and / or its pharmaceutically acceptable salt can be incorporated into an ophthalmologically compatible formulation for delivery to the eye. The compound can be combined with an ophthalmologically acceptable preservative, cosolvent, surfactant, viscosity enhancer, penetration enhancer, buffer, sodium chloride or water to form an aqueous, sterile ophthalmic suspension or solution.

[0091] In addition to compound (I), the pharmaceutical composition of the present invention may include additional therapeutic agents. Other therapeutic agents may include, for example, other compounds and antibodies that can be used to treat ocular surface disorders. A non-limiting list of such agents includes nonsteroidal anti-inflammatory drugs, such as ketorolac, nepafenac, bromfenac, corticosteroids; drugs for dry eye, such as cyclosporine, rificid, autologous serum or other TRPV1 inhibitors. In a specific embodiment, the additional therapeutic agent is an ophthalmic steroid, such as dexamethasone, fluocinolone, loteprednol, difluprednate, fluorometholone, prednisolone, prednisone, medecins, triamcinolone, betamethasone, rimexolone or a pharmaceutically acceptable salt thereof. Other non-limiting examples of such additional therapeutic agents that may be included in the pharmaceutical composition include (Liphixister), (cyclosporine), minocycline, doxycycline or other tetracycline antibiotics. Other examples include keratolytic agents such as selenium sulfide, salicylic acid, glycolic acid, etc., or pharmaceutically acceptable salts thereof.

[0092] Without wishing to be bound by theory, it is hypothesized that blockers of the transient receptor potential vanilloid 1 (TRPV1) receptor may be useful in treating pain, such as chronic pain.

[0093] Therefore, in some embodiments, the present invention provides a method for treating ocular surface pain in a subject in need thereof, the method comprising administering to the subject an effective amount of compound (I) or a pharmaceutically acceptable salt, solvate or cocrystal thereof. In some embodiments, the present invention provides a method for alleviating ocular surface pain in a subject in need thereof, the method comprising administering to the subject an effective amount of compound (I) or a pharmaceutically acceptable salt, solvate or cocrystal thereof. In some embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, solvate or cocrystal thereof for use in treating or alleviating ocular surface pain. In some embodiments, the compound of formula I is in polymorphic form B.

[0094] In some embodiments, the ocular surface pain is episodic, ie, acute.

[0095] In some embodiments, the subject suffers from chronic ocular surface pain that persists for at least three months.

[0096] In some embodiments, the subject suffers from chronic ocular surface pain that lasts for at least two months. In some embodiments, the subject suffers from chronic ocular surface pain that lasts for at least one month. In some embodiments, the subject suffers from chronic ocular surface pain that lasts for at least four months. In some embodiments, the subject suffers from chronic ocular surface pain that lasts for at least five months. Therefore, in some embodiments, the present invention provides a method for treating chronic ocular surface pain in a subject by administering an effective amount of a compound of Formula I or a salt, solvate, polymorph or cocrystal thereof to the subject. In some embodiments, the present invention provides a method for alleviating chronic ocular surface pain in a subject by administering an effective amount of a compound of Formula I or a salt, solvate, polymorph or cocrystal thereof to the subject. The present invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt, solvate, polymorph or cocrystal thereof in the treatment of chronic ocular surface pain.

[0097] In some embodiments, administration is to the ocular surface of a subject, such as the cornea, any portion of the conjunctiva, or the cul de sac of the eye.

[0098] In some embodiments, the present invention provides for administering a compound of Formula I in an ophthalmologically compatible formulation at a concentration of about 0.5% w / v to about 3.5% w / v to a subject in need thereof. In some embodiments, the administration concentration range is about 0.5% to about 3.5% w / v, about 0.5% to about 2.5% w / v, about 0.5% 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, about 0.5% to about 2.5% w / v. In specific embodiments, the concentration of the compound of Formula I in the formulation for topical use is 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. In some embodiments, the compound of Formula I is administered to a subject at a concentration of about 5 mg / ml to about 35 mg / ml, about 5 mg / ml to about 25 mg / ml, or about 5 mg / ml to about 15 mg / ml, about 5 mg / ml to about 30 mg / ml, about 10 mg / ml to about 25 mg / ml, about 15 mg / ml to about 30 mg / ml, or about 5 mg / ml to about 25 mg / ml. In specific embodiments, the compound of Formula I is administered at a concentration of about 5 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, or about 35 mg / ml. In some embodiments, the dose / administration / eye is about 0.15 to about 1.15 mg, or about 0.15 mg, 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1.0 mg, about 1.05 mg, about 1.1 mg, or about 1.15 mg. In some embodiments, the dose / administration / eye is about 0.18 mg, about 0.37 mg, about 0.55 mg, about 0.74 mg, or about 0.92 mg. In some embodiments, the total daily dose / eye is 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. In some embodiments, the compound of formula I is administered to the subject once to six times a day, for example, once, twice, three times, or four times a day. In some embodiments, the compound of formula I is administered to the subject for at least about one month, at least about two months, or at least about three months. In some embodiments, the compound of formula I is administered to the subject for at least about 12 weeks.

[0099] In some embodiments, ocular surface pain or chronic ocular surface pain is associated with one or more of the following: dry eye disease, Sjögren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), Map-Dot-fingerprint dystrophy, Acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), Patients with ocular dystrophy, epithelial basement membrane dystrophy, corneal erosion or abrasion (including recurrent corneal erosion or abrasion), ocular surface disease, blepharitis, graft-versus-host disease, tarsal adenitis, glaucoma, conjunctivochalasis, corneal disease (including herpetic keratopathy, filamentous keratopathy, band or bullous keratopathy, exposure keratopathy), keratitis (including herpes simplex keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or recovering from neurotrophic keratitis.

[0100] In certain embodiments, ocular surface pain or chronic ocular surface pain is associated with dry eye or Sjogren's Syndrome. In some embodiments of the methods described herein, the subject suffers from ocular pain that lasts for at least three months after photorefractive keratectomy (PRK) surgery or laser-assisted in situ keratomileusis (LASIK) surgery.

[0101] In some embodiments, the subject has conjunctivitis, subconjunctival hemorrhage, subconjunctival scar, conjunctiva, conjunctival ulcer, superficial punctate epithelial erosion, epithelial defect, eyelid ulcer, eyelid keratinization, eyeball adhesion, eyelid adhesion, trichiasis, anterior blepharitis, lacrimal punctum self-occlusion, meibomian gland disease, corneal opacity, dry eye, distichiasis, limbal stem cell failure, or corneal vascularization.

[0102] In some embodiments, administration of a compound of Formula I results in reduced eye pain in a subject compared to a placebo. In some embodiments, when measured by a VAS score, the reduction in eye pain in a subject is at least about 3 compared to a placebo. In some embodiments, administration results in a reduction in eye pain in a subject of at least about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least about 9, or at least about 10 compared to a placebo, when measured by a VAS score. In some embodiments, administration results in a reduction in pain in a subject of at least about 10%, at least about 15%, at least about 20%, or at least about 25% compared to a placebo. In some embodiments, administration results in a reduction in pain in a subject when measured 7 days after administration of a compound of Formula I. In some embodiments, administration results in a reduction in pain in a subject when measured 14 days after administration of a compound of Formula I.

[0103] In some embodiments, administration of a compound having Formula I results in a reduction in pain in a subject of at least about 2 at about half an hour after administration, at about one hour after administration, at about 2 hours, or 2-4 hours after administration, as measured by a VAS score, compared to placebo.

[0104] In some embodiments, the reduction in pain score is produced by the difference in pain score before and after administration of Compound I to the subject. In some embodiments, the reduction in pain score as measured by the pain score is produced by the difference in VAS score before and after administration of Compound I to the subject. In some embodiments, the reduction in pain score occurs within about half an hour after administration of Compound I to the subject. In some embodiments, the reduction in pain score occurs within about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours after administration of Compound I to the subject. In other embodiments, the reduction in pain score occurs about 7 days after administration of Compound I to the subject. In some embodiments, the reduction in pain score occurs about 14 days after administration of Compound I to the subject.

[0105] In some embodiments, administration of a compound of Formula I results in reduced ocular hyperemia (eye redness) compared to placebo. In specific embodiments, administration of a compound of Formula I results in reduced Grade 1, Grade 2, Grade 3, or Grade 4 hyperemia compared to placebo. In some embodiments, administration results in a reduction in ocular hyperemia score of 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).

[0106] In some embodiments, administration of a compound having Formula I results in an improvement in the score of at least about 10%, at least about 20%, or at least about 30% on at least one question of the OPAS.

[0107] In some embodiments, administration of a compound having Formula I results in an improvement in score of at least about 10%, at least about 20%, or at least about 30% on at least one question of a visual task questionnaire.

[0108] Therefore, in some embodiments, the present invention relates to a method for treating ocular congestion in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula I, or a salt, solvate, polymorph, or cocrystal thereof. In some embodiments, the present invention relates to a method for reducing ocular congestion in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula I, or a salt, solvate, polymorph, or cocrystal thereof. In some embodiments, administration of compound I results in a reduction in ocular congestion of at least 1, at least 2, at least 3, at least 4, or at least 5 (on the McMonnies scale). In some embodiments, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate, or cocrystal thereof in the treatment of ocular congestion. In some embodiments, the present invention provides administration of a compound of formula I at a concentration of about 0.5% w / v to about 3.5% w / v to a subject in need thereof in an ophthalmologically compatible formulation. In some embodiments, the concentration range of application is about 0.5% to about 3.5% w / v, about 0.5% to about 2.5% w / v, about 0.5% 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, about 0.5% to about 2.5% w / v. In specific embodiments, the concentration of the compound of Formula I in the formulation for topical use is 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. It should be understood that the percentage values ​​can be expressed in mg / ml. In some embodiments, the dose / administration / eye is about 0.15 to about 1.15 mg, or about 0.15 mg, 0.2 mg, about 0.25 mg, 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1.0 mg, about 1.05 mg, about 1.1 mg, or about 1.15 mg. In some embodiments, the dose / administration / eye is about 0.18 mg, about 0.37 mg, about 0.55 mg, about 0.74 mg, or about 0.92 mg. In some embodiments, the total daily dose per eye is 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. In some embodiments, the compound of Formula I is administered to the subject once to six times per day, for example, once, twice, three times, or four times per day. In some embodiments, the compound of Formula I is administered to the subject for a period of at least about one month, at least about two months, or at least about three months.

[0109] In some embodiments, ocular congestion is associated with one or more of the following: dry eye disease, Sjögren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), Map-Dot-fingerprint dystrophy, Acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy ), epithelial basement membrane dystrophy, corneal erosion or abrasion (including recurrent corneal erosion or abrasion), ocular surface disease, blepharitis, graft-versus-host disease, tarsal gland inflammation, glaucoma, conjunctivochalasis, corneal lesions (including herpetic keratopathy, filamentous keratopathy, band or bullous keratopathy, exposure keratopathy), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, dry eye, or patients recovering from neurotrophic keratitis. In specific embodiments, ocular congestion is associated with dry eye disease. In some embodiments of the methods described herein, the ocular congestion persists for at least three months after photorefractive keratectomy (PRK) surgery or laser-assisted in situ keratomileusis (LASIK) surgery.

