Crystalline forms of 4 - (7-hydroxy-2-isopropyl-4-oxo - 4h - quinazolin-3-yl) - benzonitrile and formulations thereof

Abstract

To provide a pharmaceutical composition for treating or reducing ocular surface pain.SOLUTION: Provided are crystals of 4 - (7-hydroxy-2-isopropyl-4-oxo - 4H - quinazolin-3-yl) - benzonitrile (Compound I) having the structure: wherein the crystals are crystalline Form M characterized by an X-ray diffraction pattern having three or more peaks at 2 Θ values selected from 11.1, 18.5, 19.1 ± 0.2 ° 2 Θ, and pharmaceutical compositions comprising said crystals.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline Crystalline forms of (3-yl)-benzonitrile (formula I), processes for preparing them and The present invention relates to formulations of Compound I and methods for using same to treat ocular surface disorders. It also relates to methods for [Background technology]

[0002] Patients suffering from ocular surface pain, especially chronic ocular surface pain, experience a significant decrease in quality of life. Many suffer from depression, moderate to severe angina, dialysis, and disabling hip fractures. In many patients, ocular surface pain is due to underlying pathology (e.g., Remains unresolved despite treatment (e.g., recent trauma or surgery, infection or inflammation) Therefore, no other known treatments are available for long-term therapy.

[0003] The transient receptor potential vanilloid 1 (TRPV1) receptor is involved in pain signaling. Antagonism of this receptor can be beneficial in pain conditions, especially chronic pain. To alleviate this, it is desirable to administer a formulation of TRPV1 antagonists topically to the ocular surface. It would be interesting.

[0004] Formulating hydrophobic eye drops reduces their tendency to aggregate, especially within aqueous topical ophthalmic compositions. Aggregation can be particularly challenging due to the potential for aggregation to affect stability and potentially other may cause quality issues and may be due to other interactions between the drug and excipients. Therefore, various polymorphs may be incorporated into ocular formulations for delivery to the ocular surface. It is required to identify the form. Summary of the Invention

[0005] In some embodiments, the present invention provides a method for determining the angle of curvature of a given angle from 5.3, 12.3, and 22.5±0.2 degrees 2θ. characterized by an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from structure [ka] 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 In some embodiments, the present invention relates to crystalline form K′ of (-yl)-benzonitrile (Compound I). The crystal form K' of compound I has the following crystal structures: 5.3, 10.6, 12.3, 21.2, 22.5, and and 23.0±0.2°2θ. In some embodiments, the present invention provides a crystalline form of Compound I. A method for preparing form K', comprising the steps of: and evaporating a solution of compound I in ... Regarding the law.

[0006] In some embodiments, the present invention provides a method for detecting a temperature gradient from 11.1, 18.5, 19.1±0.2 degrees 2θ. characterized by an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from structure [ka] 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 In a particular embodiment, the compound is crystalline form M of (-yl)-benzonitrile (Compound I). The crystal form M of Compound I is 11.1, 12.1, 18.5, 19.1, 20.1, 21.4 An X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from ±0.2° 2θ In some embodiments, the present invention provides a method for preparing crystalline form M of compound I. 1. A method for preparing a compound I in crystalline form B from acetone at room temperature for at least 24 hours. and slurrying the mixture with

[0007] In some embodiments, the present invention provides a method for detecting a temperature difference between −6.6, 12.2, 15.8±0.2 degrees 2θ. characterized by an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from structure [ka] 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 -yl)-benzonitrile (Compound I) hydrate H B In certain embodiments, , crystalline hydrate H of compound I B 6.6, 12.2, 14.6, 15.8, 16.1 , 18.5, 20.9, 24.7 ±0.2°2θ at three or more peaks In some embodiments, the present invention provides a method for producing a crystalline silicon nanoparticle, characterized by an X-ray diffraction pattern having a peak. The crystal hydrate H of compound I B 2. A method for preparing a soluble fiber comprising the steps of: Compound I in crystalline form B was dissolved in about 1:1 of acetone and water over a period of at least 6 days, or at least 7 days. Compound I was slurried with the mixture of 1 and crystalline hydrate H B a method including providing the Regarding.

[0008] In some embodiments, the present invention provides a method for detecting a temperature difference between 11.2, 12.2, 19.1±0.2 degrees 2θ. characterized by an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from structure [ka] 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 In certain embodiments, the compound is crystalline form Q of (-yl)-benzonitrile (Compound I). The crystal forms Q of Compound I were 11.2, 12.2, 18.5, 19.1, 20.1, and 22.0. , 22.5, 23.3, 26.5±0.2°2θ at three or more peaks In some embodiments, the present invention provides a method for producing a crystalline ... 12. A method for preparing crystalline form Q of compound I according to claims 10-11, comprising the steps of: Compound I in crystalline form B was slurried in approximately 1:1 (v / v) n-butanol / dichloromethane. to obtain compound I in crystalline form Q.

[0009] In some embodiments, the present disclosure provides crystalline form K', crystalline form M, crystalline form Q, a hydrate H B and combinations thereof, and a crystalline form of Compound I selected from the group consisting of pharmaceutically acceptable salts thereof. and an excipient.

[0010] In some embodiments, the present disclosure provides crystalline form K', crystalline form M, crystalline form Q, a hydrate H B and combinations thereof, and a crystalline form of Compound I selected from the group consisting of pharmaceutically acceptable salts thereof. and an excipient for administering the pharmaceutical preparation for ocular use (e.g., topical application to the ocular surface). .

[0011] In some embodiments, the present disclosure provides a pharmaceutical preparation comprising crystalline form K' in substantially pure form. The agent is provided.

[0012] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising crystalline Form M in substantially pure form. to provide.

[0013] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising crystalline form Q in substantially pure form. to provide.

[0014] In some embodiments, the present disclosure provides hydrate H B in a substantially pure form. to provide.

[0015] In some embodiments, the present disclosure provides crystalline forms B and K′, crystalline forms B and M, crystalline forms Forms B and Q, Crystal Form B and Hydrate H B A mixture of these in a ratio of about 1:99 to about 99:1 A pharmaceutical formulation comprising the compound is provided.

[0016] In some embodiments, a pharmaceutical formulation comprising any of the crystalline forms disclosed herein is , formulated for ocular use (e.g., topical application to the ocular surface).

[0017] In some embodiments, 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) -benzonitrile (Compound I) or a salt, co-crystal, or polymorph thereof, and surfactants, suspending agents, isotonicity agents, buffers, preservatives, salts, and preservatives. Described herein are aqueous formulations containing one or more selected excipients.

[0018] In some embodiments, 4-(7-hydroxy-2-isopropyl-4-oxo-4 H-quinazolin-3-yl)-benzonitrile (Compound I) is available in the crystalline form K', crystalline form M, crystal form Q, hydrate H B or a combination thereof present in the formulation as a suspension. In additional embodiments, crystalline form K′, crystalline form M, crystalline form Q, hydrate H B or Combination of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 -yl)-benzonitrile (Compound I) in an amount of about 0.5% w / v to about 3.5% w / v It is present in the formulation.

[0019] In some embodiments, The resulting product is present as a suspension in the formulation in an amount of about 0.5% w / v to about 3.5% w / v. Crystal form K', crystal form M, crystal form Q, hydrate H B or a combination thereof, 4-(7-hydroxy 2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile ( Compound I), surfactants, suspending agents, and one or more excipients selected from the group consisting of isotonicity agents, buffers, preservatives, salts, and preservatives. Vehicle Described herein is an aqueous formulation comprising:

[0020] In some embodiments, the invention described herein comprises: Crystalline form K', crystal form M, crystal form K', in an amount of about 0.5% w / v to about 3.5% w / v. Form Q, hydrate H B or a combination thereof, 4-(7-hydroxy-2-isopropyl-4-oxopropyl) a suspension of 2-iso-4H-quinazolin-3-yl)-benzonitrile (Compound I); nonionic surfactants; suspending agents; Isotonic agent; buffer; salt; and Optionally, a preservative It is a formulation comprising:

[0021] In some embodiments, the present disclosure provides: Crystalline form K', crystal form M, crystal form K', in an amount of about 0.5% w / v to about 3.5% w / v. Form Q, hydrate H B or a combination thereof, 4-(7-hydroxy-2-isopropyl-4-oxopropyl) a suspension of 2-iso-4H-quinazolin-3-yl)-benzonitrile (Compound I); selected from the group consisting of nonionic, anionic, cationic surfactants and combinations thereof surfactants; suspending agents; Isotonic agent; buffer; Optionally, salt; optionally a preservative; and Water (qs) sufficient to make 100% The present invention relates to a formulation comprising:

[0022] In some embodiments, the formulation comprises a non-ionic surfactant. In some embodiments of the formulation, the nonionic surfactant is a polysorbate surfactant. , block copolymer of ethylene oxide, propylene oxide surfactant, poloxamer , tyloxapol, and combinations thereof.

[0023] In some embodiments of the formulations described herein, the non-ionic surfactant may be at least at least about 0.001% w / v, at least about 0.01% w / v, at least about 0.02% w / v, at least about 0.03% w / v, or at least about 0.04% w / v; and About 1% w / v or less, about 0.5% w / v or less, about 0.3% w / v or less, or about 0.2% w / v Tyloxane present in an amount of about 0.1% w / v or less, or about 0.08% w / v or less In some embodiments, tyloxapol is about 0.03% w / v to 0. It is present in an amount of about 0.08% w / v or about 0.05% w / v.

[0024] In some embodiments of the formulations described herein, the nonionic surfactant is Poloxamer in an amount of about 15% w / v to about 20% w / v of the active ingredient.

[0025] In some embodiments of the formulations described herein, the suspending agent is a carbomer, hydrochloride, Hydroxypropyl methylcellulose (hypromellose), polyethylene glycol and its combinations In some embodiments, the suspending agent is selected from the group consisting of at least about 0. 0.5% w / v, at least about 0.1% w / v, or at least about 0.2% w / v, and in an amount of about 1.0% w / v or less, about 0.6% w / v or less, or about 0.5% w / v or less Carbomer present in the formulation. In some embodiments, the carbomer is 0.1% It is present in the formulation in an amount of from about 0.3% w / v to about 0.2% w / v.

[0026] In some embodiments of the formulations described herein, the suspending agent has a viscosity of at least about 0.0 5% w / v, at least about 0.1% w / v, or at least about 0.25% w / v, and less than about 1.8% w / v, less than about 1.0% w / v, less than about 0.8% w / v, or less than about 0.6% Hydroxypropyl methylcellulose present in the formulation in amounts less than w / v. In some embodiments, the suspending agent has a molecular weight of about 200 Da to about 20,000 Da. In some embodiments, the suspending agent is polyethylene glycol (PEG). % w / v to about 9% w / v, about 5% w / v to about 8% w / v, or about 7% w / v EG400 or about 1% w / v to about 4% w / v, about 1% w / v to about 3% w / v, or about 2 % w / v concentration of PEG 6000.

[0027] In some embodiments of the formulations described herein, the suspension contains substantially all of the cal It is a Bomer homopolymer type B.

[0028] In some embodiments of the formulations described herein, the osmotic agent comprises a polyol. The compound is selected from the group consisting of:

[0029] In some embodiments of the formulations described herein, the polyol is mannitol, Glycerin, xylitol, sorbitol and propylene glycol and combinations thereof In some embodiments, the polyol is selected from the group selected from about 0.05% w / v ~ approx. 10% w / v, approx. 0.1% w / v ~ approx. 8% w / v, approx. 0.1% w / v ~ approx. 7% In certain embodiments, the compound is present in an amount of about 0.1% w / v to about 5% w / v. Polyols are 0.1% w / v to about 5% w / v, or about 0.2% w / v, about 0.3% w / v , approx. 0.4%w / v, approx. 0.5%w / v, approx. 1%w / v, approx. 2%w / v, approx. 2.5%w / v, about 3.0% w / v, about 3.5% w / v, about 4.0% w / v, about 4.5% w / v or about Mannitol or glycerin present in the formulation in an amount of 5% w / v.

[0030] In some embodiments of the formulations described herein, the buffer may be selected from the group consisting of acetate, ascorbic acid, PEG-1, PEG-2, PEG-3, PEG-4, PEG-5, PEG-6, PEG-7, PEG-8, PEG-9, PEG-10, PEG-11, PEG-12, PEG-13, PEG-14, PEG-15, PEG-16, PEG-17, PEG-18, Phosphate, borate, bicarbonate, carbonate, citrate, edetate (EDTA) gluconate From the group consisting of salts, lactates, phosphates, propionates and TRIS (tromethamine) In certain embodiments, the buffer is phosphate or TRIS.

[0031] In some embodiments of the formulations described herein, the salt is sodium chloride or chloride It is potassium.

[0032] In some embodiments of the formulations described herein, the suspending agent is carbopol (Carbopol The amount of sodium chloride is 60 r at about 25°C. When using the CP-42 spindle at 20 ... In some embodiments, the sodium chloride is adjusted to about 0.01% w / w. / v ~ approx. 0.5%w / v, approx. 0.02%w / v ~ approx. 0.4%w / v, approx. 0.03%w / v ~0.3%w / v, approx.0.04%w / v~0.2%w / v, approx.0.05%w / v~approx. It is present in an amount of 0.1% w / v or about 0.05% w / v.

[0033] In some embodiments of the formulations described herein, the pH of the formulation is from about 5.5 to about 8. In some embodiments, the pH of the formulation is about 6.0 to about 8.0, about 6.0 or is about 7.4.

[0034] In some embodiments, the formulations described herein comprise at least about 1.5 w / v% , at least about 3.0 w / v%, at least about 3.5 w / v%, or at least about 4.5 w / v% / v%, but not more than about 10.0 w / v%, not more than about 8.0 w / v%, not more than about 6.5 w / v% cyclodextrin in an amount of less than or equal to about 5.5 w / v% In some embodiments, the cyclodextrin comprises about 5% of the formulation. Hydroxypropyl β-cyclodextrin or sulfoalkyl ester in an amount of % w / v It is ether β-cyclodextrin.

