Methods for treating ocular surface pain

Abstract

To provide methods and medicines for treating ocular surface pain.SOLUTION: The present invention provides a method of treating ocular surface pain in a subject in need thereof, comprising ocularly administering to the subject 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Formula I) having the following structure, or a salt, solvate, polymorph, or co-crystal thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 806,682, which is hereby incorporated by reference in its entirety. No. 6,393,436, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline US201002233633A1 -Method of treating ocular surface diseases or disorders using (3-yl)-benzonitrile (Compound I) - Patent application Regarding. [Background technology]

[0003] The ocular surface, especially the cornea, is densely innervated by sensory nerves. Inflammation due to several factors including osmotic stress, tissue damage, and even nerve damage to the ocular surface Ocular surface symptoms can be modified by persistent irritation causing ocular surface stress and sensitization. A possible indicator of imbalanced ocular surface homeostasis leading to chronic ocular surface pain due to stimulation It is a home system. Summary of the Invention [Problem to be solved by the invention]

[0004] Patients suffering from ocular surface pain, especially chronic ocular surface pain, have a significantly reduced quality of life. Previous utility studies have shown that the burden of severe chronic ocular surface pain is Severe chronic ocular surface pain has been likened to vascular disease, dialysis, or disabling hip fractures. It has also been associated with homicidal ideation. In many patients, ocular surface pain may be due to underlying pathology (e.g. Remains unresolved despite treatment (e.g., recent trauma or surgery, infection, or inflammation) In addition, therapeutic agents used in the short-term management of ocular pain (e.g., nonsteroidal anti-inflammatory drugs) , steroids) cannot be used for long-term therapy. Ocular surface pain, especially chronic ocular surface pain, is a common condition when no other options exist for supplementing current therapeutic agents. There exists a long felt and unmet need for safe and effective therapeutic agents for the treatment of pain. do. [Means for solving the problem]

[0005] In one embodiment, the present disclosure provides for the treatment of ocular surface pain in a subject in need thereof. 1. A method comprising administering to a subject an effective amount of a compound of the structure: [ka] 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 -yl)-benzonitrile (formula I) or a salt, solvate, polymorph or co-crystal thereof The method includes administering an eye drop to the patient.

[0006] In some embodiments, the ocular surface pain is episodic or acute pain. In one embodiment, the ocular surface pain is chronic ocular surface pain that persists for at least about three months. It is painful (COSP)

[0007] In some embodiments, the compound of formula I is administered to the cornea of ​​the subject. In the form, the compound of formula I is about 0.5% w / v to about 3.5% w / v, about 0.5% w / v to about 3.5% w / v 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 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 certain embodiments, the compound of formula I is administered to a subject at a concentration of about 0. 5%w / v, approx. 1.0%w / v, approx. 1.5%w / v, approx. 2.0%w / v, approx. 2.5%w / In some embodiments, the medicament is administered at a concentration of about 3.0% w / v, about 3.5% w / v, or about 3.5% w / v. The compound of formula I is preferably from about 5 mg / ml to about 35 mg / ml, more preferably from about 5 mg / ml to about 25 mg / ml. / 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 In certain embodiments, the compound of formula I is administered to a subject at a concentration of about 25 mg / ml to about 25 mg / ml. is about 5mg / ml, about 10mg / ml, about 15mg / ml, about 20mg / ml, 25mg The therapeutic agent is administered at a concentration of about 10 mg / ml, about 30 mg / ml or about 35 mg / ml.

[0008] In some embodiments of the methods of treating ocular surface pain described herein, the COSP is In some embodiments, administration is associated with dry eye disease. In certain embodiments, administration results in a reduction in ocular pain associated with dry eye disease. In some embodiments, administration results in relief of dry eye, eye discomfort, eye redness, eye burning. At least about 10% of the following symptoms: tingling, roughness, foreign body sensation, or photophobia This results in a % reduced incidence.

[0009] In some embodiments of the methods for treating ocular surface pain described herein, the subject is Diseases, Sjogren's syndrome, conjunctivitis (keratoconjunctivitis, vernal keratoconjunctivitis, allergic conjunctivitis) (including corneal epithelial basement membrane dystrophy, acanthamoeba, fibromyalgia, meibomian gland Dysfunction, Thyroid Eye Disease, Rosacea, Ptosis, Keratoconus, Ocular Pain Syndrome, Stevens-J Johnson syndrome, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), Corneal dystrophies (including recurrent corneal dystrophies), epithelial basement membrane dystrophies, Corneal erosion or abrasion (including recurrent corneal erosion or abrasion), ocular surface Disease, blepharitis, graft-versus-host disease, meibomianitis, glaucoma, conjunctivochalasis, keratopathy (herpetic Keratopathy, filamentous keratopathy, band or bullous keratopathy, lagophthalmos keratopathy, keratitis (simple hepatitis) rupesvirus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis Patients recovering from pterygium, neuralgia, xerophthalmia, or neurotrophic keratitis In some embodiments of the methods described herein, the subject is suffering from laser deflection. Less common after photorefractive keratectomy (PRK) or laser in situ keratomileusis (LASIK) surgery Both patients have been suffering from ocular pain for three months.

[0010] In some embodiments, the methods of treating ocular surface pain described herein further include the step of administering to the subject an additional therapeutic agent. Administering the compound to a subject.

[0011] In some embodiments of the methods for treating ocular surface pain described herein, administration of Compound I to a subject. Administration of 10 mg / kg / day reduced the risk of death compared with placebo, as measured by visual analog scale (VAS). At least about 3, at least about 4, at least about 5, at least about 6, at least about 7, resulting in a reduction in pain score of at least about 8, at least about 9, or at least about 10. In a further embodiment, administration of Compound I to a subject results in a placebo-responsiveness as measured by VAS. At least about 6, at least about 7, at least about 8, at least about 9, or resulting in a reduction in the subject's pain score of at least about 10.

[0012] In some embodiments of the methods for treating ocular surface pain described herein, administration of Compound I to a subject. administration of at least about 10%, at least about 15%, at least resulting in a reduction in pain in a subject of about 20%, or at least about 25%. In this case, the reduction in pain score was derived from the difference in pain score before and after administration of Compound I to the subject. In some embodiments of the methods described herein, the pain response of administering Compound I to a subject is The reduction in the core occurs within about half an hour after administration of Compound I to a subject.

[0013] In some embodiments of the methods for treating ocular surface pain described herein, administration of Compound I to a subject. The administration of at least about 1 on the McMonnies scale and at least A reduction in hyperemia in a subject of about 2, at least about 3, at least about 4, or at least about 5. results.

[0014] In some embodiments of the methods for treating ocular surface pain described herein, administration of Compound I to a subject. Treatment with 100 mg of ... No change in tear rate, tear production, or intraocular pressure.

[0015] In some embodiments of the methods of treating ocular surface pain described herein, the compound of formula I is Administration for at least about 1 month, at least about 2 months, or at least about 3 months In some embodiments, the compound of formula I is administered for more than three months. In some embodiments, the compound of Formula I is administered 1 to 4 times daily. Generally, the compounds of formula I are administered once or twice daily.

[0016] In some embodiments, the present disclosure provides a compound of formula I [ka] or a salt, solvate, polymorph or co-crystal thereof.

[0017] In some embodiments, the ocular surface pain is acute or episodic ocular surface pain. In some embodiments, the ocular surface pain is relieved for at least 1 month, at least 2 months, or at least Chronic ocular surface pain lasting for at least 3 months.

[0018] In some embodiments of the uses described herein, the compound of formula I is present in an amount of about 0.5% w / v 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 .5w / 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.

[0019] In some embodiments of the uses described herein, the compound of formula I is present in an amount 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. It is administered at a concentration of 0% w / v or about 3.5% w / v.

[0020] In some embodiments, the present disclosure provides a compound of formula I [ka] or a salt, solvate, polymorph, or cocrystal thereof. The present invention relates to a pharmaceutical agent for treating or reducing facial pain.

[0021] In some embodiments, the ocular surface pain is acute or episodic ocular surface pain. In some embodiments, the ocular surface pain is relieved for at least one month, at least two months, or In some embodiments, the ocular surface pain is chronic ocular surface pain that persists due to at least In some embodiments, the ocular surface pain is chronic and lasts for at least 3 months. The compound is 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 of formula I is administered at a concentration of about 0.5% w / v, about 1 .0%w / v, approx. 1.5%w / v, approx. 2.0%w / v, approx. 2.5%w / v, approx. 3.0%w The antibody is administered at a concentration of about 3.5% w / v or about 3.5% w / v.

[0022] In some embodiments, the present disclosure provides a method for the manufacture of a medicament for treating or reducing ocular surface pain. In the formula I [ka] or a salt, solvate, polymorph or co-crystal thereof.

[0023] 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 at least one month. For chronic ocular surface pain lasting for at least 2 months or at least 3 months It is.

[0024] In some embodiments of the uses described herein, the compound of formula I is present in an amount of about 0.5% w / v 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 .5w / 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 of formula I is present in an amount 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. It is administered at a concentration of 0% w / v or about 3.5% w / v.

[0026] In some embodiments, the present disclosure provides a method for reducing ocular surface pain in a subject in need thereof. 16. A method for producing a composition comprising the steps of: [ka] 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 -yl)-benzonitrile (formula I) or a salt, solvate, polymorph or co-crystal thereof The compound of formula I is administered in an amount 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 The method relates to a method in which the compound is administered at a concentration of 0.5% to about 2.5% w / v.

[0027] In some embodiments, the ocular surface pain is acute or episodic ocular surface pain. In some embodiments, the ocular surface pain is relieved for at least 1 month, at least 2 months, or at least Chronic ocular surface pain lasting for at least 3 months.

[0028] In some embodiments of the methods of reducing ocular pain described herein, the COSP is It is associated with eye diseases.

[0029] In some embodiments of the methods of reducing ocular surface pain described herein, the subject is administered Compound I. Administration of results in a reduction in the symptoms of dry eye disease.

[0030] In some embodiments of the methods of reducing ocular surface pain described herein, the subject is administered Compound I. Administration of the compound results in a reduction in ocular pain associated with dry eye disease. In some embodiments, administration of Compound I to a subject reduces symptoms of eye dryness, eye discomfort, eye redness, eye irritation, and eye discomfort. At least one of the following symptoms: burning sensation or stinging, roughness or foreign body sensation, or photophobia This results in a reduced incidence of approximately 10%.

[0031] In some embodiments, the subject in need of reduced ocular surface pain is a patient suffering from dry eye disease, schizophrenia, or a combination of both. Sjogren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), Membrane epithelial basement membrane dystrophy, Acanthamoeba, fibromyalgia, meibomian gland dysfunction, Thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Stevens-Johnson syndrome symptoms, corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystonia corneal dystrophy (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, corneal erosion or corneal abrasion (including recurrent corneal erosion or abrasion), ocular surface disease, eyelid inflammation, graft-versus-host disease, meibomianitis, glaucoma, conjunctivochalasis, keratopathy (herpetic keratopathy, thread keratopathy (including zona keratopathy, bullous keratopathy, and lagophthalmos keratopathy), keratitis (including herpes simplex virus) keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium Patients suffering from one or more of the following conditions are recovering from glaucoma, neuralgia, xerophthalmia, or neurotrophic keratitis: There are.

[0032] In some embodiments, the methods of reducing ocular surface pain described herein further comprise administering to the patient an additional therapeutic agent. Administering the compound to a subject.

[0033] In some embodiments of the methods of reducing ocular surface pain described herein, the subject is administered Compound I. Administration of the compound reduced pain before administration of the compound as measured by a visual analog scale (VAS). The present invention provides a method for treating a subject's pain by administering a medicament for a period of at least about 12 weeks in a subject's sleep. In some embodiments of the described methods, administration of Compound I to the subject is performed using a visual analogue schedule. At least about 3 and at least about 3.5% improvement compared to placebo as measured by visual analog scale (VAS) 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. In some embodiments, administration of Compound I to a subject results in a difference in efficacy compared to placebo as measured by VAS. In comparison, at least about 6, at least about 7, at least about 8, at least about 9 or less The therapeutic effect of the present invention results in a reduction in the subject's pain score of at least about 10.

[0034] In some embodiments of the methods of reducing ocular surface pain described herein, the subject is administered Compound I. administration of at least about 10%, at least about 15%, at least The methods described herein result in a reduction in pain in a subject of about 20% or at least about 25%. In some embodiments of the method, the reduction in pain score is measured before and after administration of Compound I to the subject. This results from differences in pain scores.

[0035] In some embodiments of the methods of reducing ocular surface pain described herein, the subject is administered Compound I. administration of at least about 1, at least about 2, at least about 3, resulting in a reduction in hyperemia in the subject of at least about 4, or at least about 5.

[0036] In some embodiments, the present disclosure provides a method for reducing ocular hyperemia in a subject in need thereof. A method of making a composition comprising the steps of: [ka] 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 -yl)-benzonitrile (formula I) or a salt, solvate, polymorph or co-crystal thereof The compound of formula I is administered in an amount 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 The method relates to a method in which the compound is administered at a concentration of 0.5% to about 2.5% w / v.

[0037] In some embodiments of the methods described herein, administering Compound I to a subject comprises administering to a subject a subject a subject comprising At least about 1, at least about 2, at least about 3, at least about 4 or results in a reduction in ocular redness of at least about 5. In one embodiment, administration of Compound I to a subject may result in dry eye, eye discomfort, eye burning or stinging. At least about 10% reduction in one or more of the symptoms of skin roughness, roughness or foreign body sensation, or photophobia. Resulting in a survival rate.

[0038] In some embodiments of the method for reducing ocular congestion, the subject is diagnosed with dry eye disease, Sjogren's disease, syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), corneal epithelial basal Membranous dystrophy, Acanthamoeba, Fibromyalgia, Meibomian gland dysfunction, Thyroid eye disease , rosacea, ptosis, keratoconus, ocular pain syndrome, Stevens-Johnson syndrome, cornea Epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy ( recurrent corneal dystrophy, epithelial basement membrane dystrophy, corneal erosion or Membrane abrasions (including recurrent corneal erosions or abrasions), ocular surface disease, blepharitis, grafts Host-versus-host disease, meibomianitis, glaucoma, conjunctival laxity, keratopathy (herpetic keratopathy, filamentous keratopathy, (including zonal or bullous keratopathy and lagophthalmos keratopathy), keratitis (herpes simplex virus keratitis) ), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, Patients recovering from xerophthalmia or neurotrophic keratitis suffer from one or more of the following:

[0039] Some embodiments of the methods described herein for reducing ocular redness may further comprise the step of administering an additional therapeutic agent to a subject.

