Ophthalmic preparation containing pyridine phenyl compound as well as preparation method and application of ophthalmic preparation

Abstract

The invention belongs to the field of pharmaceutical preparations, and discloses an ophthalmic preparation containing pyridine phenyl compounds and a preparation method and application of the ophthalmic preparation. The ophthalmic preparation comprises an active ingredient pyridine phenyl compound and auxiliary materials, wherein the active ingredient pyridine phenyl compound comprises a compound shown as a general formula (II), an isomer or pharmaceutically acceptable salt thereof. The composition can be used for treating xerophthalmia, allergic conjunctivitis, macular degeneration, cataract, corneal cone, bullous keratopathy, Fuch corneal endothelial dystrophy, eye scar pemphigus, meibomian gland dysfunction, uveitis, scleritis, Stevens-Johnson syndrome, rosacea and # imgabs1 # syndrome.

Description

An ophthalmic preparation containing a pyridinephenyl compound, and its preparation method and application Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, relates to an ophthalmic preparation of a pyridinephenyl compound and a preparation method thereof, and also includes an application thereof in ophthalmic diseases. Background Art

[0002] Dry eye, also known as keratoconjunctivitis sicca, refers to a broad range of conditions characterized by abnormal tear quality, quantity, or dynamics, resulting in decreased tear film stability and accompanied by ocular discomfort or ocular surface pathology. Specific symptoms include eye irritation, visual impairment, and tear film instability. Some cases of this syndrome are caused by ocular surface inflammation, leading to lacrimal gland dysfunction. Systemic autoimmunity is also associated with this condition.

[0003] Because some toxic aldehydes are produced by the body or eye tissues and organs through metabolic mechanisms, such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4HNE), these aldehydes are highly reactive with proteins, carbohydrates, oils and DNA, leading to chemical modification of biological molecules and activation of inflammatory molecule regulators such as NF-kappaB, thereby causing damage to different organs. This is one of the causes of dry eye.

[0004] Through research, the present invention has found that small molecule drugs enter the inflamed area of ​​the eye in the form of eye drops, and through complexation reaction with aldehydes in the body, reduce aldehyde toxicity and inflammation, thereby achieving the effect of treating dry eye.

[0005] WO2020125659 discloses a pyridinephenyl aldehyde binder compound, and a series of compounds satisfying the general formula I of its isomers or pharmaceutically acceptable salts:

[0006] However, the ophthalmic preparations and their therapeutic effects on ophthalmic diseases have not been disclosed. Therefore, further research is needed to find out the effects of the ophthalmic preparations of the above-mentioned small molecule compounds on ophthalmic diseases (such as dry eye, allergic conjunctivitis, macular degeneration, cataract, keratoconus, bullous keratopathy, Fuch corneal endothelial dystrophy, ocular cicatricial pemphigoid, meibomian gland dysfunction, uveitis, scleritis, Stevens-Johnson syndrome, ocular rosacea, syndrome), and develop ophthalmic preparations with stable preparation technology and quality.

[0007] Summary of the Invention

[0008] The purpose of the present invention is to provide a safe and effective ophthalmic preparation, which has a simple preparation process, stable quality and is suitable for large-scale industrial production.

[0009] The present invention provides an ophthalmic preparation comprising an active ingredient, a pyridinephenyl compound, and excipients, wherein the excipients include a solubilizing agent, a pH regulator, an osmotic pressure regulator, an antibacterial agent, and an antioxidant, wherein the active compound comprises a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof. The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0010] in,

[0011] T1, T2, T3 and T4 are each independently selected from N, C or CR1;

[0012] L is selected from a single bond, -O-, -S-, -NR2- or -(CR3R4)n-;

[0013] R1 is selected from H, F, Cl, Br, I, OH or NH2;

[0014] R2 is selected from H, optionally substituted by 1, 2 or 3 R a Substituted C1-3 alkyl;

[0015] R3 and R4 are independently selected from H, F, Cl, Br, I, OH, NH2, CN or optionally 1, 2 or 3 R b Substituted C 1-3 alkyl;

[0016] n is selected from 1, 2 or 3;

[0017] R a and R b Each is independently selected from H, F, Cl, Br, I, OH, NH2, CN or CH3.

[0018] In some embodiments of the present invention, the above R2 is selected from H, CH3 or CH2CH3, and the CH3 and CH2CH3 are optionally substituted by 1, 2 or 3 Ra, and other variables are as defined in the present invention.

[0019] In some embodiments of the present invention, the above R2 is selected from H, CH3 or CH2CH3, and other variables are as defined in the present invention.

[0020] In some embodiments of the present invention, the above-mentioned R3 and R4 are independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3 or CH2CH3, and the CH3 and CH2CH3 are optionally substituted by 1, 2 or 3 Rb, and other variables are as defined in the present invention.

[0021] In some embodiments of the present invention, R3 and R4 are independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3 or CH2CH3, and the others are as defined in the present invention.

[0022] In some embodiments of the present invention, the above-mentioned L is selected from a single bond, -O-, -S-, -NH-, -(CH2)2- or -CH2-, and other variables are as defined in the present invention.

[0023] The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

[0024] in,

[0025] described is selected from a single bond or a double bond;

[0026] T1, T2, T3 and T4 are each independently selected from N, C or CR1;

[0027] T5 is selected from C, CR5 or C=O;

[0028] T6 is selected from C, CR6 or N;

[0029] T7 is selected from N or CR7;

[0030] When T5 is selected from C=O and T6 is selected from N, is selected from single bonds;

[0031] L is selected from a single bond, -O-, -S-, -NR2- or -(CR3R4)n-;

[0032] Each R1 is independently selected from H, F, Cl, Br, I, OH or NH2;

[0033] R2 is selected from H and C optionally substituted with 1, 2 or 3 R 1-3 alkyl;

[0034] R3 and R4 are each independently selected from H, F, Cl, Br, I, OH, NH2, CN or a C1-3 alkyl group optionally substituted with 1, 2 or 3 Rb;

[0035] R5, R6 and R7 are each independently selected from H, F, Cl, Br or I;

[0036] n is selected from 1, 2 or 3;

[0037] R a and R b Each is independently selected from H, F, Cl, Br, I, OH, NH2, CN or CH3.

[0038] In some embodiments of the present invention, the above R2 is selected from H, CH3 or CH2CH3, and the CH3 and CH2CH3 are optionally substituted by 1, 2 or 3 Ra, and other variables are as defined in the present invention.

[0039] In some embodiments of the present invention, the above R2 is selected from H, CH3 or CH2CH3, and other variables are as defined in the present invention.

[0040] In some embodiments of the present invention, the above-mentioned R3 and R4 are independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3 or CH2CH3, and the CH3 and CH2CH3 are optionally substituted by 1, 2 or 3 Rb, and other variables are as defined in the present invention.

[0041] In some embodiments of the present invention, R3 and R4 are independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3 or CH2CH3, and other variables are as defined in the present invention.

[0042] In some embodiments of the present invention, the above-mentioned L is selected from a single bond, -O-, -S-, -NH-, -(CH2)2- and -CH2-, and other variables are as defined in the present invention.

[0043] Some other solutions of the present invention are obtained by arbitrarily combining the above variables.

[0044] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from

[0045] in,

[0046] T3 and T4 are independently selected from N and CR1;

[0047] R1 and L are as defined herein.

[0048] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from

[0049] in,

[0050] R1 and L are as defined herein.

[0051] In the present invention, as one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from:

[0052] In the present invention, as one embodiment, the compound of formula (III), its isomer or pharmaceutically acceptable salt thereof:

[0053] In the present invention, as one embodiment, the compound of formula (IV), its isomer or pharmaceutically acceptable salt thereof:

[0054] In the present invention, as one embodiment, the compound of formula (V), its isomer or pharmaceutically acceptable salt thereof:

[0055] In the present invention, as one embodiment, the compound of formula (VI), its isomer or pharmaceutically acceptable salt thereof:

[0056] In the present invention, as one embodiment, the compound of formula (VII), its isomer or pharmaceutically acceptable salt thereof:

[0057] In the present invention, as one embodiment, the compound of formula (VIII), its isomer or pharmaceutically acceptable salt thereof:

[0058] In the present invention, as one embodiment, the compound of formula (III) further includes a molecule of water, that is, the compound of formula IX, its isomer or a pharmaceutically acceptable salt thereof:

[0059] In the present invention, as one embodiment, the topical external preparation 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.

[0060] In the present invention, as one embodiment, the ophthalmic preparation includes one or more solubilizing agents.

[0061] In the present invention, as one embodiment, the ophthalmic preparation includes one or more pH adjusters.

