[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2024109905A1 - 一种含有吡啶苯基类化合物的眼用制剂及其制备方法和应用 - Google Patents

一种含有吡啶苯基类化合物的眼用制剂及其制备方法和应用 Download PDF

Info

Publication number
WO2024109905A1
WO2024109905A1 PCT/CN2023/133814 CN2023133814W WO2024109905A1 WO 2024109905 A1 WO2024109905 A1 WO 2024109905A1 CN 2023133814 W CN2023133814 W CN 2023133814W WO 2024109905 A1 WO2024109905 A1 WO 2024109905A1
Authority
WO
WIPO (PCT)
Prior art keywords
ophthalmic preparation
preparation according
compound
formula
ophthalmic
Prior art date
Application number
PCT/CN2023/133814
Other languages
English (en)
French (fr)
Inventor
于婷婷
沈美月
穆利伟
粟媛
何远志
王德刚
吴守廷
Original Assignee
珠海联邦制药股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 珠海联邦制药股份有限公司 filed Critical 珠海联邦制药股份有限公司
Priority to AU2023387378A priority Critical patent/AU2023387378A1/en
Priority to CN202380070800.8A priority patent/CN119997941A/zh
Publication of WO2024109905A1 publication Critical patent/WO2024109905A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the invention belongs to the field of pharmaceutical preparations, relates to an ophthalmic preparation of a pyridine phenyl compound and a preparation method thereof, and also includes an application of the ophthalmic preparation in ophthalmic diseases.
  • Dry eye also known as keratoconjunctivitis sicca
  • keratoconjunctivitis sicca is a general term for a variety of diseases caused by abnormal tear quality or quantity or abnormal dynamics due to any reason, which leads to decreased tear film stability and is accompanied by ocular discomfort (or) ocular surface tissue lesions.
  • Specific symptoms of discomfort include: eye irritation, visual impairment and tear film instability.
  • Some of this syndrome is caused by ocular surface inflammation, resulting in loss of tear gland function.
  • systemic autoimmunity is also related to systemic autoimmunity.
  • 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, lipids 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.
  • MDA malondialdehyde
  • 4HNE 4-hydroxy-2-nonenal
  • the present invention has found that small molecule drugs enter the inflammatory site of the eye in the form of eye drops, and through complexation reaction with aldehydes in the body, the aldehyde toxicity is reduced, the inflammation is reduced, and the effect of treating dry eye is achieved.
  • WO2020125659 discloses a pyridinephenyl aldehyde binder compound, and a series of compounds satisfying the general formula I of its isomers or pharmaceutically acceptable salts:
  • 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.
  • ophthalmic diseases such as dry eye, allergic conjunctivitis, macular degeneration, cataract, keratoconus, bullous keratopathy, Fuch corneal endothelial dystrophy, ocular cicatricial pemphigoid, meibomian gland dysfunction, uveit
  • the purpose of the present invention is to provide a safe and effective ophthalmic preparation, and the ophthalmic preparation has a simple preparation process, stable quality and is suitable for large-scale industrial production.
  • the present invention provides an ophthalmic preparation, which comprises an active ingredient pyridine phenyl 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 represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • T 1 , T 2 , T 3 and T 4 are each independently selected from N, C or CR 1 ;
  • L is selected from a single bond, -O-, -S-, -NR 2 - or -(CR 3 R 4 )n-;
  • R 1 is selected from H, F, Cl, Br, I, OH or NH 2 ;
  • R2 is selected from H, C1-3 alkyl optionally substituted with 1, 2 or 3 Ra ;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN or a C 1-3 alkyl group optionally substituted by 1, 2 or 3 R b ;
  • n is selected from 1, 2 or 3;
  • Ra and Rb are each independently selected from H, F, Cl, Br, I, OH, NH2 , CN or CH3 .
  • R 2 is selected from H, CH 3 or CH 2 CH 3 , and the CH 3 and CH 2 CH 3 are optionally substituted by 1, 2 or 3 Ra , and other variables are as defined in the present invention.
  • R 2 is selected from H, CH 3 or CH 2 CH 3 , and other variables are as defined in the present invention.
  • R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 or CH 2 CH 3 , and CH 3 and CH 2 CH 3 are optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 or CH 2 CH 3 , and the others are as defined in the present invention.
  • the above L is selected from a single bond, -O-, -S-, -NH-, -(CH 2 ) 2 - or -CH 2 -, and other variables are as defined in the present invention.
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • Said is selected from a single bond or a double bond
  • T 1 , T 2 , T 3 and T 4 are each independently selected from N, C or CR 1 ;
  • T 6 is selected from C, CR 6 or N;
  • T 7 is selected from N or CR 7 ;
  • L is selected from a single bond, -O-, -S-, -NR 2 - or -(CR 3 R 4 )n-;
  • Each R 1 is independently selected from H, F, Cl, Br, I, OH or NH 2 ;
  • R2 is selected from H and C1-3 alkyl optionally substituted with 1, 2 or 3 Ra;
  • R 3 and R 4 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN or C1-3 alkyl optionally substituted with 1, 2 or 3 R b ;
  • R 5 , R 6 and R 7 are independently selected from H, F, Cl, Br or I;
  • n is selected from 1, 2 or 3;
  • Ra and Rb are each independently selected from H, F, Cl, Br, I, OH, NH2 , CN or CH3 .
  • R 2 is selected from H, CH 3 or CH 2 CH 3 , and the CH 3 and CH 2 CH 3 are optionally substituted by 1, 2 or 3 Ra , and other variables are as defined in the present invention.
  • R 2 is selected from H, CH 3 or CH 2 CH 3 , and other variables are as defined in the present invention.
  • R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 or CH 2 CH 3 , and CH 3 and CH 2 CH 3 are optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • R 3 and R 4 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 or CH 2 CH 3 , and other variables are as defined in the present invention.
  • the above L is selected from a single bond, -O-, -S-, -NH-, -(CH 2 ) 2 - and -CH 2 -, and other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • T 3 and T 4 are independently selected from N and CR 1 ;
  • R1 and L are as defined herein.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
  • R1 and L are as defined herein.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from:
  • the compound of formula (III), its isomer or its pharmaceutically acceptable salt is:
  • the compound of formula (IV), its isomer or its pharmaceutically acceptable salt is:
  • the compound of formula (VII), its isomer or its pharmaceutically acceptable salt is:
  • 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:
  • 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.
  • the ophthalmic preparation comprises one or more solubilizing agents.
  • the ophthalmic preparation comprises one or more pH adjusters.
  • the ophthalmic preparation comprises one or more osmotic pressure regulators.
  • the ophthalmic preparation comprises one or more antibacterial agents.
  • the ophthalmic preparation comprises one or more antioxidants.
  • the solubilizing agent is selected from methylated ⁇ -cyclodextrin (RM- ⁇ -CD), hydroxypropyl ⁇ -cyclodextrin (HP- ⁇ -CD), hydroxypropyl ⁇ -cyclodextrin (HP- ⁇ -CD), sulfobutyl ⁇ -cyclodextrin (SBE- ⁇ -CD), poloxamer 407, Tween 80, povidone (PVP), polyethylene glycol (PEG400), or a combination of two or more thereof.
  • RM- ⁇ -CD methylated ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • SBE- ⁇ -CD sulfobutyl ⁇ -cyclodextrin
  • poloxamer 407 Tween 80
  • PVP povidone
  • PEG400 polyethylene glycol
  • 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.
  • the osmotic pressure regulator is selected from sodium chloride, boric acid, borax, glucose, mannitol, or a combination of two or more thereof.
  • the antibacterial agent is selected from benzalkonium chloride, chlorhexidine acetate, phenylmercuric acetate, or a combination of two or more thereof.
  • the antioxidant is selected from butylated hydroxyanisole (BHA), vitamin E (VE), or a combination of two or more thereof.
  • the freeze-drying solvent is selected from 95% ethanol, tert-butyl alcohol, isopropanol, or acetonitrile.
  • the present invention provides an ophthalmic preparation, comprising an active ingredient pyridinephenyl 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 pyridinephenyl 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.
  • 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, 0.34% w/v, 0.35% w/
  • the solubilizing agent is selected from methylated ⁇ -cyclodextrin (RM- ⁇ -CD), hydroxypropyl ⁇ -cyclodextrin (HP- ⁇ -CD), hydroxypropyl ⁇ -cyclodextrin (HP- ⁇ -CD), sulfobutyl ⁇ -cyclodextrin (SBE- ⁇ -CD), poloxamer 407, Tween 80, povidone (PVP), polyethylene glycol (PEG400), or a combination of two or more thereof.
  • RM- ⁇ -CD methylated ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • HP- ⁇ -CD hydroxypropyl ⁇ -cyclodextrin
  • SBE- ⁇ -CD sulfobutyl ⁇ -cyclodextrin
  • poloxamer 407 Tween 80
  • PVP povidone
  • PEG400 polyethylene glycol
  • 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.
  • the content of the solubilizing agent hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -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.
  • the content of sulfobutyl- ⁇ -cyclodextrin 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.
  • 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.
  • 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.
  • 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.
  • 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%
  • the content of sodium chloride as the osmotic pressure regulator 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the ophthalmic preparation provided by the present invention comprises: a compound of formula (IX) and its isomers or pharmaceutically acceptable salts thereof, with a content of 0.1% w/v to 0.5% w/v; and excipients: hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD), with a content of 0.7% w/v to 3.5% w/v, preferably 1.75% w/v, 3.5% w/v, or 0.7% w/v; anhydrous disodium hydrogen phosphate, with a content of 0.81% w/v; sodium dihydrogen phosphate monohydrate, with a content of 0.12% w/v; sodium chloride, with a content of 0.25% w/v to 0.45% w/v, preferably 0.27% w/v, 0.36% w/v, or 0.4% w/v; and chlorhexidine acetate, with a content of 0.01% w/v.
  • HP- ⁇ -CD hydroxypropy
  • 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.