[0040] Certain preferred embodiments of the present invention are described in more detail below in connection with certain preferred embodiments. and the claims. [Brief description of the drawings]

[0041] [Figure 1] Model-estimated means (+ / - SE) of visual analogue scale (VAS) pain assessments over time are shown (primary PD analysis set). [Diagram 2] Histograms of oral rescue medication use incidence are shown (number of patients who did not use oral rescue medication) (secondary PD analysis set). For each period, the right bar represents subjects who received Compound I, while the left bar represents subjects who received vehicle. The percentage of patients who did not use oral rescue medication (ORM) is presented on the y-axis. n / N represents the number of patients in each treatment / total number. [Figure 3A] Figure 3: Provides the arithmetic mean (+ / -SD) of the Ocular Pain Assessment Survey (OPAS) over time for questions 4, 5, and 6 (secondary PD analysis set). Figure 3A provides the results of question 4: 24 hour ocular pain (pain level) at maximum pain, Figure 3B provides the results of question 5: 24 hour ocular pain (pain level) at minimum pain, and Figure 3C provides the results of question 6 for average 24 hour ocular pain (pain level). For each of Figures 3A, 3B, and 3C, the dashed line with "x" represents vehicle, and the solid line with a circle (o) represents Compound I. [Figure 3B] (As stated above.) [Figure 3C] (As stated above.) [Figure 4A] Figure 4: Provides the arithmetic mean (+ / -SD) of the Ocular Pain Assessment Survey (OPAS) over time for questions 22, 23, 24 and 25 (secondary PD analysis set). Figure 4A provides the results for question 22: frequency (%) of ocular pain with redness. Figure 4B provides the results for question 23: frequency (%) of ocular pain with burning sensation. Figure 4C provides the results for question 24: frequency (%) of ocular pain with sensation. Figure 4D provides the results for question 25: frequency (%) of ocular pain with tearing. For each of Figures 4A, 4B, 4C and 4D, the dashed line with "x" represents vehicle and the solid line with a circle (o) represents Compound I. [Figure 4B] (As stated above.) [Figure 4C] (As stated above.) [Figure 4D] (As stated above.) [Figure 5A] Figure 5: Figure 5A provides the arithmetic mean (SD) plasma concentrations of Compound I following topical ocular administration of 2.5% Compound I on day 1 (PK analysis set). Figure 5B provides the arithmetic mean (SD) plasma concentrations of Compound I following topical ocular administration of 2.5% Compound I on day 4 (PK analysis set). [Figure 5B] (As stated above.) [Figure 6A] Figure 6: Figure 6A provides a bar chart of ocular hyperemia over time for Compound I and Figure 6B provides a bar chart of ocular hyperemia over time for vehicle. Quadrants are S: superior, N: nasal, I: inferior and T: temporal. [Figure 6B] (As stated above.) [Figure 7] Arithmetic mean (+ / - SD) of epithelial defect size over time is provided (Safety Analysis Set) Parameter (units): Epithelial wound size (mm), Subcategory: Area (mm2). The dashed line with "x" represents vehicle and the solid line with circle (o) represents Compound I. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] The TRPV1 receptor is a transient receptor that has been characterized by molecular cloning and pharmacology. It refers to the receptor potential vanilloid 1. For example, Caterina MJ, et al., N See ature 1997;389:816-824. TRPV1 receptor activity No. WO 2005 / 120510, the entirety of which is hereby incorporated by reference. Measured as described in the brochure.

[0043] The term "effective amount" of a compound described herein is an amount that allows the compound to perform its intended function in a mammal. An effective amount of a therapeutic compound refers to the amount of a therapeutic compound that is necessary or sufficient to cause a therapeutic effect in a mammal. The amount of causative agent already present in the mammal, the age, sex and weight of the mammal and the ocular Depending on factors such as the ability of the therapeutic compounds of the present disclosure to treat a surface disorder and / or its symptoms, Therefore, it may vary.

[0044] The phrase "ophthalmologically compatible" means that excessive toxicity is avoided in response to a reasonable benefit / risk ratio. - The ocular tissue of humans and animals can be treated without toxicity, irritation, allergic reactions or other problems or complications. Refers to formulations, polymers and other materials and / or dosage forms that are suitable for use in contact with .

[0045] As used herein, the terms "treat" and "treat" in relation to a disease or disorder are used interchangeably. "Treatment" or "treatment" refers, in some embodiments, to improving a disease or disorder. That is, to slow or prevent the development of the disease or at least one of its clinical symptoms, In another embodiment, "treatment" refers to "reducing" or "treating." " is defined as a measurement of at least one physical parameter, including those that may not be discernible by the patient. In yet another embodiment, "treat" or "treat" refers to reducing or ameliorating a "Treatment" or "treatment" refers to a physical (e.g., stabilization of discernible symptoms) or physiological (e.g., stabilization of physical parameters) or both of these may modulate the disease or disorder. In yet another embodiment, "treat," "treating," or "treatment" refers to Preventing or delaying the onset or development or progression of a disease or disorder or a symptom thereof Refers to...

[0046] As used herein, the term "subject" or "patient" refers to humans, as well as primates, rabbits, Non-human mammals, including but not limited to pigs, horses, dogs, cats, sheep and cows. In certain embodiments, the subject or patient is a human. The term "patient" or "subject" refers to a person suffering from a condition (i.e., a disease or disorder) as described herein. As used herein, refers to a person who is suffering from and who would benefit from treatment. The objective is to ensure that such subjects (patients) do not suffer any biological, medical or life-threatening effects from such treatment. A subject is "in need of" treatment if he or she will benefit in quality of life. In certain embodiments, a subject is in need of at least In certain embodiments, the subject is an adult human of at least about 18 years of age. In some embodiments, the subject is a human child about 18 years of age or younger. .

[0047] As used herein, "ocular surface" refers to the anatomical portion of the cornea (epithelium, Bowman's layer, corneal lamina propria, etc.). The outer surface of the eye, including the cornea, the cornea (including the epithelium, Descemet's membrane, and endothelium), the conjunctiva, the conjunctival sac, and the limbus, i.e. Point to the face.

[0048] As used herein, ocular administration refers to administration to the cornea, conjunctiva, cul-de-sac, corneoscleral junction, i.e., the cornea. This includes administration to all parts of the eye, including all parts of the ocular surface, such as the limbus.

[0049] As used herein, "pain" includes, but is not limited to, stabbing, dull, sharp or painful. Pain refers to the sensation of actual pain, either constant or intermittent, described as a tingling sensation. However, burning, stinging, roughness, foreign body sensation, dryness, sandiness, fatigue, itching, prickling It also refers to similar related descriptors such as sensitivity to light and dry eyes.

[0050] As used herein, "ocular surface pain" refers to pain at the surface of the eye, for example, the cornea. Ocular pain is generally caused by external physical factors such as corneal surgery, inflammation, or other injury to the corneal surface. Ocular pain may be nociceptive pain caused by ocular or chemical injury stimuli. It also blocks pain messages being sent to the central nervous system and brain despite the presence of noxious stimuli. This is due to neuropathic pain, which can result from direct damage to the body's neurons. As used herein, "ocular surface pain" refers to nociceptive pain. and neuropathic pain.

[0051] As used herein, the term "visual analog scale" (VAS) refers to a scale that a subject typically uses to measure , a pain intensity scale that marks the location against a scale that aligns with the level of pain Pain was assessed on a scale of 'no pain' (score 0) and 'worst pain' or 'worst pain imaginable'. For example, Hawker, et al. al.,Arthritis Care & Research 63(11),pp. See S240-S252 (November 2011). There are several other well-designed pain scales that can be used to help. A numeric rating scale (NRS) is used in which subjects use numbers to rate their pain. The numerical scale can be 1 to 10 or 1 to 100. The FACES pain scale combines pictures and numbers to grade pain. It can be used in children over 3 years of age and in adults. The six faces range from fair to very poor. A range of tones represent different facial expressions, each between 0 (smiling) and 10 (crying). The verbal pain intensity scale rates pain intensity on a scale of 1 to 100. Use verbal descriptions on a rating scale: no pain / mild pain / moderate pain Moderate pain / severe pain Very severe pain / no pain at all.

[0052] The Ocular Sensation Scale is a specific pain scale developed to measure the severity of eye pain. Caudle LE et al., Optom Vis Sci. 20 See 07 Aug;84(8):752-62. This scale measures pain, discomfort, Sensitivity or photosensitivity is usually categorized into five categories: "extreme," "severe," "moderate," "mild," or "none." This is measured by the category label.

[0053] The Ocular Pain Assessment Survey (OPAS) assesses changes in corneal and ocular surface pain and quality of life (QoL). The OPAS is a quantitative, multidimensional questionnaire specifically designed to assess pain Pain intensity, frequency of ocular and non-ocular pain, changes in QoL, contributing factors, associated factors and symptom relief Quantitative assessment of IL-16 expression allows for monitoring of therapeutic response. Ophthalmology July 123(7):1458-1468(2016 ) for more information.

[0054] As used herein, the term "visual task questionnaire" refers to the assessment of fixations that may worsen ocular pain. How much difficulty do you have performing certain tasks that require constant or prolonged staring? This refers to a questionnaire that asks subjects to subjectively rate how well their visual perception is improved. Also ask about the difficulties experienced while performing the task and associated coping mechanisms.

[0055] As used herein, ocular hyperemia refers to redness of the ocular surface. Ocular hyperemia can be caused by inflammation and / or It can be a clinical marker for eye irritation. Eye redness is scored on a scale of 0 to 5 based on standard photographs. and can be measured using the McMonnies scale.

[0056] As used herein, "placebo" refers to a total amount of a drug composition that does not contain any administered drug. This refers to an eye drop preparation containing all of the above ingredients.

[0057] As used herein, the term "about" refers to a range of the specified value plus 10%.

[0058] As used herein, a pharmaceutical composition refers to a composition suitable for pharmaceutical use. Compositions suitable for pharmaceutical use may be sterile, homogeneous and / or isotonic. In embodiments, the composition may be administered in aqueous form, such as in pre-filled syringes or other single or multi-dose doses. In certain embodiments of the present invention, the pharmaceutical composition is ophthalmically compatible. and for ocular administration to a human subject, e.g., by topical or other known delivery methods. This is preferable.

[0059] As used herein, "compound of formula I" or "Compound I" "Formula I" and "compound I" are used interchangeably and are shown below. The structure name is 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazo It means a compound having a benzonitrile group, and is known to those skilled in the art and has both No. 2005 / 113636, to Chen et al., which is hereby incorporated by reference in its entirety. No. 20510 and U.S. Pat. No. 8,349,852 ("Quinaz olinone derivatives useful as vanilloid The compounds can be synthesized using the procedures described in "Antagonists" below. [ka]

[0060] Additionally or alternatively, various crystalline forms and polymorphic forms of Compound I may be used.

[0061] In some embodiments, compound I is a compound as described in U.S. Pat. No. 8,349,852 (see In some embodiments, the polymorphic form B is as described in Polymorph B: 9.3, 10.6 and 14.4±0.2 o Three 2θ values ​​to be selected from 2θ In some embodiments, the compound is characterized by an X-ray diffraction pattern having peaks equal to or greater than 100 nm. , and polymorph B is 9.3, 10.6, 14.4, 15.5, 17.9, 19.9, and 23.4 ±0.2 o 2θ, which has three or more peaks at 2θ values ​​selected from It can be characterized as follows.

[0062] Any chemical formula given herein represents unlabeled and isotopically labeled forms of the compound. It is also contemplated that isotopically labeled compounds are compounds in which one or more atoms have a selected atomic mass or molecular weight. According to the formula given herein except that the atoms are replaced by the atoms having the quantification numbers Isotopes that may be incorporated into the compounds of the present disclosure include, for example, 3 H , 11 C. 13 C. 14 C and 15 These include isotopes of hydrogen, carbon, nitrogen, and oxygen, such as N. Thus, the method of the present invention can include, for example:3 H and 14 Radioisotopes such as C or 2 H and 13 Any one of the above isotopes, including those that exist as non-radioactive isotopes such as C It should be understood that the composition may or may not include compounds incorporating the above. Such isotope-labeled compounds are useful for metabolic studies ( 14 C), reaction rate tests (e.g. 2 Hmata teeth 3 H), positron emission tomography (PET) including drug or substrate tissue distribution assays ( Detection or measurement of the tumor using PET (positron emission tomography) or single photon emission computed tomography (SPECT) are useful in imaging techniques or in radiotherapy of patients. Isotopically labeled compounds are usually For example, suitable isotopically labeled reagents may be substituted for previously utilized non-labeled reagents to provide a novel method for the preparation of fluorophores. They may be prepared by conventional techniques known to those skilled in the art.

[0063] The present invention includes all pharma- ceutically acceptable forms of the compounds useful according to the invention provided herein. As used herein, the term "pharmacologically acceptable salt" includes embodiments that include salts thereof. refers to derivatives of the disclosed compounds, the parent compound being one that has an acid or base moiety present in it. The compound is modified by converting it into a salt form. Examples of pharma- ceutically acceptable salts include amine salts. mineral or organic acid salts of basic residues such as carboxylic acids; alkali or organic salts of acidic residues such as carboxylic acids; Pharmaceutically acceptable salts include, but are not limited to, organic salts. These include the conventional non-toxic salts of the parent compound, for example, derived from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts are prepared by conventional chemical methods, which contain a basic or acidic moiety. Typically, such salts can be synthesized from the free acid or base forms of these compounds. Form and water or organic solvent or a mixture of the two (usually ether, ethyl acetate, ethanol) (preferably in a non-aqueous medium such as alcohol, isopropanol or acetonitrile) The salts can be prepared by reacting the compound with a stoichiometric amount of an appropriate base or acid. No. 6,399,413, each of which is incorporated herein by reference in its entirety. Pharmaceutical Sciences,17th ed.,Mack Pub lishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science,66,2(1 For example, preferred pharma- ceutically acceptable salts include amine salts. Examples of basic residues include, but are not limited to, mineral or organic acid salts of basic residues such as: The salt may be a hydrochloride salt. Other examples of suitable salts are described in US Pat. No. 6,399,413, the contents of which are hereby incorporated by reference in their entirety. No. 8,349,852, which is incorporated herein by reference.

[0064] As used herein, the phrase "pharmacologically acceptable" means any compound that is acceptable to the patient based on sound medical judgment. Within the limits of reasonable benefit / risk ratio, excessive toxicity, irritation, and allergy - Use in contact with human and animal tissues without reactions or other problems or complications "compounds, substances, compositions and / or dosage forms that are suitable for

[0065] Compound (I) or a pharma- ceutically acceptable salt thereof may be incorporated into a variety of formulations for delivery. For example, topical formulations are available, as well as ophthalmically compatible solutions and suspensions. Ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, buffers, salts to form a solution. The aqueous solution may contain sodium chloride and water.

[0066] The compound of formula I is typically contained in these formulations in an amount of about 0.1% to about 5.0% w / v. In some embodiments, the concentration of Compound I for topical administration is about 0.5%. ~1.5%w / v, approx.0.5%~2.5%w / v, approx.0.5%~3.5%w / v, Approx. 0.5% to approx. 3.0%w / v, approx. 1.0% to approx. 2.5%w / v, approx. 1.5% to approx. 3.0 % w / v, in the range of about 0.5% to about 2.5% w / v. The concentration of the compound of formula I in the formulation for use is at least about 0.5% w / v, at least At least about 1.0% w / v, at least about 1.5% w / v, at least about 2.0% w / v or less In some embodiments, the formulation for topical use is at least about 2.5% w / v. The concentration of the compound of formula I is about 5.0% w / v or less, about 4.5% w / v or less, about 4.0% w / v or less. vol or less, about 3.5% w / v or less, or about 3.0% w / v or less. The concentration of the compound of formula I in the formulation for use herein 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 commonly understood that equivalent concentrations can be expressed in a variety of units. For example: For example, a concentration of 0.1% w / v can also be expressed as a 1 mg / ml solution. When expressed in units of, in some embodiments, the compound of formula I is present in an amount 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, approx. 5mg / ml ~ approx. 30mg / ml, approx. 10mg / ml ~ approx. 25mg / ml, approx. Target concentration: 15mg / ml to about 30mg / ml or about 5mg / ml to about 25mg / ml In some embodiments, the compound of formula I in a formulation for topical use is administered to The concentration is at least about 5 mg / ml, at least about 10 mg / ml, at least about 15 mg / ml, g / 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 a formulation for topical use is about 50 mg / mL. ml or less, about 45 mg / ml or less, about 40 mg / ml or less, about 35 mg / ml or less, or about In certain embodiments, the compound of formula I is at about 5 mg / ml, about 10mg / ml, approx. 15mg / ml, approx. 20mg / ml, approx. 25mg / ml, approx. 30mg / ml or about 35 mg / ml.

[0067] In some embodiments, the formulation is administered to the ocular surface relying on the routine discretion of a skilled clinician. In some embodiments, the formulation is delivered once, twice, three or more times daily. is administered four times.

[0068] Unless otherwise specified, weights or dosages referred to herein for compounds of Formula I The amounts are weights or doses of the compounds themselves, not their salts or prodrugs, and are not intended to be For example, the methods, compositions and methods disclosed herein may be varied to achieve a desired therapeutic effect. The weight or dosage of the corresponding salt of the compound suitable for combination or administration may be determined by the salt and the compound itself. The ratio of the molecular weights of the two bodies can be calculated.

