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

Abstract

Ophthalmic compositions comprising 4 - (7-hydroxy-2-isopropyl-4-oxo - 4H - quinazolin-3-yl) - benzonitrile (Compound I) are provided.SOLUTION: The present invention provides crystalline Form E of 4 - (7-hydroxy-2-isopropyl-4-oxo - 4H - quinazolin-3-yl) - benzonitrile (Compound I). Further provided are methods of preparing crystalline Form E of Compound I comprising heating a hydrate form of Compound I to a temperature greater than 250 °C. or 260 °C. to provide Compound I as crystalline Form E. Further provided are ophthalmic compositions comprising crystalline Form E of Compound I.SELECTED DRAWING: None

Description

[Technical Field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 806,697, which is hereby incorporated by reference. is incorporated herein by reference in its entirety.

[0002] 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]

[0003] 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.

[0004] The transient receptor potential vanilloid 1 (TRPV1) receptor is involved in pain signaling. Antagonism of this receptor may 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. Summary of the Invention [Problem to be solved by the invention]

[0005] 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 morphology. [Means for solving the problem]

[0006] In some embodiments, the present invention provides a method for detecting the temperature gradient from 7.2, 12.7, and 21.4±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 A of (-yl)-benzonitrile (Compound I). , and the crystalline form A of compound I has the following values: 7.2, 12.7, 13.9, 18.1, 21.4, 25. X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from 1 and 26.8±0.2°2θ In some embodiments, the present disclosure provides a method for preparing a compound I. A method for preparing crystalline form A comprises cooling a hot solution of the free base of Compound I in methanol. and cooling to about 0°C to crystallize Compound I as crystalline form A. Regarding the law.

[0007] In some embodiments, the present invention provides a method for detecting a concentration of 100 ppm or less from 7.4, 14.9, 19.1 ± 0.2 degrees 2θ. Characterized by an X-ray diffraction pattern with three or more peaks at selected 2θ values ,structure [ka] 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 In some embodiments, the present invention relates to crystalline form C of (-yl)-benzonitrile (Compound I). , and the crystalline form C of Compound I has the following peaks: 7.4, 14.1, 14.9, 16.4, 19.1, 26. X-ray diffraction with three or more peaks at 2θ values ​​selected from 1, 31.2±0.2°2θ In some embodiments, the present invention provides a crystalline form of Compound I. A method for preparing Form C, comprising heating Compound I in crystalline Form A at a temperature of at least about 250°C, or to a temperature of at least about 270°C, or about 280°C. .

[0008] In some embodiments, the present invention provides a method for detecting a temperature difference between 12.7, 16.7, 22.6±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 E of (-yl)-benzonitrile (Compound I). , and the crystalline form E of Compound I is 12.7, 15.1, 16.7, 22.6, 27.1, 27 X-ray diffraction with three or more peaks at 2θ values ​​selected from 0.7, 28.5±0.2°2θ In some embodiments, the present invention provides a method for preparing a compound I crystalline cellulose, characterized by a folding pattern. A method for preparing crystalline form E, comprising heating a hydrate form of Compound I at a temperature above about 250°C or about 260°C. and heating the compound I to a temperature higher than 100° C. to provide compound I as crystalline form E. .

[0009] In some embodiments, the present invention provides a method for producing a compound comprising the steps of: [ka] 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 This relates to the crystalline hydrate of (-yl)-benzonitrile (Compound I).

[0010] In some embodiments, the crystalline hydrate of Compound I has a solubility of 6.6, 14.4, 18.3±0 by an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from .2°2θ In some embodiments, the crystalline hydrate of Compound I is characterized as having an average molecular weight of 6.6, 11.9, or 12.9. , 14.4, 18.3, 23.9, 26.5, 29.2 ± 0.2° 2θ selected from It is characterized by an X-ray diffraction pattern with three or more peaks at θ values. In an embodiment, the present invention provides a method for preparing a crystalline hydrate of Compound I, comprising the steps of: Equilibrate a slurry of Compound I in a mixture with a solvent to crystallize Compound I as a crystalline hydrate. In some embodiments, the water-miscible solvent is acetone. In some embodiments, the equilibration is for about 12 hours, about 18 hours, or about 24 hours. Or it is carried out over a period of about 48 hours.

[0011] In some embodiments, the present invention provides a method for producing a compound comprising the steps of: [ka] 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 This relates to a crystalline methanol solvate of (-yl)-benzonitrile (Compound I).

[0012] In some embodiments, the crystalline methanol solvate of Compound I has a pH of 6.1, 14.5, or 15. , 22.7±0.2°2θ, or an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from In some embodiments, the crystalline form of Compound I is characterized by a turnover. The solvates were 6.1, 12.2, 14.5, 18.0, 22.7, and 24.6 ± 0.2°2 Characterized by an X-ray diffraction pattern with three or more peaks at 2θ values ​​selected from θ In some embodiments, the present invention provides a crystalline methanol solvate of Compound I. A method for preparing Compound I by equilibrating a slurry of Compound I in methanol to convert Compound I into a polymorphic form. and obtaining Compound I as Form G, thereby providing Compound I as a crystalline methanol solvate. In some embodiments, equilibration is carried out at room temperature for at least about 24 hours. It will be carried out.

[0013] In some embodiments, the present invention provides a method for producing a compound comprising the steps of: [ka] 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 Regarding the crystalline acetonitrile solvate (form J) of (-yl)-benzonitrile (compound I) do.

[0014] In some embodiments, the crystalline acetonitrile solvate of Compound I has a pH of 8.2, 17. X-ray diffraction with three or more peaks at 2θ values ​​selected from 0.0, 23.8±0.2°2θ In some embodiments, the crystalline acetone of Compound I is characterized by a folding pattern. Nitrile solvates were 8.2, 11.8, 17.0, 22.8, 23.8, and 27.6±0 by an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from .2°2θ In some embodiments, the present invention provides a crystalline acetonitrile of Compound I. A method for preparing a solvate comprising equilibrating a slurry of Compound I in acetonitrile. and providing Compound I as a crystalline acetonitrile solvate. In some embodiments, equilibration is carried out at room temperature for at least about 24 hours.

[0015] In some embodiments, the present invention provides a method for detecting a concentration of 5.3, 12.3, 22.4±0.2 degrees 2θ. Characterized by an X-ray diffraction pattern with three or more peaks at selected 2θ values ,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). , and the crystal form K of compound I was 5.3, 6.5, 10.5, 12.3, 17.2, 19.3 , 22.4±0.2°2θ, or an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from In some embodiments, the present invention provides a crystalline form of Compound I. A method for preparing Form K, comprising crystallizing by evaporation of a solution of Compound I in acetone, providing compound I as crystalline form K.

[0016] In some embodiments, the present invention provides a method for determining the wavelength of an optical fiber selected from 7.1, 8.7, 10.6±0.2 degrees 2θ. characterized by an X-ray diffraction pattern having three or more peaks at selected 2θ values, structure [ka] 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 In some embodiments, the present invention relates to crystalline form L of (-yl)-benzonitrile (Compound I). , the crystalline form L of compound I has the following values: 3.5, 7.1, 8.7, 10.6, 12.2, 19.1, An X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from 22.4±0.2°2θ In some embodiments, the present invention provides a crystalline form of Compound I. A method for preparing compound L comprises adding a hydrocarbon solvent to a solution of compound I in acetone to form compound L. In some embodiments, the method further comprises providing compound I in crystalline form L. The hydrochloric solvent is hexane.

[0017] In some embodiments, the present disclosure provides an effective amount of crystalline form A, crystalline form C, crystalline form D, or , crystalline form E, crystalline form F, crystalline form L, crystalline form K, and combinations thereof and a crystalline form of Compound I according to any of the crystalline forms described above, and a pharmaceutically acceptable excipient. The present invention provides a pharmaceutical formulation comprising:

[0018] In some embodiments, the present disclosure provides a method for the preparation of crystalline form B, crystalline form A, and crystalline form B in an effective amount. C, crystalline form D, crystalline form E, crystalline form F, crystalline form L, crystalline form K and combinations thereof and a pharmaceutically acceptable excipient, Pharmaceutical formulations for ocular use (eg, topical application to the ocular surface) are provided.

[0019] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising crystalline Form A in substantially pure form. to provide.

[0020] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising crystalline Form C in substantially pure form. to provide.

[0021] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising crystalline Form E in substantially pure form. to provide.

[0022] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising crystalline Form F in substantially pure form. to provide.

[0023] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising crystalline form K in substantially pure form. to provide.

[0024] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising crystalline Form L in substantially pure form. to provide.

[0025] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a mixture of two or more crystalline forms of Compound I. A pharmaceutical formulation is provided.

[0026] In some embodiments, the present disclosure provides crystalline forms B and E, crystalline forms B and F, crystalline forms A mixture of crystalline forms B and C, crystalline forms A and C, and crystalline forms A and F in a ratio of about 1:99 to about 99:1. A pharmaceutical formulation containing the compound is provided.

[0027] In some embodiments, a pharmaceutical formulation comprising any of the crystalline forms disclosed herein is , formulated for ophthalmic use (eg, topical application to the ocular surface).

[0028] In some embodiments, provided herein is an aqueous formulation comprising: 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, an osmotic agent, a buffer, a preservative, a salt, and a preservative selected from the group consisting of Aqueous formulations are described that include one or more excipients.

[0029] In some embodiments, 4-(7-hydroxy-2-isopropyl-4-oxo-4 H-quinazolin-3-yl)-benzonitrile (Compound I) or its salts, co-crystals or The polymorph is present as a suspension in the formulation. 7-Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)benzoate Zonitrile (Compound I) or a salt, co-crystal, or polymorph thereof may be present in an amount of from about 0.5% w / v to about 3 Present in the formulation in an amount of 0.5% w / v.

[0030] In some embodiments, the present invention provides: 4-, which is 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)-be benzonitrile (Compound I) or a salt, co-crystal or polymorph thereof, surfactants, suspending agents, and one or more excipients selected from the group consisting of osmotic agents, buffers, preservatives, salts and preservatives; An aqueous formulation comprising:

[0031] In some embodiments, the invention described herein comprises: 4-(7-hydroxy-2-isopropyl)propanol in an amount of about 0.5% w / v to about 3.5% w / v (4-oxo-4H-quinazolin-3-yl)-benzonitrile (Compound I) or a suspension of a salt, co-crystal or polymorph of nonionic surfactants; suspending agents; osmotic agents; buffer; salt; and The formulation optionally contains a preservative.

[0032] In some embodiments, the present disclosure provides: 4-(7-hydroxy-2-isopropyl)propanol in an amount of about 0.5% w / v to about 3.5% w / v (4-oxo-4H-quinazolin-3-yl)-benzonitrile (Compound I) or a suspension of a salt, co-crystal or polymorph of A surfactant selected from the group consisting of nonionic, anionic, cationic surfactants and combinations thereof. surfactants; suspending agents; osmotic agents; buffer; Optionally, salt; optionally a preservative; and For formulations containing sufficient quantity (qs) of water up to 100%.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] In some embodiments of the formulations described herein, the suspending agent is a carbomer, hydrochloride, Hydroxypropylmethylcellulose (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.

[0037] 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.

[0038] In some embodiments of the formulations described herein, the suspension contains substantially all of the cal It is a Bomer homopolymer type B.

[0039] In some embodiments of the formulations described herein, the osmotic agent comprises a polyol. The compound is selected from the group consisting of:

[0040] 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 , about 0.4%w / v, about 0.5%w / v, about 1%w / v, about 2%w / v, about 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.

[0041] 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.

[0042] In some embodiments of the formulations described herein, the salt is sodium chloride or chloride It is potassium.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] In some embodiments, the present disclosure provides: Compound I or a salt, co-crystal, or polycrystal thereof in an amount of about 0.5% w / v to about 2.5% w / v shape, Tyloxapol, poloxamer or its analogues in an amount of about 0.01% w / v to 0.2% w / v a nonionic surfactant which is a combination of; Hydroxypropyl methylcellulose, polyethylene glycol or carbomer homopoly A suspension that is of the MerB type; at least one polyol in an amount of about 0.05% w / v to about 10% w / v; osmotic agents; Buffers that are edetate, phosphate, borate, or combinations thereof salt; and Contains up to 100% qs water; and The pH of the formulation ranges from about 5.5 to about 8.0.