[0035] In some embodiments, the present disclosure provides: Crystalline form K', crystal form M, crystal form K' in an amount of about 0.5% w / v to about 2.5% w / v Q, hydrate H B or a combination thereof, The nonionic surfactants include tyloxapol, polyisoprene, and PEG-100 in an amount of about 0.01-0.2% w / v. loxamer or a combination thereof; The suspending agent may be hydroxypropyl methylcellulose, polyethylene glycol or carbamazepine. - homopolymer type B; The tonicity agent may comprise at least one polio inhibitor in an amount of about 0.05% w / v to about 10% w / v. It is a rule; the buffer is edetate, phosphate, borate or a combination thereof; salt; and Contains up to 100% qs water; and The pH of the formulation ranges from about 5.5 to about 8.0.

[0036] In some embodiments, the present disclosure provides: About 0.5% w / v, about 1.0% w / v, about 1.5% w / v, about 2.0% w / v, or about 2 Crystalline form K', crystal form M, crystal form Q, hydrate H, present in an amount of 0.5% w / v B or a combination thereof, Compound I Tyloxapol in an amount of about 0.04 w / v to about 0.06% w / v, about 0.005 to 0 a nonionic surfactant which is a poloxamer or a combination thereof in an amount of .12% w / v; Hydroxypropyl methylcellulose in an amount of about 0.1% w / v to about 0.8% w / v , polyethylene glycol in an amount of about 2% w / v to about 8% w / v, about 0.05% w / Carbomer homopolymer type B or combinations thereof in an amount of about 0.5% w / v to about 0.5% w / v turbiding agents; Isotonicity enhancer, which is mannitol or glycerin in an amount of about 0.1% w / v to about 5% w / v Agents; a buffer that is edetate, phosphate, borate, tromethamine, or a combination thereof; Sodium chloride in an amount of 0.01% w / v to about 1% w / v; and Contains up to 100% qs water; and The formulation has a pH ranging from about 5.5 to about 8.0.

[0037] In some embodiments, the present disclosure provides: About 0.5% w / v, about 1.0% w / v, about 1.5% w / v, about 2.0% w / v, or about 2 Crystalline form K', Crystalline form M, Crystalline form Q, Hydrate H in an amount of 0.5% w / v B Or The combination of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline- a suspension of 3-yl)-benzonitrile (Compound I), Tyloxapol in an amount of about 0.04 w / v to about 0.06% w / v; Carbomer homopolymer type B in an amount of about 0.05% w / v to about 0.4% w / v; glycerin in an amount of about 0.5% w / v to about 5% w / v; Selected from the group consisting of edetate, phosphate, borate, tromethamine, and combinations thereof. buffer solutions; Sodium chloride in an amount of 0.01% w / v to about 1% w / v; and Up to 100% qs water A formulation comprising: The formulation has a pH in the range of about 5.5 to about 8.0.

[0038] In some embodiments of the formulations described herein, Compound I is polymorphic Form B.

[0039] In some embodiments, the formulations described herein have a viscosity of about 20 cP to about 200 cP. It has viscosity.

[0040] In some embodiments, the formulations described herein contain from about 200 to about 450 per kilogram. It has an osmolality of milliosmoles per gram (mOsm / kg).

[0041] In some embodiments of the formulations described herein, the D 90 (Compound I The diameter (90% of which is made up of smaller particles) is less than about 10 μm, less than about 8 μm, and less than about 6 μm. In some embodiments, the diameter of the compound is less than about 4 μm, less than about 3 μm, or less than about 2 μm. D of compound I in the preparation 50 (the diameter at which 50% of Compound I is composed of smaller particles) is approximately Less than 10 μm, less than about 8 μm, less than about 6 μm, less than about 4 μm, less than about 3 μm, less than about 2 μm In some embodiments, the D of Compound I in the formulation 10 (Compound I The diameter (of which 10% of particles are smaller) is less than about 5 μm, less than about 4 μm, and less than about 3 μm. The thickness is less than about 1 μm, less than about 2 μm, less than about 1 μm, or about 0.3 μm.

[0042] In some embodiments, the present disclosure provides treatment of ocular surface pain in a subject in need thereof. 10. A method for treating a skin ulcer comprising administering to a subject a subject having the following composition: [ka] 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 -yl)-benzonitrile (compound of formula I) or a salt, solvate, polymorph or conjugate thereof The method includes administering a crystal to a subject.

[0043] 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 In some embodiments, the compound of Formula I is a compound of Formula I. The composition is administered to the cornea of ​​the subject.

[0044] In some embodiments, the COSP is associated with dry eye disease. In embodiments, administration results in a reduction in the symptoms of dry eye disease. In some embodiments, administration results in a reduction in pain associated with dry eye disease. Symptoms include dry eyes, eye discomfort, bloodshot eyes, burning or stinging in the eyes, roughness or foreign body sensation. The present invention provides a reduced incidence of at least about 10% in one or more of the following: irritability, dizziness, or photophobia.

[0045] In some embodiments, the subject is diagnosed with dry eye disease, Sjogren's syndrome, conjunctivitis (keratoconjunctivitis), or Conjunctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), corneal epithelial basement membrane dystrophy, Acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, eczema Keratoconus, ocular pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy Corneal dystrophy (including LASIK-induced corneal neuropathy) corneal erosion or abrasion (including recurrent corneal ulcers) ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, corneal abrasion, ocular erosion, corneal abrasion, ocular surface disease, blepharitis, graft-versus-host disease, ocular surface ... Conjunctivitis, glaucoma, conjunctival laxity, keratopathy (herpetic keratopathy, filamentous keratopathy, band-like or bullous keratopathy) Keratopathy (including lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis , episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, nerve Patients recovering from nutritional keratitis or undergoing photorefractive keratectomy (PRK) surgery or persists for at least 3 months after laser in situ keratomileusis (LASIK) surgery suffer from one or more of the following eye pain conditions:

[0046] In some embodiments, the methods include administering an additional therapeutic agent to the subject.

[0047] In some embodiments, administration provides a decrease in serotonin levels by at least about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least resulting in a reduction in pain score on the visual acuity scale (VAS) of about 9 or at least about 10 In some embodiments, the reduction in VAS score is measured before and after administration of Compound I to the subject. The reduction in VAS score results from the difference in VAS score. In some embodiments, the reduction in VAS score results from the difference in VAS score. within about half an hour, about one hour, about two hours, about four hours, or within about one hour after administration of Compound I to a subject Occurs in approximately 2 to 4 hours.

[0048] In some embodiments, administration of Compound I may result in a response rate of 0.01 to 0.01 on the McMonnies scale: At least about 1, at least about 2, at least about 3, at least about 4, or at least about 5 resulting in a reduction in congestion in the subject.

[0049] In some embodiments, administration results in an improvement in best corrected visual acuity, intraocular pressure, slits, and the like compared to placebo. Changes in one or more of the following: light biomicroscopy, mydriasis, blink rate, tear production, and corneal staining. It does not bring about transformation.

[0050] In some embodiments, the compound of formula I is in the form of a formulation described herein. In some embodiments, the formulation is administered for at least about 1, about 2, or about 3 months. In some embodiments, the formulation is administered one to four times daily.

[0051] In some embodiments, the present disclosure provides a method for treating ocular surface pain comprising administering to a subject the method of the present disclosure a method for treating ocular surface pain. In some embodiments of the above uses, the ocular surface pain is treated by: paroxysmal (e.g., bronchial) attacks lasting at least 1 month, at least 2 months, or at least 3 months Acute (e.g., acute) ocular surface pain or chronic ocular surface pain.

[0052] In some embodiments, the present disclosure provides a method for reducing ocular surface pain in a subject in need thereof. 1. A method for carrying out a method 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 method includes administering an eye drop to the patient.

[0053] In some embodiments, the ocular surface pain is paroxysmal (e.g., acute) ocular surface pain; The ocular surface pain is chronic ocular surface pain (COSP). In some embodiments, COSP is associated with dry eye disease.

[0054] In some embodiments, administration results in a reduction in the symptoms of dry eye disease.

[0055] In some embodiments, administration results in a reduction in pain associated with dry eye disease. In some embodiments, administration may be associated with dryness of the eye, eye discomfort, eye redness, or burning or stinging of the eye. At least about 10% reduction in one or more of the symptoms of: Brings about survival rate.

[0056] In some embodiments, the subject is diagnosed with dry eye disease, Sjogren's syndrome, conjunctivitis (keratoconjunctivitis), or Conjunctivitis, vernal keratoconjunctivitis, allergic conjunctivitis), corneal epithelial basement membrane dystrophy, Acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, eczema Keratoconus, ocular pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy Corneal dystrophy (including LASIK-induced corneal neuropathy) corneal erosion or abrasion (including recurrent corneal ulcers) ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, corneal abrasion, ocular erosion, corneal abrasion, ocular surface disease, blepharitis, graft-versus-host disease, ocular surface ... Conjunctivitis, glaucoma, conjunctival laxity, keratopathy (herpetic keratopathy, filamentous keratopathy, band-like or bullous keratopathy) Keratopathy (including lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis , episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia or glaucoma In some embodiments, the patient is suffering from one or more of the following: The subjects were those who underwent photorefractive keratectomy (PRK) or laser ablation (LA) surgery. Suffering from persistent ocular pain for at least 3 months after SIK surgery. In some embodiments, the methods include administering an additional therapeutic agent to the subject.

[0057] In some embodiments, administration provides a decrease in serotonin levels by at least about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 about 4, at least about 5, at least about 6, at least about 7, at least about 8, at least resulting in a reduction in pain score on the visual acuity scale (VAS) of about 9 or at least about 10 In some embodiments, administration provides a reduction in serotonin levels by at least about 6, at least about 10, or at least about 20% compared to placebo. a reduction in VAS pain score of about 7, at least about 8, at least about 9, or at least about 10 In some embodiments, the reduction in pain score is measured prior to administration of Compound I to the subject. In another embodiment, the reduction in pain score results from the difference in pain scores after administration of Compound I. In some embodiments, the reduction in pain score occurs about 7 days after administration of the compound to the subject. This occurs approximately 14 days after administration of Compound I to the subject.

[0058] In some embodiments, administration is at least In about 1, at least about 2, at least about 3, at least about 4, or at least about 5 subjects This results in a reduction of congestion.

[0059] In some embodiments, administration results in a VAS score that is at least as high as the VAS score prior to administration of the compound. Both treatments result in a reduction in pain scores on the visual analog scale (VAS) of approximately 3.

[0060] In some embodiments of the recited methods, the compound of Formula I is, as described herein, It is administered in the form of a formulation.

[0061] Certain preferred embodiments of the present invention are described in detail in the following preferred embodiments and claims. This will become apparent from the more detailed description below. [Brief explanation of the drawings]

[0062] [Figure 1] 1 provides an X-ray diffraction pattern of crystalline form K′ of Compound I. [Figure 2] 1 provides a differential scanning calorimetry scan of crystalline form K′ of Compound I. [Figure 3] 1 provides a scanning electron image of crystalline form K′ of Compound I. [Figure 4] 1 provides an X-ray powder diffraction pattern of crystalline form M of Compound I. [Figure 5] 1 provides an alternating differential scanning calorimetry scan of crystalline Form M of Compound I. [Figure 6] 1 provides a scanning electron image of crystalline Form M of Compound I. [Figure 7] 1 provides an X-ray powder diffraction pattern of hydrate HB of Compound I. [Figure 8] 1 provides an alternating differential scanning calorimetry scan of crystalline Form M of Compound I. [Figure 9] 1 provides a scanning electron image of hydrate HB of Compound I. [Figure 10] 1 provides an X-ray powder diffraction pattern of crystalline form Q of Compound I. [Figure 11] 1 provides an alternating differential scanning calorimetry scan of crystalline form Q of Compound I. [Figure 12] 1 provides a scanning electron image of crystalline form Q of Compound I. DETAILED DESCRIPTION OF THE INVENTION

[0063] The TRPV1 receptor is a transient receptor that has been characterized by molecular cloning and pharmacology. This refers to receptor potential vanilloid 1. For example, Caterina MJ, et al.,. See Nature 1997;389:816-824. The properties are described in WO 2005 / 120510, which is hereby incorporated by reference in its entirety. Measurements are taken as described in the brochure.

[0064] The term "effective amount" of a compound described herein is an amount sufficient 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 produce a therapeutic effect in a mammal. the amount of causative agent already present in the mammal, the age, sex and body weight of the mammal and the ocular Depending on factors such as the ability of the therapeutic compounds of the present disclosure to treat the surface disorder and / or its symptoms, Therefore, it may vary.

[0065] The phrase "ophthalmologically compatible" means that the patient is provided with a reasonable benefit / risk ratio without excessive toxicity. on human and animal ocular tissues without adverse reactions, 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 .

[0066] As used herein, the terms "treat" and "treat" in relation to a disease or disorder are used interchangeably. "Treating" or "treating" in some embodiments refers to ameliorating (or improving) a disease or disorder. i.e., slowing or preventing the development of the disease or at least one of its clinical symptoms, or In another embodiment, "treatment" refers to "reducing" or "treating." " is defined as the measurement of at least one physical parameter, including those that may not be discernible by the patient. In yet another embodiment, "treating" or "treating" refers to reducing or ameliorating the disease. "Treatment" or "treatment" refers to any effect, whether physical (e.g., stabilization of discernible symptoms), physiological (e.g., modulating the disease or disorder by either or both of the following: In yet another embodiment, "treat," "treating," or "treatment" refers to the treatment of a disease. refers to preventing or delaying the onset, development, or progression of a disease or disorder or its symptoms. vinegar.

[0067] 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 a disease and who would benefit from treatment. The effect is that such subject (patient) will not suffer any biological, medical or life-threatening effects from such treatment. In certain embodiments, a subject is "in need of" treatment if they would benefit in quality. In some embodiments, the subject is an adult human at least about 18 years of age. In some embodiments, the subject is a child under the age of about 18. .

[0068] As used herein, "ocular surface" refers to the anatomical surface of the cornea (epithelium, Bowman's layer, corneal septum, the outer surface of the eye, including the stroma, Descemet's membrane, and endothelium), the conjunctiva, the conjunctival sac, and the limbus, i.e., the edge Point to the face.