[0069] Compound (I) and / or its pharma- ceutically acceptable salts are ophthalmologically suitable for delivery to the eye. The compounds may be incorporated into a suitable formulation to form an aqueous sterile ophthalmic suspension or solution. In order to achieve this, ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, It may be combined with sodium chloride and water.

[0070] The pharmaceutical composition of the present invention may contain an additional therapeutic agent in addition to Compound (I). The agents may include, for example, other compounds and antibodies useful in the treatment of ocular surface disorders. A non-exhaustive list of: ketorolac, nepafenac, bromfenac, corticosteroids Nonsteroidal anti-inflammatory drugs such as cyclosporine, lifitegrast, autologous serum, etc. In certain embodiments, the additional agent may be a TRPV1 inhibitor. Treatments include dexamethasone, fluocinolone, loteprednol, difluprednate, Fluorometholone, prednisolone, prednisone, medrysone, triamcinolone, benzamidine Ophthalmic steroids such as tamethasone, rimexolone, and their pharma- ceutically acceptable salts. Further non-limiting examples of such additional therapeutic agents that may be included in the pharmaceutical composition include: dra® (Liftegrast), Restasis® (Cyclosporin) cyclosporine, minocycline, doxycycline or other tetracycline antibiotics. Other examples include selenium disulfide, salicylic acid, glycolic acid, etc. Examples of keratolytic agents include keratolytic agents such as commercially available salts thereof.

[0071] Without being bound by theory, blockers of the transient receptor potential vanilloid 1 (TRPV1) It is hypothesized that these compounds may be useful in the treatment of pain, for example chronic pain.

[0072] Thus, in some embodiments, the present invention provides for the treatment of ocular surface pain in a subject in need thereof. The present invention provides a method for administering to a subject a therapeutically effective amount of Compound (I) or a pharmaceutical composition thereof. In some embodiments, the method includes administering to the subject a therapeutically acceptable salt, solvate, or cocrystal thereof. In one aspect, the present invention provides a method for reducing ocular surface pain in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of The method comprises administering to a subject a therapeutically effective amount of Compound (I) or a pharma- ceutically acceptable salt, solvate, or co-crystal thereof. In some embodiments, the present invention relates to a method for treating ocular surface pain or The present invention relates to a compound of formula I or a pharma- ceutically acceptable salt, solvate or cocrystal thereof in a reduced In some embodiments, the compound of formula I is polymorphic form B.

[0073] In some embodiments, the ocular surface pain is episodic or acute.

[0074] In some embodiments, the subject is suffering from episodic or acute ocular pain. In some embodiments, the subject suffers from chronic ocular surface pain lasting for at least three months. In some embodiments, the subject suffers from chronic ocular surface pain lasting for at least two months. In some embodiments, the subject suffers from chronic ocular surface pain lasting at least one month. In some embodiments, the subject suffers from chronic ocular surface pain lasting at least 4 months. In some embodiments, the subject is diagnosed with chronic ocular surface pain lasting at least 5 months. Thus, in some embodiments, the present invention provides an effective amount of a compound of formula I or a salt, solvate, polymorph, or cocrystal thereof in a subject by administering to the subject In some embodiments, the present invention provides a method for treating chronic ocular surface pain. by administering to a subject an amount of a compound of formula I or a salt, solvate, polymorph, or co-crystal thereof Thus, a method for reducing chronic ocular surface pain in a subject is provided. The use of a compound of formula I or a pharma- ceutically acceptable salt, solvate, polymorph or the like thereof in the treatment of pain. provides for the use of cocrystals.

[0075] In some embodiments, administration is to the ocular surface of a subject, e.g., the cornea, conjunctiva, or conjunctival sac of the eye. This applies to any part of the

[0076] In some embodiments, the present invention provides an ophthalmic solution at a concentration of about 0.5% w / v to about 3.5% w / v. The present invention provides for administration of a compound of formula I to a subject in need thereof in a pharmaceutical compatible formulation. In some embodiments, the concentration for administration is about 0.5% w / v to about 3.5% w / v, about 0.5%w / v ~ approx. 2.5%w / v, approx. 0.5%w / v ~ approx. 1.5%w / v, approx. 0.5% w / v ~ approx. 3.0% w / v, approx. 1.0% w / v ~ approx. 2.5% w / v, approx. 1.5% w / v ~ About 3.0% w / v, in the range of about 0.5% w / v to about 2.5% w / v. In the present invention, the concentration of the compound of formula I in a formulation for topical use is about 0.5% w / v, about 1. 0%w / v, approx. 1.5%w / v, approx. 2.0%w / v, approx. 2.5%w / v, approx. 3.0%w / or about 3.5% w / v. In some embodiments, the compound of formula I is 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 1 5mg / ml, about 5mg / ml to about 30mg / ml, about 10mg / ml to about 25mg / m l. Concentration of about 15 mg / ml to about 30 mg / ml or about 5 mg / ml to about 25 mg / ml In certain embodiments, the compound of formula I is administered to a subject at about 5 mg / ml, about 10 mg / ml, or about 20 mg / ml. / ml, about 15mg / ml, about 20mg / ml, 25mg / ml, about 30mg / ml or It is administered at a concentration of about 35 mg / ml. In some embodiments, it is administered at a concentration of about 35 mg / ml per dose per eye. The dose is about 0.15 to about 1.15 mg, or about 0.15 mg, 0.2 mg, or about 0.25 mg. g, approx. 0.3 mg, approx. 0.35 mg, approx. 0.4 mg, approx. 0.45 mg, approx. 0.5 mg, approx. 0.55mg, about 0.6mg, about 0.65mg, about 0.7mg, about 0.75mg, about 0. 8mg, approx. 0.85mg, approx. 0.9mg, approx. 0.95mg, approx. 1.0mg, approx. 1.05m g, about 1.1 mg, or about 1.15 mg. In some embodiments, the dose per eye is The dose per unit is about 0.18 mg, about 0.37 mg, about 0.55 mg, about 0.74 mg or 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 In some embodiments, the compound of formula I is The composition is administered to a subject 1-6 times per day, for example, 1, 2, 3, or 4 times per day. In embodiments, the compound of formula I is administered for at least about 1 month, at least about 2 months, or at least In some embodiments, the compound of formula I is administered to the subject for a period of about three months. is also administered to the subject for approximately 12 weeks.

[0077] In some embodiments, the ocular surface pain or chronic ocular surface pain is caused by dry eye disease, shavings, or the like. Glenn's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), epicorneal Basement membrane dystrophy, Acanthamoeba, Fibromyalgia, Meibomian gland dysfunction, Thyroid Ophthalmopathy, Rosacea, Ptosis, Keratoconus, Ocular Pain Syndrome, Stevens-Johnson Syndrome , corneal epitheliopathy, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy corneal dystrophy (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, corneal erosion or corneal abrasions (including recurrent corneal erosions or abrasions), ocular surface diseases, blepharitis, Graft-versus-host disease, meibomianitis, glaucoma, conjunctival laxity, keratopathy (herpetic keratopathy, filiform keratopathy) keratitis (including herpes simplex virus, keratopathy, zona, bullous keratopathy, lagophthalmos, etc.) keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, It is accompanied by one or more of the following symptoms in patients recovering from neuralgia, xerophthalmia, or neurotrophic keratitis.

[0078] In certain embodiments, the ocular surface pain or chronic ocular surface pain is caused by dry eye disease or Sjager's disease. In some embodiments of the methods described herein, the subject is A few cases after photorefractive keratectomy (PRK) or laser in situ keratomileusis (LASIK) surgery Patients have suffered from ocular pain that has lasted for at least 3 months.

[0079] In some embodiments, the subject is diagnosed with conjunctivitis, subconjunctival hemorrhage, subconjunctival scarring, conjunctival membrane, conjunctival Ulcer, punctate superficial epithelial erosion, epithelial defect, eyelid margin ulcer, eyelid margin keratinization, blepharocele, eyelid adhesion, Trichiasis, anterior blepharitis, lacrimal punctum obstruction, meibomian gland disease, corneal opacification, dry eye , bilateral eyelids, limbal stem cell failure, or corneal neovascularization.

[0080] In some embodiments, administration of a compound of formula I reduces ocular pain in a subject compared to a placebo. In some embodiments, the reduction in ocular pain in a subject is measured by a VAS score In some embodiments, the serotonin level is at least about 3 compared to placebo when measured above. administration results in a difference of at least about 4, as measured on a VAS score, compared to placebo; At least about 5, at least about 6, at least about 7, at least about 8, at least about 9 or results in a reduction in ocular pain in at least about 10 subjects. In some embodiments, administration is at least about 10%, at least about 15%, at least about 20%, or % or at least about 25% reduction in pain in the subject. The administration of the compound of formula I results in a reduction in pain in the subject as measured 7 days after administration. In some embodiments, the administration of the compound of Formula I results in a subject having This results in a reduction in pain.

[0081] In some embodiments, administration of the compound of formula I occurs about half an hour after administration, about one hour after administration, or about one hour after administration. After about 2 hours, about 2 hours, or about 2 to 4 hours, the subjects were compared with placebo as measured by VAS scores. In comparison, it results in a reduction in pain in the subject of at least about 2.

[0082] In some embodiments, the reduction in pain score is measured before and after administration of Compound I to a subject. This results from the difference in pain scores. In some embodiments, pain as measured by VAS The reduction in score results from the difference in pain scores before and after administration of Compound I to the subject. In some embodiments, the reduction in pain score occurs within about 30 minutes after administration of Compound I to the subject. In some embodiments, the reduction in pain score is about 1 hour after administration of Compound I to the subject. In other embodiments, the reaction occurs within about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours. In some embodiments, the reduction in pain scores occurs approximately 7 days after administration of Compound I to the subject. In one embodiment, the reduction in pain score occurs about 14 days after administration of Compound I to the subject.

[0083] In some embodiments, administration of a compound of formula I results in reduced ocular hyperplasia compared to placebo. In certain embodiments, administration of a compound of formula I results in: to result in reduced Grade 1, Grade 2, Grade 3, or Grade 4 hyperemia. In some embodiments, administration provides a response of at least about 1 on the McMonnies scale, at least A reduction in ocular hyperemia score of about 2, at least about 3, at least about 4, or at least about 5. Glass.

[0084] In some embodiments, administration of a compound of formula I provides a response to at least one question of the OPAS. an improvement in score of at least about 10%, at least about 20%, or at least about 30% relative to results.

[0085] In some embodiments, administration of a compound of formula I results in at least one visual task questionnaire. At least about 10%, at least about 20%, or at least about 30% of the questions Brings core improvements.

[0086] Therefore, in some embodiments, the present invention provides treatment for ocular hyperemia in a patient in need thereof. The method comprises administering to a subject an effective amount of a compound of formula I or a salt, solvate, polymorph or the like thereof. In some embodiments, the present invention relates to a method for administering a cocrystal to a subject. A method for reducing ocular redness in a subject in need thereof, comprising administering an effective amount of a compound of formula I or a salt, solvate, polymorph, or co-crystal thereof, In some embodiments, administration of Compound I provides a response of at least at least 1, at least 2, at least 3, at least 4, or at least 5 reduction in ocular redness. In some embodiments, the present invention provides a compound of formula I or Use of a pharma- ceutically acceptable salt, solvate or cocrystal thereof is provided. In one embodiment, the present invention provides an ophthalmologically compatible formulation at a concentration of about 0.5% w / v to about 3.5% w / v. The present invention provides for the administration of a compound of formula I to a subject in need thereof. The concentration for administration is about 0.5% w / v to about 3.5% w / v, about 0.5% w / v to Approximately 2.5%w / v, approximately 0.5%w / v~approximately 1.5%w / v, approximately 0.5%w / v~approximately 3.0 %w / v, approx. 1.0%w / v ~ approx. 2.5%w / v, approx. 1.5%w / v ~ approx. 3.0%w / v In certain embodiments, the range is from about 0.5% w / v to about 2.5% w / v. The concentration of the compound of formula I in the formulation for use is about 0.5% w / v, about 1.0% w / v, about 1. 0.5% w / v, about 2.0% w / v, about 2.5% w / v, about 3.0% w / v or about 3.5% It is understood that the percentages may be expressed in mg / ml. In some embodiments, the dose per administration per eye is about 0.15 to about 1.15 mg or about 0.15mg, 0.2mg, approx. 0.25mg, 0.3mg, approx. 0.35mg, approx. 0.4m g, about 0.45mg, about 0.5mg, about 0.55mg, about 0.6mg, about 0.65mg, Approximately 0.7mg, approximately 0.75mg, approximately 0.8mg, approximately 0.85mg, approximately 0.9mg, approximately 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 per administration per eye is about 0.18 mg, about 0.37 mg, or about 0.5 mg. g, about 0.55 mg, about 0.74 mg, or about 0.92 mg. The total daily dose per eye is about 0.5 to about 3.5 mg or about 0.5 mg to about 1.0 mg. g, 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 1 to 6 times per day, for example, 1, 2, 3 or 4 times per day. In some embodiments, the compound of formula I is administered to the subject four times. The subject is administered for a period of at least about one month, at least about two months, or at least about three months.

[0087] In some embodiments, the ocular congestion is caused by dry eye disease, Sjogren's syndrome, conjunctivitis ( keratoconjunctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), corneal epithelial basement membrane dystrophy , Acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, Keratoconus, Ocular pain syndrome, Stevens-Johnson syndrome, Corneal epitheliopathy, Corneal nerve Disorders (including LASIK-induced corneal neuropathy), corneal dystrophies (recurrent corneal dysplasia) rheumatoid arthritis, epithelial basement membrane dystrophy, corneal erosion or abrasion (recurrent Corneal erosion or abrasion), ocular surface disease, blepharitis, graft-versus-host disease, myocardial infarction, Conjunctivitis, glaucoma, conjunctival laxity, keratopathy (herpetic keratopathy, filamentous keratopathy, band-like or blister-like keratopathy) keratopathy (including lagophthalmos keratopathy), keratitis (including herpes simplex virus keratitis), iris inflammation, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia or In certain embodiments, the present invention relates to a patient recovering from neurotrophic keratitis. is associated with dry eye disease. So, eye redness can be treated with photorefractive keratectomy (PRK) or laser keratomileusis ( Lasts for at least three months after LASIK surgery.

[0088] In some embodiments, the ocular surface pain or chronic ocular surface pain is associated with dry eye disease. In some embodiments, administration of a compound of formula I reduces the symptoms of dry eye disease. Dry eye disease is generally characterized by inflammation of the ocular surface and lacrimal glands and poor tear quality. Dry eye is understood to be a complex, multifactorial condition characterized by a decrease in the amount of blood in the blood. Up to 30% of eye disease patients may have chronic eye disease, i.e., have had eye disease for at least 12 weeks or 3 months. The patient is believed to be suffering from ocular surface pain that persists for months. Thus, in some embodiments The present invention provides a method for treating dry eyes, eye discomfort, eye congestion, burning or stinging in the eyes, roughness or At least about 10% of the symptoms of dry eye disease, including one or more of: foreign body sensation or photophobia, The reduction may be at least about 15%, at least about 20%, or at least about 30%.