  • the preparation method of the ophthalmic preparation adopts rotary evaporation process, concentrated dilution method and freeze drying method.
  • the ophthalmic preparations of the present invention were tested for stability and changes in content and related substances. The results showed that the ophthalmic preparations provided by the present invention were stable in nature, and there were no significant differences in related substances and content.
  • the dosage form of the ophthalmic preparation provided by the present invention can be a liquid preparation, which can be eye drops, eye washes or intraocular injection solutions as an exemplary illustration, semi-solid ophthalmic preparations can be eye ointments, eye creams, or eye gels as an exemplary illustration, and solid ophthalmic preparations can be eye masks, eye pills, and intraocular inserts as an exemplary illustration.
  • the ophthalmic preparation provided by the present invention is used in the preparation of a drug for treating ophthalmic diseases, wherein the use 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.
  • the ophthalmic preparation provided by the present invention is used to induce a C57BL/6 mouse dry eye model by subcutaneous injection of scopolamine hydrobromide solution in the lower limbs, and to induce a SD rat dry eye model by dropping a hypertonic sodium chloride solution into the eye to examine its therapeutic effect.
  • the results show that the ophthalmic preparation of the present invention can improve the tear secretion and corneal damage of dry eye model mice.
  • the pharmacokinetics of the New Zealand rabbit eye are studied, and the active ingredients are distributed in a higher concentration in the cornea and conjunctiva of the ocular surface tissues, which is beneficial to the treatment of eye diseases, and the distribution concentration in the fundus is lower, and the risk of causing adverse reactions in the fundus is lower.
  • pharmaceutically acceptable salt refers to salts of the compounds of the present invention, prepared from compounds having specific substituents discovered by the present invention with relatively nontoxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or 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, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; 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, etc.), and salts of organic acids such as glucuronic acid.
  • Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or
  • salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.
  • compounds provided by the present invention also exist in prodrug form.
  • Prodrugs of compounds described herein easily undergo chemical changes under physiological conditions to be converted into compounds of the present invention.
  • prodrugs can be converted to compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention.
  • Optically active (R)- and (S)-isomers and 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.
  • 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.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine).
  • the compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium (3H), iodine-125 (125I) or C-14 (14C).
  • deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • 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.
  • oxygen it means that two hydrogen atoms are replaced.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituent can be arbitrary on the basis of chemical achievable.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituent 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.
  • substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom of it.
  • pyridyl as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.
  • connection direction is arbitrary.
  • 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 the reading order from left to right to form Combinations of linkers, substituents, and/or variations thereof are permissible only if such combinations result in stable compounds.
  • 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).
  • 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.
  • C 1-3 alkyl is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy, etc.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc.
  • Cn-n+m or Cn - Cn+m includes any specific case of n to n+m carbon atoms, for example, C1-12 includes C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , and also includes any range from n to n+m, for example, C1-12 includes C1-3 , C1-6 , C1-9, C3-6 , C3-9 , C3-12 , C6-9 , C6-12 , and C13 .
  • n-membered to n+m-membered means that the number of atoms in the ring is n to n+m
  • 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.
  • 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 affinity substitution reaction).
  • representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-brosylate, p-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • 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 (such as 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-butyldi
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of 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.
  • 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 (
  • 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 synthetic 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.
  • 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; B
  • THF tetrahydrofuran
  • Boc2O di -tert-butyl dicarbonate
  • TFA trifluoroacetic acid
  • DIPEA diisopropylethylamine
  • SOCl2 stands for thionyl chloride
  • CS2 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
  • Figure 1 XRPD spectrum of the compound of formula (IX) using Cu-K ⁇ radiation.
  • FIG4 Tear secretion in the mouse dry eye model of Examples 105, 106, and 107.
  • FIG5 Corneal fluorescence staining scores of the mouse dry eye model of Examples 105, 106, and 107.
  • FIG6 Tear secretion in the rat dry eye model of Examples 105 and 107.
  • FIG. 7 Corneal fluorescence staining scores of the rat dry eye model of Examples 105 and 107.
  • FIG8 Tear film breakup time of the rat dry eye model of Examples 105 and 107.
  • Figure 9 Conjunctival edema scoring.
  • Figure 10 Conjunctival hyperemia scoring.
  • Figure 11 Pathological results of HE staining.
  • the active compound of the present invention is an insoluble or almost insoluble compound in water.
  • Examples 1 to 11 were prepared according to the specific process in Table 1. The results showed that the compound of formula (IX) could not be dissolved after different dissolution promoters and heating operations in Examples 1, 4, 5, 6, 7, 9 and 10. The dissolution promoters in Examples 2, 3, 8 and 11 had a certain dissolution promoting effect.
  • the active compound formula (IX), propylene glycol, PEG400, Tween 80 and other excipients were weighed and placed in a vial, and the active compound was ultrasonically dissolved in the above excipients to obtain a concentrated solution.
  • the above concentrated solution was added dropwise to the medium in the prescribed amount. Examples 12 to 30 were obtained, and the dissolution of the active compound was observed.
  • the specific data are shown in Table 2. Examples 20 to 23 can obtain a relatively stable 5 mg/ml active compound solution.
  • the active compound formula (IX) and HP- ⁇ -CD were weighed and dissolved in 95% ethanol.
  • the above solution was placed in a rotary evaporator to dry the solvent to obtain a solid inclusion compound, which was placed in purified water to dissolve.
  • a 5 mg/mL solution was prepared using purified water/pH 6.8 phosphate medium, and the dissolution was observed.
  • the specific results are shown in Table 3.
  • the HP- ⁇ -CD inclusion complex of the active compound can be obtained in Examples 31 to 41.
  • the HP- ⁇ -CD inclusion complexes of Examples 33, 35, 36, 37, 38, 40 and 41 can be dissolved into clear and transparent aqueous solutions without generating precipitation.
  • Example 36, Example 37 and Example 38 were sterilized at 121°C for 15 min.
  • the eye drops of Example 36 and Example 37 appeared turbid, while the eye drops of Example 38 remained clear after sterilization.
  • Example 40 and Example 41 The eye drops prepared in Example 40 and Example 41 were sterilized at 121°C for 15 min, and the results of the main components and the largest single impurity are shown in Table 4.
  • the main components of Example 40 and Example 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.
  • Example 42 was first rotary evaporated at room temperature until the solution changed from clear to white and solid precipitated. Then it was transferred to a 50°C water bath, and the vacuum degree was adjusted. When it started to boil at 0.085 MPa, it was rotary evaporated for 1 hour, and the inclusion compound was scraped out.
  • Example 43 was directly placed in a 50°C water bath, and the vacuum degree was adjusted to 0.085 MPa. It was rotary evaporated for 1 hour, and the inclusion compound was scraped out.
  • the stability results of Example 42 and Example 43 before and after rotary evaporation are shown in Table 6.
  • the stability of the rotary evaporated solution at 50°C was investigated in Example 44 and Example 45. The results are shown in Table 7.
  • Example 42 and Example 43 The test results show that: before and after rotary evaporation of Example 42 and Example 43, the related substances of the active compound formula (IX) remain basically unchanged, and the rotary evaporation process does not affect the stability of the active compound. Before rotary evaporation of Example 44 and Example 45, the solution was kept at 50°C for less than 2 hours, and the related substances of the active compound remained basically unchanged.
  • HP- ⁇ -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 to stir and dissolve them, and purified water was slowly added thereto 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 the re-dissolution.
  • Example 46 is a white loose porous solid with good morphology
  • Example 47 is a white loose porous solid with splashing solid powder.
  • the solutions of Example 46 and Example 47 after redissolution are slightly turbid.
  • Example 48, Example 49, Example 50 According to the prescription in Table 9, the active compound of formula (IX), HP- ⁇ -CD, tert-butyl-p-hydroxyanisole (BHA), and vitamin E (VE) were placed in a beaker, isopropanol was added, and after stirring evenly, a certain amount of purified water was slowly added thereto to obtain a clear solution and then freeze-dried.