[0069] As used herein, "pain" includes, but is not limited to, stabbing, dull, sharp or Pain refers to the sensation of real pain, either constant or intermittent, described as a tingling sensation. No burning, stinging, roughness, foreign body sensation, dryness, sandy, tired, itchy, prickling It also refers to similar related descriptors such as sensitivity to light and rash.

[0070] As used herein, ocular administration refers to administration to the cornea, conjunctiva, conjunctival sac, and 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.

[0071] 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 can be nociceptive pain caused by chemical or damaging stimuli. It also blocks pain messages sent to the central nervous system and brain despite the presence of noxious stimuli. This stems from neuropathic pain, which can result from direct damage to the body's neurons. As used herein, "ocular surface pain" refers to nociceptive pain. This includes both neuropathic and muscular pain.

[0072] As used herein, the term "visual analog scale" (VAS) refers to a scale that a subject typically uses to measure their On the pain intensity scale, mark the location relative to the scale to align with the level of pain. Pain was assessed on a scale of 'no pain' (score of 0) and 'worst pain' or 'worst pain imaginable'. Pain is marked on a scale of 1 to 100. For example, Hawker, et al. al.,Arthritis Care & Research 63(11),pp. See S240-S252 (November 2011). Assess pain severity. There are several other well-designed pain scales that can be used to help. A numerical rating scale (NRS) is used in which subjects use numbers to rate pain. The numerical scale can be 1 to 10 or 1 to 100. The FACES pain scale combines pictures and numbers to rate pain. It can be used in children over 3 years of age and in adults. Six faces range from good to very poor. Represents different facial expressions in a range of tones, each ranging from 0 (smiling) to 10 (crying). The verbal pain intensity scale assigns a numerical rating of pain intensity to a rating. Use verbal descriptions on a rating scale: no pain / mild pain / moderate pain Moderate pain / severe pain Very severe pain / no pain at all.

[0073] The Ocular Sensation Scale is a specialized 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. is measured by the category label.

[0074] 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 vasopressin levels allows for monitoring of therapeutic response. Ophthalmology July 123(7):1458-1468(2016 ) for more information.

[0075] As used herein, the term "visual task questionnaire" refers to the assessment of fixations that may exacerbate 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 the degree of visual impairment. The participants were also asked about the difficulties they experienced while performing the task and the associated coping mechanisms.

[0076] 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 typically assessed based on standard photographs. It is measured using the McMonnies scale with values ​​from 0 to 5.

[0077] As used herein, "placebo" refers to the entirety of a drug composition that does not contain any administered drug. It refers to an eye drop preparation containing all the ingredients.

[0078] As used herein, the term "about" refers to a range of the specified value plus 10%.

[0079] As used herein, a "polymorph" is a compound that has the same chemical composition but forms crystals. Refers to crystalline forms that have different spatial arrangements of molecules, atoms and / or ions.

[0080] As used herein, a "solvate" refers to one or more compounds incorporated into a crystalline lattice structure. A crystalline form of a molecule, atom, and / or ion that further contains a number of molecules of a solvent. The solvent molecules in the solvate may be present in an ordered and / or disordered arrangement. It may contain either stoichiometric or non-stoichiometric amounts of solvent molecules. A solvate with a hydroxyl group can result from partial loss of solvent from a solvate. The product may be present as a dimer or oligomer containing two or more molecules of compound I within the crystal lattice structure. It can exist.

[0081] As used herein, "amorphous" refers to a material that is not crystalline, that is composed of molecules, atoms and / or ions. Amorphous solids do not exhibit definitive X-ray diffraction patterns.

[0082] As used herein, "substantially pure" when used in reference to a form The purity of Compound I is greater than 90% by weight, based on its weight, for example, 90, 91, 92, 9 Purity of greater than 3, 94, 95, 96, 97, 98 and 99% by weight, and also, for example, about 10 The remaining material may be other forms of the compound and and / or reaction and / or processing impurities arising from their preparation. The crystalline forms of Compound I are known at this time and can be obtained by means generally accepted in the art. It may be considered substantially pure by having a purity of greater than 90% by weight as measured by The remaining less than 10% by weight of the material may be other forms of Compound I and / or reaction impurities and / or Contains processing impurities.

[0083] As used herein, "compound of Formula I," "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-quinazoline) It refers to compounds having a benzonitrile group, and is known to those skilled in the art and has both Chen et al., International Publication No. 2005 / 112624, the entire disclosure of which is hereby incorporated by reference. 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]

[0084] As used herein, "crystal form" in upper or lower case "crystalline form," "modified form," or "multiple forms" The terms "crystalline form" or "polymorphic form" are used interchangeably and refer to a crystalline or polymorphic form of Compound I. Compound I may be used in amorphous or crystalline form. Additionally or alternatively, Various crystalline and polymorphic forms of Compound (I) may be used. A "polymorphic form" or "polymorph" of Compound (I) refers to a crystalline hydrate or other crystalline form of Compound (I). The term "solvates" is intended to encompass both hydroxyl and hydroxypropyl solvates.

[0085] 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. by the formula given herein except that the atoms are replaced by atoms having the quantification numbers Isotopes that can be incorporated into 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. Therefore, the method of the present invention can be carried out, for example, by 3 H and 14 Radioactive isotopes such as C or 2 H and 13 Any one of the aforementioned isotopes, including those that exist as non-radioactive isotopes such as C It should be understood that the composition may or may contain 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 ( detection or imaging techniques such as 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 typically For example, by using appropriate isotopically labeled reagents in place of previously utilized unlabeled reagents, They may be prepared by conventional techniques known to those skilled in the art.

[0086] The present invention includes all pharmaceutically acceptable carriers of the compounds useful according to the invention provided herein. As used herein, "pharmaceutically acceptable salts" includes embodiments that include salts thereof. refers to derivatives of the disclosed compounds, the parent compound being a derivative of the disclosed compound, with any acid or base moiety present removed from its parent compound. The compound is modified by converting it into a salt form. Examples of pharmaceutically 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 from compounds containing 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 non-aqueous media such as alcohol, isopropanol or acetonitrile) It can be prepared by reacting with a stoichiometric amount of an appropriate base or acid. The text is based on Remington's Paper 1999, each of which is incorporated herein by reference in its entirety. Pharmaceutical Sciences,17th ed.,Mack Pub Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science,66,2(1 977). For example, preferred pharmaceutically 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 the hydrochloride salt. Other examples of suitable salts are listed in US Pat. No. 6,49 ... the contents of which are hereby incorporated by reference in their entirety. This can be found in US Pat. No. 8,349,852.

[0087] As used herein, the phrase "pharmaceutically acceptable" means any substance that is acceptable to the public using sound medical judgment. within the limits of reasonable benefit / risk ratios, without excessive toxicity, irritation, or allergies. - Use in contact with human and animal tissues without reactions or other problems or complications "compounds, substances, compositions and / or dosage forms" refers to those compounds, substances, compositions and / or dosage forms that are suitable for

[0088] Unless otherwise indicated, all ingredient concentrations are in % weight / volume (%w / v) units. As is commonly understood, % w / v values ​​are used to calculate the percentage of a particular component or ingredient in a formulation. It is generally understood that equivalent concentrations can be expressed in different units, e.g. , a concentration of 0.1% w / v can also be expressed as a 1 mg / ml solution.

[0089] Unless otherwise specified, weights or dosages referred to herein for compounds of Formula I are , or salts or prodrugs thereof, which may differ to achieve the desired therapeutic effect. For example, the weight or dosage of the compound itself is not the weight or dosage of the compound itself. The weight or dosage of the corresponding salt of a compound suitable for combination depends on the molecular weight of the salt and the compound itself. It can be calculated based on a ratio.

[0090] Crystalline Form B of Compound I is disclosed in U.S. Pat. No. 8,349, incorporated herein by reference. Polymorph B is described in U.S. Pat. No. 852. Polymorph B has 9.3, 10.6 and 14.4±0.2 characterized by an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from In some embodiments, polymorph B is represented by the formulas 9.3, 10.6, 14.4, 15. Three or more 2θ values ​​selected from 0.5, 17.9, 19.9, and 23.4±0.2°2θ It is characterized by an X-ray diffraction pattern with peaks.

[0091] Crystalline Form of Compound I In one aspect, the present invention provides a method for manufacturing a holographic optical fiber having a wavelength of 100 nm or less selected from 5.3, 12.3, and 22.5±0.2 degrees 2θ. 4-(7-hydroxy- 2-Isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound In some embodiments, crystalline form K' of compound I is Select from 5.3, 10.6, 12.3, 21.2, 22.5, and 23.0±0.2°2θ It is characterized by an X-ray diffraction pattern having three or more peaks at selected 2θ values. In some embodiments, the crystalline form K′ is selected from the group consisting of 5.3, 10.6, 12.3, 17.0, 1 7.3, 19.4, 20.3, 21.2, 22.5, 23.0, 24.8, 27.1, 3 2θ values ​​selected from 2.0±0.2°2θ, 3 or more, 4 or more, 5 or more, 6 or more They are characterized by an X-ray diffraction pattern with seven or more peaks. In one embodiment, the present invention provides a method for preparing crystalline form K′ of compound I, comprising: A solution of Compound I in n-butanol / dichloromethane (v / v) was evaporated to obtain Compound I. as crystalline form K'.

[0092] In one embodiment, crystalline form K' of compound I is provided in substantially pure form. This crystalline form K' of compound I in substantially pure form can be used in pharmaceutical compositions, such as those described herein. In some embodiments, the present disclosure provides crystalline form K'. In some embodiments, the present disclosure provides a pharmaceutical formulation comprising Compound I of formula (I). An ophthalmic suspension is provided, wherein at least 10%, at least about 20%, at least about 10% of Compound I is at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least At least about 70%, at least about 80%, or at least 90% is present as crystalline form K'. do.

[0093] In one aspect, the present invention provides an optical fiber having a wavelength of 11.1, 18.5, 19.1±0.2 degrees 2θ. 4-(7-hydroxy-2-methyl ... -isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound In a particular embodiment, crystalline form M of compound I is 11.1, 2θ selected from 12.1, 18.5, 19.1, 20.1, 21.4±0.2°2θ It is characterized by an X-ray diffraction pattern with three or more peaks at In embodiments, crystalline form M is selected from the group consisting of 11.1, 12.1, 18.5, 19.1, 20.1, 21 .4, 21.7, 22.2, 23.1, 26.4, 273, 29.7±0.2°2θ 3 or more, 4 or more, 5 or more, 6 or more, or 7 or more peaks at the selected 2θ values In some embodiments, the present invention provides a method for producing a crystalline silicon nanoparticle having an X-ray diffraction pattern of A method for preparing crystalline form M of compound I, comprising: The crystallization of crystalline form B is continued for at least 2 days, at least 3 days, at least 4 days, or at least 5 days. Alternatively, crystalline form M may be obtained by a method comprising the steps of: Crystalline Form B of Compound I was isolated by precipitation in a 1:1 mixture of acetone, ethanol, and ethanol at 0°C for 2 weeks. obtained by slurrying in ethanol / water, methanol, or 1:1 methanol / water. can be done.

[0094] In one embodiment, crystalline form M of compound I is provided in substantially pure form. This crystalline Form M of Compound I in a substantially pure form can be used in pharmaceutical compositions, such as those described herein. In some embodiments, the present disclosure provides a compound in crystalline form M. In some embodiments, the present disclosure provides pharmaceutical formulations comprising Compound I. a suspension, wherein at least 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least About 70%, at least about 80% or at least 90% is present as crystalline form M.

[0095] In one aspect, the present invention provides a method for producing a 2θ angle selected from 6.6, 12.2, 15.8±0.2 degrees 2θ. 4-(7-hydroxy-2- Isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Compound I ) crystalline hydrate H B In certain embodiments, the crystalline hydrate H of compound I is B , _6 .6, _12.2, _14.6, 15.8, 16.1, 18.5, 20.9, 24.7± An X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from 0.2° 2θ In some embodiments, the hydrate H B 6.6, 11.7, _12 .2, _14.6, 15.8, 16.1, 18.5, 19.7, 20.9, 24.7, 2 2θ values ​​selected from 6.5, 27.7, 29.3±0.2°2θ, and 3 or more, 4 or more characterized by an X-ray diffraction pattern with five or more, six or more, or seven or more peaks In some embodiments, the present invention provides a crystalline hydrate of Compound I, H B Prepare The method of claim 1, wherein the solubility is increased by at least 5 days, at least 6 days, or at least 7 days at room temperature. Crystalline Form B of Compound I was slurried in a mixture of acetone and water in a ratio of about 1:1 to form a crystalline form of Compound I. Crystalline hydrate H B and providing the compound as a compound of formula (I).

[0096] In one embodiment, hydrate H of Compound I B is provided in substantially pure form. This hydrate H of compound I in pure form B may be used in pharmaceutical compositions, e.g., In some embodiments, the present disclosure provides for the preparation of Compound I as a hydrate. H B In some embodiments, the present disclosure provides a pharmaceutical formulation comprising Compound I. An ophthalmic suspension is provided, wherein at least 10%, at least about 20%, at least about 10% of Compound I is At least about 30%, at least about 40%, at least about 50%, at least about 60%, or at least At least about 70%, at least about 80%, or at least 90% of the hydrate H B Exist as do.

[0097] In one aspect, the present invention provides an optical fiber having an optical axis selected from 11.2, 12.2, 19.1±0.2 degrees 2θ. 4-(7-hydroxy-2-methyl ... -isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound In certain embodiments, crystalline form Q of compound I is 11.2, 12.2, 18.5, 19.1, 20.1, 22.0, 22.5, 23.3, 26.5± An X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from 0.2° 2θ In some embodiments, crystalline form A is characterized by: 11.2, 12.2, 17. .7, 18.5, 19.1, 20.1, 22.0, 22.5, 23.3, 24.2, 24 2θ values ​​selected from 0.6, 26.5, 28.5±0.2°2θ, 3 or more, 4 or more characterized by an X-ray diffraction pattern having five or more, six or more, or seven or more peaks. In some embodiments, the present invention provides compounds of compound I according to claims 10-11. A method for preparing crystalline form Q of compound I, comprising dissolving crystalline form B of compound I in about a 1:1 (v / v) ratio of n-butanol. and slurrying in methanol / dichloromethane to obtain Compound I as crystalline form Q. Regarding the method.