[0047] 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. Compound I or a salt, co-crystal or polymorph thereof, present in an amount of 5% w / v; Tyloxapol in an amount of about 0.04% w / v to about 0.06% w / v, about 0.005% A non-ionic surfactant, which is a poloxamer or a combination thereof, in an amount of 0.12% w / v to 0.12% w / v surfactants; 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; Osmolality of mannitol or glycerin in amounts 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.

[0048] 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. 4-(7-hydroxy-2-isopropyl-4-oxo-4H- Quinazolin-3-yl)-benzonitrile (Compound I) or its salts, co-crystals or polymorphs Body suspension, 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 A formulation containing up to 100% qs water, The formulation has a pH in the range of about 5.5 to about 8.0.

[0049] In some embodiments of the formulations described herein, Compound I is polymorphic Form B. .

[0050] 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. 4-(7-hydroxy-2-isopropyl-4-oxo-4H- a suspension of polymorphic form B of quinazolin-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; and A formulation containing up to 100% qs water, The formulation has a pH in the range of about 5.5 to about 8.0.

[0051] In some embodiments, the formulation comprises: About 0.5% w / v, about 1.0% w / v, about 1.5% w / v, about 2.0% w / v or about 2. Compound I in an amount of 5% w / v, approximately 0.05% w / v tyloxapol; approximately 0.2% w / v carbomer homopolymer type B; approximately 2.0% w / v glycerin; Tromethamine buffer; and Hydrochloric acid to adjust the pH to about 6.4 to about 8.4; about 0.05% w / v sodium chloride; and Contains up to 100% qs water, Contains no preservatives.

[0052] In some embodiments of the formulations described herein, polymorphic Form B of Compound I is 9. Three or more peaks at 2θ values ​​selected from 3, 10.6 and 14.4±0.2°2θ It is characterized by an X-ray diffraction pattern having

[0053] In some embodiments, the formulations described herein have a viscosity of about 20 cP to about 200 cP. It has viscosity.

[0054] 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).

[0055] 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.

[0056] In some embodiments of the formulations described herein, the formulations have a shelf life of 6 months at room temperature. After piping, less than about 10%, less than about 8%, less than about 7%, less than about 6%, less than about 5%, less than about 4%, exhibiting less than about 3% or less than about 2% precipitation.

[0057] In some embodiments of the formulations described herein, the amount of Compound I in the formulation is maintained at refrigerated temperature. After about 6 months, about 8 months, about 10 months, about 12 months, about 15 months or At least 90% of the original amount after about 18 months.

[0058] In some embodiments of the formulations described herein, the amount of Compound I in the formulation is maintained at refrigerated temperature. at least about 91% and at least about 92% of the original amount after about 18 months of storage under , at least about 93%, at least about 94%, at least about 95%, at least 96%, At least about 97% or at least about 98%.

[0059] In some embodiments of the formulations described herein, the formulations remain stable after 6 months under refrigeration. The degradation products were determined by the addition of 0.1% trifluoroacetic acid (TFA) to the ethanol. ) When analyzed by HPMC using a water / acetonitrile mobile phase gradient, the compound It has a relative retention time of 1.23 compared to I.

[0060] In some embodiments of the formulations described herein, about 10% or more of Compound I in the formulation The following decomposes after 12 weeks of storage at 40°C.

[0061] In some embodiments of the formulations described herein, Compound I is present in crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F, crystalline form I ... B, crystal form C, crystal form E, crystal form F, crystal form G, crystal form J, crystal form K, crystal It is a crystalline form selected from the group consisting of form L and combinations thereof.

[0062] In some embodiments of the formulations described herein, Compound I is present in crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F, crystalline form I ... B, crystalline form C, crystalline form E, crystalline form F, crystalline form K, crystalline form L and combinations thereof The crystalline form is selected from the group consisting of:

[0063] In some embodiments, the present disclosure provides: A quantity of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 -yl)-benzonitrile (Compound I) or a salt, co-crystal or polymorph thereof, nonionic surfactants; suspending agents; osmotic agents; buffer; salt; optionally a preservative; and Mixing with water up to 100% qs; and The present invention relates to a method for preparing a formulation, which comprises adjusting the pH to a range of about 5.5 to about 8.0.

[0064] In some embodiments, the method of making the formulations disclosed herein comprises preparing a stock suspension and In some embodiments, the stock suspension comprises the addition of Compound I to form a desired particle size. In some embodiments, the D of Compound I in the formulation is 90 ( The diameter of the particles (90% of which are smaller than Compound I) is less than about 10 μm, less than about 8 μm. In some embodiments, the average particle size is less than about 6 μm, less than about 4 μm, less than about 3 μm, or about 2 μm. In this case, the D of Compound I in the formulation 50 (50% of Compound I is composed of smaller particles) diameter) is less than about 10 μm, less than about 8 μm, less than about 6 μm, less than about 4 μm, less than about 3 μm, In some embodiments, the D of Compound I in the formulation is less than about 2 μm or about 1 μm. 10 (diameter of particles smaller than 10% of Compound I) is less than about 5 μm, less than about 4 μm less than about 3 μm, less than about 2 μm, less than about 1 μm, or about 0.3 μm.

[0065] 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.

[0066] 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.

[0067] 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 The present invention provides a reduced incidence of at least about 10% in one or more of the following: irritability, dizziness, or photophobia.

[0068] In some embodiments, the subject is diagnosed with dry eye disease, Sjogren's syndrome, conjunctivitis (keratitis), 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:

[0069] In some embodiments, the methods include administering an additional therapeutic agent to the subject.

[0070] 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 method according to claims 101 to 102 is based on the difference in VAS scores. The reduction in core may occur within about half an hour, about one hour, about two hours, or about one or more hours after administration of Compound I to a subject. Occurs within 4 hours or about 2 to 4 hours.

[0071] In some embodiments, administration of Compound I may result in a response rate of 1: 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.

[0072] 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.

[0073] 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.

[0074] 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 The pain may be acute (e.g., acute) or chronic (e.g., chronic) ocular surface pain.

[0075] 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.

[0076] 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.

[0077] In some embodiments, administration results in a reduction in the symptoms of dry eye disease.

[0078] 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.

[0079] In some embodiments, the subject is diagnosed with dry eye disease, Sjogren's syndrome, conjunctivitis (keratitis), 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] In some embodiments, the present disclosure provides a method for treating or reducing ocular surface pain in a subject in need thereof. 1. A method performed on a subject, comprising: [ka] The compound 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolidinyl) A method for treating a subject comprising administering to the subject a formulation containing (benzo-3-yl)-benzonitrile (Compound I). Regarding the law, The formulations resulted in a Cmax of Compound I in the rabbit cornea that was approximately 1.5 to approximately 3 times the Cmax in the conjunctiva. , Cmax is the maximum concentration of Compound I in a particular tissue after administration of a single dose. In some embodiments, Compound I is administered in a formulation described herein.

[0085] In some embodiments, the present disclosure provides a method for treating or reducing ocular surface pain in a subject in need thereof. 1. A method performed on a subject, comprising: [ka] The compound 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolidinyl) A method for treating a subject comprising administering to the subject a formulation containing (benzo-3-yl)-benzonitrile (Compound I). Regarding the method, the formulation exhibited a Cmax in rabbit corneas that was approximately 500 times that of Compound I in plasma. Cmax of Compound I is the chemical reaction in a particular tissue after administration of a single dose. In some embodiments, Compound I is a maximal concentration of Compound I described herein. It is administered as a formulation.

[0086] 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]

[0087] [Figure 1] 1 provides an overlay of experimental and calculated XRPD patterns of crystalline Form A of Compound I. [Figure 2] 1 provides an X-ray powder diffraction pattern of crystalline Form A of Compound I. [Figure 3] 1 provides an overlay of experimental and calculated XRPD patterns of crystalline Form C of Compound I. [Figure 4] 1 provides an X-ray powder diffraction pattern of crystalline Form C of Compound I. [Figure 5] 1 provides an overlay of experimental and calculated XRPD patterns of crystalline Form E of Compound I. [Figure 6] 1 provides the X-ray powder diffraction pattern of crystalline Form E of Compound I. [Figure 7] 1 provides the X-ray powder diffraction pattern of crystalline form F of Compound I (hydrate HA). [Figure 8] 1 provides an overlay of experimental and calculated XRPD patterns of crystalline form G of Compound I (methanol solvate SB). [Figure 9] 1 provides the X-ray powder diffraction pattern of crystalline form G of Compound I (methanol solvate SB). [Figure 10] 1 provides the X-ray powder diffraction pattern of crystalline form J of Compound I (acetonitrile solvate SA). [Figure 11] 1 provides an X-ray powder diffraction pattern of crystalline form K of Compound I. [Figure 12] 1 provides an X-ray powder diffraction pattern of crystalline form L of Compound I. [Figure 13]1 illustrates the relationship between polymorphic and solvated / hydrated forms of the free base of Compound I and exemplary methods for their conversion. [Figure 14A] Figure 14A shows the percent of Compound I in the exploratory formulations described in Table 13 over 12 weeks at room temperature. In Figure 14A, the formulation with a percent of Compound I of about 75% of the original at 12 weeks is the formulation of Compound I as a solution. [Figure 14B] Figure 14B shows the percent Compound I in the exploratory formulations after 12 weeks at 40° C. In Figure 1B, the formulation with a percent Compound I of about 20% of the original at 12 weeks is the formulation of Compound I as a solution. [Figure 15] 1 shows the powder X-ray diffraction patterns of Compound I recovered from 12-week stability samples versus controls. DETAILED DESCRIPTION OF THE INVENTION

[0088] 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. Measured as described in the brochure.

[0089] 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.

[0090] 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 .

[0091] 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.

[0092] 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. .

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] As used herein, the term "about" refers to a range of the specified value plus 10%.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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 3, 94, 95, 96, 97, 98 and 99% by weight, and furthermore, 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.

[0108] 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]

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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

[0113] 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.

[0114] 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.

[0115] 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.

[0116] Crystalline Form of Compound I In one aspect, the present invention provides a method for determining the angle of refraction selected from 7.2, 12.7 and 21.4±0.2 degrees 2θ. Compound I, characterized by an X-ray diffraction pattern having three or more peaks at 2θ values. In some embodiments, crystalline form A is 7.2, 12.7, 1 2θ selected from 3.9, 18.1, 21.4, 25.1 and 26.8±0.2°2θ It is characterized by an X-ray diffraction pattern with three or more peaks at In embodiments, crystalline form A is 7.2, 12.7, 13.3, 13.9, 14.5, 15. 6, 18.1, 19.9, 21.4, 22.8, 25.1, 26.8, 27.8, 29. 3 or more, 4 or more, 5 or more, 6 or more 2θ values ​​selected from 0±0.2°2θ It is characterized by an X-ray diffraction pattern with seven or more peaks.

[0117] Crystalline Form A can be obtained by cooling a hot solution of the free base of Compound I in methanol to approximately 0°C. and can be prepared by crystallizing Compound I as crystalline form A.

[0118] In one embodiment, crystalline Form A of Compound I is provided in substantially pure form. This crystalline Form A 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 A. 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 A.

[0119] In one aspect, the present invention provides a method for producing a 2θ angle selected from 7.4, 14.9, 19.1±0.2 degrees 2θ. Compound I is characterized by an X-ray diffraction pattern having three or more peaks at θ values. In some embodiments, crystalline form C is selected from the group consisting of 7.4, 14.1, 14 At 2θ values ​​selected from 0.9, 16.4, 19.1, 26.1, 31.2±0.2°2θ Characterized by an X-ray diffraction pattern with three or more peaks. In the crystal form C, the molecular weights were 7.4, 14.1, 14.9, 16.4, 19.1, 24.8, Three or more, four or more 2θ values ​​selected from 26.1, 28.4, 31.2±0.2°2θ characterized by an X-ray diffraction pattern having five or more, six or more, or seven or more peaks It can be done.

