Preparations of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile

Abstract

To provide formulations of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile, and methods for making the formulations, and methods for treating ocular surface disease and methods for treating ocular surface pain by using the formulations.SOLUTION: The present invention provides an aqueous formulation of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile, or a salt, co-crystal, or polymorph thereof, and one or more excipients selected from the group consisting of a surfactant, a suspending agent, a tonicity agent, a buffer, a salt, and a preservative.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This disclosure relates to 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline) Preparations of -3-yl-benzonitrile (formula I) and treatment of ocular surface diseases using the same. This relates to methods for reducing ocular surface pain. [Background technology]

[0002] The surface of the eye, especially the cornea, is densely innervated by sensory nerves. This condition is caused by several factors, including osmotic stress and tissue damage, as well as nerve damage to the ocular surface. It can be altered by inflammation caused by this. Symptoms on the ocular surface are caused by stress on the ocular surface and An unbalanced ocular surface that causes chronic ocular surface pain due to persistent irritation that leads to sensitization. It is a warning system that indicates homeostasis.

[0003] Patients suffering from ocular surface pain, especially chronic ocular surface pain, experience a significant decrease in their quality of life. It has the following characteristics. In efficacy trials to date, the burden of severe chronic ocular surface pain has been reduced to moderate or It has been likened to severe angina pectoris, dialysis, or hip fractures that result in disability. Ocular surface pain is also associated with depression and suicidal ideation. In many patients, ocular surface pain Pain requires treatment of the underlying pathology (e.g., recent trauma or surgery, infection, or inflammation). It remains unresolved elsewhere. Furthermore, treatments used for the short-term management of ocular pain ( For example, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, and antibiotics are used for long-term therapy. It cannot be used. Therefore, if there are no other options to improve safety and the patient's quality of life. An effective formulation for the symptomatic treatment of ocular surface pain, or a long-desired supplement to current treatments There is still a need that has not yet been addressed.

[0004] While topical administration of aqueous compositions is non-invasive and very convenient, there remains the problem of formulating hydrophobic compounds into stable aqueous formulations. Agglomeration is particularly problematic for hydrophobic ophthalmic drugs that tend to agglomerate within aqueous topical ophthalmic compositions. Agglomeration can cause stability and potentially other quality issues with the composition, and can also result from other interactions between the drug and excipients. Given the above, it would be particularly desirable to provide an ophthalmic composition that can be topically administered for the treatment of ocular surface disorders, particularly for the treatment of ocular surface pain.

[0005]

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

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[0007] [Non-licensed Document 1] Caterina MJ,et al.,.Nature 1997;389:816-824 [Non-licensed Document 2] Hawker,et al.,Arthritis Care & Research 63(11),pp.S240-S252(November 2011) [Non-licensed Document 3] Caudle LEet al.,Optom Vis Sci.2007 Aug;84(8):752-62 [Non-licensed Document 4] Qazi et al.,Ophthalmology July 123(7):1458-1468(2016) [Non-licensed Document 5] Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418 [Non-licensed Document 6] Journal of Pharmaceutical Science,66,2(1977) [Non-licensed Document 7] Craig JP, et al., The Ocular Surface 2017;15:276-83 [Non-licensed Document 8] Buckley,RJ,Int Ophthalmol Clin,1988 28(4):p.303-8 [Non-licensed Document 9] Kumar,S.,Acta Ophthalmologica,2009.87(2):p.133-147 [Non-licensed Document 10] Bonini, S., et al., Ophthalmology, 2000. 107(6): p. 1157 - 63

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Summary of the Invention

[0008] In some embodiments, as described herein, 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) - Benzonitrile (compound I) or its salts, cocrystals, or polymorphs, Furthermore, selected from the group consisting of surfactants, suspending agents, isotonic agents, buffers, salts, and preservatives. An aqueous formulation containing one or more excipients is described.

[0009] In some embodiments, 4-(7-hydroxy-2-isopropyl-4-oxo-4 H-Quinazolin-3-yl)-benzonitrile (compound I) or its salt, cocrystal, or The polymorph is present in the formulation as a suspension. In alternative or additional embodiments, 4-(7- (Hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzo Tolyl (compound I) or its salts, cocrystals, or polymorphs are present in concentrations of approximately 0.5% w / v to approximately 3%. It is present in the formulation at a concentration of 5% w / v.

[0010] In some embodiments, the Specified Version At concentrations of approximately 0.5% w / v to approximately 3.5% w / v, 4- is present as a suspension in the formulation. (7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3-yl)-be Nzonitrile (compound I) or its salts, cocrystals, or polymorphs, Surfactants, Suspensioning agent, Furthermore, one or more excipients selected from the group consisting of isotonic agents, buffers, salts, and preservatives. The aqueous formulations included are listed.

[0011] In some embodiments, the present invention as described herein 4-(7-hydroxy-2-isopropyl alcohol) in amounts of approximately 0.5% w / v to approximately 3.5% w / v Pyr-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or so Salts, cocrystals, or suspensions of polymorphs of Nonionic surfactants; Suspending agent; Isotonic agent; Buffering agent; salt; and This is a formulation that includes a preservative, chosen at the discretion of the user.

[0012] In some embodiments, this disclosure is, 4-(7-hydroxy-2-isopropyl alcohol) in amounts of approximately 0.5% w / v to approximately 3.5% w / v Pyr-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or so Salts, cocrystals, or suspensions of polymorphs of Selected from the group consisting of nonionic, anionic, cationic surfactants, and combinations thereof. Selected surfactants; Suspending agent; Isotonic agent; Buffering agent; Salt by choice; Preservatives by choice; and This relates to formulations containing a sufficient amount (qs) of water up to 100%.

[0013] In some embodiments, the formulation includes a nonionic surfactant. In some embodiments of the formulation, the nonionic surfactant is a polysorbate surfactant. ethylene oxide block copolymer, propylene oxide surfactant, poloxamer The group is selected from thyroxapole and combinations thereof.

[0014] In some embodiments of the formulations described herein, the nonionic surfactant is present in small amounts. 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 Approximately 1% w / v or less, approximately 0.5% w / v or less, approximately 0.3% w / v or less, or approximately 0.2% w / v The amount present at w / v or less, approximately 0.1% w / v or less, or approximately 0.08% w / v or less is significant. It is tyroxapol. In some embodiments, tyroxapol is about 0.03% w / v It is present in amounts of ~0.08% w / v, or approximately 0.05% w / v.

[0015] In some embodiments of the formulations described herein, the nonionic surfactant is used in the formulation. This is a poloxamer at concentrations of approximately 15% w / v to 20% w / v.

[0016] In some embodiments of the formulations described herein, the suspending agent is carbomer, hydr Roxypropyl methylcellulose (hypromellose), polyethylene glycol, and A combination of these is selected from the group. In some embodiments, the suspending agent is less Both are approximately 0.05% w / v, at least approximately 0.1% w / v, or at least approximately 0.2% w / v is and is approximately 1.0% w / v or less, approximately 0.6% w / v or less, or approximately 0.5% w / v or less. The carbomer present in the formulation in the amounts shown below. In some embodiments, carbomer - is present in the formulation at an amount of 0.1% w / v to approximately 0.3% w / v, or approximately 0.2% w / v. exist.

[0017] In some embodiments of the formulations described herein, the suspending agent is at least about 0. It is 0.5% w / v, at least about 0.1% w / v, or at least about 0.25% w / v. and less than approximately 1.8% w / v, less than approximately 1.0% w / v, less than approximately 0.8% w / v, or approximately 0 Hydroxypropyl methylcellulose present in the formulation at an amount of less than 0.6% w / v Yes. In some embodiments, the suspending agent is a molecule with a molecular weight of about 200 Da to about 20,000 Da. It is polyethylene glycol (PEG) having a certain amount. In some embodiments, it is suspended The agent is approximately 4% w / v to 9% w / v, approximately 5% w / v to 8% w / v, or approximately 7% w / v PEG400 at a concentration of v, or approximately 1% w / v to approximately 4% w / v, approximately 1% w / v to approximately 3% w / v This is PEG6000 at a concentration of v, or approximately 2% w / v.

[0018] In some embodiments of the formulations described herein, the suspending agent is substantially all Cal It is a Bomber homopolymer type B.

[0019] In some embodiments of the formulations described herein, the isotonic agent is derived from a polyol. Selected from the group.

[0020] In some embodiments of the formulations described herein, the polyol is mannitol, Glycerin, xylitol, sorbitol, and propylene glycol, and combinations thereof Selected from a group selected from the combination. In some embodiments, the polyol is about 0. 05%w / v ~ approx. 10%w / v, approx. 0.1%w / v ~ approx. 8%w / v, approx. 0.1%w / v ~ It is present in amounts of approximately 7% w / v, and from approximately 0.1% w / v to approximately 5% w / v. Specific embodiments So, polyols are 0.1% w / v to about 5% w / v, or about 0.2% w / v, about 0.3% w / v %w / v, approx. 0.4%w / v, approx. 0.5%w / v, approx. 1%w / v, approx. 2%w / v, approx. 2. 5%w / v, approx. 3.0%w / v, approx. 3.5%w / v, approx. 4.0%w / v, approx. 4.5%w / Mannitol or glycerin present in the formulation in an amount of v, or approximately 5% w / v. .

[0021] In some embodiments of the formulations described herein, the buffering agent is an acetate, ascorbic acid Salt, borate, bicarbonate, carbonate, citrate, EDTA, gluconate A group consisting of phosphates, lactates, phosphates, propionates, and TRIS (tromethamine). They are selected from among. In certain embodiments, the buffer is a phosphate or TRIS.

[0022] In some embodiments of the formulations described herein, the salt is sodium chloride or chloride It is potassium.

[0023] In some embodiments of the formulations described herein, the suspending agent is Carbopol (Cal It is a Bomer homopolymer (Type B), and the amount of sodium chloride is approximately 60 rpm at 25°C. When using spindle CP-42, the viscosity of the formulation is approximately 20 cP to approximately 200 cP. The amount is adjusted to approximately 0.01% w / v. In some embodiments, the sodium chloride is approximately 0.01% w / v. ~0.5%w / v, approx.0.02%w / v~0.4%w / v, approx.0.03%w / v~approx. 0.3%w / v, approx. 0.04%w / v ~ approx. 0.2%w / v, approx. 0.05%w / v ~ approx. 0. It is present at a concentration of 1% w / v, or approximately 0.05% w / v.

[0024] In some embodiments of the formulations described herein, the pH of the formulation is approximately 5.5 to approximately 8. It is 0. In some embodiments, the pH of the formulation is about 6.0 to about 8.0, about 6.0. Or it is about 7.4. In some embodiments, the pH of the formulation is about 5.0 to about 8.0, about 5.5 to approximately 7.5, approximately 5.0 to approximately 7.4, approximately 5.5 to approximately 7.4, approximately 6.0 to approximately 8.0, approximately The ranges are approximately 6.5 to 8.0, approximately 6.0 to 7.4, or approximately 6.5 to 7.4.

[0025] In some embodiments, the formulations described herein are further 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 It is 0.5 w / v%, but approximately 10.0 w / v% or less, approximately 8.0 w / v% or less, approximately 6.5 w / Select from the group consisting of cyclodextrins in an amount of v% or less, or approximately 5.5 w / v% or less. Includes additional drugs of selection. In some embodiments, cyclodextrin is about the composition of the formulation. Hydroxypropyl β-cyclodextrin or sulfoalkyl in a 5% w / v amount It is ether β-cyclodextrin.

[0026] In some embodiments, this disclosure is, Compound I or its salt, cocrystal, or in an amount of approximately 0.5% w / v to approximately 2.5% w / v polymorph, Tyroxapol, poloxamer, or in amounts of approximately 0.01% w / v to 0.2% w / v These combinations are nonionic surfactants; Hydroxypropyl methylcellulose, polyethylene glycol, or carbomer homopoly A suspending agent of type B; An isotonic agent which is at least one polyol in an amount of approximately 0.05% w / v to approximately 10% w / v; Buffering agents consisting of edetates, phosphates, borates, or combinations thereof. salt; and Contains up to 100% qs of water; and This relates to pharmaceutical formulations with a pH in the range of approximately 5.5 to 8.0.

[0027] In some embodiments, this disclosure is, Approximately 0.5% w / v, approximately 1.0% w / v, approximately 1.5% w / v, approximately 2.0% w / v, or approximately 2 Compound I or its salt, cocrystal, or polymorph present in an amount of 0.5% w / v, Tyroxapole at concentrations of approximately 0.04% w / v to approximately 0.06% w / v, approximately 0.005% Poloxamers at w / v ~ 0.12% w / v, or non-iomatic combinations thereof. Non-toxic surfactant; Hydroxypropyl methylcellulose in amounts of approximately 0.1% w / v to approximately 0.8% w / v% Polyethylene glycol in amounts of approximately 2% w / v to approximately 8% w / v, approximately 0.05% w / Carbomer homopolymer type B, or a combination thereof, in an amount of approximately 0.5% w / v A certain suspending agent; An isotonic agent, such as mannitol or glycerin, in an amount of approximately 0.1% w / v to approximately 5% w / v; Buffers such as edetates, phosphates, borates, tromethamine, or combinations thereof; Sodium chloride in amounts ranging from 0.01% w / v to approximately 1% w / v; and Contains up to 100% qs of water; and This relates to a pharmaceutical formulation having a pH in the range of approximately 5.5 to 8.0.

[0028] In some embodiments, this disclosure is, Approximately 0.5% w / v, approximately 1.0% w / v, approximately 1.5% w / v, approximately 2.0% w / v, or approximately 2 4-(7-hydroxy-2-isopropyl-4-oxo-4H in 0.5% w / v -Quinazolin-3-yl)-benzonitrile (compound I) or its salt, cocrystal, or Suspension of polymorphs, Tyroxapole in amounts of approximately 0.04% w / v to approximately 0.06% w / v; Carbomer homopolymer type B in amounts of approximately 0.05% w / v to approximately 0.4% w / v; Glycerin in amounts of approximately 0.5% w / v to approximately 5% w / v; Select from the group consisting of edetate, phosphate, borate, tromethamine, and combinations thereof. Selected buffering agent; Sodium chloride in amounts ranging from 0.01% w / v to approximately 1% w / v; and A formulation containing up to 100% water; This relates to a pharmaceutical formulation having a pH in the range of approximately 5.5 to 8.0.

[0029] In some embodiments of the formulations described herein, compound I is polymorph B. .

[0030] In some embodiments, this disclosure is, Approximately 0.5% w / v, approximately 1.0% w / v, approximately 1.5% w / v, approximately 2.0% w / v, or approximately 2 4-(7-hydroxy-2-isopropyl-4-oxo-4H in 0.5% w / v A suspension of polymorph B of (-quinazolin-3-yl)-benzonitrile (compound I), Tyroxapole in amounts of approximately 0.04% w / v to approximately 0.06% w / v; Carbomer homopolymer type B in amounts of approximately 0.05% w / v to approximately 0.4% w / v; Glycerin in amounts of approximately 0.5% w / v to approximately 5% w / v; A mild solution selected from edetate, phosphate, borate, tromethamine, or a combination thereof. A shocking agent; Sodium chloride in amounts ranging from 0.01% w / v to approximately 1% w / v; and A formulation containing up to 100% water; This relates to a pharmaceutical formulation having a pH in the range of approximately 5.5 to 8.0.

[0031] In some embodiments, the formulation is Approximately 0.5% w / v, approximately 1.0% w / v, approximately 1.5% w / v, approximately 2.0% w / v, or approximately 2 Compound I in a 0.5% w / v amount, Approximately 0.05% w / v tyroxapole; Carbomer homopolymer type B with approximately 0.2% w / v; Approximately 2.0% w / v glycerin; Tromethamine buffer; and Hydrochloric acid to adjust the pH to approximately 6.4 to 8.4; Approximately 0.05% w / v sodium chloride; and Contains up to 100% qs water; The formulation does not contain preservatives.

[0032] In some embodiments of the formulations described herein, polymorph B of compound I is 9. Three or more peaks at a 2θ value selected from 3, 10.6, and 14.4 ± 0.2°2θ. Characterized by an X-ray diffraction pattern having [specific characteristics].

[0033] In some embodiments, the formulations described herein are approximately 20 cP to approximately 200 cP. It has viscosity.

[0034] In some embodiments, the formulations described herein have a yield of approximately 200 to 450 kilograms. It has a gravimetric osmole concentration of milliosmoles (mOsm / kg) per ram.

[0035] In some embodiments of the formulations described herein, compound I is D 90 (of compound I) Diameter (90% of which consists of smaller particles): less than approximately 10 μm, less than approximately 8 μm, and about 6 μm. It is less than m, less than approximately 4 μm, less than approximately 3 μm, or approximately 2 μm. In some embodiments, D of compound I in the formulation 50 (The diameter in which 50% of compound I consists of smaller particles) is, Less than approximately 10 μm, less than approximately 8 μm, less than approximately 6 μm, less than approximately 4 μm, less than approximately 3 μm, approximately 2 μm It is less than or about 1 μm. In some embodiments, the D of compound I in the formulation 10 (compound The diameter of substance I, which is composed of 10% smaller particles, is approximately less than 5 μm, approximately less than 4 μm, approximately It is less than 3 μm, approximately less than 2 μm, approximately less than 1 μm, or approximately 0.3 μm.

[0036] In some embodiments of the formulations described herein, the formulations are stored at room temperature for 6 months. Approximately less than 10%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4% after the tube. It exhibits a precipitate of less than approximately 3% or less than approximately 2%.

[0037] In some embodiments of the formulations described herein, the amount of compound I in the formulation is refrigerated. After approximately 6 months, 8 months, 10 months, 12 months, and 15 months of storage below, It is at least 90% of the initial amount after approximately 18 months.

[0038] In some embodiments of the formulations described herein, the amount of compound I in the formulation is refrigerated. At least approximately 91% and at least approximately 92% of the original amount after about 18 months of storage under the following conditions. , at least about 93%, at least about 94%, at least about 95%, at least 96%, It is at least approximately 97% or at least approximately 98%.

[0039] In some embodiments of the formulations described herein, the formulations are refrigerated for 6 months. It contains approximately 10% or less of degradation products, and the degradation products include 0.1% trifluoroacetic acid (TFA). 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.

[0040] In some embodiments of the formulations described herein, about 10% of compound I in the formulation is The bottom part decomposes after 12 weeks of storage at 40°C.

[0041] In some embodiments, this disclosure is, A certain amount of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3) -yl)-benzonitrile (compound I) or its salt, cocrystal, or polymorph, Nonionic surfactants; Suspending agent; Isotonic agent; Buffering agent; salt; Preservatives by choice; and Mixing up to 100% qs of water; and This invention relates to a method for preparing a pharmaceutical product, which includes adjusting the pH to a range of approximately 5.5 to 8.0.

[0042] In some embodiments, the method for preparing the formulations disclosed herein involves a stored suspension and This includes the addition of compound I. In some embodiments, the stored suspension is converted to a desired particle size. It is ground to obtain compound I. In some embodiments, compound I in the formulation is D 90 ( Compound I consists of 90% smaller particles (diameter) of approximately 10 μm or less, and approximately 8 μm or less. These are full, less than approximately 6 μm, less than approximately 4 μm, less than approximately 3 μm, or approximately 2 μm. Several implementations In terms of form, compound I in the formulation is D 50 (50% of compound I consists of smaller particles) The diameter is approximately less than 10 μm, less than 8 μm, less than 6 μm, less than 4 μm, and less than 3 μm. , less than approximately 2 μm, or approximately 1 μm. In some embodiments, the D of compound I in the formulation 10 (The diameter of compound I, where 10% of the particles are smaller) is less than approximately 5 μm, approximately 4 μm. It is less than m, less than approximately 3 μm, less than approximately 2 μm, less than approximately 1 μm, or approximately 0.3 μm.

[0043] In one embodiment, the present disclosure is a method for treating ocular surface pain in a subject requiring treatment. Structure: [ka] Having an effective amount of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazo Phosphate-3-yl)-benzonitrile (Formula I) The present invention provides a method that includes instilling eye drops of a salt, solvate, polymorph, or cocrystal thereof. do.

[0044] In some embodiments, ocular surface pain is accidental or acute pain. In terms of treatment form, the ocular surface pain is chronic ocular surface pain (COSP) that lasts for at least approximately 3 months. .

[0045] In some embodiments, the compound of formula I is administered to the cornea of ​​the subject. Morphologically, the compound of formula I has concentrations of approximately 0.5% w / v to approximately 3.5% w / v, and approximately 0.5% w / v to Approximately 2.5% w / v, or approximately 0.5% w / v to approximately 1.5% w / v, approximately 0.5% w / v to approximately 3 .0%w / v, approx. 1.0%w / v ~ approx. 2.5%w / v, approx. 1.5%w / v ~ approx. 3.0%w It is administered to the subject at a concentration of / v, or approximately 0.5% w / v to approximately 2.5% w / v. Specific implementation Morphologically, the compound of formula I is present in concentrations of approximately 0.5% w / v, approximately 1.0% w / v, and approximately 1.5% w / v. Concentrations of approximately 2.0% w / v, 2.5% w / v, 3.0% w / v, or 3.5% w / v It is administered as follows.

[0046] In some embodiments of the methods for treating ocular surface pain described herein, COSP This is associated with dry eye disease. In some embodiments, administration is used to treat the symptoms of dry eye disease. It results in a reduction in certain cases. In certain embodiments, administration is used for ocular pain associated with dry eye disease. In some embodiments, administration results in a reduction of dry eyes, eye discomfort, and eye congestion. One or more of the following symptoms may occur: bleeding, burning or stinging sensation in the eye, roughness or foreign body sensation, or photophobia. This results in a reduction in the incidence rate of at least approximately 10%.

[0047] In some embodiments of the methods for treating ocular surface pain described herein, the subject is: Dry eye disease, Sjögren's syndrome, conjunctivitis (keratoconjunctivitis, vernal keratoconjunctivitis, allergic conjunctivitis) (including conjunctivitis), corneal epithelial basement membrane dystrophy, Acanthamoeba, fibromyalgia, Mycobacterium Bohm's gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Steve Johnson syndrome, corneal epithelial disease, corneal neuropathy (LASIK-induced corneal neuropathy) (including), corneal dystrophy (including recurrent corneal dystrophy), epithelial basement membrane dystrophy Fees, corneal erosions, or corneal abrasions (including recurrent corneal erosions or abrasions) ocular surface diseases, blepharitis, graft-versus-host disease, meibomian gland inflammation, glaucoma, conjunctival laxity, keratopathy (including herpes zoster keratopathy, filamentous keratopathy, shingle or bullous keratopathy, lagophthalmos), keratitis ( (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, eyelashes Patients recovering from trichorrhizosis, pterygium, neuralgia, xerophthalmos, neurotrophic keratitis, or Laser refractive keratotomy (PRK) or laser corneal reshaping (LASIK) You are experiencing one or more types of ocular pain that have persisted for at least three months after surgery.

[0048] In some embodiments, the method for treating ocular surface pain described herein is additional This includes administering therapeutic agents to the target.

[0049] In some embodiments of the methods for treating ocular surface pain described herein, compound I When administered to the target population, the placebo effect was measured on a visual analog scale (VAS). Compared to, at least approximately 3, at least approximately 4, at least approximately 5, at least approximately 6, less In pain scores of approximately 7, at least approximately 8, at least approximately 9, or at least approximately 10 This results in a reduction. In a further embodiment, administration of compound I to a subject is measured on a VAS. When compared to a placebo, the effect is at least about 6, at least about 7, at least about 8, less This results in a reduction in pain scores for at least 9 or at least 10 subjects.

[0050] In some embodiments of the methods for treating ocular surface pain described herein, compound I Administration to the target population showed a difference of at least approximately 10%, at least approximately 15%, compared to placebo. It results in a pain reduction of at least 20%, or at least 25%, in the target population. In several embodiments, the reduction in pain score is observed before and after administration of compound I to the subject. This results from the difference in pain scores. In some embodiments of the methods described herein, The reduction in pain scores after administration of compound I to the target subject was observed approximately 30 minutes after administration of compound I to the target subject. It will occur within minutes.

[0051] In some embodiments of the methods for treating ocular surface pain described herein, compound I Administration to the target population results in at least approximately 1 on the McMonnies scale, and at least Reduction of hyperemia in approximately 2, at least approximately 3, at least approximately 4, or at least approximately 5 subjects. It brings about.

[0052] In some embodiments of the methods for treating ocular surface pain described herein, compound I Administration to the target subject should be within approximately 30 minutes, within approximately 1 hour, and within approximately 2 hours after administration of compound I to the target subject. It results in a reduction in pain scores within or approximately 4 hours.

[0053] In some embodiments of the methods described herein, the administration of compound I to a subject is M On the cMonnies scale, at least about 1, at least about 2, at least about 3 This results in a reduction of congestion in at least approximately 4, or at least approximately 5, subjects.

[0054] In some embodiments of the methods described herein, the administration of compound I to a subject is performed Compared to a racebo, the results were: best corrected visual acuity, intraocular pressure, slit-lamp biomicroscopy, pupil dilation, and blinking. It does not cause any change in one or more of the following: rate or tear production.

[0055] In some embodiments of the methods described herein, the compound of formula I is described herein. It is administered in the form of the formulation described herein. Several implementations of the method described herein In this scenario, the formulation is administered for at least approximately 1, 2, or 3 months. Several implementations In this scenario, the preparation is administered once to four times a day.