[0098] In one embodiment, crystalline form Q of compound I is provided in substantially pure form. This crystalline Form Q of Compound I in pure form can be used in pharmaceutical compositions, e.g., as described herein. In some embodiments, the present disclosure provides compound I in a crystalline form. In some embodiments, the present disclosure provides a pharmaceutical formulation comprising Compound I in an ophthalmic form. a suspension, wherein at least 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least About 70%, at least about 80%, or at least 90% is present as crystalline form Q.

[0099] In some embodiments, the present invention provides formulations of compounds of Formula I. In some embodiments, the formulation is an aqueous suspension of the compound of Formula I. In some embodiments, the suspension is about 0.5% w / v to about 1.5% w / v, about 0.5% w / v to about 2.5% w / v, about 0 .5%w / v ~ approx. 3.5%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 ~ approx. In some embodiments, the topical ophthalmic solution contains a compound of Formula I at a concentration of 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 About 1.0% w / v, at least about 1.5% w / v, at least about 2.0% w / v or less In some embodiments, in formulations for topical use, 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 In certain embodiments, the amount of HCl is about 3.5% w / v or less, about 3.0% w / v 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 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 / v When expressed in mg / ml, in some embodiments, The compound of formula I may be used in an amount of from about 5 mg / ml to about 35 mg / ml, from about 5 mg / ml to about 25 mg / ml / ml or about 5mg / ml to about 15mg / ml, about 5mg / ml to about 30mg / ml, about 10 mg / ml to about 25 mg / ml, about 15 mg / ml to about 30 mg / ml, or about 5 mg In some embodiments, topical administration is administered to a subject at a concentration of about 25 mg / ml to about 25 mg / ml. The concentration of the compound of formula I in the formulation for such use is at least about 5 mg / ml, at least About 10 mg / ml, at least about 15 mg / ml, at least about 20 mg / ml or less In some embodiments, in formulations for topical use, The concentration of the compound of formula I is about 50 mg / ml or less, about 45 mg / ml or less, about 40 mg / ml or less ml or less, about 35 mg / ml or less, or about 30 mg / ml or less. , the compound of formula I is about 5 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25mg / ml, about 30mg / ml or about 35mg / ml In some embodiments, the compound of formula I is crystalline form K', crystalline form M, crystalline form Q, Hydrate H B or a combination thereof. In some embodiments, Compound I is present in the form of It is present in substantially pure form as crystalline form K' in the ophthalmic formulations described herein. In some embodiments, Compound I is present in substantially pure form in the ophthalmic formulations described herein as crystalline M In some embodiments, Compound I is present in the ophthalmic formulations described herein. Hydrate H in qualitatively pure form BIn some embodiments, compound I is present as: It is present in substantially pure form as crystalline form Q in the ophthalmic formulations described herein. In embodiments, Compound I is present in the formulation as a mixture of two or more crystalline forms in different ratios. In some embodiments, compound I has crystalline forms B and K′, crystalline forms B and M, Crystal form B and hydrate H B , crystalline forms B and Q, crystalline form M and hydrate H B Approximately 1:99 It exists as a mixture in a ratio of about 99:1.

[0100] In some embodiments, the formulation further comprises at least one ophthalmically acceptable excipient. Included.

[0101] In some embodiments, the formulation includes an ophthalmically acceptable surfactant. In embodiments, the surfactant is an anionic surfactant. The ionic surfactants are C 10 ~C 22 Alkyl sulfate, C 10 ~C 22 Alkyl (oligo Oxyalkylene) sulfate, C4-C 22 Alkyl sulfosuccinate ester, C 10 ~C 22 Acyl sarcosinate and C 10 ~C 22 alkyl carboxylates; The oligooxyalkylene moiety may be 1 to 5 oxy-C1-C6 alkylene moieties, e.g. , oxyethylene moiety. Anionic surfactants are those containing alkali metals, e.g., naphthalene, ammonium, C1-C3 alkylammonium, tri(C1-C3 alkanol)ammonium ammonium, for example, triethanolammonium, di(C1-C3 alkanol)ammonium and ammonium cations. The surfactant concentration is about 0.005 to 0.1 g / L or 0.005 to 0.05 g / L. In some embodiments, the surfactant is a cationic surfactant. Non-limiting examples of surfactants include alkylamine salts, alkylamine polyoxyethylene fatty acid triethanolamine monoester salt, acylaminoethyl diethylamine amine salt, fatty acid polyamine condensate, alkyl imidazoline, 1-acylaminoethyl-2 -alkylimidazoline, 1-hydroxyethyl-2-alkylimidazoline, , its salts such as chlorhexidine, chlorhexidine or its salts, e.g., chlorhexidine In some embodiments, the cationic surfactant is about 0.001% w / v to about 5% w / v, or about 0.001% w / v to about 1% w / v, or about 0.001% w / v to about 0.1% w / v, or about 0.001% w / v to about 0.01% w / v, or from about 0.001% w / v to about 0.005% w / v.

[0102] In certain embodiments, the surfactant is a non-ionic surfactant. In this embodiment, nonionic surfactants include polysorbate surfactants, ethylene oxide and propanediol. Propylene oxide block copolymer surfactants (e.g., Pluronic or Tetronic types) poloxamer, tyloxapol, or a combination thereof. The alcohols are non-ionic liquid polymers of the alkylaryl polyether alcohol type. Poloxamers consist of two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)). Consists of a central hydrophobic chain of adjacent polyoxypropylene (poly(propylene oxide)) In certain embodiments, the nonionic triblock copolymer is a nonionic triblock copolymer. The active agent is tyloxapol. In some embodiments, the tyloxapol comprises at least At least about 0.001% w / v, at least about 0.01% w / v, at least about 0.02% w / v / v, at least about 0.03% w / v, at least about 0.04% w / v, and about 1 % w / v or less, about 0.5% w / v or less, about 0.3% w / v or less, or about 0.2% w / v or less , present in an amount of about 0.1% w / v or less, or about 0.08% w / v or less. In the form, the nonionic surfactant is about 0.03% w / v to 0.08% w / v or about 0. Tyloxapol present in an amount of 0.05% w / v.

[0103] In some embodiments, the formulation comprises about 15% w / v to 20% w / v poloxamer surfactant. In some embodiments, the formulation comprises about 15%, about 15.5%, about 16%, Approximately 16.5%, approximately 17%, approximately 17.5%, approximately 18%, approximately 18.5%, approximately 19%, approximately 19. 5% or about 20% w / v poloxamer. In certain embodiments, the formulation contains about 17. In a further particular embodiment, the poloxamer comprises 5% w / v of poloxamer. In certain embodiments, the surfactant is substantially all tyloxamer 407. It is a rule.

[0104] In some embodiments, the formulation comprises a suspending agent. In some embodiments, the suspending agent , carbomer, hydroxypropyl methylcellulose (hypromellose), polyethylene glycols or combinations thereof. Carbomers have a network of cross-linked polymer chains. The polymer is characterized as having carboxylic acid functional groups. Carbomers are often copolymers of olefins and may contain 2 to 7 carbon atoms per functional group. For example, crosslinked with allyl sucrose or allyl ether of pentaerythritol The most commonly used synthetic high molecular weight polymers of acrylic acid are water-soluble and water-swellable carbomers. Carbomer is available from various suppliers under the trade name CARBOPOL®. In certain embodiments, the carbomer is carbomer homopolymer type B. In an embodiment, the carbomer is CARBOPOL® 934P (Carbomer 93 4P), 940, or 974P. In some embodiments, the suspending agent is carbomer. and at least about 0.05% w / v, at least about 0.1% w / v or at least about 0.2% w / v and not more than about 1.0% w / v, not more than about 0.6% w / v, or not more than about 0.5% w / v In certain embodiments, the suspending agent is carbomer. and in an amount of 0.1% w / v to about 0.3% w / v or about 0.2% w / v of the formulation exists within.

[0105] In some embodiments, the suspending agent is hydroxypropyl methylcellulose. In certain embodiments, the hydroxypropyl methylcellulose is at least about 0.05% w / w / v, at least about 0.1% w / v or at least about 0.25% w / v, and less than about 0.8% w / v, less than about 1.0% w / v, less than about 0.8% w / v or less than about 0.6% w / v In some embodiments, hydroxypropyl methyl Cellulose: about 0.1% w / v to about 0.8% w / v; about 0.1% w / v to about 0.6% w / v; approx. 0.25%w / v ~ approx. 0.8%w / v; approx. 0.4%w / v ~ approx. 0.6%w / v is present in the formulation in an amount of

[0106] In some embodiments, the suspending agent is a polyethylene glycol having a molecular weight of at least about 200 Da. In some embodiments, the PEG is at least about 400, 1,000, 2,000, 3,000, 4,000, 6,000 or about 10,0 In some embodiments, the suspending agent has a molecular weight of about 200 Da to about 200 Da. It is a polyethylene glycol (PEG) with a molecular weight of 1,000 Da. In embodiments, the PEG is about 400, 1,000, 2,000, 3,000, 4,000, In some embodiments, PEG has a molecular weight of about 6,000 or about 10,000 Da. is at least about 1% w / v, at least about 2% w / v, or at least about 3% w / v and in an amount of less than about 10% w / v, less than about 9% w / v, or less than about 8% w / v in the formulation In certain embodiments, the suspending agent is present in about 4% w / v to about 9% w / v, about 5% w / v In certain embodiments, the PEG 400 is at a concentration of about 8% w / v or about 7% w / v. The suspension may be about 1% w / v to about 4% w / v, about 1% w / v to about 3% w / v, or about 2% w / v The concentration of PEG6000 is

[0107] In certain embodiments, the suspending agent is a combination of two or more suspending agents. The suspending agent is substantially all carbomer.

[0108] In some embodiments, the suspending agent may provide the formulation with a desired viscosity. The appropriate viscosity allows Compound I to remain suspended in the formulation without settling or solidification. In some embodiments, the viscosity of the formulation is about 10 cP to about 200 cP (centipoise), about 20 cP to about 200 cP, or about 20 cP to about 1 In some embodiments, the formulation viscosity is at least about 10 cP, 20 cP, or Viscosity measurements for the formulations are 50 cP, 50 cP, 100 cP, or at least about 150 cP. Brookf using spindle CP-42 at either 3 rpm or 60 rpm Viscosity is measured using a finield viscometer. Viscosity is usually measured at room temperature, i.e., 25°C. .

[0109] In some embodiments, the formulation comprises an osmotic agent. As used herein, the term "polyol" refers to any of the following: At least one hydroxyl group at each of two adjacent carbon atoms that are not in a trans configuration The polyol may be any compound having a hydroxyl group. The polyol may be any compound having a hydroxyl group such that the resulting complex is water-soluble and As long as it is pharmaceutically acceptable, it may be linear or cyclic, substituted or unsubstituted, or a mixture thereof. Examples of such compounds include: sugars, sugar alcohols, sugar acids and uronic acids. In some embodiments, the osmotic agent is mannitol, glycerin, xylitol , sorbitol and propylene glycol or combinations thereof. , polyols such as sugars, sugar alcohols and sugar acids. In certain embodiments, the composition comprises: In some embodiments, the polysaccharide in the formulation comprises mannitol, glycerin, or a combination thereof. The amount of riol ranges from about 0.05% w / v to about 10% w / v, from about 0.1% w / v to about 8% w / v % w / v, about 0.1% w / v to about 7% w / v, and about 0.1% w / v to about 5% w / v. In an embodiment, the osmotic agent is mannitol or glycerin, which is present at 0.1% w / v ~ about 5% w / v or about 0.2% w / v, about 0.3% w / v, about 0.4% w / v, about 0.5 %w / v, approx. 1%w / v, approx. 2%w / v, approx. 2.5%w / v, approx. 3.0%w / v, approx. 3. in the formulation in an amount of 5% w / v, about 4.0% w / v, about 4.5% w / v or about 5% w / v In certain embodiments, the osmotic agent is mannitol. The osmotic agent is glycerin.

[0110] In some embodiments, the formulation comprises a buffer. Examples of buffer substances include acetate, Ascorbate, borate, bicarbonate, carbonate, citrate, edetate (EDTA ) Gluconate, lactate, phosphate, propionate and TRIS (tromethamine) buffers In certain embodiments, the buffer is a phosphate buffer system. In this example, the buffer is a tromethamine buffer. The amount of buffer substance added is usually physiologically The amount of water used is the amount necessary to ensure and maintain a pH range acceptable for some embodiments. The pH ranges are about 4 to about 9, about 4.5 to about 8.5, about 5.0 to about 8.0, and about 5.5 to about In some embodiments, the pH is about 6.0, about 6.4 to about 8.4. 0. In certain embodiments, the pH is about 7.4.

[0111] In some embodiments, the formulation comprises a salt. In some embodiments, the salt is sodium chloride. In certain embodiments, the chlorine is sodium chloride, potassium chloride, calcium chloride, or magnesium chloride. In certain embodiments, the salt is sodium chloride. In certain embodiments, the salt is at least about 0.01% w / w / v, at least about 0.02% w / v, at least about 0.03% w / v, at least about 0 0.04% w / v and not more than about 0.5% w / v, not more than about 0.4% w / v, not more than about 0.3% w / v or less, about 0.2% w / v or less, or about 0.1% w / v or less. In certain embodiments, the salt is present in an amount of about 0.01% w / v to about 0.5% w / v, about 0.02% w / v, ~0.4%w / v, approx.0.03%w / v~0.3%w / v, approx.0.04%w / v~approx. 0.2% w / v, about 0.05% w / v to about 0.1% w / v. In embodiments, the salt is sodium chloride and is present at about 0.02% w / v to about 0.07% w / v v or about 0.05% w / v.