[0062] In the present invention, as one embodiment, the ophthalmic preparation includes one or more osmotic pressure regulators.

[0063] In the present invention, as one embodiment, the ophthalmic preparation includes one or more antibacterial agents.

[0064] In one embodiment of the present invention, the ophthalmic preparation includes one or more antioxidants.

[0065] In the present invention, as one of the embodiments, the solubilizing agent is selected from methylated-β-cyclodextrin (RM-β-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD), hydroxypropyl-γ-cyclodextrin (HP-γ-CD), sulfobutyl-β-cyclodextrin (SBE-β-CD), poloxamer 407, Tween 80, povidone (PVP), polyethylene glycol (PEG400), or a combination of two or more thereof.

[0066] In the present invention, as one embodiment, the pH adjuster is selected from sodium dihydrogen phosphate monohydrate, anhydrous disodium hydrogen phosphate, borax, boric acid, citric acid dihydrate, hydrochloric acid, sodium hydroxide, or a combination of two or more thereof.

[0067] In the present invention, as one of the embodiments, the osmotic pressure regulator is selected from sodium chloride, boric acid, borax, glucose, mannitol, or a combination of two or more thereof.

[0068] In the present invention, as one of the embodiments, the antibacterial agent is selected from benzalkonium chloride, chlorhexidine acetate, phenylmercuric acetate, or a combination of two or more thereof.

[0069] In the present invention, as one embodiment, the antioxidant is selected from butylated hydroxyanisole (BHA), vitamin E (VE), or a combination of two or more thereof.

[0070] In the present invention, as one of the embodiments, the freeze-drying solvent is selected from 95% ethanol, tert-butanol, isopropanol, or acetonitrile.

[0071] The present invention provides an ophthalmic preparation comprising an active ingredient, a pyridinylphenyl compound, one or more solubilizing agents, one or more pH regulators, one or more osmotic pressure regulators, one or more antibacterial agents, and one or more antioxidants, wherein the pyridinylphenyl compound comprises a compound of formula (III), formula (IV), formula (V), (VI), (VII), formula VIII, or formula (IX), an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0072] In the ophthalmic preparation provided by the present invention, the content of the active ingredient is 0.05-0.6% 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, 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.

[0073] In the ophthalmic preparation provided by the present invention, the solubilizing agent is selected from methylated-β-cyclodextrin (RM-β-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD), hydroxypropyl-γ-cyclodextrin (HP-γ-CD), sulfobutyl-β-cyclodextrin (SBE-β-CD), poloxamer 407, Tween 80, povidone (PVP), polyethylene glycol (PEG400), or a combination of two or more thereof.

[0074] In the ophthalmic preparation provided by the present invention, the content of the solubilizing agent 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. / 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, 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.

[0075] In the ophthalmic preparation provided by the present invention, the content of the solubilizing agent hydroxypropyl-β-cyclodextrin (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.

[0076] In the ophthalmic preparation provided by the present invention, the content of the sulfobutyl-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.

[0077] In the ophthalmic preparation provided by the present invention, the content of the pH regulator is 0.12-20% 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 / 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.

[0078] In the ophthalmic preparation provided by the present invention, the content of the pH adjuster sodium dihydrogen phosphate monohydrate is 0.1% w / v to 0.5% w / v, preferably 0.12% w / v to 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.

[0079] In the ophthalmic preparation provided by the present invention, the content of the pH adjuster anhydrous disodium 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.

[0080] In the ophthalmic preparation provided by the present invention, the content of the osmotic pressure regulator 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 / 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, 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.

[0081] In the ophthalmic preparation provided by the present invention, the content of the osmotic pressure regulator sodium chloride 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.

[0082] In the ophthalmic preparation provided by the present invention, the content of the antibacterial agent 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.

[0083] In the ophthalmic preparation provided by the present invention, the content of the antibacterial agent benzalkonium chloride is 0.001% w / v to 0.02% w / v, preferably 0.002% w / v to 0.018% w / v, further 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.

[0084] In the ophthalmic preparation provided by the present invention, the content of the antibacterial agent chlorhexidine acetate is 0.001% w / v to 0.02% w / v, preferably 0.002% w / v to 0.018% w / v, further 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.

[0085] 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.

[0086] The ophthalmic preparation provided by the present invention comprises: a compound of formula (IX) and its isomers or pharmaceutically acceptable salts thereof, in an amount of 0.1% w / v to 0.5% w / v; and excipients: hydroxypropyl-β-cyclodextrin (HP-β-CD), in an amount of 0.7% w / v to 3.5% w / v, preferably 1.75% w / v, 3.5% w / v, or 0.7% w / v; anhydrous disodium hydrogen phosphate, in an amount of 0.81% w / v; sodium dihydrogen phosphate monohydrate, in an amount of 0.12% w / v; sodium chloride, in an amount 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, in an amount of 0.01% w / v.

[0087] In the ophthalmic preparation provided by the present invention, the pH value of the ophthalmic preparation ranges from 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 8, 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.

[0088] The ophthalmic preparation provided by the present invention is prepared by a rotary evaporation process, a concentrated dilution method, and a freeze-drying method.

[0089] The ophthalmic preparations of the present invention were tested for stability, and the changes in content and related substances were determined. The results showed that the ophthalmic preparations provided by the present invention were stable, and there were no significant differences in related substances and content.

[0090] The ophthalmic preparations provided by the present invention may be in the form of liquid preparations, which may be eye drops, eye washes or intraocular injection solutions as examples; semisolid ophthalmic preparations may be eye ointments, eye creams or eye gels as examples; and solid ophthalmic preparations may be eye masks, eye pills or intraocular inserts as examples.

[0091] The ophthalmic preparation provided by the present invention is used in the preparation of a medicament for treating ophthalmic diseases, wherein the ophthalmic preparation is preferably used for treating dry eye, allergic conjunctivitis, macular degeneration, cataract, keratoconus, bullous keratopathy, Fuch corneal endothelial dystrophy, ocular cicatricial pemphigoid, meibomian gland dysfunction, uveitis, scleritis, Stevens-Johnson syndrome, ocular rosacea, or syndrome.

[0092] The ophthalmic preparation provided by the present invention was tested for its therapeutic efficacy in a dry eye model induced by subcutaneous injection of scopolamine hydrobromide solution into the lower limbs of C57BL / 6 mice and a dry eye model induced by eye drops of hypertonic sodium chloride solution in SD rats. The results demonstrated that the ophthalmic preparation of the present invention improved tear secretion and corneal damage in dry eye model mice. Pharmacokinetic studies in New Zealand rabbits revealed that the active ingredient has a high concentration in the cornea and conjunctiva of the ocular surface tissues, which is beneficial for the treatment of ocular diseases. The concentration in the fundus is low, which reduces the risk of causing adverse reactions in the fundus.

[0093] Definition and Description

[0094] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered as undefined or unclear in the absence of a specific definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0095] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts 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, and methanesulfonic acid; and 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 and can be converted into either base or acid addition salts.

[0096] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0097] In addition to the form of salts, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0098] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrates. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention.

[0099] Optically active (R)- and (S)-isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereoisomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine). The compounds of the present invention may contain unnatural ratios of atomic isotopes on one or more atoms constituting the compound. For example, compounds can be labeled with radioactive isotopes, such as tritium (3H), iodine-125 (125I), or carbon-14 (14C). Another example is that deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced therapeutic efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0100] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0101] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When 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 it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0102] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0103] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0104] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0105] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A. When the listed substituents do not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom of the substituent. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring. When the listed linking group does not specify its connection direction, its connection direction is arbitrary. For example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0106] Unless otherwise specified, the term "C1-6 alkyl" is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C1-6 alkyl group includes C1-5, C1-4, C1-3, C1-2, C2-6, C2-4, C6 and C5 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C1-6 alkyl groups 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 “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 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 “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0109] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0110] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., an affine substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chloro, bromo, iodo; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, etc.; acyloxy groups such as acetoxy and trifluoroacetoxy, etc.

[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 amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(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 the hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups 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 well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0113] The solvent used in the present invention is commercially available. The present invention uses the following abbreviations: 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-chloroperoxybenzoic acid; eq represents equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents PE; DIAD represents diisopropyl azodicarboxylate; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, which is an amine protecting group; BOC represents tert-butyloxycarbonyl, which is an 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 stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl2 stands for thionyl chloride; CS2 stands for carbon disulfide; TsOH stands for p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS stands for N-chlorosuccinimide; n-Bu4NF stands for tetrabutylammonium fluoride; iPrOH stands for 2-propanol; mp stands for melting point; LDA stands for lithium diisopropylamide; LiHMD S represents lithium hexamethyldisilazide; Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; LiAlH4 represents lithium aluminum tetrahydride; Pd(dba)2 represents tris(dibenzylideneacetone)dipalladium; mCPBA represents meta-chloroperbenzoic acid; pd(dppf)Cl2 represents [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium; DBU represents 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0114] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names. BRIEF DESCRIPTION OF THE DRAWINGS

[0115] Figure 1: XRPD spectrum of the compound of formula (IX) using Cu-Kα radiation.