[0056] In some embodiments, this disclosure is intended for use in the treatment of ocular surface pain. The invention relates to the formulation as described in [reference]. In some embodiments, ocular surface pain is acute or It is incidental ocular surface pain. In some embodiments, the ocular surface pain lasts for at least one month. The condition is chronic ocular surface pain that lasts for at least two months, or at least three months.

[0057] In some embodiments, this disclosure relates to reducing ocular surface pain in the target population where it is needed. Law, structure: [ka] 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3) -I)-benzonitrile (Formula I) Or relating to a method that includes instilling eye drops of a salt, solvate, polymorph, or cocrystal thereof. ru.

[0058] In some embodiments, ocular surface pain is acute or incidental ocular surface pain. In that embodiment, ocular surface pain lasts for at least one month, at least two months, or less It is also chronic ocular surface pain that lasts for 3 months. In some embodiments, COSP is dryer It is accompanied by a disease.

[0059] In some embodiments of the methods for reducing cancer pain described herein, COSP is , accompanied by dry eye disease. Some of the methods for reducing ocular surface pain described herein In this embodiment, administration of compound I to a subject results in a reduction of symptoms of dry eye disease. vinegar.

[0060] In some embodiments of the methods for reducing ocular surface pain described herein, compound I Administration to the target population results in a reduction of ocular pain associated with dry eye disease. In some embodiments of the described method, administration of compound I to a subject causes dry eyes, eye Discomfort, redness of the eyes, burning or stinging sensation in the eyes, roughness or foreign body sensation, or photophobia This results in a reduction of at least approximately 10% in the incidence rate of one or more conditions.

[0061] In some embodiments, subjects who need to reduce ocular surface pain include those with dry eye disease. Sjögren's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and 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 epithelial disease, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dysplasia Trophy (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, corneal cornea or corneal abrasions (including recurrent corneal erosions or corneal abrasions), ocular surface diseases, eye Blepharitis, graft-versus-host disease, meibomian gland inflammation, glaucoma, conjunctival laxity, keratopathy (herpetic keratopathy, Filamentous keratopathy, zoular or bullous keratopathy, lagophthalmos, keratitis (herpes simplex virus) (including keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium , one or more patients who have recovered from neuralgia, xerophthalmos, or neurotrophic keratitis They are affected. In some embodiments, the subject is laser refractive keratotomy (PRK). Eyes that have persisted for at least 3 months after surgery or laser corneal reshaping (LASIK) surgery. I suffer from sexual pain.

[0062] In some embodiments, the method for reducing ocular surface pain described herein is additional This includes administering therapeutic agents to the target.

[0063] In some embodiments of the methods for reducing ocular surface pain described herein, compound I When administered to a target, the compound's dosage is measured on a visual analog scale (VAS). Compared to pre-administration pain scores, it resulted in a reduction in pain scores in at least approximately 3 subjects. In some embodiments of the methods described herein, the administration of compound I to a subject is: When measured on a visual analog scale (VAS), compared to placebo, at least Also about 3, at least about 4, at least about 5, at least about 6, at least about 7, and at least This also results in a reduction of approximately 8, at least approximately 9, or at least approximately 10 points in the pain score. In some embodiments of the method described in the specification, administration of compound I to a subject is performed using VAS. When measured above, compared to placebo, it is at least about 6, at least about 7, and at least This also resulted in a reduction in pain scores for approximately 8, at least approximately 9, or at least approximately 10 subjects. In other embodiments, the reduction in pain scores occurred approximately 7 days after administration of compound I to the subject. This occurs. In some embodiments, the reduction in pain score is due to the application of compound I to the target. It occurs approximately 14 days after administration.

[0064] In some embodiments of the methods for reducing ocular surface pain described herein, compound I Administration to the target population showed a difference of at least approximately 10%, at least approximately 15%, compared to placebo. It results in a reduction in pain of at least 20%, or at least 25%, of the target population. In some embodiments of the methods described in the document, the reduction in pain scores is due to compound I This is derived from the difference in pain scores before and after administration to the subject. In other embodiments, pain scores The reduction in compound I occurs approximately 7 days after administration to the subject. In some embodiments, The reduction in pain scores occurs approximately 14 days after administration of compound I to the subjects.

[0065] In some embodiments of the methods for reducing ocular surface pain described herein, compound I Administration to the target population results in at least approximately 1 on the McMonnies scale, and at least Reduction of hyperemia in approximately 2, at least approximately 3, at least approximately 4, or at least approximately 5 subjects. It brings about.

[0066] In some embodiments of the methods described herein, the compound of formula I is described herein. It is administered as a listed preparation.

[0067] In some embodiments, the present disclosure describes a method for reducing ocular congestion in the target area where it is needed. It exists, structure: [ka] 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3) -I)-benzonitrile (Formula I) Or relating to a method that includes instilling eye drops of a salt, solvate, polymorph, or cocrystal thereof. The compound of formula I has a concentration of approximately 0.5% w / v to approximately 3.5% w / v, and approximately 0.5% w / v to approximately 2.5% w / v. %w / v, or approximately 0.5%w / v to approximately 1.5%w / v, approximately 0.5%w / v to approximately 3.0%w / v, approximately 1.0%w / v~approximately 2.5%w / v, approximately 1.5%w / v~approximately 3.0%w / v, or It is administered at a concentration of approximately 0.5% w / v to approximately 2.5% w / v.

[0068] In some embodiments of the methods described herein, the reduction in ocular congestion is McM On the Onnies scale, at least about 1, at least about 2, at least about 3, It is at least about 4, or at least about 5.

[0069] In some embodiments, administration of compound I causes dry eyes, eye discomfort, eye burning, etc. At least one of the following is a stinging pain, a rough or foreign body sensation, or photophobia. This results in a 0% reduction in the incidence rate.

[0070] In some embodiments of the methods described herein, the subjects are dry eye disease, sclera - Glenn's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), cornea Epithelial basement membrane dystrophy, Acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid gland Adenoid ophthalmopathy, rosacea, ptosis, keratoconus, ocular pain syndrome, Stevens-Johnson syndrome Group, corneal epithelial disease, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy Fies (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, corneal erosion or corneal abrasions (including recurrent corneal erosions or abrasions), ocular surface diseases, blepharitis graft-versus-host disease, meibomian gland inflammation, glaucoma, conjunctival laxity, keratopathy (herpetic keratopathy, filamentous keratopathy) Keratopathy, including keratopathy, zoular or bullous keratopathy, and lagophthalmos, keratitis (herpes simplex virus) (including keratitis), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuropathy Patients recovering from menstrual pain, dry eyes, neurotrophic keratitis, or laser refractive cornea At least 3 months after excision (PRK) surgery or laser corneal reshaping (LASIK) surgery You are experiencing one or more of the following eye pains that persist for a month.

[0071] Some embodiments of the methods described herein for reducing ocular congestion may further provide additional treatment. This includes administering therapeutic drugs to the target.

[0072] In some embodiments of the methods described herein, the compound of formula I is described herein. It is administered as a listed preparation.

[0073] In some embodiments, the present disclosure treats or reduces ocular surface pain in subjects where it is needed. A method of reduction, structure: [ka] Compound 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazori This includes administering preparations containing 0-3-yl)-benzonitrile (compound I) to individuals. Regarding the law, The formulation yields a Cmax compound I of rabbit cornea that is approximately 1.5 to 3 times the Cmax of the conjunctiva. Cmax is the maximum concentration of compound I in a specific tissue after a single dose administration. In several embodiments, compound I is administered as a formulation described herein.

[0074] In some embodiments, the present disclosure treats or reduces ocular surface pain in subjects where it is needed. A method of reduction, structure: [ka] Compound 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazori This includes administering preparations containing 0-3-yl)-benzonitrile (compound I) to individuals. Regarding the law, The formulation contains compound I in rabbit cornea at a level approximately 500 times higher than the Cmax of compound I in plasma. Cmax is the maximum value of compound I in a particular tissue after a single dose administration. It is highly concentrated. In some embodiments, compound I is used as a formulation described herein. It will be administered.

[0075] Certain preferred embodiments of the present invention are certain preferred embodiments and claims. This will become clear from the following more detailed explanation. [Brief explanation of the drawing]

[0076] [Figure 1-1]Figure 1: Figure 1A shows the percentage of Compound I in the exploratory formulations described in Table 2 over 12 weeks at room temperature. In Figure 1A, formulations with approximately 70% of the initial percentage of Compound I after 12 weeks are formulations of Compound I as a solution. Figure 1B shows the percentage of Compound I in the exploratory formulations after 12 weeks at 40°C. In Figure 1B, formulations with approximately 20% of the initial percentage of Compound I after 12 weeks are formulations of Compound I as a solution. [Figure 1-2] (As stated above.) [Figure 2] Figure 2 shows the powder X-ray diffraction pattern of compound I recovered from a 12-week stable sample compared to the control. [Figure 3] Figure 3 shows the model-estimated mean (+ / -SE) of visual analog scale (VAS) pain assessment over time (main PD analysis set). [Figure 4] Figure 4 shows a histogram of the frequency of oral rescue drug use (number of patients who did not use oral rescue drugs) (secondary PD analysis set). For each period, the bars on the right represent subjects who received compound I, while the bars on the left represent subjects who received the solvent. The percentage of patients who did not use oral rescue drugs (ORM) is shown on the y-axis. n / N represents the number of patients / total for each treatment. [Figure 5-1] Figure 5: Figure 5 provides the arithmetic mean (+ / -SD) of the Ocular Pain Assessment Survey (OPAS) over time for questions 4, 5, and 6 (secondary PD analysis set). Figure 5A provides the results from question 4: 24 hours of eye pain at the most painful time (pain level), Figure 5B provides the results from question 5: 24 hours of eye pain at the least painful time (pain level), and Figure 5C provides the results from question 6: 24 hours of eye pain at the average (pain level). In each of Figures 5A, 5B, and 5C, dashed lines with "×" represent the solvent, and solid lines with circles (○) represent compound I. [Figure 5-2] (As stated above.) [Figure 5-3] (As stated above.) [Figure 6-1]Figure 6: Figure 6 provides the arithmetic mean (+ / -SD) of the Ocular Pain Assessment Survey (OPAS) over time for questions 22, 23, 24, and 25 (secondary PD analysis set). Figure 6A provides the results from question 22: frequency (%) of eye pain with redness. Figure 6B provides the results from question 23: frequency (%) of eye pain with burning sensation. Figure 6C provides the results from question 24: frequency (%) of eye pain with hypersensitivity. Figure 6D provides the results from question 25: frequency (%) of eye pain with lacrimation. In each of Figures 6A, 6B, 6C, and 6D, the dashed line with "×" represents the solvent, and the solid line with circle (○) represents compound I. [Figure 6-2] (As stated above.) [Figure 6-3] (As stated above.) [Figure 6-4] (As stated above.) [Figure 7-1] Figure 7: Figure 7A shows the arithmetic mean (SD) plasma concentration of Compound I (PK analysis set) after topical instillation of 2.5% Compound I on day 1. Figure 7B shows the arithmetic mean (SD) plasma concentration of Compound I (PK analysis set) after topical instillation of 2.5% Compound I on day 4. [Figure 7-2] (As stated above.) [Figure 8-1] Figure 8: Figure 8A provides a bar graph of ocular congestion over time for compound I, and Figure 8B provides a bar graph of ocular congestion over time for solvent. The quadrants are S: superior, N: nasal, I: inferior, and T: temporal. [Figure 8-2] (As stated above.) [Figure 9] Figure 9 shows the arithmetic mean (+ / -SD) of epithelial defect size over time (safety analysis set) parameters (units): epithelial injury size (mm), subcategory: area (mm2). Dashed lines with "×" represent solvents, and solid lines with circles (○) represent compound I. [Modes for carrying out the invention]

[0077] The TRPV1 receptor has been characterized by molecular cloning and pharmacology. This refers to the sex receptor potential vanilloid 1. For example, see (Non-Patent Document 1). TRPV 1. Receptor activity is as fully incorporated herein by reference (Patent Document 1). Measured as described.

[0078] The compounds described herein in the term "effective amount" perform their intended function in mammals. This refers to the amount of therapeutic compound necessary or sufficient for the treatment of a mammal. The effective amount of therapeutic compound is the amount of odor in mammals. The amount of the causative substance already present, age, sex, and body weight of the mammal, and in mammals The ability of the therapeutic compounds of this disclosure to treat ocular surface disorders and / or symptoms thereof, etc. It can fluctuate depending on the cause.

[0079] The phrase "ophthalmologically suitable" corresponds to a reasonable benefit / risk ratio, meaning excessive toxicity. Human and animal eye tissue without sexual, irritation, allergic reactions, or other problems or complications. This refers to formulations, polymers, and other substances and / or dosage forms that are suitable for use in contact with fabrics. vinegar.

[0080] As used herein, the terms "to treat" and "to treat" are used in relation to a disease or disorder. "To" or "treatment" in some embodiments means to improve a disease or disorder ( That is, to delay or prevent the development of at least one of the disease or its clinical symptoms or It refers to reducing. In another embodiment, it means "to treat," "to treat," or "treatment." "This refers to at least one physical parameter that may not be identifiable by the patient. This refers to reducing or improving the condition. In yet another embodiment, it means "to treat" or "to treat". "To do" or "treatment" means physically (e.g., stabilizing identifiable symptoms), physiologically ( For example, stabilizing physical parameters) or both of these methods can regulate a disease or disorder. This refers to. In yet another embodiment, "to treat," "the act of treating," or "treatment" means To prevent or delay the onset, development, or progression of a disease or disorder or its symptoms. To point.

[0081] As used herein, the terms “subject” or “patient” refer to humans as well as primates, rabbits, Non-human mammals include, but are not limited to, pigs, horses, dogs, cats, sheep, and cows. Refers to an animal. In certain embodiments, the subject or patient is human. In some embodiments, The terms "patient" or "subject" refer to the pathological conditions (i.e., diseases or disorders) described herein. This refers to a person who is suffering from the condition and who would benefit from treatment. When used herein, The subjects (patients) are those who are biologically, medically, or otherwise affected by such treatment. If one benefits in quality, then the treatment "is necessary". In certain embodiments, the subject is few At the very least, the subjects are adult humans aged approximately 18 years. In some embodiments, the subjects are approximately 18 years old to approximately The subject is a 75-year-old adult human. In some embodiments, the subject is a child approximately 18 years of age or younger. ru.

[0082] As used herein, "ocular surface" refers anatomically to the cornea (epithelium, Bowman's layer, corneal pulp). The outer part of the eye, including the corneal margin, conjunctiva, conjunctival sac, and corneal margin (which includes the membrane, Descemet's membrane, and endothelium). It refers to the surface.

[0083] When used herein, eye drops are intended for use on the cornea, conjunctiva, conjunctival sac and corneal margin, i.e., the margin, etc. This includes administration to all parts of the eye, including all parts of the ocular surface.

[0084] As used herein, “pain” means, but is not limited to, stabbing, dull, sharp, It also refers to a constant or intermittent sensation of actual pain, which is sometimes described as a throbbing or tingling sensation. It is not definitively defined, but symptoms include burning, stinging, roughness, foreign body sensation, dryness, sandiness, fatigue, and itchiness. This refers to similar related descriptive terms such as prickling or sensitivity to light.

[0085] As used herein, “ocular surface pain” refers to pain on the surface of the eye, such as the cornea. Ocular pain is generally caused by external physical factors such as corneal surgery, inflammation, or other damage to the corneal surface. It may be nociceptive pain caused by a physical or chemical injury. Ocular pain is Furthermore, the pain message sent to the central nervous system and brain despite the presence of noxious stimuli Neuropathic pain that can result from direct damage to the body's neurons. It may be caused by nociception. As used herein, “ocular surface pain” means nociception. This includes both dysphagia and neuropathic pain.

[0086] As used herein, the term “Visual Analog Scale” (VAS) means that the subject matter is typically A pain intensity scale that marks the position on a scale aligned with the pain level. Yes. Pain is categorized as "no pain" (score of 0) and "worst pain" or "worst pain imaginable." It is marked within the range of "pain" (score of 100). For example, see (Non-Patent Document 2). Please refer to the following. Several other well-established methods that can be used to help assess the degree of pain. There is a pain scale that measures pain. It is a numerical evaluation scale in which subjects use numbers to rate their pain. Kale (NRS) is often used. The numerical scale is 1-10 or 1-100. It's possible. The Wong-Baker Faces pain scale is used for pain grading. It combines pictures and numbers. It can be used by children over 3 years old and adults. The six faces represent different expressions ranging from good to very bad. Each one is 0 (smiling) Assigned to a numerical grade between 10 (crying) and 10 (experiencing pain in a verbal sense). The degree scale is a scale used to grade pain intensity using verbal expressions. Ru: No pain / Mild pain / Moderate pain / Severe pain / Very severe pain / No pain Pain.

[0087] The Ocular Sensation Scale is a special pain scale developed to measure the severity of pain in the eye area. This is the scale. (See Non-Patent Document 3). This scale measures pain, discomfort, or lightness. Sensitivity is usually categorized into five levels: "extreme," "severe," "moderate," "mild," or "none." It is measured by the label.

[0088] The Ocular Pain Assessment Survey (OPAS) measures corneal and ocular surface pain and changes in quality of life (QoL). OPAS is a quantitative, multidimensional questionnaire specifically designed for evaluating pain. Pain intensity, frequency of eye pain and non-eye pain, changes in QoL, factors that exacerbate the condition, related factors, and easing of symptoms. The sum can be quantitatively evaluated to enable monitoring of the treatment response. (See Non-Patent Document 4) I want to be treated that way.

[0089] As used herein, the term “Visual Work Questionnaire” means a fixed ophthalmic pain that may worsen the condition. To what extent is it difficult to perform certain tasks that require constant or prolonged gazing? This refers to a questionnaire used to subjectively grade subjects. This questionnaire is also visual. Also inquire about coping mechanisms related to difficulties experienced during work.

[0090] As used herein, ocular hyperemia refers to redness of the ocular surface. Ocular hyperemia can be a clinical marker for inflammation and / or ocular irritation. Ocular hyperemia can be measured using the McMonnies scale with values from 0 to 5 based on standard photographs.

[0091] As used herein, "placebo" refers to an ophthalmic preparation containing all components of a drug composition that does not contain the drug being administered.

[0092] As used herein, the term "about" refers to a range of +10% of the specified value.

[0093] As used herein, "compound of formula I", "Compound I", "formula I", and "compound I" are used interchangeably and refer to a compound having the name of the structure shown below 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile, and can be synthesized using the procedures described in both Chen et al. (Patent Document 1) and ( Patent Document 2) ("Quinazolinone derivatives useful as vanilloid antagonists"), both of which are incorporated herein by reference in their entirety.

Chemical Formula

[0094] Compound I can be used in amorphous or crystalline form. Additionally or alternatively, chemical Various crystals and polymorphic forms of compound (I) can be used. As used herein, the compound "polymorphic form" or "polymorph" of (I) is intended to include crystalline hydrates or other crystalline solvates of compound (I).

[0095] Any chemical formula given herein is also intended to represent both unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have a structure shown by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of the present disclosure include, for example, isotopes of hydrogen, carbon, nitrogen, and oxygen such as 3 H, 11 C, 13 C, 11 C, 13 C, 14 C, 15 C, and 14 C, 15 C, and 15 N. Thus, the methods of the present invention can include, or can optionally include, compounds incorporating one or more of any of the foregoing isotopes, such as radioactive isotopes such as 3 H and 14 C, or non-radioactive isotopes such as 3 H and 14 C. It should be understood that such isotopically labeled compounds are useful in metabolic studies (e.g., with 14 C), reaction rate tests (e.g., with 2 H or 2 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPEC 3 H or 13 C), or in the radioactive treatment of patients, including assays of the tissue distribution of drugs or substrates. 14 C), reaction rate tests (e.g., with 2 H or 3 H), assays of the tissue distribution of drugs or substrates, including positron emission tomography (PET) or single photon emission computed tomography (SPEC 2 H or 3 H), assays of the tissue distribution of drugs or substrates, including positron emission tomography (PET) or single photon emission computed tomography (SPEC T), or in the radioactive treatment of patients. Isotopically labeled compounds are usually prepared, for example, by replacing a suitable isotope T) such as detection or imaging techniques, or in the radioactive treatment of patients. Isotopically labeled compounds are usually prepared, for example, by replacing a suitable isotope in place of a previously utilized unlabeled reagent. It can be prepared using a labeling reagent by conventional methods known to those skilled in the art.

[0096] The present invention provides for all pharmaceutically acceptable compounds useful according to the present invention. Embodiments include those comprising salts. In use herein, "pharmaceutically acceptable salt" This refers to a derivative of the disclosed compound, and the parent compound has an acidic or base portion present. Modification occurs by converting to a salt form. Examples of pharmaceutically acceptable salts include amines. Mineral or organic acid salts of basic residues such as carboxylic acids; alkali salts or acidic salts of acidic residues such as carboxylic acids. Examples include, but are not limited to, biosalts. Pharmaceutically acceptable salts include, Examples of the parent compounds include ordinary non-toxic salts derived from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts contain a basic or acidic portion, determined by conventional chemical methods. They can be synthesized from the parent compounds. Typically, such salts are derived from the free acids or salts of these compounds. A base form and water or an organic solvent, or a mixture of the two (usually ether, ethyl acetate, (A non-aqueous medium such as ethanol, isopropanol, or acetonitrile is preferred.) It can be prepared by reacting it with a suitable stoichiometric amount of a suitable base or acid. The list of salts is incorporated herein by reference, each in whole (Non-Patent Document 5) and (Non-patent document 6) is found to be, for example, a preferred pharmaceutically acceptable salt is Examples include, but are not limited to, mineral or organic salts of basic residues such as amines. For example, a salt may be a hydrochloride salt. Other examples of suitable salts are provided herein in whole. This can be found in the referenced (Patent Document 2).

[0097] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, substances, compositions, and / or dosage forms that, within the scope of sound medical judgment, correspond to a reasonable benefit / risk ratio and are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic -reaction, or other problems or complications. Unless otherwise indicated, all component concentrations are presented in units of % weight / volume (% w / v). As is generally understood, the % w / v value refers to the amount of a particular constituent or component in the formulation. It is generally understood that equivalent concentrations may be expressed in different units. For example, a concentration of 0.1% w / v can also be expressed as a 1 mg / ml solution.

[0098] Unless otherwise specified, the weights or dosages referred to herein with respect to the compounds of formula I are those of the compound itself and not those of its salts or prodrugs, which may vary to achieve the desired therapeutic effect. For example, the weight or dosage of the corresponding salt of a compound suitable for the methods, compositions, or combinations disclosed herein can be calculated based on the ratio of the molecular weights of the salt and the compound itself. It is generally understood that equivalent concentrations may be expressed in different units. For example, a concentration of 0.1% w / v can also be expressed as a 1 mg / ml solution.

[0099] Unless otherwise specified, the weights or dosages referred to herein with respect to the compounds of formula I are those of the compound itself and not those of its salts or prodrugs, which may vary to achieve the desired therapeutic effect. For example, the weight or dosage of the corresponding salt of a compound suitable for the methods, compositions, or combinations disclosed herein can be calculated based on the ratio of the molecular weights of the salt and the compound itself. The present invention provides formulations of compounds of formula I. In some embodiments, the formulation is an aqueous suspension of a compound of formula I. In some embodiments, the suspension has a concentration of from about 0.5% w / v to about 1.5% w / v, from about 0.5% w / v to about 2.5% w / v, from about 0.5% w / v to about 3.5% w / v, from about 0.5% w / v to about 3.0% w / v, from about 1.0% w / v to about 2.5% w / v,

[0100] The present invention provides formulations of compounds of formula I. In some embodiments, the formulation is an aqueous suspension of a compound of formula I. In some embodiments, the suspension has a concentration of from about 0.5% w / v to about 1.5% w / v, from about 0.5% w / v to about 2.5% w / v, from about 0.5% w / v to about 3.5% w / v, from about 0.5% w / v to about 3.0% w / v, from about 1.0% w / v to about 2.5% w / v, w / v, from about 1.5% w / v to about 3.0% w / v, from about 0.5% w / v to about 2.5% w / v at a concentration of the formula 1.5% w / v to about 3.0% w / v, from about 0.5% w / v to about 2.5% w / v at a concentration of the formula Contains compound I. In some embodiments, formula I is present in formulations for topical ocular use. The concentration of the compound is at least about 0.5% w / v, at least about 1.0% w / v, and less Both are approximately 1.5% w / v, at least approximately 2.0% w / v, or at least approximately 2.5% w / v. In some embodiments, the concentration of the compound of formula I in a formulation for topical use is , approx. 5.0%w / v or less, approx. 4.5%w / v or less, approx. 4.0%w / v or less, approx. 3.5%w It is less than or equal to / v, or about 3.0% w / v or less. In certain embodiments, for local use The concentrations of compound I in the formulation are approximately 0.5% w / v, approximately 1.0% w / v, and approximately 1.5% w / v. / v, approximately 2.0% w / v, approximately 2.5% w / v, approximately 3.0% w / v, or approximately 3.5% w / v In some embodiments, when expressed in units of mg / ml, the compound of formula I is... Approximately 5 mg / ml to approximately 35 mg / ml, approximately 5 mg / ml to approximately 25 mg / ml, or approximately 5 mg g / ml ~ approx. 15 mg / ml, approx. 5 mg / ml ~ approx. 30 mg / ml, approx. 10 mg / ml ~ Approximately 25 mg / ml, approximately 15 mg / ml to approximately 30 mg / ml, or approximately 5 mg / ml to approximately 25 mg / ml It is administered to the subject at a concentration of mg / ml. In some embodiments, for topical use The concentration of compound I in the formulation is at least about 5 mg / ml and at least about 10 mg / m³. l, at least about 15 mg / ml, at least about 20 mg / ml, or at least about 25 The concentration is mg / ml. In some embodiments, the compound of formula I in a formulation for topical use The concentration of the substance is approximately 50 mg / ml or less, approximately 45 mg / ml or less, approximately 40 mg / ml or less, approximately The concentration is 35 mg / ml or less, or approximately 30 mg / ml or less. In certain embodiments, the chemical formula I is used. The combined formulations are approximately 5 mg / ml, approximately 10 mg / ml, approximately 15 mg / ml, approximately 20 mg / ml, and approximately It is administered at concentrations of 25 mg / ml, approximately 30 mg / ml, or approximately 35 mg / ml.