[0110] In some embodiments, ocular surface pain or chronic ocular surface pain is associated with dry eye. In some embodiments, the administration of a compound of Formula I results in a reduction in the symptoms of dry eye. Dry eye is generally considered to be a complex, multifactorial condition characterized by inflammation of the ocular surface and lacrimal glands and a reduction in the quality and / or quantity of tears. It is believed that up to 30% of dry eye patients suffer from ocular surface pain that may be chronic, i.e., lasting at least 12 weeks or 3 months. Therefore, in some embodiments, the present invention results in a reduction in the symptoms of dry eye of at least about 10%, at least about 15%, at least about 20%, or at least about 30%, including one or more of dry eye, eye discomfort, eye congestion, eye burning or stinging, gritty or foreign body sensation, or photophobia.

[0111] In some embodiments, the present invention relates to a method for treating dry eye disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula I, or a salt, solvate, polymorph, or cocrystal thereof. In some embodiments, the present invention relates to a method for treating dry eye disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula I, or a salt, solvate, polymorph, or cocrystal thereof, wherein the compound of formula I is safe for at least 2 months, at least 3 months, at least 4 months, or at least 5 months of administration. In a specific embodiment, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt, solvate, or cocrystal thereof in the treatment of dry eye disease. In some embodiments, the present invention results in at least about 10% reduction in the symptoms of dry eye disease, the symptoms including dry eyes, eye discomfort, eye congestion, eye burning or stinging, grit or foreign body sensation, or photophobia. In some embodiments, the present invention provides administration of a compound of formula I at a concentration of about 0.5% w / v to about 3.5% w / v in an ophthalmologically compatible formulation to a subject in need thereof. In some embodiments, the concentration range for administration is about 0.5% to about 3.5% w / v, about 0.5% to about 2.5% w / v, about 0.5% 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, about 0.5% to about 2.5% w / v. In specific embodiments, the concentration of the compound of Formula I in the formulation for topical use is 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. In some embodiments, the dose / administration / eye is about 0.15 to about 1.15 mg, or about 0.15 mg, 0.2 mg, about 0.25 mg, 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, about 0.9 mg, about 0.95 mg, about 1.0 mg, about 1.05 mg, about 1.1 mg, or about 1.15 mg. In some embodiments, the dose / administration / eye is about 0.18 mg, about 0.37 mg, about 0.55 mg, about 0.74 mg, or about 0.92 mg. In some embodiments, the total daily dose / eye is 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. In some embodiments, the compound of Formula I is administered to the subject once to six times per day, for example once, twice, three times, or four times per day.In some embodiments, the compound having Formula I is administered to the subject for a period of at least about one month, at least about two months, or at least about three months.

[0112] In some embodiments of the methods described herein, administration of a compound of Formula I does not result in a change in one or more of best corrected visual acuity, slit lamp biomicroscopy, dilated pupil examination, blink rate, tear production, intraocular pressure compared to placebo (e.g., less than 5% difference, less than 4% difference, or less than 3% difference). In some embodiments of the methods described herein, administration of a compound of Formula I does not result in a delay in wound healing compared to placebo in patients in need thereof.

[0113] Patient population

[0114] In specific embodiments, the subject to be treated by the methods provided herein suffers from an ocular surface disorder. Non-limiting examples of ocular surface disorders include chronic ocular surface pain (COSP), dry eye disease, Sjögren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), Map-Dot-fingerprint dystrophy, Acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), corneal dystrophy ... The invention relates to patients with ocular diseases, such as keratitis, keratitis, epithelial basement membrane dystrophy, corneal erosion or abrasion (including recurrent corneal erosion or abrasion), ocular surface disease, blepharitis, graft-versus-host disease, tarsal gland inflammation, glaucoma, conjunctivochalasis, corneal disease (including herpetic keratopathy, filamentous keratopathy, band or bullous keratopathy, exposure keratopathy), keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, dry eye, or patients recovering from neurotrophic keratitis. In some embodiments, the subject suffers from eye pain that lasts for at least three months after photorefractive keratectomy (PRK) surgery or laser-assisted in situ keratomileusis (LASIK) surgery.

[0115] In certain embodiments, the methods provided herein are used to treat or alleviate ocular surface pain, such as acute ocular surface pain.

[0116] In certain embodiments, the methods provided herein are used to treat or alleviate ocular surface pain, such as chronic ocular surface pain (COSP). In particular aspects, COSP is characterized as persistent ocular surface pain (e.g., persistent severe ocular surface pain), which can disturb or interfere with conventional daily activities. In particular aspects, COSP may cause poor quality of life and may last for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months. In certain aspects, COSP may last for at least about 2 months or at least about 3 months. In other aspects, COSP may last for at least 3 months or at least 4 months. In particular aspects, despite adhering to other therapies for its potential disease (e.g., ocular surface disorders (such as dry eye or Sjögren's syndrome) etc.), the symptoms of the patient suffering from COSP continue.

[0117] In some embodiments, the subject to be treated suffers from ocular neuropathic pain (ONP). ONP is a series of eye pain disorders that may be caused by damage or disease affecting nerves, such as corneal nerves. Symptoms of ONP may include one or more of the following: eye pain, sensitivity to light, hyperalgesia or dysesthesia (abnormal sensations) (such as dryness, stinging or foreign body sensation), pain caused by normal non-painful stimuli (allodynia). Gabapentin and other neuropathic analgesics can be used to blunt the sensation of sensory nerve irritation or nerve irritation.

[0118] In some embodiments, the subject to be treated suffers from exposure keratopathy. EK is damage to the cornea, mainly caused by prolonged exposure of the ocular surface to the external environment. EK can cause ulcers, microbial keratitis, and permanent vision loss from scarring. Patients at risk of EK include those with conditions that interfere with the ability to protect the cornea; or due to incomplete eyelid closure (e.g., lagophthalmos, exophthalmos, eyelid malposition), insufficient blink reflex, insufficient blink rate (e.g., caused by neurological diseases (e.g., Parkinson's disease, neuromuscular diseases)) and / or reduced protective lubrication of the cornea. Symptoms of EK include foreign body sensation, burning, increased tears, and intermittent blurred vision (from unstable tear film), pain, and photophobia. Standard treatment includes regular use of artificial tears and lubricating ointments and punctal plugs every night.

[0119] In some embodiments, the subject to be treated suffers from keratoconjunctivitis. Keratoconjunctivitis is an inflammatory process involving both the conjunctiva and the cornea. Surface inflammation of the cornea (keratitis) usually occurs in association with viral and bacterial conjunctivitis (e.g., in adults). Depending on the underlying cause of the inflammation, the following types of keratoconjunctivitis are distinguished:

[0120] Keratoconjunctivitis sicca is caused by inflammation (due to dryness);

[0121] Vernal keratoconjunctivitis (VKC) occurs seasonally and is thought to be due to allergens;

[0122] Atopic keratoconjunctivitis is a manifestation of atopy;

[0123] Epidemic keratoconjunctivitis or adenoviral keratoconjunctivitis is caused by infection with adenovirus;

[0124] Infectious bovine keratoconjunctivitis (IBK) is a disease affecting cattle caused by the bacterium Moraxella bovis;

[0125] Pink eye in sheep and goats is primarily caused by Chlamydia theropoda;

[0126] Superior limbal keratoconjunctivitis is thought to be caused by mechanical trauma;

[0127] Photoelectric keratoconjunctivitis (electric eye inflammation) refers to inflammation caused by photoelectric ultraviolet (UV) rays.

[0128] In some embodiments, the subject to be treated suffers from dry eye. As used herein, the term "dry eye" refers to insufficient tear production and / or abnormal tear composition. Dry eye syndrome disease (DEDS) (also referred to as dry eye syndrome), keratoconjunctivitis sicca or keratitis sicca, or tear dysfunction syndrome, or burning eye syndrome is due to any defect in the tear film layer. Dry eye is a multifactorial disease of tears and ocular surface, which causes symptoms of discomfort, visual impairment, and tear film instability, and causes potential damage to the ocular surface (characterized by loss of homeostasis of the tear film), and is accompanied by ocular symptoms, wherein tear film instability and high osmotic pressure, ocular surface inflammation and damage, and neurosensory abnormalities play a causal role (Craig JP, et al., The Ocular Surface [eye surface] 2017; 15: 276-83). It may be accompanied by increased tear film osmotic pressure and ocular surface inflammation. Dry eye may range from mild to moderate to severe forms. Symptoms of dry eye syndrome include a gritty, foreign body sensation, burning, photophobia, and decreased vision, tearing, stinging, itching, a sandy or gritty sensation, discharge, frequent blinking, frosted or clumped eyelashes (often worse upon waking), redness, blurred or fluctuating vision (worse when reading, on the computer, watching television, driving, or playing video games), light sensitivity, eye pain and / or headache, heavy eyelids, and eye fatigue. Causes of dry eye disease include, but are not limited to, the following: idiopathic, congenital tear deficiency, sicca, tear gland ablation, and sensory denervation; collagen vascular diseases, including rheumatoid arthritis, Wegener's granulomatosis, and systemic lupus erythematosus; Sjögren's syndrome and autoimmune diseases associated with Sjögren's syndrome; lipid tear layer abnormalities due to blepharitis or rosacea; mucin tear layer abnormalities due to vitamin A deficiency; trachoma, diphtheria keratoconjunctivitis; mucocutaneous disorders; aging; menopause; and diabetes. Signs and / or symptoms of dry eye as defined herein may also be caused by other conditions, including, but not limited to, the following: prolonged visual tasks; working at a computer; being in a dry environment; warm or cold winds or drafts; seasonal changes; eye irritation from contact lenses, LASIK and other refractive surgery; fatigue; and medications, such as isotretinoin, sedatives, diuretics, tricyclic antidepressants, antihypertensives, oral contraceptives, antihistamines, nasal decongestants, beta-blockers, phenothiazines, atropine, and opioids (e.g., morphine) for pain relief.

[0129] Diagnostic tests for dry eye include assessment of corneal sensation using, for example, a cotton swab applicator or, more precisely, a Cochet-Bonnet sensory meter (corneal hyperesthesia and / or decreased sensation may be present in severe and chronic dry eye); measurement of tear breakup time using, for example, fluorescein-impregnated strips moistened with unpreserved saline solution or more objective computerized methods (without the need for fluorescein instillation); ocular surface staining, for example, fluorescein sodium, rose bengal, lissamine green; and Schirmer testing (relatively insensitive in patients with mild dry eye). tear meniscus; measuring levels of MMP-9 (MMP-9 has been shown to be elevated in the tears of patients with dry eye, and levels correlate with findings in patients with moderate to severe dry eye); measuring tear osmolarity and tear film interferometry; and performing the Sjo test (detects SS-A (anti-Ro) and SS-B (anti-La) autoantibodies, salivary gland protein 1 (SP-1), carbonic anhydrase 6 (CA6), and parotid secretory protein (PSP), SP-1, CA6, and PSP in serum).

[0130] Artificial tears, lubricating ointments, and corticosteroids (e.g., loteprednol 0.5% eye drops four times a day) are used as initial treatment. Prescription drugs include cyclosporine, lifitegrast, diquafosol, rebamepide, and corticosteroids (e.g., loteprednol 0.5% eye drops four times a day).