  • Example 51 was freeze-dried after only using a certain amount of purified water to disperse the active compound. The effects of different excipients on impurities under the freeze-drying process were investigated. The main components and impurity content data of Examples 48 to 51 are shown in Table 10.
  • Example 49 when Example 490 with the addition of antioxidant BHA, had a maximum single impurity of 2.03%. After a 5-day stability test at 60°C, compared with Example 48, the main component content of Examples 49 and 50 was reduced to varying degrees. Adding antioxidants BHA or VE is not conducive to the stability of the active compound eye drops.
  • Multi-dose packaged eye drops need to add antibacterial agents to avoid microbial contamination during use.
  • the effects of two antibacterial agents, benzalkonium chloride and chlorhexidine acetate, on the stability of the prescription were investigated through Examples 52, 55 and 56.
  • the preliminary stability of the eye drops of Examples 52, 55 and 56 was investigated at 25°C and 40°C in the dark for 5 days, and the results are shown in Table 13.
  • Example 56 has better short-term stability in terms of the number and level of impurity growth, and the antibacterial agent chlorhexidine acetate is more suitable for active compound eye drops.
  • Example 53 and Example 54 were packaged in low-density polyethylene medicinal eye drop bottles (PE), brown polyester medicinal eye drop bottles (PET) and ampoule bottles, respectively, and placed at 25°C in the dark to investigate the preliminary compatibility of the packaging materials.
  • the stability data is shown in Table 14.
  • Example 52 produced by the isopropanol freeze-drying process showed crystallization after long-term storage.
  • Example 53 and Example 54 with different packaging systems were placed at 25°C for 15 days, and the eye drops did not crystallize and the impurities did not change significantly.
  • Examples 57 to 60 were re-dissolved, dilute hydrochloric acid and dilute sodium hydroxide were used to adjust the pH, and the appropriate pH of the active compound formula (IX) eye drops was examined.
  • the stability results of Examples 57 to 60 at 60°C for 5 days are shown in Table 15. The results show that the stability of the eye drops under alkaline conditions is better than that under acidic conditions.
  • Example 61 The stability data of Examples 61 to 63 are shown in Table 16. Compared with Example 61, there is no significant change in the related substances of Example 62, and the addition of the antibacterial agent chlorhexidine acetate will not affect the stability of the active compound formula (IX) eye drops. Compared with Example 62, there is no significant change in the related substances of Example 63, and the increase in the amount of the chaotropic agent HP- ⁇ -CD will not affect the stability of the active compound.
  • Example 64 and Example 66 were placed in a water bath at 80°C and heated in the dark, and two ampoules were taken out 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.
  • Example 64 the 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 related substances increased by 0.30%, 0.47% and 0.57% after 0.5, 1 and 2 hours at 80°C, respectively.
  • Example 66 containing SBE- ⁇ -CD has worse thermal stability.
  • Examples 68 to 87 were prepared.
  • the active compound of formula (IX) and HP- ⁇ -CD were weighed and placed in a 10 ml vial. Purified water in the prescription ratio was added, and stirred or shaken at different water bath temperatures until dissolved. The dissolution of the active compound under different concentration process conditions was compared.
  • Example 79 was diluted 1 times and 5 times to obtain Example 88 and Example 89.
  • Example 80 was diluted 1 times and 5 times to obtain Example 90 and Example 91.
  • Example 69 Example 70, Example 75-83, Example 85, and Example 86, under the concentration conditions of Table 19, the active compound of formula (IX) can be completely dissolved in a relatively short time. Under the concentration process conditions, the amount of HP- ⁇ -CD, the concentration of HP- ⁇ -CD and the concentration temperature have a great influence on the dissolution process of the active compound.
  • test results show that the content of active compound remains basically stable after being observed at 60°C for 10 days and at 25°C, 30°C, and 40°C for 20 days, indicating that the thermal stability of the cyclodextrin aqueous solutions containing active compounds in Examples 67, Examples 78 to 80, and Examples 88 to 91 is acceptable; in Example 80, a yellow precipitate appears after 5 days of observation under the lighting conditions of the influencing factor test, indicating that the cyclodextrin aqueous solution containing the active compound is unstable to strong light.
  • Example 92 was prepared according to the prescription ratio in Table 24. A certain amount of purified water was added to a beaker, heated to 70°C in a water bath, HP- ⁇ -CD was added and stirred to dissolve, then the active compound of formula (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 it was shaken to dissolve.
  • Table 24 A certain amount of purified water was added to a beaker, heated to 70°C in a water bath, HP- ⁇ -CD was added and stirred to dissolve, then the active compound of formula (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
  • 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 up to 100ml. Filtered in sequence through 0.45 ⁇ m and 0.22 ⁇ m mixed membranes, the filtrate was sealed in 5ml borosilicate glass ampoules at 5ml/branch. Eye drops were obtained.
  • Example 92 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 investigation, 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.
  • Example 92 The results show that the related substances of Example 92 increased significantly after sterilization under different conditions.
  • the total impurities of the sample sterilized at 115°C for 30 minutes increased by 1.507%, and the total impurities of the sample sterilized at 121°C for 15 minutes and 30 minutes increased by 1.687% and 2.195%, respectively.
  • the thermal stability of Example 92 is poor and cannot withstand moist heat sterilization. After Example 92 was observed at 60°C for 5 and 10 days, the related substances increased respectively, and other indicators remained basically stable.
  • 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, heated to 60 ° C, HP- ⁇ -CD was added and stirred to dissolve, and then the active compound formula (IX) was added and heated to 70 ° C and stirred for 60 min until completely dissolved; the solution was transferred to a 500 ml volumetric flask, and the beaker was rinsed with about 200 g of purified water in small amounts for multiple times, and the rinse water was transferred to the volumetric flask, chlorhexidine acetate was added and shaken to dissolve, and then 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 500 ml, shake well, and the density of the solution was calculated to be 1.0166 g/ml according to the mass volume ratio. The solution was sealed in a 5 ml medium borosilicate glass
  • Example 93 was placed at about 1.5m under a 40W fluorescent lamp indoors, and samples were taken at 0, 2, 4 and 6 hours to test the properties, pH and related substances of the samples. The test results are shown in Table 28. The results show that Example 93 remained basically stable when placed at about 1.5m under a fluorescent lamp indoors for 6 hours, and the liquid preparation and filling in production can be carried out under normal indoor lighting.
  • Example 94 Add chlorhexidine acetate to a 500ml beaker, stir until dissolved, add sodium chloride, sodium dihydrogen phosphate monohydrate, and anhydrous disodium hydrogen phosphate in sequence, stir until dissolved, add water to 250ml, stir well, and filter through 0.45 ⁇ m and 0.22 ⁇ m mixed filter membranes to obtain Example 94.
  • Example 94 The pH of Example 94 is 7.75. Take the solution of Example 94, adjust the pH to 6.96 with 1mol/L HCl and 5mol/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 30min, 121°C for 15min and 121°C for 30min, respectively, and 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 5ml ampoules and placed at 60°C for observation. 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 31.
  • Example 94 The results show that the related substances in Example 94 increased significantly after sterilization under different conditions.
  • the thermal stability of Example 94 is poor and cannot withstand moist heat sterilization.
  • the sample stability of Example 96 at pH 8.54 is the best.
  • the pH of the eye drops in Example 94 is more suitable.
  • Example 97 and Example 98 Add chlorhexidine acetate to a 500 ml beaker, 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 well, and filter through 0.45 ⁇ m and 0.22 ⁇ m mixed filter membranes to obtain Example 97 and Example 98.
  • Example 94, 97 and 98 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.
  • 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°C ⁇ 2°C, and add HP- ⁇ -CD in small amounts and multiple times while stirring.
  • Concentrated solution dilution and volume adjustment weigh 7.5kg of 20°C ⁇ 25°C water for injection into a stainless steel barrel, start the mixer to stir, add the concentrated solution into the stainless steel barrel, take a small amount of 20°C ⁇ 25°C water for injection, rinse the beaker for preparing the concentrated solution 4 to 6 times, transfer all the rinses to the stainless steel barrel, and stir evenly.
  • Add the prescribed amount of sodium chloride, sodium dihydrogen phosphate monohydrate, and anhydrous disodium hydrogen phosphate in sequence stir to dissolve.
  • Filtration and filling Before production begins, the filter element is tested for integrity, and the liquid preparation tank, the BFS machine and its material delivery pipeline are flushed and sterilized with online steam, maintaining ⁇ 121°C pure steam sterilization for 30 minutes. After debugging the equipment, filtration and filling begins. After production is completed, the filter element is tested for integrity.
  • sulfobutyl- ⁇ -cyclodextrin SBE- ⁇ -CD
  • phosphate buffer 0.15 ml of dimethyl sulfoxide
  • SBE- ⁇ -CD sulfobutyl- ⁇ -cyclodextrin