[0101] In some embodiments, compounds of formula I are incorporated herein by reference (patent text) As described in Reference 2), it exists as polymorph B. In some embodiments, the polymorph B is CuK α When recorded using radiation, 9.3, 10.6, and 14.4 ± 0. X-ray diffraction patterns with three or more peaks at 2θ values ​​selected from 2°2θ are particularly distinctive. It is marked. In some embodiments, polymorph B is CuK α Recorded using radiation When this happens, the values ​​are 9.3, 10.6, 14.4, 15.5, 17.9, 19.9, and 23.4±0. X-ray diffraction patterns with three or more peaks at 2θ values ​​selected from 0.2°2θ Characterized. In some embodiments, polymorph B is CuK α Recording using radiation When this happens, 9.3, 10.6, 12.8, 14.4, 15.5, 17.9, 19.9, Three or more pinpoint values ​​selected from 21.3, 23.4, and 28.0 ± 0.2°2θ Characterized by an X-ray diffraction pattern with a distinctive mark.

[0102] In some embodiments of the formulations described herein, the D of compound I in the formulation 90 ( Compound I, composed of 90% smaller particles, has a diameter of less than approximately 10 μm and less than approximately 8 μm. These are less than approximately 6 μm, less than approximately 4 μm, less than approximately 3 μm, or approximately 2 μm. Several implementations In this state, compound I in the formulation is D 50 (50% of compound I is composed of smaller particles) The diameters are approximately less than 10 μm, less than 8 μm, less than 6 μm, less than 4 μm, and less than 3 μm. It is less than approximately 2 μm or approximately 1 μm. In some embodiments, the D1 of compound I in the formulation 0 (diameter where 10% of compound I consists of smaller particles) is approximately less than 5 μm, approximately 4 μm. It is less than approximately 3 μm, less than approximately 2 μm, less than approximately 1 μm, or approximately 0.3 μm.

[0103] In some embodiments, the formulation further comprises at least one ophthalmologically acceptable excipient. Includes.

[0104] In some embodiments, the formulation contains an ophthalmologically acceptable surfactant. In the embodiment, the surfactant is an anionic surfactant. In a particular embodiment, an On-occurring 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 Selected from alkylcarboxylate salts; The oligooxyalkylene portion consists of 1 to 5 oxy-C1 to C6 alkylene portions, for example. , has an oxyethylene portion. Anionic surfactants are alkali metals, for example, sodium C1-C3 alkylammonium, tri(C1-C3 alkanol) ammonia For example, triethanolammonium, di(C1-C3 alkanol)ammonium and may have a countercation selected from ammonium cations. Anionic domain in the formulation The concentration of the surfactant is approximately 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-exclusive examples of surfactants include alkylamine salts and alkylamine polyoxyethylene salts. Len adducts, fatty acid triethanolamine monoester salts, acylaminoethyldiethyl Amine salt, fatty acid polyamine condensate, alkylimidazoline, 1-acylaminoethyl- Examples include 2-alkylimidazolines and 1-hydroxyethyl-2-alkylimidazolines. and salts thereof such as chlorhexidine, chlorhexidine or its salts, for example, chlorhex Examples include chydin gluconates. In some embodiments, cationic surfactants are Approximately 0.001% w / v to approximately 5% w / v, or approximately 0.001% w / v to approximately 1% w / v, Approximately 0.001%w / v to approximately 0.1%w / v, or approximately 0.001%w / v to approximately 0.01%w Present in the formulation at an amount of / v, or approximately 0.001% w / v to approximately 0.005% w / v. .

[0105] In certain embodiments, the surfactant is a nonionic surfactant. In this context, nonionic surfactants include polysorbate surfactants, ethylene oxide and p Block copolymer surfactants of propyl oxide (e.g., Pluronic or Tetronic) (A type of surfactant), poloxamer, tyroxapole, or a combination thereof. Kisapol is an alkylaryl polyether alcohol type nonionic liquid polymer. Yes, there is. Poloxamer is a hydrophilic compound of polyoxyethylene (poly(ethylene oxide)). Hydrophobicity of the polyoxypropylene (poly(propylene oxide)) core adjacent to the property chain It is a nonionic triblock copolymer composed of chains. In certain embodiments, it is nonionic. The surfactant is tyroxapole. In some embodiments, tyroxapole is At least about 0.001% w / v, at least about 0.01% w / v, at least about 0.0 It is 2% w / v, at least about 0.03% w / v, at least about 0.04% w / v, and Approximately 1% w / v or less, approximately 0.5% w / v or less, approximately 0.3% w / v or less, or approximately 0.2% w / v It is present at concentrations below / v, approximately 0.1% w / v, or approximately 0.08% w / v. In certain embodiments, the nonionic surfactant is present in an amount of approximately 0.03% w / v to 0.08% w / v , or tyroxapole present in an amount of approximately 0.05% w / v. Specific Embodiments Therefore, virtually all surfactants are tyroxapole.

[0106] In some embodiments, the formulation has a poloxamer interface of about 15% w / v to 20% w / v. Contains an activator. In some embodiments, the formulation contains about 15%, about 15.5%, about 16%, Approximately 16.5%, approximately 17%, approximately 17.5%, approximately 18%, approximately 18.5%, approximately 19%, approximately 19%. It contains 5%, or about 20%, w / v poloxamer. In certain embodiments, the formulation contains about 17 Contains approximately 18% w / v or 17.5% w / v poloxamers. Further details In a particular embodiment, the poloxamer is a poloxamer 407. In a specific embodiment, The surfactant is virtually all tyroxapole.

[0107] In some embodiments, the formulation includes a suspending agent. The ingredients are carbomer, hydroxypropyl methylcellulose (hypromellose), and polyethylene. Lenglycol, or a combination thereof. Carbomer is a network of cross-linked polymer chains. It is a carboxyvinyl polymer having a carboxylic acid functional group. The polymer has a carboxylic acid functional group. It is often characterized in this way, and preferably contains 2 to 7 carbon atoms per functional group. Carbomers, i.e., synthetic high molecular weight polymers of acrylic acid, are, for example, pentae. Lythritol is crosslinked with allyl ether or allyl ether, and in particular, water It is a soluble and water-swellable carbomer. Carbomer is available from various suppliers under the trade name CARB. Available under OPOL®. In certain embodiments, carbomer is carbomer. It is a type B carbomer homopolymer. In certain embodiments, the carbomer is CARBOPOL (Registered trademark) 934P (Carbomer 934P), 940, or 974P. In the embodiment, the suspending agent is carbomer and is at least about 0.05% w / v, and less It is at least about 0.1% w / v, or at least about 0.2% w / v, and also about 1.0% w / It is present in the formulation at amounts of v or less, approximately 0.6% w / v or less, or approximately 0.5% w / v or less. In certain embodiments, the suspending agent is carbomer, and the concentration is 0.1% w / v ~ approximately 0.3%. It is present in the formulation at a concentration of %w / v, or approximately 0.2%w / v.

[0108] In some embodiments, the suspending agent is hydroxypropyl methylcellulose. In certain embodiments, hydroxypropyl methylcellulose is present in an amount of at least about 0.05% w / v, at least about 0.1% w / v, or at least about 0.25% w / v, and Approximately less than 1.8% w / v, approximately less than 1.0% w / v, approximately less than 0.8% w / v, or approximately 0.6% It is present in the formulation in amounts less than w / v. In some embodiments, hydroxypropyl Methylcellulose is approximately 0.1% w / v to approximately 0.8% w / v; approximately 0.1% w / v to approximately 0 .6%w / v; approx. 0.25%w / v ~ approx. 0.8%w / v; approx. 0.4%w / v ~ approx. 0.6% It is present in the formulation in w / v amounts.

[0109] In some embodiments, the suspending agent is a poly(P) having a molecular weight of at least about 200 Da. It is ethylene glycol (PEG). In some embodiments, PEG is at least Approximately 400, 1,000, 2,000, 3,000, 4,000, 6,000, or approximately 10 It has a molecular weight of ,000 Da. In some embodiments, the suspending agent has a molecular weight of about 200 Da~ This is polyethylene glycol (PEG) with a molecular weight of approximately 20,000 Da. In that embodiment, PEG is approximately 400, 1,000, 2,000, 3,000, 4,0 It has a molecular weight of 00, 6,000, or about 10,000 Da. In some embodiments, PEG contains at least approximately 1% w / v, at least approximately 2% w / v, and at least approximately 3% w / It is v and in amounts less than approximately 10% w / v, less than approximately 9% w / v, or less than approximately 8% w / v It is present in the formulation. In certain embodiments, the suspending agent is present in an amount of about 4% w / v to about 9% w / v. PEG400 with a concentration of approximately 5% w / v to approximately 8% w / v, or approximately 7% w / v. In the method, the suspending agent is approximately 1% w / v to 4% w / v, and approximately 1% w / v to 3% w / v. or PEG6000 at a concentration of approximately 2% w / v.

[0110] In certain embodiments, the suspending agent is a combination of two or more suspending agents. Other embodiments Therefore, virtually all suspending agents are carbomers.

[0111] In some embodiments, the suspending agent may provide a formulation of a desired viscosity. Without being affected, the suspending agent is thought to be able to increase the viscosity of the formulation. The formulation maintains compound I in a suspended state within the formulation without precipitation or solidification. It is beneficial. In some embodiments, the formulation viscosity is about 10 cP to about 200 cP (centipoles). As, approximately 20 cP to 200 cP, or approximately 20 cP to 150 cP. In the embodiment, the formulation viscosity is at least about 10 cP, 20 cP, 50 cP, 100 cP, Or at least about 150 cP. Viscosity measurements for the formulation are 3 rpm or 60 rp Measure using a Brookfield viscometer with a CP-42 spindle at any of the m values. Viscosity is determined. It is typically measured at room temperature, i.e., 25°C.

[0112] In some embodiments, the formulation includes an isotonic agent. The agent is a polyol. As used herein, the term "polyol" means relative to each other. and at least one hydroxyl group in each of two adjacent carbon atoms that are not in trans configuration It contains any compound having a polyol group. The polyol is such that the resulting complex is water-soluble and To the extent pharmaceutically acceptable, linear or cyclic, substituted or unsubstituted, or mixtures thereof. It is possible. Examples of such compounds include sugars, sugar alcohols, sugar acids, and uronic acids. In some embodiments, the isotonic agent is mannitol, glycerin, xylitol. This includes, but is not limited to, sorbitol and propylene glycol, or combinations thereof. These are polyols such as sugars, sugar alcohols, and sugar acids, which are not combined. In certain embodiments, the combination The product comprises mannitol, glycerin, or a combination thereof. In some embodiments, The amount of polyol in the formulation is approximately 0.05% w / v to approximately 10% w / v, and approximately 0.1% w / v. ~8% w / v, ~0.1% w / v to ~7% w / v, ~0.1% w / v to ~5% w / v Yes. In certain embodiments, the isotonic agent is mannitol or glycerin, which is 0 0.1% w / v to approximately 5% w / v, or approximately 0.2% w / v, approximately 0.3% w / v, approximately 0.4% w / v, approx. 0.5%w / v, approx. 1%w / v, approx. 2%w / v, approx. 2.5%w / v, approx. 3.0% w / v, approximately 3.5% w / v, approximately 4.0% w / v, approximately 4.5% w / v, or approximately 5% w / v It is present in the formulation in terms of quantity. In certain embodiments, the isotonic agent is mannitol. In certain embodiments, the isotonic agent is glycerin.

[0113] In some embodiments, the formulation includes a buffering agent. Non-limiting examples of buffering substances include Acetate, ascorbate, borate, bicarbonate, carbonate, citrate, EDTA (EDTA), gluconate, lactate, phosphate, propionate and TRIS (Tromeda) Examples include phosphate buffers. In certain embodiments, the buffer is a phosphate buffer system. In a particular embodiment, the buffer is a tromethamine buffer. The amount of buffering substance added is This is typically the amount necessary to ensure and maintain a physiologically acceptable pH range. In that embodiment, the pH range is approximately 4 to approximately 9, approximately 4.5 to approximately 8.5, and approximately 5.0 to approximately 8.0 The range is approximately 5.5 to 8.0 and approximately 6.4 to 8.4. In some embodiments, p H is approximately 6.0. In certain embodiments, pH is approximately 7.4. In terms of form, the pH of the formulations is approximately 5.0 to 8.0, approximately 5.5 to 7.5, and approximately 5.0 to 7. 4. Approximately 5.5 to 7.4, approximately 6.0 to 8.0, approximately 6.5 to 8.0, approximately 6.0 to 7. 4, or approximately 6.5 to 7.4.

[0114] In some embodiments, the formulation contains a salt. In some embodiments, the salt is sodium chloride It is potassium chloride, calcium chloride, or magnesium chloride. Specific embodiments So, the salt is sodium chloride. In certain embodiments, the salt is at least about 0.01% w / v, at least about 0.02% w / v, at least about 0.03% w / v, at least about It is 0.04% w / v, and also approximately 0.5% w / v or less, approximately 0.4% w / v or less, and approximately 0.3% w / v. Present in amounts below %w / v, approximately 0.2%w / v, or approximately 0.1%w / v. In certain embodiments, the salt is approximately 0.01% w / v to approximately 0.5% w / v, approximately 0.02% w / v ~ approx. 0.4%w / v, approx. 0.03%w / v ~ approx. 0.3%w / v, approx. 0.04%w / v It is present in amounts of approximately 0.2% w / v, approximately 0.05% w / v, and approximately 0.1% w / v. In a specific embodiment, the salt is sodium chloride and contains approximately 0.02% w / v to approximately 0.07% It is present in the formulation in w / v or approximately 0.05% w / v amounts.

[0115] In some embodiments, the formulations described herein are approximately 200 to 450 kilograms. Milliosmoles per cubic meter (mOsm / kg), approximately 200 to approximately 400 mOsm / kg, approximately 20 Osmolality by weight: 0 to approximately 300 mOsm / kg, or approximately 240 to approximately 360 mOsm / kg It has a degree.

[0116] In some embodiments, the formulation may also be self-preserving and free of preservatives. In other embodiments, the formulation includes a preservative. In some embodiments, the preservative is a por Rehexylmethylene biguanidine (PHMB), polymeric quaternary ammonium compounds (e.g.) For example, polyquaternium-1), benzalkonium chloride (BAK), chlorite preservatives or Examples of chlorine-containing preservatives include, but are not limited to, other substances.

[0117] In some embodiments, the preservative is an ophthalmologically acceptable polymeric quaternary ammonium compound. It is a compound. This type of compound is described in (Patent Document 3); (Patent Document 4); (Patent Document 5). ;(Patent Document 6);(Patent Document 7);(Patent Document 8);and(Patent Document 9);and(Patent Document 9); As described in authorized reference 10) (Dziabo et al.), in certain embodiments, polymeric Ammonium compounds are polypropylene compounds with a number average molecular weight between 2,000 and 30,000. Polyquataniu, also known as QUAD® or ONAMERM®. It is M1. In a further specific embodiment, the number average molecular weight is 3,000 to 14,000. It is between these two points.

[0118] When used, polymeric quaternary ammonium compounds generally have a formulation of 0.00001 Used in quantities exceeding w / v%, exceeding 0.0003 w / v%, or exceeding 0.0007 w / v%. It is used. Furthermore, when polymeric quaternary ammonium compounds are used in formulations, Generally, the formulation contains less than approximately 0.03 w / v%, less than approximately 0.003 w / v%, or approximately 0.0015%. It is used at concentrations less than w / v%. In some embodiments, polymeric tetraphosphate in the formulation. The concentration of ammonium compounds is as follows: exceeding approximately 0.0003 w / v% Less than approximately 0.003 w / v%; greater than approximately 0.0003 w / v% but less than approximately 0.0015 w / v% Less than; greater than approximately 0.0007 w / v% but less than approximately 0.003 w / v%; and approximately 0.000 More than 7 w / v% but less than approximately 0.0015 w / v%. In certain embodiments, the formulation is approximately 0 Contains polyquaternium-1 at a concentration of 0.001% w / v.

[0119] In some embodiments, the formulation contains at least about 0.0005 w / v% of the formulation, about 0. Concentrations greater than 0.001 w / v% or 0.007 w / v%, and approximately 0.1 w / v% of the ophthalmic composition. B at concentrations less than / v%, less than approximately 0.02 w / v%, or less than approximately 0.0035 w / v% Contains AK. Either the lower limit for BAK concentration is greater than the upper limit for BAK concentration. It is particularly intended to be used in combination with any of the following. In certain embodiments, in the composition The concentration of BAK is as follows: it is above approximately 0.001 w / v%, but is approximately 0.02 w / Less than v%; greater than approximately 0.001 w / v% but less than approximately 0.0035 w / v%; approximately 0.007 w / v% is greater than approximately 0.02 w / v% but less than approximately 0.02 w / v%; and w / v% is greater than approximately 0.007 w / v% but less than approximately 0.007 w / v%. Less than 0.0035 w / v%.

[0120] In some embodiments, the Specified Version 4-(7-hydroxy-2-isopropyl alcohol) in amounts of approximately 0.5% w / v to approximately 3.5% w / v Pyr-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or so Salts, co-crystals, or polymorphs of Furthermore, a group consisting of surfactants, suspending agents, isotonic agents, buffers, preservatives, salts, and preservatives. An aqueous formulation containing one or more excipients selected from there is described.

[0121] In some embodiments, the Specified Version At concentrations of approximately 0.5% w / v to approximately 3.5% w / v, 4- is present as a suspension in the formulation. (7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3-yl)-be Nzonitrile (compound I) or its salts, cocrystals, or polymorphs, Furthermore, a group consisting of surfactants, suspending agents, isotonic agents, buffers, preservatives, salts, and preservatives. An aqueous formulation containing one or more excipients selected from there is described.

[0122] In some embodiments, the Specified Version 4-(7-hydroxy-2-isopropyl-4-o) present as a suspension in the formulation Xo-4H-quinazolin-3-yl)-benzonitrile (compound I) or its salt, cocrystal , or polymorph, Furthermore, a group consisting of surfactants, suspending agents, isotonic agents, buffers, preservatives, salts, and preservatives. An aqueous formulation containing one or more excipients selected from there is described.

[0123] In some embodiments, the Specified Version 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl) - Suspension of benzonitrile (compound I) or its salt, cocrystal, or polymorph, Furthermore, a group consisting of surfactants, suspending agents, isotonic agents, buffers, preservatives, salts, and preservatives. An aqueous formulation containing one or more excipients selected from there is described.

[0124] In some embodiments, the Specified Version At concentrations of approximately 0.5% w / v to approximately 3.5% w / v, 4- is present as a suspension in the formulation. (7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3-yl)-be Nzonitrile (compound I) or its salts, cocrystals, or polymorphs, Surfactants, Suspensioning agent, in addition, one or more selected from the group consisting of isotonic agents, buffers, preservatives, salts, and preservatives. Aqueous formulations containing excipients are described.

[0125] In some embodiments, the invention described herein is At concentrations of approximately 0.5% w / v to approximately 3.5% w / v, 4- is present as a suspension in the formulation. (7-hydroxy-2-isopropyl-4-oxo-4H-quinazoline-3-yl)-be Nzonitrile (compound I) or its salts, cocrystals, or polymorphs, Nonionic surfactants; Suspending agent; Isotonic agent; Buffering agent; salt; and This is a formulation that includes a preservative, chosen at the discretion of the user.

[0126] In some embodiments, the invention described herein is 4-(7-hydroxy-2-isopropyl alcohol) in amounts of approximately 0.5% w / v to approximately 3.5% w / v Pyr-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or so Salts, cocrystals, or suspensions of polymorphs of Nonionic surfactants; Suspending agent; Isotonic agent; Buffering agent; salt; Preservatives by choice; and This is a formulation containing up to 100% QS water.

[0127] In some embodiments, the invention described herein is 4-(7-hydroxy-2-isopropyl alcohol) in amounts of approximately 0.5% w / v to approximately 2.5% w / v Pyr-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or so Salts, cocrystals, or suspensions of polymorphs of Tyroxapol, poloxamer, or in amounts of approximately 0.01% w / v to 0.2% w / v Nonionic surfactants selected from these combinations; Hydroxypropyl methylcellulose, polyethylene glycol, or carbomer homopoly A suspending agent selected from type B; An isotonic agent selected from polyols in an amount of approximately 0.05% w / v to approximately 10% w / v; Buffers selected from edetates, phosphates, borates, or combinations thereof; salt; and Contains up to 100% qs of water; and This formulation contains a pH range of approximately 5.5 to 8.0.

[0128] In some embodiments, the invention described herein is Approximately 0.5% w / v, approximately 1.0% w / v, approximately 1.5% w / v, approximately 2.0% w / v, or approximately 2 4-(7-hydroxy-2-isopropyl-4-oxo-4H in 0.5% w / v -Quinazolin-3-yl)-benzonitrile (compound I) or its salt, cocrystal, or Suspension of polymorphs, Tyroxapole at concentrations of approximately 0.04% w / v to approximately 0.06% w / v, approximately 0.005% Poloxamers at w / v ~ 0.12% w / v, or selected from combinations thereof. nonionic surfactants; Hydroxypropyl methylcellulose in amounts of approximately 0.1% w / v to approximately 0.8% w / v% Polyethylene glycol in amounts of approximately 2% w / v to approximately 8% w / v, approximately 0.05% w / Carbomer homopolymer type B, or a combination thereof, in an amount of approximately 0.5% w / v A suspending agent selected from among; Selected from mannitol or glycerin in amounts of approximately 0.1% w / v to approximately 5% w / v isotonic agents; A mild solution selected from edetate, phosphate, borate, tromethamine, or a combination thereof. A shocking agent; Sodium chloride in amounts ranging from 0.01% w / v to approximately 1% w / v; up to 100% QS water, and This formulation contains a pH range of approximately 5.5 to 8.0.

[0129] In some embodiments, the invention described herein is Approximately 0.5% w / v, approximately 1.0% w / v, approximately 1.5% w / v, approximately 2.0% w / v, or approximately 2 4-(7-hydroxy-2-isopropyl-4-oxo-4H in 0.5% w / v -Quinazolin-3-yl)-benzonitrile (compound I) or its salt, cocrystal, or Suspension of polymorphs, Tyroxapole in amounts of approximately 0.04% w / v to approximately 0.06% w / v; Carbomer homopolymer type B in amounts of approximately 0.05% w / v to approximately 0.4% w / v; Glycerin in amounts of approximately 0.5% w / v to approximately 5% w / v; A mild solution selected from edetate, phosphate, borate, tromethamine, or a combination thereof. A shocking agent; Sodium chloride in amounts ranging from 0.01% w / v to approximately 1% w / v; up to 100% QS water, and This formulation contains a pH range of approximately 5.5 to 8.0.

[0130] In some embodiments, the invention described herein is Approximately 0.5% w / v, approximately 1.0% w / v, approximately 1.5% w / v, approximately 2.0% w / v, or approximately 2 4-(7-hydroxy-2-isopropyl-4-oxo-4H in 0.5% w / v A suspension of polymorph B of (-quinazolin-3-yl)-benzonitrile (compound I), Tyroxapole in amounts of approximately 0.04% w / v to approximately 0.06% w / v; Carbomer homopolymer type B in amounts of approximately 0.05% w / v to approximately 0.4% w / v; Glycerin in amounts of approximately 0.5% w / v to approximately 5% w / v; A mild solution selected from edetate, phosphate, borate, tromethamine, or a combination thereof. A shocking agent; Sodium chloride in amounts ranging from 0.01% w / v to approximately 1% w / v; up to 100% QS water, and This formulation contains a pH range of approximately 5.5 to 8.0.

[0131] In some embodiments, the invention described herein is Approximately 0.5% w / v, approximately 1.0% w / v, approximately 1.5% w / v, approximately 2.0% w / v, or approximately 2 4-(7-hydroxy-2-isopropyl-4-oxo-4H in 0.5% w / v A suspension of polymorph B of (-quinazolin-3-yl)-benzonitrile (compound I), Approximately 0.05% w / v tyroxapole; Carbomer homopolymer type B with approximately 0.2% w / v; Approximately 2.0% w / v glycerin; Tromethamine buffer; Approximately 0.05% w / v sodium chloride; and up to 100% QS water, and The formulation contains a pH range of approximately 6.4 to 8.4; The formulation does not contain preservatives.

[0132] In some embodiments, an acid such as hydrochloric acid, sodium hydroxide, or a combination thereof is used. A base is used to adjust the pH of the formulation. In certain embodiments, hydrochloric acid is used to adjust the pH. Adjust to approximately 6.0 or 7.4.

[0133] In some embodiments, the formulations described herein are aqueous, i.e., they It contains at least approximately 90%, at least approximately 92%, or at least approximately 95% water.