[0131] The term "tear film dysfunction" refers to a state when the tear film breaks down at different locations of the cornea and conjunctiva, which not only causes irritation symptoms, but also causes unstable and intermittent changes in vision. For example, dry eye syndrome is characterized by tear film dysfunction. Symptoms of tear film dysfunction include tearing, burning, stinging, itching, sand or gravel sensation, scratching or foreign body sensation, secretion, frequent blinking, frosted or clumped eyelashes (usually worse when waking up), redness, blurred vision or fluctuations in vision (worse when reading, computer, watching TV, driving, or playing video games), light sensitivity, eye pain and / or headache, heavy eyelids, and eye fatigue.

[0132] Adenoviral keratoconjunctivitis, also known as epidemic keratoconjunctivitis, is a common and highly contagious viral infection of the eye. The clinical course of adenoviral keratoconjunctivitis is divided into an acute phase with varying intensity of conjunctival inflammation, with or without corneal involvement, and a chronic phase with corneal opacities.

[0133] Vernal keratoconjunctivitis (VKC) is an atopic disorder of the external ocular surface characterized by symptoms consisting of severe itching, photophobia, foreign body sensation, mucous secretion (often referred to as "dizziness"), blepharospasm, and blurred vision (Buckley, RJ, Int Ophthalmol Clin, 1988 28(4):303-8; Kumar, S., Acta Ophthalmologica, 2009. 87(2):133-147). It is usually bilateral but may be asymmetric in nature. It typically affects young males in a seasonal manner in hot, dry climates; it may have a perennial form in 23% of patients (Kumar, S., Acta Ophthalmologica, 2009. 87(2): 133-147; Bonini, S., et al., Ophthalmology, 2000. 107(6): 1157-63).

[0134] The signs of VKC can be divided into conjunctival, limbal, and corneal signs:

[0135] Conjunctival signs include diffuse conjunctival injection and discrete giant tarsal papillae > 1 mm in diameter;

[0136] Limbal signs include thickening and opacification of the limbal conjunctiva, and gelatinous and sometimes confluent limbal papillae. Perilimbal Horner-Trantas spots are focal white limbal spots composed of degenerated epithelial cells and eosinophils (Buckley, RJ, Int Ophthalmol Clin, 1988. 28(4): 303-8);

[0137] • Corneal signs vary depending on the severity of the disease process and include macroscopic erosions, corneal ulcers, and scarring (Buckley, RJ, Int Ophthalmol Clin, 1988. 28(4): 303-8).

[0138] Active VKC patients (defined as moderate to severe ocular discomfort, including photophobia, papillary protrusions on the upper eyelid conjunctiva, or Horner-Trantas points on the limbus that can be clearly identified during examination) show significantly increased symptoms and signs of ocular surface disease. Inactive VKC patients (defined as no symptoms or mild discomfort, and no corneal abnormalities during examination) show increased photophobia, conjunctival lissamine green staining and Schirmer test values, as well as reduced fluorescein lysis time (BUT) and corneal sensitivity. The syndrome seems to affect the ocular surface at all stages (active and static), thereby determining abnormalities in tear film stability, epithelial integrity and corneal nerve function (Villani E. et al., Medicine [Medicine] (Baltimore [Baltimore]). October 2015; 94 (42): e1648).

[0139] The following factors are thought to play a role in VKC: IgE release through mast cells mediates the response; activated eosinophils, monocytes, and neutrophils; and CD4 T-helper-2 driven type IV hypersensitivity reactions with immunomodulators such as IL-4, IL-5, and bFGF (Buckley, RJ, Int Ophthalmol Clin, 1988. 28(4): 303-8; Kumar, S., Acta Ophthalmologica, 2009. 87(2): 133-147; La Rosa, M., et al., Ital J Pediatr, 2013. 39: 18).

[0140] Treatment consists of cool compresses and eyelid scrubs, saline eye drops to help relieve symptoms, and topical antihistamines, nonsteroidal anti-inflammatory drugs or corticosteroids (such as poorly absorbed corticosteroids (fluoromethelone, loteprednol, remexolone), optical mast cell stabilizers (cromolyn, nedocromil, and lodoxamide), topical cyclosporine A, or tacrolimus. See, e.g., Oray, M. and E. Toker, Cornea, 2013. 32(8): 1149-54; Vichyanond, P. and P. Kosrirukvongs, Curr Allergy Asthma Rep, 2013. 13(3): 308-14; Barot, RK et al., J Clin Diagn Res. 2016 Jun; 10(6): NC05-9; Wan Q et al., Ophthalmic Res. 2018; 59(3): 126-134.

[0141] In contrast to VKC, which develops before the age of 10, atopic keratoconjunctivitis (AKC) typically has an older age of onset (in the twenties to the fifth decade). Conjunctival involvement is typically on the upper tarsal plate in VKC and on the lower tarsal plate in AKC. AKC is typically more chronic in nature and more commonly results in corneal and conjunctival scarring.

[0142] Sjögren's syndrome (which is associated with dry eye) is a chronic inflammatory disorder characterized by exocrine gland dysfunction (including saliva and lacrimal glands), which in many cases leads to severe dry eye signs. The main symptoms are dry eyes (keratitis sicca or keratoconjunctivitis sicca) and dry mouth (xerostomia). Severe dry eye may cause corneal pain, corneal scarring, ulcers, infections and even perforations. Differential diagnosis includes illnesses such as adult blepharitis, dry eye and juvenile idiopathic arthritis uveitis and corneal diseases (e.g., superficial punctate, filamentous, neurotrophic, exposed). The treatment of Sjögren's syndrome is intended to maintain the integrity of the tear film by preserving, increasing and / or replacing the defective tear secretions. Thus, treatment of Sjögren's syndrome includes artificial tears and lubricating ointments; autologous serum eye drops; oral omega-6 essential fatty acids; fluid-vented, gas-permeable scleral lenses; topical corticosteroids; punctal occlusion to reduce tear drainage; small lateral tarsal fissure closure; humidification of the environment; hydrophilic bandage lenses; bromhexine and 3-isobutyl-1-methylxanthine (IBMX) (to enhance tear production / secretion); agents that stimulate muscarinic receptors (pilocarpine and cevimeline); immunosuppressants such as methotrexate, antimalarials, cyclophosphamide, leflunomide, or tumor necrosis factor (TNF), such as infliximab (a monoclonal antibody to TNF-α); cyclosporine A; and bandage contact lenses.

[0143] Steven-Johnson's syndrome (SJS) is a dermatological emergency or a severe skin reaction characterized by the presence of epidermal and mucosal bullous lesions involving less than 10% of the total body surface area. Early symptoms of SJS include fever and flu-like symptoms that may precede or occur simultaneously with a macular rash involving the trunk and face. As the disease progresses, the macular rash coalesces, the affected areas develop bullae, and the epidermal layer eventually sloughs off. In the acute phase of SJS-TEN, 80% of patients will have eye involvement.

[0144] A high fever (>102.2), fatigue, arthralgia, a macular rash involving the trunk, neck, and face, and a recent history of exposure to a new drug or a recent increase in the dose of an existing drug are indicators for diagnosing SJS. A skin biopsy of the affected area can be performed to confirm the diagnosis. Granulysin can be used as a marker for diagnosing SJS. The concentration of granulysin in the bullous fluid is associated with the severity of the acute phase of SJS (Chung WH, et al. Nat Med. [Natural Medicine] 2008; 14(12): 1343-50).

[0145] The ocular manifestations of SJS include conjunctivitis, subconjunctival hemorrhage, subconjunctival scar, conjunctiva, conjunctival ulcer, superficial punctate epithelial erosion, epithelial defect, eyelid ulcer, eyelid keratinization, eyeball adhesion, eyelid adhesion, trichiasis, anterior blepharitis, lacrimal puncta self-occlusion, meibomian gland disease, corneal opacity, dry eye, double eyelids, limbal stem cell failure, corneal vascularization. The ocular treatment of SJS includes saline eye drops, preservative-free artificial tears and ointments to provide adequate lubrication and reduce epithelial damage. Patients with any corneal or conjunctival epithelial defect should be treated with preventive topical antibiotics (preferably fourth-generation fluoroquinolones). Patients with mild or moderate eye involvement (less than one-third of the eyelid margin involved, conjunctival defect less than 1 cm in maximum diameter, and no corneal epithelial defect) are usually treated daily with topical moxifloxacin 0.5% (four times a day), cyclosporine 0.05% (twice a day), and topical steroids (prednisolone acetate 1% four to eight times a day or dexamethasone 0.1% twice a day). In addition to the treatments listed above, patients with severe or very severe eye involvement (greater than one-third of the eyelid margin involved, conjunctival defect greater than 1 cm, and corneal epithelial defect) also receive amniotic membrane (AM) transplantation.

[0146] In some embodiments, the subject to be treated suffers from corneal epithelial disease. Corneal epithelial disease is a disease involving the corneal epithelium, for example manifested by changes in the barrier function of the corneal epithelium.

[0147] In some embodiments, the subject to be treated suffers from corneal neuropathy or corneal neuralgia. Corneal neuropathy or corneal neuralgia is a disorder related to corneal pain caused by nerve fibers (i.e., sensory fibers) in the damaged cornea. One of the examples of corneal neuropathy is LASIK-induced corneal neuropathy. Corneal neuropathy can usually be identified and diagnosed by dry eye examination. Although the cause and risk factors are not clear, patients with dry eye-like symptoms, increased corneal sensitivity and changes in corneal nerve morphology, but no signs of dryness, may suffer from corneal neuropathy.

[0148] In some embodiments, the subject to be treated suffers from an ocular surface disease or disorder. The term "ocular surface disease" or "ocular surface disorder" encompasses disease entities and associated symptoms caused by a variety of abnormalities, including abnormal eyelid anatomy or function, abnormal or altered tear production or composition, and associated subclinical signs. Many diseases can cause ocular surface disorders. Patients with ocular surface disorders may show clinical signs common to several diseases, and include chronic punctate keratopathy, filamentary keratopathy, recurrent corneal erosions, bacterial conjunctivitis, culture-negative conjunctivitis, cicatricial (scarring) conjunctivitis, persistent epithelial defects, infectious keratitis, corneal melting, and ocular surface failure. The most common ocular surface disorders are caused by tear film abnormalities and / or eyelid gland dysfunction ("blepharitis").

[0149] In certain embodiments, the subject to be treated suffers from neurotrophic keratitis or neurotrophic keratopathy. Neurotrophic keratitis or neurotrophic keratopathy (NK) is a corneal degenerative disease characterized by reduced or lack of corneal sensitivity. In NK, the corneal innervation of the trigeminal nerve is impaired. Since the corneal sensory innervation in NK is impaired, patients usually do not complain of ocular surface symptoms. However, due to irregular epithelium or epithelial defects (PED), scarring, or edema, blurred vision may be reported. NK is generally divided into three different stages according to the "Mackie classification". Phase II NK is defined by recurrent or persistent epithelial defects, which are most common in the upper half of the cornea. One of the treatments that can be used for Phase II NK includes local nerve growth factor. Due to nerve remodeling, patients usually feel pain during treatment with NGF.