  • Example 103 the amount of sulfobutyl- ⁇ -cyclodextrin used is large, and dimethyl sulfoxide has local toxicity and low systemic toxicity, and is not suitable for eye drops. Compared with Examples 66 and 67, which have simple excipient compositions and do not contain dimethyl sulfoxide, Example 103 has poor stability and higher safety risks.
  • the XRPD spectrum analysis data of 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 starting point at 101.7 ⁇ 3.0°C and 158.7 ⁇ 3.0°C, 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.
  • 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°C ⁇ 2°C, and add HP- ⁇ -CD in small amounts and multiple times while stirring.
  • Concentrated solution dilution and volume adjustment weigh 7.5kg of 20°C ⁇ 25°C water for injection into a stainless steel barrel, start the mixer to stir, add the concentrated solution into the stainless steel barrel, take a small amount of 20°C ⁇ 25°C water for injection, rinse the beaker for preparing the concentrated solution 4 to 6 times, transfer all the rinses to the stainless steel barrel, and stir evenly.
  • Filtration and filling Before production begins, the filter element is tested for integrity, and the liquid preparation tank, the BFS machine and its material delivery pipeline are flushed and sterilized with online steam, maintaining ⁇ 121°C pure steam sterilization for 30 minutes. After debugging the equipment, filtration and filling begins. After production is completed, the filter element is tested for integrity.
  • 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 Example 105, Example 106, and Example 107 on the model.
  • 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), high concentration group (5 mg/mL) (Example 107, G5), with 8 animals in each group, all female.
  • negative control group normal saline, G1
  • model control group solvent
  • Example 105, G3 low concentration group (1 mg/mL)
  • medium concentration group 2.5 mg/mL
  • Example 106, G4 medium concentration group
  • high concentration group 5 mg/mL
  • 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 point should be avoided.
  • Animals in each test group were given eye drops in both eyes at D1, 3 ⁇ L/eye/time, 4 times/day, with an interval of about 3 hours, for a total of 12 days (3 times at D12).
  • Animals in the negative control group and model control group were given an equal volume of solvent in both eyes. Tear secretion in both eyes was measured about 30 minutes after the second administration at D7 and D12, and corneal fluorescence staining was scored about 30 minutes after the third administration at D7 and D12. After the determination of the indicators at D12, the animals were euthanized by cervical dislocation.
  • Example 105, Example 106, and Example 107 can all have good therapeutic effects on the mouse dry eye model induced by scopolamine hydrobromide solution, and they mainly improve the tear secretion and corneal damage of the dry eye model mice.
  • the dry eye model of SD rats was induced by eye drops of hypertonic sodium chloride solution to examine the therapeutic effects of Example 105 and Example 107 on the model.
  • the animals in each group were modeled at D1.
  • a pipette was used to draw 20 ⁇ L of sodium chloride solution (osmotic pressure of 500 mOsmol/L) and dripped into the conjunctival sac of both eyes of the animals, 5 times/day, 20 ⁇ L/time, with an interval of about 2 hours each time, for 21 consecutive days. After the dripping, the eyelids of the animals were passively closed for about 90 seconds.
  • All animals in each group were given eye drops at D1, 10 ⁇ L/eye/time, 4 times/day, with an interval of about 3 hours for a total of 21 days, and were weighed once a week during the administration period.
  • the corneal fluorescence staining scores, tear secretion volume and tear film breakup time of the animals were measured at D0, D14 and D21.
  • the low concentration group (1 mg/mL) and high concentration group (5 mg/mL) can increase the tear secretion of dry eye model rats, reduce corneal fluorescence staining scores, and improve tear film breakup time compared with the model control group. Specific results are shown in Tables 41, 42, 43 and Figures 6, 7 and 8.
  • 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, which is mainly manifested in that continuous eye drops for about 2 weeks can significantly improve the tear secretion, corneal damage and tear film stability of the dry eye model rats.
  • mice 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. Each group of animals was administered with eye drops in the left eye, 5 mg/mL (Example 107), and the dosage volume of each test group was 100 ⁇ l/eye. Plasma, corneal tissue, conjunctival tissue, and retinal tissue samples were collected from each group of animals 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.
  • Example 107 shows that after ocular administration of Example 107, the active ingredient has a higher concentration distribution in the cornea and conjunctiva of the ocular surface tissue, which is beneficial to the treatment of ocular surface diseases; the distribution concentration of the active ingredient in the retina of the fundus tissue is low, and the risk of causing adverse reactions in the fundus is low. Therefore, the pharmacokinetic properties of Example 107 are beneficial to the treatment of ocular surface diseases.
  • the allergic conjunctivitis mouse model was prepared by subcutaneous injection of ragweed pollen in the footpad for sensitization and local eye drop stimulation.
  • the clinical symptoms of the mouse eyes, eye observation scores, pathological HE, and the therapeutic effects of the low concentration group (1 mg/mL) (Example 105), the medium concentration group (2.5 mg/mL) (Example 106), and the high concentration group (5 mg/mL) (Example 107) on the allergic conjunctivitis mice were evaluated.
  • model sensitization drug ragweed pollen tarsal joint injection
  • ragweed pollen eye drops weigh 168 mg ragweed pollen and dissolve it in 1.12 ml PBS; weigh 189 mg ragweed pollen and dissolve it in 1.26 ml PBS (phosphate buffered saline); weigh 144 mg ragweed pollen and dissolve it in 0.96 ml PBS.
  • Example 105 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).
  • ragweed pollen tarsal joint sensitization injection was injected subcutaneously into the foot pad of mice, 65 ⁇ L/mouse; on days 10-13, ragweed pollen eye drops were dripped into the right eyes of mice in the model group for stimulation, 10 ⁇ L/mouse/time, once a day for 4 consecutive days.
  • Drug intervention treatment was started 30 minutes after each eye drop stimulation, 4 times a day, for 4 consecutive days.
  • the blank group and the model group were treated with the same amount of solvent; the test drug treatment group was treated with the corresponding dose of compound; the drug administration was divided into two times, 10 ⁇ L/time, with an interval of 1 minute, 4 times/mouse/day, for 4 consecutive days.
  • the ocular observation score observe the allergic reaction of the eyes, including conjunctival edema and conjunctival congestion, and score them as 0-3 points according to the severity (including none, mild, moderate and severe).
  • the scoring criteria for conjunctival edema are: mild localized conjunctival edema is 1 point; diffuse edema and involvement of the fornix is 2 points; conjunctival edema leading to shallow narrowing of the conjunctival sac is 3 points.
  • the scoring criteria for conjunctival congestion are: mild diffuse vascular congestion is 1 point; diffuse congestion and obvious near the fornix is 2 points; congestion with subconjunctival hemorrhage is 3 points.
  • the paraffin sections were baked, dewaxed and hydrated.
  • the hydrated sections were placed in a hematoxylin aqueous solution for staining for 3 minutes, differentiated with hydrochloric acid ethanol differentiation solution for 15 seconds, washed with water, blued with blue solution for 15 seconds, rinsed with running water, eosin stained for 3 minutes, rinsed with running water, dehydrated, transparent, sealed, and examined under a microscope.
  • the experimental data were analyzed by one-way ANOVA (*p ⁇ 0.05, **p ⁇ 0.01) for each group using GraphPad Prism 5 and IBM SPSS Statistics 19.0 software.
  • the score of the model group was significantly increased compared with the blank group; compared with the model group, the low concentration group (1mg/mL), the medium concentration group (2.5mg/mL), and the high concentration group (5mg/mL) can significantly reduce the score (p ⁇ 0.05 or p ⁇ 0.01), and improve conjunctival edema and conjunctival hyperemia.
  • the above results suggest that the low, medium, and high concentration groups have the effect of improving conjunctival edema and conjunctival hyperemia in mice with allergic conjunctivitis induced by ragweed pollen.
  • the specific test results are shown in Figures 9 and 10.
  • the pathological results showed that the conjunctiva of the blank group was intact, with no obvious damage, and some samples showed congestion of blood vessels, accompanied by a small amount of inflammatory cell infiltration; the conjunctiva of the model group showed varying degrees of thickening or thinning, disordered arrangement of conjunctival epithelial cells, obvious inflammatory cell infiltration, and no obvious capillary hyperplasia and congestion under the conjunctiva.
  • the conjunctival structure of the low concentration (1 mg/mL) group was relatively intact, and a small amount of inflammatory cell infiltration and congestion could be seen in some samples; in the medium concentration (2.5 mg/mL) group, the conjunctival epithelial cells were seen to fall off, and the conjunctiva was also thickened, with a small amount of inflammatory cell infiltration and congestion; in the high concentration (5 mg/mL) group, the conjunctival epithelial cells of some samples were irregularly arranged, thinned, and a small amount of inflammatory cell infiltration and congestion samples could be seen; the above results indicate that the low, medium and high concentration groups can improve the abnormal conjunctival structure and inflammatory cell infiltration of mice with allergic conjunctivitis.
  • the test results are shown in Figure 11.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明属于药物制剂领域，公开了一种含有吡啶苯基类化合物的眼用制剂及其制备方法和应用。该眼用制剂包括活性成分吡啶苯基类化合物及辅料，活性成分吡啶苯基类化合物包括式（II）通式化合物、其异构体或其药学上可接受的盐。其可用于干眼症、过敏性结膜炎、黄斑变性、白内障、角膜圆锥、大疱性角膜病变、Fuch角膜内皮营养不良、眼部疤痕性类天疱疮、睑板腺功能障碍、葡萄膜炎、巩膜炎、Stevens-Johnson综合征、眼红斑痤疮、Sjögren综合征。