[0134] Without being bound by theory, the viscosity of a formulation containing carbomer homopolymer type B is pH The viscosity increases as the pH is adjusted from acidic to neutral, but decreases with increasing ionic strength. It is thought that by using tromethamine as a buffer, We found that pH increased without a substantial increase in ON intensity. Furthermore, we were not constrained by theory. Without being absorbed, the inventors also found that glycerin increases the osmotic pressure of the formulation and its ionic strength. It was found that it could be adjusted without causing any problems. Glycerin also showed sufficient tolerance and It is non-irritating and also acts as a water-retaining agent and an additional viscosity agent.

[0135] Without being bound by any particular theory, the inventors also consider interfaces in formulations. The presence of the activator acts as a wetting agent for the compound of formula I, thereby reducing the size of the particles of compound I. This provides moisture with water while reducing the possibility of irritation and foaming, and also improves the redispersibility of the suspension. They found a way to help.

[0136] In some embodiments, the formulations described herein further include additional components. In certain embodiments, the formulation is a cyclodextrin derivative, for example, β-cyclodextrin Includes trine derivatives, γ-cyclodextrin derivatives, or combinations thereof. Specific implementations In this state, cyclodextrin is hydroxypropyl β-cyclodextrin or sulfo It is an alkyl ether β-cyclodextrin. If present, cyclodextrin inducer The conductor has at least approximately 1.5 w / v%, at least approximately 3.0 w / v%, and at least approximately 3. 5 w / v% or at least approximately 4.5 w / v%, but less than or equal to approximately 10.0 w / v%, approximately 8. It is present in amounts of 0% w / v or less, approximately 6.5 w / v% or less, or approximately 5.5 w / v% or less. Obtain. In certain embodiments, the formulation contains about 5% w / v hydroxypropyl β-cyclodextrin. It contains either string or sulfoalkyl ether β-cyclodextrin.

[0137] In some embodiments, the formulation of the present invention comprises an additional therapeutic agent in addition to compound (I). Further therapeutic agents include, for example, other compounds and antibodies useful for treating ocular surface disorders. This may include: a non-exclusive list of such drugs includes ketorolac, nepafenac, Nonsteroidal anti-inflammatory drugs such as bromfenac and corticosteroids; cyclosporine, Examples of medications for dry eye conditions include Livitegrast or other TRPV1 inhibitors. In certain embodiments, additional therapeutic agents include dexamethasone, fluocinolone, and roth Prednol, Difluprednate, Fluorometholone, Prednisolone, Prednisone medrizone, triamcinolone, betamethasone, rimexolone, or a pharmaceutically acceptable thereof These are ophthalmic steroids such as salts. Such additional therapeutic agents may be included in pharmaceutical compositions. Further non-exclusive examples of therapeutic agents include Xiidra® (Refitegrast) Restasis (registered trademark) (cyclosporine), minocycline, doxycycline Examples include selenium disulfide or other tetracycline antibiotics. Examples of keratolytic agents include salicylic acid, glycolic acid, or pharmaceutically acceptable salts thereof. It can be done.

[0138] In some embodiments, the formulation is stored at a refrigerated temperature (e.g., 4°C). In some embodiments, the formulation is warmed to room temperature before administration.

[0139] In some embodiments, the suspension is packaged in single-dose containers. In this configuration, the formulation is packaged in containers containing multiple doses.

[0140] The formulations described herein may be administered 1 to 6 times daily, at the customary discretion of an experienced clinician. It is delivered to the surface of the eye. In some embodiments, the formulation is administered once, two, three, or four times a day. To be given.

[0141] In some embodiments, the formulation exhibits less than 10% precipitation after storage at room temperature for 6 months. In some embodiments, the formulation exhibits a concentration of less than 8% after storage at room temperature for 6 months. Sedimentation of less than approximately 7%, less than approximately 6%, less than approximately 5%, less than approximately 4%, less than approximately 3%, or less than approximately 2% It exhibits the following behavior. The precipitation behavior is generally known to those skilled in the art, as described herein, for example. It is measured by the method.

[0142] In some embodiments, the amount of compound I in the formulation is stored under refrigeration (e.g., about 4°C). After approximately 6 months in the tube, at least 90% of the initial amount remains. In some embodiments, in the formulation... The amount of compound I was found to be approximately 8 months, 10 months, 12 months, and 15 months after storage under refrigeration. After several months, or approximately 18 months, it is at least about 90% of the initial amount. In terms of application methods, the amount of compound I in the formulation is approximately 6 months after storage under refrigeration (e.g., about 4°C). In the first amount, at least about 91%, at least about 92%, at least about 93%, At least about 94%, at least about 95%, at least 96%, at least about 97%, or less At least approximately 98%. In some embodiments, the amount of compound I in the formulation is under refrigeration. After approximately 18 months of storage, at least about 91% of the original amount, at least about 92%, and less At least 93%, at least 94%, at least 95%, at least 96%, and less It is at least about 97% or at least about 98%. The amount of compound I in the formulation is, for example, HP Measurements are taken using methods generally known to those skilled in the art, such as LC and LC / MS.

[0143] In some embodiments, the formulation shows approximately 10% or less of degradation products after 6 months under refrigeration. The breakdown product is in a 0.1% trifluoroacetic acid (TFA) water / acetonitrile mobile phase. When analyzed by HPMC using the gradient, the relative value is 1.23 compared to compound I. It has a retention period. In some embodiments, the formulation retains about 9% or less after 6 months under refrigeration. Approximately 8% or less, approximately 7% or less, approximately 6% or less, approximately 5% or less, approximately 4% or less, approximately 3% or less, or approximately 2% Contains less than % of degradation products.

[0144] In some embodiments, less than 10% of compound I in the formulation is present at 40°C for 12 weeks. It decomposes during storage. In certain embodiments, compound I in the formulation is approximately 9% or less, approximately 8% or less. Approximately 7% or less, approximately 6% or less, approximately 5% or less, approximately 4% or less, approximately 3% or less, and approximately 2% or less at 40℃ It will be disassembled during 12 weeks of storage.

[0145] In some embodiments, the pharmaceutical formulation of the present invention includes an additional therapeutic agent in addition to compound (I). May include. Further therapeutic agents include, for example, other compounds useful for treating ocular surface disorders and This may include antibodies. A non-exclusive list of such drugs includes ketorolac and nepafena. Nonsteroidal anti-inflammatory drugs such as chlorophyll, bromfenac, and corticosteroids; cyclospolico For dry eye conditions, such as nasal mucus, refitegrast, autologous serum, or other TRPV1 inhibitors. Examples of drugs include: In certain embodiments, additional therapeutic agents include dexamethasone, fluosin, and Nolon, Loteprednol, Difluprednate, Fluorometholone, Prednisolone, Prednisone, medrizone, triamcinolone, betamethasone, rimexolone, or the same These are ophthalmic steroids such as pharmaceutically acceptable salts. These may be included in pharmaceutical compositions. Further non-limiting examples of additional therapeutic agents include Xiidra(registered trademark) (Refine Tegrast, Restasis (registered trademark) (cyclosporine), minocycline, Examples include xycycline or other tetracycline antibiotics. Other examples include: Corneal selenium disulfide, salicylic acid, glycolic acid, or pharmaceutically acceptable salts thereof. Solubilizers are one example.

[0146] Manufacturing method In some embodiments, the present invention relates to a method for preparing a pharmaceutical formulation of compound I.

[0147] In some embodiments, the formulation contains a certain amount of 4-(7-hydroxy-2-isopropyl -4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or its salt , cocrystals or polymorphs, surfactants, suspending agents, isotonic agents, buffers, preservatives, salts, It is prepared by mixing one or more excipients selected from the group consisting of and preservatives. ru.

[0148] In some embodiments, the formulation contains a certain amount of 4-(7-hydroxy-2-isopropyl -4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or its salt , cocrystal, or polymorph, Nonionic surfactants; Suspending agent; Isotonic agent; Buffering agent; salt; Preservatives by choice; and Mixing up to 100% qs of water; and It is prepared by adjusting the pH to a range of approximately 5.5 to 8.0.

[0149] In some embodiments, compound I is optionally used with a surfactant to retain water. It is added as a storage suspension. In some embodiments, compound I is added to the storage suspension. It is present in an amount of 10%. In alternative or additional embodiments, the storage suspension of compound I is further , containing 0.2% tyroxapol. In some embodiments, the storage suspension of compound I is The compound I is then ground to obtain a desired particle size. In some embodiments, the compound in the formulation is pulverized. Combined item I D 90 (The diameter of compound I, where 90% of the particles are smaller, is approximately 10 μm) Less than approximately 8 μm, less than approximately 6 μm, less than approximately 4 μm, less than approximately 3 μm, or approximately 2 μm. In some embodiments, the D of compound I in the formulation 50 (50% of compound I is smaller) The diameter of the particles is approximately less than 10 μm, less than 8 μm, less than 6 μm, and less than 4 μm. The particle size is full, less than approximately 3 μm, less than approximately 2 μm, or approximately 1 μm. In some embodiments, the formulation Compound I inside D 10 (The diameter of compound I, where 10% of the particles are smaller) is approximately 5 Less than μm, less than approximately 4 μm, less than approximately 3 μm, less than approximately 2 μm, less than approximately 1 μm, or approximately 0.3 μm It is m.

[0150] In some embodiments, a 10% w / v slurry of compound I is placed on a roller mill for about 6 minutes. The material is ground in a ball mill at 0 rpm for approximately 2 or 3 hours.

[0151] In certain embodiments, nonionic surfactants, suspending agents, isotonic agents, buffering agents, and salts are used. As described above. In some embodiments, the formulation does not contain preservatives.

[0152] An exemplary method for preparing a 1.5% w / v compound I suspension is described below. 1. Along with polybutylene terephthalate, PTFE-lined cap, and magnetic stirrer Tare weight of a clean, dry glass Schott bottle. 2. Put a batch amount of Compound I solvent (containing a suspending agent, isotonic agent, surfactant, and salt) into the bottle. Add (the pH has been adjusted to the final pH). Seal and sterilize the mixing container with steam (F 0≧30). 3. Transfer the container to a horizontal laminar flow workbench and allow it to cool. 4. Aseptically weigh the batch amount of sterile 10% compound I / 0.2% surfactant into a mixing container. Add. If necessary, sterilize (either steam sterilization or sterile filter) purified water qs and Adjust to the final batch weight and stir until uniform. 5. Fill a sterile dispensing bottle with the 1.5% suspension aseptically. Insert the suspension tip and twist until firm. Tighten the screws, insert the chip, and seal it. 6. Remove the filled units from the laminar flow workbench and label them. Final pH and Measure the gravimetric osmolality.

[0153] How to use Without being constrained by theory, transient receptor potential vanilloid 1 (TRPV1) blockers are It is hypothesized that it may be useful in treating pain, such as chronic pain.

[0154] Therefore, in some embodiments, the present invention relates to ocular surface pain in the target area. A method is provided for treating the following, the method comprising an effective amount of compound (I), or its pharmaceutically acceptable This includes administering a salt, solvate, or cocrystal to the target. In some embodiments, The present invention provides a method for reducing ocular surface pain in the target area, and the method an effective amount of compound (I), or a pharmaceutically acceptable salt, solvate, or cocrystal thereof This includes administering to a target. In some embodiments, the present invention is used for the treatment of ocular surface pain. The use of a compound of formula I, or its pharmaceutically acceptable salt, solvate, or cocrystal. Provided. In some embodiments, the compound of formula I is polymorphic form B. Specific implementations In this configuration, the method described herein is performed by administering a formulation of compound I described above. Therefore, the present invention provides a formulation of compound I as described herein. This provides a method for treating ocular surface pain by doing so. In certain embodiments, the method involves multiple This involves administering a formulation containing compound I as form B.

[0155] In some embodiments, the subject suffers from accidental or acute ocular pain. In that embodiment, the subject suffers from chronic ocular surface pain that has lasted for at least 3 months. In some embodiments, the subject suffers from chronic ocular surface pain that has lasted for at least two months. In some embodiments, the subjects suffer from chronic ocular surface pain lasting 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 diagnosed with chronic ocular surface pain lasting at least 5 months. He is afflicted. Therefore, in some embodiments, the present invention provides an effective amount of the compound of formula I. By administering either its salt, solvate, polymorph, or cocrystal to the target, The present invention provides a method for treating chronic ocular surface pain. In some embodiments, the present invention provides a method for treating chronic ocular surface pain. An effective amount of the compound of formula I, or its salt, solvate, polymorph, or cocrystal, is administered to the target. This invention provides a method for reducing chronic ocular surface pain in the subject. Compounds of formula I, or pharmaceutically acceptable salts, solvates thereof, in the treatment of ocular surface pain. The use of a form or cocrystal is provided. In some embodiments, the compound of formula I is used It is contained in the formulation as described in the specification. In a particular embodiment, the method is as follows: The administration is a preparation containing compound I.

[0156] In some embodiments, the formulation is applied to the target ocular surface, for example, the cornea, conjunctiva, or cornea of ​​the eye. It is administered to any part of the sac.

[0157] In some embodiments, the present invention provides ocular ophthalmos with concentrations ranging from about 0.5% w / v to about 3.5% w / v. This provides the administration of the compound of formula I to the target population in a scientifically suitable formulation. In some embodiments, the concentration for administration is approximately 0.5% w / v to approximately 3.5% w / v, approximately 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 ~ The range is approximately 3.0% w / v, and approximately 0.5% w / v to approximately 2.5% w / v. Several implementations Morphologically, the concentration of compound I in ophthalmologically suitable formulations is at least approximately 0.5% w / v. At least about 1.0% w / v, at least about 1.5% w / v, at least about 2.0% w / v, or at least about 2.5% w / v. In some embodiments, local use The concentration of compound I in the formulation is approximately 5.0% w / v or less, and approximately 4.5% w / v or less. It is approximately 4.0% w / v or less, approximately 3.5% w / v or less, or approximately 3.0% w / v or less. In this embodiment, the concentration of compound I in the 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 The concentration is 0.0% w / v, or approximately 3.5% w / v. In some embodiments, the dose is administered per eye. The dosage per serving is approximately 0.15 to 1.15 mg, or approximately 0.15 mg, 0.2 mg, or 0 .25mg, about 0.3mg, about 0.35mg, about 0.4mg, about 0.45mg, about 0.5 mg, about 0.55mg, about 0.6mg, about 0.65mg, about 0.7mg, about 0.75mg Approximately 0.8 mg, approximately 0.85 mg, approximately 0.9 mg, approximately 0.95 mg, approximately 1.0 mg, approximately 1 The amount is 0.05 mg, approximately 1.1 mg, or approximately 1.15 mg. In some embodiments, the ophthalmic patch The dosage per administration is approximately 0.18 mg, 0.37 mg, 0.55 mg, and 0. 74 mg, or approximately 0.92 mg. In some embodiments, the total daily dose per eye is The dosage is approximately 0.5 to 3.5 mg, or approximately 0.5 mg, 1.0 mg, 1.5 mg, and 2 mg. The amounts are 0.0 mg, approximately 2.5 mg, approximately 3.0 mg, or approximately 3.5 mg. Several embodiments The compound of formula I is administered to the subject 1 to 6 times a day, for example, 1, 2, 3, or 4 times a day. In some embodiments, the compound of formula I is used for at least about 1 month, at least about 2 months. It is administered to the subject for a period of months, or at least about 3 months. In some embodiments, Formula I The compound is administered to the subject for at least approximately 12 weeks.

[0158] In some embodiments, ocular surface pain or chronic ocular surface pain is a dry eye disease, shank Glenn's syndrome, conjunctivitis (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), corneal ulcers Dermose-basement membrane dystrophy, Acanthamoeba disease, fibromyalgia, meibomian gland dysfunction, thyroiditis Adenopathy, rosacea, ptosis, keratoconus, ocular pain syndrome, Stevens-Johnson syndrome , corneal epithelial disease, corneal neuropathy (including LASIK-induced corneal neuropathy), corneal dystrophy (including recurrent corneal dystrophy), epithelial basement membrane dystrophy, corneal erosion, etc. This includes corneal abrasions (including recurrent corneal erosions or corneal abrasions), ocular surface diseases, blepharitis, Graft-versus-host disease, meibomian gland inflammation, glaucoma, conjunctival laxity, keratopathy (herpetic keratopathy, filiform keratopathy) (including membranous keratopathy, shingle or bullous keratopathy, lagophthalmic keratopathy), keratitis (herpes simplex virus keratopathy) (including corneal inflammation), iritis, episcleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, nerve The patient is experiencing one or more of the following: pain, dry eyes, or recovery from neurotrophic keratitis.

[0159] In certain embodiments, ocular surface pain or chronic ocular surface pain is a dry eye disease or sjögren's disease. It is associated with Lenn syndrome. In some embodiments of the methods described herein, the subject is Lenn syndrome. After refractive keratotomy (PRK) or laser corneal reshaping (LASIK) surgery, I have been suffering from eye pain that has lasted for at least three months.

[0160] In some embodiments, the subject is conjunctivitis, subconjunctival hemorrhage, subconjunctival scarring, conjunctival membrane, conjunctiva Ulcer, punctate superficial epithelial erosion, epithelial defect, eyelid margin ulcer, eyelid margin keratinization, eyelid bulb adhesion, eyelid adhesion, Trichiasis, anterior blepharitis, punctal occlusion, meibomian gland disease, corneal opacity, dry eye They suffer from trichiasis, corneal margin stem cell deficiency, or corneal neovascularization.

[0161] In some embodiments, administration of the compound of formula I compared with placebo resulted in the target ocular pain. This results in a reduction in pain. In some embodiments, the reduction in ocular pain in the subject is When measured on a VAS score, it is at least about 3 compared to placebo. In this embodiment, the dose, when measured on the VAS score, is less than that of placebo. At least about 4, at least about 5, at least about 6, at least about 7, at least about 8, less It results in a reduction in ocular pain in at least 9, or at least 10, of the subjects. In this embodiment, administration is performed approximately 1 hour, 2 hours, or 2-4 hours after administration, with the placebo and Compared to that, at least about 10%, at least about 15%, at least about 20%, or less Both result in a reduction in pain in approximately 25% of subjects. In some embodiments, administration is When measured 7 days after administration of the compound of formula I, it results in a reduction in the subject's pain. In some embodiments, the administration is measured 14 days after administration of the compound of formula I, and the target This results in a reduction in pain.

[0162] In some embodiments, administration of the compound of formula I is measured by the VAS score approximately 30 minutes after administration. When measured, it shows a reduction in pain in at least approximately 2 subjects compared to placebo. To drip.

[0163] In some embodiments, the reduction in pain score is observed prior to administration of compound I to the subject. This arises from the difference in pain scores between the two. In some embodiments, it is measured by a VAS. The reduction in pain scores was due to the difference in VAS scores before and after administration of compound I to the subjects. This results from. In some embodiments, the reduction in the VAS score is due to the target of compound I. This occurs within approximately 30 minutes after administration. In some embodiments, the reduction in pain score is Approximately 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or approximately after administration of compound I to the target. It occurs within 6 hours. In some embodiments, the administration is 7 days after administration of the compound of formula I. When measured, it results in a reduction in the pain of the subject. In some embodiments, the administration When measured 14 days after administration of the compound of formula I, it results in a reduction in the subject's pain. .

[0164] In some embodiments, administration of the compound of formula I is performed to meet at least one of the questions of OPAS. In contrast, an improvement of at least approximately 10%, at least approximately 20%, or at least approximately 30% of the score It brings good.

[0165] In some embodiments, administration of a compound of formula I is performed on at least one visual work questionnaire. For each question, at least about 10%, at least about 20%, or at least about 30% It will lead to an improvement in the score.

[0166] In some embodiments, administration of the compound of formula I resulted in ocular congestion (eye congestion) compared to placebo. It results in a reduction of redness. In some embodiments, administration of the compound of formula I is compared to placebo. Compared to other methods, it shows a reduction in ocular redness of grade 1, grade 2, grade 3, or grade 4. In some embodiments, the dose is less than the McMonnies scale. Each eye is approximately 1, at least 2, at least 3, at least 4, or at least 5. This results in a reduction in the congestion score.

[0167] Therefore, in some embodiments, the present invention treats ocular congestion in the subject requiring treatment. A method for treating or reducing a compound of formula I, or its salt, solvate, polymorph, Alternatively, the present invention relates to a method that includes administering a cocrystal to a target. Dosage of compound I is at least approximately 1 on the McMonnies scale, at least approximately 2. A reduction in ocular congestion of at least approximately 3, at least approximately 4, or at least approximately 5. In some embodiments, the present invention relates to the treatment or reduction of ocular congestion using compounds of formula I. The use of a pharmaceutically acceptable salt, solvate, or cocrystal thereof is provided. In one embodiment, the present invention provides ophthalmologically suitable solutions at concentrations of approximately 0.5% w / v to approximately 3.5% w / v. The formulation provides administration of the compound of formula I to the target subject as required. In the embodiment, the concentration for administration is approximately 0.5% w / v to approximately 3.5% w / v, approximately 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 ~ approx. 3.0 %w / v, in the range of approximately 0.5%w / v to approximately 2.5%w / v. In a particular embodiment, the station The concentration of compound I in formulations for local use is approximately 0.5% w / v, approximately 1.0% w / v. v, approximately 1.5% w / v, approximately 2.0% w / v, approximately 2.5% w / v, approximately 3.0% w / v, or It is approximately 3.5% w / v. In some embodiments, the dose per eye is approximately 0.15 to approximately 1.15 mg, or approximately 0.15 mg, 0.2 mg, approximately 0.25 mg, 0.3 mg, about 0.35mg, about 0.4mg, 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 0.85mg, approximately 0.9mg, approximately 0.95mg, approximately 1.0mg, approximately 1.05mg, approximately 1.1 The dose per eye is mg, or approximately 1.15 mg. In some embodiments, the dose per eye is The amounts are approximately 0.18 mg, 0.37 mg, 0.55 mg, 0.74 mg, or 0. The dose is 92 mg. In some embodiments, the total daily dose per eye is approximately 0.5 to approximately 3 0.5 mg, or approximately 0.5 mg, approximately 1.0 mg, approximately 1.5 mg, approximately 2.0 mg, approximately 2.5 mg The amount is approximately 3.0 mg or 3.5 mg. In some embodiments, the compound of formula I is used. It is administered to the subject 1 to 6 times a day, for example, 1, 2, 3, or 4 times a day. Several implementations In terms of form, the compound of formula I lasts for at least about 1 month, at least about 2 months, or at least The drug is administered to the subject for a period of approximately 3 months. In certain embodiments, the compound of formula I is described herein. It is administered in the listed formulation.

[0168] In some embodiments, conjunctivitis is associated with dry eye disease, Sjögren's syndrome, and conjunctivitis. (including keratoconjunctivitis, vernal keratoconjunctivitis, and allergic conjunctivitis), corneal epithelial basement membrane dystrophy Acanthamoeba, fibromyalgia, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, Keratoconus, ocular pain syndrome, Stevens-Johnson syndrome, corneal epitheliopathy, corneal nerve Disorders (including LASIK-induced corneal neuropathy), corneal dystrophy (recurrent corneal dystrophy) (including Lophii), epithelial basement membrane dystrophy, corneal erosion or corneal abrasion (recurrent) (including corneal erosion or abrasion), ocular surface diseases, blepharitis, graft-versus-host disease, meibomian disease Gland inflammation, glaucoma, conjunctival laxity, keratopathy (herpes zoster keratopathy, filamentous keratopathy, zoan or bullous keratopathy) (including lagophthalmos, lagophthalmos), keratitis (including herpes simplex virus keratitis), iritis, Epicleritis, corneal surgery, multiple sclerosis, trichiasis, pterygium, neuralgia, xerophthalmoplegia, or neuropathy. One or more patients recovering from transtrophic keratitis. In certain embodiments, the eye Conjunctivitis is associated with dry eye disease. In some embodiments of the methods described herein, Eye redness can be treated with laser refractive keratotomy (PRK) or laser corneal reshaping (LAS). IK) Lasts for at least 3 months after surgery.

[0169] In some embodiments, ocular surface pain or chronic ocular surface pain is accompanied by dry eye disease. In some embodiments, administration of the compound of formula I reduces the symptoms of dry eye disease. It causes. Dry eye disease generally involves inflammation of the ocular surface and lacrimal glands, as well as the quality and / or quantity of tears. It is understood to be a complex and multifactorial pathological condition characterized by a reduction in [unclear]. Up to 30% of patients with eye disease have a chronic condition, meaning they have been ill for at least 12 weeks or 3 months. It is thought that you are suffering from persistent ocular surface pain. Therefore, several In embodiments, the present invention addresses dry eyes, eye discomfort, eye redness, burning or stinging sensations in the eyes, and nausea. In the symptoms of dry eye disease, including one or more of the following: flaccidity, foreign body sensation, or photophobia. This will result in a reduction of at least approximately 10%.