[0116] Figure 2: DSC spectrum of the compound of formula (IX).

[0117] Figure 3: TGA spectrum of the compound of formula (IX).

[0118] Figure 4: Tear secretion in the mouse dry eye model of Examples 105, 106, and 107.

[0119] Figure 5: Corneal fluorescent staining scores of the mouse dry eye model of Examples 105, 106, and 107.

[0120] Figure 6: Tear secretion in the rat dry eye model of Examples 105 and 107.

[0121] Figure 7: Corneal fluorescent staining scores of the rat dry eye model of Examples 105 and 107.

[0122] FIG8 : Tear film breakup time of the rat dry eye model of Examples 105 and 107.

[0123] Figure 9: Conjunctival edema scoring.

[0124] Figure 10: Conjunctival hyperemia scoring.

[0125] Figure 11: Pathological results of HE staining. DETAILED DESCRIPTION

[0126] The present invention is further described in detail by the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0127] Examples 1 to 11

[0128] The active compound of the present invention, Formula (IX), is insoluble or nearly insoluble in water. Examples 1-11 were prepared according to the specific process in Table 1. The results showed that the compound of Formula (IX) remained insoluble even after different solubilizers and heating in Examples 1, 4, 5, 6, 7, 9, and 10. The solubilizers in Examples 2, 3, 8, and 11 demonstrated a moderate solubility-enhancing effect.

[0129] Table 1

[0130] Examples 12 to 30

[0131] According to the formulation in Table 2, the active compound (Formula (IX), propylene glycol, PEG400, Tween 80, and other excipients were weighed and placed in a vial. The active compound was sonicated and dissolved in the excipients to obtain a concentrated solution. This concentrated solution was added dropwise to the prescribed amount of medium. Examples 12 to 30 were obtained, and the dissolution of the active compound was observed. Specific data are shown in Table 2. Examples 20 to 23 produced relatively stable 5 mg / ml solutions of the active compound.

[0132] Table 2

[0133] Examples 31 to 41

[0134] The active compound (Formula (IX)) and HP-β-CD were weighed according to Table 3 and dissolved in 95% ethanol. The solution was placed in a rotary evaporator to remove the solvent to obtain a solid inclusion complex. This solid inclusion complex was then dissolved in purified water. Depending on the amount of active compound added, a 5 mg / mL solution was prepared using purified water / pH 6.8 phosphate medium, and the dissolution was observed. The results are shown in Table 3.

[0135] Table 3 Note: The active compounds of Examples 39 to 41 were fed as per the

[0136] After rotary evaporation, the HP-β-CD inclusion complexes of the active compounds were obtained in Examples 31 to 41. The HP-β-CD inclusion complexes of Examples 33, 35, 36, 37, 38, 40, and 41 were dissolved into clear, transparent aqueous solutions without precipitation.

[0137] The eye drops of Example 36, Example 37 and Example 38 were sterilized at 121° C. for 15 min. The eye drops of Example 36 and Example 37 became turbid, while the eye drops of Example 38 remained clear after sterilization.

[0138] The eye drops prepared in Examples 40 and 41 were sterilized at 121°C for 15 minutes. The main component and the largest single impurity were shown in Table 4. The main component of Examples 40 and 41 decreased by 0.62% and 0.61% before and after sterilization, respectively; the largest single impurity increased by 1.61% and 1.35% before and after sterilization, respectively.

[0139] Table 4

[0140] Examples 42 to 45

[0141] According to Table 5, 10 ml of isopropanol was taken and placed in a 50 ml beaker. The active compound was added and stirred to dissolve. 4.00 g of HP-β-CD was added and stirred evenly. 10 ml of isopropanol was added and ultrasonicated for 12 minutes to obtain a clear solution. Example 42 was first rotary evaporated at room temperature until the solution turned from clear to white and solid precipitated. Then, it was transferred to a 50°C water bath and the vacuum was adjusted. When the vacuum was 0.085 MPa, it began to boil. The inclusion compound was rotary evaporated for 1 hour and the inclusion compound was scraped out. Example 43 was directly placed in a 50°C water bath, the vacuum was adjusted to 0.085 MPa, the inclusion compound was rotary evaporated for 1 hour and the inclusion compound was scraped out. The stability results of Examples 42 and 43 before and after rotary evaporation are shown in Table 6. The stability of the rotary evaporated solution at 50°C was investigated in Examples 44 and 45. The results are shown in Table 7.

[0142] Table 5

[0143] Table 6

[0144] Table 7

[0145] The test results showed that the related substances of the active compound (IX) remained essentially unchanged before and after rotary evaporation in Examples 42 and 43, indicating that the rotary evaporation process had little effect on the stability of the active compound. The related substances of the active compound remained essentially unchanged in Examples 44 and 45 when the solutions were kept at 50°C for less than 2 hours before rotary evaporation.

[0146] Examples 46-47

[0147] HP-β-CD and the active compound of formula (IX) were placed in a beaker according to the ratio in Table 8. An organic solvent was added and stirred to dissolve the mixture. Purified water was then slowly added to obtain a clear solution, which was then freeze-dried to investigate the effects of different solvents on the state of the intermediate after freeze-drying and its re-dissolution.

[0148] Table 8

[0149] The test results showed that the intermediate of Example 46 was a white, loose, porous solid with good morphology; the intermediate of Example 47 was a white, loose, porous solid with some splattering of solid powder. The solutions of both Examples 46 and 47 were slightly turbid after reconstitution.

[0150] Examples 48 to 51

[0151] In Examples 48, 49, and 50, the active compound (Formula (IX), HP-β-CD, butylated hydroxyanisole (BHA), and vitamin E (VE) were placed in a beaker according to the formulation in Table 9. Isopropyl alcohol was added and the mixture was stirred thoroughly. A certain amount of purified water was then slowly added to obtain a clear solution, which was then lyophilized. In Example 51, the active compound was dispersed using only a certain amount of purified water and then lyophilized. The effects of different excipients on impurities during the lyophilization process were investigated. The main components and impurity content data for Examples 48-51 are shown in Table 10.

[0152] Table 9

[0153] Table 10

[0154] The results showed that there was no significant change in the related substances of Example 48 and Example 51, and the addition of HP-β-CD did not affect the stability of the active compounds.

[0155] Compared to Example 48, Example 490, which added the antioxidant BHA, achieved a maximum single impurity concentration of 2.03%. A 5-day stability test at 60°C revealed that the main component content in Examples 49 and 50 decreased to varying degrees compared to Example 48. Adding antioxidants like BHA or VE negatively impacted the stability of the active compound eye drops.

[0156] Examples 52 to 63

[0157] According to the prescription ratio in Table 11, weigh the active compound (Formula (IX)) and disperse it in isopropanol with stirring until the solution is clear. Slowly add HP-β-CD while stirring until the solution is clear. Slowly add purified water in the prescribed ratio to the isopropanol solution while stirring and stir for 1 hour to obtain a clear solution. Freeze-dry the solution in a vacuum freeze dryer to obtain a fluffy white lyophilized powder. The lyophilization curve is shown in Table 12. Dissolve the inclusion compound lyophilized powder in the reconstitution medium. Filter through a mixed filter membrane with 0.45μm and then 0.22μm filters to obtain the active compound eye drops. Fill the sample packaging in 2ml bottles. This is the resulting eye drops.

[0158] Multi-dose eye drops require the addition of antibacterial agents to prevent microbial contamination during use. Examples 52, 55, and 56 were used to investigate the effects of two antibacterial agents, benzalkonium chloride and chlorhexidine acetate, on formulation stability. The initial stability of the eye drops in Examples 52, 55, and 56 was investigated for 5 days in the dark at 25°C and 40°C. The results are shown in Table 13. Assessing the number and level of impurity growth, Example 56 exhibited better short-term stability than Example 57, suggesting that the antibacterial agent chlorhexidine acetate is more suitable for active compound eye drops.