[0112] In some embodiments, the formulations described herein contain from about 200 to about 450 kilograms. Milliosmoles per kg (mOsm / kg), approximately 200 to approximately 400 mOsm / kg, approximately 20 Osmolality of 0 to about 300 mOsm / kg or about 240 to about 360 mOsm / kg It has.

[0113] In some embodiments, the formulations may also be self-preserving and preservative-free. In embodiments, the formulation includes a preservative. In some embodiments, the preservative is polyhexane. Silmethylenebiguanidine (PHMB), polymeric quaternary ammonium compounds (e.g., Polyquaternium-1), benzalkonium chloride (BAK), chlorite preservatives or other These include, but are not limited to, chlorine-containing preservatives such as those.

[0114] In some embodiments, the preservative is an ophthalmically acceptable polymeric quaternary ammonium Compounds of this type are described in U.S. Pat. No. 3,931,319; U.S. Pat. No. 4,027,020; U.S. Pat. No. 4,407,791; U.S. Pat. ,525,346; U.S. Pat. No. 4,836,986; U.S. Pat. No. 5,0 37,647; and U.S. Pat. No. 5,300,287; and International Publication No. 91 / 09523 (Dziabo et al.). In this state, the polymeric ammonium compounds have a number average molecular weight between 2,000 and 30,000. Also known as POLYQUAD® or ONAMERM® In a further specific embodiment, the number average molecular weight is 3.0 The range is between 00 and 14,000.

[0115] When used, polymeric quaternary ammonium compounds generally comprise 0.00001% of the formulation. Used in amounts greater than 0.0003 w / v% or greater than 0.0007 w / v% Furthermore, polymeric quaternary ammonium compounds, when used in formulations, generally less than about 0.03 w / v%, less than about 0.003 w / v%, or less than about 0.0015 w / v% of the formulation In some embodiments, the polymeric quaternary amino acid in the formulation is used at a concentration of less than 500 ppm. The concentrations of ammonium compounds are as follows: greater than about 0.0003 w / v% but not greater than about 0 Less than 0.003 w / v%; greater than about 0.0003 w / v% but less than about 0.0015 w / v% greater than about 0.0007 w / v% but less than about 0.003 w / v%; and about 0.0007 w In certain embodiments, the formulation comprises more than about 0.0015 w / v%. Contains Polyquaternium 1 at a concentration of 0.1% w / v.

[0116] In some embodiments, the formulation comprises at least about 0.0005 w / v% of the formulation, about 0. 0.001 w / v% or more than 0.007 w / v% and about 0.1 w / v of the ophthalmic composition %, less than about 0.02 w / v% or less than about 0.0035 w / v% Any of the lower limits for the concentration of BAK must be equal to any of the upper limits for the concentration of BAK. It is specifically contemplated that these compounds may be used in combination. In certain embodiments, the BA in the composition The concentration of K is as follows: greater than about 0.001 w / v% but less than about 0.02 w / v% Less than about 0.001 w / v% but less than about 0.0035 w / v%; about 0.007 w / v % but less than about 0.02 w / v%; and greater than about 0.007 w / v% but less than about 0.00 Less than 35 w / v%.

[0117] In some embodiments, 4-(7-hydroxy-2-isopropyl)propanol in an amount of about 0.5% w / v to about 3.5% w / v propyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Compound I) or salts, co-crystals or polymorphs thereof, and Selected from the group consisting of surfactants, suspending agents, isotonicity agents, buffers, preservatives, salts and preservatives One or more excipients Described herein is an aqueous formulation comprising:

[0118] In some embodiments, 4. Present as a suspension in the formulation in an amount of about 0.5% w / v to about 3.5% w / v -(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)- Benzonitrile (Compound I) or a salt, co-crystal, or polymorph thereof, and Selected from the group consisting of surfactants, suspending agents, isotonicity agents, buffers, preservatives, salts and preservatives One or more excipients Described herein is an aqueous formulation comprising:

[0119] In some embodiments, 4-(7-hydroxy-2-isopropyl-4-oxopropyl) (iso-4H-quinazolin-3-yl)-benzonitrile (Compound I) or its salts, co-crystals or or polymorphs, and Selected from the group consisting of surfactants, suspending agents, isotonicity agents, buffers, preservatives, salts and preservatives One or more excipients Described herein is an aqueous formulation comprising:

[0120] In some embodiments, As a suspension, 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline (3-methyl-3-phenyl-2-methyl ... Beauty Selected from the group consisting of surfactants, suspending agents, isotonicity agents, buffers, preservatives, salts and preservatives One or more excipients Described herein is an aqueous formulation comprising:

[0121] In some embodiments, The resulting product is present as a suspension in the formulation in an amount of about 0.5% w / v to about 3.5% w / v. Crystal form K', crystal form M, crystal form Q, hydrate H B or a combination thereof, 4-(7-hydroxy 2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile ( Compound I), surfactants, suspending agents, and one or more excipients selected from the group consisting of isotonicity agents, buffers, preservatives, salts, and preservatives. Vehicle Described herein is an aqueous formulation comprising:

[0122] In some embodiments, the invention described herein comprises: The resulting product is present as a suspension in the formulation in an amount of about 0.5% w / v to about 3.5% w / v. Crystal form K', crystal form M, crystal form Q, hydrate H B or a combination thereof, 4-(7-hydroxy 2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile ( Compound I), nonionic surfactants; suspending agents; Isotonic agent; buffer; salt; and Optionally, a preservative It is a formulation comprising:

[0123] In some embodiments, the invention described herein comprises: Crystalline form K', crystal form M, crystal form K', in an amount of about 0.5% w / v to about 3.5% w / v. Form Q, hydrate H B or a combination thereof, 4-(7-hydroxy-2-isopropyl-4-oxopropyl) a suspension of 2-iso-4H-quinazolin-3-yl)-benzonitrile (Compound I); nonionic surfactants; suspending agents; Isotonic agent; buffer; salt; optionally a preservative; and Up to 100% qs water It is a formulation comprising:

[0124] In some embodiments, the invention described herein comprises: Crystalline form K', crystal form M, crystal form K', in an amount of about 0.5% w / v to about 2.5% w / v. Form Q, hydrate H Bor a combination thereof, 4-(7-hydroxy-2-isopropyl-4-oxopropyl) a suspension of 2-iso-4H-quinazolin-3-yl)-benzonitrile (Compound I); Tyloxapol, poloxamer, or combinations thereof, in an amount of about 0.01 to 0.2% w / v a nonionic surfactant selected from the group consisting of: Hydroxypropyl methylcellulose, polyethylene glycol or carbomer homopoly a suspending agent selected from the group consisting of mer-B type; a tonicity agent selected from polyols in an amount of about 0.05% w / v to about 10% w / v ; a buffer selected from edetate, phosphate, borate or a combination thereof; salt; and Up to 100% qs water A formulation comprising: The formulation has a pH in the range of about 5.5 to about 8.0.

[0125] In some embodiments, the invention described herein comprises: About 0.5% w / v, about 1.0% w / v, about 1.5% w / v, about 2.0% w / v, or about 2 Crystalline form K', Crystalline form M, Crystalline form Q, Hydrate H in an amount of 0.5% w / v B Or The combination of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline- a suspension of 3-yl)-benzonitrile (Compound I), Tyloxapol in an amount of about 0.04 w / v to about 0.06% w / v, about 0.005 to 0 a non-ionic surfactant selected from poloxamers or combinations thereof in an amount of 0.12% w / v activators; Hydroxypropyl methylcellulose in an amount of about 0.1% w / v to about 0.8% w / v , polyethylene glycol in an amount of about 2% w / v to about 8% w / v, about 0.05% w / Carbomer homopolymer type B or combinations thereof in an amount of v to about 0.5% w / v Suspension agent; selected from mannitol or glycerin in an amount of about 0.1% w / v to about 5% w / v tonicity agents; a buffer selected from edetate, phosphate, borate, tromethamine or a combination thereof; Sodium chloride in an amount of 0.01% w / v to about 1% w / v; Up to 100% qs water A formulation comprising: The formulation has a pH in the range of about 5.5 to about 8.0.

[0126] In some embodiments, the invention described herein comprises: About 0.5% w / v, about 1.0% w / v, about 1.5% w / v, about 2.0% w / v, or about 2 Crystalline form K', Crystalline form M, Crystalline form Q, Hydrate H in an amount of 0.5% w / v B Or The combination of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline- a suspension of 3-yl)-benzonitrile (Compound I), Tyloxapol in an amount of about 0.04 w / v to about 0.06% w / v; Carbomer homopolymer type B in an amount of about 0.05% w / v to about 0.4% w / v; glycerin in an amount of about 0.5% w / v to about 5% w / v; a buffer selected from edetate, phosphate, borate, tromethamine or a combination thereof; Sodium chloride in an amount of 0.01% w / v to about 1% w / v; Up to 100% qs water A formulation comprising: The formulation has a pH in the range of about 5.5 to about 8.0.

[0127] In some embodiments, an acid or base such as hydrochloric acid, sodium hydroxide, or a combination thereof In certain embodiments, hydrochloric acid is used to adjust the pH of the formulation to about 6. Adjust to 0 or about 7.4.

[0128] In some embodiments, the formulations described herein are aqueous, i.e., they comprises at least about 90%, at least about 92%, or at least about 95% water.

[0129] In some embodiments, the formulations described herein further comprise additional components. In certain embodiments, the formulation comprises a cyclodextrin derivative, e.g., β-cyclodextrin. In certain embodiments, the compound may comprise a cyclodextrin derivative, a γ-cyclodextrin derivative, a γ-cyclodextrin derivative, or a combination thereof. The cyclodextrin is hydroxypropyl β-cyclodextrin or sulfoalcohol. alkyl ether β-cyclodextrin. Cyclodextrin derivatives, if present is at least about 1.5 w / v%, at least about 3.0 w / v%, at least about 3.5 w / v% / v% or at least about 4.5 w / v%, but not more than about 10.0 w / v%, about 8.0% It may be present in an amount of about 6.5% w / v or less, about 6.5% w / v or less, or about 5.5% w / v or less. In certain embodiments, the formulation contains about 5% w / v hydroxypropyl β-cyclodextrin. The compounds contain either sulfoalkyl ether β-cyclodextrin or sulfoalkyl ether β-cyclodextrin.

[0130] In some embodiments, the formulations of the present invention may include additional therapeutic agents in addition to Compound I. Additional therapeutic agents include, for example, other compounds and antibodies useful in treating ocular surface disorders. A non-limiting list of such drugs includes ketorolac, nepafenac, bromocriptine, and benzodiazepine. Nonsteroidal anti-inflammatory drugs such as mufenac, corticosteroids; cyclosporine, These include medications for dry eye disease such as tetegrast or other TRPV1 inhibitors. In certain embodiments, the additional therapeutic agent is dexamethasone, fluocinolone, lotepred Nol, difluprednate, fluorometholone, prednisolone, prednisone, med rizone, triamcinolone, betamethasone, rimexolone or a pharmaceutically acceptable salt thereof Further examples of such additional therapeutic agents that may be included in the pharmaceutical composition include ophthalmic steroids, such as: Non-limiting examples include Xiidra® (lifitegrast), Res Tasis® (cyclosporine), minocycline, doxycycline or other Other examples include selenium disulfide, salicylic acid, and tetracycline antibiotics. and keratolytic agents such as acids, glycolic acid, and the like, or pharmaceutically acceptable salts thereof.

[0131] In some embodiments, the formulation is stored at refrigerated temperatures (e.g., 4°C). In some embodiments, the formulation is allowed to warm to room temperature prior to administration.

[0132] In some embodiments, the suspension is packaged in a single-dose container. In some embodiments, the formulations are packaged in multi-dose containers.

[0133] The formulations described herein may be administered one to six times daily, according to the routine discretion of a skilled clinician. In some embodiments, the formulation is administered 1, 2, 3, or 4 times daily. will be done.

[0134] In some embodiments, the pharmaceutical formulations of the present invention contain an additional therapeutic agent in addition to Compound (I). The additional therapeutic agent may include, for example, other compounds useful in treating ocular surface disorders and A non-limiting list of such drugs may include ketorolac, nepafena, nonsteroidal anti-inflammatory drugs such as cyclosporine, bromfenac, and corticosteroids; Medications for dry eye disease include benzodiazepine, lifitegrast, or other TRPV1 inhibitors. In certain embodiments, the additional therapeutic agent is dexamethasone, fluocinolone, lorlatinib, or lorlatinib. Teprednol, difluprednate, fluorometholone, prednisolone, prednisolone medrysone, triamcinolone, betamethasone, rimexolone or any of its pharmaceutically acceptable salts Such additional therapeutic agents that may be included in the pharmaceutical composition are ophthalmic steroids, such as salts thereof. Further non-limiting examples of therapeutic agents include Xiidra® (lifitegrast) , Restasis® (cyclosporine), minocycline, doxycycline Other examples include selenium disulfide, Keratolytic agents such as salicylic acid, glycolic acid, etc., or pharmaceutically acceptable salts thereof are included. can be done.

[0135] Production method In some embodiments, the formulation comprises an amount of 4-(7-hydroxy-2-isopropyl -4-oxo-4H-quinazolin-3-yl)-benzonitrile (Compound I) or a salt thereof , co-crystals or polymorphs and surfactants, suspending agents, osmotic agents, buffers, preservatives, salts and The pharmaceutical composition is prepared by mixing the pharmaceutical composition with one or more excipients selected from the group consisting of:

[0136] In some embodiments, the present invention provides methods of making pharmaceutical formulations of Compound I. In some embodiments, the formulation comprises an amount of 4-(7-hydroxy-2-isopropyl- 4-oxo-4H-quinazolin-3-yl)-benzonitrile (Compound I) or a salt thereof, Co-crystals or polymorphs, nonionic surfactants; suspending agents; osmotic agents; buffer; salt; optionally a preservative; and Mixing with water up to 100% qs; and It is prepared by adjusting the pH to a range of about 5.5 to about 8.0.

[0137] How to use Without being bound by theory, transient receptor potential vanilloid 1 (TRPV1) blockers It is hypothesized that these compounds may be useful in the treatment of pain, for example, chronic pain.