[0089] In some embodiments, the present invention provides a method for treating dry eye disease in a subject in need thereof. The method comprises administering to a patient an effective amount of a compound of formula I or a salt, solvate, polymorph, or co-crystal thereof. In some embodiments, the present invention relates to a method for treating a subject in need thereof, comprising administering to the subject The method of treating dry eye disease in a subject comprising administering to said subject an effective amount of a compound of formula I or its For a method comprising administering to a subject a salt, solvate, polymorph, or co-crystal of a compound of formula I The mixture may be aged for at least 2 months, at least 3 months, at least 4 months, or at least 5 months. In certain embodiments, the present invention provides a method for treating dry eye disease, comprising administering Use of compounds of formula I or pharma- ceutically acceptable salts, solvates or co-crystals thereof in therapy In some embodiments, the present invention provides a method for treating dry eye, eye discomfort, eye redness, eye pain, and eye discomfort. Dry eye symptoms including one or more of the following: burning or stinging sensation, roughness or foreign body sensation, or photophobia In some embodiments, the present invention provides a method for treating a patient suffering from a disease comprising administering to said patient at least about 10% of said symptoms. In an ophthalmologically compatible formulation at a concentration of about 0.5% w / v to about 3.5% w / v The present invention provides for administration of a compound of formula I to a subject. In some embodiments, the concentration for administration is The concentration is about 0.5% w / v to about 3.5% w / v, about 0.5% w / v to about 2.5% w / v, about 0.5%w / v ~ approx. 1.5%w / v, approx. 0.5%w / v ~ approx. 3.0%w / v, approx. 1.0% w / v ~ approx. 2.5% w / v, approx. 1.5% w / v ~ approx. 3.0% w / v, approx. 0.5% w / v ~ In certain embodiments, the formula in a formulation for topical use is in the range of about 2.5% w / v. The concentrations of compound I are about 0.5% w / v, about 1.0% w / v, about 1.5% w / v, and 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 per administration per eye is about 0.15 to about 1.15 mg or about 0.15mg, 0.2mg, approx. 0.25mg, 0.3mg, approx. 0.35mg, approx. 0.4m g, about 0.45mg, about 0.5mg, about 0.55mg, about 0.6mg, about 0.65mg, Approximately 0.7mg, approximately 0.75mg, approximately 0.8mg, approximately 0.85mg, approximately 0.9mg, approximately 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 per administration per eye is about 0.18 mg, about 0.37 mg, or about 0.5 mg. g, about 0.55 mg, about 0.74 mg, or about 0.92 mg. The total daily dose per eye is about 0.5 to about 3.5 mg or about 0.5 mg to about 1.0 mg. g, 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 1 to 6 times per day, for example, 1, 2, 3 or 4 times per day. In some embodiments, the compound of formula I is administered to the subject four times. The subject is administered for a period of at least about one month, at least about two months, or at least about three months.

[0090] In some embodiments of the methods described herein, the administration of a compound of formula I is Compared with the 10-year-old boy, best corrected visual acuity, slit-lamp biomicroscopy, mydriatic examination, blink rate, and tear production were significantly improved. does not result in a change in one or more of the following: In some embodiments of the methods described herein, the compound of formula I is Administration of the compound reduced the delay in wound healing compared to placebo in patients in need. Does not cause.

[0091] Patient population In certain embodiments, the subject to be treated by the methods described herein is , suffering from an ocular surface disorder. Non-limiting examples of ocular surface disorders include chronic ocular surface pain (COS) and chronic ocular surface pain (COS). OSP), dry eye disease, Sjogren's syndrome, conjunctivitis (keratoconjunctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), corneal epithelial basement membrane dystrophy, Acanthamoeba, fibromuscular pain, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (LASIK-induced corneal neuropathy), corneal dystrophies (including recurrent corneal dystrophies), epithelial basal Membrane dystrophy, corneal erosion or abrasion (recurrent corneal erosion or abrasion (including wounds), ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, glaucoma, conjunctival laxity keratopathy (including herpetic keratopathy, filamentous keratopathy, band or bullous keratopathy, and lagophthalmos keratopathy) keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, Recovering from idiopathic sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia or neurotrophic keratitis In some embodiments, the subject is a patient undergoing laser photorefractive keratectomy. At least 3 months after PRK or LASIK surgery The patient has suffered from persistent eye pain for many years.

[0092] In certain embodiments, the methods provided herein are directed to treating ocular surface pain, such as acute ocular surface pain. The present invention is intended to treat or reduce the

[0093] In certain embodiments, the methods provided herein are directed to treating chronic ocular surface pain (COSP), etc. In certain embodiments, the COSP is Persistent symptoms that may distract or interfere with normal daily activities The condition is characterized as persistent ocular surface pain (e.g., persistent severe ocular surface pain). In some cases, COSP may result in an inadequate quality of life and persists for at least 1 month. At least 2 months, at least 3 months, at least 4 months, at least 5 months or less In some embodiments, the COSP lasts for at least about 2 months or at least about 6 months. In other embodiments, the COSP may last for at least about 3 months. In certain embodiments, subjects with COSP may have symptoms that persist for at least four months. For a certain disease (e.g., ocular surface disorders such as dry eye disease or Sjögren's syndrome) Symptoms persist despite compliance with other therapy as indicated.

[0094] In some embodiments, the subject to be treated is a patient suffering from ocular neuropathic pain (ONP). ONP is an ocular disorder that may result from an injury or disease affecting the nerves, e.g., the corneal nerves. ONP is a group of disorders that cause pain in the eyes. Symptoms of ONP include eye pain, sensitivity to light, hyperalgesia or dry eyes. Abnormal sensations (paresthesia) such as dryness, tingling, or a foreign body sensation, in response to stimuli that normally do not cause pain This may include a disorder of the pain caused by the schizophrenia (allodynia). Pain medications may be used to dull the sensation of sensory nerve stimuli or nerve stimuli.

[0095] In some embodiments, the subject to be treated is suffering from lagophthalmos. EK is damage to the cornea that primarily results from prolonged exposure of the ocular surface to the external environment. EK can result in permanent vision loss from ulcers, microbial keratitis, and scarring. Patients at risk for K include those with incomplete eyelid closure (e.g., lagophthalmos, exophthalmos, lid closure) position of the eye), insufficient blink reflex, insufficient blink rate (e.g., neurological disorders, e.g., Parkinson's disease, caused by neuromuscular diseases) and / or the protective lubrication of the cornea Patients with conditions that impair the cornea's ability to protect itself, either through Symptoms of EK include a foreign body sensation, burning sensation, increased tearing, and intermittent blurred vision (unstable vision). Symptoms include dry eye (caused by poor tear film), pain, and photophobia. Standard treatment is a nighttime lubricating ointment. Frequent use of artificial tears and punctal plugs.

[0096] In some embodiments, the subject to be treated is suffering from keratoconjunctivitis. Conjunctivitis is an inflammatory process involving both the conjunctiva and the cornea. Inflammation of the superficial layers of the cornea (keratitis) It commonly occurs, for example, in association with viral and bacterial conjunctivitis in adults. The following types of conjunctivitis are distinguished based on the underlying cause of the inflammation: Keratoconjunctivitis sicca is caused by inflammation resulting from dryness; · Vernal keratoconjunctivitis (VKC) is seasonal and thought to be allergen-induced; Atopic keratoconjunctivitis is one manifestation of atopy; Epidemic keratoconjunctivitis or adenoviral keratoconjunctivitis is caused by adenovirus infection. Rubbed; Infectious bovine keratoconjunctivitis (IBK) is caused by the bacterium Moraxella bovis. bovis, a disease that affects cattle; Pink eye in sheep and goats is mainly caused by Chlamydophila pecorum. dophila pecorum); · Superior limbic keratoconjunctivitis is thought to be caused by structural trauma; Keratoconjunctivitis Electric ophthalmia (Arc Eye) refers to inflammation caused by photoconductive UV light. Taste.

[0097] In some embodiments, the subject to be treated is suffering from dry eye. As used herein, the term "dry eye" refers to insufficient tear production and / or abnormal tear production. Dry eye syndrome, keratoconjunctivitis sicca or keratitis sicca, or tear dysfunction Dry eye syndrome (DEDS), also known as dry eye syndrome or burning eye syndrome, is a condition characterized by dry eye. Dry eye is characterized by a loss of tear film homeostasis. Discomfort due to potential damage to the ocular surface with accompanying ocular symptoms, visual disturbances, tear film instability It is a multifactorial disorder of the tears and ocular surface that results in a range of clinical symptoms, including tear film instability and hypercalcaemia. Osmotic pressure, ocular surface inflammation and injury, and neuroparesthesia play a pathogenetic role. (Craig JP,et al.,The Ocular Surface 2017 ;15:276-83). It is accompanied by increased tear film osmolality and inflammation of the ocular surface. Dry eye disorder can range from mild to moderate to severe. Symptoms of Lyme syndrome include roughness, foreign body sensation, burning sensation, photophobia and decreased vision. Tearing, stinging, itching, gritty or rough feeling, eye discharge, frequent blinking, pus or crust on eyelashes redness, blurred or oscillating vision (usually worse when waking up), (worsened when watching television, driving or playing video games), photosensitivity, eye pain and / or Other symptoms include headaches, eyelid heaviness, and eye strain. Causes of dry eye disease include: These include, but are not limited to: unknown cause, congenital anlacrimation, xerophthalmia, tear Gland resection and sensory denervation; rheumatoid arthritis, Wegener's granulomatosis and systemic lupus erythematosus collagen vascular disease including vascular degeneration; Sjogren's syndrome and autoimmune diseases associated with Sjogren's syndrome Immune disorders; lipid tear film abnormalities caused by blepharitis or rosacea; Vitamin A deficiency Mucinous tear film abnormalities caused by trachoma, diphtheria keratoconjunctivitis, skin mucosa membrane disorder; aging; menopause; and diabetes. Dry eye symptoms as defined herein and and / or symptoms may be precipitated by other conditions, including but not limited to: Possible causes: visual work for long periods of time; computer work; exposure to dry environments; hot air or cold air or air currents; seasonal changes; eye irritation; contact lenses, LASIK and others refractive surgery; fatigue; and isotretinoin, sedatives, diuretics, tricyclic antidepressants, antihypertensives Medicines, oral contraceptives, antihistamines, nasal decongestants, beta-blockers, phenothiazines, atothiazines, Drugs such as pain relieving opiates such as morphine and morphine.

[0098] Diagnostic tests for dry eye include, for example, the cotton swab or, more specifically, the Cochet- Assessment of corneal sensation using a Bonnet aesthesiometer (corneal hypersensitivity and / or hyposensitivity were evaluated) may be present in severe and chronic dry eye disease); e.g., preservative-free Fluorescein-impregnated strips or fluorescein drops moistened with saline solution were used. Measurement of tear film breakup time using a more objective computerized method that does not require For example, staining of the ocular surface with sodium fluorescein, rose bengal, or lissamine green Performing the Schirmer test (relatively insensitive for patients with mild dry eye) ); test for delayed tear clearance; tear meniscus height; measurement of MMP-9 levels MMP-9 has been shown to be elevated in the tears of patients with dry eye disease. and levels correlate with test results in patients with moderate to severe dry eye) ;Measurement of tear osmolality and tear film interferometry;Performance of Sjo test ( Serum SS-A (anti-Ro) and SS-B (anti-La) antibodies, salivary gland protein 1 (SP- 1), carbonic anhydrase 6 (CA6) and parotid secretory protein (PSP), SP-1, CA 6 and PSP detection).

[0099] Artificial tears, lubricating ointments, corticosteroids (e.g., loteprednol 0.4 times daily) Prescription medications include cyclosporine, rifabutin, and cyclosporine. Fitegrast, diquafosol, levamepidol, corticosteroids (e.g., four times a day) Loteprednol 0.5% eye drops.

[0100] The term "tear film dysfunction" refers to when the tear film is disrupted at different locations on the cornea and conjunctiva. This condition causes not only symptoms of irritation, but also unstable and intermittent fluctuations in vision. For example, dry eye syndrome is characterized by tear film dysfunction. Symptoms include tearing, burning, stinging, itching, a gritty or rough feeling, tingling or itching. symptoms include foreign body sensation, eye discharge, frequent blinking, pus or crusting of the eyelashes (usually worse when waking up), Redness, blurred or trembling vision (when reading, using a computer, watching television, driving or playing video games) Symptoms include: sensitivity to light, eye pain and / or headache, heavy eyelids, and eye strain. Can be obtained.

[0101] Adenoviral keratoconjunctivitis, also known as epidemic keratoconjunctivitis, is a common and highly contagious Adenoviral keratoconjunctivitis is a viral infection of the eye. The clinical course of adenoviral keratoconjunctivitis involves the cornea. It is divided into an acute stage with various degrees of conjunctival inflammation with or without corneal opacity and a chronic stage with corneal opacity. can be done.

[0102] Vernal keratoconjunctivitis (VKC) is characterized by severe itching, photophobia, foreign body sensation, and mucoid discharge from the eye ("sticky" blepharospasm, ocular palsy, characterized by symptoms of blepharospasm and blurred vision It is an atopic condition of the outer surface (Buckley, RJ, Int Ophthalm ol Clin,1988 28(4):p.303-8;Kumar,S.,Acta Ophthalmologica, 2009.87(2):p.133-147). It is usually bilateral, but may be asymmetric in nature. It typically affects young males in dry climates; 23% of patients have a perennial form. (Kumar, S., Acta Ophthalmologica, 2009. 87(2):p.133-147;Bonini,S.,et al.,Ophthal biology, 2000.107(6):p.1157-63).

[0103] The manifestations of VKC can be divided into conjunctival, limbal and corneal manifestations: Conjunctival signs include diffuse conjunctival hyperemia and discrete upper tarsal lesions measuring more than 1 mm in diameter. Giant papillae are mentioned; Limbal signs include thickening and opacification of the limbal conjunctiva and the appearance and occasional appearance of gelatinous material. The peripheral limbal Horner-Trantas points are Localized limbal white spots consisting of degenerated epithelial cells and eosinophils (Buckley, R .J.,Int Ophthalmol Clin,1988 28(4):p.303 -8); Corneal manifestations vary depending on the severity of the disease process and may include large erosions, corneal ulcers and scarring. (Buckley, RJ, Int Ophthalmol Clin, 19 88 28(4):p.303-8).

[0104] Patients with active VKC (photophobia, papilla on the superior tarsal conjunctiva, or clearly visible corneal limbus on examination) ocular discomfort (defined as moderate to severe ocular discomfort including Horner-Trantas points) showed a marked increase in symptoms and signs of superficial disease. Patients with inactive VKC (asymptomatic or Mild discomfort and no corneal abnormalities during testing) were not associated with photophobia, conjunctival rhinitis, or Increase in the samine green staining and Schirmer test values ​​and the fluorescein breakdown time (B The syndrome was associated with decreased tear film stability, epithelial cell integrity, and corneal sensitivity. Abnormalities in the function of the corneal nerve and corneal nerve were observed at all stages (progression and resting state). It appears that the ocular surface is affected by the ne(Baltimore).2015 Oct;94(42):e1648).

[0105] The following factors are thought to play a role in VKC: IgE released from mast cells; activated eosinophils; by leukocytes, monocytes and neutrophils and immune regulators such as IL-4, IL-5 and bFGF. The response is mediated through CD4 T-helper-2-driven IV hypersensitivity (Buckl ey,RJ,Int Ophthalmol Clin,1988 28(4):p .303-8;Kumar,S.,Acta Ophthalmologica,200 9.87(2):p.133-147;La Rosa,M.,et al.,Ital J Pediatr,2013.39:p.18).

[0106] Treatment consists of cold compresses and irrigation of the eyelids, saline eye drops, topical antihistamines, Nonsteroidal anti-inflammatory drugs or corticosteroids, e.g., low-absorption corticosteroids ( Fluorometholone, loteprednol, rimexolone, etc.), local mast cell stabilizers ( lomolyn sodium, nedocromil sodium and lodoxamide), topical cyclosporine -A or tacrolimus may help relieve symptoms. and E.Toker,Cornea,2013.32(8):p.1149-54; Vichyanond, P. and P. Kosrirukvongs, Curr Al. lergy Asthma Rep,2013.13(3):p.308-14;Bar ot,RK et al.,J Clin Diagn Res.2016 Jun;1 0(6):NC05-9;Wan Q et al., Ophthalmic Res. Please see 2018;59(3):126-134.

[0107] Atopic keratoconjunctivitis (AKC) usually develops before age 10, whereas VKC usually develops between ages 20 and 30. The age of onset is 50 years older. Conjunctival involvement is classically seen in VKC, with the upper tarsal plate and A In KC, it occurs at the lower tarsal plate. AKC is usually more chronic in nature and more commonly occurs at the cornea. It causes membranous and conjunctival scarring.

