Ophthalmic preparations containing pyridine phenyl compounds, methods for their preparation and use - Patent Application 20070122997

Abstract

The present invention relates to pharmaceutical preparations and discloses an ophthalmic formulation containing a pyridine phenyl compound, its preparation method, and use. The ophthalmic formulation comprises an active ingredient, a pyridine phenyl compound, and an excipient. The active ingredient, a pyridine phenyl compound, includes a compound of formula (II), an isomer thereof, or a pharmaceutically acceptable salt thereof. The ophthalmic formulation can be used to treat dry eye disease, allergic conjunctivitis, macular degeneration, cataracts, keratoconus, bullous keratopathy, Fuchs' corneal endothelial dystrophy, ocular cicatricial pemphigoid, meibomian gland dysfunction, uveitis, scleritis, Stevens-Johnson syndrome, ocular rosacea, and Sjögren's syndrome. [Formula 1] JPEG2025538598000077.jpg45170

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceutical preparations and relates to an ophthalmic formulation of a pyridine phenyl compound, a method for preparing same, and its use in ophthalmic diseases. [Background technology]

[0002] Dry eye disease, also known as keratoconjunctivitis sicca, refers to a variety of disorders caused by abnormalities in the quality, quantity, or rate of tear production, resulting in decreased tear film stability and associated ocular discomfort or ocular surface tissue damage. Specific symptoms of discomfort include eye irritation, blurred vision, and an unstable tear film. Some syndromes are caused by inflammation of the ocular surface, leading to loss of lacrimal gland function. Furthermore, these syndromes are also associated with systemic autoimmunity.

[0003] Due to the production of toxic aldehydes such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4HNE) by metabolic mechanisms in the body or eye organs, these aldehydes highly react with proteins, carbohydrates, lipids and DNA, leading to the chemical modification of biomolecules and the activation of inflammatory molecular regulators such as NF-kappa B, thereby promoting damage to various organs, which is one of the causes of dry eye disease.

[0004] According to the present invention, a small molecule drug is administered in the form of eye drops to the site of inflammation in the eye via a complexation reaction with endogenous aldehydes, thereby reducing the toxicity of aldehydes, alleviating inflammation, and achieving the effect of treating dry eye disease.

[0005] WO2020 / 125659 discloses pyridine phenylaldehyde-linked compounds and a series of compounds satisfying formula (I), including their isomers or pharmaceutically acceptable salts:

[0006] [ka] [Prior art documents] [Patent documents]

[0007] [Patent Document 1] WO2020 / 125659 Summary of the Invention [Problem to be solved by the invention]

[0008] However, its ophthalmic formulation and its therapeutic effect on ophthalmic diseases have not yet been disclosed. Therefore, further research is needed to discover the efficacy and safety of ophthalmic formulations containing the above-mentioned small molecule compounds for ophthalmic diseases such as dry eye disease, allergic conjunctivitis, macular degeneration, cataract, keratoconus, bullous keratopathy, Fuchs' endothelial corneal dystrophy, ocular cicatricial pemphigoid, meibomian gland dysfunction, uveitis, scleritis, Stevens-Johnson syndrome, ocular rosacea, and Sjogren's syndrome, as well as to develop ophthalmic formulations with stable preparation methods and quality. [Means for solving the problem]

[0009] An object of the present invention is to provide a safe and effective ophthalmic formulation that has a simple preparation method and stable quality, and is suitable for industrial production.

[0010] The present invention provides an ophthalmic formulation comprising an active ingredient, i.e., a pyridine phenyl compound, and excipients, wherein the excipients comprise a solubilizing agent, a pH modifier, an osmolality adjusting agent, an antimicrobial preservative, and an antioxidant, and the active compound comprises a compound of formula (I), its isomer, or a pharmaceutically acceptable salt thereof. The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0011] [ka]

[0012] (In the formula, T1, T2, T3 and T4 are each independently selected from N, C or CR1; L is selected from a single bond, —O—, —S—, —NR—, or —(CR—R—); R1 is selected from H, F, Cl, Br, I, OH or NH2; R2 is H and one, two or three R a C1-3 alkyl groups optionally substituted with R3 and R4 are each H, F, Cl, Br, I, OH, NH2, CN, or one, two, or three R b and n is selected from 1, 2 or 3; R a and R b are each independently selected from H, F, Cl, Br, I, OH, NH2, CN, or CH3

[0013] In some embodiments of the present invention, R2 above is selected from H, CH3 or CH2CH3, and CH3 and CH2CH3 are selected from one, two or three R a and other variables are as defined herein.

[0014] In some embodiments of the present invention, R2 above is selected from H, CH3, or CH2CH3, and other variables are as defined herein.

[0015] In some embodiments of the invention, R and R are each independently selected from H, F, Cl, Br, I, OH, NH, CN, CH, or CHCH, and CH and CHCH are independently selected from one, two, or three R b and optionally substituted with: Other variables are as defined herein.

[0016] In some embodiments of the invention, R and R are each independently selected from H, F, Cl, Br, I, OH, NH, CN, CH, or CHCH. Other variables are as defined herein.

[0017] In some embodiments of the present invention, L above is selected from a single bond, —O—, —S—, —NH—, —(CH 2 ) 2 —, or —CH 2 —, and other variables are as defined herein.

[0018] The present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0019] [ka]

[0020] (In the formula,

[0021] [ka]

[0022] is selected from a single bond or a double bond; T1, T2, T3 and T4 are each independently selected from N, C or CR1; T5 is selected from C, CR5 or C=O; T6 is selected from C, CR6 or N; T7 is selected from N or CR7; When T5 is selected from C=O and T6 is selected from N,

[0023] [ka]

[0024] is selected from a single bond, L is selected from a single bond, —O—, —S—, —NR—, or —(CR—R—); each R1 is independently selected from H, F, Cl, Br, I, OH, or NH2; R2 is H and one, two or three R a C1-3 alkyl groups optionally substituted with R3 and R4 are each H, F, Cl, Br, I, OH, NH2, CN, or one, two, or three R b and R5, R6 and R7 are each independently selected from H, F, Cl, Br or I; n is selected from 1, 2 or 3; R a and R b are each independently selected from H, F, Cl, Br, I, OH, NH2, CN, or CH3

[0025] In some embodiments of the present invention, R2 above is selected from H, CH3 or CH2CH3, and CH3 and CH2CH3 are selected from one, two or three R a and other variables are as defined herein.

[0026] In some embodiments of the present invention, R2 above is selected from H, CH3, or CH2CH3, and other variables are as defined herein.

[0027] In some embodiments of the invention, R and R are each independently selected from H, F, Cl, Br, I, OH, NH, CN, CH, or CHCH, where CH and CHCH are optionally substituted with one, two, or three R. Other variables are as defined herein.

[0028] In some embodiments of the present invention, R3 and R4 above are each independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3, or CH2CH3, and other variables are as defined herein.

[0029] In some embodiments of the present invention, L above is selected from a single bond, —O—, —S—, —NH—, —(CH 2 ) 2 —, and —CH 2 —, and other variables are as defined herein.

[0030] There are also several technical solutions of the present invention that can be obtained by any combination of the above variables.

[0031] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from the following compounds:

[0032] [ka]

[0033] (In the formula, T3 and T4 are independently selected from N and CR1, respectively; R1 and L are as defined in the present invention.

[0034] In some embodiments of the invention, the compound or a pharmaceutically acceptable salt thereof is selected from the following compounds:

[0035] [ka]

[0036] (In the formula, R1 and L are as defined in the present invention.

[0037] In one embodiment of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds:

[0038] [ka]

[0039] In the present invention, one embodiment is a compound of formula (III), an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0040] [ka]

[0041] In the present invention, one embodiment is a compound of formula (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0042] [ka]

[0043] In the present invention, one embodiment is a compound of formula (V), an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0044] [ka]

[0045] In the present invention, one embodiment is a compound of formula (VI), an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0046] [ka]

[0047] In the present invention, one embodiment is a compound of formula (VII), an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0048] [ka]

[0049] In the present invention, one embodiment is a compound of formula (VIII), an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0050] [ka]

[0051] In one embodiment of the present invention, the compound of formula (III) further contains one water molecule, which is the compound of the following formula IX, an isomer thereof, or a pharmaceutically acceptable salt thereof:

[0052] [ka]

[0053] In one embodiment of the present invention, the ophthalmic formulation comprises one of the compounds of formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) or formula (IX) disclosed in the present invention.

[0054] In one embodiment of the present invention, the ophthalmic formulation comprises one or more solubilizing agents.

[0055] In one embodiment of the present invention, the ophthalmic formulation comprises one or more pH modifying agents.

[0056] In one embodiment of the present invention, the ophthalmic formulation comprises one or more osmolality adjusting agents.

[0057] In one embodiment of the present invention, the ophthalmic formulation comprises one or more antimicrobial preservatives.

[0058] In one embodiment of the present invention, the ophthalmic formulation comprises one or more antioxidants.

[0059] In one embodiment of the present invention, the solubilizer is selected from methylated-β-cyclodextrin (RM-β-CD), hydroxypropyl betadex (HP-β-CD), hydroxypropyl-γ-cyclodextrin (HP-γ-CD), sulfobutylether-β-cyclodextrin (SBE-β-CD), poloxamer 407, polysorbate 80, povidone (PVP), polyethylene glycol (PEG400), or a combination of two or more thereof.

[0060] In one embodiment of the present invention, the pH modifier is selected from sodium dihydrogen phosphate monohydrate, sodium hydrogen phosphate, borax, boric acid, citric acid dihydrate, hydrochloric acid, sodium hydroxide, or a combination of two or more thereof.

[0061] In one embodiment of the present invention, the tonicity adjusting agent is selected from sodium chloride, boric acid, borax, glucose, mannitol, or a combination of two or more thereof.

[0062] In one embodiment of the present invention, the antimicrobial preservative is selected from benzalkonium chloride, chlorhexidine acetate, phenylmercuric acetate, or a combination of two or more thereof.

[0063] In one embodiment of the present invention, the antioxidant is selected from butylated hydroxyanisole (BHA), vitamin E (VE), or a combination of two or more thereof.

[0064] In one embodiment of the present invention, the lyophilization solvent is selected from 95% ethanol, tert-butanol, isopropanol, or acetonitrile.

[0065] The present invention provides an ophthalmic formulation comprising an active ingredient, a pyridine phenyl compound, one or more solubilizing agents, one or more pH modifiers, one or more osmolality adjusting agents, one or more antimicrobial preservatives, and one or more antioxidants, wherein the pyridine phenyl compound comprises a compound of Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula VIII, or Formula (IX), an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0066] [ka]

[0067] In the ophthalmic preparation provided by the present invention, the content of the active ingredient is 0.05 to 0.6% w / v, preferably 0.1% w / v, 0.11% w / v, 0.12% w / v, 0.13% w / v, 0.14% w / v, 0.15% w / v, 0.16% w / v, 0.17% w / v, 0.18% w / v, 0.19% w / v, 0.2% w / v, 0.21% w / v, 0.22% w / v, 0.23% w / v, 0.24% w / v, 0.25% w / v, 0.26% w / v, 0.27% w / v, 0.28% w / v, 0.29% w / v, 0.3% w / v, 0.31% w / v, 0.32% w / v, or 0.33% w / v. 0.34%w / v, 0.35%w / v, 0.36%w / v, 0.37%w / v, 0.38%w / v, 0.39%w / v, 0.4%w / v, 0.41%w / v, 0.42%w / v, 0.43%w / v, 0.44%w / v, 0. 45%w / v, 0.46%w / v, 0.47%w / v, 0.48%w / v, 0.49%w / v, 0.5%w / v, 0.51%w / v, 0.52%w / v, 0.53%w / v, 0.54%w / v or 0.55%w / v.