[0150] In certain embodiments, the subject to be treated suffers from blepharitis. Blepharitis is an inflammatory condition of the eyelid margin, which may cause permanent changes in the eyelid margin or loss of vision, due to superficial keratopathy, corneal neovascularization and ulceration. According to the anatomical position, blepharitis can be divided into anterior and posterior. Anterior blepharitis affects the eyelid skin, eyelash roots and eyelash follicles, and includes the traditional classification of staphylococcal and seborrheic blepharitis. Posterior blepharitis affects the meibomian glands and glandular pores, and its main cause is meibomian gland dysfunction. The symptoms of chronic blepharitis may include redness, burning sensation, irritation, tearing, eyelid caking and adhesion and visual problems (such as photophobia and blurred vision). The long-term management of symptoms may include the routine operation of cleaning the eyelids every day and the use of therapeutic agents, which reduce infection and inflammation. Treatment includes topical or systemic antibiotics such as bacitracin or erythromycin; oral antibiotics such as tetracyclines (tetracycline, doxycycline, minocycline) or macrolides (erythromycin, azithromycin); topical steroids such as corticosteroids (e.g., loteprednol, fluomeprol); topical combinations of antibiotics and corticosteroids (e.g., tobramycin / dexamethasone or tobramycin / loteprednol); topical cyclosporine 0.05%.

[0151] In some embodiments, the subject to be treated suffers from meibomian gland dysfunction. The meibomian gland is a holo-secreting exocrine gland located at the edge of the eyelid inside the tarsus and is responsible for the supply of meibum, an oily substance that prevents the evaporation of the tear film of the eye. Meibomian gland dysfunction (MGD), also known as meibomian gland inflammation, posterior blepharitis or meibomian gland inflammation, is a chronic, diffuse abnormality of the meibomian glands, which is usually characterized by terminal duct obstruction and / or qualitative / quantitative changes in glandular secretions (Nelson JD, et al., Invest Ophthalmol Vis Sci [Investigation in Ophthalmology and Visual Science] 2011; 52: 1930-7). It may lead to tear film changes, eye irritation symptoms, clinically significant inflammation, and ocular surface disease. MGD often causes dry eyes and may lead to blepharitis. In some cases, topical steroids and topical / oral antibiotics are also prescribed to reduce inflammation. Intense pulsed light (IPL) treatments or other mechanical treatments that apply heat and pressure to express the glands (such as LipiFlow) have also been shown to reduce inflammation and improve glandular function in patients.

[0152] In some embodiments, the subject to be treated suffers from graft-versus-host disease. Graft-versus-host disease (GVHD) is an inflammatory disease unique to allogeneic transplantation. This is an attack of transplanted leukocytes on the tissues of the recipient, even if the donor and recipient are the same HLA. Acute graft-versus-host disease usually occurs in the first three months after transplantation, and may involve the skin, intestines, or liver. Corticosteroids (e.g., prednisone) are standard treatments. Chronic graft-versus-host disease may also occur after allogeneic transplantation, and it is the main source of late complications. In addition to inflammation, chronic graft-versus-host disease may cause fibrosis, or the development of scar tissue (similar to scleroderma or other autoimmune diseases), and may cause functional failure, and require long-term immunosuppressive therapy.

[0153] In some embodiments, the subject to be treated suffers from ocular graft-versus-host disease. GVHD occurs in patients who receive allogeneic blood stem cell transplants. It may occur in patients with acute or chronic GVHD, although it is more common in patients with the chronic form. Approximately 40%-90% of patients with chronic GVHD develop eye symptoms. Eye manifestations may include moderate to severe keratoconjunctivitis sicca, bilateral marginal keratitis, anterior uveitis, corneal ulcers, or neovascularization. Treatment includes topical lubricants, including preservative-free artificial tears, autologous serum tears, and other topical and systemic immunosuppressive treatments; systemic steroids; topical cyclosporine 0.5%.

[0154] Examples

[0155] The following examples are included to demonstrate non-limiting embodiments of the invention.

[0156] Example 1. First-in-human study of Compound I to assess safety and pharmacokinetics

[0157] This example describes the first in-human study of Compound I in healthy volunteers. A total of 54 subjects were administered study drug. Part 1 of this in-human study administered single ascending doses of Compound I at 0.15%, 1.5%, 2.5% w / v (1 drop) as eye drops.

[0158] Part 2 tested multiple ascending doses (MAD) of Compound I administered as eye drops: (i) 1 drop of 0.15%, 1.5%, 2.5%, 4 times a day (once every 6 hours) for 7 days, or (ii) 1 drop of 2.5%, 8 times a day (once every 3 hours) for 7 days.

[0159] Part 3 was to evaluate the anesthetic properties of Compound I through anesthetic metric assessment. Part 3 of the study had four groups, namely Compound I, vehicle, tetracaine (0.5% ophthalmic solution, used as a positive control), and diclofenac sodium (0.1% ophthalmic solution, used as an active NSAID comparator). The ocular anesthetic was selected because it has established anesthetic effects; however, it is not a standard of care due to its negative impact on wound healing. NSAIDs are currently the standard of care for corneal pain after PRK, with minimal anesthetics but significant pain control properties. Vehicle eye drops were used as a negative control to better determine potential anesthetic effects. Twelve healthy subjects who met the eligibility criteria were randomized to receive a single eye drop of 4 study treatments, each on 1 of 4 different study days (Days 1, 4, 7, and 10). Each subject was randomized to receive study treatment according to one of the following four sequences:

[0160] Sequence 1: Anesthetic, NSAID, Compound I 2.5%, Vehicle

[0161] Sequence 2: NSAID, vehicle, anesthetic, compound I 2.5%

[0162] Sequence 3: Vehicle, Compound I 2.5%, NSAID, Anesthetic

[0163] Sequence 4: Compound I 2.5%, anesthetic, vehicle, NSAID

[0164] Safety Assessment: Safety assessment consisted of the following: collection of all adverse events (AEs), serious adverse events (SAEs), including systemic and ocular adverse events, as well as their severity and relationship to study drug. Systemic safety assessment included regular monitoring of hematology, blood chemistry, and urinalysis at the study center, and regular assessment of physical examination, vital signs (systolic and diastolic blood pressure, pulse rate, and temperature), ECG, pregnancy and, during the MAD portion, fertility assessments and hand immersion tests at 49°C. Ocular safety assessments included Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity, intraocular pressure, slit-lamp biomicroscopy, corneal staining, and dilated pupil examinations.

[0165] The subjects were selected according to the following inclusion and exclusion criteria.

[0166] Inclusion criteria:

[0167] · Written informed consent was obtained before any assessment was performed.

[0168] Healthy male and female subjects aged between 18 and 50 years (inclusive) who are in good health (determined by medical history, physical examination, vital signs, ECG and laboratory tests) at screening.

[0169] At Screening and Baseline, vital signs (systolic and diastolic blood pressure (BP) and pulse rate) will be assessed in a seated position after the subject has been sitting still for at least 3 minutes and again after standing for 3 minutes. Seated vital signs must be within the following normal ranges:

[0170] Oral temperature between 35.0°C and 37.5°C

[0171] Systolic blood pressure (SBP) 90-150 mmHg

[0172] Diastolic blood pressure (DBP) 50-90 mmHg

[0173] Pulse rate 40bpm to 100bpm

[0174] · Subjects need to weigh at least 50 kg to participate in the study, with a body mass index (BMI) in the range of 18-29 kg / m2. BMI = weight (kg) / [height (m)] 2

[0175] ·The subjects are able to communicate well with the investigators to understand and comply with the study requirements.

[0176] For Part 3, the subject's baseline level of ocular sensitivity should be within the range of 50 mm to 60 mm, inclusive, as measured by the Cochet-Bonnet sensory meter.

[0177] Exclusion criteria:

[0178] Women of childbearing potential, defined as all women who are physiologically capable of becoming pregnant unless they are using effective contraception during the period of study treatment.

[0179] - Subjects who exhibit any medical condition (systemic or ocular) that, in the opinion of the Investigator and based on the contents of the Investigator's Brochure, precludes safe administration of the test article or precludes safe participation in this study.

[0180] Part 3 (sensational measurements): Subjects who used contact lenses at the time of the study or had used contact lenses within the past 3 years were excluded to minimize differences in corneal sensitivity due to contact lens use.

[0181] · History of any ocular surgery or laser within 6 months prior to screening. History of any chronic eye disease other than refractive error, incipient cataract, strabismic amblyopia, or anisometropic amblyopia. Subjects with a history of acute eye disease (e.g., infection, corneal abrasion, or allergy) within 6 months of screening are eligible if the disease is not active.

[0182] Any active eye condition currently requiring the use of topical eye drops.

[0183] Subjects using continuous positive airway pressure or other sleep apnea devices.

[0184] Safety Results from First-in-Human Studies

[0185] Based on the results of parts 1, 2, and 3, the maximum tolerated dose (MTD) was determined to be the maximum feasible concentration of 2.5%, 8 times daily for 7 days. No dose-limiting adverse events were found at this dose level. With the exception of ocular irritation of moderate severity, which led to discontinuation of treatment in one patient in the 2.5% 4 times daily cohort, all adverse events suspected of a causal relationship to Compound I were mild. The most common ocular adverse events in patients treated with Compound I were corneal staining, hyperemia, and mild anterior chamber inflammation, at levels similar to placebo. Table 1 shows a summary of adverse events in the SAD study.

[0186] Table 1. Overall incidence of AEs - number of events and subjects (Part 1: SAD) (Safety Analysis Set)

[0187]

[0188]

[0189] N = number of subjects enrolled and receiving study drug nE = number of treatment-emergent AEs in category

[0190] nS = number of subjects with at least one treatment-emergent AE in the category, percentages based on number of subjects

[0191] Table 2 shows a summary of adverse events in the SAD study.

[0192] Table 2. Overall incidence of AEs - number of events and subjects (Part 2: MAD) (Safety Analysis Set)

[0193]

[0194] N = number of subjects enrolled and receiving study drug nE = number of treatment-emergent AEs in category

[0195] nS = number of subjects with at least one treatment-emergent AE in the category, percentages based on number of subjects

[0196] a On Day 6, a subject receiving 2.5% Compound I 4 times daily developed ocular discharge, ocular hyperemia (mild in both eyes), and left eye irritation (moderate), leading to discontinuation of study drug administration.

[0197] For the hand immersion test, all subjects in the treatment cohort withdrew their hand from the 49°C water within a time interval of 0 to ≤50 seconds. No subject lasted more than 22 seconds, and no meaningful changes in immersion time were observed between Compound I and vehicle-treated subjects. Therefore, the results indicate that Compound I does not alter the temperature sensitivity of the subjects.

[0198] Sensory measurement research (Part 3)

[0199] This first-in-human study further evaluated the potential anesthetic effect of topical ophthalmic 2.5% Compound I by sensorimometry testing, i.e., measurement of filament length (cm) at the threshold of perceived corneal contact.

[0200] The results showed that tetracaine 0.5% had an anesthetic effect with an action time of about 10 minutes (positive control). Based on the known clinical experience of diclofenac, it is expected that diclofenac 0.1% and the vehicle have no anesthetic effect on the cornea. Compound I 2.50% did not show an anesthetic effect at any time point after treatment.

[0201] For measures of corneal sensitivity, statistical and clinical significance was observed when comparing the least squares means (test vs. reference) for:

[0202] Tetracaine 0.5% (N=12) vs. vehicle (N=12) at 2.5, 10, and 20 minutes post-dose;

[0203] Tetracaine 0.5% (N=12) versus diclofenac 0.1% (N=12) at 2.5, 10, and 20 minutes after administration;

[0204] · 2.5 and 10 minutes after administration, Compound I 2.5% (N=11) versus tetracaine 0.5% (N=12);

[0205] There was no difference in corneal sensitivity between Compound I 2.5% and vehicle, with all p values ​​greater than or equal to 0.395 at the pre-specified time point of 30 minutes post-dose. This study demonstrated the lack of anesthetic effect of Compound I 2.5% compared to tetracaine 0.5% (a drug with anesthetic effects as a positive control) and vehicle (placebo).