[0120] Crystalline form C can be prepared by heating crystalline form A.

[0121] In one embodiment, crystalline Form C of Compound I is provided in substantially pure form. This crystalline Form C 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 C. 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 C.

[0122] In one aspect, the present invention provides an optical fiber having a wavelength of 12.7, 16.7, 22.6±0.2 degrees 2θ. Compound I, characterized by an X-ray diffraction pattern having three or more peaks at 2θ values. In some embodiments, crystalline form E is crystalline form E of 12.7, 15.1, 2θ selected from 16.7, 22.6, 27.1, 27.7, 28.5±0.2°2θ It is characterized by an X-ray diffraction pattern with three or more peaks at In some embodiments, polymorph E of Compound I has an onset melting temperature of about 281° C. In embodiments, crystalline form E is 9.1, 11.9, 12.7, 13.8, 15.1, 16. 7, 18.3, 21.3, 22.6, 24.4, 27.1, 27.7, 28.5, 37. 3 or more, 4 or more, 5 or more, 6 or more 2θ values ​​selected from 8±0.2°2θ It is characterized by an X-ray diffraction pattern with seven or more peaks.

[0123] Crystalline Form E can be obtained by heating the hydrate form of Compound I to a temperature above about 250°C or about 260°C. to obtain Compound I as crystalline Form E. Alternatively, the heating may be carried out in a dryer.

[0124] In one embodiment, crystalline Form E of Compound I is provided in substantially pure form. This crystalline Form E 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 E. 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 E.

[0125] In one aspect, the present invention relates to a crystalline hydrate of Compound I (polymorph F). The crystalline hydrate of Compound I is selected from the following forms: 6.6, 14.4, 18.3±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 hydrate is 6.6, 11.9, 14.4, 18.3, 23 Three or more peaks were detected at 2θ values ​​selected from 0.9, 26.5, and 29.2±0.2°2θ. It is characterized by an X-ray diffraction pattern.

[0126] In some embodiments, the crystalline hydrate has a molecular weight of 6.7, 11.9, 12.8, 14.4, 1 5.6, 16.3, 18.3, 19.5, 22.7, 23.9, 24.7, 25.6, 2 3 or more, 4 or more, 5 or more 2θ values ​​selected from 6.5, 29.2±0.2°2θ , characterized by an X-ray diffraction pattern having six or more or seven or more peaks.

[0127] Crystalline Form F can be obtained by equilibration of a slurry of Compound I in a mixture of water and a water-miscible solvent. It can be prepared by crystallizing compound I as crystalline form F. In certain embodiments, The water-miscible solvent is acetone. In some embodiments, equilibration is performed for about 12 hours. In some embodiments, the equilibration is carried out for 18 hours, or for about 24 hours, or for about 48 hours. The polymerization is carried out at room temperature, ie, about 25°C.

[0128] In one embodiment, crystalline Form F of Compound I is provided in substantially pure form. This crystalline Form F 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 Compound I as a crystalline hydrate. In some embodiments, the present disclosure provides pharmaceutical formulations comprising polymorphic Form F. and an ophthalmic suspension of Compound I, wherein at least 10% of Compound I, 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% are crystalline hydrates It exists as polymorph F.

[0129] In one aspect, the present invention relates to a crystalline methanol solvate form (polymorph G) of Compound I. In some embodiments, the crystalline methanol solvate of Compound I has a viscosity of 6.1, 14.5 , 22.7±0.2°2θ, or an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from In some embodiments, the crystalline methanol solvate is characterized by a turn. , 6.1, 12.2, 14.5, 18.0, 22.7, 24.6±0.2°2θ selectable It is characterized by an X-ray diffraction pattern with three or more peaks at the 2θ values ​​specified.

[0130] Polymorph Form G was prepared by equilibrating a slurry of Compound I in methanol to obtain crystalline Form G. In some embodiments, the equilibration is for about 12 hours. In some embodiments, the incubation time is about 18 hours, about 24 hours, or about 48 hours. Equilibration is carried out at room temperature, ie, about 25°C.

[0131] In one embodiment, crystalline Form G of Compound I is provided in substantially pure form. This crystalline Form G 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 for the preparation of Compound I as a crystalline metabolite. In some embodiments, the present disclosure provides pharmaceutical formulations comprising benzoylcholinesterase inhibitors as a benzoylcholinesterase inhibitor in the polymorph form (polymorph G). provides an ophthalmic suspension of Compound I, wherein at least 10% of Compound I, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least At least about 60%, at least about 70%, at least about 80%, or at least 90% crystalline metal It exists as a ethanol solvate (polymorph G).

[0132] In one aspect, the present invention relates to a crystalline acetonitrile solvate (crystalline form J). In some embodiments, the crystalline acetonitrile solvate of Compound I has a viscosity of 8.2, 17.0, An X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from 23.8±0.2°2θ In some embodiments, the crystalline acetonitrile solvate is Select from 8.2, 11.8, 17.0, 22.8, 23.8, 27.6±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 acetonitrile solvate is 8.2, 11.8, 17. 3 at 2θ values ​​selected from 0, 22.8, 23.8, 27.6, 31.4±0.2°2θ an X-ray diffraction pattern having one or more, four or more, five or more, six or more, or seven or more peaks It is characterized by:

[0133] Crystalline acetonitrile solvate: Equilibrate a slurry of Compound I with acetonitrile In some embodiments, the compound in the slurry may be prepared by crystalline Form A. In some embodiments, equilibration is for about 12 hours, about 18 hours, or about 24 hours. In some embodiments, equilibration is performed at room temperature, i.e., about 25° C. It will be carried out in.

[0134] In one embodiment, the crystalline acetonitrile solvate of Compound I is in substantially pure form. This crystalline acetonitrile solvate of Compound I in substantially pure form is provided. They may be used in pharmaceutical compositions, such as ophthalmic formulations, as described herein. In one embodiment, the present disclosure provides pharmaceutical compositions comprising Compound I as a crystalline acetonitrile solvate (polymorph J). In some embodiments, the present disclosure provides an ophthalmic suspension of Compound I. wherein at least 10%, at least about 20%, at least about 30%, or at least about 10% of Compound I 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 a crystalline acetonitrile solvate (polymorph J) It exists as.

[0135] In one aspect, the present invention provides a method for producing a 20° C. optical fiber comprising the steps of: 5.3, 12.3, 22.4±0.2° 2θ; Compound I is characterized by an X-ray diffraction pattern having three or more peaks at θ values. In some embodiments, crystalline form K is 5.3, 6.5, 10. 3 at 2θ values ​​selected from 5, 12.3, 17.2, 19.3, and 22.4±0.2°2θ and characterized by an X-ray diffraction pattern having one or more, four or more, five or more, or six or more peaks. be assigned.

[0136] Crystalline Form K was obtained by evaporative crystallization of Compound I in acetone. It can be prepared by crystallization from HCl.

[0137] In one embodiment, crystalline form K of compound I is provided in substantially pure form. This crystalline Form K of Compound I in a substantially pure form can be used in pharmaceutical compositions, e.g., as described herein. In some embodiments, the present disclosure provides compound I in polymorph K. In some embodiments, the present disclosure provides a pharmaceutical formulation comprising Compound I as an ophthalmic solution. 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 polymorph K.

[0138] In one aspect, the present invention provides a 2θ angle selected from 7.1, 8.7, 10.6±0.2 degrees 2θ. The results of Compound I are characterized by an X-ray diffraction pattern with three or more peaks at In some embodiments, crystalline form L is selected from the group consisting of 3.5, 7.1, 8.7, Three or more 2θ values ​​selected from 10.6, 12.2, 19.1, 22.4±0.2°2θ In some embodiments, the compound is characterized by an X-ray diffraction pattern having peaks above 1000 nm. , crystalline form L is 3.5, 7.1, 8.7, 10.6, 11.1, 12.2, 19.1, Three or more, four or more 2θ values ​​selected from 21.1, 22.4, 23.4±0.2°2θ characterized by an X-ray diffraction pattern having five or more, six or more, or seven or more peaks It can be done.

[0139] Crystalline form L was obtained by precipitation of a solution of compound I in acetone by adding a hydrocarbon solvent. It can be prepared by crystallizing compound I in crystalline form L. In certain embodiments, the hydrocarbon solvent is pentane, hexane, or heptane. The hydrocarbon solvent is hexane.

[0140] In one embodiment, crystalline form L of compound I is provided in substantially pure form. This crystalline Form L of Compound I in a substantially pure form can be used in pharmaceutical compositions, e.g., as described herein. In some embodiments, the present disclosure provides compound I in polymorph form L In some embodiments, the present disclosure provides a pharmaceutical formulation comprising Compound I as an ophthalmic solution. 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 the Form L polymorph.

[0141] 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 present in polymorph A, polymorph B, polymorph C, polymorph E. , polymorph F (hydrate H A ), polymorph J (acetonitrile solvate S A ), polymorph G (meta Nol solvate S B ), polymorph K, polymorph L or a combination thereof. In embodiments, Compound I is present in substantially pure form in the ophthalmic formulations described herein. In some embodiments, Compound I is present in the ophthalmic formulations described herein. It exists in qualitatively pure form as polymorph A. In some embodiments, compound I is It is present in substantially pure form as Polymorph C in the ophthalmic formulations described herein. In embodiments, Compound I is present in the ophthalmic formulations described herein as a polymorph in substantially pure form. In some embodiments, compound I is present as E in the ophthalmic formulations described herein. It exists in substantially pure form as polymorph F. In some embodiments, compound I is , which is present in the ophthalmic formulations described herein in substantially pure form as polymorph K. In some embodiments, Compound I is present in the ophthalmic formulations described herein in a substantially pure form. In certain embodiments, compound I exists as Form L. In certain embodiments, compound I exists as Form L in two or more different polymorphic forms. In some embodiments, Compound I is present in the formulation as a mixture of polymorphic Form B and E, polymorphs B and F, polymorphs B and C, polymorphs A and C, polymorphs A and F in a ratio of about 1:9 It exists as a mixture in a ratio of 9 to about 99:1.

[0142] In some embodiments, the formulation further comprises at least one ophthalmically acceptable excipient. Included.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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

[0148] 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

[0149] In certain embodiments, the suspending agent is a combination of two or more suspending agents. The suspending agent is substantially all carbomer.

[0150] 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. .

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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%.

[0159] 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:

[0160] 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:

[0161] 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:

[0162] 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:

[0163] In some embodiments, the present invention provides: 4-, which is 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)-be benzonitrile (Compound I) or a salt, co-crystal or polymorph thereof, surfactants, suspending agents, and one or more excipients selected from the group consisting of osmotic agents, buffers, preservatives, salts and preservatives; An aqueous formulation comprising:

[0164] In some embodiments, the invention described herein comprises: 4-, which is 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)-be benzonitrile (Compound I) or a salt, co-crystal or polymorph thereof, nonionic surfactants; suspending agents; osmotic agents; buffer; salt; and The formulation optionally contains a preservative.

[0165] In some embodiments, the invention described herein comprises: 4-(7-hydroxy-2-isopropyl)propanol in an amount of about 0.5% w / v to about 3.5% w / v (4-oxo-4H-quinazolin-3-yl)-benzonitrile (Compound I) or a suspension of a salt, co-crystal or polymorph of nonionic surfactants; suspending agents; osmotic agents; buffer; salt; optionally a preservative; and Formulations containing up to 100% qs water.