[0068] In the ophthalmic formulations provided herein, the solubilizing agent is selected from methylated-β-cyclodextrin (RM-β-CD), hydroxypropyl betadex (HP-β-CD), hydroxypropyl-γ-cyclodextrin (HP-γ-CD), sulfobutylether-β-cyclodextrin (SBE-β-CD), poloxamer 407, polysorbate 80, povidone (PVP), polyethylene glycol (PEG400), or a combination of two or more thereof.

[0069] In the ophthalmic preparation provided by the present invention, the content of the solubilizer is 0.2% to 15% w / v, preferably 0.3% w / v, 0.4% w / v, 0.5% w / v, 0.6% w / v, 0.65% w / v, 0.7% w / v, 0.75% w / v, 0.8% w / v, 0.85% w / v, 0.9% w / v, 0.95% w / v, 1.0% w / v, 1.1% w / v, 1.2% w / v, 1.3% w / v, 1.4% w / v, 1.5% w / v, 1.55% w / v, 1.6% w / v, 1.65% w / v, 1.7% w / v, 1.75% w / v, 1.8% w / v, 1.9% w / v, or 2.0% w / v. 2.1%w / v, 2.2%w / v, 2.3%w / v, 2.4%w / v, 2.5%w / v, 2.6%w / v, 2.7%w / v, 2.8 %w / v, 2.9%w / v, 3.0%w / v, 3.3%w / v, 3.5%w / v, 3.6%w / v, 3.8%w / v, 4.0%w / v , 4.2%w / v, 4.4%w / v, 4.5%w / v, 4.6%w / v, 4.8%w / v, 5.0%w / v, 5.2%w / v, 5.4 %w / v, 5.5%w / v, 5.6%w / v, 5.8%w / v, 6.0%w / v, 6.2%w / v, 6.5%w / v, 6.8%w / v 7.0%w / v, 7.2%w / v, 7.4%w / v, 7.5%w / v, 7.6%w / v, 7.8%w / v, 8.0%w / v, 8.2%w / v, 8.5%w / v, 8.6%w / v 8.8%w / v, 9.0%w / v, 9.2%w / v, 9.4%w / v, 9.5%w / v, 9.6%w / v, 9.8%w / v or 9.9%w / v.

[0070] In the ophthalmic preparation provided by the present invention, the content of the solubilizing agent hydroxypropyl betadex (HP-β-CD) is 0.5% w / v to 12% w / v, preferably 0.7% w / v to 10% w / v, more preferably 1% w / v to 8% w / v, and most preferably 1.2% w / v, 1.7% w / v, 1.75% w / v, 2% w / v, 2.5% w / v, 2.8% w / v, 3% w / v, 3.3% w / v, 3.5% w / v, 4% w / v, 4.4% w / v, 5% w / v, 5.5% w / v, 6% w / v, 7% w / v, 7.5% w / v, or 8% w / v.

[0071] In the ophthalmic preparation provided by the present invention, the content of sulfobutylether-β-cyclodextrin (SBE-β-CD) is selected from 4% to 13%, preferably 4.3% w / v, 5% w / v, 6% w / v, 7% w / v, 8% w / v, 9% w / v, 10% w / v, 11% w / v, 12% w / v, or 12.5% ​​w / v.

[0072] In the ophthalmic preparation provided by the present invention, the content of the pH modifier is 0.12 to 20% w / v, preferably 0.2% w / v, 0.25% w / v, 0.3% w / v, 0.35% w / v, 0.4% w / v, 0.47% w / v, 0.5% w / v, 0.6% w / v, 0.7% w / v, 0.8% w / v, 0.81% w / v, or 0. 9%w / v, 1%w / v, 2%w / v, 3%w / v, 4%w / v, 5%w / v, 6%w / v, 7%w / v, 8%w / v, 9%w / v, 10%w / v, 11%w / v, 12%w / v, 13%w / v, 14%w / v, 15%w / v, 16%w / v, 17%w / v, 18%w / v, 19%w / v or 20%w / v.

[0073] In the ophthalmic preparation provided by the present invention, the content of the pH modifier, sodium dihydrogen phosphate monohydrate, is 0.1% w / v to 0.5% w / v, preferably 0.12% w / v to 0.45% w / v, and more preferably 0.15% w / v, 0.2% w / v, 0.25% w / v, 0.3% w / v, 0.35% w / v, or 0.4% w / v.

[0074] In the ophthalmic preparation provided by the present invention, the content of the pH modifier sodium hydrogen phosphate is 0.3% w / v to 1% w / v, preferably 0.4% w / v to 0.9% w / v, and more preferably 0.45% w / v, 0.47% w / v, 0.5% w / v, 0.55% w / v, 0.6% w / v, 0.65% w / v, 0.7% w / v, 0.75% w / v, or 0.81% w / v.

[0075] In the ophthalmic preparation provided by the present invention, the content of the osmolality adjusting agent is 0.1% to 1% w / v, preferably 0.2% w / v, 0.21% w / v, 0.22% w / v, 0.23% w / v, 0.24% w / v, 0.25% w / v, 0.26% w / v, 0.27% w / v, 0.28% w / v, 0.29% w / v, 0.3% w / v, 0.31% w / v, 0.32% w / v, 0.33% w / v, 0.34% w / v, 0.35% w / v, 0.36% w / v, 0.37% w / v, 0.38% w / v, 0.39% w / v, 0.4% w / v, 0.42% w / v, 0.44% w / v, or 0.45% w / v. 0.46% w / v, 0.48% w / v, 0.5% w / v, 0.55% w / v, 0.6% w / v, 0.65% w / v, 0.7% w / v, 0.75% w / v, 0.8% w / v, 0.85% w / v, 0.9% w / v or 0.95% w / v.

[0076] In the ophthalmic preparation provided by the present invention, the content of the osmolality adjuster, sodium chloride, is 0.2% w / v to 0.8% w / v, preferably 0.25% w / v to 0.7% w / v, and more preferably 0.26% w / v, 0.27% w / v, 0.3% w / v, 0.34% w / v, 0.36% w / v, 0.4% w / v, 0.45% w / v, 0.5% w / v, 0.55% w / v, 0.6% w / v, or 0.65% w / v.

[0077] In the ophthalmic preparations provided by the present invention, the content of the antimicrobial preservative is 0.001% w / v to 0.02% w / v, preferably 0.002% w / v to 0.018% w / v, more preferably 0.003% w / v to 0.016% w / v, and most preferably 0.004% w / v, 0.0045% w / v, 0.005% w / v, 0.0055% w / v, 0.006% w / v, 0.0065% w / v, 0.007% w / v, 0.0075% w / v, 0.008% w / v, 0.0085% w / v, 0.009% w / v, 0.01% w / v, 0.012% w / v, 0.014% w / v, or 0.015% w / v.

[0078] In the ophthalmic preparations provided by the present invention, the content of the benzalkonium chloride antimicrobial preservative is 0.001% w / v to 0.02% w / v, preferably 0.002% w / v to 0.018% w / v, more preferably 0.003% w / v to 0.016% w / v, and most preferably 0.004% w / v, 0.0045% w / v, 0.005% w / v, 0.0055% w / v, 0.006% w / v, 0.0065% w / v, 0.007% w / v, 0.0075% w / v, 0.008% w / v, 0.0085% w / v, 0.009% w / v, 0.01% w / v, 0.012% w / v, 0.014% w / v, or 0.015% w / v.

[0079] In the ophthalmic preparations provided by the present invention, the content of the chlorhexidine acetate antimicrobial preservative is 0.001% w / v to 0.02% w / v, preferably 0.002% w / v to 0.018% w / v, more preferably 0.003% w / v to 0.016% w / v, and most preferably 0.004% w / v, 0.0045% w / v, 0.005% w / v, 0.0055% w / v, 0.006% w / v, 0.0065% w / v, 0.007% w / v, 0.0075% w / v, 0.008% w / v, 0.0085% w / v, 0.009% w / v, 0.01% w / v, 0.012% w / v, 0.014% w / v, or 0.015% w / v.

[0080] In the ophthalmic preparation provided by the present invention, the content of the antioxidant is 0.1% to 0.8% w / v, preferably 0.2% w / v, 0.3% w / v, 0.4% w / v, 0.5% w / v, 0.6% w / v, or 0.7% w / v.

[0081] The ophthalmic formulation provided by the present invention comprises the compound of formula (IX) and its isomer or a pharmaceutically acceptable salt thereof at a content of 0.1% w / v to 0.5% w / v, and further comprises excipients: hydroxypropyl betadex (HP-β-CD) at a content of 0.7% w / v to 3.5% w / v, preferably 1.75% w / v, 3.5% w / v, or 0.7% w / v, sodium hydrogen phosphate dibasic phosphate at a content of 0.81% w / v, sodium dihydrogen phosphate monohydrate at a content of 0.12% w / v, sodium chloride at a content of 0.25% w / v to 0.45% w / v, preferably 0.27% w / v, 0.36% w / v, or 0.4% w / v, and chlorhexidine acetate at a content of 0.01% w / v.

[0082] In the ophthalmic preparation provided by the present invention, the pH range of the ophthalmic preparation is 5.0 to 9.0, preferably 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 6.91, 6.92, 6.93 , 6.94, 6.95, 6.96, 6.97, 6.98, 6.99, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.72, 7.73, 7.74, 7.75, 7.76, 7.77, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.53, 8.54, 8.55 8.56, 8.57, 8.58, 8.59, 8.6, 8.7, 8.8 or 8.9.

[0083] Methods for preparing the ophthalmic formulations provided in the present invention include rotary solvent evaporation processes, concentration dilution methods, and freeze-drying methods.

[0084] The ophthalmic formulations of the present invention are measured for changes in content and related substances through stability studies. The results show that the properties of the ophthalmic formulations provided by the present application are consistent, and there are no significant differences in related substances and content.

[0085] The dosage form of the ophthalmic preparation provided by the present invention can be a liquid preparation, such as eye drops, eye washes or intraocular injection solutions, a semi-solid ophthalmic preparation, such as an ophthalmic ointment, an ophthalmic cream or an ophthalmic gel, and a solid ophthalmic preparation, such as an ophthalmic film, an ophthalmic pellet and an intraocular insert.

[0086] The present invention provides an ophthalmic formulation for use in the preparation of a medicament for treating an ophthalmic disorder, preferably in the case of dry eye disease, allergic conjunctivitis, macular degeneration, cataract, keratoconus, bullous keratopathy, Fuchs' endothelial corneal dystrophy, ocular cicatricial pemphigoid, meibomian gland dysfunction, uveitis, scleritis, Stevens-Johnson syndrome, ocular rosacea or Sjogren's syndrome.

[0087] The therapeutic effect of the ophthalmic formulation provided by the present invention was investigated by inducing a dry eye disease model in C57BL / 6 mice by subcutaneous injection of scopolamine hydrobromide solution into the lower limbs, and in SD rats by instilling a hypertonic sodium chloride solution. The results showed that the ophthalmic formulation of the present application can improve tear secretion and corneal damage in the dry eye disease model mice. A pharmacokinetic study in the eyes of New Zealand rabbits found that the active ingredient had a high concentration distribution in the corneal and conjunctival tissues of the ocular surface, which is beneficial for the treatment of ocular diseases, and a low concentration distribution in the fundus, indicating a lower risk of causing adverse reactions in the fundus.