[0170] In some embodiments, the present invention treats dry eye disease in the target population. A method for obtaining an effective amount of the compound of formula I, or its salt, solvate, polymorph, or compound The present invention relates to a method including administering to crystals. In some embodiments, the present invention is necessary A method for treating dry eye disease in a subject, comprising an effective amount of the compound of formula I, The present invention relates to a method that involves administering a salt, solvate, polymorph, or cocrystal thereof to a target, The compound of formula I lasts for at least 2 months, at least 3 months, at least 4 months, or less Both are safe for administration over a period of 5 months. In certain embodiments, the present invention is dry Compounds of formula I, or pharmaceutically acceptable salts, solvates thereof, in the treatment of eye diseases The invention provides the use of cocrystals. In some embodiments, the present invention addresses dry eyes and eye discomfort. One of the following: eye redness, eye burning or stinging, roughness or foreign body sensation, or photophobia. In the symptoms of dry eye disease including the above, at least about 10%, at least about 15%, and a small percentage. This results in a reduction of at least approximately 20%, or at least approximately 30%. In some embodiments, The present invention relates to a formulation that is ophthalmologically suitable at a concentration of approximately 0.5% w / v to approximately 3.5% w / v. The present invention provides the administration of a compound of formula I to a target that requires administration. In some embodiments, The recommended concentrations for administration are approximately 0.5% w / v to 3.5% w / v, and approximately 0.5% w / v to 2.5% w / v. %w / v, approx. 0.5%w / v ~ approx. 1.5%w / v, approx. 0.5%w / v ~ approx. 3.0%w / v , about 1.0%w / v~about 2.5%w / v, about 1.5%w / v~about 3.0%w / v, about 0. The range is 5% w / v to approximately 2.5% w / v. In certain embodiments, for local use... The concentrations of compound I in the formulation are approximately 0.5% w / v, approximately 1.0% w / v, and approximately 1.5% w / v. / v, approximately 2.0% w / v, approximately 2.5% w / v, approximately 3.0% w / v, or approximately 3.5% w / v In some embodiments, the dose per eye is approximately 0.15 to approximately 1. 15 mg, or approximately 0.15 mg, 0.2 mg, approximately 0.25 mg, 0.3 mg, approximately 0.35 mg mg, about 0.4mg, about 0.45mg, about 0.5mg, about 0.55mg, about 0.6mg, Approx. 0.65mg, approx. 0.7mg, approx. 0.75mg, approx. 0.8mg, approx. 0.85mg, approx. 0 0.9 mg, approximately 0.95 mg, approximately 1.0 mg, approximately 1.05 mg, approximately 1.1 mg, or approximately 1. It is 15 mg. In some embodiments, the dose per eye is approximately 0.18 This is approximately mg, 0.37 mg, 0.55 mg, 0.74 mg, or 0.92 mg. In some embodiments, the total daily dose per eye is approximately 0.5 to approximately 3.5 mg, or approximately 0.5mg, approximately 1.0mg, approximately 1.5mg, approximately 2.0mg, approximately 2.5mg, approximately 3.0mg , or about 3.5 mg. In some embodiments, the compound of formula I is taken 1 to 6 times a day. For example, it is administered to the subject once, two, three, or four times a day. In some embodiments, Formula I The compound is tested for a period of at least approximately 1 month, at least approximately 2 months, or at least approximately 3 months. It is administered to elephants. In some embodiments, the compound of formula I is used in the formulation described herein. It is administered as such.

[0171] In some embodiments of the methods described herein, the administration of the compound of formula I is a placebo. Compared to B, the best corrected visual acuity, slit-lamp biomicroscopy, pupil dilation, blinking speed, and tear production were measured. No change in one or more of the following (e.g., difference of less than 5%) A difference of less than 4%, or a difference of less than 3%. In some embodiments of the methods described herein In patients requiring it, administration of the compound of formula I promotes wound healing compared to placebo. It does not cause delays.

[0172] Patient group In certain embodiments, the subject to be treated by the method described herein is , suffering from ocular surface disorders. Non-specific examples of ocular surface disorders include chronic ocular pain (C OSP), dry eye disease, Sjögren's syndrome, conjunctivitis (keratoconjunctivitis, vernal keratoconjunctivitis, etc.) (including allergic conjunctivitis), corneal epithelial basement membrane dystrophy, Acanthamoeba, fibromuscular Pain disorders, meibomian gland dysfunction, thyroid eye disease, rosacea, ptosis, keratoconus, ocular pain syndrome, Stevens-Johnson syndrome, corneal epithelial disease, corneal neuropathy (LASIK-induced corneal neuropathy) (including neuropathy), corneal dystrophy (including recurrent corneal dystrophy), epithelial basal Membrane dystrophy, corneal erosion or corneal abrasion (recurrent corneal erosion or corneal abrasion) (Including injuries), ocular surface diseases, blepharitis, graft-versus-host disease, meibomian gland inflammation, glaucoma, conjunctival laxity Diseases, keratopathy (including herpes zoster keratopathy, filamentous keratopathy, zoan or bullous keratopathy, and lagophthalmos) , keratitis (including herpes simplex virus keratitis), iritis, episcleritis, corneal surgery, multiple Recovering from sclerosis, trichiasis, pterygium, neuralgia, xerophthalmos, or neurotrophic keratitis Patients who have undergone laser refractive keratotomy are among those who have undergone the procedure. In some embodiments, the subject is a patient who has undergone laser refractive keratotomy. Persisting for at least 3 months after PRK surgery or LASIK surgery I am suffering from eye pain.

[0173] In certain embodiments, the method provided herein relates to ocular surface pain such as acute ocular surface pain. It is intended to treat or reduce the condition.

[0174] In certain embodiments, the methods provided herein are used for chronic ocular surface pain (COSP), etc. This is for treating or reducing ocular surface pain. In certain embodiments, COSP This may distract from or interfere with normal daily activities. It is characterized as persistent ocular surface pain (e.g., persistent severe ocular surface pain). In the embodiment, COSP may result in an insufficient quality of life, and at least one Month, at least two months, at least three months, at least four months, at least five months, or It can last for at least 6 months. In some embodiments, COSP lasts for at least about 2 months. Or it may last for at least about 3 months. In other embodiments, COSP may last for at least 3 months or This can last for at least four months. In certain embodiments, objects having COSPs are those In the case of underlying diseases (for example, ocular surface disorders such as dry eye disease or Sjögren's syndrome) Symptoms persist despite being suitable for other therapies that have been indicated as necessary.

[0175] In some embodiments, the subject to be treated is ocular neuropathic pain (ONP). He suffers from ONP. ONP can result from a disorder or disease affecting the nerves, such as the corneal nerve. It is a series of disorders of sexual pain. Symptoms of ONP include eye pain, photophobia, hyperalgesia or dry eyes. Abnormal sensations such as dryness, stinging, or the feeling of a foreign body (perceptual abnormalities), or stimuli that do not normally cause pain. This may include one of the abnormalities of pain (allodynia) caused by gabapentin and others. These neuropathic pain medications can be used to numb sensory nerve stimulation or the sensation of nerve stimulation. .

[0176] In some embodiments, the subject to be treated is suffering from lagophthalmos. EK is corneal damage resulting primarily from prolonged exposure of the eye surface to the external environment. EK can result in permanent vision loss from ulcers, microbial keratitis, and scarring. Patients at risk of K include those with incomplete eyelid closure (e.g., lagophthalmos, exophthalmos, or palpebral ophthalmos). (Positional abnormalities), insufficient blink reflex, insufficient blinking speed (e.g., neurological disorders, e.g., Parkinson's disease, neuromuscular diseases (caused by these conditions) and / or protective lubrication of the cornea Patients suffering from conditions that impair the corneal protective ability due to any of the following factors are listed. Symptoms of EK include a foreign body sensation, burning sensation, increased tearing, and intermittent blurred vision (anxiety). Symptoms include pain and photophobia (caused by a persistent tear film). Standard treatment involves nighttime lubricating ointment. Frequent use of artificial tears and punctal plugs is one example.

[0177] 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. It is an inflammation of the superficial layer of the cornea (keratitis). It generally 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. • Dry keratoconjunctivitis is caused by inflammation resulting from dryness; Vernal keratoconjunctivitis (VKC) occurs seasonally and is thought to be caused by allergens; Atopic keratoconjunctivitis is one of the symptoms of atopic dermatitis; • Epidemic keratoconjunctivitis or adenoviral keratoconjunctivitis is caused by adenovirus infection. To be overtaken; Bovine infectious keratoconjunctivitis (IBK) is caused by the bacterium Moraxella bovis. It is a disease affecting cattle caused by bovis; Pink eyes in sheep and goats are mainly caused by Chlamydophila pecorum. Caused by (dophila pecorum); • Ligumic keratoconjunctivitis is thought to be caused by organic trauma; • Keratoconjunctivitis and photoophthalmia (arc eye) are inflammations caused by photoelectric UV light. It tastes good.

[0178] In some embodiments, the subject to be treated suffers from dry eye. As used herein, the term “dry eye” means insufficient tear production and / or abnormal tear production. This refers to the composition of the tear film. Conditions include dry eye syndrome, keratoconjunctivitis sicca, or keratitis sicca, or tear film dysfunction. Dry eye syndrome (DEDS), also known as the syndrome or burning eye syndrome, is a condition in which the tear film... It is caused by a defect in one of the layers. Dry eye is characterized by the loss of homeostasis of the tear film. Furthermore, discomfort, visual impairment, and tear film instability may occur due to potential damage to the ocular surface accompanied by ocular symptoms. It is a multifactorial disease of the tear film and ocular surface that presents qualitative symptoms, and here, tear film instability and high Osmotic pressure, inflammation and damage to the ocular surface, and neurosensory abnormalities play a role in the pathogenesis. (Non-patent document 7) This is accompanied by an increase in the molar osmotic pressure of the tear film and inflammation of the ocular surface. In some cases, dry eye disorders can range from mild to moderate to severe. Symptoms of Lyai syndrome include roughness, foreign body sensation, burning sensation, photophobia, and decreased vision. , tearing, stinging, itching, sandy or gritty feeling, discharge from the eye, frequent blinking, pus or Solidification (usually worsens upon waking), redness, blurred vision or vibrational vision (reading, computer, (Worsens when watching TV, driving, or playing video games), photosensitivity, eye pain, and Symptoms include eye strain, headache, heavy eyelids, and eye fatigue. Causes of dry eye disease include the following: These include, but are not limited to: unexplained causes, congenital antearrhea, and xerophthalmoplegia. , lacrimal gland excision, and removal of sensory nerve innervation; rheumatoid arthritis, Wegener's granulomatosis, and systemic erythema Collagen disease vascular disorders including erythematosus; Sjögren's syndrome and Sjögren's syndrome Autoimmune diseases associated with it; abnormalities in the lipid tear film caused by blepharitis or rosacea; vitamins Mucinous tear film abnormalities caused by A deficiency; trachoma, diphtheriae keratoconjunctivitis Skin and mucous membrane disorders; aging; menopause; and diabetes. Dry eye as defined herein. Signs and / or symptoms may also be triggered by other circumstances, including but not limited to the following: May be triggered by: prolonged visual work; computer work; being in a dry environment Things; warm or cold air or airflow; seasonal changes; eye irritation; contact lenses, LAS IK and other refractive surgery; fatigue; and isotretinoin, sedatives, diuretics, tricyclic antidepressants. Antihypertensive drugs, oral contraceptives, antihistamines, nasal congestion decongestants, beta-blockers, phenotia Drugs such as din, atropine, and analgesic opioids like morphine.

[0179] Diagnostic tests for dry eye include, for example, a cotton swab or, more precisely, a cotton swab. Evaluation of corneal sensory function using a Bonnet sensory meter (corneal hypersensitivity and / or decreased sensation are , which may be present in severe and chronic dry eye diseases; for example, without preservatives Fluorescein permeable flakes or fluorescein drops moistened with physiological saline solution are required. Measurement of tear film breakup time using a more objective computer-based method that is not necessary; for example The ocular surface is stained with sodium fluorescein, rose bengal, and lysamine green. Implementation; implementation of the Schirmer test (patients with mild dry eye are relatively insensitive) (Aspects of tear clearance delay); examination of tear meniscus height; measurement of MMP-9 level (MMP-9 has been shown to be elevated in the tears of patients with dry eye disease.) (The level correlates with test results in patients with moderate to severe dry eye.) Measurement of molar osmotic pressure concentration of tear film and interferometry of the tear film; Sjo test ( SS-A (anti-Ro) and SS-B (anti-La) antibodies in serum, salivary gland protein 1 (SP- 1) Carbonic anhydrase 6 (CA6), and parotid secretory protein (PSP), SP-1, C Includes A6 and PSP detection.

[0180] Artificial tears, lubricating ointments, corticosteroids (e.g., Loteprednol 0 4 times a day) 0.5% eye drops are used as the first-line treatment. Prescription medications include cyclosporine, ri Phytegalast, diquafosol, levamepide, corticosteroids (for example, 4 times a day) Examples include Loteprednol 0.5% eye drops.

[0181] The term "lacrimal membrane dysfunction" refers to a condition where the lacrimal membrane is ruptured in different locations on the cornea and conjunctiva. This refers to a state that causes not only symptoms of stimulation 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, sandy or gritty feeling, tingling, or Symptoms include a foreign body sensation, discharge from the eye, frequent blinking, pus or hardening of the eyelashes (usually worsening upon waking), Redness, blurred vision, or vibrational vision (when reading, using a computer, watching television, driving, or playing video games). Symptoms worsen when doing [something], photosensitivity, eye pain and / or headache, eyelid heaviness, and eye strain. It can be listed.

[0182] Adenovirus keratoconjunctivitis, also known as epidemic keratoconjunctivitis, is a common and highly contagious disease. It is a viral infection of the eye. The clinical course of adenoviral keratoconjunctivitis involves the cornea. It is divided into an acute phase with conjunctivitis of varying degrees, with or without corneal opacity, and a chronic phase with corneal opacity. It gets kicked.

[0183] Vernal keratoconjunctivitis (VKC) is characterized by severe itching, photophobia, foreign body sensation, and mucous discharge ("sticky" discharge) from the eyes. (Often described as such), an eye characterized by symptoms consisting of blepharospasm and blurred vision. It is an atopic condition of the outer surface ((Non-Patent Document 8); (Non-Patent Document 9)). Although bilateral, it can actually be asymmetrical. This occurs in a seasonal pattern in hot, dry climates. It typically affects young men; 23% of patients may have a form that persists throughout the four seasons. ((Non-patent document 9); (Non-patent document 10)).

[0184] The signs of corneal keratitis (VKC) can be divided into signs of the conjunctiva, corneal margin, and cornea: Conjunctival signs include diffuse conjunctival hyperemia and a discrete upper tarsal plate with a diameter exceeding 1 mm. Large nipples are one example; Signs of corneal margin include thickening and opacity of the corneal margin and conjunctiva, as well as the appearance and time of gelatinous tissue. Examples include the occurrence of dense corneal marginal papillae. Horner-Trantus points on the surrounding corneal margin are These are localized white spots on the corneal margin consisting of altered epithelial cells and eosinophils ((Non-Patent Document 8)). ; Corneal signs vary depending on the severity of the disease process, including large erosions, corneal ulcers, and scars. Includes traces ((Non-Patent Document 8)).

[0185] Patients with ongoing corneal keratitis (photophobia, corneal sphincter on the upper tarsal conjunctiva, or cornea clearly recognizable during examination) (Defined as moderate to severe ocular discomfort including horner's-trantus points at the rim) A significant increase in symptoms and signs of ocular surface disease was observed. Inactive VKC patients (asymptomatic or (Defined as mild discomfort and no corneal abnormalities at the time of testing) includes photophobia and conjunctivitis. Increased lysamine green staining and Schirmer test values, and during destruction by fluorescein. It showed decreased BUT and corneal sensitivity. This syndrome affects tear film stability and epithelial cell unity. When abnormalities in corneal nerve function are detected, all stages (progressing and quiescent states) are identified. ) appears to be affecting the surface of the eye ((Non-Patent Document 11)).

[0186] The following factors are thought to play a role in VKC: IgE-mediated mast cell release; activated eosin. Spheres, mononuclear cells and neutrophils, as well as immunomodulatory substances such as IL-4, IL-5, and bFGF Mediating the reaction via the hypersensitivity of CD4 T-helper-2 driven type IV ((non-patented) Reference 8); (Non-patent reference 9); (Non-patent reference 12)).

[0187] Treatment consists of cold compresses and eyelid washing, and saline eye drops, local antihistamines, Nonsteroidal anti-inflammatory drugs or corticosteroids, for example, low-absorption corticosteroids ( Fluorometholone, loteprednol, rimexolone, etc.), topical mast cell stabilizers ( Romolin sodium, nedocromil sodium, and rhodoxamide), topical cyclospoli It may help alleviate symptoms when used with N-A or tacrolimus. For example, (non-patent document) References 13): (Non-Patent Document 14); (Non-Patent Document 15); (Non-Patent Document 16) were consulted. stomach.

[0188] Atopic keratoconjunctivitis (AKC) usually develops before the age of 10 due to venous keratoconjunctivitis (VKC), but is more common in those aged 20- It has a higher age of onset, typically 50 years old. Conjunctival complications are classically seen in VKC, involving the upper tarsal plate and A In KC, it occurs in the lower tarsal plate. AKC is usually more chronic and more commonly occurs in the corner. It causes scarring of the membrane and conjunctiva.

[0189] Sjögren's syndrome (Sjögren's syndrome with dry eyes) is often a severe form of dry eye syndrome. It is characterized by dysfunction of exocrine glands, including the salivary and lacrimal glands, which causes lycoagulation. It is a chronic inflammatory disorder. The main symptoms are dry eye (keratitis sicca or keratoconjunctivitis sicca) and This is dry mouth (xerostomia). Severe dry eye can cause corneal pain, corneal scarring, ulcers, infection, and These can cause perforation. Differential diagnosis includes adult blepharitis, dry eye disease, and juvenile Arthritis of unknown cause, uveitis, and keratopathy, such as punctate superficial keratopathy and fibrous keratopathy. This includes conditions such as membranous keratopathy, neuropathic keratopathy, and lagophthalmic keratopathy. Treatment for Sjögren's syndrome is , maintaining the integrity of the tear film by preserving, enhancing, and / or supplementing insufficient tear secretion. It is directed towards them. Therefore, the treatment for Sjögren's syndrome includes artificial tears and lubricating ointments. Autologous serum eye drops; Oral omega-6 essential fatty acids; Fluid-permeable, gas-permeable scleral lenses Topical corticosteroids; punctal occlusion to reduce tear drainage; minor lateral tarsal plate Suturing; humidification of the environment; hydrophilic bandage lenses; bromhexine and 3-isobutyl-1 - Methylxanthine (IBMX) (enhances tear production / secretion); stimulates muscarinic receptors. Drugs (pilocarpine and cevimeline); immunosuppressants, such as methotrexate, anti-immunotherapy. Lariatic drugs, cyclophosphamide, leflunomide, or tumor necrosis factor (TNF), for example, Infliximab, a monoclonal antibody against TNF-alpha; cyclosporine A; Bandage contact lenses are one example.

[0190] Stevens-Johnson syndrome (SJS) is a skin emergency or a condition affecting 1% of the total surface area. One type characterized by the presence of vesicular lesions of the epithelium and mucosa, including less than 0%. This is a severe skin reaction. The initial symptoms of SJS include fever and flu-like symptoms, and This may precede or occur simultaneously with the onset of maculoplasty, including on the body and face. As it progresses, the macules gather together, the affected areas develop into blisters, and eventually the epithelial layer is removed. During the acute phase of SJS-TEN, 80% of patients will experience ocular complications. .

[0191] High fever (>102.2°C), fatigue, joint pain, maculoplasty including the torso, neck and face, and new Constellation of recent drug exposure history or recent dose increases of current drug therapy However, this is an indicator used for diagnosing SJS. A skin biopsy of the affected area confirms the diagnosis. It may be performed for this purpose. Granulosin is used as a marker for the diagnosis of SJS. It is possible. The concentration of granulosin in the blister fluid correlates with the severity of acute SJS. (Non-patent document 17)).

[0192] Ocular symptoms in SJS include conjunctivitis, subconjunctival hemorrhage, subconjunctival scarring, conjunctival membrane, and conjunctiva. Ulcer, punctate superficial epithelial erosion, epithelial defect, eyelid margin ulcer, eyelid margin keratinization, eyelid bulb adhesion, eyelid adhesion, Trichiasis, anterior blepharitis, punctal occlusion, meibomian gland disease, corneal opacity, dry eye These include trichiasis, corneal margin stem cell failure, and corneal neovascularization. Treatment of the eye in SJS This includes saline eye drops, preservative-free artificial tears, and sufficient lubrication and epithelium. It consists of an ointment that reduces damage. Patients with any corneal or conjunctival epithelial defect should use prophylactic treatment. Treatment is performed with topical antibiotics, preferably fourth-generation fluoroquinolones. Mild or moderate. Ocular complications (less than one-third of eyelid margin complications, conjunctival defects with a maximum diameter of less than 1 cm, and corneal defects) Patients with no membrane epithelial defect usually receive topical moxifloxacin 0.5% four times daily. Cyclosporine 0.05% twice daily, and topical steroids (prednisolone 4-8 times daily) Treatment is given with 1% benzoate acetate or 0.1% dexamethasone twice daily. Severe or extremely Severe ocular complications (more than one-third of eyelid margin complications, conjunctival defects exceeding 1 cm, and corneal defects) may occur. Patients with membrane epithelial defects receive amniotic membrane (AM) transplantation in addition to the above treatments.

[0193] In some embodiments, the subject to be treated is suffering from corneal epithelial disease. Corneal epithelial disorders involve the corneal epithelium, for example, manifesting as changes in the corneal epithelial barrier function. It is a disease.

[0194] In some embodiments, the subject to be treated is corneal nerve disorder or corneal neuralgia. He suffers from corneal neuropathy or corneal neuralgia, which is a condition caused by damage to nerve fibers and sensory fibers in the cornea. It is a disorder involving corneal pain caused by injury. One example of corneal neuropathy is LA. This is SIK-induced corneal neuropathy. Corneal neuropathy is generally diagnosed through dry eye examinations. It can be identified and diagnosed. The cause and risk factors are not yet clear, but dry eye-like symptoms may be present. Patients who have increased corneal sensitivity and changes in corneal nerve morphology but no signs of dryness have corneal nerve They may suffer from menstrual disorders.

[0195] In some embodiments, the subject to be treated is suffering from an eye surface disease or disorder. The term "ocular surface disease" or "ocular surface disorder" refers to an abnormality in the anatomical form or function of the eyelid. , various abnormalities including abnormal or altered tear production or composition, and associated asymptomatic signs This includes the underlying diseases and related symptoms. Many diseases can cause ocular surface disorders. Patients with ocular surface disorders may present with clinical signs common to several diseases, and Chronic punctate keratopathy, filamentous keratopathy, recurrent corneal erosion, bacterial conjunctivitis, culture-negative conjunctivitis, scarring This may include regenerative (scarring) conjunctivitis, persistent epithelial defects, infectious keratitis, corneal lysis, and ocular surface defects. The most common ocular surface disorders are lacrimal film abnormalities and / or dysfunction of the glands in the eyelid ("blepharitis"). It originates from '').

[0196] In some embodiments, the subject to be treated is neurotrophic keratitis or neurotrophic keratitis. He has neurotrophic keratopathy. Neurotrophic keratitis or neurotrophic keratopathy (NK) is a condition affecting the cornea. It is a corneal degenerative disease characterized by decreased or absent receptivity. In NK, the trident Corneal innervation via the keratinocyte is impaired. Because corneal sensory innervation is impaired in the NK cell, Patients typically do not complain of symptoms on the ocular surface. However, blurred vision may be caused by irregular epithelium or epithelial defects. It may be reported due to PED (Pediatric Epiphysis), scarring, or edema. NK is usually "Mackie's It is divided into three different stages depending on the "type". Stage II NK is the most common It is generally defined as a recurrent or persistent epithelial defect in the upper half of the cornea. Stage I One of the treatments that may be used in NK is one that contains local nerve growth factor. Patients usually have Pain is experienced during NGF treatment to facilitate the reshaping of the ligament.

[0197] In some embodiments, the subject to be treated is suffering from blepharitis. Inflammation is an inflammatory condition of the peripheral eyelid, characterized by persistent deterioration of the peripheral eyelid or superficial keratopathy. This may cause vision loss, corneal neovascularization, and ulcers. Blepharitis can be divided into anterior and posterior parts. Anterior blepharitis involves the eyelid skin, the base of the eyelashes, and affecting the ciliary follicles, and including the conventional classifications of staphylococcal and seborrheic blepharitis. Posterior eyelid The inflammation affects the meibomian glands and their openings, and the primary cause is meibomian gland dysfunction. Symptoms of blepharitis include redness, burning, irritation, tearing, eyelid scabs and sticking, and photophobia and blurred vision. Any visual problems may be included. Long-term symptom management involves daily eyelid washing routines and infection control. Treatment may include the use of therapeutic agents to reduce inflammation. Treatment may include topical or systemic antibiotics. For example, bacitracin or erythromycin; oral antibiotics, for example, tetracycline Electron antibiotics (tetracycline, doxycycline, minocycline) or macrolase Corticosteroids (erythromycin, azithromycin); topical steroids, for example, Thicosteroids, for example, roteprednol etavonate, fluorometholone; Tobramy Antibiotics such as dexamethasone or tobramycin / loteprednol and corticosteroids Topical combinations of steroids; for example, topical cyclosporine 0.05%.