[0159] Examples 53 and 54 were packaged in low-density polyethylene (PE) medicinal eye drop bottles, brown polyester (PET) medicinal eye drop bottles, and ampoules, respectively, and stored in the dark at 25°C to evaluate preliminary packaging material compatibility. Stability data is shown in Table 14. Example 52, produced using the isopropyl alcohol freeze-drying process, exhibited crystallization upon long-term storage. Examples 53 and 54, produced using different packaging systems, showed no crystallization and no significant change in impurities after storage at 25°C for 15 days.

[0160] During reconstitution of Examples 57-60, dilute hydrochloric acid and dilute sodium hydroxide were used to adjust the pH to investigate the appropriate pH for the active compound (Formula (IX)) eye drops. The stability results of Examples 57-60 at 60°C for 5 days are shown in Table 15. These results demonstrate that the eye drops exhibited better stability under slightly alkaline conditions than under acidic conditions.

[0161] The stability data for Examples 61-63 are shown in Table 16. Compared to Example 61, there was no significant change in the related substances in Example 62, indicating that the addition of the antibacterial agent chlorhexidine acetate did not affect the stability of the active compound, Formula (IX), in the eye drops. Compared to Example 62, there was no significant change in the related substances in Example 63, indicating that increasing the amount of the solubilizing agent HP-β-CD did not affect the stability of the active compound.

[0162] Table 11

[0163] Table 12

[0164] Table 13

[0165] Table 14

[0166] Table 15

[0167] Table 16

[0168] Examples 64 to 67

[0169] According to the prescription ratio in Table 17, heat 30g of purified water to 80°C, weigh hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutyl-β-cyclodextrin (SBE-β-CD), and add small amounts of the purified water to dissolve them while stirring. Weigh the active compound formula (IX) in the prescribed amount and add small amounts of the cyclodextrin solution to the cyclodextrin solution while stirring. The active compounds in Examples 64, 66, and 67 can be completely dissolved within 2 hours. Add purified water to Examples 64 to 66 to make up to 60ml and stir evenly. The above solution is encapsulated in borosilicate glass ampoules, 4ml / ampoules, and a total of 10 ampoules are packed. The eye drops are obtained.

[0170] Example 64 and Example 66 were placed in a water bath at 80°C and heated in the dark. Two ampoules were removed at 0.5, 1, 2, 4, and 6 hours, respectively, and samples were sent for determination of content and related substances. The results are shown in Table 18.

[0171] In Example 64, the content of related substances increased by 0.03%, 0.10%, and 0.21% after 0.5, 1, and 2 hours at 80°C, respectively. In Example 66, the content of related substances increased by 0.30%, 0.47%, and 0.57% after 0.5, 1, and 2 hours at 80°C, respectively. Compared with Example 64, Example 66, which contains SBE-β-CD, has poorer thermal stability.

[0172] Table 17

[0173] Table 18

[0174] Examples 68 to 91

[0175] Examples 68-87 were prepared according to the formulation ratios in Table 19. The active compound (Formula (IX)) and HP-β-CD were weighed and placed in a 10 ml vial. Purified water in the formulation ratio was added and stirred or shaken at different water bath temperatures until dissolved. The effects of different concentration conditions on the dissolution of the active compound were compared. Example 79 was diluted 1-fold and 5-fold to obtain Examples 88 and 89. Example 80 was diluted 1-fold and 5-fold to obtain Examples 90 and 91.

[0176] In Examples 69, 70, 75-83, 85, and 86, the active compound of formula (IX) was completely dissolved in a relatively short period of time under the concentration conditions listed in Table 19. Under the concentration process conditions, the amount of HP-β-CD, the concentration of HP-β-CD, and the concentration temperature significantly affected the dissolution of the active compound.

[0177] Table 19

[0178] The stability of aqueous solutions of the active compound inclusion complexes of the examples listed in Table 20 and the photostability of Example 80 were investigated. The results are shown in Tables 21, 22, and 23.

[0179] The test results show that the content of the active compound remains basically stable after 10 days of observation at 60°C and 20 days at 25°C, 30°C, and 40°C, indicating that the thermal stability of the cyclodextrin aqueous solutions containing the active compounds of Examples 67, Examples 78 to 80, and Examples 88 to 91 is acceptable; Example 80 shows a yellow precipitate after 5 days of observation under the light conditions of the influencing factor test, indicating that the cyclodextrin aqueous solution containing the active compound is unstable to strong light.

[0180] Table 20

[0181] Table 21

[0182] Table 22

[0183] Table 23

[0184] Example 92

[0185] Example 92 was prepared according to the prescription ratio in Table 24. A certain amount of purified water was added to a beaker, heated in a water bath to 70°C, HP-β-CD was added and stirred to dissolve, then the active compound (IX) was 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 with purified water in small amounts several times, the rinse water was transferred to the volumetric flask, chlorhexidine acetate was added, and the solution was shaken to dissolve. Anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate monohydrate, and sodium chloride were added in sequence, shaken to dissolve, and purified water was added to make the volume 100ml. Filtered through 0.45μm and 0.22μm mixed membranes in sequence, the filtrate was sealed in 5ml borosilicate glass ampoules at a rate of 5ml / piece. Eye drops were obtained.

[0186] The eye drops of Example 92 were sterilized at 115°C for 30 min, 121°C for 15 min, and 121°C for 30 min, and the properties, pH, and related substances of the samples were tested. The results are shown in Table 25. Example 92 was placed at 60°C for observation, and samples were taken at 0, 5, and 10 days to test the properties, content, and related substances of the samples. The test results are shown in Table 26.

[0187] Table 24

[0188] Table 25

[0189] Table 26

[0190] The results showed that Example 92 showed a significant increase in related substances after sterilization under different conditions. The total impurities in the sample sterilized at 115°C for 30 minutes increased by 1.507%, while those sterilized at 121°C for 15 and 30 minutes increased by 1.687% and 2.195%, respectively. Example 92 exhibited poor thermal stability and could not withstand moist heat sterilization. After sterilization at 60°C for 5 and 10 days, the related substances in Example 92 increased, respectively, while other indicators remained largely stable.

[0191] Example 93

[0192] Example 93 was prepared according to the prescription ratio 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 and stirred to dissolve. The active compound (IX) was added and the temperature was raised to 70°C and stirred for 60 min until completely dissolved. The solution was transferred to a 500 ml volumetric flask. The beaker was rinsed with approximately 200 g of purified water in small amounts several times. The rinse water was also transferred to the volumetric flask. Chlorhexidine acetate was added and shaken to dissolve. Anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate monohydrate, and sodium chloride were added in sequence. The solution was shaken to dissolve and purified water was added to 500 ml. The solution was mixed well. The density of the solution was calculated to be 1.0166 g / ml based on the mass-to-volume ratio. The solution was sealed in 5 ml borosilicate glass ampoules at a rate of 5 ml per vial to obtain the eye drops.

[0193] Example 93 was placed approximately 1.5 m indoors under a 40-watt fluorescent lamp. Samples were taken at 0, 2, 4, and 6 hours for testing of properties, pH, and related substances. The test results are shown in Table 28. The results showed that Example 93 remained essentially stable after being placed approximately 1.5 m indoors under the fluorescent lamp for 6 hours. Liquid preparation and filling during production can be carried out under normal indoor lighting.

[0194] Table 27

[0195] Table 28

[0196] Examples 94 to 96

[0197] Weigh 10.00g of purified water into a 50ml beaker and heat to 75°C in a waterbath. Add HP-β-CD according to the amount prescribed in Table 29 and stir until dissolved. Add the active compound (Formula (IX)) while stirring until dissolved. Add the cyclodextrin solution containing the active compound to a 500ml beaker containing 126ml of purified water. Rinse the 50ml beaker several times with purified water, transferring the rinses to the 500ml beaker. Add chlorhexidine acetate to the 500ml beaker and stir until dissolved. Then, add sodium chloride, sodium dihydrogen phosphate monohydrate, and anhydrous disodium hydrogen phosphate in sequence. Stir until dissolved, add water to 250ml, stir thoroughly, and filter through a 0.45μm and then a 0.22μm mixed filter membrane to obtain Example 94.

[0198] The pH of Example 94 is 7.75. Take the solution of Example 94, adjust the pH to 6.96 with 1 mol / L HCl and 5 mol / L NaOH, respectively, to obtain Example 95; adjust the pH to 8.54 to obtain Example 96. The eye drops of Example 94 were sterilized at 115°C for 30 min, 121°C for 15 min, and 121°C for 30 min, respectively. The properties, pH, and related substances of the samples were tested. The results are shown in Table 30. The eye drops of Example 94, Example 95, and Example 96 were respectively filled into 5 ml ampoules and placed at 60°C for observation. Samples were taken on days 0, 5, and 10 to test the properties, content, and related substances of the samples. The test results are shown in Table 31.