[0088] (Definitions and Explanations) Unless otherwise specified, the following terms and phrases used herein are intended to have the meanings set forth below. A specific term or phrase should not be considered indefinite or unclear in the absence of a specific definition, but should be understood in accordance with its ordinary meaning. Where trade names appear herein, they are intended to refer to the corresponding product or its active ingredient(s). As used herein, the term "pharmaceutically acceptable" refers to compounds, substances, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0089] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared from a compound having specific substituents discovered by the present invention and a relatively non-toxic acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of base in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts, or similar salts. When a compound of the present application contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of acid in a pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, hydrogensulfate, hydroiodic acid, phosphorous acid, and the like, and salts of organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like, as well as salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, which allows these compounds to be converted into either base or acid addition salts.

[0090] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains an acidic or basic group by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or free base form of the compound with a stoichiometric amount of the appropriate base or acid in water, an organic solvent, or a mixture of both.

[0091] The compounds provided by the present invention exist in salt form as well as in prodrug form. The prodrugs of the compounds described herein are easily converted into the compounds of the present invention under physiological conditions by chemical changes. Furthermore, the prodrugs can be converted into the compounds of the present invention in vivo by chemical or biochemical methods.

[0092] Certain compounds of the present invention can exist in unsolvated forms or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the present invention.

[0093] Optically active (R)- and (S)-isomers, as well as D- and L-isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. If a single enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, in which case the resulting diastereomeric mixture is separated and the auxiliary cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a non-diastereomeric salt can be formed with an appropriate optically active acid or base, followed by conventional methods known in the art for diastereomeric resolution, followed by recovery of the pure enantiomer. Furthermore, separation of enantiomers and diastereomers is typically achieved using chromatography employing chiral stationary phases, optionally combined with chemical derivatization (e.g., formation of carbamates from amines). The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds can be labeled with radioactive isotopes, such as tritium (H), iodine-125 (I), or carbon-14 (C). For example, hydrogen can be replaced by deuterium to form a deuterated drug, in which case the carbon-deuterium bond is stronger than a carbon-hydrogen bond and provides advantages over non-deuterated drugs, such as reduced toxic side effects, improved drug stability, enhanced efficacy, and longer biological half-life. All isotopic variations of the compounds of the present application, whether radioactive or not, are included within the scope of the present invention.

[0094] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances in which the event or circumstance occurs as well as instances in which it does not occur.

[0095] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and the substituent may include deuterium and hydrogen variants, provided that the valence of the particular atom is normal and the resulting compound is stable. If the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that the group may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be arbitrarily determined based on chemical feasibility.

[0096] When any variable (e.g., R) occurs more than one time in a compound composition or structure, its definition is independent at each occurrence. Thus, for example, if a group is substituted with zero to two R groups, that group may also be optionally substituted with up to two R groups, and each occurrence of R has an independent option. Furthermore, combinations of substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0097] When the number of linking groups is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0098] When one of the variables is selected from a single bond, the two groups linked to the single bond are directly linked, such as ALZ, where L represents a single bond, meaning that the structure is, in fact, AZ.

[0099] If a substituent is absent, it means that the substituent is absent (e.g., AX where X is absent), and the structure is actually A. If a listed substituent does not specify which atom is linked to the substituted group through which the substituent can be bonded through any of those atoms, e.g., a pyridyl group as a substituent can be bonded to the substituted group through any carbon atom on the pyridine ring. If a listed linking group does not specify the direction of the bond, the direction of the bond can be determined, e.g., by the linking group

[0100] [ka]

[0101] (L is -MW-) is optional, and -MW- is attached to ring A and ring B in the same direction as reading from left to right.

[0102] [ka]

[0103] or in the opposite direction.

[0104] [ka]

[0105] Combinations of linking groups, substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0106] Unless otherwise specified, the term "Ci_6 alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group of 1 to 6 carbon atoms. Ci_6 alkyl includes C1_5, C1_4, C1_3, C1_2, C2_6, C2_4, C6, and C5 alkyl, etc. It can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine). Examples of Ci_6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, and t-butyl), pentyl (including n-pentyl, isopentyl, and neopentyl), hexyl, etc.

[0107] Unless otherwise specified, the term "C1-3 alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group of 1 to 3 carbon atoms. C1-3 alkyl includes C1-2 and C2-3 alkyl, etc. It can be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine). Examples of C1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0108] Unless otherwise specified, the term "C1-3 alkoxyl" refers to an alkyl group containing 1 to 3 carbon atoms attached to the remainder of the molecule via an oxygen atom. C1-3 alkoxyl includes C1-2, C2-3, C3, and C2 alkoxyl, etc. Examples of C1-3 alkoxyl include, but are not limited to, methoxyl, ethoxyl, propoxyl (including n-propoxyl and iso-propoxyl), etc.

[0109] Unless otherwise specified, C n ~ n+m or C n ~C n+m includes any specific case of n to n+m carbons, e.g., C1 12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11and C 12 and any range within the range of n to n+m, for example, C1 to 12 are C1~3, C1~6, C1~9, C3~6, C3~9, C3~ 12 , C6~9, C6~ 12 and C9~ 12 Similarly, an n-membered ring to an n+m-membered ring refers to a ring having n to n+m atoms, and for example, a 3- to 12-membered ring includes 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, and 12-membered rings, and also includes any range within the range of n to n+m, and for example, a 3- to 12-membered ring includes 3- to 6-, 3- to 9-, 5- to 6-, 5- to 7-, 6- to 7-, 6- to 8-, and 6- to 10-membered rings, etc.

[0110] The term "leaving group" refers to a functional group or atom that can be displaced by another functional group or atom by a substitution reaction (e.g., nucleophilic substitution). For example, representative leaving groups include trifluoromethanesulfonate; chloro, bromo, iodo; sulfonate such as mesylate, tosylate, brosylate, p-toluenesulfonate, and the like; acyloxy such as acetoxy, trifluoroacetoxy, and the like.

[0111] The term "protecting group" includes, but is not limited to, an "amino-protecting group," a "hydroxy-protecting group," or a "thiol-protecting group." The term "amino-protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen of an amino group. Representative amino-protecting groups include, but are not limited to, acyl such as formyl, alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl), alkoxycarbonyl such as tert-butoxycarbonyl (Boc), aryloxycarbonyl such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc), arylmethyl such as benzyl (Bn), trityl (Tr), 1,1-di-(4'-methoxyphenyl)methyl, silyl such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like. The term "hydroxy-protecting group" refers to a protecting group suitable for preventing side reactions at a hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl such as methyl, ethyl, and tert-butyl; acyl such as alkanoyl (e.g., acetyl); arylmethyl such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM); silyl such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and the like.

[0112] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, their combination with other chemical synthetic methods, and equivalent alternatives known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0113] The solvents used in the present invention are commercially available. The following abbreviations are used in the present invention: aq represents water; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperbenzoic acid; eq represents equivalents; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; and CBz represents the benzyloxycarbonyl amine protecting group. BOC represents the tert-butoxycarbonyl amine protecting group. HOAc represents acetic acid. NaCNBH3 represents sodium cyanoborohydride. rt represents room temperature. O / N represents overnight. THF represents tetrahydrofuran. Boc2O represents di-tert-butyl dicarbonate. TFA represents trifluoroacetic acid. DIPEA represents diisopropylethylamine. SOCl2 represents thionyl chloride. CS2 represents carbon disulfide. TsOH represents p-toluenesulfonic acid. NFSI represents N-fluoro-N-(phenylsulfonyl)benzenesulfonamide. NCS represents N-chlorosuccinimide. n-Bu4NF represents tetrabutylammonium fluoride. iPrOH represents isopropanol. mp represents melting point. LDA represents lithium diisopropylamide. LiHMDS represents lithium hexamethyldisilazide. Xantphos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. LiAlH4 is lithium aluminum hydride. Pd(dba)2 is tris(dibenzylidene-acetone)dipalladium. mCPBA is meta-chloroperbenzoic acid. pd(dppf)Cl2 is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium.DBU represents 1,8-diaza-bicyclo[5.4.0]undec-7-ene.

[0114] Compounds are named according to conventional naming principles in the field or using ChemDraw® software naming; commercially available compounds use the supplier's catalog name. [Brief explanation of the drawings]

[0115] [Figure 1] 1 is an XRPD spectrum of the compound of formula (IX) using Cu-Kα radiation. [Figure 2] 1 is a DSC spectrum of the compound of formula (IX). [Figure 3] 1 is a TGA spectrum of the compound of formula (IX). [Figure 4] 1 is a graph of tear production in a mouse model of dry eye disease for Examples 105, 106, and 107. [Figure 5] 1 is a graph of corneal fluorescein staining scores in a mouse model of dry eye disease for Examples 105, 106, and 107. [Figure 6] 1 is a graph of tear production in a rat model of dry eye disease for Examples 105 and 107. [Figure 7] 1 is a graph of corneal fluorescein staining scores in a rat model of dry eye disease for Examples 105 and 107. [Figure 8] 1 is a graph of tear film breakup time in a rat model of dry eye disease for Examples 105 and 107. [Figure 9] 1 is a graph of chemosis scores. [Figure 10] 1 is a graph of conjunctival hyperemia scores. [Figure 11] FIG. 1 shows the pathological results of H&E staining. DETAILED DESCRIPTION OF THE INVENTION

[0116] The present invention is further illustrated in detail by the following examples, which are for illustrative purposes and are not intended to limit the scope of the invention.

[0117] Examples 1 to 11 The active compound of formula (IX) of the present invention is a water-insoluble or almost water-insoluble compound. Examples 1 to 11 were prepared according to the specific processes in Table 1. The results showed that the compound of formula (IX) in Examples 1, 4, 5, 6, 7, 9, and 10 was still insoluble after various solubilizing agents, heating, and other operations. The solubilizing agents used in Examples 2, 3, 8, and 11 had some promoting effect on solubility.

[0118] [Table 1]

[0119] Examples 12 to 30 According to the formulation in Table 2, the active compound of formula (IX), propylene glycol, PEG400, polysorbate 80, and other excipients were weighed and placed in a vial. The active compound was sonicated to dissolve the excipients, resulting in a concentrated solution. This concentrated solution was added dropwise to a specified amount of vehicle. Examples 12 to 30 were obtained. The dissolution of the active compound was observed. Specific data are shown in Table 2. In Examples 20 to 23, a relatively stable solution of 5 mg / mL of the active compound was obtained.

[0120] [Table 2]

[0121] Examples 31 to 41 According to Table 3, the active compound of formula (IX) and HP-β-CD were dissolved in 95% ethanol. The solution was then placed on a rotary evaporator to dry the solvent, resulting in a solid inclusion complex. This solid was dissolved in purified water, and a 5 mg / mL solution was prepared using purified water / phosphate medium at pH 6.8, based on the amount of active compound added. Dissolution was observed. Specific results are shown in Table 3.

[0122] [Table 3]

[0123] In Examples 31 to 41, the HP-β-CD inclusion complexes of the active compounds were obtained after rotary evaporation. The HP-β-CD inclusion complexes of Examples 33, 35, 36, 37, 38, 40, and 41 dissolved and became clear, transparent aqueous solutions without precipitation.

[0124] The eye drops of Examples 36, 37, and 38 were sterilized at 121° C. for 15 minutes. The eye drops of Examples 36 and 37 became cloudy, while the eye drops of Example 38 remained clear after sterilization.

[0125] The eye drops prepared in Examples 40 and 41 were sterilized at 121°C for 15 minutes, and the major components and the maximum single impurities are shown in Table 4. The major components of Examples 40 and 41 decreased by 0.62% and 0.61%, respectively, before and after sterilization, and the maximum single impurities increased by 1.61% and 1.35%, respectively, before and after sterilization.