[0198] In some embodiments, the subjects to be treated are those suffering from meibomian gland dysfunction. The meibomian glands are involved in supplying meibomian oil, an oily substance that prevents the evaporation of the tear film in the eye. It is a total secretory exocrine gland located in the peripheral part of the eyelid inside the tarsal plate. Meibomian gland inflammation, posterior Meibomian gland dysfunction (MGD), also known as blepharitis or inflammation of the meibomian glands, is a condition in which Generally characterized by terminal ductal obstruction and / or qualitative / quantitative changes in glandular secretion It is a chronic diffuse abnormality of Bohm's glands (Non-Patent Literature 18). It is a degeneration of the tear film. It can cause eye irritation, clinically apparent inflammation, and ocular surface disease. MGD is a type of dry eye. It often causes this and can be a contributing factor to blepharitis. In some cases, topical steroids Intense pulse therapy is also prescribed to reduce inflammation. IPL (intense pulsed light) therapy or other mechanical treatments that use heat and pressure to stimulate glandular activity. (For example, LipiFlow) also reduces inflammation and improves glandular function in patients. It has been shown that this is the case.

[0199] In some embodiments, the subjects to be treated are suffering from graft-versus-host disease. Graft-versus-host disease (GVHD) is an inflammatory disease unique to allogeneic transplantation. Even if the donor and recipient have the same HLA, complications can still occur in the recipient's tissue. This is an attack by the transplanted white blood cells. Acute graft-versus-host disease usually occurs within the first three days after transplantation. It occurs within months and may involve the skin, intestines, or liver. Prednisone and other corticosteroids are used. Costeroids are the standard treatment. Chronic graft-versus-host disease also occurs after allogeneic transplantation. This is a major cause of late-onset complications. In addition to inflammation, chronic graft-versus-host disease is a major cause of scleroderma. It may cause fibrosis or scar tissue formation, similar to other autoimmune diseases. Furthermore, it may lead to functional impairment and the need for long-term immunosuppressive therapy.

[0200] In some embodiments, the subjects to be treated are those suffering from ocular graft-versus-host disease. GVHD occurs in patients who have undergone allogeneic hematopoietic stem cell transplantation. It may occur in patients with sexually transmitted or chronic GVHD, but in patients with chronic forms It is more common in certain individuals. Approximately 40-90% of patients with chronic GVHD experience eye problems. Symptoms will develop. Eye symptoms include moderate to severe keratoconjunctivitis sicca and bilateral peripheral keratoconjunctivitis. This may include corneal inflammation, anterior uveitis, corneal ulcer, or neovascularization. Treatment may include preservatives. Topical lubricants containing artificial tears, autologous serum tears, and other topical and systemic immunosuppressive therapies; systemic Sex steroids; topical cyclosporine 0.5% is an example. [Examples]

[0201] The following examples are included to illustrate non-limiting embodiments of the present invention. Those skilled in the art will understand the present invention. Modifications may be made to the specific embodiments described in the details, and the present invention may still be made. They will understand that similar results can be obtained without deviating from the purpose and scope. cormorant.

[0202] Example 1. Solubility of Compound I As described above, compound I is barely soluble in various media. The solubility of compound I in the medium is shown in Table 1.

[0203] [Table 1]

[0204] Example 2. Exploratory formulation for stability testing Based on the limited solubility of compound I in various solvents and water, suspension for development Liquid formulations were investigated. The following five formulations were prepared and tested for stability. The formulations were then compressed tightly. The mixture was stored in sealed glass vials at room temperature and 40°C. At weeks 6, 8, and 12, the chemical mixture was... The stability of substance I was evaluated in the sample.

[0205] [Table 2]

[0206] The formulations prepared in Table 2 are subjected to the assay of compound I as shown in Table 3. The assay was performed using an exploratory UPLC developed for this purpose.

[0207] [Table 3]

[0208] The results from the stability tests of compound I at room temperature and 40°C are shown in Figure 1A and Figure 1A, respectively. This is shown in Figure 1B. In Figure 1A, approximately 70% of the original amount of compound I was lost after 12 weeks. The formulation containing the cent is a formulation of compound I as a solution. In Figure 1B, at 12 weeks The initial formulation, which contained approximately 20% of compound I, was a formulation of compound I as a solution. Yes. As can be seen in Figures 1A and 1B, compound I was found to be present at 40°C for 12 weeks. Even then, it remains in a stable form in suspension without significant degradation. In contrast, The compound I portion (FID121513) in the supernatant solution was initially... It is broken down to about 20% of its original volume.

[0209] At the end of the experiment, compound I was recovered from the four suspensions and its crystalline form was determined by powder X-ray diffraction. Changes in the state were evaluated. Compound I and 12 weeks of stability were recovered from the sample. The X-ray diffraction pattern of compound I (control) stored at temperature is shown in Figure 2. Figure 2 As shown there, compound I in each of the four exploratory formulations is at room temperature or 40°C Even after 12 weeks of storage, it retains its polymorphic form.

[0210] In addition, suspension FID 121744 (shown in Table 6) and 1% thyroxenol A 10% compound I slurry was subjected to dry heat sterilization at 171°C for 1 hour. The X-ray diffraction pattern of material I was identical to that of the untreated sample.

[0211] Example 3. Viscosity range discovery test of compound I suspension Various suspension formulations of compound I were evaluated for viscosity and compound I precipitation. It contains Carbopol (carbomer homopolymer type B) and various amounts of sodium chloride. A series of preservative-free suspensions of compound I were prepared. The composition of the formulations is shown in Table 4. ru.

[0212] [Table 4]

[0213] The suspension was visually evaluated for homogeneity. Suspension containing only 0.1% carbomer. The turbidity, FID 121845, was not homogeneous and therefore could not be further evaluated. Sodium hydroxide is known to reduce the viscosity of carbomer-containing suspensions, and therefore Therefore, sodium chloride is added to the four remaining suspensions in a certain amount, and then 0.2, 0.3 , 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.

[0214] The results of viscosity tests for 28 types of suspensions are shown in Table 5.

[0215] [Table 5]

[0216] As can be seen in Table 5, the relationship between the amounts of carbomer and sodium chloride is as follows: It affects the viscosity of the liquid.

[0217] Further preservative-free suspension of compound I containing carbopol as a suspending agent The set was prepared for viscosity range discovery and precipitation testing. 10 ml suspension after 6 months. The composition, viscosity, and precipitation time of these compounds are shown in Table 6.

[0218] [Table 6]

[0219] A series of further suspensions were prepared, including a preservative containing hypromellose as a suspending agent. The viscosity of these substances was measured. The precipitation properties were measured as follows: a well-mixed constant amount The suspension was filled into a 10 ml glass graduated cylinder. The graduated cylinder was polished. The sample was sealed with a stopper and Parafilm® and left to stand at room temperature for 6 months. The prepared suspension was evaluated by visual inspection. The composition of 10 ml of the suspension after 6 months, and their The viscosity and precipitation time are shown in Table 7.

[0220] [Table 7]

[0221] Based on the results shown in Tables 6 and 7, the product may or may not contain a preservative and may be suspended. A suspension of compound I having either carbomer or hypromellose as a phosphate agent is acceptable. The viscosity and precipitation properties could be achieved as described above. The viscosity was measured at 60 rpm and room temperature using a CP52 spindle, approximately 2 The range is 0 cPs to 200 cPs.

[0222] Example 4. pH-dependent stability screening of Compound I suspension. To test the pH stability of the compound I suspension, the formulations listed in Table 8 below were prepared. All samples contain 0.1% compound I to maintain consistency in drug concentration. Since the drug is not soluble in any of the samples, 0.1% tyroxapol is used as a surfactant. It was used as an agent to promote the resuspension of substances in the samples. All samples (except TRIS samples) ) contains an equivalent amount of phosphate buffer. Place all samples into a 20 mL glass vial. The sample was placed at 60°C. At each assay time point, the sample was equilibrated to room temperature and voltected. The drug was resuspended, and the sample was diluted to a concentration that fell within the linear range of the calibration curve.

[0223] [Table 8]

[0224] The amount of compound I in the stable sample is Waters XBridge Shield RP18 column (3.5 μm, 3.0 × 150 mm, 30°C), mobile phase A: 0.1% water A gradient of TFA and mobile phase B (0.1% TFA in acetonitrile) was used for the injection of 10 μl. Depending on the volume and flow rate of 0.8 ml / min, high-performance liquid chromatography (HPMC) can be performed. Tests were conducted on days 0, 4, 7, and 11. In addition, the current results were obtained with a relative retention time (RRT) of 1.23. The main decomposition products were tracked. The results of the stability tests are shown in Table 9.

[0225] [Table 9]

[0226] The major decomposition products shown in Table 9 crystallize and become larger as their concentration increases. Crystal formation was observed. Therefore, the formulations shown in Table 10 below were prepared. The mixture was prepared, and the formation of decomposition products was analyzed.

[0227] [Table 10]

[0228] The data on the stability of compound I in the compositions shown in Table 10 are as follows: It is shown.

[0229] [Table 11]

[0230] Data regarding the increase in decomposition products are shown in Table 12.

[0231] [Table 12]

[0232] Based on the stability data in the table above, the stability of compound I is within the pH range of 5 to 8. It was concluded that it would fluctuate significantly. Furthermore, compound I in SBE-cyclodextrin The increased solubility led to a decrease in stability.

[0233] Example 5. Stability of 2.5%, 1.5%, 0.5%, and 1.5% ophthalmic suspensions of Compound I. sex As shown in Table 18 below, eye drop suspensions of compound I in concentrations of 0.15%, 0.5%, and 1.5%. The stability of some lots with % and 2.5% (initial pH of 7.34-7.7) over time is... The chemical, physical, and microbiological stability characteristics of the product are evaluated by monitoring them. Chemical stability was assessed by monitoring compound I and its impurities. Physical stability is measured by pH, gravimetric osmolality, viscosity, appearance, and powder X-ray diffraction (XRPD). Identity and particle size were monitored. Microbiological stability was evaluated by monitoring the particles. It was monitored by performing bacterial tests. Tests were conducted on the ophthalmic suspension of compound I and From the stability observation limit (across different lots and various sampling times over the test period) A summary of the results (in the enclosed area) is presented in Table 13.

[0234] [Table 13]

[0235] In addition to the parameters mentioned above, viscosity was monitored and tested under various storage conditions. It was found that the initial viscosity at each point in time was within 10%. Particle size measurements and sterility were also found to be within 10%. The stability was within the observation limit. Furthermore, the inventors unexpectedly found that in the final stage of manufacturing... Compound I, which has been micronized by ball milling, undergoes polymorphism without changing its crystalline properties. We found that morphology B was maintained.

[0236] Embodiment 6. Acute toxicity test of exploratory formulations Table 2 shows four formulations derived from exploratory stability studies: FID 121522, FID 121511, FID 121512, and FID 121513 were used as controls for sterile irrigation. The solution was administered five times daily to male NZW rabbits. Four exploratory formulations or controls were used. No toxicity was observed in this regard.

[0237] Embodiment 7. Pharmacokinetic study of exploratory formulations Pharmacokinetic studies were conducted, and the four exploratory formulations provided in Table 2 are FID 1215. 22, Male N by FID 121511, FID 121512, FID 121513 The uptake of compound I in the eyes after a single localized bilateral administration in ZW rabbits was determined. The results are shown in Table 14.

[0238] [Table 14]

[0239] As can be seen in Table 14, the highest exposure level of compound I occurred in the cornea. This is 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 level observed in [location] and approximately the level observed in plasma The magnification was 500x. In the cornea, C for a suspension containing poloxamer 407 max teeth C regarding two suspensions containing hypromellose max Approximately twice that amount and relating to solution formulations ru C max It was approximately 38 times. Regarding the three types of suspensions, C in the cornea max teeth, 30nM IC 50 It was in the range of approximately 500 to 1200 times, C min IC5 The range was approximately 50 to 130 times 0.

[0240] Embodiment 8. Further pharmacokinetic studies of the formulations. Based on results from exploratory formulations, the results after a single topical bilateral administration in male colored rabbits showed promising results. Further formulations will be prepared for additional pharmacokinetic studies of compound I against corneal and aqueous humor concentrations. These formulations are shown in Table 15.

[0241] [Table 15]

[0242] The results of the pharmacokinetic studies are shown in Table 16.

[0243] [Table 16]

[0244] As shown in Table 16, C for compound I max and C min is compound I The highest level of exposure occurs in the cornea, approximately 3-6 times the level observed in aqueous humor. This indicates that it has twice the level. In the cornea, C for a 0.5% suspension. max is, 0 The levels were approximately three times higher than in a 0.05% suspension and approximately sixteen times higher than in a 0.01% suspension. And, regarding C in a 0.5% suspension max This is approximately three times the amount of a 0.05% suspension and 0.01 The % suspension was approximately 9 times higher. Regarding the three types of suspensions, the corneal C max is 30 nM IC 50 It was in the range of approximately 38 to 600 times, C min IC 50 Of The range was between 0.5 and 7 times.

[0245] Pharmacokinetic studies were conducted, and the formulations FID121746 and FID1217 listed in Table 15 were selected. Using 45 and FID121744, in male colored rabbits, the ophthalm of After a single bilateral administration, and when using and not using bandage contact lenses. The corneal and aqueous humor concentrations of compound I after anterior keratectomy were determined.

[0246] The results of the pharmacokinetic studies are shown in Table 17.

[0247] [Table 17]

[0248] Example 9. Toxicity wound healing test using compound I suspension formulation. Toxic wound healing tests were conducted to determine the difference between using and not using bandage contact lenses. QID locality of compound I after unilateral laser refractive keratolectomy in rabbits Corneal wound healing after bilateral administration was evaluated. The compound I formulation used in this study was This is listed in Table 18. For comparison, ketrolactromethamine (ACULAR LS (registered) The product used a registered trademark and a dexamethasone (MAXIDEX®) preparation.

[0249] [Table 18]

[0250] The test results showed that after 3 days, using bandage contact lenses, the values ​​were 0.5, 1.5, and The average wound area of ​​the cornea treated with a 2.5% compound I suspension was compared to that of a bandage cone. Corneas treated with ACULAR LS and MAXIDEX using Tact lenses, Vande This concerns corneas treated with solvents without the use of contact lenses, as well as untreated corneas. It was demonstrated that the values ​​were smaller than 0.5, 1.5 and using bandage contact lenses. The average wound area of ​​the cornea treated with a 2.5% compound I suspension was compared to the bandage contour. Cornea treated with solvent using contact lenses and bandage without using contact lenses 2 The results were comparable to those observed in corneas treated with 0.5% compound I.

[0251] Example 10. Bacteriostatic / stability test of exemplary compound I suspension. A series of five prototype sterile suspension formulations containing 0.5% compound I were prepared, and the official pharmacopoeia was used. Five species: S. aureus, P. aeruginosa inosa), E. coli, C. albicans And bacteriostatic / fungal effects using A. brasiliensis. Screening was performed on the following. The criteria for determining bacteriostasis were based on the number of microorganisms (CFU / mL). The logarithmic increase was less than 0.5. All tested formulations showed acceptable levels of bacteriostatic activity. It exhibited fungicidal activity. In addition, a 2.5% suspension of compound I (FID 121 by another method) (Same as 744), and suspension solvents were also prepared and used for bacteriostatic / fungal activity screening. It was cleaned. The bacteriostatic / fungal effect is approximately 10 6 Inoculum and / or about 10 5 Vaccination The bacterial suspension was used for observation over a period of three days.

[0252] Example 11. First human trial of compound I This example describes the first human trial of compound I conducted in healthy volunteers. A total of 54 subjects were administered the drug and the drug therapy was tested. Part 1 of the initial human trial was In eye drops, single dose escalating doses of 0.15% w / v, 1.5% w / v, 2.5% w / v ( One drop of compound I was administered.

[0253] Part 2 tests compound I in repeated dose escalation (MAD) and as eye drops (i) 1 drop 0.15%, 1.5%, 2.5%, four times a day (every six hours) for seven days, or (ii) 2 drops of one drop. The drug was administered at a concentration of 0.5%, eight times a day (every three hours) for seven days (the above therapeutic dose).

[0254] Part 3 was a sensory measurement evaluation to assess the anesthetic properties of compound I. Section 3 has four sections, and it consists of Compound I, Solvent, and Tetracaine (0.5% ophthalmic solution). (The solution is used as a positive control) and diclofenac sodium (0.1% ophthalmic solution, (Used as a comparator drug for active NSAIDs). Due to its established anesthetic effect, it was used in the eyes. An anesthetic was chosen; however, it was not used in standard treatment due to its negative impact on wound healing. There is no such thing. NSAIDs have minimal anesthetic properties but significant pain control characteristics, PRK This is the current standard treatment for subsequent corneal pain. Solvent eye drops are used as a negative control. This enables a more accurate assessment of the potential anesthetic effect. 12 healthy individuals who met the eligibility criteria. Each participant was randomized to one of four different trial days (days 1, 4, 7, and 10). Each participant received one of four experimental eye drops during the trial period. Each participant was randomized. The experimental treatment was administered in one of the following four sequences. • Order 1: Anesthetic agent, NSAID, Compound I 2.5%, solvent • Order 2: NSAID, solvent, anesthetic, compound I 2.5% • Order 3: Solvent, Compound I 2.5%, NSAID, Anesthetic Order 4: Compound I 2.5%, anesthetic, solvent, NSAID

[0255] Safety evaluation: The safety evaluation includes all adverse events (AEs), including systemic and ocular adverse events. Severe adverse events (SAEs) are collected along with their severity and association with the investigational drug. The systemic safety assessment consisted of blood, blood chemistry, and urinalysis performed at the testing facility. Regular monitoring and physical examination, vital signs (systolic and diastolic blood pressure, pulse rate, and Body temperature, ECG, regular assessment of pregnancy, and hand temperature at 49°C during the fertility and MAD part. This included periodic evaluation of immersion tests. Ocular safety evaluation was conducted in the Early Treatment Trial for Diabetic Retinopathy (ET). DRS included visual acuity, intraocular pressure, slit-lamp biomicroscopy, corneal staining, and dilated fundus examination.

[0256] The subjects were selected based on the following inclusion and exclusion criteria.

[0257] Inclusion criteria: • Informed consent was obtained before any of the assessments were conducted. • Must be between 18 and 50 years old (including the age in question), and have a past medical history, physical examination, vital signs, and EC (European Consultation Laboratory). G, and healthy men in good health as determined by clinical tests at the time of screening. For women only. • During screening and at baseline, the subject must remain still for at least 3 minutes before standing again. Three minutes later, vital signs (systolic and diastolic blood pressure and pulse rate) were assessed in a seated position. The following were required: The vital signs in a seated position were to be within the normal range. Oral body temperature between 35.0 and 37.5°C Systolic blood pressure (SBP), 90-150 mmHg • Diastolic blood pressure (DBP), 50-90 mmHg • Pulse rate: 40-100 bpm • Participants must weigh at least 50 kg and meet the Body Mass Index (BM) requirements to participate in this study. I) is 18-29 kg / m 2 It was required to be within the range of BMI = weight (kg) / [Height (m)] 2 • Participants who were able to communicate well with the principal investigator in order to understand and comply with the requirements of the trial. Regarding Part 3, the baseline level of ocular sensitivity in the subjects was determined to be Cochet- When measured by a bonnet sensor, the range is 50-60 mm (including the value in question). .

[0258] Exclusion criteria: • All women who did not use an effective method of contraception during the administration of the experimental treatment will have a physiological response. A woman who is capable of becoming pregnant, defined as a woman who is capable of becoming pregnant. • At the discretion of the principal investigator, and based on the contents of the principal investigator's booklet, the test item Any medical condition (general or ocular) that would impede safe administration or safe participation in this study The object shown. • Part 3 (Sensory Measurement): Subjects who were wearing contact lenses at the time of the test or in the past 3 years The target of this study is to minimize the diversity of corneal sensitivity caused by contact lens use. It was excluded for that reason. • A history of any eye surgery or laser treatment within the past six months prior to screening. A history of any chronic eye disease other than refractive errors, initial cataracts, strabismus, amblyopia, or anisometropic amblyopia. Acute eye disease (infection, corneal abrasion, or allergy) within the past 6 months of cleaning Subjects with a history of the disease were eligible if the disease was not active. • Any ongoing eye condition requiring the use of topical eye drops. • Patients using continuous positive airway pressure (CPAP) or other sleep apnea devices.

[0259] Safety results from the initial human trials Based on the results from Parts 1, 2, and 3, the maximum tolerated dose (MTD) is set at 2.5%. The highest possible concentration identified was eight doses per day for seven days. Dose-limiting adverse events were identified at this dose level. It was not identified by Bell. All adverse events with suspected causal relationship to compound I were classified as 2 0.5% Moderate treatment interruption occurred in one patient out of a cohort receiving treatment four times a day. Except for eye irritation of a certain severity, the other conditions were of mild severity. In patients treated with compound I... The most common ocular adverse events were corneal discoloration and redness, at levels similar to those observed with placebo. The patient also had mild anterior chamber inflammation. A summary of adverse events in the SAD trial is shown in Table 19.

[0260] [Table 19]

[0261] A summary of adverse events in the MAD trial is shown in Table 20.

[0262] [Table 20]

[0263] Regarding the hand immersion test, all subjects in the treatment cohort underwent a time interval of 0 to ≤ 50 seconds. Then, the hands were withdrawn from the 49°C water. No subjects lasted longer than 22 seconds and were treated with compound I. Significant changes in immersion time were observed between the treated subjects and the subjects treated with the solvent. No such change occurred. Therefore, this result indicates that compound I does not alter the temperature sensitivity of the subject. vinegar.

[0264] Sensory measurement test (Part 3) The initial human trials further involved sensory measurement tests, specifically when the threshold for corneal touch is perceived. By measuring the length (cm) of the filaments, 2.5% of compound I in the local eye was determined. The potential anesthetic effect was evaluated.

[0265] Analysis of the results showed that tetracaine 0.5% had an activity duration of approximately 10 minutes (positive control). It was shown to have an anesthetic effect accompanied by [unclear]. Both diclofenac 0.1% and the solvent were [unclear]. As expected based on known clinical trials with clofenac, it has an anesthetic effect on the cornea. Compound I did not have an anesthetic effect at any point after treatment. They did not show it.

[0266] Regarding the measurement of corneal sensitivity, the least squares mean (test drug vs. reference) will be compared for the following: To the extent that statistical and clinical significance was observed: • Tetracaine 0.5% (N=12) vs. solvent (N=12) administration at 2.5 minutes, 10 minutes, and 2 minutes. 0 minutes; • 2.5% tetracaine (N=12) vs. 0.1% diclofenac (N=12) administration. 5 minutes, 10 minutes, and 20 minutes; • 2.5 minutes after administration of Compound I 2.5% (N=11) versus Tetracaine 0.5% (N=12) and 10 minutes

[0267] No difference in corneal sensitivity was observed between compound I 2.5% and the solvent, and all p-values ​​were not met. The measured value was 0.395 or higher at the scheduled time of 30 minutes after administration. This test was conducted using tetracaine. When comparing 0.5% (a drug with anesthetic effect as a positive control) with the solvent (placebo) This demonstrated the lack of anesthetic effect of 2.5% compound I.

[0268] Summary of pharmacokinetics in the initial human trials Topical application of both single and repeated suspensions of compound I at concentrations of 0.15%, 1.5%, and 2.5%. Following ocular administration, the plasma PK profile showed rapid absorption of compound I into the systemic circulation, and Low-concentration exposure yielded moderate variability across the entire study group. The dose range from 0.15% to 2.5% was... The increase resulted in a systemic exposure that was not dose-proportional. The accumulation of compound I at steady state The accumulation was minor after administration of 0.15%, 1.5%, or 2.5% suspension four times daily. (Approximately 1.7 times) and even after administering 2.5% eight times a day for seven days, the symptoms remained mild (approximately 1.3 times). .

[0269] Example 12. Clinical trial of compound I for the treatment of postoperative pain. This embodiment describes postoperative ocular conditions in patients undergoing laser refractive keratotomy (PRK) surgery. Compound I(4-(7-hydroxy-2-isopropyl-4-oxo- This document describes the clinical trials of 4H-quinazolin-3-yl)-benzonitrile. The agents are shown in Table 18.

[0270] [Table 21]

[0271] Test design The trial involved administering a compound as eye drops in addition to standard treatment in patients after PRK surgery. I was a proof-of-concept, double-blind, randomized, solvent-controlled trial. PRK surgery is a laser ablation procedure. This procedure, performed as an outpatient under local anesthesia, involves removing the corneal epithelium to expose the corneal stroma due to burning. The administration of compound I was performed in one eye from immediately after surgery (time 0) to 72 hours later. The medication is administered as a single 2.5% (0.925 mg / drop) eye drop four times a day (every six hours). there were.

[0272] The solvent is administered to one eye from immediately after surgery (time 0) to the final dose at 72 hours. It was a single-dose eye drop administered four times a day (every six hours).

[0273] The trial consisted of two treatment periods using a crossover design. Patients underwent PRK. The patient underwent surgery on two separate occasions (periods) (one eye per surgery). The patient was randomized, After treatment 1, either compound I or the solvent was received, and after treatment 2, the other compound was received.

[0274] 40 patients were given two treatments: compound I during period 1, then the solvent during period 2, and Patients were randomized in a 1:1 ratio to the solvent during period 1, and then to compound I during period 2. The subject underwent PRK surgery on the eye under study (Day 1, Periods 1 and 2) and received 4 doses per day for 72 hours afterward. One drop was administered at a time. The first eyes of the study subjects were screened and examined by the patient and the principal investigator. The non-dominant eye was determined by agreement. The patient had a period of 1 year after surgery on the first eye. Patients will be brought in for follow-up visits on days 2, 3, 4, and 8, and will be followed up until wound healing is complete. This involved optional daily visits for follow-up examinations. The second eye surgery was performed on either If complications were observed, the procedure was not performed.