[0166] In some embodiments, the invention described herein comprises: 4-(7-hydroxy-2-isopropyl)propanol in an amount of about 0.5% w / v to about 2.5% w / v (4-oxo-4H-quinazolin-3-yl)-benzonitrile (Compound I) or a suspension of a salt, co-crystal or polymorph of Tyloxapol, poloxamer or its analogues in an amount of about 0.01% w / v to 0.2% w / v a nonionic surfactant selected from the combination of Hydroxypropyl methylcellulose, polyethylene glycol or carbomer homopoly a suspending agent selected from the group consisting of mer-B type; an osmotic 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 Contains up to 100% qs water; and The formulation has a pH ranging from about 5.5 to about 8.0.

[0167] 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. 4-(7-hydroxy-2-isopropyl-4-oxo-4H- Quinazolin-3-yl)-benzonitrile (Compound I) or its salts, co-crystals or polymorphs Body suspension, Tyloxapol in an amount of about 0.04% w / v to about 0.06% w / v, about 0.005% a non-isopropyl alcohol selected from poloxamers or combinations thereof in an amount of 0.12% w / v to 0.12% w / v ionic surfactants; 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 osmotic 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; Water up to 100% qs, and The formulation has a pH ranging from about 5.5 to about 8.0.

[0168] 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. 4-(7-hydroxy-2-isopropyl-4-oxo-4H- Quinazolin-3-yl)-benzonitrile (Compound I) or its salts, co-crystals or polymorphs Body suspension, 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; Water up to 100% qs, and The formulation has a pH ranging from about 5.5 to about 8.0.

[0169] 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. 4-(7-hydroxy-2-isopropyl-4-oxo-4H- a suspension of polymorphic form B of quinazolin-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; Water up to 100% qs, and The formulation has a pH ranging from about 5.5 to about 8.0.

[0170] 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. 4-(7-hydroxy-2-isopropyl-4-oxo-4H- a suspension of polymorphic form B of quinazolin-3-yl)-benzonitrile (Compound I); approximately 0.05% w / v tyloxapol; approximately 0.2% w / v carbomer homopolymer type B; approximately 2.0% w / v glycerin; Tromethamine buffer; about 0.05% w / v sodium chloride; and Water up to 100% qs, and a formulation comprising a pH in the range of about 6.4 to about 8.4; The formulation does not contain preservatives.

[0171] 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.

[0172] 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.

[0173] Without being bound by theory, the viscosity of formulations with carbomer homopolymer type B varies with pH. increases as the pH is adjusted from acidic to neutral, but the viscosity decreases with increasing ionic strength. The present inventors have found that the use of tromethamine as a buffer solution reduces the It was found that increasing the pH did not result in a substantial increase in the on-state strength. Without this, the inventors have found that glycerin increases the osmolality of the formulation by increasing its ionic strength. It has also been found that glycerin is well tolerated and non-irritating. and also acts as a water-retaining agent and additional viscosity agent.

[0174] Without being bound to any particular theory, the inventors believe that the surfactants in the formulation The inclusion of the agent also acts as a wetting agent for the compound of formula I, thereby preventing the particles of compound I from adhering to the surface. Provides water wetting while reducing the potential for irritation and foaming and facilitating redispersion of the suspension was found to promote

[0175] 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.

[0176] 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.

[0177] 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.

[0178] In some embodiments, the suspension is packaged in a single-dose container. In some embodiments, the formulations are packaged in multi-dose containers.

[0179] 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.

[0180] In some embodiments, the formulation exhibits less than about 10% precipitation after 6 months of storage at room temperature. In some embodiments, the formulation retains less than about 8%, less than about 7%, or less than about 8% of its original volume after 6 months of storage at room temperature. %, less than about 6%, less than about 5%, less than about 4%, less than about 3%, or less than about 2% sedimentation The precipitation behavior can be determined by methods commonly known to those skilled in the art, for example, as described herein. Therefore, it is measured.

[0181] In some embodiments, the amount of Compound I in the formulation is maintained at a temperature suitable for storage under refrigeration (e.g., about 4°C). After about 6 months of administration, the amount is at least 90% of the original amount. The amount of Compound I was about 8 months, about 10 months, about 12 months, and about 15 months after storage under refrigeration. At least about 90% of the original amount after about 18 months or after about 18 months. In this formulation, the amount of Compound I in the formulation remains constant after about 6 months of storage under refrigeration (e.g., about 4°C). At least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 100%, at least about 101%, at least about 102%, at least about 103%, at least about 104%, at least about 105%, at least about 106%, at least about 107%, at least about 94%, at least about 95%, at least 96%, at least about 97% or less In some embodiments, the amount of Compound I in the formulation is at least about 98% under refrigeration. At least about 91%, at least about 92%, or at least about 93% of the original amount after about 18 months of storage at least about 93%, at least about 94%, at least about 95%, at least 96%, The amount of Compound I in the formulation is, for example, about 97% or at least about 98%. C, LC / MS, or other methods commonly known to those skilled in the art.

[0182] In some embodiments, the formulation contains no more than about 10% degradation products after 6 months under refrigeration. The degradation products were analyzed using a 0.1% trifluoroacetic acid (TFA) water / acetonitrile mobile phase. When analyzed by HPMC using a gradient of 1.23 relative to compound I In some embodiments, the formulation has a shelf life of about 9% or less after 6 months under refrigeration. About 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, or about 2% The following degradation products are included:

[0183] In some embodiments, about 10% or less of Compound I in the formulation remains at 40° C. for 12 weeks. In certain embodiments, the amount of Compound I in the formulation is about 9% or less, about 8% or less, or Approximately 7% or less, approximately 6% or less, approximately 5% or less, approximately 4% or less, approximately 3% or less, approximately 2% or less at 40°C Decomposes after 12 weeks of storage at room temperature.

[0184] 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.

[0185] 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:

[0186] 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.

[0187] In some embodiments, Compound I is stored in water, optionally with a surfactant. In some embodiments, Compound I is added as a storage suspension. In alternative or additional embodiments, the stock suspension of Compound I is present in an amount of 0. In some embodiments, the stock suspension of Compound I further comprises 2% tyloxapol. In some embodiments, the compound I in the formulation is milled to obtain the desired particle size. Compound I D 90 (diameter of the smaller particles of which 90% of Compound I is composed) is approximately 10 μm less than about 8 μm, less than about 6 μm, less than about 4 μm, less than about 3 μm, or about 2 μm. In some embodiments, the D of Compound I in the formulation 50 (50% of compound I is smaller particles Diameter (composed of particles) is less than about 10 μm, less than about 8 μm, less than about 6 μm, less than about 4 μm In some embodiments, the particle size of the formulation is less than about 3 μm, less than about 2 μm, or about 1 μm. Compound I D 10 (diameter of particles smaller than 10% of Compound I) is approximately 5 μm less than about 4 μm, less than about 3 μm, less than about 2 μm, less than about 1 μm, or about 0.3 μm do.

[0188] In certain embodiments, the non-ionic surfactants, suspending agents, osmotic agents, buffers, and salts are In some embodiments, the formulation is preservative-free.

[0189] An exemplary method for the preparation of a 1.5% w / v Compound I suspension is described below. 1. Polybutylene terephthalate, with PTFE-lined cap and magnetic stir bar A clean, dry glass Schott bottle is tared. 2. Add the batch amount of Compound I solvent (including suspending agent, osmotic agent, surfactant, and salt) to the bottle. Add HCl (adjusted to final pH). Seal and sterilize the compounding vessel with steam (F0 ≥ 30). 3. Transfer the container to a horizontal laminar flow workbench and allow to cool. 4. Aseptically weigh out the batch amount of sterile 10% Compound I / 0.2% surfactant into a compounding vessel. If necessary, add sterile (either steam sterilized or sterile filtered) purified water. Adjust to final batch weight and mix until uniform. 5.1.5% suspension is aseptically filled into sterile dispensing bottles. Insert the suspension tip and twist to seal. Tighten to seat the tip and seal. 6. Remove the filled unit from the laminar flow workbench and label it. Osmolality values ​​are determined.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] 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.

[0194] 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.

[0195] In some embodiments, the ocular surface pain or chronic ocular surface pain is caused by dry eye disease, shaving, or other conditions. 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.

[0196] 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, synophthalmos, blepharophimosis, trichiasis, anterior blepharitis, lacrimal punctum obstruction, meibomian gland disease , corneal opacity, dry eyes, lash hyperplasia, limbal stem cell failure, or corneal neovascularization are.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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

[0204] 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. In some embodiments, the compound of formula I is administered to a subject at least about 1 or 4 times. 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 compound of formula I is administered in the formulations described herein.

[0205] 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.

[0206] 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%.

[0207] 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.

[0208] 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

[0209] 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.

[0210] 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

[0211] 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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).

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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).

[0221] 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).

[0222] 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 and the retina 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).

[0223] 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).

[0224] 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.

[0225] 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.

[0226] 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:

[0227] 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 .

[0228] 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).

[0229] 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.

[0230] 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

[0231] 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.

[0232] 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

[0233] 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.

[0234] 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%.

[0235] 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.

[0236] 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.

[0237] 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]

[0238] The following examples are included to demonstrate non-limiting embodiments of the invention.

[0239] General Test Conditions The following procedures were utilized under each test condition.

[0240] Equilibration with solvent at 25°C For equilibration at 25°C, approximately 50 mg of compound I was placed in a water bath at 25°C ± 0.1°C, and 1 ml The solution was filtered and air dried for 10 minutes. The components were examined by XRPD (X-ray powder diffraction). If differences were observed, further examination was indicated. Appropriate measurements were carried out (e.g., DSC, TG, IR, SEM).

[0241] Equilibration with solvent at 50°C For equilibration with a solvent at 50°C, approximately 50 mg of compound I was placed in a water bath at 50°C ± 0.1°C. The solution was equilibrated with 1 ml of solvent for 24 hours. The filtrate was used as described in the specific examples. .

[0242] Crystallization from hot saturated solutions To crystallize Compound I from a hot saturated solution, approximately 300 mg of the drug substance was added to a minimum amount of solvent at 60°C. The solution was dissolved in a solvent and filtered hot. No remaining crystals were visible. The solution was placed in an ice bath and stirred. The precipitate was collected on a filter, dried, and examined as above. It can be modified as described in the examples.

[0243] Precipitation by adding solvent In the case of precipitation of compound I by adding a solvent, compound I is dissolved in a solvent in which it is highly soluble. A solvent in which Compound I is highly insoluble was added. The precipitate was treated as described in the specific examples. did.

[0244] 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) was recorded between

[0245] 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 degree of measurement error is within 100°, and it should be considered that this degree of measurement error is related to the above-mentioned 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.

[0246] thermogravimetric method The TGA instrument used to test the crystalline form was a Metter TGA851e T The sample was 10 to 20 milligrams and heated to a temperature between 30°C and approximately 300°C. The analysis was carried out at a heating rate of 20°C / min within the temperature range.

[0247] Differential scanning calorimetry (DSC) The DSC instrument used to examine the crystal morphology was a Mettler DSC822e or The DSC cell / sample chamber was a Perkin Elmer DSC7. The instrument was purged 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 DSC pan and measured against an empty reference pan. Approximately 1 to 3 mg of sample powder was placed on the bottom of the pan and gently tapped to separate the sample from the pan. The weight of the sample was measured accurately and recorded to the nearest hundredth of a milligram. The temperature was programmed to heat at 10°C / min in the range of 30°C to 300°C. Ta.

[0248] Example 1. Preparation of Crystalline Form A Crystalline Form A was obtained by converting the hydrochloride salt of Compound I into the free base. Crystallization was carried out by cooling hot methanol to 0°C, where the compound was identified as crystalline form A. and crystallized.