[0108] Sjögren's syndrome (Sjögren's syndrome with dry eye) is a condition that often causes severe dry eye. Characterized by dysfunction of exocrine glands, including the salivary and lacrimal glands, causing rheumatoid arthritis It is a chronic inflammatory disorder. The main symptoms are dry eye (keratitis sicca or keratoconjunctivitis sicca) and Severe dry eye can lead to corneal pain, scarring, ulcers, infection, and The differential diagnosis is adult blepharitis, dry eye disease, and juvenile blepharitis. Arthritis of unknown etiology, uveitis, and keratopathy, e.g., superficial punctate keratopathy, fibrous keratopathy Sjögren's syndrome includes conditions such as keratopathy, neuropathic keratopathy, and lagophthalmos. To maintain the integrity of the tear film by preserving, enhancing and / or replenishing insufficient tear secretion Therefore, treatment for Sjögren's syndrome includes artificial tears and lubricating ointments; Autologous serum eye drops; oral omega-6 essential fatty acids; fluid- and gas-permeable scleral lenses; topical corticosteroids; punctal occlusion to reduce tear drainage; small lateral tarsorrhaphy surgery; humidification of environment; hydrophilic bandage lens; bromhexine and 3-isobutyl-1-methyl Tiruxanthine (IBMX) (increases tear production / secretion); a drug that stimulates muscarinic receptors agents (pilocarpine and cevimeline); immunosuppressants, e.g., methotrexate, antimalarials; anti-inflammatory drugs, cyclophosphamide, leflunomide or tumor necrosis factor (TNF), e.g. Liximab, a monoclonal antibody against TNF-alpha; cyclosporine A; Examples of such contact lenses include:

[0109] Stevens-Johnson syndrome (SJS) is a skin emergency or a rash affecting one entire surface area of ​​the skin. One type is characterized by the presence of vesicular lesions of the epithelium and mucosa that involve less than 0.0% of the It is a severe skin reaction. Early symptoms of SJS include fever and flu-like symptoms. This may precede or occur simultaneously with the development of a macular rash involving the torso and face. As the skin grows, the patches gather and the involved areas develop into blisters, eventually resulting in loss of the epithelial layer. During the acute phase of SJS-TEN, 80% of patients will have ocular complications. .

[0110] High fever (>102.2), fatigue, joint pain, macular rash involving the body, neck and face, and new medications A constellation of recent history of exposure to a substance or recent dose increase of current medication is the indicator used to diagnose SJS. A skin biopsy of the affected area is required to confirm the diagnosis. Granulysin can be used as a marker for the diagnosis of SJS. Granulysin levels in blister fluid correlate with the severity of acute SJS (C hung WH,et al.Nat Med.2008;14(12):1343-5 0).

[0111] Eye symptoms in SJS include conjunctivitis, subconjunctival hemorrhage, subconjunctival scarring, conjunctival membranes, and conjunctival Ulcer, punctate superficial epithelial erosion, epithelial defect, eyelid margin ulcer, eyelid margin keratinization, blepharocele, eyelid adhesion, Trichiasis, anterior blepharitis, lacrimal punctum obstruction, meibomian gland disease, corneal opacification, dry eye These include corneal hyperplasia, limbal stem cell failure, and corneal neovascularization. The artificial tears are saline eye drops, preservative-free artificial tears, and other solutions that provide adequate lubrication and irritation to the epithelium. Patients with any corneal or conjunctival epithelial defects should be treated with prophylactic Treated with topical antibiotics, preferably fourth generation fluoroquinolones. Mild or moderate Ocular complications (less than one third of eyelid margin complications, conjunctival defects less than 1 cm in maximum diameter and corneal Patients with glaucoma (no epithelial defect) are usually treated with topical moxifloxacin 0.5% four times a day and topical moxifloxacin 0.5% four times a day. Cyclosporine 0.05% twice daily and topical steroids (prednisolone 4-8 times daily) Severe or very severe, the condition is treated with 1% bronchodilator or 0.1% dexamethasone twice daily. ocular complications of more than one-third of the eyelid margin, conjunctival defects of more than 1 cm, and corneal epithelial defects of more than 1 cm Patients with pulmonary septal defect (PSD) receive amniotic membrane (AM) transplantation in addition to the above treatment.

[0112] In some embodiments, the subject to be treated is suffering from corneal epitheliopathy. Corneal epitheliopathy is a condition involving the corneal epithelium that manifests itself in alterations of the corneal epithelial barrier function. It is a disease that occurs

[0113] In some embodiments, the subject to be treated is a patient suffering from corneal neuropathy or corneal neuralgia. Corneal neuropathy or corneal neuralgia is caused by the loss of nerve and sensory fibers in the cornea. It is a disorder involving corneal pain caused by injury. One example of corneal neuropathy is LA SIK-induced corneal neuropathy. Corneal neuropathy is generally diagnosed by dry eye testing. Although the causes and risk factors are still unclear, dry eye-like symptoms, Patients with increased corneal sensitivity and changes in corneal nerve morphology, but without signs of dryness, may have corneal nerve dysfunction. May suffer from menstrual disorders.

[0114] In some embodiments, the subject to be treated is suffering from an ocular surface disease or disorder. The term "ocular surface disease" or "ocular surface disorder" refers to abnormal ocular lid anatomy or function. This can be caused by a variety of abnormalities, including abnormal or altered tear production or composition and associated asymptomatic manifestations. Many diseases can cause ocular surface disorders. Patients with surface lesions may present with clinical signs common to several diseases and may be chronic. punctate keratopathy, filamentous keratopathy, recurrent corneal erosion, bacterial conjunctivitis, culture-negative conjunctivitis, cicatricial conjunctivitis May include adult (cicatricial) conjunctivitis, persistent epithelial defects, infectious keratitis, corneal melting, and ocular surface failure The most common ocular surface disorders are tear film abnormalities and / or dysfunction of the glands in the eyelids ("blepharitis"). )

[0115] In some embodiments, the subject to be treated is a patient suffering from neurotrophic keratitis or neurotrophic keratitis. Neurotrophic keratopathy (NK) is a condition that affects the cornea. It is a degenerative corneal disease characterized by reduced or absent corneal sensitivity. Corneal innervation via the cornea is impaired. Corneal sensory innervation is impaired in NK. Patients usually do not complain of ocular surface symptoms. However, blurred vision may be due to irregular epithelium or epithelial defects. NK may be reported due to primary edema (PED), scarring, or edema. Stage II NK is the most common. Stage II is defined by recurrent or persistent epithelial defects in the upper half of the cornea. One treatment that can be used in NK involves topical nerve growth factor. Patients usually Due to remodeling of the retina, patients experience pain during treatment with NGF.

[0116] In some embodiments, the subject to be treated is suffering from blepharitis. Eyelid inflammation is an inflammatory condition of the eyelid margin that manifests as persistent changes or superficial keratopathy in the eyelid margin. This can cause vision loss, corneal neovascularization and ulceration. Therefore, blepharitis can be divided into anterior and posterior. Anterior blepharitis affects the eyelid skin, the base of the eyelashes and the eyelids. It affects the eyelash follicles and includes the traditional classification of staphylococcal and seborrheic blepharitis. It affects the meibomian glands and their orifices, and the primary cause is meibomian gland dysfunction. Symptoms of blepharitis include redness, burning sensation, irritation, tearing, eyelid crusting and sticking, and visual disturbances such as photophobia and blurred vision. Long-term symptom management involves a daily eyelid washing routine and prevention of infection and inflammation. Treatments may include the use of therapeutic agents that reduce the oral antibiotics, such as tetracycline antibiotics; Biological substances (tetracycline, doxycycline, minocycline) or macrolide antibiotics Biologics (erythromycin, azithromycin); topical steroids, e.g., corticosteroids Steroids, eg, loteprednol etabonate, fluorometholone; tobramycin / Antibiotics such as dexamethasone or tobramycin / loteprednol and corticosteroids topical combinations of cyclosporine and cyclosporine 0.05%.

[0117] In some embodiments, the subject to be treated is suffering from meibomian gland dysfunction. The meibomian glands are involved in the production of meibum, an oily substance that prevents evaporation of the eye's tear film. It is a holocrine exocrine gland located in the peripheral area of ​​the eyelid inside the tarsal plate. Meibomian gland dysfunction (MGD), also known as blepharitis or inflammation of the meibomian glands, is a Myopathy is generally characterized by terminal duct obstruction and / or qualitative / quantitative changes in glandular secretions. It is a chronic diffuse abnormality of the Baumian gland (Nelson JD, et al., Inve st Ophthalmol Vis Sci 2011;52:1930-7). can cause alterations of the tear film, eye irritation, clinically significant inflammation and ocular surface disease. D often causes dry eyes and can contribute to blepharitis. In addition, topical steroids and topical / oral antibiotics are also prescribed to reduce inflammation. Intense Pulsed Light (IPL) therapy or other devices that apply heat and pressure to activate the glands Mechanical treatments (e.g., LipiFlow) reduce inflammation and improve glandular function in patients. It has also been shown to be beneficial.

[0118] In some embodiments, the subject to be treated is suffering from graft-versus-host disease. Graft-versus-host disease (GVHD) is an inflammatory disease that is unique to allogeneic transplants. Even if the donor and recipient have identical HLA, Acute graft-versus-host disease usually occurs within the first three It develops over a period of months and may involve the skin, intestine, or liver. Steroids are the standard treatment. Chronic graft-versus-host disease may also develop after allogeneic transplantation. In addition to inflammation, chronic graft-versus-host disease is a major cause of late complications. It may cause the development of fibrosis or scar tissue, similar to other autoimmune diseases, and may be functional. It may result in disability and the need for long-term immunosuppressive therapy.

[0119] In some embodiments, the subject to be treated is afflicted with ocular graft-versus-host disease. GVHD occurs in patients who have undergone allogeneic blood stem cell transplantation. It may occur in patients with chronic or chronic GVHD, but Approximately 40-90% of patients with chronic GVHD have ocular Ocular symptoms include moderate to severe keratoconjunctivitis sicca, bilateral peripheral keratoconjunctivitis, and Treatment may include ocular ocular inflammation, ocular ocular inflammation, anterior uveitis, corneal ulcers, or neovascularization. topical lubricants, including artificial tears, autologous serum tears and other topical and systemic immunosuppressive treatments; Sex steroids; topical cyclosporine 0.5%. EXAMPLES

[0120] The following examples are included to demonstrate non-limiting embodiments of the invention.

[0121] Example 1. First-in-human study of Compound I for safety and pharmacokinetic assessment This example describes a first-in-human study of Compound I conducted in healthy volunteers. 54 subjects were given the study drug. Part 1 of the first-in-human study included 0.15%, 1. Single ascending doses of Compound I were administered via eye drops at 5%, 2.5% w / v (1 drop).

[0122] In Part 2 of Compound I, (i) 1% at 0.15%, 1.5%, or 2.5% for 7 days drops four times daily (every 6 hours), or (ii) 2.5% 1 drop eight times daily for 7 days. Tested in multiple ascending doses (MAD) administered as (supratherapeutic) eye drops (every 3 hours) did.

[0123] Part 3 was a sensory assessment to evaluate the anesthesia properties of Compound I. Part 3 consisted of Compound I, vehicle, and tetracaine (0.5% ophthalmic solution, used as a positive control). ) and diclofenac sodium (0.1% ophthalmic solution, active NSAID comparator The study had four arms using ophthalmoplegics (used as a sedative). It was chosen for its numbing effect, which was not considered to be a standard procedure due to its adverse effects on wound healing. NSAIDs are the current standard of care for corneal pain after PRK and are used with minimal It is numbing but has significant pain control properties. To better determine the potential numbing effect, To allow for this, vehicle eye drops were used as a negative control. Twelve people who met the eligibility criteria The healthy subjects received a single eye drop on each of four different study days (Days 1, 4, 7, and 10). Subjects were randomized to receive one of four study treatments. Each subject received one of four sequences: Patients were randomized to receive one of the study treatments. Sequence 1: Anesthesia, NSAID, Compound I 2.5%, Vehicle Sequence 2: NSAID, vehicle, numbing agent, Compound I 2.5% Sequence 3: vehicle, Compound I 2.5%, NSAID, numbing agent Sequence 4: Compound I 2.5%, numbing agent, vehicle, NSAID

[0124] Safety Assessment: The safety assessment included all adverse events, including systemic and ocular events. Adverse events (AEs) and serious adverse events (SAEs) were assessed according to their severity and study drug The systemic safety assessment consisted of collecting data from the study centre along with the Regular monitoring of hematology, blood chemistry and urinalysis performed at the hospital, as well as physical examination, vital signs, (systolic and diastolic blood pressure, pulse rate and temperature), ECG, pregnancy and infertility assessment and The assessment included periodic assessment of 49°C hand immersion testing during the MAD part. Assessment includes Early Treatment Diabetic Retinopathy Study (ETDRS), visual acuity, intraocular pressure, and slit lamp. This included biomicroscopy, corneal staining, and dilated fundus examination.

[0125] Subjects were selected based on the inclusion and exclusion criteria described below.

[0126] Selection criteria: Written informed consent was obtained prior to all assessments. Determined at screening based on medical history, physical exam, vital signs, ECG and laboratory tests Healthy male and female subjects aged 18 to 50 years (inclusive) who were in good health at the time of the study. At screening and baseline, subjects were required to sit and stand for at least 3 minutes After 3 minutes in the sitting position, vital signs (systolic and diastolic blood pressure (BP) and pulse rate) were recorded. Sitting vital signs were required to be within normal ranges as follows: ·Oral body temperature 35.0~37.5℃ Systolic blood pressure 90-150mmHg (SBP) Diastolic blood pressure 50-90mmHg (DBP) Pulse rate: 40-100 bpm Subjects must weigh at least 50 kg and be aged 18-24 years to participate in the study. Participants were required to have a body mass index (BMI) within the range of 9 kg / m2. BMI = body weight (kg) / [Height (m)] 2 Communicate with the investigators sufficiently to understand and comply with the requirements of the study The subject for which this was possible. In part 3, the subject's baseline level of ocular perception was measured using the Cochet-Bonnet aesthesiometer. should have been within the range of 50-60 mm (inclusive) when

[0127] Exclusion criteria: All women of physiological reproductive potential unless they are using an effective method of contraception at the time of study treatment Women of childbearing potential are defined as any woman who is In the opinion of the investigator and based on the contents of the Investigator Brochure, the safe administration or Any medical condition (systemic or ocular) that may prevent safe participation in this study. The target. Part 3 (perceptual measurement): whether they had worn contact lenses at the time of the test or for the past 3 years The subjects who had been using contact lenses for a long time were asked to minimize the variability of corneal sensitivity caused by contact lens use. were excluded because History of any eye surgery or laser within the past 6 months prior to screening. History of any chronic eye disease other than primary cataract, strabismus or anisometropic amblyopia. Acute eye disease (e.g., infection, corneal abrasion, or allergy) within the past 6 months of screening Subjects with a medical history were eligible as long as their disease was not active. Any currently active eye condition that required the use of topical eye drops. Subjects using continuous positive airway pressure devices or other sleep apnea devices.

[0128] Safety Results from First-in-Human Studies Based on the results from parts 1, 2, and 3, the maximum tolerated dose (MTD) was The maximum feasible concentration was identified as 2.5% taken eight times daily. Dose-limiting adverse events were: No adverse events were identified at this dose level. All cases were of moderate severity leading to treatment discontinuation in one patient in the 2.5% qd cohort. All adverse events except eye irritation were mild in severity. The SAD study produced placebo-like levels of corneal staining, hyperemia, and mild anterior chamber inflammation. A summary of adverse events from the study is shown in Table 1.

[0129] [Table 1]

[0130] A summary of adverse events from the SAD trials is shown in Table 2.