[0126] [Table 4]

[0127] Examples 42 to 45 According to Table 5, 10 mL of isopropanol was taken and placed in a 50 mL beaker, magnetically stirred, and the active compound was added and stirred until dissolved. 4.00 g of HP-β-CD was added and thoroughly stirred. Then, 10 mL of isopropanol was added and sonicated for 12 minutes to obtain a clear solution. In Example 42, the solution was first evaporated by rotary evaporation at room temperature until it turned from clear to white and a solid precipitated. It was then transferred to a 50°C water bath and adjusted to a vacuum of 0.085 MPa. It boiled and was subjected to rotary evaporation for 1 hour, resulting in the precipitation of small pieces of the inclusion compound. In Example 43, the active compound was directly placed in a 50°C water bath and the vacuum was adjusted to 0.085 MPa. Rotary evaporation was performed for 1 hour, resulting in the precipitation of small pieces of the inclusion compound. The stability results for Examples 42 and 43 before and after rotary evaporation are shown in Table 6. In Examples 44 and 45, the stability of rotary solvent evaporation solutions was studied at 50° C. The results are shown in Table 7.

[0128] [Table 5]

[0129] [Table 6]

[0130] [Table 7]

[0131] The experimental results show that in Examples 42 and 43, the related substances of the active compound of formula (IX) remained essentially unchanged before and after rotary evaporation, and the rotary evaporation process does not substantially affect the stability of the active compound. The solutions of Examples 44 and 45 were kept at 50°C for 2 hours before rotary evaporation, and the related substances of the active compound remained essentially unchanged.

[0132] Examples 46-47 HP-β-CD and the active compound of formula (IX) were placed in a beaker according to the ratios in Table 8, and an organic solvent was added. The mixture was stirred to dissolve, and purified water was slowly added to obtain a clear solution. This solution was freeze-dried, and the effects of various solvents on the intermediate state and the reconstitution after freeze-drying were investigated.

[0133] [Table 8]

[0134] The experimental results showed that the intermediate of Example 46 was a white, loose, porous solid with good geometry. The intermediate of Example 47 was a white, porous solid with loose pores, and the solid powder scattered. The solutions of Examples 46 and 47 were slightly cloudy after reconstitution.

[0135] Examples 48 to 51 In Examples 48, 49, and 50, the active compound of formula (IX), HP-β-CD, butylated hydroxyanisole (BHA), and vitamin E (VE) were placed in a beaker according to the formulation in Table 9, and isopropanol was added. After thorough stirring, a certain amount of purified water was slowly added to obtain a clear solution, which was then freeze-dried. In Example 51, only purified water was used quantitatively to disperse the active compound before freeze-drying. The effects of various excipients on impurities during the freeze-drying process were investigated. The data for the main components and impurity content of Examples 48 to 51 are shown in Table 10.

[0136] [Table 9]

[0137] [Table 10]

[0138] The results showed that there was no significant change in the related substances of Example 48 and Example 51, indicating that the addition of HP-β-CD did not affect the stability of the active compounds.

[0139] Example 49, which contained the antioxidant BHA, achieved a maximum single impurity of 2.03% at time 0 compared to Example 48. After a 5-day stability test at 60°C, it was found that the contents of the major components in Examples 49 and 50 showed various degrees of reduction compared to Example 48. The addition of antioxidants BHA or VE does not lead to stabilization of the eye drops of the active compound.

[0140] Examples 52 to 63 According to the formulation ratio in Table 11, the active compound of formula (IX) was weighed and dispersed in isopropanol with stirring until the solution became clear. HP-β-CD was slowly added under stirring until the solution became clear. A specified amount of purified water was slowly added to the above isopropanol solution under stirring, and the mixture was stirred for 1 hour to obtain a clear solution. The above solution was freeze-dried in a vacuum freeze dryer to obtain a loose white freeze-dried powder. The freeze-drying curve is shown in Table 12. The freeze-dried powder of the inclusion compound was dissolved in a reconstitution medium and filtered sequentially through 0.45 μm and 0.22 μm composite filter membranes to obtain eye drops of the active compound, which were then filled in 2 mL sample packages per bottle to obtain eye drops.

[0141] For multi-dose packaged eye drops, the addition of an antimicrobial preservative is necessary to prevent microbial contamination during use. The effects of two antimicrobial preservatives, benzalkonium chloride and chlorhexidine acetate, on formulation stability were investigated in Examples 52, 55, and 56. The preliminary stability of the eye drops from Examples 52, 55, and 56 was investigated by storing them at 25°C and 40°C in the dark for 5 days. The results are shown in Table 13. Based on the number of impurities and their growth levels, Example 56 had superior short-term stability compared to Example 57, indicating that the chlorhexidine acetate antimicrobial preservative is more suitable for eye drops of active compounds.

[0142] Examples 53 and 54 were packaged in a low-density polyethylene (PE) pharmaceutical eye drop bottle, an amber polyester (PET) pharmaceutical eye drop bottle, and an ampoule, respectively. They were stored in the dark at 25°C to examine the preliminary suitability of the packaging materials. Safety data are shown in Table 14. Example 52, produced using an isopropanol freeze-drying process, showed crystallization after long-term storage. Examples 53 and 54 with various packaging systems were stored at 25°C for 15 days, and no crystallization occurred, nor was there any significant change in the impurities in the eye drops.

[0143] When the products from Examples 57 to 60 were reconstituted, the pH was adjusted using dilute hydrochloric acid and dilute sodium hydroxide to determine the appropriate acidity and alkalinity for the eye drops containing the active compound of formula (IX). The stability results for Examples 57 to 60 at 60°C for 5 days are shown in Table 15. The results indicate that the stability of the eye drops under weakly alkaline conditions is superior to that under acidic conditions.

[0144] The safety data for Examples 61 to 63 are shown in Table 16. There was no significant change in the related substances of Example 62 compared to Example 61, and the addition of chlorhexidine acetate antimicrobial preservative did not affect the stability of the eye drops of the active compound of Formula (IX). There was no significant change in the related substances of Example 63 compared to Example 62, and increasing the amount of HP-β-CD added as a solubilizer did not affect the stability of the active compound.

[0145] [Table 11] [Table 12]

[0146] [Table 13]

[0147] [Table 14]

[0148] [Table 15]

[0149] [Table 16]

[0150] Examples 64 to 67 According to the formulation ratios in Table 17, 30 g of purified water was heated to 80°C, and hydroxypropyl betadex (HP-β-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD) were added in small batches under stirring to dissolve. A specified amount of the active compound of formula (IX) was weighed out individually and added in small batches to the cyclodextrin solution under stirring. The active compounds in Examples 64, 66, and 67 were able to completely dissolve within 2 hours. In Examples 64 to 66, purified water was added to a volume of 60 mL and stirred uniformly. The above solution was sealed into medium-sized borosilicate glass ampoules at 4 mL per vial, for a total of 10 vials, to obtain ready-to-use eye drops.

[0151] The products obtained in Example 64 and Example 66 were heated in a water bath at 80°C in the dark. Two ampoules were taken at 0.5, 1, 2, 4 and 6 hours, respectively, and samples were sent for determining the content and related substances. The results are shown in Table 18.

[0152] Example 64 showed increases in related substances of 0.03%, 0.10%, and 0.21% after 0.5, 1, and 2 hours, respectively, at 80° C. Example 66 showed increases in related substances of 0.30%, 0.47%, and 0.57% after 0.5, 1, and 2 hours at 80° C. Example 66, which contains SBE-β-CD, is less thermally stable than Example 64.

[0153] [Table 17]

[0154] [Table 18]

[0155] Examples 68 to 91 Examples 68 to 87 were prepared according to the formulation ratios in Table 19. The active compound of formula (IX) and HP-β-CD were weighed and placed in a 10 mL vial. Purified water was added according to the formulation ratio while stirring or shaking at various water bath temperatures until dissolved. The dissolution of the active compound under various concentration process conditions was compared. Example 79 was diluted 1-fold and 5-fold to obtain Examples 88 and 89. Examples 90 and 91 were obtained by diluting Example 80 1-fold and 5-fold.

[0156] Under the concentration conditions listed in Table 19, the active compound of formula (IX) was completely dissolved in a short period of time in Examples 69, 70, 75-83, 85, and 86. Under the concentration process conditions, the dosage of HP-β-CD, the concentration of HP-β-CD, and the concentration process temperature had a significant effect on the dissolution process of the active compound.

[0157] [Table 19]

[0158] The stability of aqueous solutions of the active compound inclusion complexes listed in Table 20 and the photostability of Example 80 were investigated. The results are shown in Tables 21, 22 and 23.

[0159] The experimental results showed that the content of the active compound remained stable after 10 days at 60°C and after 20 days at 25°C, 30°C, and 40°C, indicating that the thermal stability of the cyclodextrin aqueous solutions containing the active compound was still acceptable in Examples 67, 78-80, and 88-91. In Example 80, yellow precipitates appeared after 5 days under the test light conditions, which was an influential factor, indicating that the cyclodextrin aqueous solutions containing the active compound were unstable to strong light.

[0160] [Table 20]

[0161] [Table 21]

[0162] [Table 22]

[0163] [Table 23]

[0164] Example 92 Example 92 was prepared according to the formulation ratios in Table 24. A specific amount of purified water was added to a beaker and heated to 70°C in a water bath. HP-β-CD was added and dissolved by stirring. The active compound of formula (IX) was then added and stirred in a water bath at 70°C for 60 minutes until completely dissolved. The solution was transferred to a 100mL volumetric flask. The beaker was rinsed several times with small amounts of purified water, and the rinse water was transferred to the volumetric flask. Chlorhexidine acetate was added and shaken to dissolve. Sodium hydrogen phosphate, sodium dihydrogen phosphate monohydrate, and sodium chloride were added in that order and shaken to dissolve. Purified water was added to the volume to make a final volume of 100mL. The solution was filtered through 0.45μm and 0.22μm composite membranes, and the filtrate was filled into 5mL medium-sized borosilicate glass ampoules at 5mL per vial to obtain an eye drop solution for use.

[0165] The eye drops of Example 92 were sterilized at 115°C for 30 minutes, 121°C for 15 minutes, and 121°C for 30 minutes, respectively. The sample properties, pH, and related substances were tested. The results are shown in Table 25. Example 92 was tested at 60°C, and samples were taken on days 0, 5, and 10 to detect the properties, content, and related substances. The test results are shown in Table 26.

[0166] [Table 24]

[0167] [Table 25]

[0168] [Table 26]

[0169] The results showed that the related substances of Example 92 increased significantly after sterilization under various conditions. The total impurities in the sample sterilized at 115°C for 30 minutes increased by 1.507%, and the total impurities in the sample sterilized at 121°C for 15 and 30 minutes increased by 1.687% and 2.195%, respectively. Example 92 has poor thermal stability and cannot withstand moist heat sterilization. After testing at 60°C for 5 and 10 days, the related substances in Example 92 increased, while other indicators remained stable.

[0170] Example 93 Example 93 was prepared according to the formulation ratios in Table 27. 21.86 g of purified water was added to a 100 mL beaker and heated to 60°C. HP-β-CD was added with stirring to dissolve. The active compound of formula (IX) was then added and heated to 70°C until completely dissolved and stirred for 60 minutes. The solution was transferred to a 500 mL volumetric flask, and the beaker was rinsed several times with approximately 200 g of purified water. The rinse water was transferred to the volumetric flask, chlorhexidine acetate was added, and the mixture was shaken to dissolve. Next, sodium hydrogen phosphate, sodium dihydrogen phosphate monohydrate, and sodium chloride were added in that order and shaken to dissolve. Purified water was added to a volume of 500 mL and the mixture was thoroughly shaken. The density of the solution was calculated to be 1.0166 g / mL based on the mass-to-volume ratio. The solution was filled into 5 mL borosilicate glass ampoules at 5 mL per vial to obtain eye drops.