[0138] Thus, in some embodiments, the present invention provides a method for treating ocular surface pain in a subject. The present invention provides a method for treating a rhodopsin-related ... In some embodiments, the present invention provides a method for administering a compound or cocrystal to a subject. A method for reducing ocular surface pain in a subject in need thereof is provided, the method comprising administering an effective amount of a compound administering compound (I) or a pharmaceutically acceptable salt, solvate or cocrystal thereof to a subject. In some embodiments, the present invention provides a compound of formula I in the treatment or reduction of ocular surface pain. The present invention provides the use of a compound or a pharmaceutically acceptable salt, solvate or co-crystal thereof. In some embodiments, the compound of formula I is polymorphic form B. In certain embodiments, the compound of formula I is polymorphic form B. The methods described herein are carried out by administering the formulations of Compound I described above. Thus, the present invention provides a method for treating a patient suffering from atopic dermatitis by administering a formulation of Compound I as described herein. In some embodiments, the method comprises administering to the ocular surface a therapeutic agent. This results in a reduction in facial pain.

[0139] In some embodiments, the subject is suffering from episodic or acute ocular pain. In some embodiments, the subject suffers from chronic ocular surface pain that has lasted for at least three months. In some embodiments, the subject suffers from chronic ocular surface pain that has lasted for at least two months. In some embodiments, the subject suffers from chronic ocular surface pain that has lasted for 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 suffering from 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 co-crystal 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. Compounds of Formula I or pharmaceutically acceptable salts, solvates, polymorphs or the like in the treatment of pain In some embodiments, the compound of formula I is a cocrystal of the formula I described herein. in the formulation as prescribed.

[0140] In some embodiments, the formulation is applied to the ocular surface of a subject, for example, the cornea, conjunctiva, or conjunctival sac of the eye. It is administered to either part of the body.

[0141] In some embodiments, the present invention provides ophthalmic solutions 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 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 ~ Approximately 3.0% w / v, in the range of approximately 0.5% w / v to approximately 2.5% w / v. In the form, the concentration of Compound I in the ophthalmically compatible formulation is at least about 0.5% w / v, At least about 1.0% w / v, at least about 1.5% w / v, at least about 2.0% w / or at least about 2.5% w / v. In some embodiments, for topical use The concentration of the compound of Formula I in the formulation for 4.0% w / v or less, about 3.5% w / v or less, or about 3.0% w / v or less. In embodiments, the concentration of the compound of Formula I in a formulation for topical use is about 0.5% w / v, Approx. 1.0%w / v, approx. 1.5%w / v, approx. 2.0%w / v, approx. 2.5%w / v, approx. 3.0 % w / v or about 3.5% w / v. In some embodiments, per dose per eye The dose is about 0.15 to about 1.15 mg or about 0.15 mg, 0.2 mg, 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, approximately 0.85mg, approximately 0.9mg, approximately 0.95mg, approximately 1.0mg, approximately 1.05m g, about 1.1 mg, or about 1.15 mg. In some embodiments, the dose per eye is The dose per dose 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 0.92 mg. 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 about 0.5 mg, about 3.0 mg, or about 3.5 mg. The compound is administered to the subject 1 to 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 3 months. The drug will also be administered to subjects for approximately 12 weeks.

[0142] In some embodiments, the ocular surface pain or chronic ocular surface pain is caused by dry eye disease, shaving, or the like. Glenn's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), epicorneal 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 erosion (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, or corneal abrasion (including recurrent corneal erosion or abrasion), ocular surface disease, blepharitis, Graft-versus-host disease, meibomianitis, glaucoma, conjunctival laxity, keratopathy (herpetic keratopathy, filiform keratopathy) membrane, band or bullous keratopathy, lagophthalmos), keratitis (herpes simplex virus) keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, Patients recovering from one or more of the following conditions: neuralgia, xerophthalmia, or neurotrophic keratitis. In some embodiments of the methods described herein, the subject has undergone photorefractive keratectomy (PRK). K) Lasts for at least 3 months after surgery or laser in situ keratomileusis (LASIK) surgery The patient suffers from ocular pain.

[0143] In certain embodiments, the ocular surface pain or chronic ocular surface pain is caused by dry eye disease or shaving. In some embodiments, the subject is diagnosed with conjunctivitis, subconjunctival hemorrhage, or rheumatoid arthritis associated with Renn's syndrome. Subconjunctival scar, conjunctival membrane, conjunctival ulcer, punctate superficial epithelial erosion, epithelial defect, eyelid margin ulcer, eyelid margin Keratosis, blepharophimosis, blepharophimosis, trichiasis, anterior blepharitis, lacrimal punctum obstruction, meibomian gland disease , corneal opacity, dry eye, lash hyperplasia, limbal stem cell failure, or corneal neovascularization are.

[0144] 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 of In some embodiments, the serotonin concentration is at least about 3 compared to placebo when measured above. administration, as measured on a VAS score of at least about 4, compared with 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 of 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.

[0145] In some embodiments, administration of the compound of Formula I occurs about one-half hour after administration, about one hour after administration, or about one hour after administration. After about 2 hours, about 2 hours, or about 2-4 hours, the subjects were compared with placebo as measured by VAS scores. In some embodiments, the administration of 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 reduces pain in the subject as measured 14 days after administration of the compound of Formula I. This results in a reduction in pain.

[0146] In some embodiments, the reduction in pain score is measured by comparing the pain scores before and after administration of Compound I to the 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 measured within about 1 hour after administration of Compound I to the subject. In some embodiments, the reaction occurs within about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours. In some embodiments, administration results in a reduction in pain in a subject as measured 7 days after administration of a compound of Formula I. In some embodiments, the administration is measured 14 days after administration of the compound of Formula I. When administered, the administration results in a reduction in pain in the subject.

[0147] 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.

[0148] 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 improvement.

[0149] In some embodiments, administration of a compound of Formula I reduces ocular hyperemia (ocular hyperemia) compared to placebo. In some embodiments, administration of a compound of Formula I results in a reduction in redness and rash. Compared to the ocular hyperemia grade 1, 2, 3, or 4 vinegar.

[0150] In some embodiments, administration is at least about 100 mg / kg on the McMonnies scale. ocular hyperemia score of 1, at least about 2, at least about 3, at least about 4, or at least about 5 This results in a reduction in

[0151] Thus, in some embodiments, the present invention provides a method for treating ocular redness in a subject in need thereof. 1. A method for treating or reducing the risk of rheumatoid arthritis, comprising administering to a patient a compound of formula I or a salt, solvate, polymorph or co-form thereof. In some embodiments, the present invention relates to a method for treating a rheumatoid arthritis, comprising administering to a subject an effective amount of a rheumatoid arthritis. The present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt, solvate or derivative thereof in the treatment of ocular hyperemia. In some embodiments, the administration is by McMonnies starch or cocrystal. In kale, at least about 1, at least about 2, at least about 3, at least about 4 or results in a reduction in ocular hyperemia score of at least about 5. In some embodiments, the present invention provides , and the required concentration in an ophthalmologically compatible formulation at a concentration of about 0.5% w / v to about 3.5% w / v. In some embodiments, the method for administration comprises administering a compound of Formula I to a subject. Concentrations are approximately 0.5% w / v to approximately 3.5% w / v, approximately 0.5% w / v to approximately 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 ~ approx. 3.0%w / v, approx. 0.5%w / v In certain embodiments, the range of the topical formulation is from about 2.5% to about 2.5% w / v. The concentration of the compound of formula I is about 0.5% w / v, about 1.0% w / v, about 1.5% w / v, about 2 The preferred range is about 0.0% 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 Approx. 0.15mg, 0.2mg, approx. 0.25mg, 0.3mg, approx. 0.35mg, approx. 0.4 mg, about 0.45mg, about 0.5mg, about 0.55mg, about 0.6mg, about 0.65mg , about 0.7mg, about 0.75mg, about 0.8mg, about 0.85mg, about 0.9mg, about 0 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 mg, about 0.55 mg, about 0.74 mg, or about 0.92 mg. In this case, the total daily dose per eye is about 0.5 to about 3.5 mg or about 0.5 mg, about 1.0 mg, or mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg or about 3.5 mg In some embodiments, the compound of Formula I is administered 1 to 6 times daily, for example, 1, 2, 3 or 4 times daily. or four times administered to a subject. In some embodiments, the compound of formula I is administered at least about 1 The compound is administered to a subject for a period of at least about two months, at least about two months, or at least about three months. In the form, the compounds of formula I are administered in the formulations described herein.

[0152] In some embodiments, the ocular redness 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 corneal dystrophies (including LASIK-induced corneal neuropathy), corneal dystrophies (recurrent corneal dystrophies) corneal erosion or abrasion (including recurrent corneal ulcers), epithelial basement membrane dystrophy corneal erosion or abrasion), ocular surface disease, blepharitis, graft-versus-host disease, myocarditis, Conjunctivitis, glaucoma, conjunctival laxity, keratopathy (herpetic keratopathy, filamentous keratopathy, band-like or bullous keratopathy) keratopathy (including herpes simplex virus keratitis), iris inflammation, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia or The present invention relates to a method for treating a patient recovering from neurotrophic keratitis, comprising administering to said patient one or more of the methods described herein. In some embodiments, ocular hyperemia is treated by photorefractive keratectomy (PRK) surgery or laser. Lasts for at least 3 months after Laser Intracranial Intubation and Skeletal Keratomileusis (LASIK) surgery.

[0153] 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 generally results in inflammation of the ocular surface and lacrimal glands and tear quality and / or Dry eye disease is understood to be a complex, multifactorial condition characterized by a decrease in blood flow. Up to 30% of patients with eye disease are thought to suffer from ocular surface pain, which can be chronic. Thus, in some embodiments, the present invention provides a method for treating dry eye, eye discomfort, eye redness, eye pain, and eye congestion. Dry eye disease including one or more of the following symptoms: burning or stinging, grittiness or foreign body sensation, or photophobia at least about 10%, at least about 15%, at least about 20%, or at least also results in a reduction of about 30%.

[0154] In some embodiments, the present invention provides a method for treating dry eye disease in a subject in need thereof. The method comprises administering an effective amount of a compound of formula I or a salt, solvate, polymorph, or co-crystal thereof to a patient of the present invention. In some embodiments, the present invention relates to a method comprising administering to a subject in need thereof 1. A method for treating dry eye disease in a subject comprising administering an effective amount of a compound of formula I or its analogs to a subject. 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 stored 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 that is safe for administration over a long period of time. Use of compounds of formula I or pharmaceutically 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 congestion. Dry eye disease including one or more of the following symptoms: burning or stinging, grittiness or foreign body sensation, or photophobia In some embodiments, the present invention provides a method for treating a patient suffering from a rheumatoid arthritis, the method comprising: In an ophthalmologically compatible formulation at a concentration of about 0.5% w / v to about 3.5% w / v, Administration of a compound of Formula I to a subject is provided. 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 approximately 0.5% w / v, approximately 1.0% w / v, approximately 1.5% w / v, and approximately 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 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 compound is administered to a subject for a period of at least about two months, or at least about three months. In embodiments, the compound of formula I is administered in a formulation as described herein.

[0155] In some embodiments of the methods described herein, the administration of a compound of Formula I is Compared with the NIH, best corrected visual acuity, slit lamp biomicroscopy, mydriasis, blink rate, and tear production were significantly improved. does not result in a change (e.g., less than a 5% difference) in one or more of the following: , less than 4% difference, or less than 3% difference). administration of a compound of formula I has been shown to improve wound healing compared to placebo in patients in need thereof This does not cause delays in the

[0156] 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 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 dystrophy (including recurrent corneal dystrophy), 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 rheumatoid sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, or neurotrophic keratitis In some embodiments, the subject is a patient undergoing laser refractive keratectomy. At least 3 months after PRK or LASIK surgery The patient has been suffering from persistent eye pain for some time.

[0157] 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

[0158] In certain embodiments, the methods provided herein are directed to treating chronic ocular surface pain (COSP), such as In certain embodiments, the COSP is Persistent pain that may distract or interfere with normal daily activities ocular surface pain (e.g., persistent severe ocular surface pain). In some cases, COSP can result in an inadequate quality of life and lasts 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 less. In other embodiments, the COSP may last for at least about 3 months. In certain embodiments, subjects with COSP may have symptoms of their underlying For certain diseases (e.g., ocular surface disorders such as dry eye disease or Sjögren's syndrome) Symptoms persist despite compliance with other indicated therapies.

[0159] In some embodiments, the subject to be treated is suffering from ocular neuropathic pain (ONP). ONP is an ocular condition that can result from an injury or disease that affects the nerves, for example, 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 dryness. 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 pain (allodynia) caused by gabapentin and other neuropathic factors. Pain medications can be used to reduce the sensation of sensory nerve stimulation or nerve stimulation.

[0160] In some embodiments, the subject to be treated is suffering from lagophthalmos keratopathy. EK is damage to the cornea that results primarily 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, ptosis) malposition), poor blink reflex, poor blink rate (e.g., neurological disorders, e.g., Parkinson's disease, caused by neuromuscular disorders) and / or the protective lubrication of the cornea Patients with conditions that impair the cornea's ability to protect itself, either through a decrease in Symptoms of EK include a foreign body sensation, burning sensation, increased tearing, and intermittent blurred vision (unstable vision). Symptoms include discomfort (due to poor tear film), pain, and photophobia. Standard treatment is a nighttime lubricating ointment. Frequent use of artificial tears and punctal plugs.

[0161] In some embodiments, the subject to be treated is suffering from keratoconjunctivitis. Conjunctivitis is an inflammatory process that involves both the conjunctiva and the cornea. Inflammation of the superficial layers of the cornea (keratitis) It commonly occurs, for example, in adults in association with viral and bacterial conjunctivitis. The following types of conjunctivitis are distinguished based on the underlying cause of the inflammation: Keratoconjunctivitis sicca is caused by inflammation due to dryness; · Vernal keratoconjunctivitis (VKC) occurs seasonally and is thought to be caused by allergens; Atopic keratoconjunctivitis is a symptom 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 primarily caused by Chlamydophila pecorum dophila pecorum); · Superior limbic keratoconjunctivitis is thought to be caused by structural trauma; Keratoconjunctivitis electroophthalmia (arc eye) refers to inflammation caused by photoelectric UV light. Taste.