[0131] [Table 2]

[0132] In the hand immersion test, all subjects in the treatment cohort were exposed to 49 The subjects were then removed from the water at 37 °C. No subjects lasted longer than 22 seconds and were treated with Compound I and vehicle. No significant change in immersion time was observed between treated subjects. Results suggest that it does not alter the elephants' temperature perception.

[0133] Perceptual Measurement Test (Part 3) In the first-in-human study, a sensory measurement test, i.e., the time when the corneal tactile threshold was perceived, was performed. The potential anesthesia effect of topical ophthalmic 2.5% Compound I was assessed by measuring filament length (cm). Further evaluated.

[0134] Tetracaine 0.5% has been shown to have a numbing effect with a duration of action of approximately 10 minutes. Analysis of the results showed that the positive control was As expected based on the above, both diclofenac 0.1% and the vehicle had a significant effect on the cornea. Compound I 2.50% did not have a paralytic effect at any time point after treatment. It had no paralyzing effect.

[0135] For measures of corneal sensitivity, statistical analysis was performed comparing least squares means (test vs. reference) for: Statistical and clinical significance was observed. Tetracaine 0.5% (N=12) vs. vehicle ( N=12), Tetracaine 0.5% (N=12) vs. diclofenac at 2.5, 10, and 20 minutes after administration Fenac 0.1% (N=12), Compound I 2.5% (N=11) vs. tetracaine 0.5% at 2.5 and 10 minutes post-dose %(N=12)

[0136] The differences in corneal sensitivity between Compound I 2.5% and vehicle all had p-values ​​of 0.395 or greater. No adverse events were observed at the scheduled time points up to 30 minutes after administration. When compared to a positive control (a drug with a numbing effect) and a vehicle (placebo), 2. The lack of anesthesia effect of 5% Compound I was demonstrated.

[0137] Pharmacokinetic summary from first-in-human studies Compound I 0.15%, 1.5% and 2.5% topical ophthalmic suspensions, both single and multiple doses Following administration of the agent, there was rapid absorption and low concentrations of Compound I into the systemic circulation with moderate variability across subjects. Plasma PK profiles demonstrated that a range of exposures was achieved, from 0.15% to 2 Dose escalation to 0.5% resulted in a less than dose-proportional increase in systemic exposure. Accumulation of substance I was minimal (approximately 1.5%–2.5% suspension) after administration of the 0.15%, 1.5%, or 2.5% suspension four times daily. The effect was 1.7-fold higher after 2.5% 8 doses per day for 7 days, and was only slightly higher (approximately 1.3-fold higher) after 2.5% 8 doses per day for 7 days.

[0138] Example 2. Clinical Trial of Compound I for the Treatment of Post-Surgical Pain In this example, the patient presented with postoperative ocular pain after photorefractive keratectomy (PRK) surgery. Compound I (4-(7-hydroxy-2-isopropyl-4-oxo-4 Clinical trials of H-quinazolin-3-yl-benzonitrile are described.

[0139] [Table 3]

[0140] Test Design The study was conducted to evaluate the efficacy and safety of cyclosporine administered as eye drops in addition to standard of care in patients after PRK surgery. This was a proof-of-concept, double-blind, randomized, vehicle-controlled study of Compound I. This is an outpatient procedure in which the corneal epithelium is removed under local anesthesia using abrasion to expose the stroma. Compound I was administered in one eye from immediately after surgery (time 0) until the final administration 72 hours later. 2.5% (25 mg / ml, 0.925 mg / drop) administered four times daily (every 6 hours) ) It was administered as a single eye drop.

[0141] Vehicle administration was performed in one eye four times daily (6 h) from immediately after surgery (time 0) until the final administration at 72 h. The infusion was a single dose administered per 100 mg dose.

[0142] The study consisted of two treatment periods using a crossover design. Patients were randomized to Patients underwent PRK surgery in one eye on a separate occasion. Subjects were randomized to receive either Compound 1 or vehicle according to Procedure 2.

[0143] Forty patients were randomly assigned to receive either Compound I in period 1, followed by vehicle or Patients were randomized 1:1 to vehicle in period 1 followed by Compound I in period 2. One drop was administered four times daily for 72 hours after PRK surgery in the study eye (Day 1, Periods 1 and 2 The first study eye was the non-dominant eye identified at screening with the consent of the patient and the investigator. Patients were followed up on days 2, 3, 4, and 8 of period 1 after surgery in the first eye. Optional daily follow-up visits to follow up patients until wound healing is complete. If any complications were noted, a second eye surgery was not performed.

[0144] The patient underwent PRK surgery in his second study (dominant) eye on day 1 of period 2. PRK surgery was performed after repair of the epithelial defect in the first eye at the discretion of the investigator. After surgery, patients received the treatment four times a day for 72 hours. Daily for 3 days (period 2, days 2-4) and 1 week after the second surgery (period 2, day 8) The patient returned to the hospital for optional daily follow-up visits until wound healing was complete. The end of study (EOS) visit was 30 days after surgery on the second eye (or if patients discontinued surgery early in Period 1). After the last dose of study drug (if treatment was terminated),

[0145] All patients were randomly assigned to receive the PRK test during periods 1 and 2 of the study, after the PRK procedure and before receiving the pain test drops. Bandage contact lenses (Air Optix® Night and Day Patients received standard of care treatment, including application of test drops of 100 mg / kg of erythritol iodide (or equivalent). After application of the first dose, topical ophthalmic antibiotics (moxifloxacin or equivalent) were administered 4 times daily. The course of prednisolone acetate was started and continued for 4-7 days. One drop of ophthalmic solution was administered four times daily, followed by tapering. Preservative-free units were administered as needed. Dosage Artificial tears were used. The first dose of test drops after each PRK procedure was administered by the site staff. Subsequent doses were self-administered. There was a 5-minute gap between the administration of eye drops in the sequence. In summary, patients underwent PRK procedures and a bandage lens was placed on the cornea. Compound I or vehicle was administered, followed approximately 5 minutes later by antibiotics, and then 5 minutes later by Minutes later, prednisolone was administered.

[0146] Rescue medication is up to 10 tablets / day or 1-2 tablets every 4 hours orally as needed. It consisted of painkillers (acetaminophen 300mg + codeine 30mg).

[0147] Additional study treatment All patients received standard of care adjunctive treatment after PRK surgery, including: Bandage contact lenses (Air Optix® Night and Day® Aqua or equivalent) Immediately after PRK surgery and after application of the first dose of test eye drops, topical ocular antibiotics (moxibustion) were administered. Start a course of floxacin or equivalent eye drops (1 drop 4 times a day) and administer 4-6 mg of floxacin or equivalent eye drops as directed by your doctor. It continued for 7 days. Prednisolone acetate eye drop: 1 drop immediately after PRK surgery and after instillation of antibiotic eye drops The treatment was initiated four times daily for one week after PRK and then tapered according to local procedures. . Preservative-free unit dose artificial tears were used as needed. Artificial tears are used for analgesic purposes. The mixture was not allowed to cool for 30 minutes.

[0148] The drops were administered sequentially with a gap of at least 5 minutes between drops administration.

[0149] Selection Criteria Eligible population for inclusion in this study had to meet all of the following criteria: Male and female patients aged 18-75 years who are eligible for bilateral PRK surgery. · Normal eye exam except for refractive error at baseline. The planned myopia correction was a spherical equivalent of -4.50 or less by manifest refraction at baseline. The diopters were confirmed to be -4.00 diopters (spherical) and 3.00 diopters astigmatism. Monovision therapy (e.g., one eye for distance and one eye for intermediate vision) Distance correction) was permitted. Written informed consent was obtained prior to all assessments.

[0150] Exclusion criteria - Monocular patients (including amblyopic patients) or those with baseline visual acuity of 20 / 80 (Snellen) or 55 Worse best corrected visual acuity than letters [Early Treatment Diabetic Retinopathy Trial (EDTRS)] (BCVA) score. Any systemic or ocular disease that affects wound healing (e.g. severe rheumatoid arthritis or or history of diabetes or keloid formation) or ocular trauma, uveitis, or History of infection or inflammation. Especially for diabetes: severe diabetes, uncontrolled diabetes disease, diabetic keratopathy, diabetic retinopathy, diabetic macular edema, diabetic nephropathy, Patients with diabetic foot ulcers or other systemic complications of diabetes were excluded. Patients with mild, well-controlled diabetes mellitus without evidence of comorbidities were recruited. Active inflammatory or infectious eye conditions, severe or progressive retinal disease and baseline Use of topical or systemic steroids or Coumadin or similar drugs within the past 6 months prior to the Patients using medication. Any corneal dystrophy (epithelial, stromal or endothelial) or any corneal disease (including significant scarring (at investigator's discretion), ocular herpes, or pterygium) person. Previous refractive or corneal surgery (e.g., LASIK, PRK, radial keratotomy, pterygium removal) , corneal transplants). Tetracaine or similar topical eye numbing agents, NSAIDs and aspirin, oral analgesics drugs (including acetaminophen and codeine), antibiotics, steroids and bandages Allergy to the drugs used in this study, including intolerance or inability to wear contact lenses. History of allergic or hypersensitivity reactions or any significant AE. - Concomitant medications or a history of chronic medical treatment, or systemic or ocular NSAIDs, analgesics, pain medications ( gabapentin or pregabalin and similar), opiates or cannabis Abuse of. Patients who have used any topical eye medications other than lubricating eye drops within 2 weeks prior to the study eye surgery Patients who met any of the following criteria were excluded. o Use of topical NSAIDs in the 30 days prior to baseline, or o Systemic / chronic use of systemic NSAIDs within 30 days prior to baseline, or o Anytime systemic NSAID use within 3 days prior to baseline, or o Use of ophthalmic cyclosporine (or similar medication) within 3 months prior to surgery. Patients weighing <50kg or 18-35kg / m 2 Have a body mass index (BMI) within the range Patients who have not. BMI = weight (kg) / [height (m)] 2 Pregnant or lactating women. Women who are not using a primary method of contraception at the time of administration of the investigational drug. Women of childbearing potential, defined as any woman who is physiologically capable of becoming pregnant, unless otherwise specified.

[0151] Because the study population was representative of all eligible patients, additional exclusions were appropriate for the investigators. It was not used.

[0152] Study population The study population consisted of 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 these, 40 patients were enrolled and randomized in the study.

[0153] Patient selection was based on review of all eligibility criteria at screening and baseline. The relevant records of eligibility criteria (e.g., checklists) were maintained at the study site in the original documentation. Patients who met any of the entry criteria were excluded from the study. Excluded.

[0154] Patient demographics are provided in Table 3.

[0155] [Table 4]

[0156] Treatment Arm Patients were assigned in a 1:1 ratio to one of two treatment sequences, each lasting 3 days: I was fooled.

[0157] [Table 5]

[0158] Compound I was administered to patients as eye drops. The drops were administered at the study site on the day of PRK surgery. During daily follow-up postoperative visits, patients were asked to administer the drops at the expected times. When on-site, the study personnel were required to administer the eye drops. The remainder of the drops were administered at home. by the patient or while the patient is at the study site for examination (e.g., postoperative 24, 48 and 72 hours) was administered.

[0159] Visual Analogue Scale Patients' subjective pain experience was recorded using a 0-100 numerical pain assessment VAS. The PRK pain score was 100, with 0 representing no pain and 100 representing the worst imaginable pain. In conventional tests, the peak was observed around 4 to 6 hours after surgery, with The most severe pain experienced by patients with pulmonary embolism was reported in 1990 (Sher et al., 2003). act Corneal Surg.Nov-Dec;9(6):425-36(199 3)), these were selected as the time points for the primary endpoint analysis. Because it is clinically important to reduce both the maximum pain experienced and overall pain, The primary endpoints were assessed at two time periods, 6 hours and 12 hours after surgery. All available VAS data were collected from an electronic device where patients marked their pain level at the appropriate time points. The data was collected using ePRO on a mobile device (a cell phone equipped with a software application). Ta.

[0160] Rescue oral analgesics: Refusing pain management medication for patients after surgery as part of a clinical trial It is unethical to recommend NS for postoperative pain after PRK, similar to the standard of care after PRK. The use of AIDs as rescue oral analgesics is suggested by review of previous clinical trials. Because the use of oral rescue medications may be a potential confounding factor for pain VAS assessment, When analyzing pain VAS scores taking into account the influence of pain medications, the following three approaches can be used: (Assuming the effect of 4 hours of rescue medication) (1) After use of rescue medication Any recorded VAS score within 4 hours was considered missing, and (2) any recorded VAS score was considered missing. (3) Any recorded VAS scores within 4 hours of rescue medication use A was also imputed from recordings obtained before rescue medication.

[0161] Primary efficacy results The mean VAS pain severity scores at 6 hours and 0 to 12 hours after surgery are shown in Table 4 and Table 5 and shown in Figure 1. The primary analysis was performed using the primary PD analysis set. It was done.

[0162] Treatment differences in mean VAS pain severity scores over 6 hours and 0-12 hours after surgery were There was statistical significance between I and vehicle with a p value of less than 0.10.

[0163] Model-based mean treatment difference (compound I-vehicle) in VAS pain severity scores 6 hours after surgery was , -11.1(90%CI:(-17.54, -4.71, p=0.005)), 0 after surgery ~12 hours -8.56 (90%CI: -14.29, -2.83, p=0.016 )). Therefore, the primary efficacy objective of the study was met.

[0164] Treatment differences in mean VAS pain severity scores over 6 hours and 0-12 hours after surgery were There was statistical significance between I and vehicle with a p value of less than 0.10.

[0165] [Table 6]

[0166] [Table 7]

[0167] Secondary efficacy results The number of patients who did not use oral rescue medication (ORM) was 0-6 hours and 0-12 hours after surgery. The mean mean mean age of 18.1 years was 0.2 and 0–24 hours after surgery, respectively. At 6 hours, a similar number of patients with Compound I versus vehicle underwent ORM (Table 6).

[0168] [Table 8]

[0169] Histogram of incidence of oral rescue medication (ORM) use (patients who did not use ORM) The number of participants is shown in Figure 2.

[0170] A summary and analysis of ORM volumes (number of pills / patient) are presented in Table 7.

[0171] [Table 9]

[0172] As seen in Table 7 and FIG. 2, Compound I vs. vehicle for each time interval during the study period. Treatment resulted in a decrease in ORM.

[0173] A summary and analysis of ORM amounts (mg / kg body weight) is presented in Table 8.

[0174] At each time interval, ORM mass (mg / kg body weight) decreased with Compound I vs. vehicle treatment. The results were as follows (Table 8). The difference in milligrams per kilogram of body weight was statistically significant (p ≤ 0.10).

[0175] [Table 10]

[0176] VAS pain severity during the first 3 days after PRK surgery After PRK surgery, patients were checked for the first 18 hours after surgery, starting 1 hour after surgery. Six of the seven time points were assessed at a p-value threshold of 0.10, which indicates that the mean mean score was significantly higher after treatment with Compound I compared to vehicle. The authors reported a statistically significant reduction in VAS pain severity scores after the treatment. was lower for Compound I than vehicle at all scheduled time points up to 36 hours after surgery. K Compound I at all time points from 36 hours to the end of the 72 hour VAS collection period after surgery. The difference between the VAS scores of the and vehicle was only slightly different, and the p-value threshold No statistically significant difference was found between scores at 0.10.

[0177] VAS pain severity scores before and after instillation of the test eye drops Postoperatively compared with 1 / 2 hour before and immediately before instillation of eye drops (i.e., 6, 18, and 24 hours). Mean changes in VAS scores at 6.5, 18.5 and 24.5 hours were observed after Compound I treatment. In the vehicle-treated eyes, the same differences were -3.1, 2.8, and 1.3, respectively. The values ​​were -5.6, 2.2 and -0.2, respectively.