[0199] The results showed that Example 94 significantly increased the levels of related substances after sterilization under different conditions. Example 94 had poor thermal stability and could not withstand moist heat sterilization. The sample of Example 96, at a pH of 8.54, had the best stability. Furthermore, considering that the ideal pH range for eye drops is 6-8, the pH of Example 94 eye drops was more appropriate.

[0200] Table 29

[0201] Table 30

[0202] Table 31

[0203] Examples 97-98

[0204] Weigh 10.00 ml of purified water into a 50 ml beaker and heat to 75°C in a water bath. Add HP-β-CD according to the amount prescribed in Table 32, stir until dissolved, and then add the active compound while stirring until dissolved. Add the cyclodextrin solution containing the active compound (IX) to a 500 ml beaker containing 126 ml of purified water, and rinse the 50 ml beaker with purified water several times, transferring the rinse liquid to the 500 ml beaker. Add chlorhexidine acetate to the 500 ml beaker and stir until dissolved. Then, add sodium chloride, sodium dihydrogen phosphate monohydrate, and anhydrous disodium hydrogen phosphate in sequence, stir until dissolved, add water to 250 ml, stir evenly, and filter through 0.45 μm and 0.22 μm mixed filter membranes to obtain Examples 97 and 98.

[0205] The osmotic pressures of Examples 94, 97, and 98 were measured, and the results are shown in Table 33. The eye drops of Examples 94, 97, and 98 were in a state close to isotonicity and slightly hypotonicity.

[0206] Table 32

[0207] Table 33

[0208] Examples 99-102

[0209] According to the prescription ratio in Table 34, Examples 99 to 102 were produced.

[0210] Production process:

[0211] Preparation of concentrated solution: Add the prescribed amount of water for injection into a beaker, place the beaker on a CNC heating magnetic stirrer for heating, control the water temperature to 77℃±2℃, and add HP-β-CD in small amounts and multiple times while stirring.

[0212] After HP-β-CD is completely dissolved, keep stirring and add the prescribed amount of active compound at one time. Control the solution temperature at 77℃±2℃ and stir until the solution is completely clear.

[0213] Dilute and adjust the concentrated solution: Weigh 7.5 kg of water for injection at 20°C to 25°C into a stainless steel drum. Start stirring with a blender. Add the concentrated solution to the drum. Rinse the beaker containing the concentrated solution with a small amount of water for injection at 20°C to 25°C four to six times. Transfer all the rinses to the drum and stir thoroughly. Add the prescribed amount of sodium chloride, sodium dihydrogen phosphate monohydrate, and anhydrous disodium hydrogen phosphate in sequence, stirring to dissolve. Adjust the solution to 15 L with water for injection at 20°C to 25°C and stir thoroughly. Take samples for testing of the intermediate's properties, content, pH, and osmotic pressure. The test results are shown in Table 35.

[0214] Filtration and filling: Before production begins, the filter element integrity is tested. The liquid preparation tank, BFS machine, and its material delivery pipelines are flushed and sterilized online with pure steam, maintaining a temperature of ≥121°C for 30 minutes. After equipment commissioning, filtration and filling begin. After production concludes, the filter element integrity is tested.

[0215] Punching: All punched products will be inspected for leaks, and then checked one by one and unqualified products will be eliminated.

[0216] Outsourcing: All qualified punched products are subjected to visual inspection, and unqualified products are eliminated. Punched products that pass leak detection and visual inspection are pillow-packaged. All packaged samples are then tested for heat seal effectiveness in a vacuum constant-temperature drying oven. Samples from finished products that pass heat seals are taken for testing of properties, content, pH value, and osmotic pressure. The test results are shown in Table 35.

[0217] The results show that the prescription ratio and preparation process of Examples 99 to 102 can produce eye drops and eye drop placebos whose properties, content, pH value and osmotic pressure meet the requirements of the 2020 edition of the Pharmacopoeia.

[0218] Table 34

[0219] Table 35

[0220] Example 103

[0221] According to the proportions in Table 36, sulfobutyl-β-cyclodextrin (SBE-β-CD) was weighed and dissolved in phosphate buffer. The prescribed amount of compound of formula (IX) was dissolved in 0.15 ml of dimethyl sulfoxide, then added to the sulfobutyl-β-cyclodextrin (SBE-β-CD) phosphate buffer and stirred continuously to obtain a clear solution.

[0222] Example 103 uses a large amount of sulfobutyl-β-cyclodextrin, and dimethyl sulfoxide has local toxicity and low systemic toxicity, making it unsuitable for use in eye drops. Compared with Examples 66 and 67, which have simpler excipient compositions and do not contain dimethyl sulfoxide, Example 103 exhibits poor stability and a higher safety risk.

[0223] Table 36

[0224] Example 104 Preparation of Compound (IX)

[0225] Synthesis route:

[0226] Step 1: Preparation of compound 2

[0227] Compound 1 (30 g, 130.4 mmol, 1 eq), bis(chloronaphthalene) borate (66.23 g, 260.80 mmol, 2 eq), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (5.32 g, 6.52 mmol, 0.1 eq) and potassium acetate (25.60 g, 260.80 mmol, 2 eq) were added to toluene (500 mL), replaced with nitrogen three times, and the reaction solution was stirred at 110 ° C for 15 hours. After completion of the reaction, the reaction solution was filtered through a pad of celite, 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) δ7.84 (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).

[0228] Step 2: Preparation of compound 4

[0229] Compound 3 (100 g, 460.79 mmol, 1 eq) was dissolved in anhydrous ethanol (1 L), and concentrated sulfuric acid (225.97 g, 2.30 mol, 122.81 mL, 5 eq) and anhydrous sodium sulfate Na2SO4 (65.45 g, 460.79 mmol, 46.75 mL, 1 eq) were added. The reaction mixture was stirred at 85°C for 48 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. Saturated aqueous sodium bicarbonate solution (1 L) was added dropwise to the reaction mixture, resulting in the formation of a large amount of solid. The filter cake was washed with water (500 mL) and the resulting solid was dried in vacuo to yield 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).

[0230] Step 3: Preparation of compound 5

[0231] Compound 4 (70.00 g, 285.63 mmol, 1 eq) was dissolved in tetrahydrofuran (1 L) and cooled to -78°C under nitrogen. Methyllithium (1.6 M, 892.59 mL, 5 eq) was slowly added dropwise to the reaction mixture, and the reaction mixture was stirred at -78°C for 3 hours. After completion of the reaction, water (100 mL) was slowly added dropwise to quench the reaction. The mixture was warmed to room temperature and diluted with saturated aqueous ammonium chloride (500 mL). The mixture was extracted with ethyl acetate (500 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was slurried with n-heptane (500 mL), filtered, and dried to give compound 5. 1H NMR (400 MHz, CDCl 3 ) 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).

[0232] Step 4: Preparation of compound 6

[0233] Compound 5 (10 g, 43.27 mmol, 1 eq), compound 2 (23.98 g, 86.55 mmol, 2 eq), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (1.77 g, 2.16 mmol, 0.05 eq), and cesium carbonate (28.20 g, 86.55 mmol, 2 eq) were added to dioxane (300 mL) and water (75 mL). The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at 80° C. for 5 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether:tetrahydrofuran = 0 to 100:40) to obtain crude compound 6. The crude product was heated to 80°C with tetrahydrofuran (4 mL / g), cooled for recrystallization, stirred at 25°C for 15 hours, filtered, and the filter cake was dried to obtain compound 6. 1H NMR (400 MHz, DMSO-d6) δ7.94 (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).

[0234] Step 5: Preparation of compound of formula (IX)

[0235] Compound 6 (8.78 g, 29.14 mmol, 1 eq) was dissolved in tetrahydrofuran (80 mL) and cooled to 0° C. under nitrogen. Methylmagnesium bromide (3 M, 97.12 mL, 10 eq) was added dropwise to the reaction solution and 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 mixture was extracted with ethyl acetate (400 mL*2). The organic phase was concentrated under reduced pressure, and the crude residue was purified by dichloromethane (3 mL / g) at 25°C, filtered and dried to obtain the 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. 150 mL of methyl tert-butyl methyl ether was added. The sample was stirred at 50°C for 12 hours, then cooled to 25°C and stirred for 4 hours. 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. After adding a magnet, the sample was stirred on a magnetic stirrer (25°C / 50°C) for one week. After centrifugation, the resulting solid sample was placed in a 40°C vacuum drying oven and dried overnight to obtain the compound of formula (IX). Molecular formula: C17H23N3O2·H2O, molecular weight: 319.40.