[0171] Example 93 was placed approximately 1.5 meters under 40 watt room fluorescent lighting, and samples were taken at 0, 2, 4, and 6 hours to test for its properties, pH, and related substances. The test results are shown in Table 28. The results indicated that Example 93 remained stable after being placed approximately 1.5 meters under room fluorescent lighting for 6 hours, and that both the formulation and filling of the liquid during production could be done under normal room lighting.

[0172] [Table 27]

[0173] [Table 28]

[0174] Examples 94 to 96 10.00g of purified water was weighed and placed in a 50mL beaker, and heated to 75℃ in a water bath. HP-β-CD was added according to the formula in Table 29, and stirred until dissolved. Then, the active compound of formula (IX) was added while stirring until dissolved. The cyclodextrin solution containing the active compound was added to a 500mL beaker containing 126mL of purified water, and the 50mL beaker was rinsed several times with purified water. The rinse solution was transferred to a 500mL beaker, and chlorhexidine acetate was added and stirred until dissolved. Then, sodium chloride, sodium dihydrogen phosphate monohydrate, and sodium hydrogen phosphate were added in order and stirred until dissolved. Water was added until the volume reached 250mL, and the mixture was thoroughly stirred. The mixture was filtered through a 0.45μm and 0.22μm composite filter membrane to obtain Example 94.

[0175] The pH of Example 94 was 7.75. The pH of the solution of Example 94 was adjusted to 6.96 using 1 mol / L HCl and 5 mol / L NaOH to obtain Example 95, and to 8.54 using 1 mol / L HCl and 5 mol / L NaOH, respectively, to obtain Example 96. The eye drops of Example 94 were sterilized at 115°C for 30 minutes, 121°C for 15 minutes, and 30 minutes at 121°C, respectively. The sample properties, pH, and related substances were tested. The results are shown in Table 30. The eye drops of Example 94, Example 95, and Example 96 were filled into 5 mL ampoules and placed at 60°C for testing. Samples were collected on days 0, 5, and 10, and their properties, content, and related substances were tested. The test results are shown in Table 31.

[0176] The results showed that the related substances in Example 94 increased significantly after sterilization under various conditions. Example 94 was not thermally stable and could not withstand moist heat sterilization. The sample in Example 96 with a pH of 8.54 showed the best stability. Furthermore, considering that the appropriate pH range for eye drops is 6 to 8, the pH of the eye drops in Example 94 is more suitable.

[0177] [Table 29]

[0178] [Table 30]

[0179] [Table 31]

[0180] Examples 97-98 10.00 mL of purified water was weighed and placed in a 50 mL beaker, and heated to 75 ° C in a water bath. HP-β-CD was added according to the formula in Table 32 and stirred until dissolved. The active compound was added under stirring until dissolved. The cyclodextrin solution containing the active compound Formula (IX) was added to a 500 mL beaker containing 126 mL of purified water, and the 50 mL beaker was rinsed several times with purified water. The rinse solution was transferred to the 500 mL beaker, chlorhexidine acetate was added and stirred until dissolved, and then sodium chloride, sodium dihydrogen phosphate monohydrate, and sodium hydrogen phosphate were added in order and stirred until dissolved. Water was added until the solution reached 250 mL, stirred thoroughly, and filtered through a 0.45 μm and 0.22 μm composite filter membrane to obtain Examples 97 and 98.

[0181] The osmolality of Examples 94, 97, and 98 was measured, and the results are shown in Table 33. The eye drops of Examples 94, 97, and 98 were in a nearly isotonic to slightly hypotonic state.

[0182] [Table 32]

[0183] [Table 33]

[0184] Examples 99 to 102 According to the formulation ratios in Table 34, Examples 99 to 102 were prepared.

[0185] Production process: Preparation of concentrated solution: A specified amount of water for injection was added to a beaker, and the beaker was placed on a CNC heating type magnetic stirrer to heat the water to a temperature of 77°C ± 2°C. HP-β-CD was added in small batches under stirring.

[0186] After the HP-β-CD was completely dissolved, the specified amount of the active compound was added in one portion while maintaining stirring, and the solution temperature was controlled at 77°C ± 2°C, and stirring was continued until the solution became completely clear.

[0187] The concentrated solution was diluted to adjust the volume: 7.5 kg of water for injection at 20-25°C was weighed into a stainless steel bucket, the mixer was started, and the concentrated solution was added to the stainless steel bucket. The beaker containing the concentrated solution was rinsed 4-6 times with small amounts of water for injection at 20-25°C. All rinse solutions were transferred to the stainless steel bucket and stirred thoroughly. The specified amounts of sodium chloride, sodium dihydrogen phosphate monohydrate, and sodium hydrogen phosphate were added in order and stirred to dissolve. The solution was diluted to 15 L with water for injection at 20-25°C and stirred thoroughly. Samples were taken for testing the intermediate properties, content, pH, and osmolality. The test results are shown in Table 35.

[0188] Filtration and filling: Before starting production, the filter cartridges were integrity tested, and the mixing tank, blow-fill-seal (BFS) machine and its material conveying pipelines were flash-sterilized with steam in place, maintaining a temperature of ≥ 121°C for 30 minutes for pure steam sterilization. The equipment was then turned on, and filtration and filling were initiated. After the product was completed, an integrity test was performed on the filter cartridges.

[0189] Punching: All punched products were subjected to leak detection and then each bottle was inspected to remove any non-conforming products.

[0190] Packaging: All qualified punched products were inspected by light, non-conforming products were removed, and the punched products that passed the leak detection and light inspection were pillow-packed, and the heat-sealing effectiveness of all packaged samples was tested by using a constant temperature vacuum drying oven, and samples were taken from the qualified heat-sealed final products for inspection, and the properties, content, pH value and osmotic pressure of the final products were tested. The test results are shown in Table 35.

[0191] The results showed that the formulation ratios and preparation processes of Examples 99 to 102 could produce eye drops and placebo eye drops with properties, content, pH value, and osmotic pressure that comply with the 2020 Pharmacopoeia regulations.

[0192] [Table 34]

[0193] [Table 35]

[0194] Example 103 Sulfobutylether-β-cyclodextrin (SBE-β-CD) was weighed and dissolved in phosphate buffer solution according to the formulation ratio in Table 36. A specified amount of the compound of formula (IX) was dissolved in 0.15 mL of dimethyl sulfoxide, and then added to the sulfobutylether-β-cyclodextrin (SBE-β-CD) phosphate buffer solution under continuous stirring to obtain a clear solution.

[0195] In Example 103, the amount of sulfobutylether-β-cyclodextrin used was high, and the fact that dimethyl sulfoxide has local toxicity and low systemic toxicity makes it unsuitable for use in eye drops. Example 103 has a simple excipient composition and is less stable and poses a higher safety risk than Examples 66 and 67, which do not contain dimethyl sulfoxide.

[0196] [Table 36]

[0197] Preparation of Compound (IX) in Example 104

[0198] [ka]

[0199] Synthetic Route:

[0200] [ka]

[0201] Step 1: Preparation of Compound 2 Compound 1 (30 g, 130.4 mmol, 1 equiv.), bis(pinacolato)diboron (66.23 g, 260.80 mmol, 2 equiv.), [1,1-bis(diphenylphosphine)ferrocene]palladium(II) chloride dichloromethane adduct (5.32 g, 6.52 mmol, 0.1 equiv.), and potassium acetate (25.60 g, 260.80 mmol, 2 equiv.) were added to toluene (500 mL) and purged with nitrogen three times. The reaction solution was stirred at 110 °C for 15 h. After completion of the reaction, the reaction solution was filtered through a pad of diatomaceous earth. The filtrate was concentrated, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 0 to 100:6) to give compound 2. 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J=8.0 Hz, 1H), 7.06 (s, 1H), 7.04 (d, J=8.0 Hz, 1H), 5.65 (brs, 2H), 3.87 (s, 3H), 1.35 (s, 12H).

[0202] Step 2: Preparation of Compound 4 Compound 3 (100 g, 460.79 mmol, 1 equiv.) was dissolved in absolute ethanol (1 L), followed by the addition of concentrated sulfuric acid (225.97 g, 2.30 mol, 122.81 mL, 5 equiv.) and anhydrous sodium sulfate NaSO (65.45 g, 460.79 mmol, 46.75 mL, 1 equiv.). The reaction mixture was stirred at 85 °C for 48 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature. A saturated solution of sodium bicarbonate (1 L) was added dropwise to the reaction mixture, forming a large amount of solid, which was filtered and the filter cake washed with water (500 mL). The resulting solid was dried under vacuum to give compound 4. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=1.8 Hz, 1H), 7.26 (s, 1H), 4.47 (q, J=7.1 Hz, 2H), 1.46 (t, J=7.2 Hz, 3H).

[0203] Step 3: Preparation of Compound 5 Compound 4 (70.00 g, 285.63 mmol, 1 eq) was dissolved in tetrahydrofuran (1 L) and cooled to -78 °C under nitrogen protection. Methyllithium (1.6 M, 892.59 mL, 5 eq) was slowly added dropwise to the reaction solution, which was then stirred at -78 °C for 3 hours. After the reaction was completed, water (100 mL) was slowly added dropwise to quench the reaction. The solution was warmed to room temperature, diluted with saturated aqueous ammonium chloride (500 mL), and extracted with ethyl acetate (500 mL * 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was stirred with n-heptane (500 mL), filtered, and dried to give compound 5. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=1.9 Hz, 1H), 6.98 (d, J=1.9 Hz, 1H), 4.57 (br s, 2H), 1.57 (s, 6H).

[0204] Step 4: Preparation of Compound 6 Compound 5 (10 g, 43.27 mmol, 1 equiv.), compound 2 (23.98 g, 86.55 mmol, 2 equiv.), [1,1-bis(diphenylphosphine)ferrocene]palladium(II) chloride dichloromethane adduct (1.77 g, 2.16 mmol, 0.05 equiv.), and cesium carbonate (28.20 g, 86.55 mmol, 2 equiv.) were added to dioxane (300 mL) and water (75 mL). The atmosphere was purged with nitrogen three times, and the reaction solution was stirred at 80 °C for 5 h. After completion of the reaction, the reaction solution was concentrated, and the residue was subjected to column chromatography (petroleum ether:tetrahydrofuran = 0 to 100:40) to obtain crude compound 6. This crude product was heated to 80 °C with tetrahydrofuran (4 mL / g), cooled, stirred at 25 °C for 15 h for recrystallization, and filtered. The filter cake was dried to give compound 6. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 1.6 Hz, 1H), 7.77-7.75 (m, 3H), 5.69 (s, 2H), 5.50 (s, 1H), 3.81 (s, 3H), 1.52 (s, 6H).