[0206] Summary of Pharmacokinetics in Human Studies

[0207] After single and multiple topical ocular suspension doses of Compound I 0.15%, 1.5% and 2.5%, the plasma PK profiles showed that Compound I was rapidly absorbed into the systemic circulation and reached low concentrations of exposure with moderate variability between subjects. The increase in dose from 0.15% to 2.5% resulted in a less than dose-proportional increase in systemic exposure. After 4 administrations of 0.15%, 1.5% or 2.5% suspension for 7 days, the accumulation of Compound I at steady state was minimal (approximately 1.7-fold), and 8 times a day for 7 days after 2.5% for 7 days was also minimal (approximately 1.3-fold).

[0208] Example 2. Clinical study of compound Ⅰ in the treatment of postoperative pain

[0209] This example describes a clinical study of Compound I (4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile) for the treatment of postoperative eye pain in patients undergoing photorefractive keratectomy (PRK).

[0210] Research objectives

[0211]

[0212]

[0213] Study Design

[0214] This study is a conceptual, double-masked, randomized, vehicle-controlled study of Compound I administered as eye drops in addition to standard treatment in patients after PRK surgery. PRK surgery is performed as an outpatient procedure under local anesthesia, in which the corneal epithelium is removed to expose the stroma for laser ablation. The dose of Compound I is 2.5% (25 mg / ml, 0.925 mg / drop) single drop eye drops, applied four times a day (every six hours) in one eye from immediately after surgery (time 0) to the last dose (72 hours).

[0215] Doses of vehicle were administered as a single drop four times daily (every six hours) in one eye from immediately postoperatively (time 0) to the last dose (72 hours).

[0216] The study included 2 treatment periods using a crossover design. Patients received PRK surgery in two separate situations (periods), one eye at a time. Patients were randomized to receive compound 1 or vehicle after surgery 1, and the other after surgery 2.

[0217] Forty patients were randomly divided into two sequences in a 1:1 ratio: Compound I during the 1st period, followed by vehicle during the 2nd period, or vehicle during the 1st period, followed by Compound I during the 2nd period. After PRK surgery in the study eye (Day 1, 1st and 2nd period), one drop was applied to each patient, four times a day, for 72 hours. The initial study eye was the non-dominant eye established at the time of screening and determined with the consent of the patient and the investigator. The patient returned for follow-up on the 2nd, 3rd, 4th and 8th days of the 1st period after the first eye surgery, wherein follow-up was optionally performed every day to track the patient until wound healing was complete. If any complications were found, the second eye surgery was not performed.

[0218] Patients undergo PRK surgery on the second study eye (dominant eye) on Day 1 of Period 2. PRK surgery is performed at the discretion of the investigator after the epithelial defect in the first eye has resolved. After PRK surgery, patients receive contralateral treatment four times a day for 72 hours. Patients return daily for the first 3 days after surgery (Period 2, Days 2-4) and return in Week 1 (Period 2, Day 8) after the second surgery, with optional daily follow-up to track patients until wound healing is complete. End of Study (EOS) follow-up is performed 30 days after the second ocular surgery (or after the final dose of the study product when the patient ends treatment as early as Period 1).

[0219] During periods 1 and 2 of the study, all patients received standard of care treatment, including the use of bandage contact lenses after PRK surgery and before receiving study eye drops for pain relief (Air Night and Aqua or equivalent). After the first dose of study eye drops is applied, a course of topical ocular antibiotics (moxifloxacin or equivalent 1 drop eye drops four times a day) is started and continued for 4-7 days. After PRK, one drop of ophthalmic prednisolone acetate is applied four times a day for one week, and then the dose is gradually reduced. Preservative-free unit dose artificial tears are used as needed. The first dose of study eye drops after each PRK surgery is applied by site staff. Subsequent doses are self-administered. The interval between eye drop applications is 5 minutes. In summary, patients undergo PRK surgery, a bandage lens is placed on the cornea, and Compound I or vehicle is applied; antibiotics are applied approximately 5 minutes later, and prednisolone is used 5 minutes later.

[0220] Rescue medication consisted of the following: oral analgesics (acetaminophen 300 mg + codeine 30 mg) as needed, up to 10 tablets / day or 1-2 tablets every 4 hours.

[0221] Additional study treatment

[0222] All patients received standard adjuvant therapy after PRK surgery, including:

[0223] Bandage contact lenses (Air Night and Aqua or equivalent)

[0224] A course of topical ocular antibiotics (moxifloxacin or equivalent 1 drop four times daily) was initiated immediately after PRK surgery and after the first dose of study eye drops and continued for 4-7 days, depending on the managing physician.

[0225] Prednisolone acetate ophthalmic: Start one drop four times a day immediately after PRK surgery and after instillation of antibiotic eye drops and apply for 1 week after PRK, then taper according to local procedures.

[0226] Use preservative-free unit-dose artificial tears as needed. Cooling of artificial tears for analgesia is not permitted.

[0227] The eye drops were administered sequentially, with an interval of at least 5 minutes between eye drop administrations.

[0228] Inclusion Criteria

[0229] Eligible groups for inclusion in this study must meet all of the following criteria:

[0230] Male and female patients aged 18 to 75 years who are eligible for bilateral PRK surgery.

[0231] Normal eye examination at baseline, but with refractive error.

[0232] Manifest refraction at baseline confirms that the planned myopia correction requires no more than -4.00 diopters (spherical) and 3.00 diopters of astigmatism, with a spherical lens equivalent no higher than -4.50. Monovision treatment (e.g., correction for distance in one eye and intermediate distance in the other eye) is permitted.

[0233] · Written informed consent was obtained before any assessment was performed.

[0234] Exclusion criteria

[0235] Patients with monovision (including amblyopia) or best-corrected visual acuity (BCVA) score less than 20 / 80 (Snellen) or 55 letters [Early Treatment Diabetic Retinopathy Study (EDTRS)] at baseline.

[0236] Any systemic or ocular disease that affects wound healing (e.g. severe rheumatoid arthritis or diabetes or history of keloid formation) or history of ocular trauma, uveitis, infection or inflammation within 6 months prior to baseline. Specifically for diabetes: patients with severe diabetes, uncontrolled diabetes, diabetic keratopathy, diabetic retinopathy, diabetic macular edema, diabetic nephropathy, diabetic foot ulcers or other systemic complications of diabetes were excluded. Patients with mild well-controlled diabetes were included without evidence of ocular or systemic complications of diabetes.

[0237] Patients with active inflammatory or infectious eye disease, severe or progressive retinal disease, and use of topical or systemic steroids or coumadin or similar medications within the last 6 months prior to baseline.

[0238] Patients with any corneal dystrophy (epithelial, stromal, or endothelial) or any corneal disease including severe scarring (at the discretion of the investigator), ocular herpes, or pterygium.

[0239] Previous refractive or corneal surgery (e.g., LASIK, PRK, radial keratotomy, pterygium removal, corneal transplant).

[0240] · History of allergic or hypersensitivity reaction or major AE to any medication used in this study (including tetracaine or similar local ocular anesthetics, NSAIDs and aspirin, oral analgesics (including acetaminophen and codeine), antibiotics, steroids) and inability to tolerate or wear bandage contact lenses

[0241] Concurrent or prolonged treatment with, or abuse of, systemic or ophthalmic NSAIDs, analgesics, analgesics (including gabapentin or pregabalin and similar drugs), opioids, or marijuana.

[0242] Patients who used any topical ophthalmic medications other than lubricating eye drops within two weeks before surgery on the study eye were excluded. Patients who met the following criteria were excluded:

[0243] ο Use of topical NSAIDs within 30 days prior to baseline or

[0244] ο Systemic / chronic use of systemic NSAIDs within 30 days prior to baseline, or

[0245] ο Occasional use of systemic NSAIDs within 3 days prior to baseline, or

[0246] o Use of ophthalmic cyclosporine (or similar drugs) within 3 months before surgery.

[0247] Weight < 50 kg or body mass index (BMI) between 18 and 35 kg / m 2 Patients within the range. BMI = weight (kg) / [height (m)] 2

[0248] Pregnant or lactating (lactating) women. Women of childbearing potential are defined as all women who are physiologically capable of becoming pregnant unless they are using a basic method of contraception during the period of administration of the study drug.

[0249] The researchers did not apply additional exclusions to make the study population representative of all eligible patients.

[0250] Study Group

[0251] The study population included male and female patients aged 18 to 75 years (inclusive) who were eligible for PRK surgery. A total of 40 patients were planned. A total of 44 patients were screened, of whom 40 were enrolled in the study and randomized.

[0252] Patient selection was determined based on a review of all eligibility criteria at Screening and Baseline. Relevant records of the eligibility criteria (e.g., checklists) were stored with the source files at the study site. Deviation from any of the participation criteria excluded the patient from the study.

[0253] Table 3 provides the patient demographic information.

[0254] Table 3. Patient demographics by treatment sequence (safety analysis set)

[0255]

[0256] BMI = Body Mass Index

[0257] Treatment Group

[0258] Patients were assigned in a 1:1 ratio to one of the following 2 treatment sequences, with each period lasting 3 days.

[0259]

[0260] Compound I was administered to the patient as eye drops. On the day of PRK surgery, the investigators administered eye drops at the study site. In the daily follow-up after surgery, the investigators were asked to administer eye drops when the patient was at the site during the expected eye drop administration time. The remaining eye drops were administered by the patient at home or when the patient was followed up at the study site (e.g., 24, 48, and 72 hours after surgery).

[0261] Visual Analogue Scale

[0262] The patient's subjective pain experience was recorded using the VAS, which is a numeric pain assessment between 0 and 100, where 0 represents no pain and 100 represents the worst imaginable pain. Previous studies of PRK pain have shown that the most severe pain occurs within the first 12 hours after surgery, with a peak around 4-6 hours after surgery (Sher et al., Refract Corneal Surg. [Refractive Corneal Surgery] Nov-Dec; 9(6):425-36 (1993)), which were the time points selected for the primary endpoint analysis. Because it is clinically important to reduce the maximum pain and overall pain experienced by patients in the immediate postoperative period, the two periods of 6 hours to up to 12 hours after surgery were used as the primary endpoints. All evaluable VAS data were collected using the ePRO, an electronic device (a mobile phone with a software application) that allows patients to record their pain levels at appropriate time points.

[0263] Rescue oral analgesics: It would be unethical to deny patients postoperative analgesia as part of a clinical trial. A review of clinical trials suggests that NSAIDs can be used as rescue oral analgesics for postoperative pain after PRK, similar to standard care after PRK. Because the use of rescue oral medications could be a potential confounder of pain VAS assessments, three approaches were used to account for the effect of pain medications when analyzing pain VAS scores (assuming a 4-hour rescue medication effect): (1) any VAS score recorded within 4 hours after the use of rescue medications was considered lost; (2) all recorded VAS scores were used; and (3) any VAS score recorded within 4 hours after the use of rescue medications was imputed using the score recorded before the use of rescue medications.

[0264] Main efficacy results

[0265] Tables 4 and 5 show the mean VAS pain severity scores at 6 hours and 0-12 hours after surgery, respectively, and Figure 1 The primary analysis was performed using the primary PD analysis set.