[0178] Ocular Pain Assessment Survey (OPAS) OPAS was established in 2010 by the National Eye Institute. Developed in response to needs identified from the Corneal and Ocular Surface Pain (UTE) Workshop and a validated instrument for quantifying and monitoring quality of life. Qazi et al. al., Ophthalmology July 123(7):1458-1468( See the OPAS pain severity global rating scale by Qazi et al. According to the survey, patients were scored on a scale of 0 (no pain) to 10 (severe pain) or 0% (all) regarding the frequency of symptoms. Patients were graded as having no symptoms (none) to 100% (always). They were asked to complete an OPAS survey / questionnaire at the end of the treatment period and on day 8. No statistical analysis of the OPAS results was performed. Of the total 27 OPAS questions, seven questions The results of the survey are presented below.

[0179] On day 2, the most painful ocular pain level (question 4) and the least painful ocular pain level (question 5) and average ocular pain level (question 6) for the intensity of ocular pain in the past 24 hours. All responses were numerically favorable for Compound I compared to vehicle (Figure 3A, Figure 3B, Figure 3 C).

[0180] The following symptoms: redness (question 22), burning sensation (question 23), light sensitivity (question 24) and tearing ( In question 25, how often did you experience eye pain with the eye dropout? All answers were positive compared to the control. Compound I was favorable (Figures 4A, 4B, 4C, and 4D). Patients who received the drug experienced fewer symptoms of redness, burning sensation, light sensitivity (photophobia) and vomiting compared with patients who received a placebo. They experienced lower levels of ocular pain accompanied by tearing.

[0181] Summary of eye examination results Ocular Pain Assessment Survey (OPAS) showed better pain relief during the treatment period of Compound I versus vehicle. Pain control and quality of life were demonstrated in patients. On the second day, the maximum pain level (question 4) and the minimum pain level (question 5) ) and average ocular pain level (question 6) in the past 24 hours. All responses favored Compound I compared to vehicle (Figures 3A-3C). The following symptoms: redness (question 22), burning sensation (question 23), light sensitivity (question 24) and tearing ( In question 25), how often did you experience eye pain with the drug? All answers were positive compared to the vehicle. Compound I was advantageous in this regard (FIGS. 4A to 4D). Compared with ½ hour and immediately before instillation of eye drops (i.e., 6, 18, and 24 hours) The mean change in VAS score at 6.5, 18.5, and 24.5 hours after surgery was In treated eyes, the differences were -3.1, 2.8, and 1.3, respectively. In vehicle-treated eyes, the same differences were were −5.6, 2.2, and −0.2, respectively.

[0182] Pharmacokinetics Pharmacokinetic assessment Pharmacokinetic (PK) samples were collected over the following time periods using the PK blood collection windows shown in Table 9. The data were collected at time points defined in the clinical schedule.

[0183] [Table 11]

[0184] All blood samples (3 mL) were obtained by direct venipuncture or by using an indwelling catheter inserted into a forearm vein. After each blood tube was withdrawn, the contents of the tube and the anticoagulant ( Immediately and gently invert 8-10 times to ensure mixing with the 3 mL K2EDTA. Avoid prolonged contact between the sample and the rubber stopper and keep the sample in a wet condition until centrifugation. The tubes were placed upright in a test tube rack surrounded by a filter.

[0185] Within 30 minutes, centrifuge the samples at approximately 2000 G for 10 minutes at approximately 5°C. (Alternatively, samples were placed on ice and centrifuged at room temperature). Immediately after centrifugation, the entire supernatant was Transfer the supernatant (approximately 1.5 mL) into the first 1.8 mL NUNC 2D barcoded cryovial. After the plasma was thoroughly mixed, half of the plasma was transferred from the first cryovial to the second cryovial. The samples were transferred to cryovials and the caps were secured. The appropriate PK cryolabel was applied to each cryovial. The vials were then attached with transparent tape and the labels were immediately placed on dry ice for cryopreservation. The vials were frozen and then kept frozen at ≤ -20°C until transport to the central laboratory. The vials were shipped in batches every two weeks.

[0186] Compound I was quantified in plasma using a validated LC-MS / MS method. The lower limit of quantification (LL The OQ was 0.05 ng / mL. Concentrations were expressed in ng / mL. The bandage contact lenses (BCLs) exposed to the study drug were collected and the residual Residual drug exposure was analyzed (LLOQ: 5.00 ng / mL in 0.55 mL extracted fluid or Concentrations below the LLOQ were reported as “zero” and missing data were The data was recorded as such.

[0187] Using actual recorded sampling times and non-compartmental methods, Phoenix Plasma concentration-time analysis was performed using WinNonlin® (Version 6.4) The following relevant PK parameters were obtained from the data: Cmax, Tmax, AUClast (calculated The nominal values, Clast and Tlast, were determined by 0, 24 and 72 hour tests. The pre-administration concentration was determined. The linear trapezoidal rule was used to calculate AUClast. No PK parameters were calculated from the Ctlenz Compound I concentration data.

[0188] Plasma Pharmacokinetics of Compound I The arithmetic mean plasma concentration-time profile and PK parameters of Compound I were , as presented in Figures 5A and 5B and Table 10.

[0189] Following topical unilateral administration of Compound I, absorption into the systemic circulation was rapid, with initial (day 1, range 0.1 67-2.00 hours) and after the 13th dose (day 4, range 0.00-2.08 hours) The median Tmax was 0.459 hours and 0.467 hours, respectively. 34 / 40 patients and 33 / 40 (Cmax) or 31 / 40 (AUCl) on day 4 The Cmax was determined and the AUClast was calculated for patients with ast. All were below the limit of quantification and were imputed as 0.00 ng / mL. Trough (6-hour dose) before the fifth dose (24 hours after the first dose, time point 0 hours on day 2) The mean concentration (CV%) at the end of the dosing interval and before the next dose was 1.25 ng / m L (54.9%), before the 13th dose on day 4 (72 hours after the 1st dose, time on day 4 At time 0, the mean plasma concentration was slightly higher at 1.99 ng / mL (76.3%).

[0190] Concentrations were generally low, ranging from 0.195 to 7.56 ng / m over repeated QID administrations over 4 days. The observed Cmax was in the range of 0.261 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 the 4th day, it was 2.40 ng / mL (63.5%). ) or 5.3-fold. The corresponding mean AUClast (CV%) value was 0.638 ng·h / mL (46.0%) and 4.38 ng·h / mL (67.0%) (4 days (a 6.9-fold increase over the past 10 years).

[0191] [Table 12]

[0192] Bandage Contact Lenses Bandage contact lenses (BCLs) were collected from 40 patients on the fourth day of dose administration. Compound I was analyzed using the BCL summary statistics from three IMP non-compliant patients. Thirty-seven evaluations were performed, including one value from a patient with no plasma PK available due to the exclusion of The mean concentration (CV%) of compound I in 0.55 mL of extracted fluid was 85. 00 ng / mL (73.1%), with a wide range of 284 to 22,600 ng / mL. These concentrations were 4680ng / lens (0.55mL x 8500ng / mL). This translates into an estimated mean of 100 and a range of 156-12,400 ng / lens. The mean dose was 0.51 mg, which is very small compared to the 0.925 mg dose of Compound I administered. The percentages and range were 0.017% to 1.3%. This indicates that BCL is a topical ophthalmic compound I. This suggests that the drug is absorbed and retained in amounts that are negligible compared to the topical ocular dose.

[0193] Summary pharmacodynamic results Absorption of Compound I into the systemic circulation was measured using either a single (initial dose) or repeated 4 times daily topical administration. After ocular administration, onset was also rapid (median plasma Tmax was approximately 0.5 hours). Following both single and multiple topical ocular administration of Compound I, systemic exposure was low and was observed after repeated administration over a 4-day period. The range was 0.195 ng / mL to 7.56 ng / mL over QID dosing, with moderate The mean Cmax was 0.454 ng / mL on day 1 after the first dose and 0.58 ng / mL on day 4 after the first dose. After the 13th dose, the mean blood glucose level was 2.40 ng / mL. The CV% values ​​for Cmax and AUClast after a single dose were 49.9, respectively. % and 46.0%. The corresponding values ​​after repeated dosing were 63.5% and 67.0%. there were. The mean Cmax after repeated administration (2.40 ng / mL) was 1.0 times higher than that after a single dose on day 1 (0. 454ng / mL). Similarly, the mean AUClast was 5.3-fold lower for the repeat vs single These data were 6.9-fold higher after treatment (4.38 vs. 0.638 ng·h / mL). , suggesting accumulation over four days of 2.5% Compound I given four times daily. Bandage contact lenses (BCLs) were collected from 40 patients on the fourth day of dose administration. The mean concentration (CV%) in 0.55 mL of extracted fluid was 8500 ng / mL (73.1 %), translating to an estimated 4680 ng / lens. This is very small compared to the 0.925 mg dose of substance I, which is 0.51% of the dose and 0.017 This indicates that BCL is able to absorb and retain topical ophthalmic Compound I. This suggests that the dose is negligible compared to the topical ocular dose.

[0194] safety The safety assessment included all AEs and SAEs, along with their severity and relationship to the study drug. Table 11 shows common signs and symptoms in the post-PRK setting. Symptoms and symptoms that exceed the listed ranges in either severity or duration. Only symptoms were reported as AEs.

[0195] [Table 13]

[0196] One week refers to the visit on the 8th day after surgery (the 6th visit of treatment period 1), including any acceptable window. The table shows the resolution of the symptoms before the start of the study, Based on a compiled experience including common and expected clinical signs following quasi-PRK surgery It was developed with feedback from all investigators and surgeons.

[0197] One month is the time until the EOS consultation, or when the EOS consultation is not performed or between the study surgeries. More than one week means resolution within 37 days after surgery.

[0198] Adverse and serious adverse events were assessed based on both systemic and ocular assessments. The general safety assessment included periodic assessments of height and weight, vital signs, and Including indications, medication error reporting including misuse / abuse, pregnancy reporting and initial safety monitoring Misuse / abuse, pregnancy reporting, and initial safety monitoring were not assessed in the studies. The ocular safety assessment included the following: Best corrected visual acuity (BCVA) and uncorrected visual acuity (UCVA): 4 meters (13 feet) ) or 1 meter (for patients who cannot read a 4 meter chart) ETDRS visual acuity chart BCVA was measured at each visit using a BCVA scale. BCVA scoring was calculated based on the number of correctly read letters. The results were based on the number of patients with very poor vision plus 30. If the letters were also unreadable, the exponential valve, manual valve and light-sensitive valve were tested. · Intraocular pressure (IOP): IOP measurements were performed using applanation tonometry or TonoPen. Dilated Ophthalmoscopy: Dilated Ophthalmoscopy is an ophthalmoscopic examination of the vitreous, retina / macula / choroid and optic nerve. The examination included retinal tears / detachments, retinal hemorrhages, vitreous hemorrhage density, vitreous hemorrhage, and retinal hemorrhage. The patient is scored according to the grading criteria, and abnormal findings are evaluated. did. Ocular hyperemia: Conjunctival redness in each eye measured with a slit lamp according to the McMonnies scale. Membrane redness was graded. Redness was graded in 4 areas of each eye (superior, inferior, temporal, nasal). The severity of the lesions was graded from 0 to 5. Size of epithelial defect by slit lamp examination: Narrow at an oblique observation angle to the light source beam A bright slit beam was used to section the cornea 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 dimension of the surgical epithelial wound ( The horizontal dimension (wound width) and vertical dimension (wound height) were estimated. The wound was closed and the wound size was reduced to the horizontal dimension (wound height). The evaluation was performed until the measurement was reported as 0 and the vertical dimension was reported as 0. Slit-lamp biomicroscopy: Slit-lamp biomicroscopy was performed on both eyes according to the grading criteria. Ocular signs (lid / conjunctiva, cornea, lens and iris / anterior chamber) were evaluated. Blink rate: Blinking is the spontaneous closure of both eyes by the eyelids in the absence of any external stimulus trigger. Each blink assessment was performed for 2 min (or The test was continued for a minimum of 1 minute (as close to 2 minutes as possible), and the average blink rate was calculated. Blink rates were calculated averaged in blinks / min. Tear production (Schirmer test without numbing agents): The test was performed simultaneously in both eyes without numbing agents. Tear secretion was measured by measuring the length of the strip moistened by tears in millimeters. Measurements were rounded to the nearest whole number. Corneal staining: This test involves the application of a sodium fluorescein strip to the lower conjunctival sac. The strip is then wiped clean with a drop of sterile saline. The tear film was moistened and patted to remove excess saline. After blinking several times to ensure dispersion, five zones (center plus four quadrants) Each was scored from 0 to 3 (0 = normal, no staining; 1 = mild, superficial speckled micropunctate staining; 2 = mild, superficial speckled micropunctate staining; = moderate, macro-punctate staining with some coalesced areas and 3 = severe, numerous coalesced macro The lesions were graded on a scale of punctate areas and / or patches.

[0199] Safety assessment The study saw no deaths, SAEs, drug discontinuations, or study discontinuations due to AEs. A total of 18 AEs were reported in 10 patients (25% of 40 enrolled patients), of which Twelve occurred after treatment with Compound I, five after treatment with vehicle, and one after administration of the test drug. An adverse event occurred in one patient prior to dosing. All AEs were either mild or moderate in severity.

[0200] A total of 10 patients (25%) experienced at least one treatment-emergent AE, with 5 10 patients experienced a single AE and 5 patients experienced 2 or more AEs. AEs were experienced only during treatment with Compound I, and two patients experienced AEs only during treatment with the vehicle. 13 patients experienced AEs during treatment with both Compound I and vehicle, and 3 patients experienced AEs during treatment with both Compound I and vehicle. One AE (headache) occurred prior to administration of study drug.

[0201] Four patients (10% of 40 enrolled patients) experienced six ocular AEs, all of which were mild to severe. The severity of all AEs was 0.01 (3 eyes treated with Compound I and 3 eyes treated with vehicle). None of the 6 ocular AEs were suspected to be related to the study drug (Compound I or vehicle). Five of these events were considered by the investigator to be related to the PRK procedure (two in the Compound I-treated eye and one in the 3 times belonged to the vehicle-treated eye).

[0202] Seven patients (17.5%) had 12 non-ocular AEs (six treated with Compound I). Four patients (1 eye, 2 eyes treated with vehicle, and 1 patient during the no drug period) were included. Five AEs (0%) were of moderate severity (4 Compound I-treated eyes and 1 vehicle-treated eye). The remaining AEs were mild in severity. All AEs were not reported by the investigator. No other findings were speculated to be related to Compound I.

[0203] Table 12 provides the overall incidence of adverse events.

[0204] [Table 14]

[0205] Eye Safety Assessment Best corrected visual acuity (BCVA) and uncorrected visual acuity (UCVA): Compound I administration was continued throughout the study. No trends or clear differences were observed between Compound I-treated and vehicle-treated eyes. Therefore, Compound I suppressed pain without adversely affecting BCVA and UCVA. Data suggest that it reduces pain.

[0206] Intraocular pressure (IOP): Trends across planned time points throughout the study were consistent between Compound I-treated eyes and No significant differences were observed between the vehicle-treated eye and the control eye. There was a slight increase in mean IOP values ​​(<5mmHg) over the study period. The small changes were not clinically significant.

[0207] Dilated fundus examination: Abnormal findings were investigated over scheduled time points in Compound I and vehicle-treated eyes. Not reported by the physician.

[0208] Ocular hyperemia: Bar charts of ocular hyperemia over time for Compound I and placebo treated eyes are shown in Table 1. The results are presented in Figures 6A and 6B. Figures 6A and 6B show the results of the third and fourth day groups, respectively. Grade 4 and grade 3 ocular hyperemia (as measured by the McMonnies scale) are shown. On day 2 (24 hours after PRK surgery), Compound I-treated eyes had fewer Grade 4 hyperemia (in all quadrants) was observed. In the upper quadrants, the p-value for this difference was On day 3 (48 hours after surgery), Compound I-treated eyes had a significantly higher AF than vehicle-treated eyes. Fewer grade 3 hyperemias were observed. Any observations were captured as AEs. I couldn't.