Description

一种含有吡啶苯基类化合物的眼用制剂及其制备方法和应用 技术领域
本发明属于药物制剂领域，涉及吡啶苯基类化合物的眼用制剂及其制备方法，还包括其在眼科疾病中的应用。
背景技术
干眼症又称角结膜干燥症，是指任何原因造成的泪液质或量异常或动力学异常，导致泪膜稳定性下降，并伴有眼部不适(或)眼表组织病变特征的多种疾病的总称。具体不适症状表现为：眼部刺激，视觉障碍和泪膜不稳定。这种综合症有的是由眼表炎症引起，导致泪腺功能缺失。此外，它也与系统性自身免疫有关。
由于体内或眼部组织器官通过代谢机制等产生一些有毒的醛，比如丙二醛(MDA)、4-羟基-2-壬烯醛(4HNE)等，这些醛类与蛋白质、碳水化合物、油脂和DNA高度反应，导致化学修饰生物分子，激活炎症分子调节物如NF-kappaB，从而促使不同器官受损，这是干眼症诱因之一。
本发明通过研究，小分子药物以滴眼形式进入眼部炎症部位，通过与体内醛络合反应，从而降低醛毒性，降低炎症，达到治疗干眼症作用。
WO2020125659公开了一种吡啶苯基类醛结合剂化合物，及其异构体或药学上接受的盐的一系列满足时I通式的化合物：
但尚未公开其眼用制剂及其眼用制剂在眼科疾病方面的治疗作用。因此，需要更深入研究发现上述小分子化合物的眼用制剂对眼科疾病(如干眼症、过敏性结膜炎、黄斑变性、白内障、角膜圆锥、大疱性角膜病变、Fuch角膜内皮营养不良、眼部疤痕性类天疱疮、睑板腺功能障碍、葡萄膜炎、巩膜炎、Stevens-Johnson综合征、眼红斑痤疮、 综合征)的疗效和安全性，并且开发制备工艺、质量稳定的眼用制剂。
发明内容
本发明的目的在于提供一种安全有效的眼用制剂，并且该眼用制剂的制备工艺简单，质量稳定，适合工业化大生产。
本发明提供一种眼用制剂，所述眼用制剂包括活性成分吡啶苯基类化合物及辅料，其中辅料包括促溶剂、pH调节剂、渗透压调节剂、抑菌剂、抗氧剂，其中所述活性化合物包括式(I)通式化合物、其异构体或其药学上可接受的盐。本发明提供了式(I)所示化合物或其药学上可接受的盐，
其中，
T1、T2、T3和T4分别独立地选自N、C或CR1；
L选自单键、-O-、-S-、-NR2-或-(CR3R4)n-；
R1选自H、F、Cl、Br、I、OH或NH2；
R2选自H、任选被1、2或3个Ra取代的C1-3烷基；
R3、R4分别独立地选自H、F、Cl、Br、I、OH、NH2、CN或任选被1、2或3个Rb取代的C1-3烷基；
n选自1、2或3；
Ra和Rb分别独立地选自H、F、Cl、Br、I、OH、NH2、CN或CH3。
本发明的一些方案中，上述R2选自H、CH3或CH2CH3，所述CH3和CH2CH3任选被1、2或3个Ra取代，其他变量如本发明所定义。
本发明的一些方案中，上述R2选自H、CH3或CH2CH3，其他变量如本发明所定义。
本发明的一些方案中，上述R3和R4分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、CH3或CH2CH3，所述CH3和CH2CH3任选被1、2或3个Rb取代，其他变量如本发明所定义。
本发明的一些方案中，上述R3和R4分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、CH3或CH2CH3，其他如本发明所定义。
本发明的一些方案中，上述L选自单键、-O-、-S-、-NH-、-(CH2)2-或-CH2-，其他变量如本发明所定义。
本发明提供了式(II)所示化合物或其药学上可接受的盐，
其中，
所述选自单键或双键；
T1、T2、T3和T4分别独立地选自N、C或CR1；
T5选自C、CR5或C＝O；
T6选自C、CR6或N；
T7选自N或CR7；
当T5选自C＝O，T6选自N时，所述选自单键；
L选自单键、-O-、-S-、-NR2-或-(CR3R4)n-；
各R1分别独立地选自H、F、Cl、Br、I、OH或NH2；
R2选自H和任选被1、2或3个Ra取代的C1-3烷基；
R3和R4分别独立地选自H、F、Cl、Br、I、OH、NH2、CN或任选被1、2或3个Rb取代的C1-3烷基；
R5、R6和R7分别独立地选自H、F、Cl、Br或I；
n选自1、2或3；
Ra和Rb分别独立地选自H、F、Cl、Br、I、OH、NH2、CN或CH3。
本发明的一些方案中，上述R2选自H、CH3或CH2CH3，所述CH3和CH2CH3任选被1、2或3个Ra取代，其他变量如本发明所定义。
本发明的一些方案中，上述R2选自H、CH3或CH2CH3，其他变量如本发明所定义。
本发明的一些方案中，上述R3和R4分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、CH3或CH2CH3，所述CH3和CH2CH3任选被1、2或3个Rb取代，其他变量如本发明所定义。
本发明的一些方案中，上述R3和R4分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、CH3或CH2CH3，其他变量如本发明所定义。
本发明的一些方案中，上述L选自单键、-O-、-S-、-NH-、-(CH2)2-和-CH2-，其他变量如本发明所定义。
本发明还有一些方案是由上述各变量任意组合而来。
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自
其中，
T3、T4分别独立地选自N和CR1；
R1和L如本发明所定义。
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自
其中，
R1和L如本发明所定义。
在本发明中，作为实施方案之一，所述式(I)化合物或其药学上可接受的盐，其选自：