[0249] The differential scanning calorimetry curve for crystalline form A shows a small endothermic event at about 264°C followed by It showed a melting point of approximately 269°C. Figure 1 shows the simulated and measured X-ray diffraction patterns of crystalline form A. The X-ray powder diffraction pattern of crystalline form A is shown in Figure 2, and the peak list is The single crystal data for crystalline form A of Compound I are as follows: This is: Molecular formula:C 18 H 15 N3O2 Molecular weight (free acid): 305.34 Lattice parameters: spatial symmetry monoclinic space group P21 / n Cell volume (Å 3 ) 3157.2 Crystal density (g / cm 3 ) 1.285 a(Å) 16.285 b(Å) 7.977 c(Å) 24.640 β(°) 99.046 z8

[0250] [Table 1]

[0251] Example 2. Preparation of Crystalline Form C Crystalline Form C can be obtained by heating Crystalline Form A to about 250°C in a thermogravimetric analyzer or by Crystalline Form B was obtained by heating at 250°C for 80 minutes. 1:1 mixture with Crystalline Form B In this study, crystalline form C was converted to crystalline form B with isopropanol. In a :1 mixture, crystalline form C was solvated in methanol to form S B (crystal form G) Ta.

[0252] FIG. 3 shows the overlay of the simulated and measured X-ray diffraction patterns of crystalline form C. The X-ray powder diffraction pattern of Form C is shown in Figure 4, and the peak list is shown in Table 2. The lattice parameters for morph C are: Spatial symmetry Orthorhombic space group Pna21 Cell volume (Å 3 ) 3078.3 Crystal density (g / cm 3 ) 1.318 a(Å) 15.685 b(Å) 8.281 c(Å) 23.697 z8

[0253] [Table 2]

[0254] Example 3. Preparation of Crystalline Form E Approximately 1000 mg of Compound I in polymorphic form B was dissolved in 20 ml of acetone / ml of acetone at 25°C for 1 week. The solid was equilibrated with a 1:1 mixture of water and then filtered. XRPD analysis of the recovered solid showed and modified H A (hydrate form) pattern was observed. Approximately 1000 mg of hydrate H A , 2 After heating in an oven at 60° C. for about 16 minutes, crystalline form E was obtained.

[0255] [Table 3]

[0256] [Table 4]

[0257] Crystalline Form E was found to be non-hygroscopic. The maximum water uptake was up to 92% of the phase. Humidity is less than 0.1% at 25°C.

[0258] Crystalline form E exhibited an onset melting temperature of about 281°C as measured by DSC. As can be seen, crystalline form E converts to crystalline form B when equilibrated with ethanol. The solubility of crystalline form E was measured at 25°C. Analysis was performed by HPLC and the results are shown in Table 5. show.

[0259] [Table 5]

[0260] FIG. 5 shows the overlay of the simulated and measured X-ray diffraction patterns of crystalline form E. The X-ray powder diffraction pattern of Form E is shown in Figure 6, and the peak list is as shown in Table 6. The lattice parameters for crystal form E are: spatial symmetry triclinic space group P-1 Cell volume (Å 3 ) 1637.8 Crystal density (g / cm 3 ) 1.238 a(Å) 8.592 b(Å) 13.046 c(Å) 14.935 α(Å) 90.34 β(Å) 90.23 γ(Å) 78.03 z4

[0261] [Table 6]

[0262] Example 4. Crystalline Form F (Hydrate H A Preparation of Hydrate H A (Crystalline Form F) is the crystalline form A or crystalline form B in acetone / water (1:1) at 25°C. The DSC curve was obtained by equilibration of a slurry of crystalline form B. The DSC curve shows a 0.89% solubility at about 89°C due to evaporation of water. It exhibits a broad endotherm at 264 °C followed by several endothermic transitions above 264 °C. Single crystal analysis This confirms the presence of 1 mole of water in the crystal structure (calculated water content is 5.6%). It was recognized.

[0263] The X-ray powder diffraction pattern of crystalline form F is shown in Figure 7, and the peak list is shown in Table 7. do.

[0264] [Table 7]

[0265] Example 5. Crystalline Form G of Compound I (Methanol Solvate S B Preparation of Methanol solvate S of compound I B (Crystal form G) is a crystalline form in methanol at 25°C. It was obtained by equilibration of a slurry of Form A. Single crystal structure analysis carried out at 100 K showed that TGA analysis of the sample showed the presence of 1 mole of methanol, up to 0.2%. The amount of residual solvent (calculated methanol content is 9.5% for the monosolvate) Therefore, the solvent evaporates easily.

[0266] FIG. 8 shows the overlay of the simulated and measured X-ray diffraction patterns of crystalline form G. The X-ray powder diffraction pattern of Form G is shown in Figure 9, and the peak list is as shown in Table 8. The lattice parameters for morphology G are: spatial symmetry triclinic space group P-1 Cell volume (Å 3 ) 1849.3 Crystal density (g / cm 3 ) 1.212 a(Å) 8.242 b(Å) 14.478 c(Å) 16.064 α(Å) 80.49 β(Å) 78.33 γ(Å) 85.18 z4

[0267] [Table 8]

[0268] Example 6. Crystalline Form J of Compound I (Acetonitrile Solvate S A Preparation of Acetonitrile solvate S of compound I A (Crystalline form J) can be dissolved in acetonitrile at 25°C. The crystal structure was obtained by equilibration of a slurry of crystalline form A of 1,2-dimethyl-2,4-trimethyl-1,3 ... The presence of 1 mole of acetonitrile (calculated acetonitrile content is 11.9%) was shown.

[0269] The X-ray powder diffraction pattern of crystalline form J is shown in Figure 10, and the peak list is shown in Table 9. The lattice parameters for crystalline form J are: spatial symmetry monoclinic space group P21 / n Cell volume (Å 3 ) 1833.5 Crystal density (g / cm 3 ) 1.255 a(Å) 15.545 b(Å) 5.770 c(Å) 21.348 β(°) 106.75 z4

[0270] [Table 9]

[0271] Example 7. Preparation of Crystalline Form K Crystalline Form K was obtained by evaporative crystallization of Compound I from acetone at 25°C. was prepared by dissolving crystalline form A in sufficient acetone at room temperature and allowing the solvent to evaporate at ambient conditions. Crystalline form K was obtained. The X-ray powder diffraction pattern of crystalline form K is shown in Figure 11, and the peak list is As shown in Table 9.

[0272] [Table 10]

[0273] Example 8. Preparation of crystalline form L Approximately 60 mg of Compound I as crystalline form B was dissolved in 4 ml of acetone. Approximately 20 ml of hexane was added to the solution until crystallization of Compound I occurred in the form of crystalline form L. The suspension was filtered and the isolated powder was characterized by X-ray powder diffraction. The DSC curve was It shows a broad endotherm at about 65°C followed by further smaller endothermic and exothermic events. , suggesting that crystalline form L is in fact a solvated form.

[0274] The X-ray powder diffraction pattern of crystalline form L is shown in Figure 12, and the peak list is shown in Table 11. is.

[0275] [Table 11]

[0276] Example 9. Solubility of Compound I As noted above, Compound I is barely soluble in a variety of media. The solubility of Compound I in the media is shown in Table 12.

[0277] [Table 12]

[0278] Example 10. Exploratory Formulations for Stability Studies Due to the limited solubility of Compound I in various solvents and water, suspensions were developed for development. Liquid formulations were investigated. The following five formulations were prepared and tested for stability: The compounds were stored in sealed glass vials at room temperature and 40°C. Samples were evaluated for I stability.

[0279] [Table 13]

[0280] The formulations prepared in Table 13 were assayed for Compound I as shown in Table 14. The assay was performed using an exploratory UPLC system developed for this purpose.

[0281] [Table 14]

[0282] Results from the stability study of Compound I at room temperature and 40°C are shown in Figure 14A, respectively. and Figure 14B. In Figure 14A, approximately 70% of the original Compound I was detected at 12 weeks. is a formulation of Compound I as a solution. Formulations with a percent of Compound I of about 20% of the original at 12 weeks were obtained with Compound I as a solution. As can be seen in Figures 1A and 1B, Compound I exhibits a 12% solubility in water at 40°C. It remains in a stable form in suspension without significant degradation even after 1 week. In contrast, the portion of Compound I in the supernatant solution was approximately 20% of the initial amount after 12 weeks at 40°C. Decompose until.

[0283] At the end of the study, Compound I was recovered from the four suspensions and confirmed to be in crystalline form by powder X-ray diffraction. The changes in the morphology of Compound I and the laboratory specimens recovered from the 12-week stability samples were evaluated. The X-ray diffraction pattern of Compound I (control) stored at room temperature is presented in Figure 15. As shown in Figure 15, Compound I in each of the four exploratory formulations was measured at room temperature or 4°C. It retains its polymorphic form even after 12 weeks of storage at 0°C.

[0284] Suspension FID 121744 (shown in Table 17) and 1% tyloxapol The 10% Compound I slurry was subjected to dry heat sterilization at 171°C for 1 hour. The X-ray diffraction pattern was identical to that of the untreated sample.

[0285] Example 11. Viscosity Range Finding Study of Compound I Suspensions Various suspension formulations of Compound I were evaluated for viscosity and precipitation of Compound I. Carbopol (Carbomer homopolymer type B) and various amounts of sodium chloride. A series of preservative-free Compound I suspensions were prepared. The formulation compositions are shown in Table 15. can be.

[0286] [Table 15]

[0287] The suspensions were visually assessed for homogeneity. The turbid liquid, FID 121845, was not homogeneous and therefore was not further evaluated. Sodium chloride is known to reduce the viscosity of carbomer-containing suspensions, and therefore To do this, add 0.2, 0.3 and 100 ml of sodium chloride to the remaining four aliquots of the suspension. , 0.4 and 0.5% carbomer and 0, 0.05, 0.1, 0.15, 0.2, 0.2 A total of 28 suspensions with concentrations of 5 and 0.3% sodium chloride were obtained.

[0288] The results of the viscosity testing of the 28 suspensions are shown in Table 16.

[0289] [Table 16]

[0290] As can be seen in Table 16, the relationship between the amount of carbomer and sodium chloride is of concern. Affects the viscosity of the suspension.

[0291] Further characterization of preservative-free suspensions of Compound I containing Carbopol as a suspending agent. The suspension was prepared for viscosity range detection and sedimentation testing. The compositions, their viscosities and settling times are shown in Table 17.

[0292] [Table 17]

[0293] preparing a series of further suspensions containing hypromellose as a suspending agent and a preservative; Their viscosity was measured. Sedimentation properties were measured as follows: The suspension was filled into a 10 ml glass graduated cylinder. The contents were sealed with a stopper and parafilm and left to stand at room temperature for 6 months. The composition of 10 ml of suspensions, their viscosity and sedimentation after 6 months were evaluated by visual inspection. The times are shown in Table 18.

[0294] [Table 18]

[0295] Based on the results shown in Tables 9-12, the suspensions with and without preservatives were Compound I suspensions with either carbomer or hypromellose as the saturating agent are acceptable. The viscosity and sedimentation properties could be achieved.

[0296] Example 12. pH-dependent stability screening of Compound I suspensions To test the pH stability of Compound I suspensions, the formulations listed in Table 19 below were prepared. All samples contained 0.1% Compound I to ensure consistency of drug concentration. Since the drug was not soluble in any of the samples, 0.1% tyloxapol was used as a surfactant. was used as a dispersant to facilitate resuspension of material in the samples. All samples (except the TRIS samples) (The above) contains an equivalent amount of phosphate buffer. All samples were placed in 20 mL glass vials. At each assay time point, the samples were equilibrated to room temperature and vortexed. The drug was resuspended by centrifugation and the samples were diluted to concentrations that fell within the linear range of the standard curve.

[0297] [Table 19]

[0298] The amount of Compound I in the stability samples was determined using Waters XBridge Shield RP18 column (3.5 μm, 3.0 × 150 mm, 30 °C), mobile phase A 0.1% in water Using a gradient of 0.1% TFA in TFA and mobile phase B acetonitrile, 10 μl injection The volume was analyzed by high performance liquid chromatography (HPMC) at a flow rate of 0.8 ml / min. It was tested on days 0, 4, 7, and 11. In addition, it appeared at a relative retention time (RRT) of 1.23. The major degradants were followed. The results of the stability study are shown in Table 20.