[0205] Step 5: Preparation of Compounds of Formula (IX) Compound 6 (8.78 g, 29.14 mmol, 1 equiv.) was dissolved in tetrahydrofuran (80 mL) and cooled to 0°C under nitrogen protection. Methylmagnesium bromide (3 M, 97.12 mL, 10 equiv.) was added dropwise to the reaction solution, which was then stirred at 0°C for 1 hour. After completion of the reaction, saturated aqueous ammonium chloride solution (400 mL) was slowly added to quench the reaction, and the solution was extracted with ethyl acetate (400 mL * 2). The organic phase was concentrated under reduced pressure, and the residue was purified with dichloromethane (3 mL / g) at 25°C, filtered, and dried to obtain a product with a molecular weight of 301.40. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=1.8 Hz, 1H), 7.15-7.01 (m, 2H), 6.82 (d, J=1.6 Hz, 1H), 6.69 (dd, J=1.5, 8.0 Hz, 1H), 5.59 (br s, 2H), 5.51 (br s, 2H), 5.44 (s, 1H), 5.23 (s, 1H), 1.51 (d, J=3.6 Hz, 12H). 11.9 g of the above product was weighed and added to a round-bottom flask, and 150 mL of methyl tert-butyl ether was added. The mixture was stirred at 50°C for 12 hours, then cooled to 25°C and stirred for 4 hours. The mixture was filtered and dried to obtain a solid compound of formula (IX). Approximately 50 mg of the above compound of formula (IX) was further weighed and added to a 2.0 mL glass vial. An appropriate amount of solvent or solvent mixture was added to form a suspension. A magnetic pole was added, and the suspension was stirred on a magnetic heating stirrer (25°C / 50°C) for 1 week and centrifuged to obtain a solid sample, which was dried in a vacuum drying oven at 40°C overnight to obtain a compound of formula (IX). This compound has the molecular formula C 17 H 23 It has N3O2·H2O and a molecular weight of 319.40.

[0206] The XRPD spectral analysis data for the compound of formula (IX) above is shown in Table 37, and the spectrum is shown in Figure 1. The differential scanning calorimetry curve for compound (IX) shows endothermic peak onsets at 101.7±3.0°C and 158.7±3.0°C, respectively, as shown in Figure 2. The thermogravimetric analysis curve shows a weight loss of 5.477% at 120.00±3.0°C, as shown in Figure 3.

[0207] [Table 37]

[0208] Examples 105 to 107 According to the formulation ratios in Table 38, Examples 105 to 107 were prepared.

[0209] Production process: Preparation of concentrated solution: A specified amount of water for injection was added to a beaker, and the beaker was placed on a CNC heating type magnetic stirrer and heated to a water temperature of 77°C ± 2°C. HP-β-CD was added in small batches under stirring.

[0210] After the HP-β-CD was completely dissolved, the specified amount of the active compound was added in one portion while maintaining stirring, and the solution temperature was controlled at 77°C ± 2°C, and stirring was continued until the solution became completely clear.

[0211] Dilute the concentrated solution to adjust the volume: weigh 7.5 kg of water for injection at 20-25°C and add it to a stainless steel bucket. Start stirring the mixer. Add the concentrated solution to the stainless steel bucket. Rinse the beaker containing the concentrated solution 4-6 times with small amounts of water for injection at 20-25°C. Transfer all the rinse solution to the stainless steel bucket and stir thoroughly. Add the specified amounts of sodium chloride, sodium dihydrogen phosphate monohydrate, and sodium hydrogen phosphate in order and stir to dissolve. Dilute this solution with water for injection at 20-25°C to 15 L and stir thoroughly.

[0212] Filtration and filling: Before starting production, integrity test was performed on the filter cartridge, and steam sterilization in place was performed by flashing the mixing tank, blow-fill-seal (BFS) machine and its material conveying pipeline, and sterilization by pure steam was performed at a temperature of ≥ 121°C for 30 minutes, and the equipment was turned on to start filtration and filling, and integrity test was performed on the filter cartridge after the product was completed.

[0213] Punching: All punched products were subjected to leak detection and then each bottle was inspected to remove any non-conforming products.

[0214] Packaging: All qualified die-cut products were subjected to light inspection, non-conforming products were removed, and the die-cut products that passed leak detection and light inspection were pillow-packaged, and the heat-sealing effectiveness of all packaged samples was tested by using a constant temperature vacuum drying oven.

[0215] The results show that the formulation ratios and preparation methods of Examples 105 to 107 can produce products with controllable quality and stable properties.

[0216] [Table 38]

[0217] Experimental Example 1: Experimental study on the effects of a mouse model of dry eye disease Objective of the experiment: The therapeutic effects of Examples 105, 106 and 107 were investigated in a C57BL / 6 mouse model of dry eye disease by subcutaneous injection of scopolamine hydrobromide solution into the lower limbs.

[0218] Experimental process: According to the tear production, the animals were randomly and equally divided into five groups: negative control group (physiological saline, G1), model control group (solvent, Example 102, G2), low concentration group (1 mg / mL) (Example 105, G3), medium concentration group (2.5 mg / mL) (Example 106, G4) and high concentration group (5 mg / mL) (Example 107, G5). Each group consisted of eight animals, all female.

[0219] Animals in each group were subcutaneously injected with 5 mg / mL scopolamine hydrobromide solution at approximately 3-hour intervals into both lower limbs on D1 (4 times / day, 0.1 mL / injection) for 12 consecutive days (3 doses on D12). Animals in the negative control group were subcutaneously injected with an equal volume of saline into both lower limbs, avoiding repeated injections at the same injection point.

[0220] Animals in each test group were administered 3 μL / dose in both eyes four times daily, approximately 3 hours apart, for a total of 12 days on D1 (three doses on D12). Animals in the negative control and model control groups received an equal volume of vehicle via eye drops in both eyes. Approximately 30 minutes after the second dose on D7 and D12, tear production in both eyes was measured, and approximately 30 minutes after the third dose on D7 and D12, corneal fluorescein staining scores were evaluated. After completion of the index measurements on D12, the animals were euthanized using cervical dislocation.

[0221] Test Results: The low-concentration group (1 mg / mL), the medium-concentration group (2.5 mg / mL), and the high-concentration group (5 mg / mL) all had good therapeutic effects on the mouse model of dry eye disease induced by scopolamine hydrobromide solution, mainly improving tear production and corneal damage in the dry eye disease model mice. Based on the comprehensive evaluation of tear production (Table 39, Figure 4) and corneal fluorescein staining (Table 40, Figure 5) scores, the high-concentration group (5 mg / mL) showed the best therapeutic effect.

[0222] [Table 39]

[0223] [Table 40]

[0224] Conclusions from the experiment: Examples 105, 106 and 107 have good therapeutic effects on a mouse model of dry eye disease induced by a scopolamine hydrobromide solution, and mainly improve tear secretion and corneal damage in the mouse model of dry eye disease.

[0225] Experimental Example 2: Experimental study on the effect of a hyperosmolar dry eye disease model in rats Objective of the experiment: To investigate the therapeutic effects of Example 105 and Example 107 on SD rat model of dry eye disease induced by eye drops of hypertonic sodium chloride solution.

[0226] Experimental process: Twenty eligible female SD rats were selected for adaptation observation and bilateral corneal fluorescein staining score evaluation. Tear production measurements were performed on these animals. Animals with corneal problems, abnormal fluorescein staining, and significantly different bilateral tear production were excluded. Animals with significantly different bilateral tear production were selected for grouping. Based on the average bilateral tear production, the animals were randomly and equally divided into three groups: a model control group (Example 102, G1), a low-concentration group (1 mg / mL) (Example 105, G2), and a high-concentration group (5 mg / mL) (Example 107, G3). Each group consisted of four animals with eight eyes, and the day of grouping was recorded as D0.

[0227] On Day 1, animals in each group were modeled, and 20 μL of sodium chloride solution (osmolarity 500 mOsmol / L) was aspirated using a pipette and instilled into the conjunctival sac of both eyes at 20 μL / instillation, 5 times daily, approximately 2 hours apart, for 21 consecutive days. After instillation, the eyelids of the animals were passively closed for approximately 90 seconds.

[0228] On D1, all animals in each group received 10 μL of eye drops per eye, four times per day, approximately 3 hours apart, for a total of 21 days. During the administration period, animals were weighed once a week. Corneal fluorescein staining scores, tear production, and tear breakup time measurements were performed on both eyes on D0, D14, and D21.

[0229] Test Results: In a rat model of dry eye disease, the low-concentration group (1 mg / mL) and the high-concentration group (5 mg / mL) increased tear secretion, reduced corneal fluorescein staining scores, and improved tear breakup time compared to the model control group. Specific results are shown in Tables 41, 42, and 43 and Figures 6, 7, and 8.

[0230] [Table 41]

[0231] [Table 42]

[0232] [Table 43]

[0233] Conclusions from the experiment: The low-concentration group (1 mg / mL) and the high-concentration group (5 mg / mL) had good therapeutic effects on a rat model of dry eye disease induced by hypertonic sodium chloride solution, and this therapeutic effect was mainly manifested in that the tear secretion volume, corneal damage, and tear film stability of the dry eye disease model rats could be significantly improved after 2 weeks of continuous eye drop administration of the drug.

[0234] Experimental Example 3: Pharmacokinetic study in the eyes of New Zealand rabbits Six New Zealand rabbits that passed the adaptive observation were selected and divided into two groups, with three rabbits in each group: a 0.5-hour sampling group and a 2-hour sampling group. The animals in each group were administered 5 mg / mL by eye drop in the left eye (Example 107) at a volume of 100 μL / eye for each experimental group. After administration, plasma, corneal tissue, conjunctival tissue, and retinal tissue samples were collected from each group of animals at 0.5 and 2 hours. LC-MS method was applied to determine the concentration of the active ingredient in the biological samples. Specific results are shown in Tables 44 and 45.

[0235] [Table 44]

[0236] [Table 45]

[0237] Experimental results show that after administering Example 107 to the eye, the active ingredient is distributed in the corneal tissue and conjunctival tissue of the eye surface at high concentration, which is beneficial for the treatment of eye surface diseases.The distribution concentration of active ingredient in retinal tissue is low, which reduces the risk of adverse reactions in the fundus of the eye.Therefore, the pharmacokinetic properties of Example 107 are beneficial for the treatment of eye surface diseases.

[0238] Experimental Example 4: Experimental study on the effect of ragweed pollen-induced allergic conjunctivitis model in mice Objective of the experiment: A mouse model of allergic conjunctivitis was prepared by subcutaneous injection of ragweed pollen into the footpad for sensitization and local irritation by eye drops. Clinical symptoms of the mouse eyes, ocular observation scores, and pathological H&E were detected, and the therapeutic effects of the low concentration group (1 mg / mL) (Example 105), the medium concentration group (2.5 mg / mL) (Example 106), and the high concentration group (5 mg / mL) (Example 107) on mice with allergic conjunctivitis were evaluated.

[0239] Experimental process: 1.1 Animals Healthy BALB / c mice, 5-7 weeks old, 50 mice, half male and half female

[0240] 1.2 Preparation of main reagents 1.2.1 Preparation of model sensitization drug (tarsal joint injection of ragweed pollen): 22.3 mg of ragweed pollen was weighed and dissolved in 7.25 mL of alum adjuvant.

[0241] 1.2.2 Preparation of model irritant drug (ragweed pollen eye drops): 168 mg of ragweed pollen was weighed and dissolved in 1.12 mL of PBS. 189 mg of ragweed pollen was weighed and dissolved in 1.26 mL of PBS (phosphate buffered saline). 144 mg of ragweed pollen was weighed and dissolved in 0.96 mL of PBS.

[0242] 1.2.3 Test Articles Low concentration group (1 mg / mL) (Example 105), medium concentration group (2.5 mg / mL) (Example 106), high concentration group (5 mg / mL) (Example 107) and blank group (Example 102).