[0236] The XRPD pattern analysis data for the compound of formula (IX) are shown in Table 37, and the spectrum is shown in Figure 1. The differential scanning calorimetry curve of the compound of formula (IX) has an endothermic peak onset at 101.7±3.0°C and 158.7±3.0°C, respectively, as shown in Figure 2. Its thermogravimetric analysis curve shows a weight loss of 5.477% at 120.00°C±3.0°C, as shown in Figure 3.

[0237] Table 37 XRPD pattern analysis data of compound of formula (IX)

[0238] Examples 105-107

[0239] According to the prescription ratio in Table 38, Examples 105 to 107 were produced.

[0240] Production process:

[0241] Preparation of concentrated solution: Add the prescribed amount of water for injection into a beaker, place the beaker on a CNC heating magnetic stirrer for heating, control the water temperature to 77℃±2℃, and add HP-β-CD in small amounts and multiple times while stirring.

[0242] After HP-β-CD is completely dissolved, keep stirring and add the prescribed amount of active compound at one time. Control the solution temperature at 77℃±2℃ and stir until the solution is completely clear.

[0243] To dilute and adjust the concentrated solution: Weigh 7.5 kg of 20°C-25°C water for injection into a stainless steel drum. Start stirring with a blender. Add the concentrated solution to the drum. Rinse the beaker containing the concentrated solution with a small amount of 20°C-25°C water for injection 4-6 times. Transfer all rinses to the drum and stir thoroughly. Add the prescribed amount of sodium chloride, sodium dihydrogen phosphate monohydrate, and anhydrous disodium hydrogen phosphate in sequence, stirring to dissolve. Adjust the volume of the solution to 15 L with 20°C-25°C water for injection and stir thoroughly.

[0244] Filtration and filling: Before production begins, the filter element integrity is tested. The liquid preparation tank, BFS machine, and its material delivery pipelines are flushed and sterilized online with pure steam, maintaining a temperature of ≥121°C for 30 minutes. After equipment commissioning, filtration and filling begin. After production concludes, the filter element integrity is tested.

[0245] Punching: All punched products will be inspected for leaks, and then checked one by one and unqualified products will be eliminated.

[0246] Outsourcing: All punched products that pass the inspection are inspected by light and unqualified products are eliminated. Punched products that pass the leak inspection and light inspection are pillow-packed. All packaged samples are tested for heat sealing effectiveness in a vacuum constant temperature drying oven.

[0247] The results show that the formulation ratios and preparation processes of Examples 105 to 107 can produce products with controllable quality and stable properties.

[0248] Table 38

[0249] Experimental Example 1: Experimental study on the effect of dry eye model in mice

[0250] Purpose of the experiment:

[0251] The dry eye model of C57BL / 6 mice was induced by subcutaneous injection of scopolamine hydrobromide solution into the lower limbs to examine the therapeutic effects of Examples 105, 106, and 107 on the model.

[0252] Experimental process:

[0253] According to the tear secretion volume, the animals were randomly and evenly divided into 5 groups, namely, negative control group (normal 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), with 8 animals in each group, all female.

[0254] All animals in each group were injected alternately with 5 mg / mL scopolamine hydrobromide solution subcutaneously on both lower limbs on D1, 4 times / day, 0.1 mL / time, with an interval of about 3 hours between each injection, for 12 consecutive days (3 doses on D12). The animals in the negative control group were injected with an equal volume of normal saline subcutaneously on both lower limbs. Multiple consecutive injections at the same injection site should be avoided.

[0255] Animals in each test group received eye drops in both eyes on Day 1 (3 μL / eye / time), four times daily, with dosing intervals of approximately 3 hours, for a total of 12 days (three doses from Day 12). Animals in the negative control and model control groups received an equal volume of vehicle in both eyes. Tear secretion was measured approximately 30 minutes after the second dose on Days 7 and 12, respectively. Corneal fluorescence staining was performed approximately 30 minutes after the third dose on Days 7 and 12. After completion of measurements on Day 12, animals were euthanized by cervical dislocation.

[0256] Experimental results:

[0257] The low-concentration group (1 mg / mL), the medium-concentration group (2.5 mg / mL), and the high-concentration group (5 mg / mL) all demonstrated a significant therapeutic effect on the dry eye model induced by scopolamine hydrobromide solution in mice, primarily improving tear secretion and corneal damage. Based on tear secretion (Table 39, Figure 4) and corneal fluorescence staining (Table 40, Figure 5) scores, the high-concentration group (5 mg / mL) demonstrated the greatest therapeutic effect.

[0258] Table 39 Effect of dry eye model on tear secretion in mice Note: Compared with D0, #P<0.05; ##P<0.01; compared with G1 group, *P<0.05; **P<0.01; compared with G2 group, &P<0.05; &&P<0.01.

[0259] Table 40 Effect of corneal fluorescence staining scores on dry eye model mice Note: Compared with D0, #P<0.05; ##P<0.01; compared with G1 group, *P<0.05; **P<0.01; compared with G2 group, &P<0.05; &&P<0.01.

[0260] Experimental conclusion:

[0261] Example 105, Example 106, and Example 107 all have good therapeutic effects on the dry eye model of mice induced by scopolamine hydrobromide solution, mainly improving the tear secretion and corneal damage of the dry eye model mice.

[0262] Experimental Example 2: Experimental study on the effect of hypertonic dry eye model in rats

[0263] Purpose of the experiment:

[0264] The dry eye model of SD rats was induced by eye drops of hypertonic sodium chloride solution to examine the therapeutic effects of Examples 105 and 107 on the model.

[0265] Experimental process:

[0266] Twenty female SD rats that passed the adaptive observation were selected, and the animals were scored for corneal fluorescence staining and tear secretion was measured. Animals with abnormal corneal fluorescence staining and large differences in tear secretion between the two eyes were eliminated. Animals with significant differences in tear secretion between the two eyes were selected for grouping. According to the mean tear secretion volume of the two eyes, the animals were randomly and evenly 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 4 animals and 8 eyes. The day of grouping was designated as D0.

[0267] All animals in each group were modeled on D1. A pipette was used to draw 20 μL of sodium chloride solution (osmotic pressure of 500 mOsmol / L) and instilled into the conjunctival sac of both eyes of the animals, 5 times / day, 20 μL / time, with an interval of about 2 hours between each instillation, for 21 consecutive days. After instillation, the eyelids of the animals were passively closed for about 90 seconds.

[0268] Animals in each group were administered eye drops on day 1 (10 μL / eye / time), four times daily, with dosing intervals of approximately 3 hours for a total of 21 days. Animals were weighed weekly during the dosing period. Corneal fluorescence staining scores, tear secretion, and tear film breakup time were measured on days 0, 14, and 21.

[0269] Experimental results:

[0270] Compared with the model control group, the low-concentration group (1 mg / mL) and the high-concentration group (5 mg / mL) increased tear secretion, reduced corneal fluorescence staining scores, and improved tear film breakup time in dry eye model rats. Specific results are shown in Tables 41, 42, 43 and Figures 6, 7, and 8.

[0271] Table 41 Effect of tear secretion on dry eye model rats Note: Compared with group G1, *P<0.05; **P<0.01.

[0272] Table 42 Effect of corneal fluorescence staining scores in dry eye model rats Note: Compared with group G1, *P<0.05; **P<0.01.

[0273] Table 43 Tear film breakup time Note: Compared with G1 group, *P<0.05; **P<0.01

[0274] Experimental conclusion:

[0275] The low-concentration group (1 mg / mL) and the high-concentration group (5 mg / mL) have a good therapeutic effect on the rat dry eye model induced by hypertonic sodium chloride solution. The main manifestation is that after about 2 weeks of continuous eye drop administration, the tear secretion, corneal damage and tear film stability of the dry eye model rats can be significantly improved.

[0276] Experimental Example 3: Pharmacokinetic study in New Zealand rabbit eyes

[0277] Six New Zealand rabbits that passed the adaptability observation were selected and divided into two groups, 3 rabbits in each group, namely the 0.5h sampling group and the 2h sampling group. The animals in each group were administered with 5 mg / mL (Example 107) by eye drops in the left eye. The administration volume of each test group was 100 μl / eye. Plasma, corneal tissue, conjunctival tissue, and retinal tissue samples were collected from the animals in each group 0.5h and 2h after administration, respectively. The concentration of the active ingredient in the biological samples was determined by LC-MS. The specific results are shown in Tables 44 and 45.