[0299] [Table 20]

[0300] The major degradants shown in Table 20 crystallized and became larger as their concentrations increased. It was observed that the formulations shown in Table 21 below formed small crystals. were prepared and analyzed for degradant formation.

[0301] [Table 21]

[0302] Data on the stability of Compound I in the compositions shown in Table 21 are shown in Table 22 below.

[0303] [Table 22]

[0304] Data on degradant growth are shown in Table 23.

[0305] [Table 23]

[0306] Based on the stability data in the table above, the stability of Compound I is expected to be stable over the pH range of 5-8. Furthermore, it was concluded that the concentration of compound I in SBE-cyclodextrin varied significantly. The increased solubility of resulted in a decrease in stability.

[0307] Example 13. Stability of 2.5%, 1.5%, 0.5% and 1.5% Ophthalmic Suspensions of Compound I sex Ophthalmic suspensions of Compound I as set forth in Table 29 below, 0.15%, 0.5%, 1. The stability of several lots of 5% and 2.5% (initial pH 7.34-7.7) has been shown to be stable over time. by periodically monitoring the chemical, physical and microbiological stability characteristics of the product. Chemical stability was assessed by monitoring Compound I and its impurities. Physical stability was assessed by pH, osmolality, viscosity, appearance, and X-ray powder diffraction (XRPD). Microbiological stability was assessed by monitoring the identity and particle size of the samples. The results were monitored by conducting a bacterial test. from the stability observation limits (for different lots and various sampling times over the study period). A summary of the results (in the range) is presented in Table 24.

[0308] [Table 24]

[0309] In addition to the above parameters, viscosity was monitored and tested under each storage condition. The viscosity was found to be within 10% of the initial viscosity at each time point. Particle size measurements and sterility were also stable. This was within the observation limit.

[0310] Embodiment 14. Acute toxicity testing of exploratory formulations Four formulations from exploratory stability studies in Table 13: FID 121522, FID 121511, FID 121512, and FID 121513 were sterile irrigated as controls. The four exploratory formulations or control groups were administered five times daily in male New Zealand White rabbits using a solution. No toxicity was observed with the treatment.

[0311] Embodiment 15. Pharmacokinetic testing of exploratory formulations Pharmacokinetic studies were conducted on the same four exploratory formulations provided in Table 13: FID 1 21522, FID 121511, FID 121512, FID 121513 The ocular uptake of Compound I was determined after a single topical bilateral administration in male NZW rabbits. The results are shown in Table 25.

[0312] [Table 25]

[0313] As can be seen in Table 25, the highest exposure of Compound I was in the cornea, which was approximately 1.5 to 3 times the level observed in the conjunctiva, as well as in the aqueous humor and iris-ciliary body. Approximately 10 times the levels observed in the blood and approximately 10 times the levels observed in plasma. 500 times. C for suspensions containing poloxamer 407 in the cornea max teeth , C for two suspensions containing hypromellose maxApproximately twice as much as that for solution formulations RuC max The C in the cornea for the three suspensions was approximately 38 times higher than that of the max teeth, IC of 30 nM 50 The range was approximately 500 to 1200 times that of C min is IC5 The range was approximately 50 to 130 times that of 0.

[0314] Embodiment 16. Pharmacokinetic testing of additional formulations Based on results from an exploratory formulation, the efficacy of chemotherapeutic agents in male pigmented rabbits after a single topical bilateral administration was evaluated. Additional formulations were prepared to determine additional corneal and aqueous humor concentrations of Compound I. These formulations are shown in Table 26.

[0315] [Table 26]

[0316] Results from the pharmacokinetic study are shown in Table 27.

[0317] [Table 27]

[0318] As shown in Table 27, C for Compound I max and C min is Compound I The highest exposure to α-glucan is in the cornea, approximately 3-6 times the level observed in the aqueous humor. In the cornea, the C max is 0 The concentration was approximately three times that of the 0.05% suspension and approximately 16 times that of the 0.01% suspension. C for 0.5% suspension max is approximately three times that of the 0.05% suspension and 0.01 The C in the cornea of ​​the three suspensions was approximately 9 times that of the % suspension. max is 30 nM IC 50 The range was approximately 38 to 600 times that of C min is IC 50 Oyo The range was 0.5 to 7 times.

[0319] Pharmacokinetic studies were conducted to determine the efficacy of the formulations FID121746, FID121747, and FID121748 described in Table 26. 45 and FID121744 in the intact eye of male pigmented rabbits. After a single, targeted bilateral dose and with and without a bandage contact lens. Corneal and aqueous humor concentrations of Compound I were determined after anterior keratectomy.

[0320] Results from the pharmacokinetic study are shown in Table 28.

[0321] [Table 28]

[0322] Example 17. Toxicity wound healing test using Compound I suspension formulation Toxicity wound healing studies were performed with and without bandage contact lenses. QID topical administration of Compound I after unilateral laser photorefractive keratectomy in rabbits Corneal wound healing was evaluated after targeted bilateral administration. The Compound I formulation used in this study was The results are listed in Table 29. For comparison, ketorolac tromethamine (ACULAR LS) The formulations used were acetaminophen (Denver®) and dexamethasone (MAXIDEX®).

[0323] [Table 29]

[0324] The test results were obtained after 3 days using a bandage contact lens at 0.5, 1.5 and The mean wound area for corneas treated with 2.5% Compound I suspension was 1.0%. Corneas treated with ACULAR LS and MAXIDEX using a tact lens, bandages For solvent-treated corneas without a contact lens and for untreated corneas It was demonstrated that the suction pressure was smaller than that of 0.5, 1.5 and 1.6 mm using a bandage contact lens. The mean wound area for corneas treated with 2.5% Compound I suspension was 1.2 mm in diameter and 1.2 mm in length. Corneas treated with solvent and bandage contact lenses without contact lenses The results were comparable to those for corneas treated with 0.5% Compound I.

[0325] Example 18. Bacteriostasis / Stability Testing of Exemplary Compound I Suspensions A series of five experimental sterile suspension formulations containing 0.5% Compound I were prepared and used in the compendial Five species of organisms: S. aureus, P. aeruginosa, inosa), E. coli, C. albicans and A. brasiliensis (A. brasiliensis) for bacteriostatic / fungistatic effects The criteria for bacteriostasis were the number of microorganisms (CFU / mL) and the All formulations tested demonstrated acceptable levels of bacteriostasis. In addition, a 2.5% Compound I suspension (alternatively FID 121 744) and suspension solvent were also prepared and screened for bacteriostatic / fungistatic activity screening. The bacteriostatic / fungistatic effect was approximately 10 6 of inoculum and / or about 10 5 Inoculum of The solution was used and observed for three days.

[0326] 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. Three or more peaks at 2θ values ​​selected from 7.2, 12.7 and 21.4±0.2° 2θ The structure is characterized by an X-ray diffraction pattern having a 【Chemistry 1】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 Crystalline Form A of (-yl)-benzonitrile (Compound I).

2. 7.2, 12.7, 13.9, 18.1, 21.4, 25.1 and 26.8±0.2° characterized by an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from 2. The crystalline form A of compound I according to claim 1 .

3. A method for preparing crystalline form A of compound I according to claim 1 or 2, comprising the steps of: and cooling to about 0° C. to crystallize Compound I. and crystallizing as Form A.

4. Three or more peaks at 2θ values ​​selected from 7.4, 14.9, and 19.1±0.2° 2θ The structure is characterized by an X-ray diffraction pattern having the formula 【Chemistry 2】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 Crystalline Form C of (-yl)-benzonitrile (Compound I).

5. ７．４、１４．１、１４．９、１６．４、１９．１、２６．１、３１．２±０．２°２ characterized by an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from θ 5. The crystalline form C of compound I of claim 4,

6. 6. A method for preparing crystalline form C of compound I according to claim 4 or 5, comprising: Compound I in the above is heated to a temperature of at least about 250°C, or at least about 270°C, or at least about 280°C. The method comprises heating to a temperature.

7. Three or more peaks at 2θ values ​​selected from 12.7, 16.7, and 22.6±0.2° 2θ The structure is characterized by an X-ray diffraction pattern having a 【Transformation 3】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 Crystalline Form E of (-yl)-benzonitrile (Compound I).

8. １２．７、１５．１、１６．７、２２．６、２７．１、２７．７、２８．５±０．２° characterized by an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from 8. The crystalline form E of compound I according to claim 7,

9. 9. A method for preparing crystalline form E of compound I according to claim 7 or 8, comprising: The solute form may be heated to a temperature greater than about 250° C. or about 260° C. to convert Compound I to crystalline Form E. providing the same as

10. structure 【Chemistry 4】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 -yl)-benzonitrile (Compound I) crystalline hydrate.

11. Three or more peaks at 2θ values ​​selected from 6.6, 14.4, and 18.3±0.2° 2θ 11. The crystalline form of Compound I according to claim 10, characterized by an X-ray diffraction pattern having the formula: Hydrate.

12. ６．６、１１．９、１４．４、１８．３、２３．９、２６．５、２９．２±０．２°２ characterized by an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from θ 11. The crystalline hydrate of Compound I according to claim 10,

13. A method for preparing the crystalline hydrate of Compound I according to any one of claims 10 to 12. and equilibrating a slurry of Compound I in a mixture of water and a water-miscible solvent to form Compound I. crystallization as a crystalline hydrate.

14. 14. The method of claim 13, wherein the water-miscible solvent is acetone.

15. The equilibration may be for about 12 hours, about 18 hours, about 24 hours, or about 48 hours. The method of claim 13, wherein

16. structure 【Transformation 5】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 A crystalline methanol solvate of (-yl)-benzonitrile (Compound I).

17. Three or more peaks at 2θ values ​​selected from 6.1, 14.5, and 22.7±0.2° 2θ 17. The crystalline form of Compound I according to claim 16, characterized by an X-ray diffraction pattern having the formula: Soluble methanol solvate.

18. Select from 6.1, 12.2, 14.5, 18.0, 22.7, 24.6±0.2°2θ The compound is characterized by an X-ray diffraction pattern having three or more peaks at 2θ values ​​corresponding to the above formula.

17. The crystalline methanol solvate of Compound I according to claim 16.

19. A method for preparing a crystalline methanol solvate of Compound I according to any one of claims 16 to 18. A method for preparing Compound I in a polymorphic form by equilibrating a slurry of Compound I in methanol. G to provide Compound I as said crystalline methanol solvate. 。

20. 20. The method of claim 19, wherein the equilibration is carried out at room temperature for at least about 24 hours. How to do it.

21. structure 【Transformation 6】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 Crystalline acetonitrile solvate (Form J) of (-yl)-benzonitrile (Compound I).

22. Three or more peaks at 2θ values ​​selected from 8.2, 17.0, and 23.8±0.2° 2θ 22. The crystalline form of Compound I according to claim 21, characterized by an X-ray diffraction pattern having the formula: Soluble acetonitrile solvate.

23. Select from 8.2, 11.8, 17.0, 22.8, 23.8, 27.6±0.2°2θ The compound is characterized by an X-ray diffraction pattern having three or more peaks at 2θ values ​​corresponding to the above formula.

22. The crystalline acetonitrile solvate of Compound I according to claim 21.

24. A crystalline acetonitrile solvate of Compound I according to any one of claims 21 to 23. A method for preparing Compound I by equilibrating a slurry of Compound I in acetonitrile. as said crystalline acetonitrile solvate.

25. 25. The method of claim 24, wherein the equilibration is carried out at room temperature for at least about 24 hours. How to do it.

26. Three or more peaks at 2θ values ​​selected from 5.3, 12.3, and 22.4±0.2° 2θ The structure is characterized by an X-ray diffraction pattern having the formula 【Transformation 7】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 Crystalline form K of (-yl)-benzonitrile (Compound I).

27. 5.3, 6.5, 10.5, 12.3, 17.2, 19.3, 22.4±0.2°2θ characterized by an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from 27. The crystalline form K of compound I of claim 26.