[0162] In some embodiments, the subject to be treated suffers from dry eye. As used herein, the term "dry eye" refers to insufficient tear production and / or abnormal tear 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 caused by an increase in the tear film Dry eye is characterized by a loss of tear film homeostasis. discomfort due to potential damage to the ocular surface with associated ocular symptoms, visual disturbances, and tear film instability It is a multifactorial disorder of the tears and ocular surface that results in a range of qualitative symptoms, including tear film instability and hypercalcemia. Osmotic pressure, ocular surface inflammation and damage, 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 ocular surface inflammation. Dry eye disorder can range from mild to moderate to severe. Symptoms of Reye 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 hard eyelashes redness, blurred or oscillating vision (usually worse when waking up), (worsened when watching TV, driving, or playing video games), light sensitivity, eye pain and / or Other symptoms include headaches, heavy eyelids, and eye strain. Causes of dry eye disease include: These include, but are not limited to: unknown cause, congenital anlacrimation, dry eye, tear Gland resection and sensory denervation; rheumatoid arthritis, Wegener's granulomatosis, and systemic lupus erythematosus Collagen vascular diseases including vasculopathy; 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 disorders; 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: May also be caused by: prolonged visual work; computer work; exposure to dry environments; hot air or cold wind or air currents; seasonal changes; eye irritation; contact lenses, LASIK and other refractive surgery; fatigue; and isotretinoin, sedatives, diuretics, tricyclic antidepressants, antihypertensives medicines, oral contraceptives, antihistamines, nasal decongestants, beta-blockers, phenothiazines, atomicites Drugs such as pain-relieving opiates such as thiazolinone and morphine.

[0163] Diagnostic tests for dry eye include, for example, cotton swabs or, more specifically, Cochet- Assessment of corneal sensory function using a Bonnet aesthesiometer (corneal hypersensitivity and / or hyposensitivity were assessed) may be present in severe and chronic dry eye disease); e.g., preservative-free Fluorescein-impregnated strips or fluorescein drops moistened with saline solution are required. Measurement of tear film breakup time using more objective computerized methods that do 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); Testing for delayed tear clearance; tear meniscus height; and measurement of MMP-9 levels. MMP-9 has been shown to be elevated in the tears of patients with dry eye disease. 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).

[0164] Artificial tears, lubricating ointment, corticosteroids (e.g., loteprednol 0.4 times daily) Prescription medications include cyclosporine, rifabutin, and cyclosporine. Fitegrast, diquafosol, levamepide, corticosteroids (e.g., 4 times daily) Loteprednol 0.5% eye drops.

[0165] The term "tear film dysfunction" refers to when the tear film is broken down 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 sandy or rough feeling, tingling or foreign body sensation, eye discharge, frequent blinking, pus or crusting of eyelashes (usually worse when waking up), Redness, blurred or trembling vision (while reading, using a computer, watching television, driving or playing video games) Symptoms include: light sensitivity, eye pain and / or headache, heavy eyelids, and eye strain (worsened when It can be obtained.

[0166] 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. It can be done.

[0167] Vernal keratoconjunctivitis (VKC) is characterized by severe itching, photophobia, foreign body sensation, and mucous discharge ("sticky"). blepharospasm, often described as blepharospasm, a condition characterized by symptoms consisting 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 characteristically affects young men 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).

[0168] The signs of VKC can be divided into conjunctival, limbal and corneal signs: Conjunctival signs include diffuse conjunctival hyperemia and discrete upper tarsal lesions greater 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 These are focal limbal white spots consisting of altered 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. including scars (Buckley, RJ, Int Ophthalmol Clin, 19 88 28(4):p.303-8).

[0169] Patients with active VKC (photophobia, papilla on the superior tarsal conjunctiva, or clearly visible corneal limbus on examination) ocular discomfort) is defined as moderate to severe ocular discomfort, including Horner-Trantas points. showed a significant increase in symptoms and signs of superficial disease. Patients with inactive VKC (asymptomatic or Mild discomfort and absence of corneal abnormalities at the time of testing) is 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 nerves were observed at all stages (progression and resting state). It appears to affect the ocular surface (Villani E. et al., Medici ne(Baltimore).2015 Oct;94(42):e1648).

[0170] The following factors are thought to play a role in VKC: IgE released from mast cells; activated eosinophils; by leukocytes, monocytes, and neutrophils, and immunomodulatory substances 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).

[0171] Treatment consists of cold compresses and irrigation of the eyelids, saline eye drops, topical antihistamines, Nonsteroidal anti-inflammatory drugs or corticosteroids, such as poorly absorbed corticosteroids ( fluorometholone, loteprednol, rimexolone, etc.), topical 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. See 2018;59(3):126-134.

[0172] 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 in the lower tarsal plate. AKC is usually more chronic in nature and more commonly occurs in the cornea. It causes membranous and conjunctival scarring.

[0173] 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 lyea It is a chronic inflammatory disorder. The main symptoms are dry eyes (keratitis sicca or keratoconjunctivitis sicca) and Severe dry eye can lead to corneal pain, scarring, ulcers, infection, and even In some cases, perforation may occur. The differential diagnosis is adult blepharitis, dry eye disease, and juvenile blepharitis. Arthritis of unknown cause, uveitis, and keratopathy, such as superficial punctate keratopathy and fibrous keratitis Sjögren's syndrome includes conditions such as keratopathy, neuropathic keratopathy, and lagophthalmos. To maintain tear film integrity by preserving, enhancing, and / or replenishing insufficient tear secretion Therefore, treatments for Sjögren's syndrome include 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 Humidifying the environment; Hydrophilic bandage lenses; Bromhexine and 3-isobutyl-1-methyl Tiruxanthine (IBMX) (increases tear production / secretion); a drug that stimulates muscarinic receptors immunosuppressants, e.g., methotrexate, antimalarials; anti-inflammatory drugs, cyclophosphamide, leflunomide or tumor necrosis factors (TNF), e.g., influenza Liximab, a monoclonal antibody against TNF-alpha; cyclosporine A; Bande Examples of such contact lenses include:

[0174] Stevens-Johnson syndrome (SJS) is a skin emergency or a condition that affects one part of the entire surface area of ​​the body. One type characterized by the presence of vesicular lesions of the epithelium and mucosa, involving less than 0% It is a severe skin reaction. Early symptoms of SJS include fever and flu-like symptoms, which This may precede or occur simultaneously with the development of a macular rash involving the body and face. As the disease progresses, the macules gather together, the involved areas develop into blisters, and eventually the epithelial layer is removed. During the acute phase of SJS-TEN, 80% of patients will have ocular complications .

[0175] 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 substances or recent dose increases of current medications is an 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. The concentration of granulysin in blister fluid correlates with the severity of acute SJS (C hung WH,et al.Nat Med.2008;14(12):1343-5 0).

[0176] Eye symptoms in SJS include conjunctivitis, subconjunctival hemorrhage, subconjunctival scarring, conjunctival membranes, and conjunctival Ulcers, punctate superficial epithelial erosions, epithelial defects, eyelid margin ulcers, eyelid margin keratinization, blepharohematosis, eyelid adhesion, Trichiasis, anterior blepharitis, self-obstruction of lacrimal puncta, meibomian gland disease, corneal opacification, dry eye These include corneal hypertrichosis, limbal stem cell failure, and corneal neovascularization. saline eye drops, preservative-free artificial tears, and other solutions that provide adequate lubrication and help to soothe the epithelium Patients with any corneal or conjunctival epithelial defects should be treated with prophylactic Treated with topical antibiotics, such as 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 epithelial defects) Patients with schizophrenia (no deficiency) typically receive topical moxifloxacin 0.5% four times a day, or topical moxifloxacin 0.5% twice a day. of cyclosporine 0.05% and topical steroids (prednisolone acetate 4-8 times daily) Treated with dexamethasone 0.1% twice daily or dexamethasone 0.1% twice daily. Ocular complications (lid margin complications exceeding one-third, conjunctival defects exceeding 1 cm, and corneal epithelial defects) Patients with ) receive amniotic membrane (AM) transplantation in addition to the above treatment.

[0177] 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

[0178] 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 that involves 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. The causes and risk factors are still unclear, but symptoms such as dry eye, Patients with increased corneal sensitivity and altered corneal nerve morphology but without signs of dryness may have corneal nerve damage. May suffer from menstrual disorders.

[0179] In some embodiments, the subject to be treated is suffering from an ocular surface disease or disorder. The terms "ocular surface disease" or "ocular surface disorder" refer to abnormal eyelid 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 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"). ) comes from

[0180] 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 causes corneal sensitivity. It is a degenerative corneal disease characterized by reduced or absent sensitivity. Corneal innervation by the nerve 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 PED, scarring, or edema. Stage II NK is the most common stage. Stage II is defined by recurrent or persistent epithelial defects in the upper half of the cornea. One of the treatments that can be used in NK involves topical nerve growth factor. Patients usually Due to the remodeling of the sarcoid, pain is experienced during treatment with NGF.

[0181] In some embodiments, the subject to be treated is suffering from blepharitis. Eyelid inflammation is an inflammatory condition of the eyelid margin that can cause persistent changes in the eyelid margin or superficial keratopathy. This can cause vision loss, corneal neovascularization, and ulcers. Therefore, blepharitis can be divided into anterior and posterior. Anterior blepharitis affects the eyelid skin, the base of the eyelashes, and the 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, irritation, tearing, crusting and sticking of the eyelids, and visual disturbances such as photophobia and blurred vision. Long-term symptom management involves a daily eyelid cleaning routine and prevention of infection and inflammation. Treatments may include the use of therapeutic agents that reduce the risk of ulcerative colitis. Treatments may include topical or systemic antibiotics, e.g., oral antibiotics, such as bacitracin or erythromycin; Biologics (tetracycline, doxycycline, minocycline) or macrolide antibiotics 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 topical cyclosporine 0.05%.

[0182] In some embodiments, the subject to be treated is suffering from meibomian gland dysfunction. The meibomian glands are responsible for supplying 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 within the tarsal plate. Meibomian gland dysfunction (MGD), also known as blepharitis or inflammation of the meibomian glands, is a Mycobacterium tuberculosis is generally characterized by terminal duct obstruction and / or qualitative / quantitative changes in glandular secretion. 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 tear film alterations, eye irritation, clinically significant inflammation, and ocular surface disease. D often causes dry eyes and can contribute to blepharitis. 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.

[0183] 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 the same HLA, Acute graft-versus-host disease usually occurs within the first three weeks after transplantation. It occurs over a period of months and may involve the skin, intestinal tract, or liver. Steroids are the standard treatment. Chronic graft-versus-host disease may also occur after allogeneic transplantation. In addition to inflammation, chronic graft-versus-host disease is a major cause of late complications. Similar to other autoimmune diseases, it can cause the development of fibrosis or scar tissue and is functionally It can lead to disability and the need for long-term immunosuppressive therapy.

[0184] In some embodiments, the subject to be treated is suffering from ocular graft-versus-host disease. GVHD occurs in patients who have undergone allogeneic blood stem cell transplantation. It can occur in patients with advanced or chronic GVHD, but is more common in patients with the chronic form. Approximately 40-90% of patients with chronic GVHD develop ocular Ocular symptoms include moderate to severe keratoconjunctivitis sicca, bilateral peripheral keratoconjunctivitis, and Treatment may include uveitis, anterior uveitis, corneal ulcers, or neovascularization. No artificial tears, including topical lubricants, autologous serum tears, and other topical and systemic immunosuppressive treatments; systemic Sex steroids; topical cyclosporine 0.5%. [Example]

[0185] The following examples are included to demonstrate non-limiting embodiments of the invention.

[0186] General Test Conditions X-ray diffraction The X-ray powder diffraction (XRPD) patterns described herein were obtained using CuK α Using radiation, Br The XRPD patterns were recorded on a Kerker D8 Advance diffractometer. (2θ) between

[0187] Those skilled in the art will understand that X-ray diffraction patterns are obtained with measurement errors depending on the measurement conditions used. In particular, it will be understood that intensities in an X-ray diffraction pattern may be used. It is generally known that the intensity may increase or decrease depending on the measurement conditions. Relative intensity is also used. It should further be understood that this may vary depending on the experimental conditions and the wavelength of the X-ray radiation. The agreement in 2θ diffraction angles between the sample and the reference is 0.2 for the same crystalline form. The measurement error is within 100° and should be considered to be related to the above diffraction angle. Consequently, the crystalline forms of the present invention are compatible with the X-ray diffraction patterns depicted in the attached drawings disclosed herein. It is understood that the crystal form is not limited to one that provides an X-ray diffraction pattern that is completely identical to the pattern. The X-ray diffraction pattern should be substantially the same as that shown in the attached drawing. Any crystalline form provided falls within the scope of the present invention. The ability to ascertain gender is within the skill of one in the art.

[0188] thermogravimetric method The TGA instrument used to test the crystalline form was a TA Discovery TGA. A 10-20 milligram sample was heated at a temperature range between 30°C and approximately 300°C. The analysis was carried out at a heating rate of 10°C / min.

[0189] Differential scanning calorimetry (DSC) The DSC instrument used to test the crystal morphology is a TA Discovery DSC. The DSC cell / sample chamber was filled with ultra-high purity nitrogen gas at 20-50 ml / min. The instrument was calibrated with high purity indium. The sample was placed in an open aluminum D Approximately 1-3 mg of sample powder was placed in an SC pan and measured against an empty reference pan. The sample was placed on the bottom of the pan and gently tapped down to make contact with the pan. The sample was accurately weighed. The instrument was operated at a temperature range between 0°C and 300°C and recorded to the nearest hundredth of a milligram. The temperature was programmed to heat at 10°C / min.

[0190] Example 1. Preparation and characterization of crystalline form K' Crystalline form K' was prepared by dissolving 0.75 ml of n-butanol / dichloromethane (50:50 v / v As an example, the results of 50 mg of Compound I were obtained from a clear solution of 50 mg of Compound I in 100 mL of ethanol. Crystal form B was used to obtain a solution of compound I. The clear solution was allowed to evaporate at ambient conditions, and the crystals Form K' was obtained.