[0275] The patient underwent PRK surgery on the second target eye (dominant eye) on day 1 of period 2. The PRK surgery was performed after the initial epithelial defect in the eye had healed and at the discretion of the principal investigator. After the PRK surgery, the patient received four conflicting treatments per day for 72 hours. The patient initially... Three days after the first surgery (period 2, days 2-4) and one week after the second surgery (period 2, day 8) Optional daily visits are required to track patients until wound healing is complete. The patient was accompanied by a hospital visit. The end-of-surgery (EOS) visit was 30 days after the second eye surgery (or the patient was able to...) If treatment was completed early in Period 1, the test was performed after the final dose of the investigational product.

[0276] All patients received the test eye drops for post-PRK treatment and pain during periods 1 and 2 of the study. Pre-reception bandage contact lenses (Air Optix® Night) Standard treatment including the application of and Day(registered trademark) Aqua or equivalent was received. Topical antibiotics for the eye (moxifloxacin or equivalent, one drop four times a day) This was initiated after the application of the first dose of the test eye drops and continued for 4-7 days. One week after PRK. During this time, one eye drop of prednisolone acetate was administered four times a day, and then gradually reduced. Preservative Artificial tears in unit doses that did not contain the active ingredient were used as needed. Test eye drops after each PRK treatment. The first dose of the medication was administered by on-site staff. Subsequent doses were administered by the patient themselves. The eye drops were administered sequentially, with a 5-minute interval allowed between doses. In summary, the patient was P The patient underwent RK treatment, had a bandage lens placed on the cornea, and was administered compound I or a solvent; Five minutes later, an antibiotic was administered, and five minutes after that, prednisolone was administered.

[0277] Rescue medication may be taken as needed, up to a total of 10 tablets per day or 1-2 tablets every 4 hours. It consisted of pain medication (300mg acetaminophen + 30mg codeine).

[0278] Additional experimental treatments All patients, • Bandage contact lenses (Air Optix® Night and Day (registered trademark) Aqua or equivalent) • A series of topical antibiotics for the eye (one drop of moxifloxacin or equivalent four times a day) The first dose (of the procedure) is administered by the attending physician immediately after the PRK surgery and after the first administration of the test eye drops. This continued for 4 to 7 days. • Prednisolone acetate eye drops: One drop four times a day, immediately after PRK surgery and as an antibiotic eye drop. Treatment is initiated after eye drops, administered for one week after PRK, and then gradually reduced by local treatment. Ta. • Preservative-free unit-dose artificial tears were used as needed. Artificial tears provide analgesia. Cooling was not permitted for the sake of the effect. The patient received standard adjuvant treatment after PRK surgery, including [specific treatment details].

[0279] The eye drops were administered sequentially with at least a 5-minute interval between administrations.

[0280] Inclusion Criteria The population eligible for inclusion in this study had to meet all of the following criteria: tta: • Male and female patients aged 18-75 who are eligible for bilateral PRK surgery. • Standard ophthalmological examination excluding refractive errors at baseline • Has an equivalent spherical frequency not higher than -4.50, as confirmed by subjective refraction at baseline. Furthermore, planned astigmatism not exceeding -4.00 diopters (spherical) and 3.00 diopters. Myopia correction was required. Monocular vision treatment (far vision in one eye and intermediate vision in the other eye) Corrections (such as those related to the condition) were permitted. • Informed consent was obtained before any of the assessments were conducted.

[0281] Exclusion criteria • Patients with one eye (including amblyopia) or with a baseline of 20 / 80 (Snellen) or 55 letters [ Worse than the Best Corrected Visual Acuity (BCVA) score in the Early Treatment Trial for Diabetic Retinopathy (EDTRS). • Any systemic or ocular disease (severe) that affects wound healing during the 6 months prior to baseline (e.g., a history of rheumatoid arthritis, diabetes, or keloid formation) or eye injury, uveitis, infection History of infection or inflammation. In particular, diabetes: severe diabetes, uncontrolled diabetes, diabetes. Diabetic keratopathy, diabetic retinopathy, diabetic macular edema, diabetic nephropathy, diabetic foot ulcers, or others Patients with systemic complications of diabetes were excluded. Ocular or systemic complications of diabetes Patients with mild, well-controlled diabetes who did not have evidence of needing treatment were included. • Progressive inflammatory or infectious eye conditions, severe or This includes progressive retinal disease, and the use of topical or systemic steroids, or coumadin or similar substances. Patients who are using the drug. • Any corneal dystrophy (epithelium, corneal stroma, or endothelium) or any corneal disease ( Patients with significant scarring (including, at the discretion of the principal investigator, ocular herpes, or pterygium). • Previous refractive surgery or corneal surgery (LASIK, PRK, radial keratotomy, pterygium removal) (e.g., corneal transplantation). • Tetracaine or similar topical ophthalmic anesthetics, NSAIDs and aspirin, oral analgesics (aspirin) This study includes use of toaminophen and codeine, antibiotics, and steroids. A history of allergic or hypersensitivity reactions to any of the drugs, or of serious adverse events. The bandage contact lenses cannot be used or worn. • Combination therapy or NSAIDs, analgesics, and pain medications for the whole body or eyes (gabapentin) Long-term therapy or abuse of opiates or cannabis (including pregabalin and analogues) Medical history for the purpose. • Within two weeks prior to surgery in the eye being tested, any localized eye treatment other than lubricating eye drops may be administered. Patients who received drug therapy were excluded. Patients who met any of the following criteria were excluded: ○ Use of topical NSAIDs in the 30 days prior to baseline, or Planned / long-term use of systemic NSAIDs within 30 days prior to baseline, or ○ Irregular use of systemic NSAIDs within 3 days prior to baseline, or ○ Use of cyclosporine (or similar drug therapy) on the eye within 3 days prior to surgery. • Body weight <50kg, or 18-35kg / m² 2 Having a Body Mass Index (BMI) within the range Patients without BMI. BMI = weight (kg) / [height (m)] 2 • Pregnant or breastfeeding women. All women must avoid basic contraception during administration of the investigational drug. Fertility is defined as being physiologically capable of becoming pregnant if no fertilization methods are used. A woman who has a certain quality.

[0282] Further exclusions may be made by the principal investigator to ensure the study population is a sample of all eligible patients. That wasn't applied.

[0283] Test group The study population consisted of men and women between the ages of 18 and 75 (inclusive) who were eligible for PRK surgery. It consisted of patients of the sexes. A total of 40 patients were scheduled. A total of 44 patients were screened. The participants were selected, and of those, 40 were enrolled in the trial and randomized.

[0284] Patient selection is based on screening and testing of all eligibility criteria at baseline. The criteria for eligibility were established. Proper records of eligibility criteria (e.g., checklists) are required by the testing institution. It was stored together with the source documentation. Any deviation from the registration criteria will result in the registration of the test. The patient was removed from the record.

[0285] Patient demographics are provided in Table 21.

[0286] [Table 22]

[0287] treatment department Patients are divided in a 1:1 ratio into one of the following two treatment sequences, each lasting 3 days. I was right.

[0288] [Table 23]

[0289] Compound I was administered to the patient as eye drops. The eye drops were administered to the test staff on the day of the PRK surgery. It was administered in the trial site. During daily postoperative follow-up visits, the patient received eye drops. If they were on site during the expected time, the test staff were required to administer eye drops. It was requested. Or, if the patient was at the testing site in order to come to the hospital (for example, 24, 48 and after surgery) (After 72 hours), the remaining eye drops were administered at home by the patient.

[0290] Vision scale In patient-subjective pain assessments, 0 represents no pain, and 100 represents the worst pain imaginable. Pain levels were recorded using a Visual Analog Scale (VAS), a numerical rating of pain between 0 and 100. Previous studies on pain have shown that the most severe pain peaks around 4-6 hours post-surgery. It was shown that these were experienced within the first 12 hours (Non-Patent Document 19), and these were the primary assessments. This was the point in time selected for value analysis. The greatest experience a patient has during the period immediately following surgery. Since reducing both pain and overall pain was clinically important, 6 hours post-surgery The two periods up to 12 hours were evaluated as primary endpoints. All evaluable VAs were evaluated. S data is collected using ePRO, which is an electronic device (software application). (A mobile phone with a function) and on ePRO, the patient recorded their pain level at the appropriate time. .

[0291] Rescue oral analgesics: Pain control medication for postoperative patients as part of a clinical trial. Refusing is unethical. A review of previous clinical trials has shown that NSAIDs are PR Used as a rescue oral analgesic for postoperative pain after PRK, similar to standard treatment after K. It was shown that the use of oral rescue medications is a potential confounding factor in pain VAS assessment. Therefore, when analyzing pain VAS scores, three approaches are used to determine pain medication The effects were explained (assuming the rescue drug's effect lasts for 4 hours): (1) Rescue It is assumed that no VAS scores were recorded within 4 hours of drug use. (2) All recorded VAS scores were used; and (3) Rescue medication was used. Any VAS score recorded within the last four hours is counted as the score obtained before the rescue medication was administered. Therefore, it was completed.

[0292] Key efficacy results The mean VAS pain severity scores at 6 hours and 0-12 hours post-surgery are shown in Table 22 and Table 22, respectively. The results are presented in Table 23 and shown in Figure 3. The main analysis is the main PD analysis set. It was carried out using [this method].

[0293] Mean VAS pain severity score at 6 hours and 0-12 hours post-surgery between compound I and the solvent The difference in treatment in group A was statistically significant, with a p-value of less than 0.10.

[0294] Model-based mean difference in VAS pain severity score at 6 hours post-surgery due to treatment (Compound I - Solvent) is -11.1 (90% CI: (-17.54, -4.71; p = (0.005), and -8.56 (90% CI: (-14.2)) at 0-12 hours post-surgery. 9, -2.83; p=0.016). Therefore, the primary efficacy objective of this study was It was satisfied.

[0295] Mean VAS pain severity score at 6 hours and 0-12 hours post-surgery between compound I and the solvent The difference in treatment in group A was statistically significant, with a p-value of less than 0.10.

[0296] [Table 24]

[0297] [Table 25]

[0298] Secondary efficacy results The number of patients who did not use oral rescue medication (ORM) was 0-1 in the 0-6 hours post-surgery period. Compared to eyes treated with the solvent at 2 hours and 0-24 hours, eyes treated with compound I The levels were higher in the eye. 36 hours after surgery, the same number of patients showed a reaction to compound I in relation to the solvent. ORM was administered (Table 24).

[0299] [Table 26]

[0300] History of the frequency of oral rescue medication (ORM) use (number of patients who did not use ORM) Grams are shown in Figure 4.

[0301] An overview and analysis of ORM quantities (number of pills per patient) are presented in Table 25.

[0302] [Table 27]

[0303] As can be seen in Table 25 and Figure 4, at all time intervals during this test, the solvent treatment Less ORM was taken between doses of compound I compared to treatment.

[0304] The details and analysis of ORM amounts (mg / kg body weight) are presented in Table 26.

[0305] At all time intervals, the amount of ORM (mg / kg body weight) is the amount of compound compared to solvent therapy. The incidence was lower in group I (Table 26). Postoperative periods: 0-6 hours, 0-24 hours, 0-48 hours. The difference in milligrams per kilogram of body weight over time and between 0 and 72 hours is statistically significant. The result was statistically significant (p ≤ 0.10).

[0306] [Table 28]

[0307] VAS pain severity scale for the first 3 days after PRK surgery After PRK surgery, patients begin taking medication one hour after surgery and continue taking it within the first 18 hours after surgery. At six of the seven observed time points, compound I was found to be superior to the solvent at a p-value threshold of 0.10. A statistically significantly lower VAS pain severity score was reported after treatment. The score is related to Compound I at all scheduled time points up to 36 hours post-surgery, including 36 hours post-surgery. The levels were lower than those of the solvent. The VAS collection period was from 36 to 72 hours after PRK surgery. At all points in time, the difference between the VAS score of compound I and the VAS score of the solvent was only a small amount. The difference was slight, and at a p-value threshold of 0.10, there was no statistically significant difference between the scores.

[0308] VAS pain severity scores before and after instillation of the test eye drops. At 6.5, 18.5, and 24.5 hours after surgery, and 30 minutes prior to those times, and immediately after instillation of eye drops. Change in mean VAS score compared to previous time (i.e., times 6, 18, and 24) The values ​​for eyes treated with compound I were -3.1, 2.8, and 1.3, respectively. For eyes treated with the solvent, the same differences were -5.6, 2.2, and -0.2, respectively. there were.

[0309] Ocular Pain Assessment Survey (OPAS) OPAS was presented at the 2010 National Eye Institute Workshop. Developed to address the needs identified from the patch, this system addresses corneal and ocular surface pain and quality of life. This is a reasonable means for quantification and monitoring. (See Non-Patent Document 4) I would like to see the overall pain severity grading scale in Qazi et al.'s OPAS, which was used in the study. According to the scale, 0 (no pain) to 10 (severe pain) or 0% (none) to 100% (always) The frequency of the symptoms was graded. Patients were asked about their symptoms on day 2 and day 4 (depending on the test drug). The OPAS survey / questionnaire was completed at the end of the treatment period and on day 8. The OPAS results were then compiled. No comprehensive analysis was performed. Out of 27 OPAS questions in total, the results for 7 questions were lower. It will be presented to you.

[0310] On day 2, what is the level of eye pain you feel most (Question 4) and the level of eye pain you feel least (Question 5)? Question 6: The level of pain and the average level of eye pain (Question 6) for the previous 24 hours. In all three cases, compound I was numerically favorable compared to the solvent (Figure 5A). (Figures 5B, 5C).

[0311] Eye pain can manifest as the following symptoms: redness (question 22), burning sensation (question 23), and hypersensitivity to light (question 23). 24) And in the question about the frequency of tearing (question 25), all answers were compared to the solvent. Compound I was favored (Figures 6A, 6B, 6C, and 6D). Therefore, compound I was selected. Patients who received the drug experienced redness, burning sensation, and photosensitivity compared to patients who received a placebo. Lower levels were observed in photophobia (excitement) and eye pain accompanied by tearing.

[0312] Summary of results from an exploratory perspective • The Ocular Pain Assessment Survey (OPAS) was performed during the treatment period of compound I compared to the solvent treatment period. This demonstrated improved pain control and quality of life. • On day 2, what level of eye pain did you experience most (Question 4) and what level of pain did you experience least (Question 5)? Question 6: The level of pain and the average level of eye pain (Question 6) for the previous 24 hours. In all three cases, compound I was favored compared to the solvent (Figures 5A-5C). • Eye pain with the following symptoms: redness (question 22), burning sensation (question 23), hypersensitivity to light (question 23) 24) And in the question about the frequency of tearing (question 25), all answers were compared to the solvent. Compound I was favored (Figures 6A-6D). • At 6.5, 18.5, and 24.5 hours after surgery, and 30 minutes prior to that, and immediately after instillation of eye drops. VAS scores from the previous comparison (i.e., times 6, 18, and 24) were treated with compound I. For the eyes treated with the solvent, the values ​​were -3.1, 2.8, and 1.3, respectively. Therefore, the corresponding differences were -5.6, 2.2, and -0.2, respectively.

[0313] Pharmacokinetics Pharmacokinetic evaluation Pharmacokinetic (PK) samples will be collected at the time specified in the above hospital visit schedule. The PK blood sample collection range was as shown in Table 27.

[0314] [Table 29]

[0315] All blood samples (3 mL) were collected via direct venipuncture or indwelling catheter inserted into a forearm vein. The blood was drawn from the arm by one of the doctors. Immediately after each tube of blood was withdrawn... Gently knock the patient over 8-10 times to collect the contents of the tube and the anticoagulant (3mL K2 EDTA). Ensure thorough mixing. Avoid prolonged contact between the rubber stopper and the sample until centrifugation. The tube was placed upright in a test tube rack surrounded by moist ice.

[0316] Within 30 minutes, the sample was centrifuged at approximately 2000G at approximately 5°C for 10 minutes (or the sample (Place on ice and centrifuge at room temperature). Immediately after centrifugation, remove all of the supernatant (approximately 1.5 ml). L) was transferred to the first 1.8 mL NUNC 2D barcoded cryovial. After thoroughly mixing the plasma, transfer half of the plasma from the first cryovial to the second cryovial. Transferred to a bottle and secured with a cap. Attach the appropriate PK cryolabel to each cryovial. The label was secured with clear tape. The cryovial was quickly frozen on dry ice. The vials were then sealed and kept frozen at ≤-20°C until shipment to the central testing laboratory. Shipped in the weekly batch.

[0317] Compound I was quantified in plasma using a valid LC-MS / MS method. The limit of quantification (LLOQ) was 0.05 ng / mL. The concentration is expressed in units of ng per mL. It was represented in the position. Where feasible, bandage contact exposed to the test drug. The lenses (BCLs) were collected and analyzed for residual drug exposure after treatment (LLO). Q: 5.00 ng / mL or 2.75 ng / BCL in 0.55 mL of extract solution Concentrations below LLOQ are reported as "zero," and non-existent data are labeled accordingly. It was done.

[0318] The following PK parameters are based on the actual recorded sampling time and Phoenix (quotient). Non-compartment storage by WinNonlin (registered trademark) (version 6.4) The following methods were used to determine validity: Cmax, Tm from plasma concentration-time data. ax, AUClast (calculated), Clast, and Tlast. Pre-administration concentration is nominal. Determined by testing at 0, 24, and 72 hours. The linear trapezoidal formula was used in AUClast. Used for the calculation. The PK parameter is the concentration of bandage contact lens compound I. The calculation was not performed based on the data.

[0319] Plasma pharmacokinetics of compound I The arithmetic mean plasma concentration-time profile and PK parameters of compound I are shown in Figures 7A and 7A. This is presented in 7B and Table 28.

[0320] After unilateral topical administration of compound I, absorption into the systemic circulation is rapid, and after the first dose (1 day) Day 1; range 0.167~2.00 hours, Figure 7A) and 13th session (Day 4; range 0.00~2 .08, Figure 7B) The median Tmax at 0.459 hours and 0.467 hours after administration, respectively. It was found that Cmax was determined, and AUClast was found in 34 / 40 patients on day 1 and 4 Calculated for patients with 33 / 40 (Cmax) or 31 / 40 (AUClast) on day 1. All pre-administration concentrations on day 1 were below the lower limit of quantification and were supplemented as 0.00 ng / mL. This was done. Before the 5th dose on day 2 (24 hours after the 1st dose; at 0 hours on day 2) The trough value (at the end of the 6-hour dosing interval and before the next dosing) mean concentration (CV%) was 1.25 The concentration was ng / mL (54.9%), and this was the 13th dose on day 4 (72 hours after the first dose). At 0 hours on day 4, the level was slightly higher at 1.99 ng / mL (76.3%).

[0321] The concentration is usually low, ranging from 0.195 to 7.56 ng / mL over 4 days of repeated QID administration. A range of Cmax and AUClast values ​​of 0.261 to 14.5 ng* hours / mL were observed. The arithmetic mean Cmax (CV%) after the first dose on day 1 was 0.454 ng / mL. 49.9%, and after the 13th dose on day 4, it was 2.40 ng / mL (63.5%). Yes, that is, it was 5.3 times higher. The corresponding mean AUClast (CV%) value was 0. At 638 ng* hours / mL (46.0%) and 4.38 ng* hours / mL (67.0%) Yes, it indicates a 6.9-fold increase over a four-day period.

[0322] [Table 30]

[0323] Bandage contact lenses Bandage contact lenses (BCLs) were collected from 40 patients who received the treatment on day 4. Compound I was analyzed. Values ​​from patients who did not adhere to the three IMPs were approximate for BCL. Excluding from the statistics, 37 values ​​including one value from a patient who does not have available plasma PK. This remained as something that could be evaluated. Average concentration of compound I in 0.55 mL of extract (CV%) ) was 8500 ng / mL (73.1%), with a broad range of 284-22600 ng / mL. The range was as follows: These concentrations were 4680 ng / lens (0.55 mL × 8500 ng / Estimated average (mL), converted to a range of 156-12400 ng / lens. BCL The amount was very small compared to the administered dose of compound I (0.925 mg): mean 0. 51%, and in the range of 0.017% to 1.3% of the dose. This is because BCL is localized in the eye. It absorbs and retains compound I, but in amounts negligible compared to the local dose in the eye. To indicate something.

[0324] Summary of pharmacokinetic results Compound I after either a single dose (first administration) or repeated topical instillation four times daily. Absorption into the systemic circulation was rapid (median plasma Tmax was approximately 0.5 hours). . • Systemic exposure was low after both single and repeated topical instillation of compound I, followed by 4-day repeated QID administration. The range is from 0.195 ng / mL to 7.56 ng / mL, indicating moderate variability. The average Cmax was 0.454 ng / mL after the first dose on day 1, and on day 4. The blood glucose level was 2.40 ng / mL after the 13th dose to the eye. • The CV% values ​​for Cmax and AUClast after a single dose were 49.9% and 49.9%, respectively. The initial rate was 46.0%. The corresponding values ​​after repeated administration were 63.5% and 67.0%, respectively. . • The mean Cmax (2.40 ng / mL) after repeated administration was (0.45) after a single dose on day 1. It was 5.3 times higher than 4 ng / mL. Similarly, the mean AUClast was compared to after a single dose. The risk was 6.9 times higher after repeated administration (4.38 compared to 0.638 ng* / hour / mL). These data showed accumulation over a 4-day period with four doses of 2.5% compound I administered daily. • Bandage contact lenses (BCLs) were administered to 40 patients on day 4. The average concentration (CV%) in 0.55 mL of the extracted liquid was 8500 ng / mL (73 This is 0.1%, which translates to an estimated 4680 ng / lens. The amount in BCL is 0.9 The percentage was very low for compound I administered at a 25 mg dose: 0.51%, and the percentage was The range is 0.017% to 1.3%. This is because BCL absorbs compound I locally in the eye. Furthermore, it is maintained, but at a negligible amount compared to the local dose in the eye.

[0325] safety Safety assessment includes all AEs and SAEs, along with their severity and relationship to the investigational drug. The data was collected from the following sources. Table 29 shows the common signs and symptoms in the post-PRK surgery situation. Includes a list of signs and symptoms. Signs and symptoms that are higher than the listed range of either severity or duration. Only the symptoms were reported as AE.

[0326] [Table 31]

[0327] One week includes the 8th postoperative visit (6th visit in treatment period 1), which is within an acceptable range. Or, recovery up to the 11th visit in treatment period 2. The table shows standard PRK surgery. All major clinical symptoms based on collected experience, including those that commonly occur and are expected later. It was created before the start of the trial, along with feedback from the principal investigator and surgeons.

[0328] One month until the EOS visit, or if the EOS visit is not performed or during the trial surgery. If recovery takes longer than one week, it indicates recovery within 37 days of surgery.

[0329] Adverse events and severe adverse events included assessments of both the whole body and the eyes. (Whole body safety assessment) This includes height and weight, signs of life, reports of medication errors including misuse / abuse, reports of pregnancy, and early This included safety monitoring of misuse / abuse, pregnancy reporting, and early safety monitoring. This was not evaluated in relation to this study. The ocular safety evaluation included the following: • Best corrected visual acuity (BCVA) and uncorrected visual acuity (UCVA): 4 meters (13 feet) ) or ETDRS visual acuity at 1 meter (for patients who could not read the 4-meter chart) Measurements were taken at each visit using a table. BCVA scoring was done by assigning 30 points to the letters that were read correctly. It was done based on the sum of the numbers. The patient had to read one of the largest letters within one meter. If visual acuity was too weak to perform the test, the immediate index, immediate manual visual acuity, and light perception were tested. • Intraocular pressure (IOP): IOP measurement is performed using applanation tonometry or Tonopen. Ta. • Expanded fundus examination: The expanded fundus examination is a fundus examination of the vitreous humor, retina / macula / choroid, and optic nerve. Includes assessment. Retinal tear / detachment, retinal hemorrhage, vitreous hemorrhage density, classification of vitreous opacity and An evaluation of abnormal findings was conducted and scored according to classification criteria. • Conjunctival congestion: Conjunctival congestion in each eye under a slit lamp according to the McMonnies redness scale. Conjunctival redness was classified. Redness was observed in four areas of each eye (superior, inferior, temporal, and nasal). The severity of each area was evaluated using a scoring system from 0 to 5. • Size of epithelial defect observed in slit-lamp testing: oblique viewing angle relative to the source beam and slit beam. Using degrees, the cornea is divided to visualize the vertical and horizontal boundaries of corneal wounds. Calibrated By adjusting the width and height of the slit beam, the maximum horizontal width of the surgical epithelial wound can be achieved. The horizontal and vertical dimensions (height of the wound) were estimated. Wound closure and the horizontal and vertical dimensions of 0 were estimated. The evaluation was conducted up to the point of reporting the dimensions. • Slit-lamp biomicroscopy: Eye signs (eyelids / conjunctiva, cornea, lens, and iris / anterior chamber) Both eyes were evaluated by slit-lamp biomicroscopy according to classification criteria. • Blinking speed: Blinking is the paroxysmal closure of both eyelids in the absence of external stimulation. Defined as (duration < 1 second). Each blink evaluation was performed for 2 minutes (or a minimum of 1 minute). (Get as close to 2 minutes as possible) Then, the obtained blink rate is averaged to get the blink rate per minute The flapping speed was calculated. • Tear production (Schirmer test without anesthesia): This test involves anesthesia in both eyes simultaneously. It was performed without any intervention. Tear secretion is measured in millimeters in length of a fragment moistened by tears. It was measured. The measurement was performed on the nearest integer. • Corneal staining: This test involves applying a moist end of a fluorescein sodium sac to the inferior conjunctival sac. This was performed by gently bringing the samples into contact. The samples were moistened with one drop of sterile saline solution. The excess saline solution was removed by flicking it with a finger. The patient had five areas (center and four others) For each quadrant, 0-3 (0 = normal, no staining; 1 = mild, minute surface spots) Punctate staining; 2 = moderate, large punctate staining with some adherent areas, and 3 = severe Before classifying the entire tear film into scales of numerous adherent, minute dot-like areas and / or spots, I blinked several times to ensure the pigment was evenly distributed throughout my body.