28. 28. A method for preparing crystalline form K of compound I according to claim 26 or 27, comprising the step of: and crystallizing Compound I by evaporation of a solution of Compound I in the presence of HCl to provide Compound I as crystalline Form K. and a method comprising:

29. Three or more peaks at 2θ values ​​selected from 7.1, 8.7, and 10.6±0.2° 2θ characterized by an X-ray diffraction pattern having the structure 【Transformation 8】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 Crystalline form L of (-yl)-benzonitrile (Compound I).

30. 3.5, 7.1, 8.7, 10.6, 12.2, 19.1, 22.4±0.2°2θ The X-ray diffraction pattern is characterized by having three or more peaks at 2θ values ​​selected from the group consisting of:

30. The crystalline form L of compound I of claim 29, wherein

31. 31. A method for preparing crystalline form L of compound I according to claim 29 or 30, comprising: adding a solvent to a solution of Compound I in acetone to provide Compound I as crystalline form L; A method comprising:

32. 32. The method of claim 31 , wherein the hydrocarbon solvent is hexane.

33. An effective amount of crystalline form A, crystalline form C, crystalline form B, crystalline form C, or crystalline form D according to any one of claims 1 to 32. Crystalline Form D, Crystalline Form E, Crystalline Form F, Crystalline Form L, Crystalline Form K, and combinations thereof A crystalline form of Compound I according to any one of claims 1 to 32, selected from pharmaceutically acceptable salts thereof. and a pharmaceutical formulation comprising an excipient capable of

34. 34. The pharmaceutical formulation of claim 33, comprising the crystalline form A in substantially pure form.

35. 34. The pharmaceutical formulation of claim 33, comprising crystalline form C in substantially pure form.

36. 34. The pharmaceutical formulation of claim 33, comprising the crystalline form E in substantially pure form.

37. 34. The pharmaceutical formulation of claim 33, comprising crystalline form F in substantially pure form.

38. 34. The pharmaceutical formulation of claim 33, comprising the crystalline form K in substantially pure form.

39. 34. The pharmaceutical formulation of claim 33, comprising the crystalline form L in substantially pure form.

40. 34. The pharmaceutical formulation of claim 33, comprising a mixture of two or more crystalline forms of Compound I.

41. Crystalline forms B and E, Crystalline forms B and F, Crystalline forms B and C, Crystalline forms A and C, Crystalline forms 41. The medicament of claim 40, comprising a mixture of Forms A and F in a ratio of about 1:99 to about 99:

1. formulation.

42. 42. The pharmaceutical preparation of any one of claims 33 to 41, which is formulated for ophthalmic use.

43. 1. An aqueous formulation comprising: 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, an osmotic agent, a buffer, a preservative, a salt, and a preservative selected from the group consisting of An aqueous formulation comprising one or more excipients.

44. The 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3- In the formulation, 44. The aqueous formulation of claim 43, which is present as a suspension at

45. The 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3- yl)-benzonitrile (Compound I) or a salt, co-crystal, or polymorph thereof, is about 0.5% 45. The method of claim 43 or 44, wherein the composition is present in the formulation in an amount of from about 3.5% w / v to about 3.5% w / v. Aqueous formulation of the above.

46. 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 its salts, co-crystals or polymorphs, surfactants, suspending agents, and one or more excipients selected from the group consisting of osmotic agents, buffers, preservatives, salts and preservatives; 46. ​​The aqueous formulation according to any one of claims 43 to 45, comprising

47. It is present as a suspension in the formulation in an amount of about 0.5% w / v to about 3.5% w / v. 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl )-benzonitrile (Compound I) or a salt, co-crystal or polymorph thereof; nonionic surfactants; suspending agents; osmotic agents; Buffer; salt; and 47. The aqueous formulation of any one of claims 43 to 46, optionally comprising a preservative.

48. 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 suspensions of salts, co-crystals or polymorphs thereof; nonionic surfactants; suspending agents; osmotic agents; Buffer; optionally salt; optionally a preservative; and Formulations containing sufficient quantity (qs) of water to reach 100%.

49. The nonionic surfactants include polysorbate surfactants, ethylene oxide blockers, and the like. Polypropylene copolymer / propylene oxide surfactants, poloxamers, tyloxapol and their combinations The formulation of any one of claims 43 to 48, wherein the formulation is selected from the group consisting of:

50. The non-ionic surfactant may be at least about 0.001% w / v, at least about 0.0 1% w / v, at least about 0.02% w / v, at least about 0.03% w / v or less Both are about 0.04% w / v, and are not more than about 1% w / v, not more than about 0.5% w / v, not more than about 0. 3% w / v or less, or about 0.2% w / v or less, about 0.1% w / v or less, or about 0.08% w / v or less 50. The formulation of claim 49, wherein tyloxapol is present in an amount of no more than v.

51. 51. The formulation of claim 50, comprising tyloxapol in an amount of about 0.05% w / v.

52. The non-ionic surfactant is present in an amount of about 15% w / v to about 20% w / v of the formulation.

50. The formulation of any one of claims 43 to 49, which is a poloxamer.

53. The suspending agent may be carbomer, hydroxypropyl methylcellulose (hypromellose) , polyethylene glycol, and combinations thereof. The formulation according to any one of the preceding claims.

54. The suspending agent may be at least about 0.05% w / v, at least about 0.1% w / v or less at most about 0.2% w / v, and not more than about 1.0% w / v, not more than about 0.6% w / v, or 53. A carbomer present in the formulation in an amount of about 0.5% w / v or less. The formulation described in

55. The carbomer is present in an amount of 0.1% w / v to about 0.3% w / v or about 0.2% w / v.

55. The formulation of claim 54, wherein the formulation is present in the amount of

56. The suspending agent may be at least about 0.05% w / v, at least about 0.1% w / v or less at most about 0.25% w / v and less than about 1.8% w / v, less than about 1.0% w / v, Hydrogen present in the formulation in an amount of less than about 0.8% w / v or less than about 0.6% w / v 54. The formulation of claim 53, wherein the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose.

57. The suspending agent is polyethylene glycol having a molecular weight of about 200 Da to about 20,000 Da.

54. The formulation of claim 53, wherein the PEG-400 is chol (PEG).

58. The suspending agent may be from about 4% w / v to about 9% w / v, from about 5% w / v to about 8% w / v, or PEG 400 at a concentration of about 7% w / v or about 1% w / v to about 4% w / v, about 1% w / v to about 3% w / v 58. The formulation of claim 57, wherein the PEG 6000 is at a concentration of about 2% w / v or about 2% w / v. 。

59. Claims 43 to 55, wherein the suspending agent is substantially all carbomer homopolymer type B. The formulation according to any one of the preceding claims.

60. 60. The method of claim 43, wherein the osmotic agent is selected from the group consisting of polyols. The formulation according to claim 1.

61. The polyols include mannitol, glycerin, xylitol, sorbitol, and proline.

61. The method of claim 60, wherein the hydroxybenzoate is selected from the group selected from pyrene glycol and combinations thereof. Formulation of.

62. The polyol may be from about 0.05% w / v to about 10% w / v, from about 0.1% w / v to about 8% in an amount of about 0.1% w / v to about 7% w / v, about 0.1% w / v to about 5% w / v 62. The formulation of claim 61, wherein

63. The polyol may be from 0.1% w / v to 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, about 1% w / v, about 2% w / v, about 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 mannitol or glycerin present in the formulation in an amount of about 5% w / v.

63. The formulation of claim 62.

64. The buffer solution may be selected from acetate, ascorbate, borate, bicarbonate, carbonate, citrate, Salt, edetate (EDTA) gluconate, lactate, phosphate, propionate and TR 64. The method according to any one of claims 48 to 63, wherein the compound is selected from the group consisting of IS (tromethamine). The formulation described above.

65. 65. The formulation of claim 64, wherein the buffer is phosphate or TRIS.

66. 66. The formulation of any one of claims 43 to 65, wherein the salt is sodium chloride.

67. The suspending agent is Carbopol (Carbomer homopolymer type B) and sodium chloride. The amount of ammonium hydroxide is about 2000 kJ / min when using a spindle CP-42 at 60 rpm at about 25°C.

67. The method of claim 66, wherein the amount of the hydroxybenzoate is adjusted to provide a viscosity of the formulation of from 0 cP to about 200 cP. formulation.

68. The sodium chloride may be from about 0.01% w / v to about 0.5% w / v, about 0.02% w / v ~about 0.4%w / v, about 0.03%w / v~about 0.3%w / v, about 0.04%w / v~about in an amount of 0.2% w / v, about 0.05% w / v to about 0.1% w / v, or about 0.05% w / v 67. The formulation of claim 66, wherein the formulation is present in a

69. 69. The method according to any one of claims 48 to 68, wherein the pH of the formulation is from about 5.5 to about 8.

0. The formulation described above.

70. 70. The method of claim 69, wherein the pH of the formulation is about 6.0 to about 8.0, about 6.0, or about 7.

4. The formulation described.

71. At least about 1.5 w / v%, at least about 3.0 w / v%, at least about 3.5 w / % or at least about 4.5 w / v%, but not more than about 10.0 w / v%, about 8.0 w / v% cyclodextrin 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 71. Any one of claims 48 to 70, further comprising an additional agent selected from the group consisting of phosphorus The formulation described in paragraph .

72. The cyclodextrin may be hydroxypropyl cyclodextrin in an amount of about 5% w / v of the formulation. β-cyclodextrin or sulfoalkyl ether β-cyclodextrin.

72. The formulation of claim 71.

73. The compound I or a salt, co-crystal, or polymorph thereof is present in an amount of from about 0.5% w / v to about 2.5% w / v / v, The non-ionic surfactant may be tyloxane in an amount of about 0.01% w / v to 0.2% w / v. sapol, poloxamer, or a combination thereof; The suspending agent may be hydroxypropyl methylcellulose, polyethylene glycol or cellulose gum. Bomer homopolymer type B; The osmotic agent may comprise at least one polysaccharide in an amount of about 0.05% w / v to about 10% w / v. It is Riolu; the buffer is edetate, phosphate, borate, or a combination thereof; Salt; and containing up to 100% qs of water; and 49. The formulation of claim 48, wherein the pH ranges from about 5.5 to about 8.

0.

74. The compound I or a salt, co-crystal, or polymorph thereof may be present in an amount of about 0.5% w / v, about 1.0% w / v, or about 2.0% w / v. about 1.5% w / v, about 2.0% w / v, or about 2.5% w / v; The non-ionic surfactant may be present in an amount of about 0.04% w / v to about 0.06% w / v. loxapol, poloxamer in an amount of about 0.005% w / v to 0.12% w / v, or It is a combination of: The suspending agent may comprise hydroxypropylmethylcellulose in an amount of about 0.1% w / v to about 0.8% w / v. cellulose, polyethylene glycol in an amount of about 2% w / v to about 8% w / v, Carbomer homopolymer type B or its analogs in an amount of 0.05% w / v to about 0.5% w / v is a combination; The osmotic agent may be mannitol or glycerol in an amount of about 0.1% w / v to about 5% w / v. is phosphorus; the buffer 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 containing up to 100% qs of water; and The process according to any one of claims 48 to 73, wherein the pH ranges from about 5.5 to about 8.

0. Agent.

75. About 0.5% w / v, about 1.0% w / v, about 1.5% w / v, about 2.0% w / v or about 2 4-(7-hydroxy-2-isopropyl-4-oxo-4H) in an amount of 5% w / v -quinazolin-3-yl)-benzonitrile (Compound I) or a salt, co-crystal or polycrystal thereof suspension of forms, 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 solution; Sodium chloride in an amount of 0.01% w / v to about 1% w / v; and containing up to 100% qs of water, The formulation has a pH in the range of about 5.5 to about 8.

0.

76. 76. The formulation of any one of claims 43 to 75, wherein compound I is polymorphic form B.

77. About 0.5% w / v, about 1.0% w / v, about 1.5% w / v, about 2.0% w / v or about 2 4-(7-hydroxy-2-isopropyl-4-oxo-4H) in an amount of 5% w / v a suspension of polymorphic form B of (-quinazolin-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; and A formulation containing up to 100% qs water, The formulation has a pH in the range of about 5.5 to about 8.