本发明中，作为实施方案之一，所述的式(III)化合物、其异构体或其药学上可接受的盐：
本发明中，作为实施方案之一，所述的式(IV)化合物、其异构体或其药学上可接受的盐：
本发明中，作为实施方案之一，所述的式(V)化合物、其异构体或其药学上可接受的盐：
本发明中，作为实施方案之一，所述的式(VI)化合物、其异构体或其药学上可接受的盐：
本发明中，作为实施方案之一，所述的式(VII)化合物、其异构体或其药学上可接受的盐：
本发明中，作为实施方案之一，所述的式(VIII)化合物、其异构体或其药学上可接受的盐：
本发明中，作为实施方案之一，所述式(III)化合物还包括一分子水，即为如下式IX化合物、其异构体或其药学上可接受的盐：
本发明中，作为实施方案之一，所述局部外用制剂包含本发明公开的式(III)化合物、式(IV)化合物、式(V)化合物、式(VI)化合物、式(VII)化合物、式(VIII)化合物或式(IX)化合物中的一种。
本发明中，作为实施方案之一，所述眼用制剂包括一种或多种的促溶剂。
本发明中，作为实施方案之一，所述眼用制剂包括一种或多种的pH调节剂。
本发明中，作为实施方案之一，所述眼用制剂包括一种或多种渗透压调节剂。
本发明中，作为实施方案之一，所述眼用制剂包括一种或多种抑菌剂。
本发明中，作为实施方案之一，所述眼用制剂包括一种或多种抗氧剂。
本发明中，作为实施方案之一，所述促溶剂选自甲基化-β-环糊精(RM-β-CD)、羟丙基-β-环糊精(HP-β-CD)、羟丙基-γ-环糊精(HP-γ-CD)、磺丁基-β-环糊精(SBE-β-CD)、泊洛沙姆407、吐温80、聚维酮(PVP)、聚乙二醇(PEG400)，或它们中的两种或两种以上的组合。
本发明中，作为实施方案之一，所述pH调节剂选自磷酸二氢钠一水合物、无水磷酸氢二钠、硼砂、硼酸、枸橼酸二水合物、盐酸、氢氧化钠，或它们中的两种或两种以上的组合。
本发明中，作为实施方案之一，所述渗透压调节剂选自氯化钠、硼酸、硼砂、葡萄糖、甘露醇，或它们中的两种或两种以上的组合。
本发明中，作为实施方案之一，所述抑菌剂选自苯扎氯铵、醋酸氯己定、醋酸苯汞，或它们中的两种或两种以上的组合。
本发明中，作为实施方案之一，所述抗氧剂选自丁基羟基茴香醚(BHA)、维生素E(VE)，或它们中的两种或两种以上的组合。
本发明中，作为实施翻案之一，所述冻干溶剂选自95％的乙醇、叔丁醇、异丙醇、或乙腈。
本发明中提供一种眼用制剂，包括活性成分吡啶苯基类化合物、一种或多种促溶剂、一种或多种pH调节剂、一种或多种渗透压调节剂、一种或多种抑菌剂、一种或多种抗氧剂，其中所述吡啶苯基类化合物包括式(III)、式(IV)、式(V)、(VI)、(VII)、式VIII化合物或式(IX)化合物、其异构体或其药学上可接受的盐。