[0266] The treatment differences between Compound I and vehicle in mean VAS pain severity scores at 6 hours and during the 0-12 hours post-surgery were statistically significant with p values ​​less than 0.10.

[0267] The model-based mean treatment differences in VAS pain severity scores (Compound I-Vehicle) were -11.1 (90% CI: (-17.54, -4.71; p=0.005) at 6 hours post-surgery and -8.56 (90% CI: (-14.29, -2.83; p=0.016) during 0-12 hours post-surgery. Thus, the primary efficacy objective of this study was achieved.

[0268] The treatment differences between Compound I and vehicle in mean VAS pain severity scores at 6 hours and during the 0-12 hours post-surgery were statistically significant with p values ​​less than 0.10.

[0269] Table 4. Mean VAS pain severity scores 6 hours after surgery (primary PD analysis set)

[0270]

[0271] * To account for oral rescue medication (ORM) use, all VAS pain scores recorded up to 4 hours after ORM use were replaced with the VAS scores recorded before ORM use, according to FDA guidance 2014.

[0272] # Due to the first vendor / ePRO device failure, ePRO data for the first 10 patients (40 patients total) could not be evaluated

[0273] Table 5. Mean VAS pain severity scores 0-12 hours after surgery (primary PD analysis set)

[0274]

[0275] * To account for oral rescue medication (ORM) use, all VAS pain scores recorded up to 4 hours after ORM use were replaced with the VAS scores recorded before ORM use, according to FDA guidance 2014.

[0276] Secondary Efficacy Outcomes

[0277] At 0-6 hours, 0-12 hours, and 0-24 hours post-surgery, more patients in Compound I-treated eyes did not use oral rescue medication (ORM) compared to vehicle-treated eyes. After 36 hours post-surgery, the number of patients taking ORM was the same for Compound I compared to vehicle (Table 6).

[0278] Table 6. Summary of the incidence of oral rescue medication use (number of patients who did not use oral rescue medication) (Secondary PD Analysis Set)

[0279]

[0280] n: Number of patients who did not use oral rescue medication (ORM)

[0281] *For both treatment sequence columns, n represents the number of patients who did not use oral rescue medication (ORM) in any treatment group.

[0282] The histogram of the incidence of oral rescue medication (ORM) use (number of patients not using ORM) is shown in Figure 2 middle.

[0283] Table 7 presents a summary and analysis of ORM volume (number of pills per patient).

[0284] Table 7. Summary of the amount of rescue medication taken orally (number of pills) (Secondary PD Analysis Set)

[0285]

[0286] *: obtained from Wilcoxon signed-rank test

[0287] N = total number of patients treated per session

[0288] *: Statistical significance of p≤0.10 (for each primary endpoint refractive power calculation)

[0289] As shown in Table 7 and Figure 2 As shown, at each time interval during the study, Compound I treatment resulted in less ORM intake compared to vehicle treatment.

[0290] Table 8 lists the summary and analysis of ORM amounts (mg / kg body weight).

[0291] At each time interval, the amount of ORM (mg / kg body weight) was less during Compound I compared to vehicle treatment (Table 8). The differences in mg / kg body weight were statistically significant (p≤0.10) in the postoperative time periods 0-6 hours, 0-24 hours, 0-48 hours, and 0-72 hours.

[0292] Table 8. Summary of the amount of rescue medication taken orally (mg / kg body weight) (Secondary PD Analysis Set)

[0293]

[0294] *: obtained from Wilcoxon signed-rank test

[0295] N = total number of patients treated per session

[0296] *: Statistical significance of p≤0.10 (for each primary endpoint refractive power calculation)

[0297] Each acetaminophen / codeine tablet is considered to be 330 mg when calculating the amount (mg / kg body weight).

[0298] VAS pain severity within the first 3 days after PRK surgery

[0299] After PRK surgery, starting from the first hour after surgery, in 6 of the 7 time points examined within the first 18 hours after surgery, Compound I reported significantly lower VAS pain severity scores (p value threshold 0.10) compared to vehicle treatment. At all planned time points up to and including 36 hours after surgery (including surgery), the VAS pain severity scores of Compound I were lower than those of the vehicle. At all time points from 36 hours after PRK surgery to the end of the VAS collection period (72 hours after PRK surgery), the difference between the Compound I VAS score and the vehicle VAS score was only slightly different, and at a p value threshold of 0.10, there was no statistically significant difference between the scores.

[0300] VAS pain severity scores before and after instillation of study eye drops

[0301] For eyes treated with Compound I, the mean changes in VAS scores at postoperative time points 6.5, 18.5, and 24.5 hours compared to half an hour before and before instillation of the eye drops (i.e., at 6, 18, and 24 hours) were -3.1, 2.8, and 1.3. For eyes treated with vehicle, the same differences were -5.6, 2.2, and -0.2, respectively.

[0302] Ocular Pain Assessment Questionnaire (OPAS)

[0303] The OPAS is a validated tool for quantifying and monitoring corneal and ocular surface pain and quality of life that was developed based on needs identified at a 2010 National Eye Institute workshop. See Qazi et al., Ophthalmology Jul 123(7):1458-1468 (2016). The overall pain severity rating scale from the OPAS by Qazi et al., with scores ranging from 0 (no pain) to 10 (severe pain) or symptom frequency ranging from 0% (never) to 100% (always), was used. Patients were asked to complete the OPAS questionnaire / questionnaire on Day 2, Day 4 (at the end of the study drug treatment period), and Day 8. No statistical analysis of the OPAS results was performed. The results for seven of the 27 total OPAS questions are listed below.

[0304] In the question about eye pain intensity in the past 24 hours, all three responses were numerically favorable for Compound I compared to vehicle in terms of the most painful eye pain level in the 2 days (question 4), the least painful pain level (question 5), and the average eye pain level (question 6). Figure 3A , Figure 3B , Figure 3C ).

[0305] In the questions regarding the frequency of the following symptoms associated with eye pain: redness (question 22), burning (question 23), light sensitivity (question 24), and tearing (question 25), all responses favored Compound I over vehicle ( Figure 4A , 4B, 4C and 4D). Thus, patients administered Compound I exhibited lower levels of ocular pain associated with redness, burning, sensitivity to light (photophobia) and tearing compared to patients administered placebo.

[0306] Summary of Exploratory Ophthalmology Results

[0307] • The Ocular Pain Assessment Questionnaire (OPAS) showed that patients had better pain control and quality of life during Compound I compared to vehicle treatment.

[0308] ocular pain intensity in the past 24 hours, all 3 responses favored Compound I over vehicle in terms of the most painful ocular pain level in the 2 days (question 4), the least painful pain level (question 5), and the average ocular pain level (question 6). Figures 3A-3C ).

[0309] In the frequency question regarding the following symptoms associated with eye pain: redness (question 22), burning (question 23), light sensitivity (question 24), and tearing (question 25), all responses favored Compound I over vehicle ( Figures 4A-4D ).

[0310] For eyes treated with Compound I, the VAS scores at postoperative time points 6.5, 18.5 and 24.5 hours compared to half an hour before and before instillation of the eye drops (i.e., at 6, 18 and 24 hours) were -3.1, 2.8 and 1.3. For eyes treated with vehicle, the same differences were -5.6, 2.2 and -0.2, respectively.

[0311] Pharmacokinetics

[0312] Pharmacokinetic evaluation

[0313] Pharmacokinetic (PK) samples were collected at the time points defined in the above follow-up schedule, with the PK blood collection window shown in Table 9.

[0314] Table 9. Allowable time window for PK blood collection

[0315]

[0316]

[0317] All blood samples (3 mL) were obtained from the arm by direct venipuncture or an indwelling catheter inserted into a forearm vein. Immediately after each tube of blood was drawn, it was gently inverted 8-10 times to ensure that the blood was mixed with the anticoagulant (3 mL K2 EDTA). The samples were prevented from prolonged contact with the rubber stopper and the tubes were placed upright in a test tube rack surrounded by wet ice until centrifugation.

[0318] Within 30 minutes, centrifuge the sample at approximately 2000G for 10 minutes at approximately 5°C (or place the sample on ice and centrifuge at room temperature). After centrifugation, immediately transfer the entire supernatant (approximately 1.5 mL) to the first 1.8 mL NUNC 2D barcoded cryovial. After the plasma is thoroughly mixed, transfer half of the plasma from the first cryovial to the second cryovial and secure the lid. Apply the appropriate PK cryovial label to each cryovial and secure the label with clear tape. Freeze the cryovial immediately on dry ice and then freeze it at ≤-20°C until shipped to the central laboratory. Vials are shipped every two weeks.

[0319] Compound I was quantified in plasma using a validated LC-MS / MS method; the lower limit of quantification (LLOQ) was 0.05 ng / mL. Concentrations are expressed in ng / mL units. Where feasible, bandage contact lenses (BCLs) exposed to study drug were collected and analyzed for residual drug exposure after treatment (LLOQ: 5.00 ng / mL in 0.55 mL of extract, or 2.75 ng / BCL). Concentrations below the LLOQ were reported as "zero" and missing data were also marked as "zero".

[0320] Using actual recorded sampling times and using PhoenixTM The following PK parameters were determined to be relevant based on the plasma concentration-time data using the non-compartmental approach of ELISA (version 6.4): Cmax, Tmax, AUClast (calculated), Clast, and Tlast. Pre-dose concentrations were determined by examining at nominal 0, 24, and 72 hours. The linear trapezoidal rule was used for AUClast calculations. No PK parameters were calculated from the bandage contact lens Compound I concentration data.

[0321] Plasma pharmacokinetics of compound I

[0322] The arithmetic mean plasma concentration-time profiles and PK parameters of Compound I are shown in Figure 5A and Figure 5B and Table 10.

[0323] Following a unilateral topical ocular dose of Compound I, it was rapidly absorbed into the systemic circulation with median Tmax of 0.459 hours after the first dose (Day 1; range 0.167-2.00 hours) and 0.467 hours after the 13th dose (Day 4; range 0.00-2.08), respectively. Cmax was determined and AUClast was calculated for 34 / 40 patients on Day 1 and for 33 / 40 (Cmax) or 31 / 40 (AUClast) patients on Day 4. All pre-dose concentrations on Day 1 were below the limit of quantitation, estimated at 0.00 ng / mL. The mean trough concentration (CV%) was 1.25 ng / mL (54.9%) before Dose 5 on Day 2 (24 hours after the first dose; 0 hour time point on Day 2) and was slightly higher at 1.99 ng / mL (76.3%) before Dose 13 on Day 4 (72 hours after the first dose; 0 hour time point on Day 4).

[0324] During the 4 days of repeated QID dosing, concentrations were generally lower, with observed Cmax ranging from 0.195 ng / mL to 7.56 ng / mL and AUClast ranging from 0.261 ng*hr / mL to 14.5 ng*hr / mL. The arithmetic mean Cmax (CV%) after the first dose on day 1 was 0.454 ng / mL (49.9%), and after the 13th dose on day 4 was 2.40 ng / mL (63.5%), i.e. 5.3 times higher. The corresponding mean AUClast (CV%) values ​​were 0.638 ng*hr / mL (46.0%) and 4.38 ng*hr / mL (67.0%), which increased 6.9 times in 4 days.

[0325] Table 10. Summary Statistics of Compound I PK Parameters Following Topical Ocular Administration of 2.5% Compound I (PK Analysis Set)

[0326]

[0327]

[0328] 1 Median Tlast (range): Day 1, 2.00 hours (1.95-2.05 hours); Day 4, 2.00 hours (1.77-2.10 hours)

[0329] Clast is not shown.