[0209] Size of epithelial defect by slit lamp examination: To evaluate the rate of wound healing after administration of Compound I To evaluate the size of the epithelial defects in both Compound I and vehicle treated populations, the size of the epithelial defects was measured. The elliptical area of ​​the wound size was calculated based on the width and height of the epithelial defect measured with a slit lamp as follows: The area (mm2) was calculated as width × height × π. The difference in scar area was 2 days after PRK surgery (p values ​​for area differences were all >0.35). There were no significant differences at any time point, except for day 2 (24 hours after surgery), when the compound The difference in the mean epithelial defect area between patients treated with I versus vehicle was 11.23 mm2 (p-value = 0.034). This difference was not clinically significant immediately after surgery. Up to 24 hours, no difference was observed between Compound I-treated and vehicle-treated eyes, and the wound area was very small. On the fourth day (48 hours after surgery), almost all eyes had healed, and both compound I-treated and vehicle-treated eyes had recovered. No differences were observed between treated and untreated eyes. Compound I showed delayed wound healing compared to vehicle. There wasn't.

[0210] FIG. 7 and Table 13 provide a comparison of epithelial size defects in Compound I-treated versus vehicle-treated eyes.

[0211] [Table 15]

[0212] Slit Lamp Biomicroscopy: Slit lamp biomicroscopy is used to examine the ocular structures (eyelids / conjunctiva, cornea, iris / The examination consisted of anterior chamber, lens, aqueous humor flare, and aqueous humor inflammatory cell grade. In patients treated with both Compound I and vehicle throughout the interval, aqueous humor flare and No abnormalities were observed in hydroinflammatory cell grade, ocular structures of the iris / anterior chamber, and lens.

[0213] Blink rate: Mean blink rate fluctuated, but blink rates after Compound I and vehicle treatment were significantly higher. No trends or obvious differences between the firing rates over the scheduled time points were observed throughout the study. At the end of the study, no clinically relevant changes in blink rate were observed compared to baseline. There wasn't.

[0214] Corneal staining: Most patients had normal corneal staining measured at baseline, day 8, and EOS visits. (Grade 0) staining at baseline, day 8, or EOS visit. No clinical differences in corneal staining between Compound I vs. vehicle treated eyes were observed.

[0215] Vital signs, physical findings, and other observations related to safety: Vital sign parameters (systolic and All patients' blood pressure, diastolic blood pressure, pulse rate and temperature were within normal limits during the study. No AEs related to vital signs were observed. Electrocardiograms and special safety topics were not performed and were not evaluated. was not evaluated (according to protocol).

[0216] Summary of safety results There were no deaths, serious or serious AEs, or treatment or study discontinuations reported in this study. Ta. None of the AEs were assessed as related to the study drug (either Compound I or vehicle). Eight of 40 and five of 40 patients received Compound I and vehicle treatment, respectively. All ocular AEs were mild and balanced between Compound I and vehicle. The majority were well-known AEs related to the PRK procedure. No clinically significant differences in safety were observed between Compound I and vehicle. Compound I did not show any delay in wound healing compared to vehicle. Compound I-treated eyes that showed severe conjunctival hyperemia on the second day (24 hours after surgery) were significantly lower than vehicle-treated eyes. It was less in comparison. - After Compound I administration, compared to vehicle, BCVA, IOP, slit-lamp biomicroscopy, and mydriasis No clinically relevant changes were observed in eye exam, blink rate, tear production, corneal staining, or vital signs. I couldn't.

[0217] The incidence of AEs by priority category is shown in Table 14.

[0218] [Table 16]

[0219] All publications and patent documents cited herein are the sole disclosure of the respective patents or publications. Each of the above-mentioned references is incorporated herein by reference in its entirety as if each was specifically and individually indicated to be incorporated by reference. The present invention and its embodiments are described in detail below. However, the scope of the present invention does not include any process, manufacture, It is not intended that any limitation be imposed on any particular embodiment of compositions of matter, compounds, means, methods and / or steps. Various modifications may be made without departing from the spirit and / or essential characteristics of the present invention. Various embodiments, substitutions and variations may be made to the materials disclosed herein. Perform substantially the same function or achieve substantially the same results as the described embodiments; Subsequent modifications, substitutions and / or variations may be made in accordance with such related embodiments of the present invention. It will be readily understood from the present invention that the present invention can be utilized in a variety of ways. The scope of the present invention is defined as any process, manufacture, composition of matter, compound, means, methods and and / or steps are intended to include within their scope modifications, substitutions and variations. The claims are not to be interpreted in any particular order or with any particular elements unless expressly stated to that effect. Various changes in form and detail are within the scope of the appended claims. It should be understood that the present invention may be administered without removal.

Claims

1. A method for treating ocular surface pain in a subject in need thereof, comprising administering to said subject an effective amount of a compound comprising Construction: 【Chemistry 1】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 3. The method of claim 1, wherein the compound is selected from the group consisting of (1-methyl-1-yl)-benzonitrile (formula I) and salts, solvates, polymorphs, and co-crystals thereof. The method comprises administering instillation to the subject.

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

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

4. 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. The method of any one of claims 1 to 3, comprising administering a compound of formula I:

5. About 0.5% w / v, about 1.0% w / v, about 1.5% w / v, about 2.0% w / v, about 2. The compound of formula I is administered at a concentration of about 5% w / v, about 3.0% w / v, or about 3.5% w / v. The method of claim 4 , comprising:

6. The method according to any one of claims 1 to 5, wherein the COSP is associated with dry eye disease. Method of posting.

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

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

9. The administration may be effective to relieve symptoms such as dry eyes, eye discomfort, eye redness, eye burning or stinging, grittiness or or foreign body sensation or photophobia, resulting in at least about a 10% reduced incidence. The method according to claim 7.

10. The subject is a patient suffering from dry eye disease, Sjogren's syndrome, conjunctivitis (keratoconjunctivitis, vernal keratoconjunctivitis) , allergic conjunctivitis), corneal epithelial basement membrane dystrophy, Acanthamoeba, Streptococcus aureus Fibromyalgia, Meibomian gland dysfunction, Thyroid eye disease, Rosacea, Ptosis, Keratoconus, Ocular pain syndrome group, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (LASIK-induced corneal neuropathy), corneal dystrophies (including recurrent corneal dystrophies), epithelial Basement membrane dystrophy, corneal erosion or corneal abrasion (recurrent corneal erosion or corneal (including abrasions), ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, glaucoma, conjunctival Keratopathy (herpetic keratopathy, filamentous keratopathy, strip-shaped or bullous keratopathy, lagophthalmos keratopathy) keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, Recovered from multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, and neurotrophic keratitis. Patients undergoing photorefractive keratectomy (PRK) or laser keratomileusis surgery At least one of the following eye pain symptoms has persisted for at least 3 months after LASIK surgery: The method according to any one of claims 1 to 5, wherein the patient is suffering from a disease.

11. Any one of claims 1 to 10, further comprising administering to the subject an additional therapeutic agent. The method according to

12. The treatment was compared to placebo as measured by visual analog scale (VAS). 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. The method according to any one of claims 1 to 11.

13. The administration of the drug results in a reduction in the responsiveness of the patient to at least about 6% or less of the responsiveness of the patient compared to placebo as measured by a VAS. at least about 7, at least about 8, at least about 9, or at least about 10. A method according to any one of claims 1 to 12, resulting in a reduction of the core.

14. The administration reduces the inflammatory response by at least about 10%, at least about 15%, or 20% or at least about 25% reduction in pain in the subject.

12. The method according to any one of claims 11 to 11.

15. The reduction in pain score is determined by measuring the difference in pain score before and after administration of Compound I to the subject.

14. The method according to claim 12 or 13, resulting from

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

17. The administration may be at least about 1, at least about 2, at least about 3, or at least about 4 on the McMonnies scale.

3. A method for treating hyperemia in a subject, comprising administering to said subject a therapeutically effective amount of at least about 4 or at least about 5 mg of the active ingredient in said therapeutically effective amount of ... The method according to any one of claims 1 to 16.

18. The treatment was associated with improved best corrected visual acuity, slit lamp biomicroscopy, mydriatic examination, and schizophrenia, compared to placebo. Any of claims 1 to 17, which does not cause any change in one or more of blink rate, tear production, and intraocular pressure. The method according to any one of claims 1 to 5.

19. The compound of formula I may be administered for at least about 1 month, at least about 2 months, or at least about 19. The method of any one of claims 1 to 18, wherein the method is administered for three months.

20. 20. The method according to claim 1, wherein the compound of formula I is administered for more than 3 months. The method according to claim 5.

21. The compound of formula I according to any one of claims 1 to 20, wherein the compound is administered 1 to 4 times daily. How to.

22. A compound of formula I for use in treating or reducing ocular surface pain. 【Chemistry 2】 or a salt, solvate, polymorph or co-crystal thereof.

23. The ocular surface pain has been present for at least 1 month, at least 2 months, or at least 3 months.

23. The use of claim 22, wherein the pain is chronic ocular surface pain that persists for a period of time.

24. The compound of formula I may be administered in a concentration of from about 0.5% w / v to about 3.5% w / v, from 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.

24. The use according to claim 22 or 23, administered at a concentration of 5% w / v.

25. The compound of formula I may be administered at 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 The use according to any one of claims 22 to 24, wherein the compound is administered in a dose of 100 mg / kg or more.

26. Formula I 【Chemistry 3】 or a salt, solvate, polymorph, or cocrystal thereof. A pharmaceutical for treating or reducing facial pain.

27. The ocular surface pain has persisted for at least 1 month, at least 2 months, or at least 3 months. The pharmaceutical composition of claim 26, wherein the pain is chronic ocular surface pain that persists for a period of time.

28. The compound of formula I may be administered in a concentration of from about 0.5% w / v to about 3.5% w / v, from 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.

28. The medicament of claim 26 or 27, which is administered at a concentration of 5% w / v.

29. The compound of formula I may be administered at 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 The pharmaceutical agent according to any one of claims 26 to 28,

30. In the manufacture of a medicament for the treatment or reduction of ocular surface pain, 【Chemistry 4】 or a salt, solvate, polymorph or co-crystal thereof.

31. The ocular surface pain has been present for at least 1 month, at least 2 months, or at least 3 months.

31. The use of claim 30, wherein the pain is chronic ocular surface pain that persists for a period of time.

32. The compound of formula I may be administered in a concentration of from about 0.5% w / v to about 3.5% w / v, from 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.

32. The use according to claim 30 or 31, administered at a concentration of 5% w / v.

33. The compound of formula I may be administered at 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 The use according to any one of claims 30 to 32, wherein the compound is administered in an amount of 100 mg / kg or more.

34. 1. A method of reducing ocular surface pain in a subject in need thereof, comprising administering to a subject a compound of the structure: 【Chemistry 5】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 3. The method of claim 1, wherein the compound is selected from the group consisting of (1-methyl-1-yl)-benzonitrile (formula I) and salts, solvates, polymorphs, and co-crystals thereof. instilling into the subject an eye comprising about 0.5% w / v to about 3.5% w / v of the compound of formula I; , 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.

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

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

37. 35. The method of claim 34, wherein said administering results in a reduction in symptoms of dry eye disease.

38. 37. The method of claim 36, wherein said administration results in a reduction in said ocular pain associated with dry eye disease. How to.

39. The administration may be effective to relieve symptoms such as dry eyes, eye discomfort, eye redness, eye burning or stinging, grittiness or or foreign body sensation or photophobia by at least about 10%.

39. The method of claim 38.

40. The subject is a patient suffering from dry eye disease, Sjogren's syndrome, conjunctivitis (keratoconjunctivitis, vernal keratoconjunctivitis) , allergic conjunctivitis), corneal epithelial basement membrane dystrophy, Acanthamoeba, Streptococcus aureus Fibromyalgia, Meibomian gland dysfunction, Thyroid eye disease, Rosacea, Ptosis, Keratoconus, Ocular pain syndrome group, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (LASIK-induced corneal neuropathy), corneal dystrophies (including recurrent corneal dystrophies), epithelial Basement membrane dystrophy, corneal erosion or corneal abrasion (recurrent corneal erosion or corneal (including abrasions), ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, glaucoma, conjunctival Keratopathy (herpetic keratopathy, filamentous keratopathy, strip-shaped or bullous keratopathy, lagophthalmos keratopathy) keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, Recovered from multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, and neurotrophic keratitis. Patients undergoing photorefractive keratectomy (PRK) or laser keratomileusis surgery One or more ocular pain symptoms that persist for at least 3 months after (LASIK) surgery The method according to any one of claims 34 to 39, wherein the patient is suffering from.

41. 41. The method of claim 34, further comprising administering an additional therapeutic agent to the subject. The method according to claim 5.

42. The administration of the compound is associated with a significant reduction in the dose of the compound as measured by a visual analog scale (VAS). resulting in a reduction in the subject's pain score of at least about 3 as compared to the previous pain score. The method according to any one of claims 34 to 41.

43. The treatment was compared to placebo as measured by visual analog scale (VAS). 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. The method according to any one of claims 34 to 41.

44. The administration of the drug results in a reduction in the responsiveness of the patient to at least about 6% or less of the responsiveness of the patient compared to placebo as measured by a VAS. at least about 7, at least about 8, at least about 9, or at least about 10.

43. The method of any one of claims 34 to 42, resulting in a reduction of the core.

45. The administration reduces the inflammatory response by at least about 10%, at least about 15%, or 34. The method of claim 33, wherein the method results in a reduction in pain in the subject of about 20% or at least about 25%.

45. The method according to any one of claims 1 to 44.

46. The reduction in pain score is determined by measuring the difference in pain score before and after administration of Compound I to the subject. The method according to any one of claims 42 to 45, resulting from

47. The administration may be at least about 1, at least about 2, at least about 3, or at least about 4 on the McMonnies scale.

3. A method for treating hyperemia in a subject, comprising administering to said subject a therapeutically effective amount of at least about 4 or at least about 5 mg of the active ingredient in said therapeutically effective amount of ... The method according to any one of claims 34 to 46.

48. 1. A method for reducing ocular redness in a subject in need thereof, comprising administering to a subject a compound of the structure: 【Chemistry 6】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 3. The method of claim 1, wherein the compound is selected from the group consisting of (1-methyl-1-yl)-benzonitrile (formula I) and salts, solvates, polymorphs, and co-crystals thereof. instilling into the subject an eye comprising about 0.5% w / v to about 3.5% w / v of the compound of formula I; , 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.

49. The reduction in ocular redness may be at least about 1, at least about 2, or a slight increase in blood flow to the eye.

49. The method of claim 48, wherein the β-amino acid residue is at least about 3, at least about 4, or at least about 5.

50. The administration may be accompanied by symptoms such as dry eyes, eye discomfort, burning or stinging in the eye, grittiness or a foreign body sensation in the eye.

4. The method of claim 3, wherein the method results in at least about a 10% reduced incidence of one or more of the following: sensitization, photophobia, or photophobia.

48. The method according to claim 49,

51. The subject is a patient suffering from dry eye disease, Sjogren's syndrome, conjunctivitis (keratoconjunctivitis, vernal keratoconjunctivitis) , allergic conjunctivitis), corneal epithelial basement membrane dystrophy, Acanthamoeba, Streptococcus aureus Fibromyalgia, Meibomian gland dysfunction, Thyroid eye disease, Rosacea, Ptosis, Keratoconus, Ocular pain syndrome group, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (LASIK-induced corneal neuropathy), corneal dystrophies (including recurrent corneal dystrophies), epithelial Basement membrane dystrophy, corneal erosion or corneal abrasion (recurrent corneal erosion or corneal (including abrasions), ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, glaucoma, conjunctival Keratopathy (herpetic keratopathy, filamentous keratopathy, strip-shaped or bullous keratopathy, lagophthalmos keratopathy) keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, Recovered from multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, and neurotrophic keratitis. Patients undergoing photorefractive keratectomy (PRK) or laser keratomileusis surgery One or more ocular pain symptoms that persist for at least 3 months after (LASIK) surgery The method according to any one of claims 48 to 50, wherein the patient is suffering from

52. 52. The method of claim 48, further comprising administering an additional therapeutic agent to the subject. The method according to claim 5.

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