[0278] Table 44 Concentration of active ingredients in various biological samples

[0279] Table 45 Concentration ratio of active ingredients in various ocular tissues and plasma

[0280] Experimental results demonstrate that after ocular administration of Example 107, the active ingredient is distributed at higher concentrations in the cornea and conjunctiva, the ocular surface tissues, which is beneficial for the treatment of ocular surface diseases. The active ingredient is distributed at lower concentrations in the retina, the fundus tissue, which reduces the risk of adverse fundus reactions. Therefore, the pharmacokinetic properties of Example 107 are beneficial for the treatment of ocular surface diseases.

[0281] Experimental Example 4: Experimental study on the effect of ragweed pollen on the mouse allergic conjunctivitis model

[0282] Purpose of the experiment:

[0283] A mouse model of allergic conjunctivitis was established by subcutaneous injection of ragweed pollen into the footpad for sensitization and topical eye drops. Clinical ocular symptoms, ocular observation scores, and pathological HE were assessed. The therapeutic effects of a low-concentration group (1 mg / mL) (Example 105), a medium-concentration group (2.5 mg / mL) (Example 106), and a high-concentration group (5 mg / mL) (Example 107) on mice with allergic conjunctivitis were evaluated.

[0284] Experimental process:

[0285] 1.1 Animals

[0286] 50 healthy BALB / c mice, 5-7 weeks old, half male and half female

[0287] 1.2 Main reagent configuration

[0288] 1.2.1 Preparation of model sensitization drug (ragweed pollen tarsal joint injection): 22.3 mg of ragweed pollen was dissolved in 7.25 ml of alum adjuvant;

[0289] 1.2.2 Preparation of the model stimulation drug (ragweed pollen eye drops): Weigh 168 mg of ragweed pollen and dissolve it in 1.12 ml of PBS; weigh 189 mg of ragweed pollen and dissolve it in 1.26 ml of PBS (phosphate buffered saline); weigh 144 mg of ragweed pollen and dissolve it in 0.96 ml of PBS.

[0290] 1.2.3 Test substances

[0291] 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), blank group (Example 102).

[0292] 1.3 Animal grouping, modeling, and model validation

[0293] (1) Blank group (Example 102) (Vehicle treatment: 4 times / rat / d, single dose: 20 μL, eye drops, 4 consecutive days) (N=10)

[0294] (2) Allergic conjunctivitis model group (also referred to as model group in this experiment) (vehicle treatment, 4 times / rat / d, single dose: 20 μl, eye drops, for 4 consecutive days) (N=10)

[0295] (3) Low concentration group (1 mg / mL) (low concentration group (1 mg / mL) treatment, 4 times / rat / d, single dose: 20 μL, eye drops, continuous 4 days) (N=10)

[0296] (4) Medium concentration group (2.5 mg / mL) (medium concentration group (2.5 mg / mL) treatment, 4 times / rat / d, single dose: 20 μL, eye drops, continuous 4 days) (N=10)

[0297] (5) High concentration group (5 mg / mL) (treated with high concentration group (5 mg / mL), 4 times / rat / d, single dose: 20 μL, eye drops, for 4 consecutive days) (N=10)

[0298] Modeling: On day 0, ragweed pollen tarsal joint sensitization injection was injected subcutaneously into the foot pad of mice, 65 μL / mouse; on days 10-13, ragweed pollen eye drops were dripped into the right eye of the model group mice for stimulation, 10 μL / mouse / time, once a day for 4 consecutive days.

[0299] 1.4 Animal Dosing

[0300] Drug intervention began 30 minutes after each eye drop challenge, four times daily for four consecutive days. The blank and model groups received equal amounts of vehicle; the test drug treatment groups received the corresponding doses of the compound. Administration was divided into two doses of 10 μL / mouse, with a 1-minute interval, four times / mouse / day for four consecutive days.

[0301] 1.5 Detection indicators

[0302] 1.5.1 Clinical symptom assessment

[0303] Within 30 minutes after the last challenge, the mice's eyes were observed under a microscope for clinical symptoms and ocular observation scoring: Allergic reactions in the eyes, including conjunctival edema and conjunctival hyperemia, were observed and scored from 0 to 3 points according to severity (including none, mild, moderate, and severe). Conjunctival edema scoring criteria: mild localized conjunctival edema is scored as 1 point; diffuse edema with involvement of the fornix is ​​scored as 2 points; conjunctival edema resulting in shallow narrowing of the conjunctival sac is scored as 3 points. Conjunctival hyperemia scoring criteria: mild diffuse vascular hyperemia is scored as 1 point; diffuse hyperemia with obvious hyperemia near the fornix is ​​scored as 2 points; hyperemia with subconjunctival hemorrhage is scored as 3 points.

[0304] 1.5.2 HE staining

[0305] Experimental Procedure: The right eye and eyelid tissue of the animal were excised and fixed in 4% paraformaldehyde at room temperature for 4 hours. The tissue was then removed and rinsed with running water for several hours. After dehydration with 70%, 80%, and 90% ethanol solutions, the tissue was treated with a mixture of equal parts pure alcohol and xylene for 15 minutes. The tissue was then permeabilized twice with xylene for 15 minutes each, until transparent. The tissue was then placed in a mixture of 50% xylene and 50% paraffin for 15 minutes, followed by permeabilization with Paraffin I and Paraffin II for 60 minutes each. After paraffin embedding, the tissue was sectioned along the preselected cross-sectional orientation. The paraffin sections were baked, dewaxed, and hydrated. The rehydrated sections were stained with hematoxylin-water solution for 3 minutes, differentiated with hydrochloric acid-ethanol solution for 15 seconds, briefly washed with water, bluing solution for 15 seconds, rinsed with running water, stained with eosin for 3 minutes, rinsed with running water, dehydrated, transparentized, mounted, and examined under a microscope.

[0306] 1.6 Statistical analysis

[0307] The experimental data were analyzed by one-way ANOVA (*p < 0.05, **p < 0.01) using GraphPad Prism 5 and IBM SPSS Statistics 19.0 software.

[0308] Experimental results:

[0309] 2.1 Effects of drugs on clinical symptoms of mouse eyes

[0310] Compared with the blank group, the model group showed significantly higher scores in conjunctival edema and conjunctival hyperemia. Compared with the model group, the low-concentration (1 mg / mL), medium-concentration (2.5 mg / mL), and high-concentration (5 mg / mL) groups significantly reduced these scores (p < 0.05 or p < 0.01), improving conjunctival edema and conjunctival hyperemia. These results suggest that the low-, medium-, and high-concentration groups have an ameliorative effect on mice with ragweed pollen-induced allergic conjunctivitis. Specific experimental results are shown in Figures 9 and 10.

[0311] Table 45: Clinical symptom scores of mice with allergic conjunctivitis in the low, medium and high concentration groups

[0312] (mean ± SEM) Note: Compared with the model group, *p<0.05, **p<0.01.

[0313] 2.2 Effects of drugs on histopathology of mice with allergic conjunctivitis

[0314] Pathological results showed that the conjunctiva in the blank group was intact, with no obvious damage. Some samples showed vascular congestion, accompanied by a small amount of inflammatory cell infiltration. In the model group, the conjunctiva showed varying degrees of thickening or thinning, with disordered conjunctival epithelial cell arrangement and significant inflammatory cell infiltration. No significant capillary proliferation or congestion was observed under the conjunctiva. The conjunctiva in the low-concentration (1 mg / mL) group was relatively intact, with a small amount of inflammatory cell infiltration and congestion observed in some samples. In the medium-concentration (2.5 mg / mL) group, desquamation of conjunctival epithelial cells was observed, as well as conjunctival thickening, with a small amount of inflammatory cell infiltration and congestion. In the high-concentration (5 mg / mL) group, some samples showed irregular conjunctival epithelial cell arrangement and thinning, with a small amount of inflammatory cell infiltration and congestion. These results suggest that the low-, medium-, and high-concentration groups can improve the conjunctival structural abnormalities and inflammatory cell infiltration in mice with allergic conjunctivitis. The experimental results are shown in Figure 11.

[0315] Experimental conclusion: The low, medium and high concentration groups can have a good therapeutic effect on the ragweed pollen-induced allergic conjunctivitis model in mice, mainly improving conjunctival edema and conjunctival congestion in allergic conjunctivitis mice, and reducing conjunctival structural abnormalities and inflammatory cell infiltration.