[0330] Bandage contact lenses

[0331] Bandage contact lenses (BCL) were collected from 40 patients on day 4 of dosing and analyzed for Compound I. Values ​​from three IMP non-compliant patients were excluded from the BCL summary statistics, and 37 values ​​were evaluable, including patients without available plasma PK. The mean concentration (CV%) of Compound I in 0.55 mL of extract was 8500 ng / mL (73.1%), with a wide range of 284 ng / mL to 22600 ng / mL. These concentrations converted to an estimated mean of 4680 ng / contact lens (0.55 mL×8500 ng / mL) and a range of 156 ng / lens to 12400 ng / lens. The amounts in the BCL were very small relative to the 0.925 mg dose of Compound I: an average of 0.51% with a dose range of 0.017% to 1.3%. This suggests that the BCL absorbs and retains topical ophthalmic Compound I, but it is negligible compared to the topical ophthalmic dose.

[0332] Summary of Pharmacokinetic Results

[0333] • Following single (first dose) or 4 repeated daily topical ocular administration, Compound I was rapidly absorbed into the systemic circulation (median plasma Tmax approximately 0.5 hours).

[0334] Following single or multiple topical ophthalmic doses of Compound I, systemic exposure was low, ranging from 0.195 ng / mL to 7.56 ng / mL over 4 days of repeated QID dosing, and exhibited moderate variability. The mean Cmax was 0.454 ng / mL after the first dose on Day 1 and 2.40 ng / mL after the 13th dose on Day 4.

[0335] The CV% values ​​for Cmax and AUClast after a single dose were 49.9% and 46.0%, respectively. The corresponding values ​​after repeated administration were 63.5% and 67.0%.

[0336] The mean Cmax after repeated dosing (2.40 ng / mL) was 5.3-fold higher than the mean Cmax after a single dose on Day 1 (0.454 ng / mL). Similarly, the mean AUClast was 6.9-fold higher after repeated dosing compared to a single dose (4.38 ng*hr / mL compared to 0.638 ng*hr / mL). These data suggest accumulation over 4 days of 4 times daily dosing of 2.5% Compound I.

[0337] Bandage contact lenses (BCL) were collected from 40 patients on day 4 of dosing. The mean concentration (CV%) in the 0.55 mL extract was 8500 ng / mL (73.1%), which translates to an estimated 4680 ng / contact lens. Relative to the 0.925 mg dose of Compound I, the amount in the BCL was very small: 0.51%, with a dose range of 0.017% to 1.3%. This suggests that the BCL absorbs and retains topical ophthalmic Compound I, but it is negligible compared to the topical ophthalmic dose.

[0338] Security

[0339] Safety assessment consisted of the following: Collection of all AEs, SAEs, their severity and relationship to study drug. Table 11 includes a list of common signs and symptoms in the post-PRK surgery setting. Only signs and symptoms greater than the listed severity or duration ranges were reported as AEs.

[0340] Table 11. Signs and symptoms of PRK surgery that do not require reporting

[0341]

[0342]

[0343] One week means resolved by the 8th day post-surgery visit (Visit 6 in Treatment Period 1 or Visit 11 in Treatment Period 2), inclusive of the permitted window. The table was constructed prior to the start of the study with feedback from all principal investigators and surgeons (based on their experience with common and expected clinical presentations following standard PRK surgery).

[0344] One month indicated resolution by EOS follow-up or, in the absence of EOS follow-up or more than one week between study surgeries, resolution within 37 days of surgery.

[0345] Adverse events and serious adverse events included assessments of systemic and ocular evaluations. Systemic safety assessments included periodic assessments of height and weight, vital signs, reporting of medication errors (including misuse / abuse), pregnancy reporting, and early safety monitoring. Misuse / abuse, pregnancy reporting, and early safety monitoring were not assessed in this study. Ocular safety assessments included the following:

[0346] Best corrected visual acuity (BCVA) and uncorrected visual acuity (UCVA): Each measurement is made at 4 meters (13 feet) or 1 meter (for patients who cannot read a 4-meter chart) using the ETDRS eye chart. The BCVA score is based on the number of letters read correctly plus 30. If vision is so poor that the patient cannot see any of the largest letters at 1 meter, count fingers and test hand motion acuity and light perception.

[0347] Intraocular pressure (IOP): IOP is measured using an applanation tonometer or a tonometer pen.

[0348] Dilated mydriatic examination: The dilated mydriatic examination includes fundoscopic evaluation of the vitreous, retina / macula / choroid, and optic nerve. Retinal tears / detachments, retinal hemorrhages, vitreous hemorrhage density, vitreous opacity grading, and abnormal findings are evaluated and scored according to grading criteria.

[0349] Ocular redness: Conjunctival redness of the bulbar conjunctiva of each eye under slit lamp was graded according to the McMonnies redness scale. Redness was assessed in four areas of each eye (superior, inferior, temporal, nasal) with severity ranging from 0 to 5 in each area.

[0350] Slit lamp examination of epithelial defect size: Using an oblique viewing angle relative to the source beam and a narrow slit beam, the cornea is sectioned to visualize the vertical and horizontal boundaries of the corneal wound. By adjusting the width and height of the calibrated slit beam, the maximum horizontal (wound width) and vertical dimensions (wound height) of the surgical epithelial wound can be estimated. Assessment is performed until the wound is closed and the wound size is reported as 0 horizontal dimension and 0 vertical dimension.

[0351] • Slit-lamp biomicroscopy: Ocular signs (lid / conjunctiva, cornea, lens, and iris / anterior chamber) were assessed by slit-lamp biomicroscopy in both eyes according to grading criteria.

[0352] Blink rate: Blinking was defined as paroxysmal eyelid closure of both eyes (duration <1 second) in the absence of provocative external stimulation. Each blink assessment lasted for 2 minutes (or as close to 2 minutes as possible, with a minimum of 1 minute), and the blink rates obtained were then averaged and calculated in blinks / minute.

[0353] • Tear production (Schirmer's test, no anesthesia): Both eyes were tested simultaneously without anesthesia. Tear secretion is measured in millimeters of the length of the strip wetted by tears. Measurements were made to the nearest whole number.

[0354] Corneal staining: This test is performed by gently touching the wet end of a sodium fluorescein soaked strip to the inferior conjunctival sac. The strip is moistened with 1 drop of sterile saline and flicked to remove excess saline. The patient blinks several times to ensure that the dye is dispersed throughout the tear film, and then is graded on a scale of 0-3 (0 = normal, no staining; 1 = mild, micropunctate staining by surface stippling; 2 = moderate, large punctate staining with some merged areas, and 3 = severe, many merged large punctate areas and / or plaques) for each of the 5 zones (central plus 4 quadrants).

[0355] Safety Assessment

[0356] There were no deaths or SAEs or drug discontinuations or study discontinuations due to AEs in the study. Eighteen AEs were reported in 10 patients (25% of the 40 enrolled patients), twelve of which occurred after Compound I treatment, five after vehicle treatment, and one in one patient before taking study drug. All AEs were mild or moderate in severity.

[0357] A total of 10 patients (25%) experienced at least one treatment-emergent AE, five patients experienced a single AE, and five patients experienced more than one AE. Five patients experienced AEs only during treatment with Compound I, two patients experienced AEs only during treatment with vehicle, and three patients experienced AEs during treatment with both Compound I and vehicle. One AE (headache) occurred before administration of the first study drug.

[0358] There were six ocular AEs in four patients (10% of the 40 enrolled patients), all of which were mild (three eyes each treated with Compound I and vehicle). None of the AEs were suspected to be related to study drug (Compound I or vehicle). Five of the six ocular AEs were considered by the investigator to be related to the PRK procedure (two of which were in the Compound I-treated eye and three of which were in the vehicle-treated eye).

[0359] There were twelve non-ocular AEs in seven patients (17.5%) (six eyes treated with Compound I, two eyes treated with vehicle, and one patient during the drug-free period). Five AEs were moderate in four patients (10%) (four eyes treated with Compound I and one eye treated with vehicle). The remaining AEs were mild. No AEs were suspected by the investigator to be related to Compound I.

[0360] Table 12 provides the overall incidence of adverse events.

[0361] Table 12. Overall incidence of AEs - number of events and number of patients (safety analysis set)

[0362]

[0363] AEs that started in one period and continued into the next were counted only during the episode.

[0364] N = number of patients studied.

[0365] *No drug- or baseline-emergent AEs: AEs encountered after informed consent was obtained and before administration of any study drug (Compound I or vehicle).

[0366] Ocular safety assessment

[0367] Best Corrected Visual Acuity (BCVA) and Uncorrected Visual Acuity (UCVA): Throughout the study, administration of Compound I did not result in any trends or significant differences between Compound I and vehicle treated eyes. Therefore, the data indicate that Compound I reduced pain without adversely affecting BCVA and UCVA.

[0368] Intraocular pressure (IOP): Throughout the study, no trends were observed across the scheduled time points, nor were clear differences observed between Compound I and vehicle-treated eyes. At the end of the study, mean IOP values ​​increased slightly (<5 mmHg) compared to baseline. The small changes in mean scores during the study were not clinically significant.

[0369] Dilated Mydriatic Examination: No abnormal findings were reported by the investigator across the scheduled time points for Compound I and vehicle treated eyes.

[0370] Eye congestion: respectively Fig. 6A and 6B A bar graph of ocular hyperemia over time for Compound I and placebo treated eyes is provided in FIG. Fig. 6A and 6B Denotes grade 4 and grade 3 ocular hyperemia on day 3 and day 4, respectively (measured on the McMonnies scale). Compared with vehicle-treated eyes, compound I-treated eyes had less grade 4 hyperemia (all quadrants) on the second day after surgery (24 hours after PRK surgery). In the upper quadrant, the p-value for this difference was 0.04. On day 3 (48 hours after surgery), less grade 3 hyperemia was observed in eyes treated with compound I compared with eyes treated with vehicle. No observations were classified as AEs.

[0371] Slit lamp examination of the size of epithelial defects: In order to assess the rate of wound healing after the administration of Compound I, the size of epithelial defects in the Compound I and vehicle-treated groups was measured. The elliptical area of ​​the epithelial wound size was calculated as follows: Area (mm2) = width × height × pi, derived from the width and height of the epithelial defect measured at the slit lamp. The difference in epithelial wound area between Compound I and the vehicle was not significantly different at any time point, except on the 2nd day after PRK surgery (all p values ​​for area differences> 0.35). On the 2nd day (24 hours after surgery), the difference in the average epithelial defect area between Compound I and vehicle-treated patients was 11.23mm2 (p value = 0.034). This difference was not clinically significant during the immediate postoperative period. By the 3rd day (48 hours after surgery), there was no difference between eyes treated with Compound I and eyes treated with vehicle, and the wound area was very small. At day 4 (48 hours post-surgery), almost all eyes were healed, with no difference between eyes treated with Compound I and those treated with vehicle. Compound I showed no delay in wound healing compared to vehicle.

[0372] Figure 7 Table 13 and Table 14 provide a comparison of epithelial defect size in Compound I treated eyes versus vehicle treated eyes.

[0373] Table 13. Statistical analysis of epithelial defect size (safety analysis set)

[0374]

[0375] * Obtained from paired t-test

[0376] The size of the epithelial defect was calculated by slit-lamp examination as the area of ​​an ellipse calculated from the maximum horizontal and vertical distances from the center of the epithelial defect.