[0243] 1.3 Animal grouping, modeling, and model validation (1) Blank group (Example 102) (solvent treatment: 4 times / animal / day, single dose: 20 μL, 4 days of continuous eye drop administration) (N=10) (2) Allergic conjunctivitis model group (also known as the model group in this experiment) (vehicle treatment, 4 times / animal / day, single dose: 20 μL, 4 days, continuous eye drop administration) (N=10) (3) Low concentration group (1 mg / mL) (low concentration group (1 mg / mL) treatment, 4 times / animal / day, single dose: 20 μL, 4 days, continuous eye drop administration) (N=10) (4) Medium concentration group (2.5 mg / mL) (medium concentration group (2.5 mg / mL) treatment, 4 times / animal / day, single dose: 20 μL, 4 days, continuous eye drop administration) (N=10) (5) High concentration group (5 mg / mL) (High concentration group (5 mg / mL) treatment, 4 times / animal / day, single dose: 20 μL, 4 days, continuous eye drop administration) (N=10)

[0244] Modeling: On day 0, sensitizing injections of ragweed pollen were administered subcutaneously to the footpad of the mice at a dose of 65 μL per mouse into the tarsal joint. From day 10 to day 13, irritation injections of ragweed pollen were administered to the right eyes of the mice in the model group at a dose of 10 μL per mouse once a day for 4 consecutive days.

[0245] 1.4 Animal administration Drug intervention treatment was initiated 30 minutes after instillation into each eye, four times a day for four consecutive days. The blank and model groups were treated with an equal volume of solvent. The experimental drug treatment groups were administered with the corresponding doses of compound treatment. Administration was divided into two 20 μL doses per animal (10 μL per dose, 1 minute interval, four doses per animal per day, for four consecutive days).

[0246] 1.5 Test Indicators 1.5.1 Clinical evaluation Within 30 minutes after the last stimulation, the mice's eyes were observed microscopically for clinical signs. An ocular observation score was obtained: observations of ocular allergic reactions, including chemosis and conjunctival hyperemia, were scored from 0 to 3 based on severity (none, mild, moderate, and severe). The scoring criteria for chemosis were: mild focal chemosis (1 point); diffuse chemosis and involvement of the fornix (2 points); and shallow narrowing of the conjunctival sac due to chemosis (3 points). The scoring criteria for conjunctival hyperemia were: mild diffuse vascular hyperemia (1 point); diffuse hyperemia and obvious hyperemia near the fornix (2 points); and hyperemia accompanied by subconjunctival hemorrhage (3 points).

[0247] 1.5.2 H&E staining Experimental Procedure: Right eye and eyelid tissues were excised from animals. First, specimens were fixed in 4% paraformaldehyde at room temperature for 4 hours. The tissues were rinsed in running water for several hours, dehydrated in 70%, 80%, and 90% ethanol solutions, and then treated with a solution of equal volumes of pure alcohol and xylene for 15 minutes. Next, specimens were permeabilized twice with xylene (15 minutes each time) until the specimens were transparent. A mixture of half xylene and half paraffin was added for 15 minutes, followed by paraffin I and paraffin II, each with 60 minutes of wax infiltration. After embedding in paraffin, specimens were sliced ​​according to preselected cross-sectional directions and baked to deparaffinize and moisten. Wet slices were stained with aqueous hematoxylin for 3 minutes, differentiated in ethanolic hydrochloric acid differentiation solution for 15 seconds, rinsed briefly with water, treated with blue-tinting solution for 15 seconds, rinsed in running water, stained with eosin for 3 minutes, rinsed in running water, dehydrated, cleared, mounted, and examined microscopically.

[0248] 1.6 Statistical analysis The experimental data were analyzed using one-way ANOVA ( * p<0.05, ** p<0.01) for each group was analyzed using GraphPad Prism5 and IBM SPSS Statistics19.0 software.

[0249] Test Results: 2.1 Effects of drugs on clinical symptoms in the mouse eye The model group showed a significant improvement in chemosis and conjunctival hyperemia scores compared to the blank group. The low-concentration group (1 mg / mL), medium-concentration group (2.5 mg / mL), and high-concentration group (5 mg / mL) significantly reduced scores (p<0.05 or p<0.01) compared to the model group, improving chemosis and hyperemia. The above results suggest that the low-concentration group, medium-concentration group, and high-concentration group have the effect of improving chemosis and conjunctival hyperemia in mice with allergic conjunctivitis induced by ragweed pollen. Specific experimental results are shown in Figures 9 and 10.

[0250] [Table 46]

[0251] 2.2 Effect of drugs on histopathology in mice with allergic conjunctivitis The pathological results showed that the conjunctiva in the blank group was intact and no obvious damage was observed. Individual samples showed vascular congestion with a small amount of inflammatory cell infiltration. The model group showed varying degrees of conjunctival thickening or thinning, impaired conjunctival epithelial cell arrangement, significant inflammatory cell infiltration, and no obvious capillary proliferation or subconjunctival hyperemia. The conjunctival structure in the low-concentration (1 mg / mL) group was relatively intact, with some samples showing a small amount of inflammatory cell infiltration and visible hyperemia. In the medium-concentration (2.5 mg / mL) group, desquamation of conjunctival epithelial cells and thickening of the conjunctiva were observed, with a small amount of inflammatory cell infiltration and hyperemia still present. In the high-concentration (5 mg / mL) group, some samples showed irregular arrangement of conjunctival epithelial cells, thinning, and a small amount of inflammatory cell infiltration, resulting in hyperemia. The above results suggest that the low, medium, and high concentration groups can improve the abnormalities in conjunctival structure and infiltration of inflammatory cells in mice with allergic conjunctivitis. The results of these experiments are shown in Figure 11.

[0252] Conclusions: The low-, medium-, and high-concentration groups have a good therapeutic effect on the ragweed pollen-induced allergic conjunctivitis model in mice. These groups mainly improve conjunctival edema and conjunctival hyperemia in mice with allergic conjunctivitis, and reduce abnormalities in the conjunctival structure and inflammatory cell infiltration.

Claims

1. An ophthalmic formulation comprising a pyridine phenyl compound, characterized in that it comprises an active ingredient, a pyridine phenyl compound, and an excipient, the excipient comprises a solubilizing agent, a pH modifier, an osmolality adjusting agent, or a combination of two or more thereof; An ophthalmic formulation, wherein the active ingredient pyridine phenyl compound comprises a compound of formula (II), an isomer thereof or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, 【Chemistry 2】 is selected from a single bond or a double bond; T 1 , T 2 , T 3 and T 4 are N, C or CR, respectively. 1 are independently selected from T 5 is C, CR 5 or C=O; T 6 is C, CR 6 or N, T 7 is N or CR 7 is selected from T 5 is selected from C=O, T 6 is selected from N, 【Transformation 3】 is selected from a single bond, L is a single bond, —O—, —S—, or —NR 2 -or- (CR 3 R 4 ) n-; R 1 is H, F, Cl, Br, I, OH or NH 2 is selected from R 2 is H and one, two or three R a C optionally substituted with 1 ~ 3 alkyl groups, R 3 and R 4 are H, F, Cl, Br, I, OH, and NH, respectively. 2 , CN, or one, two or three R b C optionally substituted with 1 ~ 3 independently selected from alkyl groups, R 5 , R 6 and R 7 are each independently selected from H, F, Cl, Br, or I; n is selected from 1, 2 or 3; R a and R b are H, F, Cl, Br, I, OH, and NH, respectively. 2 , CN or CH 3 (independently selected from

2. In the compound of formula (II), its isomer or pharmaceutically acceptable salt thereof, R 2 But H, CH 3 or CH 2 CH 3 is selected from 3 and C.H. 2 CH 3 But one, two or three R a 2. The ophthalmic formulation of claim 1, optionally substituted with:

3. In the compound of formula (II), its isomer or pharmaceutically acceptable salt thereof, R 2 But H, CH 3 or CH 2 CH 3 3. The ophthalmic preparation according to claim 2, characterized in that it is selected from:

4. In the compound of formula (II), its isomer or pharmaceutically acceptable salt thereof, R 3 and R 4 are H, F, Cl, Br, I, OH, and NH, respectively. 2 , C.N., C.H. 3 or CH 2 CH 3 and wherein said CH 3 and C.H. 2 CH 3 But one, two or three R b 4. The ophthalmic preparation according to claim 1, wherein the ophthalmic preparation is optionally substituted with:

5. In the compound of formula (II), its isomer or pharmaceutically acceptable salt thereof, R 3 and R 4 are H, F, Cl, Br, I, OH, and NH, respectively. 2 , C.N., C.H. 3 or CH 2 CH 3 5. The ophthalmic formulation of claim 4, wherein the ophthalmic formulation is independently selected from the group consisting of:

6. In the compound of formula (II), its isomer or pharmaceutically acceptable salt thereof, L is a single bond, —O—, —S—, —NH—, —(CH 2 ) 2 - or -CH 2 6. The ophthalmic preparation according to claim 5, characterized in that it is selected from the group consisting of:

7. The compound of formula (II), its isomer or a pharmaceutically acceptable salt thereof, 【Chemistry 4】 (In the formula, T 3 and T 4 are N or CR, respectively. 1 are independently selected from R 1 and L is as defined in any one of claims 1 to 6.

7. An ophthalmic preparation according to claim 1, characterized in that it is selected from

8. The compound of formula (II), its isomer or a pharmaceutically acceptable salt thereof, 【Transformation 5】 (In the formula, R 1 and L is as defined in claim 7.

8. The ophthalmic preparation according to claim 7, characterized in that it is selected from:

9. The compound of formula (II), its isomer or a pharmaceutically acceptable salt thereof, 【Transformation 6】 9. The ophthalmic preparation according to claim 8, characterized in that it is selected from:

10. 10. The ophthalmic formulation of claim 1, wherein the excipient further comprises an antimicrobial preservative, an antioxidant, a lyophilization solvent, or a combination of two or more thereof.

11. 11. The ophthalmic preparation of claim 10, wherein the antioxidant is selected from butylated hydroxyanisole or vitamin E, or a combination thereof.

12. 11. The ophthalmic preparation of claim 10, wherein the antimicrobial preservative is selected from benzalkonium chloride, chlorhexidine acetate, phenylmercuric acetate, or a combination of two or more thereof.

13. 13. The ophthalmic formulation according to any one of claims 1 to 12, wherein the solubilizer is selected from methylated-β-cyclodextrin, hydroxypropyl betadex, hydroxypropyl-γ-cyclodextrin, sulfobutylether-β-cyclodextrin, poloxamer 407, polysorbate 80, povidone, polyethylene glycol, propylene glycol, glycerol, or a combination of two or more thereof.

14. 13. The ophthalmic preparation of any one of claims 1 to 12, wherein the pH modifying agent is selected from sodium dihydrogen phosphate monohydrate, sodium hydrogen phosphate, borax, boric acid, citric acid dihydrate, hydrochloric acid, sodium hydroxide, or a combination of two or more thereof.

15. 13. The ophthalmic preparation according to any one of claims 1 to 12, wherein the tonicity adjusting agent is selected from sodium chloride, boric acid, borax, glucose, mannitol or a combination of two or more thereof.

16. The ophthalmic formulation comprises a pyridine phenyl compound, one or more solubilizing agents, one or more pH modifiers, one or more osmolality adjusting agents, one or more antimicrobial preservatives, and one or more antioxidants, wherein the pyridine phenyl compound is a compound of Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), an isomer, or a pharmaceutically acceptable salt thereof: 【Transformation 7】 16. An ophthalmic formulation according to any one of claims 1 to 15, comprising:

17. The compound of formula (III) may be a monohydrate of formula (III) (compound of formula IX), an isomer thereof, or a pharmaceutically acceptable salt thereof: 【Transformation 8】 17. The ophthalmic formulation of claim 16, further comprising:

18. The content of the active ingredient is 0.05 to 0.6% w / v, preferably 0.1% w / v, 0.11% w / v, 0.12% w / v, 0.13% w / v, 0.14% w / v, 0.15% w / v, 0.16% w / v, 0.17% w / v, 0.18% w / v, 0.19% w / v, 0.2% w / v, 0.21% w / v, 0.22% w / v, 0.23% w / v, 0.24% w / v, 0.25% w / v, 0.26% w / v, 0.27% w / v, 0.28% w / v, 0.29% w / v, 0.3% w / v, 0.31% w / v, 0.32% w / v, 0.33% w / v 18. An ophthalmic formulation according to any one of claims 1 to 17, characterized in that the formulation is 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.4%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.5%, 0.51%, 0.52%, 0.53%, 0.54%, or 0.55% w / v.