本发明中提供的眼用制剂中，所述活性成分的含量为0.05～0.6％w/v，优选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、或0.55％w/v。
本发明中提供的眼用制剂中，所述促溶剂选自甲基化-β-环糊精(RM-β-CD)、羟丙基-β-环糊精(HP-β-CD)、羟丙基-γ-环糊精(HP-γ-CD)、磺丁基-β-环糊精(SBE-β-CD)、泊洛沙姆407、吐温80、聚维酮(PVP)、聚乙二醇(PEG400)，或它们中的两种或两种以上的组合。
本发明中提供的眼用制剂中，所述促溶剂的含量为0.2％～15％w/v，优选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、或9.9％w/v。
本发明中提供的眼用制剂中，所述促溶剂羟丙基-β-环糊精(HP-β-CD)的含量为0.5％w/v～12％w/v，优选0.7％w/v～10％w/v，更优选1％w/v～8％w/v，最优选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、或8％w/v。
本发明提供的眼用制剂中，所述磺丁基-β-环糊精(SBE-β-CD)的含量为选自4％～13％，优选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、或12.5％w/v。
本发明中提供的眼用制剂中，所述pH调节剂的含量为0.12～20％w/v，优选0.2％w/v、0.25％w/v、0.3％w/v、0.35％w/v、0.4％w/v、0.47％w/v、0.5％w/v、0.6％w/v、0.7％w/v、0.8％w/v、0.81％w/v、0.9％w/v、1％w/v、2％w/v、3％w/v、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、或20％w/v。
本发明中提供的眼用制剂中，所述pH调节剂磷酸二氢钠一水合物的含量为0.1％w/v～0.5％w/v，优选0.12％w/v～0.45％w/v，更优选0.15％w/v、0.2％w/v、0.25％w/v、0.3％w/v、0.35％w/v、或0.4％w/v。
本发明中提供的眼用制剂中，所述pH调节剂无水磷酸氢二钠的含量为0.3％w/v～1％w/v，优选0.4％w/v～0.9％w/v，更优选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、或0.81％w/v。
本发明中提供的眼用制剂中，所述渗透压调节剂的含量为0.1％～1％w/v，优选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、或0.95％w/v。
本发明中提供的眼用制剂中，所述渗透压调节剂氯化钠的含量为0.2％w/v～0.8％w/v，优选0.25％w/v～0.7％w/v，更优选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、或0.65％w/v。
本发明中提供的眼用制剂中，所述抑菌剂的含量为0.001％w/v～0.02％w/v，优选0.002％w/v～0.018％w/v，进一步优选0.003％w/v～0.016％w/v，最优选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、或0.015％w/v。
本发明提供的眼用制剂中，所述抑菌剂苯扎氯铵的含量为0.001％w/v～0.02％w/v，优选0.002％w/v～0.018％w/v，进一步优选0.003％w/v～0.016％w/v，最优选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、或0.015％w/v。
本发明提供的眼用制剂中，所述抑菌剂醋酸氯己定的含量为0.001％w/v～0.02％w/v，优选0.002％w/v～0.018％w/v，进一步优选0.003％w/v～0.016％w/v，最优选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、或0.015％w/v。
本发明中提供的眼用制剂中，所述抗氧剂的含量为0.1％～0.8％w/v，优选0.2％w/v、0.3％w/v、0.4％w/v、0.5％w/v、0.6％w/v、或0.7％w/v。
本发明提供的眼用制剂中，所述眼用制剂包括：式(IX)化合物及其异构体或其药学上可接受的盐，含量为0.1％w/v～0.5％w/v；还包括辅料：羟丙基-β-环糊精(HP-β-CD)，含量为0.7％w/v～3.5％w/v，优选1.75％w/v、3.5％w/v、或0.7％w/v；无水磷酸氢二钠，含量为0.81％w/v；磷酸二氢钠一水合物，含量为0.12％w/v；氯化钠，含量为0.25％w/v～0.45％w/v，优选0.27％w/v、0.36％w/v、或0.4％w/v；醋酸氯己定，含量为0.01％w/v。
本发明中提供的眼用制剂中，所述眼用制剂的pH值范围为5.0～9.0，优选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、或8.9。
本发明中提供的眼用制剂中，所述的眼用制剂的制备方法采用旋蒸工艺、浓配稀释法、冷冻干燥法。
本发明中的眼用制剂通过稳定性考虑，测定了含量、有关物质的变化，结果表明本发明提供的眼用制剂性质稳定，有关物质和含量均无显著差异。
本发明提供的眼用制剂的剂型可为液体制剂，作为示例性的说明可以为滴眼液、洗眼剂或眼内注射溶液、眼用半固体制剂作为示例性的说明可以为眼膏剂、眼用乳膏剂、或眼用凝胶剂、眼用固体制剂作为示例性的说明可以为眼膜剂、眼丸剂、眼内插入剂。
本发明提供的眼用制剂，其在制备治疗眼科疾病的药物中的用途，所述用途优选干眼症、过敏性结膜炎、黄斑变性、白内障、角膜圆锥、大疱性角膜病变、Fuch角膜内皮营养不良、眼部疤痕性类天疱疮、睑板腺功能障碍、葡萄膜炎、巩膜炎、Stevens-Johnson综合征、眼红斑痤疮、或综合征。
本发明提供的眼用制剂，通过下肢皮下注射氢溴酸东莨菪碱溶液诱发C57BL/6小鼠干眼症模型、高渗氯化钠溶液滴眼诱发SD大鼠干眼症模型考察其治疗效果，结果表明本发明的眼用制剂能够改善干眼症模型小鼠的泪液分泌量和角膜损伤情况。通过考察在新西兰兔眼部的药代动力学研究其活性成分在眼表组织角膜与结膜中有较高浓度分布，有利于眼部疾病的治疗，眼底分布浓度较低，引起眼底不良反应的风险较小。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR)0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“C1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C1-6烷基包括C1-5、C1-4、C1-3、C1-2、C2-6、C2-4、C6和C5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，术语“C1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C1-3烷基包括C1-2和C2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氧基包括C1-2、C2-3、C3和C2烷氧基等。C1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，Cn-n+m或Cn-Cn+m包括n至n+m个碳的任何一种具体情况，例如C1-12包括C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、和C12，也包括n至n+m中的任何一个范围，例如C1-12包括C1-3、C1-6、C1-9、C3-6、C3-9、C3-12、C6-9、C6-12、和C9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1，1-二-(4′-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N′，N′-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表PE；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl2代表氯化亚砜；CS2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表N-氯代丁二酰亚胺；n-Bu4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；LiHMDS代表六甲基二硅基胺基锂；Xantphos代表4，5-双二苯基膦-9，9-二甲基氧杂蒽；LiAlH4代表四氢铝锂；Pd(dba)2代表三(二亚苄基丙酮)二钯；mCPBA代表间氯过氧苯甲酸；pd(dppf)Cl2代表[1，1′-双(二苯基膦基)二茂铁]二氯化钯；DBU代表1，8-二氮杂双环[5.4.0]十一碳-7-烯。
化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。
附图说明
图1：为式(IX)化合物的Cu-Kα辐射的XRPD谱图。
图2：为式(IX)化合物的DSC谱图。
图3：为式(IX)化合物的TGA谱图。
图4：实施例105、106、107的小鼠干眼症模型的泪液分泌量。
图5：实施例105、106、107的小鼠干眼症模型的角膜荧光染色评分。
图6：实施例105、107的大鼠干眼症模型的泪液分泌量。
图7：实施例105、107的大鼠干眼症模型的角膜荧光染色评分。
图8：实施例105、107的大鼠干眼症模型的泪膜破裂时间。
图9：结膜水肿评分。
图10：结膜充血评分。
图11：HE染色的病理结果。
具体实施方式
通过以下实施例进一步详细说明本发明。这些实施例仅用于说明性目的，而并不用于限制本发明的范围。
实施例1～11
本发明活性化合物式(IX)化合物为水中不溶或几乎不溶性化合物。按照表1具体过程配制实施例1～11。结果表明，实施例1、实施例4、实施例5、实施例6、实施例7、实施例9和实施例10不同的促溶剂及加热等操作后式(IX)化合物仍无法溶解。实施例2、实施例3、实施例8和实施例11的促溶剂有一定的促溶效果。
表1
实施例12～30
按照表2处方称取活性化合物式(IX)化合物、丙二醇、PEG400、吐温80等辅料置于西林瓶中，使活性化合物超声溶解于上述辅料中，得到浓溶液。将上述浓溶液逐滴，加入至处方量的介质中。得到实施例12～30，观察活性化合物的溶解情况，具体数据见表2。实施例20～23可以得到较稳定的5mg/ml活性化合物溶液。
表2

实施例31～41
按照表3称取活性化合物式(IX)化合物与HP-β-CD溶解于95％乙醇中，将上述溶液，置于旋蒸中旋干溶剂，得到包合物固体，将其置于纯化水中溶解，根据活性化合物的加入量，使用纯化水/pH6.8磷酸盐介质配制成5mg/mL的溶液，观察溶解情况。具体结果见表3。
表3

注：实施例39～41的活性化合物按照折纯投料
经过旋蒸后，实施例31～41均可得到活性化合物的HP-β-CD包合 物。实施例33、实施例35、实施例36、实施例37、实施例38、实施例40和实施例41的HP-β-CD包合物可以溶解成澄清透明水溶液且无沉淀生成。
将实施例36、实施例37和实施例38的滴眼液经121℃ 15min灭菌，实施例36和实施例37的滴眼液出现浑浊，实施例38滴眼液灭菌后依然澄清。
实施例40和实施例41制成的滴眼液经过121℃ 15min灭菌，主成分和最大单杂结果见表4。实施例40和实施例41的主成分灭菌前后分别降低0.62％、0.61％；最大单杂灭菌前后分别升高1.61％、1.35％。
表4
实施例42～45
按照表5取异丙醇10ml，置50ml烧杯中，磁力搅拌，加入活性化合物，搅拌溶解；加HP-β-CD 4.00g，搅拌均匀后再加异丙醇10ml，超声12min得到澄清溶液。实施例42先室温旋转蒸发至溶液由澄清变白色并有固体析出，再转入50℃水浴中，调节真空度，0.085MPa时开始沸腾，旋蒸1h，刮出包合物；实施例43直接置50℃水浴中，调节真空度为0.085MPa，旋蒸1h，刮出包合物。实施例42、实施例43旋蒸前后稳定性结果见表6。实施例44、实施例45考察旋蒸溶液在50℃稳定性，结果见表7。
表5
表6