0.

78. About 0.5% w / v, about 1.0% w / v, about 1.5% w / v, about 2.0% w / v or about 2 Compound I in an amount of 5% w / v, about 0.05% w / v tyloxapol; About 0.2% w / v of Carbomer homopolymer type B; about 2.0% glycerin; Tromethamine buffer; and hydrochloric acid to adjust the pH to about 6.4 to about 8.4; About 0.05% w / v sodium chloride; and containing up to 100% qs of water, 78. The formulation of claim 77, which is preservative-free.

79. The polymorphic form B has a 2θ angle selected from 9.3, 10.6 and 14.4±0.2 degrees 2θ.

77. The method of claim 76, characterized by an X-ray diffraction pattern having three or more peaks at values 80. The formulation of any one of claims 1 to 79.

80. Using a spindle CP-42 at either 3 rpm or 60 rpm at approximately 25°C.

80. The method of any one of claims 43 to 79, having a viscosity of about 20 cP to about 200 cP when measured by a tungsten fluoride (TFT) measuring instrument. The formulation according to any one of claims 1 to 4.

81. About 200 to about 450 milliosmoles per kilogram (mOsm / kg) of weight 81. The formulation of any one of claims 43 to 80, having a molar concentration.

82. After 6 months of storage at room temperature, the 82. The method of claim 43, wherein the composition exhibits less than 5%, less than about 4%, less than about 3%, or less than about 2% sedimentation. The formulation described in any one of claims 1 to 4.

83. The amount of Compound I in the formulation was measured after about 6 months, about 8 months, and about 10 months of storage under refrigeration. At least 90% of the initial amount after about 12 months, about 15 months, or about 18 months The formulation according to any one of claims 43 to 82, wherein

84. The amount of Compound I in the formulation was found to be slightly less than the initial amount after approximately 18 months of refrigerated storage. at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about at least about 95%, at least 96%, at least about 97%, or at least about 98% 84. The formulation according to any one of claims 43 to 83.

85. Contains less than about 10% degradation products after 6 months under refrigeration, and the degradation products are less than 0.1% by HPMC using a gradient of trifluoroacetic acid (TFA) water / acetonitrile mobile phase 43. The compound of claim 43, wherein the compound has a relative retention time of 1.23 compared to compound I when analyzed by 85. The formulation according to any one of claims 1 to 84.

86. Claims: About 10% or less of Compound I in the formulation decomposes upon storage at 40°C for 12 weeks. The formulation according to any one of claims 43 to 85.

87. The compound I may be of crystalline form A, crystalline form B, crystalline form C, crystalline form E, crystalline form F, crystalline form G, crystalline form H, crystalline form I ... crystalline form G, crystalline form J, crystalline form K, crystalline form L, and combinations thereof.

87. The formulation of any one of claims 43 to 86, wherein the formulation is in a crystalline form.

88. The compound I may be of crystalline form A, crystalline form B, crystalline form C, crystalline form E, crystalline form F, crystalline form G, crystalline form H, crystalline form I ... crystalline form selected from the group consisting of crystalline form K, crystalline form L, and combinations thereof. 43-86. The formulation according to any one of claims 43 to 86.

89. An amount of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline- 3-yl)-benzonitrile (Compound I) or a salt, co-crystal or polymorph thereof; nonionic surfactants; suspending agents; osmotic agents; Buffer; salt; optionally a preservative; and Mixing water up to 100% qs; and A method of making the formulation comprising adjusting the pH to a range of about 5.5 to about 8.

0.

90. 90. The method of claim 89, wherein the Compound I is added as a stock suspension.

91. 89 or 9, wherein the stock suspension is milled to obtain a desired particle size of Compound I. The method according to claim 0.

92. A method for treating ocular surface pain in a subject in need thereof, comprising administering to said subject an effective amount of a compound comprising: Construction: 【Chemistry 9】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 -yl)-benzonitrile (compound of formula I) or a salt, solvate, polymorph or conjugate thereof a method comprising administering a compound of formula (I) to the subject.

93. 93. The method of claim 92, wherein the ocular surface pain is chronic ocular surface pain.

94. 93. The method of claim 92, wherein the compound of formula I is administered to the cornea of ​​the subject.

95. Any one of claims 92 to 94, wherein the COSP is associated with dry eye disease. The method described below.

96. 96. The method of claim 95, wherein said administering results in a reduction in symptoms of dry eye disease.

97. 96. The method of claim 95, wherein said administering results in a reduction in said pain associated with dry eye disease. Law.

98. The administration may be effective in treating dry eyes, eye discomfort, redness, burning or stinging in the eye, grittiness or itching. or foreign body sensation or photophobia by at least about 10%.

97. The method of claim 96.

99. The subject is a patient suffering from dry eye disease, Sjogren's syndrome, conjunctivitis (keratoconjunctivitis, vernal keratoconjunctivitis), , including allergic conjunctivitis), corneal epithelial basement membrane dystrophy, Acanthamoeba, Streptococcus aureus Fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome group, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (LASIK-induced corneal neuropathy), corneal dystrophies (including recurrent corneal dystrophy), epithelial Basement membrane dystrophy, corneal erosion or abrasion (recurrent corneal erosion or abrasion) including abrasions), ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, glaucoma, conjunctival Keratopathy (herpetic keratopathy, filamentous keratopathy, band or bullous keratopathy, lagophthalmos keratopathy) keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery , Multiple Sclerosis, Trichiasis, Pterygium, Neuralgia, Xerophthalmia, Neurotrophic Keratitis Patients undergoing photorefractive keratectomy (PRK) surgery or laser corneal ablation One or more of the following ocular pain symptoms persisting for at least 3 months after LASIK surgery: The method of any one of claims 92 to 98, wherein the patient is suffering from a disease.

100. 100. The method of claim 92, further comprising administering an additional therapeutic agent to the subject. The method described in paragraph .

101. The administration may provide a decrease in the serotonin concentration by at least about 3, at least about 4, at least about 5, or , at least about 6, at least about 7, at least about 8, at least about 9 or at least about Claims 92-100 resulting in a reduction in pain score on the visual acuity scale (VAS) of 10.

10. The method according to any one of the preceding claims.

102. The reduction in VAS score is determined by comparing the VAS scores before and after administration of Compound I to the subject. The method of claim 101, resulting from a difference in

103. The reduction in VAS score occurs within about half an hour after administration of Compound I to the subject. The method of claim 101 or 102.

104. The administration may result in a response of at least about 1, at least about 2 on the McMonnies scale. , at least about 3, at least about 4, or at least about 5 reduction in hyperemia in the subject. The method of any one of claims 92 to 104, wherein

105. The administration of the drug was associated with a significant improvement in best corrected visual acuity, intraocular pressure, slit lamp biomicroscopy, and diffuse stimuli compared to placebo. No changes in pupil examination, blink rate, tear production, or corneal staining. The method of any one of claims 92 to 104.

106. The compound of formula I is administered in the form of a formulation according to any one of claims 43 to 86. The method according to any one of claims 92 to 106,

107. The formulation is administered for at least about 1 month, about 2 months, or about 3 months.

107. The method of claim 106.

108. 107. The method of claim 106, wherein the formulation is administered 1 to 4 times daily.

109. A formulation according to any one of claims 1 to 86 for use in the treatment of ocular surface pain. 。

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

110. The formulation for use of claim 109, wherein the pain is chronic ocular surface pain that persists for a period of time.

111. 1. A method for reducing ocular surface pain in a subject in need thereof, comprising administering to a subject the structure: 【Chemistry 10】 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3 (-yl)-benzonitrile (Formula I) or a salt, solvate, polymorph or co-crystal thereof A method comprising administering instillation to a subject.

112. 112. The method of claim 111, wherein the ocular surface pain is chronic ocular surface pain (COSP).

113. 113. The method of claim 111 or 112, wherein the COSP is associated with dry eye disease. method.

114. 112. The method of claim 111, wherein said administration results in a reduction in symptoms of dry eye disease.

115. 114. The method of claim 113, wherein said administering results in a reduction in said pain associated with dry eye disease. method.

116. The administration may be effective in treating dry eyes, eye discomfort, redness, burning or stinging in the eye, grittiness or itching. or foreign body sensation or photophobia by at least about 10%.

116. The method of claim 115.

117. The subject is a patient suffering from dry eye disease, Sjogren's syndrome, conjunctivitis (keratoconjunctivitis, vernal keratoconjunctivitis), , including allergic conjunctivitis), corneal epithelial basement membrane dystrophy, Acanthamoeba, Streptococcus aureus Fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome group, Stevens-Johnson syndrome, corneal epitheliopathy, corneal neuropathy (LASIK-induced corneal neuropathy), corneal dystrophies (including recurrent corneal dystrophy), epithelial Basement membrane dystrophy, corneal erosion or abrasion (recurrent corneal erosion or abrasion) including abrasions), ocular surface disease, blepharitis, graft-versus-host disease, meibomianitis, glaucoma, conjunctival Keratopathy (herpetic keratopathy, filamentous keratopathy, strip-like or bullous keratopathy, lagophthalmos keratopathy) keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, Recovered from multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmia, and neurotrophic keratitis. Patients undergoing photorefractive keratectomy (PRK) or laser keratomileusis surgery One or more of the following eye pain symptoms that persist for at least 3 months after LASIK surgery: The method according to any one of claims 111 to 116, wherein the patient is suffering from

118. Any of claims 111 to 117, further comprising administering an additional therapeutic agent to the subject.

1. The method according to claim 1.

119. The administration may provide a decrease in the serotonin concentration by at least about 3, at least about 4, at least about 5, or , at least about 6, at least about 7, at least about 8, at least about 9 or at least about Claims 111 to 11 result in a reduction in pain score on the visual acuity scale (VAS) of 10.

9. The method according to any one of claims 8 to 8.

120. The administration may provide a decrease in the serotonin level by at least about 6, at least about 7, or at least about 8 percent compared to placebo. , resulting in a reduction in VAS pain score of at least about 9 or at least about 10.

119. The method of any one of claims 11 to 119.

121. The reduction in VAS score is determined by comparing the VAS scores before and after administration of Compound I to the subject. The method of claim 119 or 120, resulting from the difference between A and B.

122. The administration may result in a response of at least about 1, at least about 2 on the McMonnies scale. , at least about 3, at least about 4, or at least about 5 reduction in hyperemia in the subject. The method of any one of claims 111 to 121, wherein

123. The administration results in an improvement in visual acuity score of at least about 3 compared to the VAS score prior to administration of the compound. The method of claim 119, which results in a reduction in pain score on a visual analogue scale (VAS).

124. The compound of formula I is administered in the form of a formulation according to any one of claims 1 to 86.

124. The method according to any one of claims 111 to 123.

125. 1. A method of treating or reducing ocular surface pain in a subject in need thereof, comprising administering to a subject the structure: 【Chemistry 11】 The compound 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolidinyl) administering to the subject a formulation containing (benzo-3-yl)-benzonitrile (Compound I). fruit, The formulations provided a rabbit corneal Cmax of Compound I that was about 1.5 to about 3 times the conjunctival Cmax. and Cmax is the maximum concentration of Compound I in a particular tissue after administration of a single dose. method.

126. The compound I is administered as a formulation according to any one of claims 48 to 86. The method of claim 125.

127. 1. A method of treating or reducing ocular surface pain in a subject in need thereof, comprising: ： 【Chemistry 12】 The compound 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolidinyl) administering to the subject a formulation containing (benzo-3-yl)-benzonitrile (Compound I). fruit, The formulation exhibited a Cmax of Compound I in rabbit corneas that was approximately 500 times that of Compound I in plasma. Cmax of Compound I in a particular tissue after administration of a single dose The method is a method for determining the maximum concentration of

128. The compound I is administered as a formulation according to any one of claims 48 to 86. The method of claim 127.

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