[0330] Safety evaluation Death, SAE, drug interruption, or interruption of a test due to an AE in the test is punishable by law. There were none. In total, 18 adverse events (AEs) occurred in 10 patients (25% of the 40 registered patients). These cases were reported, with 12 occurring after treatment with compound I and 5 after treatment with the solvent. One case occurred in one patient prior to administration of the study drug. All AEs were classified by severity. The condition was either mild or moderate.

[0331] In total, 10 patients (25%) experienced at least one emergency AE during treatment, and 5 patients One patient experienced one AE, and five patients experienced two or more AEs. The five patients were AEs occurred only during treatment with compound I, and two patients experienced AEs only during treatment with the solvent. During the first treatment, three patients experienced adverse reactions (AEs) with both compound I and the solvent. There was one adverse event (headache) that occurred before administration of the test drug.

[0332] Four patients (10% of the 40 registered patients) had six ocular AEs. All cases were mild in severity (three eyes treated with compound I and solvent, respectively). No adverse events (AEs) were suspected to be related to either of the test substances (compound I or the solvent). (6 cases) Five of the ocular AEs were treated with PRK by the principal investigator (two were treated with compound I). It was thought to be related to the eye (three of which belonged to eyes treated with a solvent).

[0333] There were 12 non-ocular AEs in 7 patients (17.5%) (6 of which were due to compound I). Two of the eyes were treated with a solvent, and one was treated during a period when no drug was administered. Patients). Five AEs in four patients (10%) were of moderate severity (four of which were...). Eyes treated with compound I and one eye treated with the solvent. The remaining AEs were mild. The severity was as described. There were no suspected adverse events (AEs) related to compound I or the solvent.

[0334] Table 30 provides the overall incidence rates of adverse events.

[0335] [Table 32]

[0336] Eye safety evaluation Best corrected visual acuity (BCVA) and uncorrected visual acuity (UCVA): Administration of compound I throughout the study There was no trend or significant difference between eyes treated with compound I and the solvent. Therefore, the data does not indicate that compound I has a harmful effect on BCVA and UCVA. It demonstrates pain reduction.

[0337] Intraocular pressure (IOP): Trend over planned time points or in eyes treated with compound I and solvent No significant differences were observed between the treated eyes throughout the study. There was a slight increase (<5mmHg) in the average IOP value compared to the baseline. Slight changes in the average score during the test were not clinically problematic.

[0338] Dilated fundus examination: Abnormal findings are observed at the scheduled time for eyes treated with compound I and the solvent. This was not reported by the principal investigator over the course of the trial.

[0339] Eye redness: The bar graph shows the time course of eye redness in eyes treated with compound I and placebo. These are provided in Figures 8A and 8B, respectively. Figures 8A and 8B are provided for the third day and On day 4, grades 4 and 3 (measured by the McMonnies scale) The image shows conjunctival congestion on day 2 after surgery (24 days after PRK surgery). As can be seen in Figure 8A, In terms of time, eyes treated with compound I showed grayness compared to eyes treated with the solvent. Congestion in quadrant 4 (all quadrants) was minimal. In the upper quadrant, the p-value for this difference was 0. The result was 0.04. This was compared to eyes treated with the solvent on day 3 (48 hours after PRK surgery). Less grade 3 conjunctivitis was observed in eyes treated with compound I. The observation was not recorded as an AE.

[0340] Size of epithelial defect by slit-lamp test: To evaluate the rate of wound healing after administration of compound I. Therefore, the epithelial defect was observed in both the population treated with compound I and the population treated with the solvent. The size was measured. The oval area of ​​the epithelial wound size was calculated as follows: slit lamp From the width and height of the epithelial defect measured, the area (mm²) 2 ) = width × height × pi. Compound I and The difference in epithelial wound area between the solvent and the patient was observed at any point except on day 2 after PRK surgery. Even if present, the difference was not significant (all p-values ​​for area differences were >0.35). 2 On day 1 (24 hours post-surgery), the mean epithelium of patients treated with compound I and solvent The difference in the area of ​​defect is 11.23 mm. 2 The result was (p-value = 0.034). This difference was due to the difference immediately after surgery. There were no clinically significant problems during the period. Up to day 3 (48 hours post-surgery), compound I and There was no difference between the eyes treated with the solvent, and the wound area was very small. Day 4 (post-surgery) Within 72 hours, almost all eyes were healed, and eyes treated with compound I and those treated with the solvent were healed. There was no difference between the treated eyes. Compound I showed a delay in wound healing compared to the solvent. I didn't.

[0341] Figure 9 and Table 31 show the difference in epithelial defects in eyes treated with compound I compared to eyes treated with the solvent. This provides a comparison of the sizes.

[0342] [Table 33]

[0343] Slit-lamp biomicroscopy: Slit-lamp biomicroscopy allows us to examine the structure of the eye (eyelids / conjunctiva, cornea, iris). The examination consisted of tests on the anterior chamber, lens, aqueous humor flare, and the degree of aqueous humor inflammation. Over the period, aqueous humor flare and No abnormalities were observed in the degree of aqueous humor inflammation, the iris / anterior chamber, or the ocular structure of the lens. .

[0344] Blinking speed: There was variation in the average blinking speed; treatment with compound I and solvent Trends or significant differences in blink rate between post-treatment periods over the planned time points should be observed throughout the entire study. This was not observed. At the end of the test, compared to baseline, the blink rate was No clinically relevant changes were observed.

[0345] Corneal staining: Most patients had positive results measured at baseline, day 8, and at EOS visit. The patient exhibited normal (grade 0) staining. At baseline, on day 8, or at EOS visit, In either case, clinical results in corneal staining between eyes treated with compound I in relation to the solvent. No significant difference was observed.

[0346] Safety-related vital signs, physical findings and other observations: vital sign parameters (systolic and Diastolic blood pressure, pulse rate, and body temperature were within the normal range in all patients during the study. No life-threatening adverse events (AEs) were observed. Electrocardiograms and special safety topics were performed. And not evaluated (by protocol).

[0347] Summary of Safety Results • No deaths, serious or severe adverse events, treatment interruptions, or other incidents reported in this study occurred during the trial. There was no decision. • No adverse events (AEs) were found to be associated with the test drug (either compound I or the solvent). 4 Eight out of 0 patients and five out of 40 patients were affected by compound I and the solvent, respectively. AEs developed after treatment. All ocular AEs were mild and were in equilibrium between compound I and the solvent. Most of these were well-known adverse events (AEs) related to PRK treatment. No clinically significant differences in safety were observed between compound I and the solvent. Compound I did not show any delay in wound healing compared to the solvent. • Eyes treated with compound I showed better results on day 2 (24 hours post-surgery) compared to eyes treated with the solvent. ) showed less severe conjunctival hyperemia. Compared to the solvent, BCVA, IOP, slit-lamp biomicroscopy, and pupillary dilation after administration of compound I Clinically relevant findings observed regarding examination, blink rate, tear production, corneal staining, or vital signs. There was no change.

[0348] The incidence rates of AEs using preferred terminology are shown in Table 32.

[0349] [Table 34]

[0350] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document were specifically and individually directed to be incorporated herein by reference. The present invention and its embodiments are described in detail. However, the scope of the present invention is not intended to be limited to any particular embodiment of any process, manufacture, composition of substance, compound, means, method, and / or process described herein. Various modifications, substitutions, and variations can be made to the materials of the Disclosure without departing from the spirit and / or essential features of the present invention. Accordingly, those skilled in the art will readily understand from the present invention that later modifications, substitutions, and / or variations that substantially perform the same function as or substantially achieve the same results as the embodiments described herein can be used in accordance with such relevant embodiments of the present invention. Accordingly, the following claims are intended to encompass within their scope the modifications, substitutions, and variations to the processes, manufacture, composition of substance, compound, means, method, and / or process disclosed herein. Unless otherwise stated in intent, the claims should not be construed as being limited to the order or elements described. It should be understood that various modifications to form and detail may be made without departing from the scope of the attached claims. The present invention includes the following embodiments. <1> 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I), or its salt, cocrystal, or polymorph, One or more excipients selected from the group consisting of surfactants, suspending agents, isotonic agents, buffers, salts, and preservatives, A water-based formulation containing [a specific ingredient / method]. <2> The aforementioned 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I), or its salt, cocrystal, or polymorph, is present as a suspension in the formulation. <1> The aqueous formulation described above. <3> The aforementioned 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I), or its salt, cocrystal, or polymorph, is present in the formulation in an amount of approximately 0.5% w / v to approximately 3.5% w / v. <1> or <2> An aqueous formulation as described in any of the following. <4> Approximately 0.5% w / v to approximately 3.5% w / v of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I), or its salt, cocrystal, or polymorph, Surfactants and Suspensioning agent, Furthermore, one or more excipients selected from the group consisting of isotonic agents, buffers, salts, and preservatives, including, <1> ~ <3> An aqueous formulation as described in any of the following. <5> 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I), or its salt, cocrystal, or polymorph, which is present in the formulation as a suspension in an amount of approximately 0.5% w / v to approximately 3.5% w / v, Nonionic surfactants, Suspensioning agent, Isotonic agent, Cushioning material, Salt and, By choice, preservatives and including, <1> ~ <4> An aqueous formulation as described in any of the following. <6> A suspension of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I), or its salt, cocrystal, or polymorph, in an amount of approximately 0.5% w / v to approximately 3.5% w / v, A surfactant selected from the group consisting of nonionic surfactants, anionic surfactants, cationic surfactants, and combinations thereof, Suspensioning agent, Isotonic agent, Cushioning material, By choice, salt and By choice, preservatives and A sufficient amount (qs) of water to reach 100%, A formulation containing the above. <7> The aforementioned surfactant is a nonionic surfactant. <1> ~ <6> A preparation described in any of the following. <8> The nonionic surfactant is selected from the group consisting of polysorbate surfactants, ethylene oxide block copolymers, propylene oxide surfactants, poloxamers, tyroxapole, and combinations thereof. <7> The preparation described above. <9> The nonionic surfactant is tyroxapole, which is optionally combined with one or more of the following: a polysorbate surfactant, a block copolymer of ethylene oxide, a propylene oxide surfactant, or a poloxamer. <8> The preparation described above. <10> The nonionic surfactant is tyroxapol, which is present in an amount of 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 in an amount of about 1% w / v or less, about 0.5% w / v or less, about 0.3% w / v or less, about 0.2% w / v or less, about 0.1% w / v or less, or about 0.08% w / v or less. <7> The preparation described above. <11> Contains tyroxapole in an amount of approximately 0.03% w / v to 0.08% w / v, or approximately 0.05% w / v. <10> The preparation described above. <12> The nonionic surfactant is a poloxamer in an amount of approximately 15% w / v to approximately 20% w / v of the formulation. <1> ~ <7> A preparation described in any of the following. <13> The suspending agent is selected from the group consisting of carbomer, hydroxypropyl methylcellulose (hypromellose), polyethylene glycol, and combinations thereof. <1> ~ <12> A preparation described in any of the following. <14> The suspending agent is a carbomer present in the formulation in an amount of at least about 0.05% w / v, at least about 0.1% w / v, or at least about 0.2% w / v, and at least about 1.0% w / v or less, about 0.6% w / v or less, or about 0.5% w / v or less. <13> The preparation described above. <15> The carbomer is present in the formulation in an amount of 0.1% w / v to approximately 0.3% w / v, or approximately 0.2% w / v. <14> The preparation described above. <16> The suspending agent is hydroxypropyl methylcellulose present in the formulation in an amount of at least about 0.05% 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% w / v. <13> The preparation described above. <17> The suspending agent is polyethylene glycol (PEG) having a molecular weight of approximately 200 Da to approximately 20,000 Da. <13> The preparation described above. <18> The suspending agent is PEG400 at a concentration of approximately 4% w / v to approximately 9% w / v, approximately 5% w / v to approximately 8% w / v, or approximately 7% w / v, or PEG6000 at a concentration of approximately 1% w / v to approximately 4% w / v, approximately 1% w / v to approximately 3% w / v, or approximately 2% w / v. <17> The preparation described above. <19> The suspending agent is substantially all carbomer homopolymer type B. <1> ~ <15> A preparation described in any of the following. <20> The isotonic agent is selected from the group consisting of polyols. <1> ~ <19> A preparation described in any of the following. <21> The polyol is selected from the group consisting of mannitol, glycerin, xylitol, sorbitol, and propylene glycol, and combinations thereof. <20> The preparation described above. <22> The polyol is present in amounts of approximately 0.05% w / v to approximately 10% w / v, approximately 0.1% w / v to approximately 8% w / v, approximately 0.1% w / v to approximately 7% w / v, and approximately 0.1% w / v to approximately 5% w / v. <21> The preparation described above. <23> The polyol is mannitol or glycerin present in the formulation in amounts of 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 5% w / v. <22> The preparation described above. <24> The buffering agent is selected from the group consisting of acetate, ascorbate, borate, bicarbonate, carbonate, citrate, EDTA, gluconate, lactate, phosphate, propionate, and TRIS (tromethamine). <1> ~ <23> A preparation described in any of the following. <25> The buffering agent is a phosphate or TRIS. <24> The preparation described above. <26> The salt is sodium chloride. <1> ~ <25> A preparation described in any of the following. <27> The suspending agent is Carbopol (carbomer homopolymer type B), and the amount of sodium chloride is adjusted to produce a viscosity of approximately 20 cP to approximately 200 cP when using spindle CP-42 at 60 rpm at approximately 25°C. <19> The preparation described above. <28> The sodium chloride is present in amounts of approximately 0.01% w / v to approximately 0.5% w / v, approximately 0.02% w / v to approximately 0.4% w / v, approximately 0.03% w / v to approximately 0.3% w / v, approximately 0.04% w / v to approximately 0.2% w / v, approximately 0.05% w / v to approximately 0.1% w / v, or approximately 0.05% w / v. <26> The preparation described above. <29> The pH of the aforementioned formulation is approximately 5.0 to 8.0, approximately 5.5 to 8.0, approximately 5.5 to 7.5, approximately 5.0 to 7.4, approximately 5.5 to 7.4, approximately 6.0 to 8.0, approximately 6.5 to 8.0, approximately 6.0 to 7.4, or approximately 6.5 to 7.4. <1> ~ <28> A preparation described in any of the following. <30> The pH of the aforementioned formulation is approximately 6.0 to approximately 8.0, approximately 6.0, or approximately 7.4. <29> The preparation described above. <31> The present invention further comprises an additional agent selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl β-cyclodextrin, and sulfoalkyl ether β-cyclodextrin, in an amount of 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%, but in an amount of about 10.0 w / v% or less, about 8.0 w / v% or less, about 6.5 w / v% or less, or about 5.5 w / v% or less. <1> ~ <30> A preparation described in any of the following. <32> The present invention further includes an additional agent selected from the group consisting of cyclodextrins, in an amount of at least approximately 1.5 w / v%, at least approximately 3.0 w / v%, at least approximately 3.5 w / v%, or at least approximately 4.5 w / v%, but in an amount of approximately 10.0 w / v% or less, approximately 8.0 w / v% or less, approximately 6.5 w / v% or less, or approximately 5.5 w / v% or less. <1> ~ <31> A preparation described in any of the following. <33> The cyclodextrin is hydroxypropyl β-cyclodextrin or sulfoalkyl ether β-cyclodextrin in an amount of approximately 5% w / v of the formulation. <32> The preparation described above. <34> The aforementioned compound I, or its salt, cocrystal, or polymorph, is present in an amount of approximately 0.5% w / v to approximately 2.5% w / v. The nonionic surfactant is tyroxapole, poloxamer, or a combination thereof in an amount of approximately 0.01% w / v to 0.2% w / v; The suspending agent is hydroxypropyl methylcellulose, polyethylene glycol, or carbomer homopolymer type B; The isotonic agent is at least one polyol in an amount of about 0.05% w / v to about 10% w / v; The buffering agent is an edetate, a phosphate, a borate, or a combination thereof. salt; and Contains up to 100% qs of water; and The pH is in the range of approximately 5.5 to 8.0. <6> The preparation described above. <35> Compound I, or its salt, cocrystal, or polymorph, is present in amounts of approximately 0.5% w / v, approximately 1.0% w / v, approximately 1.5% w / v, approximately 2.0% w / v, or approximately 2.5% w / v. The nonionic surfactant is tyroxapole in an amount of about 0.04% w / v to about 0.06% w / v, poloxamer in an amount of about 15% w / v to 20% w / v, or a combination thereof; The suspending agent is approximately 0.1% w / v to approximately 0.8 w / v% of hydroxypropyl methylcellulose, approximately 2% w / v to approximately 8% w / v of polyethylene glycol, approximately 0.05% w / v to approximately 0.5% w / v of carbomer homopolymer type B, or a combination thereof; The isotonic agent is mannitol or glycerin in an amount of approximately 0.1% w / v to approximately 5% w / v; The buffering agent is edetate, phosphate, borate, tromethamine, or a combination thereof; Sodium chloride in amounts ranging from 0.01% w / v to approximately 1% w / v; and Contains up to 100% qs of water; and The pH is in the range of approximately 5.5 to 8.0. <1> ~ <34> A preparation described in any of the following. <36> A suspension of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or its salt, cocrystal, or polymorph in an amount of approximately 0.5% w / v, approximately 1.0% w / v, approximately 1.5% w / v, approximately 2.0% w / v, or approximately 2.5% w / v, Tyroxapole in amounts of approximately 0.04% w / v to approximately 0.06% w / v, Carbomer homopolymer type B in amounts of approximately 0.05% w / v to approximately 0.4% w / v, Glycerin in an amount of approximately 0.5% w / v to approximately 5% w / v, A buffering agent selected from the group consisting of edetates, phosphates, borates, tromethamine, and combinations thereof, Sodium chloride in amounts ranging from 0.01% w / v to approximately 1% w / v, Up to 100% QS water, A formulation containing; The formulation has a pH in the range of approximately 5.5 to approximately 8.0. <1> ~ <35> A preparation described in any of the following. <37> Compound I is polymorph B. <1> ~ <36> A preparation described in any of the following. <38> A suspension of polymorph B of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) in amounts of approximately 0.5% w / v, approximately 1.0% w / v, approximately 1.5% w / v, approximately 2.0% w / v, or approximately 2.5% w / v, Tyroxapole in amounts of approximately 0.04% w / v to approximately 0.06% w / v, Carbomer homopolymer type B in amounts of approximately 0.05% w / v to approximately 0.4% w / v, Glycerin in an amount of approximately 0.5% w / v to approximately 5% w / v, A buffering agent selected from edetate, phosphate, borate, tromethamine, or a combination thereof, Sodium chloride in amounts ranging from 0.01% w / v to approximately 1% w / v, Up to 100% QS water, A formulation containing; A formulation having a pH in the range of approximately 5.5 to approximately 8.0. <39> Compound I in amounts of approximately 0.5% w / v, approximately 1.0% w / v, approximately 1.5% w / v, approximately 2.0% w / v, or approximately 2.5% w / v, Approximately 0.05% w / v tyroxapole, Approximately 0.2% w / v carbomer homopolymer type B, Approximately 2.0% glycerin, Tromethamine buffer and, Hydrochloric acid to adjust the pH to approximately 6.4 to approximately 8.4, Approximately 0.05% w / v sodium chloride, Up to 100% QS water, A formulation containing; The aforementioned formulation does not contain preservatives. <38> The preparation described above. <40> The aforementioned polymorph B is characterized by an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from 9.3, 10.6, and 14.4 ± 0.2°2θ. <37> ~ <40> A preparation described in any of the following. <41> When measured at approximately 25°C using a CP-42 spindle at either 3 rpm or 60 rpm, it has a viscosity of approximately 20 cP to approximately 200 cP. <1> ~ <40> A preparation described in any of the following. <42> It has a gravimetric osmole concentration of approximately 200 to 450 milliosmoles per kilogram (mOsm / kg). <1> ~ <41> A preparation described in any of the following. <43> The aforementioned formulation exhibits a precipitate of less than approximately 10%, less than approximately 8%, less than approximately 7%, less than approximately 6%, less than approximately 5%, less than approximately 4%, less than approximately 3%, or less than approximately 2% after storage at room temperature for 6 months. <1> ~ <42> A preparation described in any of the following. <44> The amount of compound I in the aforementioned formulation is at least 90% of the initial amount after approximately 6 months, 8 months, 10 months, 12 months, 15 months, or 18 months of storage under refrigeration. <1> ~ <43> A preparation described in any of the following. <45> The amount of compound I in the formulation is at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least 96%, at least about 97%, or at least about 98% of the initial amount after about 18 months of storage under refrigeration. <1> ~ <44> A preparation described in any of the following. <46> The aforementioned formulation, after 6 months under refrigeration, has a degradation product of approximately 10% or less, and when the degradation product is analyzed by HPMC using a gradient of 0.1% trifluoroacetic acid (TFA) water / acetonitrile mobile phase, it has a relative retention time of 1.23 compared to compound I. <1> ~ <45> A preparation described in any of the following. <47> Approximately 10% or less of compound I in the aforementioned formulation decomposes during storage at 40°C for 12 weeks. <1> ~ <46> A preparation described in any of the following. <48> A certain amount of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I), or its salt, cocrystal, or polymorph, Nonionic surfactants, Suspensioning agent, Isotonic agent, Cushioning material, Salt and, By choice, preservatives and Up to 100% QS water, Mixing; and A method for preparing a pharmaceutical product, including adjusting the pH to a range of approximately 5.5 to 8.0. <49> The aforementioned compound I is added as a storage suspension. <48> Methods used. <50> The stored suspension is pulverized to obtain compound I of a desired particle size. <48> ~ <49> One of the methods described above. <51> The stored suspension is atomized into fine particles. <50> Methods used. <52> A method for treating ocular surface pain in the target population, comprising:

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Claims

1. A suspension of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or its salt, cocrystal, or polymorph in an amount of approximately 0.5% w / v to approximately 2.5% w / v; A nonionic surfactant containing tyroxapol and poloxamer in an amount of approximately 0.01% w / v to 0.2% w / v; A suspending agent selected from hydroxypropyl methylcellulose, polyethylene glycol, or carbomer homopolymer type B; With an isotonic agent selected from polyols in an amount of approximately 0.05% w / v to approximately 10% w / v; A buffering agent selected from edetate, phosphate, borate, tromethamine, or a combination thereof; Salt and; With enough water (qs) to make the total volume 100%; Includes, A suspension formulation with a pH in the range of approximately 5.5 to 8.

0.

2. 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or its salt, cocrystal, or polymorph is present in amounts of about 0.5% w / v, about 1.0% w / v, about 1.5% w / v, about 2.0% w / v, or about 2.5% w / v; The suspending agent is approximately 0.1% w / v to approximately 0.8 w / v% of hydroxypropyl methylcellulose, or approximately 2% w / v to approximately 8% w / v of polyethylene glycol, or approximately 0.05% w / v to approximately 0.5% w / v of carbomer homopolymer type B, or a combination thereof; The isotonic agent is mannitol or glycerin in an amount of about 0.1% w / v to about 5% w / v; The buffering agent is edetate, phosphate, borate, tromethamine, or a combination thereof; The salt is sodium chloride in an amount of 0.01% w / v to approximately 1% w / v. The suspension formulation according to claim 1.

3. The suspension formulation according to claim 1 or 2, wherein compound I is polymorphic form B.

4. 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or its salt, cocrystal, or polymorph is present in amounts of about 0.5% w / v, about 1.0% w / v, about 1.5% w / v, about 2.0% w / v, or about 2.5% w / v; The suspending agent is a carbomer homopolymer type B in an amount of approximately 0.05% w / v to approximately 0.4% w / v; The isotonic agent is glycerin in an amount of about 0.5% w / v to about 5% w / v; The buffering agent is edetate, phosphate, borate, tromethamine, or a combination thereof; The salt is sodium chloride in an amount of 0.01% w / v to approximately 1% w / v. A suspension formulation according to any one of claims 1 to 3.

5. 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (compound I) or its salt, cocrystal, or polymorph is present in amounts of about 0.5% w / v, about 1.0% w / v, about 1.5% w / v, about 2.0% w / v, or about 2.5% w / v; The suspending agent is a carbomer homopolymer type B in an amount of approximately 0.2% w / v; The isotonic agent is approximately 2.0% glycerin; The buffer is a tromethamine buffer; The salt is sodium chloride at approximately 0.05% w / v; The suspension formulation contains hydrochloric acid to adjust the pH to approximately 6.4 to approximately 8.4; The aforementioned suspension formulation does not contain a preservative. The suspension formulation according to claim 3.

6. The suspension formulation according to claim 3, wherein the isotonic agent is glycerin in an amount of 0.5% w / v to 5% w / v.

7. The suspension formulation according to claim 3, wherein the suspending agent is hydroxypropyl methylcellulose in an amount of 0.1% w / v to 0.8 w / v%.

8. The suspension formulation according to claim 1, wherein the isotonic agent is propylene glycol.

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