[0377] Area(mm 2 ) = width * height * pi

[0378] Slit lamp biomicroscopy: Slit lamp biomicroscopy consisted of the following: examination of ocular structures (lid / conjunctiva, cornea, iris / anterior chamber, lens, aqueous flare and aqueous inflammatory cell grade). Across the scheduled time points, no abnormalities were found in ocular structures of aqueous flare and aqueous inflammatory cell grade, iris / anterior chamber and lens in Compound I and vehicle treated patients.

[0379] Blink rate: Mean blink rate fluctuated; however, no trends or clear differences between blink rates were observed across pre-specified time points following Compound I and vehicle treatment throughout the study. At the end of the study, no clinically relevant changes in blink rate were observed compared to baseline.

[0380] Corneal Staining: At baseline, Day 8, and EOS follow-up, staining was normal (Grade 0) in most patients. No clinical differences in corneal staining were observed between eyes treated with Compound I and vehicle at baseline or Day 8 or EOS follow-up.

[0381] Vital Signs, Physical Examinations, and Other Observations Related to Safety: Vital sign parameters (systolic and diastolic blood pressure, pulse rate, and body temperature) were within normal ranges for all patients during the study. No AEs related to vital signs were observed. Electrocardiograms and special safety topic examinations were not performed (per protocol).

[0382] Summary of Safety Results

[0383] There were no deaths, serious or severe AEs, treatment discontinuations, or study discontinuations reported in this study.

[0384] No AEs were assessed to be related to study drug (Compound I or vehicle). Eight of 40 patients and five of 40 patients experienced AEs following Compound I and vehicle treatment, respectively. All ocular AEs were mild and balanced between Compound I and vehicle, with the vast majority being well-known AEs associated with PRK surgery.

[0385] No clinically meaningful safety differences were observed between Compound I and vehicle.

[0386] • Compound I showed no delay in wound healing compared to vehicle.

[0387] - Fewer eyes treated with Compound I showed severe conjunctival hyperemia on Day 2 (24 hours post-surgery) compared to vehicle-treated eyes.

[0388] No clinically relevant changes in BCVA, IOP, slit-lamp biomicroscopy, mydriasis, blink rate, tear production, corneal staining, or vital signs were observed following administration of Compound I compared to vehicle.

[0389] Table 14 lists the incidence of AEs expressed by preferred terminology.

[0390]

[0391] All publications and patent documents cited herein are incorporated herein by reference, as if each such publication or document is expressly and individually indicated to be incorporated herein by reference. The present invention and its embodiments have been described in detail. However, the scope of the present invention is not intended to be limited to the specific embodiments of any method, manufactured product, material composition, compound, means, method and / or step described in this specification. Various modifications, substitutions and changes can be made to the disclosed materials without departing from the spirit and / or essential features of the present invention. Therefore, it will be easily understood by those of ordinary skill in the art from the present invention that subsequent modifications, substitutions and / or changes that perform substantially the same functions or achieve substantially the same results as the embodiments described herein can be utilized according to such relevant embodiments of the present invention. Therefore, the following claims are intended to cover within their scope modifications, substitutions and changes to the methods, manufactured products, material compositions, compounds, means, methods and / or steps disclosed herein. Unless otherwise specified, the claims should not be understood to be limited to the described order or elements. It should be understood that various changes can be made in form and detail without departing from the scope of the appended claims.

Claims

1. 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Formula I) having the following structure: or a salt thereof for use in the manufacture of a medicament for treating or alleviating ocular surface pain in a subject in need thereof, wherein the compound of formula I is administered ocularly at a concentration of 0.5% w / v to 3.5% w / v.

2. The use according to claim 1, wherein the compound of formula I is administered ophthalmically at a concentration of 0.5% w / v to 2.5% w / v.

3. The use according to claim 1, wherein the compound of formula I is administered ophthalmically at a concentration of 0.5% w / v to 1.5 w / v.

4. The use according to claim 1, wherein the compound of formula I is administered ophthalmically at a concentration of 0.5% to 3.0% w / v.

5. The use according to claim 1, wherein the compound of formula I is administered ophthalmically at a concentration of 1.0% to 2.5% w / v.

6. The use according to claim 1, wherein the compound of formula I is administered ophthalmically at a concentration of 1.5% to 3.0% w / v.

7. The use according to claim 1, wherein the compound of formula I is administered ophthalmically at a concentration of 0.5% to 2.5% w / v.

8. The method of claim 1, wherein the subject suffers from one or more of dry eye disease, Sjögren's syndrome, conjunctivitis, Map-Dot-fingerprint dystrophy, Acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy, corneal dystrophy, epithelial basement membrane dystrophy, corneal erosion or abrasion, blepharitis, graft-versus-host disease, tarsal gland inflammation, glaucoma, conjunctivochalasis, keratitis, iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, or a patient recovering from neurotrophic keratitis, or eye pain persisting for at least three months after photorefractive keratectomy (PRK) surgery or laser-assisted in situ keratomileusis (LASIK) surgery.

9. The use according to claim 1, wherein the subject suffers from one or more of the following: ocular pain syndrome, ocular surface disease, keratopathy and dry eye.

10. The use according to claim 8, wherein the conjunctivitis is selected from keratoconjunctivitis; the corneal neuropathy is LASIK-induced corneal neuropathy; the corneal dystrophy is recurrent corneal dystrophy; the corneal erosion or abrasion is recurrent corneal erosion or abrasion; and the keratitis is herpes simplex virus keratitis.

11. The use according to claim 8, wherein the conjunctivitis is selected from vernal keratoconjunctivitis and allergic conjunctivitis.

12. The use according to claim 9, wherein the corneal lesion is selected from herpetic keratopathy, filamentous keratopathy, band or bullous keratopathy, exposure keratopathy.

13. The use according to any one of claims 1 to 12, wherein the administration results in a reduction in pain score of at least 3 compared to placebo when measured on a visual analogue scale (VAS).

14. The use according to claim 13, wherein the administration results in a reduction in pain score of at least 4 compared to placebo when measured on a visual analogue scale (VAS).

15. The use according to claim 14, wherein the administration results in a reduction in pain score of at least 5 compared to placebo when measured on a visual analogue scale (VAS).

16. The use according to claim 14, wherein the administration results in a reduction in pain score of at least 6 compared to placebo when measured on a visual analogue scale (VAS).

17. The use according to claim 14, wherein the administration results in a reduction in pain score of at least 7 compared to placebo when measured on a visual analogue scale (VAS).

18. The use according to claim 14, wherein the administration results in a reduction in pain score of at least 8 compared to placebo when measured on a visual analogue scale (VAS).

19. The use according to claim 14, wherein the administration results in a reduction in pain score of at least 9 compared to placebo when measured on a visual analogue scale (VAS).

20. The use according to claim 14, wherein the administration results in a reduction in pain score of at least 10 compared to placebo when measured on a visual analogue scale (VAS).

21. The use according to any one of claims 1-12, wherein the administration results in at least 10% reduction in pain in the subject compared to placebo.

22. The use according to claim 21, wherein the administration results in at least 15% reduction in pain in the subject compared to placebo.

23. The use of claim 21, wherein the administration results in at least 20% reduction in pain in the subject compared to placebo.

24. The use of claim 21, wherein the administration results in at least 25% reduction in pain in the subject compared to placebo.

25. The use according to any one of claims 14-20, wherein the reduction in pain score is produced by the difference in pain score before and after administration of Compound I to the subject.

26. The use according to any one of claims 14-20, wherein the reduction in VAS score occurs within half an hour after administration of Compound I to the subject.

27. The use of any one of claims 1-12, 14-20, and 22-24, wherein the administration results in a reduction in congestion of the subject of at least 1 on the McMonnies scale.

28. The use of claim 27, wherein said administration results in a reduction in said subject's congestion of at least 2 on the McMonnies scale.

29. The use of claim 27, wherein said administration results in a reduction in said subject's congestion of at least 3 on the McMonnies scale.

30. The use of claim 27, wherein said administration results in a reduction in said subject's congestion of at least 4 on the McMonnies scale.

31. The use of claim 27, wherein said administration results in a reduction in said subject's congestion of at least 5 on the McMonnies scale.

32. The use according to any one of claims 1-12, 14-20, 22-24 and 28-31, wherein the compound of formula I is administered for at least one month.

33. The use according to claim 32, wherein the compound of formula I is administered for at least two months.

34. The use according to claim 33, wherein the compound of formula I is administered for more than 3 months.

35. The use according to any one of claims 1-12, 14-20, 22-24, 28-31 and 33-34, wherein the compound of formula I is administered one to four times per day.

36. The use according to any one of claims 1-12, 14-20, 22-24, 28-31 and 33-34, wherein the ocular surface pain is chronic ocular surface pain.

37. 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Formula I) having the following structure: or a salt thereof for use in the manufacture of a medicament for alleviating ocular surface pain in a subject in need thereof; wherein the compound of formula I is administered ocularly at a concentration of 0.5% w / v to 3.5% w / v.

38. The use according to claim 37, wherein the compound of formula I is administered ophthalmically at a concentration of 0.5% w / v to 2.5% w / v.

39. The use according to claim 37, wherein the compound of formula I is administered ophthalmically at a concentration of 0.5% w / v to 1.5 w / v.

40. The use according to claim 37, wherein the compound of formula I is administered ophthalmically at a concentration of 0.5% to 3.0% w / v.

41. The use according to claim 37, wherein the compound of formula I is administered ophthalmically at a concentration of 1.0% to 2.5% w / v.

42. The use according to claim 37, wherein the compound of formula I is administered ophthalmically at a concentration of 1.5% to 3.0% w / v.

43. The use according to claim 37, wherein the compound of formula I is administered ophthalmically at a concentration of 0.5% to 2.5% w / v.

44. 4-(7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Formula I) having the following structure: or a salt thereof for use in the manufacture of a medicament for reducing ocular congestion in a subject in need thereof; wherein the compound of formula I is administered ocularly at a concentration of 0.5% w / v to 3.5% w / v.

45. The use according to claim 44, wherein the compound of formula I is administered ophthalmically at a concentration of 0.5% w / v to 2.5% w / v.

46. ​​The use according to claim 44, wherein the compound of formula I is administered ophthalmically at a concentration of 0.5% w / v to 1.5 w / v.

47. The use according to claim 44, wherein the compound of formula I is administered ophthalmically at a concentration of 0.5% to 3.0% w / v.

48. The use according to claim 44, wherein the compound of formula I is administered ophthalmically at a concentration of 1.0% to 2.5% w / v.

49. The use according to claim 44, wherein the compound of formula I is administered ophthalmically at a concentration of 1.5% to 3.0% w / v.

50. The use according to claim 44, wherein the compound of formula I is administered ophthalmically at a concentration of 0.5% to 2.5% w / v.

51. The use according to any one of claims 44-47, wherein the reduction in ocular congestion is at least 1 on the McMonnies scale.

52. The use of claim 51, wherein the reduction in ocular congestion is at least 2 on the McMonnies scale.

53. The use of claim 51, wherein the reduction in ocular congestion is at least 3 on the McMonnies scale.

54. The use of claim 51, wherein the reduction in ocular congestion is at least 4 on the McMonnies scale.

55. The use of claim 51, wherein the reduction in ocular congestion is at least 5 on the McMonnies scale.

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