[0191] In an alternative procedure, 200 mg of Compound I (e.g., crystalline form B) is dissolved in 3 mL of HCl at 25°C. The slurry was dissolved in n-butanol / dichloromethane (50:50 v / v) for 10 min. After stirring, a clear solution was obtained. The clear solution was filtered and allowed to evaporate slowly under ambient conditions for 1 hour. , then some seeds of Modification K' were added and allowed to evaporate for another 6 days. The resulting suspension was filtered and dried under vacuum at 30°C for 3 hours to obtain crystalline form K'.

[0192] The X-ray diffraction pattern for crystalline form K′ of Compound I is provided as FIG.

[0193] Crystalline form K' exhibits a final melting onset temperature of 279°C (Fig. 2), and the crystallographic Other thermal events can be observed due to the solid-solid transition of these solids into crystalline forms. Solid-state transitions are not reproducible.

[0194] Crystalline form K' is non-hygroscopic. It has a maximum moisture content of less than 0.2% at 95% RH and 25°C. Shows water uptake.

[0195] FIG. 3 shows a scanning electron image of crystalline form K′ of Compound I.

[0196] [Table 1]

[0197] Example 2. Preparation and characterization of crystalline form M Crystalline Form M was prepared by adding 1.5 g of crystalline Form B of Compound I to 6 mL of acetone. The resulting mixture was slurried at 25°C for 1 day with stirring, and then 3 mg of seeds were added. The slurry was maintained for 3 days.

[0198] Alternatively, crystalline form M can be prepared by dissolving crystalline form B of compound I in acetone, Slurry in ethanol, 1:1 ethanol / water, methanol, or 1:1 methanol / water It can be obtained by compounding.

[0199] Seeds of crystalline form M were obtained by dissolving approximately 5 ml of 1:1 methanol / water at 50°C for 2 weeks. 0 mg of crystalline form B was obtained by equilibration of the suspension.

[0200] The X-ray powder diffraction pattern of crystalline form M is shown in Figure 4, and the peak list is shown in Table 2. do.

[0201] [Table 2]

[0202] Crystalline form M has an onset of melting at 264°C, followed by recrystallization and subsequent crystallization at approximately 279°C. The DSC curve of crystalline form M of Compound I is shown in FIG.

[0203] Crystalline form M is non-hygroscopic. It has a minimum moisture content of less than 0.1% at 25°C and a maximum humidity of 95% RH. Crystal form M exhibits a higher water uptake than crystal form B in the temperature range of 20°C to 35°C. It was found to be chemically stable.

[0204] A suspension of equimolar amounts of crystalline form B and crystalline form M was prepared at 20°C, 30°C and 35°C. After equilibration with isopropyl acetate, dichloromethane, ethanol or water, the crystalline form It was found that the methyl group was almost completely converted to the M form.

[0205] Crystalline form M is thermodynamically more stable than crystal form E in the temperature range of 30°C to 45°C. It was found that equimolar suspensions of crystalline form M and crystalline form E were heated at 30°C, 35°C, and and equilibrated with isopropyl acetate, dichloromethane, ethanol or water at 45°C. After 7 days, it was found to be completely converted to Modification M. Crystalline Form E is a polymorphic form of Compound I with the following peaks:

[0206] [Table 3]

[0207] Crystalline form M is thermodynamically more stable than crystal form Q in the temperature range of 22°C to 35°C. It was found that:

[0208] Equimolar suspensions of crystalline form M and crystalline form Q were prepared at 22°C, 30°C and 35°C. After equilibration with isopropyl acetate, dichloromethane, ethanol or water, the crystalline form It was found that the compound was completely converted to form M.

[0209] The solubility of crystalline form M in water at 25° C. is 0.04 mg / mL.

[0210] FIG. 6 shows a scanning electron image of crystalline form M of Compound I.

[0211] Example 3. Hydrate H B Preparation and characterization of Approximately 2.6 g of crystalline form B of Compound I was added to 40 mL of acetone / water (1:1 by volume). The mixture was slurried with stirring at room temperature for 7 days. The solid portion was separated and slurried under ambient conditions (approximately Air-dry at 40%RH for 2-3 days to obtain hydrated H B Hydrate H B X-ray The diffraction pattern is shown in FIG. 7 and the peak list is given in Table 4.

[0212] [Table 4]

[0213] When heated in DSC, hydrate H B begins to dehydrate at approximately 104°C. It shows slight water uptake up to 70%RH and 25℃, and above 70%RH and hydrate H B can take up an additional 2.5% of water at 95% RH. Thing H B The DSC curve of the sample is shown in FIG. 8, and the SEM image is shown in FIG.

[0214] Example 4. Preparation and characterization of crystalline form Q 1 g of Compound I (crystalline form B) was dissolved in 3 mL of n-butanol / DCM (1:1 by volume). The mixture was added to the mixture, and the mixture was slurried with a stirring rod at 50°C for 1 day. 90 mg of seeds were added. The mixture was slurried for 3 days.

[0215] Seeds of crystalline form Q were prepared by precipitation in 2 ml of n-butanol / dichloromethane (5 ml) at 50°C for 5 days. The suspension was obtained by equilibration of 500 mg of crystalline form Mod B in a 1:50 (v / v) ethanol solution. It was.

[0216] The X-ray powder diffraction pattern of crystalline form Q is shown in Figure 10, and the peak list is as shown in Table 55. It is.

[0217] [Table 5]

[0218] Crystalline form Q has an onset of melting at 259°C, followed by recrystallization and subsequent crystallization at approximately 263.7°C. The DSC curve for crystalline form Q of Compound I is shown in Figure 11, which shows melting at 279.0°C and 279.0°C. and the SEM image is shown in Figure 12.

[0219] Crystalline form Q is non-hygroscopic. It has a minimum moisture content of less than 0.1% at 25°C and a maximum humidity of 95% RH. Indicates large water uptake.

[0220] All publications and patent documents cited herein are the property of their respective owners. as if each was specifically and individually indicated to be incorporated by reference herein. The present invention and its embodiments have been described in detail. However, the scope of the present invention does not extend to any process, manufacture, or method described herein. It is not intended to be limited to 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 result as the described embodiment; Subsequent modifications, substitutions and / or variations may be made in accordance with such related embodiments of the present invention. It will be readily apparent from the present invention that the present invention can be utilized in various ways. The scope of any process, manufacture, composition of matter, compound, means, methods and and / or steps are intended to encompass within their scope modifications, substitutions and variations. The claims shall not be interpreted in any order or with elements recited unless stated to that effect. Various changes in form and details may be made without departing from the scope of the appended claims. It should be understood that the present invention may be applied without removal.

Claims

1. A crystalline form K' of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Compound I) having a structure, characterized by an X-ray diffraction pattern having three or more peaks at 2θ values selected from 5.3, 12.3, and 22.5 ± 0.2° 2θ. 【Chemistry 1】

2. The crystalline form K' of Compound I according to Claim 1, characterized by an X-ray diffraction pattern having three or more peaks at 2θ values selected from 5.3, 10.6, 12.3, 21.2, 22.5, and 23.0 ± 0.2° 2θ.

3. A method for preparing the crystalline form K' of Compound I according to Claim 1 or 2, comprising evaporating a solution of Compound I in n-butanol / dichloromethane at about 1:1 (v / v) and crystallizing Compound I as the crystalline form K'.

4. A crystalline form M of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Compound I) having a structure, characterized by an X-ray diffraction pattern having three or more peaks at 2θ values selected from 11.1, 18.5, 19.1 ± 0.2° 2θ. 【Chemistry 2】

5. The crystalline form M of Compound I according to Claim 4, characterized by an X-ray diffraction pattern having three or more peaks at 2θ values selected from 11.1, 12.1, 18.5, 19.1, 20.1, 21.4 ± 0.2° 2θ.

6. A method for preparing the crystalline form M of Compound I according to Claim 4 or 5, comprising slurrying Compound I in the crystalline form B with acetone at room temperature for at least 24 hours.

7. Characterized by an X-ray diffraction pattern having three or more peaks at 2θ values selected from 6.6, 12.2, 15.8 ± 0.2° 2θ, having a structure 【Transformation 3】 -yl)-benzonitrile (Compound I) crystalline hydrate H Ｂ .

8. ６、６、＿１２．２、＿１４．６、１５．８、１６．１、１８．５、２０．９、２４． An X-ray diffraction pattern having three or more peaks at 2θ values selected from 7 ± 0.2° 2θ The crystalline hydrate H of compound I according to claim 7, characterized by Ｂ .

9. Crystalline hydrate H of compound I according to claim 7 or 8 Ｂ A method for preparing a A method comprising slurrying Compound I in the crystalline form B with acetone for at least 5 days, at least 6 days, or at least 7 days. Compound I was slurried in an approximately 1:1 mixture of acetone and water to obtain the crystalline hydrate H Ｂ Provided as

10. Characterized by an X-ray diffraction pattern having three or more peaks at 2θ values selected from 11.2, 12.2, 19.1 ± 0.2° 2θ, having a structure ​ 【Chemistry 4】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 Crystalline Form Q of (-yl)-benzonitrile (Compound I).

11. １１．２、１２．２、１８．５、１９．１、２０．１、２２．０、２２．５、２３．３ , 26.5±0.2°2θ, or an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from 11. The crystalline form Q of compound I according to claim 10, characterized by a turn.

12. Compound I in crystalline form B was slurried with approximately 1:1 (v / v) n-butanol / dichloromethane.

12. The method of claim 10 or 11, comprising: cleaving the compound I in a crystalline form Q; Method for preparing crystalline form Q of compound I.

13. The crystalline form K', the crystalline form M, the crystalline form Q, and the hydrated form according to any one of claims 1 to 12. Thing H Ｂ and combinations thereof, and a crystalline form of Compound I selected from the group consisting of pharmaceutically acceptable salts thereof. and an excipient.

14. Compound I in crystalline form K' is prepared in substantially pure form, and Compound I in crystalline form M is prepared in substantially pure form. and the crystalline form Q in substantially pure form, or the hydrate H. Ｂ In effect, 14. The pharmaceutical formulation of claim 13, comprising in pure form.

15. 15. The pharmaceutical preparation of claim 13 or 14, formulated for ocular use.

16. 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl )-benzonitrile (Compound I) or a salt, co-crystal, or polymorph thereof, and A surfactant, a suspending agent, a tonicity agent, a buffer, a preservative, a salt, and a preservative are selected from the group consisting of: One or more excipients 1. An aqueous formulation comprising:

17. The formulation may contain crystalline form K', crystalline form M, crystalline form Q, hydrate H Ｂ or a combination thereof The 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3-yl 17. The aqueous formulation of claim 16, comprising (I)-benzonitrile (Compound I).

18. The 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3- The (hydroxybenzonitrile)-benzonitrile (Compound I) is present in the formulation at about 0.5% w / v to about 3.5% w / v.

18. The aqueous formulation of claim 16 or 17, wherein the aqueous formulation is present in an amount of 0.1 wt. / v.

19. 4-(7-hydroxy-2-isopropyl methylcellulose) in an amount of about 0.5% w / v to about 3.5% w / v Propyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Compound I), surfactants, suspending agents, and one or more excipients selected from the group consisting of tonicity agents, buffers, preservatives, salts, and preservatives; 19. The aqueous formulation of claim 17 or 18, comprising:

20. In an amount of about 0.5% w / v to about 3.5% w / v, present as a suspension in the formulation. 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3-yl) (I)-benzonitrile (Compound I), nonionic surfactants; suspending agents; Isotonic agent; Buffer; salt; and Optionally, a preservative The aqueous formulation according to any one of claims 17 to 19, comprising:

21. Nonionic surfactants include polysorbate surfactants, ethylene oxide block copolymers, and Polymer / propylene oxide surfactants, poloxamers, tyloxapol and combinations thereof 18. The formulation of claim 17, selected from the group consisting of:

22. The suspending agent may be carbomer, hydroxypropyl methylcellulose (hypromellose) 20 or 21, wherein the hydroxybenzoate is selected from the group consisting of polyethylene glycol, polyethylene glycol, and combinations thereof.

1. The formulation described in 1.

23. The suspending agent may be at least about 0.05% w / v, at least about 0.1% w / v, or at least about 0.5% w / v. at least about 0.2% w / v, and not more than about 1.0% w / v, not more than about 0.6% w / v, or not more than about 23. The composition of claim 22, wherein the carbomer is present in the formulation in an amount of 0.5% or less. formulation.

24. The suspending agent may be at least about 0.05% w / v, at least about 0.1% w / v, or is at least about 0.25% w / v, and less than about 1.8% w / v, less than about 1.0% w / v, present in the formulation in an amount of less than about 0.8% w / v, or less than about 0.6% w / v. or hydroxypropyl methylcellulose; The suspending agent is polyethylene glycol having a molecular weight of about 200 to about 20,000 Da. The formulation according to any one of claims 20 to 23, wherein the PEG is PEG-12.

25. 25. The method of claim 24, wherein the suspending agent is substantially all carbomer homopolymer type B. Formulation of.

26. Any of claims 20 to 25, wherein the tonicity agent is selected from the group consisting of polyols. The formulation according to claim 1.

27. The buffer solution may be acetate, ascorbate, borate, bicarbonate, carbonate, or citrate. , edetate (EDTA), gluconate, lactate, phosphate, propionate and Tris (tromethamine) formulation.

28. 28. The formulation of any one of claims 20 to 27, wherein the salt is sodium chloride.

29. 29. The method according to claim 24, wherein the pH of the formulation is from about 5.5 to about 8.

0. The formulation described above.

30. 1. A method of treating or reducing ocular surface pain in a subject in need thereof, comprising administering an effective amount of structure: 【Transformation 5】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 -yl)-benzonitrile (compound of formula I), or a salt, solvate, polymorph, or co-crystal thereof, by instillation into the subject. How to do it.

31. The compound of formula I is administered in the form of a formulation according to any one of claims 20 to 29. The method of claim 30,

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