19. 18. The ophthalmic formulation of claim 17, wherein the solubilizing agent is selected from methylated-β-cyclodextrin, hydroxypropyl betadex, hydroxypropyl-γ-cyclodextrin, sulfobutylether-β-cyclodextrin, poloxamer 407, polysorbate 80, povidone, polyethylene glycol, propylene glycol, glycerol, or a combination of two or more thereof.

20. The content of the solubilizer is 0.2% to 15% w / v, preferably 0.3% w / v, 0.4% w / v, 0.5% w / v, 0.6% w / v, 0.65% w / v, 0.7% w / v, 0.75% w / v, 0.8% w / v, 0.85% w / v, 0.9% w / v, 0.95% w / v, 1.0% w / v, 1.1% w / v, 1.2% w / v, 1.3% w / v, 1.4% w / v, 1.5% w / v, 1.55% w / v, 1.6% w / v, 1.65% w / v, 1.7% w / v, 1.75% w / v, 1.8% w / v, 1.9% w / v, 2.0% w / v 2.1%w / v, 2.2%w / v, 2.3%w / v, 2.4%w / v, 2.5%w / v, 2.6%w / v, 2.7%w / v, 2.8 %w / v, 2.9%w / v, 3.0%w / v, 3.3%w / v, 3.5%w / v, 3.6%w / v, 3.8%w / v, 4.0%w / v , 4.2% w / v, 4.4% w / v, 4.5% w / v, 4.6% w / v, 4.8% w / v, 5.0% w / v, 5.2% w / v, 5.4 %w / v, 5.5%w / v, 5.6%w / v, 5.8%w / v, 6.0%w / v, 6.2%w / v, 6.5%w / v, 6.8%w / v 20. The ophthalmic formulation of claim 19, wherein the formulation is 7.0% w / v, 7.2% w / v, 7.4% w / v, 7.5% w / v, 7.6% w / v, 7.8% w / v, 8.0% w / v, 8.2% w / v, 8.5% w / v, 8.6% w / v, 8.8% w / v, 9.0% w / v, 9.2% w / v, 9.4% w / v, 9.5% w / v, 9.6% w / v, 9.8% w / v or 9.9% w / v.

21. 20. An ophthalmic formulation according to claim 19, characterized in that the content of hydroxypropyl betadex is 0.5% w / v to 12% w / v, preferably 0.7% w / v to 10% w / v, more preferably 1% w / v to 8% w / v, and most preferably 1.2% w / v, 1.7% w / v, 1.75% w / v, 2% w / v, 2.5% w / v, 2.8% w / v, 3% w / v, 3.3% w / v, 3.5% w / v, 4% w / v, 4.4% w / v, 5% w / v, 5.5% w / v, 6% w / v, 7% w / v, 7.5% w / v or 8% w / v.

22. 19. An ophthalmic formulation according to claim 18, characterized in that the content of sulfobutylether-β-cyclodextrin is between 4% and 13%, preferably 4.3%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12% or 12.5% ​​w / v.

23. The content of the pH modifier is 0.12 to 20% w / v, preferably 0.2% w / v, 0.25% w / v, 0.3% w / v, 0.35% w / v, 0.4% w / v, 0.47% w / v, 0.5% w / v, 0.6% w / v, 0.7% w / v, 0.8% w / v, 0.81% w / v, 0.9% w / v, 1% w / v, 2% w / v, 3% w / v, 18. The ophthalmic formulation of claim 17, wherein the ophthalmic formulation is 4% w / v, 5% w / v, 6% w / v, 7% w / v, 8% w / v, 9% w / v, 10% w / v, 11% w / v, 12% w / v, 13% w / v, 14% w / v, 15% w / v, 16% w / v, 17% w / v, 18% w / v, 19% w / v or 20% w / v.

24. 22. The ophthalmic formulation of claim 21, wherein the pH modifying agent is selected from sodium dihydrogen phosphate monohydrate, sodium hydrogen phosphate, or a combination of the two.

25. 24. An ophthalmic formulation according to claim 23, characterized in that the content of sodium dihydrogen phosphate monohydrate is between 0.1% w / v and 0.5% w / v, preferably between 0.12% w / v and 0.45% w / v, more preferably 0.15% w / v, 0.2% w / v, 0.25% w / v, 0.3% w / v, 0.35% w / v or 0.4% w / v.

26. 23. An ophthalmic formulation according to claim 22, characterized in that the content of sodium hydrogen phosphate is 0.3% w / v to 1% w / v, preferably 0.4% w / v to 0.9% w / v, more preferably 0.45% w / v, 0.47% w / v, 0.5% w / v, 0.55% w / v, 0.6% w / v, 0.65% w / v, 0.7% w / v, 0.75% w / v or 0.81% w / v.

27. The content of the osmolality adjusting agent is 0.1% to 1% w / v, preferably 0.2% w / v, 0.21% w / v, 0.22% w / v, 0.23% w / v, 0.24% w / v, 0.25% w / v, 0.26% w / v, 0.27% w / v, 0.28% w / v, 0.29% w / v, 0.3% w / v, 0.31% w / v, 0.32% w / v, 0.33% w / v, 0.34% w / v, 0.35% w / v, 0.36% w / v, 0.37% w / v, 0.38% w / v, 0.39% w / v, 0.4% w / v, 0.42% w / v, 0.44% w / v, 0.45% w / v, 18. The ophthalmic formulation of claim 17, characterized in that it is 0.46% w / v, 0.48% w / v, 0.5% w / v, 0.55% w / v, 0.6% w / v, 0.65% w / v, 0.7% w / v, 0.75% w / v, 0.8% w / v, 0.85% w / v, 0.9% w / v or 0.95% w / v.

28. 18. The ophthalmic preparation according to claim 17, characterized in that the tonicity adjusting agent is selected from sodium chloride.

29. 29. An ophthalmic formulation according to claim 28, characterized in that the sodium chloride content is 0.2% w / v to 0.8% w / v, preferably 0.25% w / v to 0.7% w / v, more preferably 0.26% w / v, 0.27% w / v, 0.3% w / v, 0.34% w / v, 0.36% w / v, 0.4% w / v, 0.45% w / v, 0.5% w / v, 0.55% w / v, 0.6% w / v or 0.65% w / v.

30. 18. An ophthalmic formulation according to claim 17, characterized in that the content of antimicrobial preservative is 0.001% w / v to 0.02% w / v, preferably 0.002% w / v to 0.018% w / v, more preferably 0.003% w / v to 0.016% w / v, most preferably 0.004% w / v, 0.0045% w / v, 0.005% w / v, 0.0055% w / v, 0.006% w / v, 0.0065% w / v, 0.007% w / v, 0.0075% w / v, 0.008% w / v, 0.0085% w / v, 0.009% w / v, 0.01% w / v, 0.012% w / v, 0.014% w / v or 0.015% w / v.

31. 18. The ophthalmic preparation of claim 17, wherein the antimicrobial preservative is selected from benzalkonium chloride or chlorhexidine acetate.

32. 32. An ophthalmic formulation according to claim 31, characterized in that the benzalkonium chloride content is 0.001% w / v to 0.02% w / v, preferably 0.002% w / v to 0.018% w / v, more preferably 0.003% w / v to 0.016% w / v, and most preferably 0.004% w / v, 0.0045% w / v, 0.005% w / v, 0.0055% w / v, 0.006% w / v, 0.0065% w / v, 0.007% w / v, 0.0075% w / v, 0.008% w / v, 0.0085% w / v, 0.009% w / v, 0.01% w / v, 0.012% w / v, 0.014% w / v or 0.015% w / v.

33. 32. The ophthalmic formulation of claim 31, characterized in that the content of chlorhexidine acetate is 0.001% w / v to 0.02% w / v, preferably 0.002% w / v to 0.018% w / v, more preferably 0.003% w / v to 0.016% w / v, and most preferably 0.004% w / v, 0.0045% w / v, 0.005% w / v, 0.0055% w / v, 0.006% w / v, 0.0065% w / v, 0.007% w / v, 0.0075% w / v, 0.008% w / v, 0.0085% w / v, 0.009% w / v, 0.01% w / v, 0.012% w / v, 0.014% w / v or 0.015% w / v.

34. 18. An ophthalmic preparation according to claim 17, characterized in that the antioxidant content is between 0.1% and 0.8% w / v, preferably 0.2% w / v, 0.3% w / v, 0.4% w / v, 0.5% w / v, 0.6% w / v or 0.7% w / v.

35. The compound of formula (IX) and its isomers or pharmaceutically acceptable salts, preferably in a content of 0.1% w / v to 0.5% w / v Hydroxypropyl Betadex, preferably at a content of 0.7% w / v to 3.5% w / v, preferably 1.75% w / v, 3.5% w / v or 0.7% w / v Sodium hydrogen phosphate, preferably at a content of 0.81% w / v Sodium dihydrogen phosphate monohydrate, preferably at a content of 0.12% w / v Sodium chloride in a content of 0.25% w / v to 0.45% w / v, preferably 0.27% w / v, 0.36% w / v, 0.4% w / v, and Preferably, chlorhexidine acetate at a content of 0.01% w / v.

18. The ophthalmic formulation of claim 17, comprising:

36. The pH range of the ophthalmic formulation is 5.0 to 9.0, preferably 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 6.91, 6.92, 6.93, 6.94, 6.95, 6.96, 6.97, 6.98, 6.99, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.72, 7.73, 7.74, 7.75, 7.76, 7.77, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.53, 8.54, 8.55 36. The ophthalmic formulation of any one of claims 1 to 35, characterized in that the formulation is 8.56, 8.57, 8.58, 8.59, 8.6, 8.7, 8.8 or 8.

9.

37. 11. The ophthalmic formulation according to claim 10, characterized in that the lyophilization solvent is selected from 95% ethanol, tert-butanol, isopropanol or acetonitrile.

38. 38. A method for preparing the ophthalmic formulation of any one of claims 1 to 37, employing a rotary solvent evaporation process, a concentrated solution-dilution method, or a freeze-drying method.

39. 38. The method for preparing an ophthalmic formulation according to any one of claims 1 to 37, wherein the ophthalmic formulation is a liquid formulation, preferably an eye drop, an eye wash or an intraocular injection solution, an ophthalmic semi-solid formulation, preferably an ophthalmic ointment, an ophthalmic cream or an ophthalmic gel, or an ophthalmic solid formulation, preferably an ophthalmic film, an ophthalmic pellet or an intraocular insert.

40. 40. Use of the ophthalmic formulation of any one of claims 1 to 37 for the preparation of a medicament for treating an ophthalmic disease, wherein the ophthalmic disease is preferably dry eye disease, allergic conjunctivitis, macular degeneration, cataract, keratoconus, bullous keratopathy, Fuchs' endothelial corneal dystrophy, ocular cicatricial pemphigoid, meibomian gland dysfunction, uveitis, scleritis, Stevens-Johnson syndrome, ocular rosacea, or Sjogren's syndrome.

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