Claims

1. An ophthalmic preparation containing a pyridinephenyl compound, characterized in that: The ophthalmic preparation comprises an active ingredient pyridinephenyl compound and excipients, wherein: The excipients include a solubilizing agent, a pH regulator, an osmotic pressure regulator, or a combination of two or more thereof. The active ingredient pyridinephenyl compound includes a compound of formula (II), an isomer thereof or a pharmaceutically acceptable salt thereof; in, described 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, is selected from single bonds; L is selected from a single bond, -O-, -S-, -NR2- or -(CR3R4)n-; R1 is selected from H, F, Cl, Br, I, OH or NH2; R2 is selected from H, optionally substituted by 1, 2 or 3 R a Substituted C 1-3 alkyl; R3 and R4 are independently selected from H, F, Cl, Br, I, OH, NH2, CN or optionally substituted by 1, 2 or 3 R b Substituted C 1-3 alkyl; 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 Each is independently selected from H, F, Cl, Br, I, OH, NH2, CN or CH3.

2. The ophthalmic preparation according to claim 1, characterized in that The compound of formula (II), its isomer or pharmaceutically acceptable salt thereof, wherein R2 is selected from H, CH3 or CH2CH3, and CH3 and CH2CH3 are optionally substituted by 1, 2 or 3 Ra.

3. The ophthalmic preparation according to claim 2, characterized in that The compound of formula (II), its isomer or pharmaceutically acceptable salt thereof, wherein R2 is selected from H, CH3 or CH2CH3.

4. The ophthalmic preparation according to any one of claims 1 to 3, characterized in that The compound of formula (II), its isomer or pharmaceutically acceptable salt thereof, wherein R3 and R4 are independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3 or CH2CH3, and the CH3 or CH2CH3 is optionally substituted by 1, 2 or 3 Rb.

5. The ophthalmic preparation according to claim 4, characterized in that The compound of formula (II), its isomer or pharmaceutically acceptable salt thereof, wherein R3 and R4 are independently selected from H, F, Cl, Br, I, OH, NH2, CN, CH3 or CH2CH3.

6. The ophthalmic preparation according to claim 5, characterized in that The compound of formula (II), its isomer or pharmaceutically acceptable salt thereof, wherein L is selected from a single bond, -O-, -S-, -NH-, -(CH2)2- or -CH2-.

7. The ophthalmic preparation according to any one of claims 1 to 6, characterized in that The compound of formula (II), its isomer or pharmaceutically acceptable salt thereof is selected from: in, T3 and T4 are each independently selected from N or CR1; R1 and L are as defined in any one of claims 1 to 6.

8. The ophthalmic preparation according to claim 7, characterized in that The compound of formula (II), its isomer or its pharmaceutically acceptable salt is selected from in, R1 and L are as defined in claim 7.

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

10. The ophthalmic preparation according to claim 1, characterized in that The auxiliary materials also include antibacterial agents, antioxidants, freeze-drying solvents, or a combination of two or more thereof.

11. The ophthalmic preparation according to claim 10, characterized in that The antioxidant is selected from butylated hydroxyanisole, vitamin E, or a combination thereof.

12. The ophthalmic preparation according to claim 10, characterized in that The antibacterial agent is selected from benzalkonium chloride, chlorhexidine acetate, phenylmercuric acetate, or a combination of two or more thereof.

13. The ophthalmic preparation according to any one of claims 1 to 12, characterized in that: The dissolution promoter is selected from methylated-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutyl-β-cyclodextrin, poloxamer 407, Tween 80, povidone, polyethylene glycol, propylene glycol, glycerol, or a combination of two or more thereof.

14. The ophthalmic preparation according to any one of claims 1 to 12, characterized in that The pH regulator is selected from sodium dihydrogen phosphate monohydrate, anhydrous disodium hydrogen phosphate, borax, boric acid, citric acid dihydrate, hydrochloric acid, sodium hydroxide, or a combination of two or more thereof.

15. The ophthalmic preparation according to any one of claims 1 to 12, characterized in that The osmotic pressure regulator is selected from sodium chloride, boric acid, borax, glucose, mannitol, or a combination of two or more thereof.

16. The ophthalmic preparation according to any one of claims 1 to 15, characterized in that The ophthalmic preparation comprises a pyridinylphenyl compound, one or more solubilizing agents, one or more pH regulators, one or more osmotic pressure regulators, one or more antibacterial agents, and one or more antioxidants, wherein the pyridinylphenyl compound comprises a compound of formula (III), formula (IV), formula (V), formula (VI), formula (VII), or formula (VIII), an isomer thereof, or a pharmaceutically acceptable salt thereof; 17. The ophthalmic preparation according to claim 16, characterized in that The compound of formula (III) also includes a monohydrate of formula (III) (compound of formula IX), an isomer thereof or a pharmaceutically acceptable salt thereof 18. The ophthalmic preparation according to claims 1 to 17, characterized in that The content of the active ingredient is 0.05-0.6% 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, 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.

19. The ophthalmic preparation according to claim 17, wherein The dissolution promoter is selected from methylated-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutyl-β-cyclodextrin, poloxamer 407, Tween 80, povidone, polyethylene glycol, propylene glycol, glycerol, or a combination of two or more thereof.

20. The ophthalmic preparation according to claim 19, characterized in that The content of the solubilizer is 0.2% - 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, 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. The ophthalmic preparation according to claim 19, wherein The content of hydroxypropyl-β-cyclodextrin is 0.5% w / v - 12% w / v, preferably 0.7% w / v - 10% w / v, more preferably 1% w / v - 8% w / v, 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. The ophthalmic preparation according to claim 18, wherein The content of sulfobutyl-β-cyclodextrin is 4% - 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.

23. The ophthalmic preparation according to claim 17, wherein The content of the pH regulator is 0.12-20% 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. / 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.

24. The ophthalmic preparation according to claim 21, wherein The pH adjuster is selected from sodium dihydrogen phosphate monohydrate, anhydrous disodium hydrogen phosphate, or a combination thereof.

25. The ophthalmic preparation according to claim 23, wherein The content of the sodium dihydrogen phosphate monohydrate is 0.1% w / v to 0.5% w / v, preferably 0.12% w / v to 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. The ophthalmic preparation according to claim 22, characterized in that The content of the anhydrous disodium 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 ophthalmic preparation according to claim 17, wherein The content of the osmotic pressure regulator 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, 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. The ophthalmic preparation according to claim 17, wherein The osmotic pressure regulator is selected from sodium chloride.

29. The ophthalmic preparation 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. The ophthalmic preparation according to claim 17, wherein The content of the antibacterial agent is 0.001% w / v to 0.02% w / v, preferably 0.002% w / v to 0.018% w / v, further 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.

31. The ophthalmic preparation according to claim 17, wherein The antibacterial agent is selected from benzalkonium chloride or chlorhexidine acetate.

32. The ophthalmic preparation according to claim 31, wherein The benzalkonium chloride has a content of 0.001% w / v to 0.02% w / v, preferably 0.002% w / v to 0.018% w / v, further 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. The ophthalmic preparation according to claim 31, wherein The content of the chlorhexidine acetate is 0.001% w / v to 0.02% w / v, preferably 0.002% w / v to 0.018% w / v, further 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. The ophthalmic preparation according to claim 17, wherein 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.

35. The ophthalmic preparation according to claim 17, wherein The ophthalmic preparation comprises: The compound of formula (IX) and its isomers or pharmaceutically acceptable salts thereof, preferably in an amount of 0.1% w / v to 0.5% w / v; Hydroxypropyl-β-cyclodextrin, preferably in an amount of 0.7% w / v to 3.5% w / v, preferably 1.75% w / v, 3.5% w / v, or 0.7% w / v; Anhydrous disodium hydrogen phosphate, preferably at 0.81% w / v; Sodium dihydrogen phosphate monohydrate, preferably in an amount of 0.12% w / v; Sodium chloride, in an amount of 0.25% w / v to 0.45% w / v, preferably 0.27% w / v, 0.36% w / v, 0.4% w / v and; Chlorhexidine acetate, preferably in an amount of 0.01% w / v.

36. The ophthalmic preparation according to claims 1 to 35, characterized in that The pH value of the ophthalmic preparation ranges from 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.

37. The ophthalmic preparation according to claim 10, wherein The freeze-drying solvent is selected from 95% ethanol, tert-butanol, isopropanol, or acetonitrile.

38. The method for preparing the ophthalmic preparation according to any one of claims 1 to 37, wherein the preparation method adopts a rotary evaporation process, a concentrate-dilution method, or a freeze-drying method.

39. The ophthalmic preparation according to any one of claims 1 to 37, wherein the preparation is a liquid preparation, preferably an eye drop, an eye wash or an intraocular injection solution; an ophthalmic semisolid preparation, preferably an eye ointment, an eye cream or an eye gel; or an ophthalmic solid preparation, preferably an eye mask, an eye pill or an intraocular insert.

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

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