表7
试验结果表明：实施例42、实施例43旋蒸前后，活性化合物式(IX)化合物有关物质基本不变，旋蒸工艺基本不影响活性化合物稳定性。实施例44和实施例45旋蒸前溶液在50℃保温2h以内，活性化合物有关物质基本不变。
实施例46～47
按照表8比例将HP-β-CD和活性化合物式(IX)化合物置于烧杯中，加入有机溶剂将其搅拌溶解后，缓慢向其中加入纯化水，得到澄清溶液后将其冻干，考察不同溶剂对冻干后中间体状态及复溶情况的影响。
表8
试验结果表明，实施例46的中间体为白色疏松多孔固体，形态良好；实施例47的中间体为白色疏松多孔固体，固体粉末有飞溅。实施例46和实施例47复溶后溶液均略微浑浊。
实施例48～51
实施例48、实施例49、实施例50按照表9处方将活性化合物式(IX)化合物、HP-β-CD、叔丁基对羟基茴香醚(BHA)、维生素E(VE)置于烧杯中，加入异丙醇，将其搅拌均匀后，缓慢向其中加入一定量的纯化水，得到澄清溶液后将其冻干。实施例51仅用定量纯化水分散活性化合物后进行冻干。考察在冻干工艺下，不同辅料对杂质的影响。实施例48～51的主成分及杂质含量数据见表10。
表9

表10
结果表明，实施例48和实施例51的有关物质无明显变化，HP-β-CD的加入不会影响活性化合物的稳定性。
实施例49与实施例48相比，加入抗氧剂BHA的实施例490时的最大单杂达到2.03％。经过60℃ 5天稳定性考察，实施例49、实施例50与实施例48相比，主成分含量均有不同程度的降低。添加抗氧剂BHA或者VE不利于活性化合物滴眼液的稳定性。
实施例52～63
按照表11处方比例，称取活性化合物式(IX)化合物并搅拌分散在异丙醇中，搅拌至溶液澄清。边搅拌边缓慢加入HP-β-CD至溶液澄清。边搅拌边向异丙醇溶液中缓慢加入处方比例的纯化水，搅拌1h得澄清溶液。将上述溶液于真空冷冻干燥机中，冻干得疏松的白色冻干粉，冻干曲线如表12。取包合物冻干粉，加入复溶介质溶解，先后用0.45μm、0.22μm混合滤膜过滤得活性化合物滴眼液，灌装于样品包装中，每瓶2ml。即得滴眼液。
多剂量包装滴眼液需要添加抑菌剂，避免使用过程中被微生物污染。通过实施例52、实施例55和实施例56来考察苯扎氯铵和醋酸氯己定这两种抑菌剂对处方稳定性的影响。将实施例52、实施例55和实施例56避光置于25℃和40℃考察5天滴眼液的初步稳定性，结果见表13。从杂质增长的个数与增长水平来评估，与实施例57相比，实施例56的短期稳定性较好，抑菌剂醋酸氯己定更为适合活性化合物滴眼液。
实施例53、实施例54分别包装于低密度聚乙烯药用滴眼剂瓶(PE)、棕色聚酯药用滴眼剂瓶(PET)以及安瓿瓶中，避光置于25℃考察初步的包材相容性，稳定性数据见表14。异丙醇冻干工艺生产的实施例52长期放置出现析晶。不同包装系统的实施例53和实施例54在25℃放置15天，滴眼液无析晶，杂质无明显变化。
实施例57～60复溶时，使用稀盐酸、稀氢氧化钠来调节pH，考察活性化合物式(IX)化合物滴眼液适宜的酸碱度。实施例57～60在60℃ 5天的稳定性结果见表15。结果表明，滴眼液在偏碱性条件下稳定性优于酸性条件下的稳定性。
实施例61～63的稳定性数据见表16。与实施例61相比，实施例62的有关物质没有明显变化，抑菌剂醋酸氯己定的加入不会影响活性化合物式(IX)化合物滴眼液的稳定性。实施例63与实施例62相比，有关物质无明显变化，促溶剂HP-β-CD加入量的增加不会影响活性化合物的稳定性。
表11
表12

表13
表14

表15
表16
实施例64～67
按照表17处方比例，将纯化水30g加热至80℃，称取羟丙基-β-环糊精(HP-β-CD)、磺丁基-β-环糊精(SBE-β-CD)搅拌下少量多次加入上述纯化水中溶解。分别称取处方量的活性化合物式(IX)化合物，搅拌下少量多次加入环糊精溶液中，其中实施例64、实施例66和实施例67中活性化合物可以在2h内完全溶解。在实施例64～66中加纯化水至60ml定容并搅拌均匀。将上述溶液封装入中硼硅玻璃安瓿中，4ml/支，共装10支。即得滴眼液。
将实施例64和实施例66置于80℃水浴中避光加热，分别于0.5、1、2、4、6h取出2支安瓿瓶，送样测定含量及有关物质。结果见表18。
实施例64在80℃考察0.5、1和2h后有关物质增加分别为0.03％、0.10％和0.21％；实施例66在80℃考察0.5、1和2h后有关物质增加分别为0.30％、0.47％和0.57％。与实施例64相比，含有SBE-β-CD的实施例66的热稳定性更差。
表17
表18
实施例68～91
按照表19处方比例制备实施例68～87，称取活性化合物式(IX)化合物和HP-β-CD置于10ml西林瓶中，加入处方比例的纯化水，在不同水浴温度搅拌或振摇至溶解，比较不同浓配工艺条件对活性化合物的溶解情况。通过实施例79稀释1倍、5倍获得实施例88、实施例89。通过实施例80稀释1倍、5倍获得实施例90、实施例91。
实施例69、实施例70、实施例75～83、实施例85、实施例86在表19的浓配条件下，活性化合物式(IX)化合物可以在较短时间内完全溶解。在浓配工艺条件下，HP-β-CD用量、HP-β-CD浓配浓度和浓配温度对活性化合物溶解过程影响较大。
表19
考察表20所列实施例的活性化合物包合物水溶液稳定性及实施例80的光稳定性。结果见表21、表22和表23。
试验结果表明，经60℃考察10天和25℃、30℃、40℃考察20天后活性化合物含量基本保持稳定，显示实施例67、实施例78～80、实施例88～91的含有活性化合物的环糊精水溶液热稳定性尚可；实施例80在影响因素试验光照条件下考察5天即出现黄色沉淀，表明含有活性化合物的环糊精水溶液对强光不稳定。
表20

表21
表22

表23
实施例92
按照表24处方比例配制实施例92。在烧杯中加入一定量纯化水，水浴加热至70℃，加入HP-β-CD并搅拌溶解后，加入活性化合物式(IX)化合物并70℃水浴搅拌60min至完全溶解；将溶液转入100ml容量瓶中，用纯化水少量多次冲洗烧杯，冲洗水一并转入容量瓶，加醋酸氯己定，振摇溶解。依次加入无水磷酸氢二钠、磷酸二氢钠一水合物、氯化钠，振摇溶解，加纯化水定容至100ml。依次经0.45μm、0.22μm混合膜过滤，将滤液按照5ml/支灌封于5ml中硼硅玻璃安瓿。即得滴眼液。
实施例92滴眼液分别经115℃灭菌30min，121℃灭菌15min和121℃灭菌30min，检测样品的性状、pH和有关物质，结果见表25。实施例92置于60℃考察，分别于0、5、10天取样检测样品性状、含量和有关物质，试验结果见表26。
表24
表25

表26
结果表明，实施例92经不同条件灭菌后有关物质明显增加，115℃灭菌30min样品总杂增加1.507％，121℃灭菌15min和30min样品总杂分别增加1.687％和2.195％。实施例92的热稳定性不佳，不可以耐受湿热灭菌。实施例92经60℃考察5、10天后，有关物质分别有所增加，其他指标基本保持稳定。
实施例93
按照表27处方比例配制实施例93。100ml烧杯中加入纯化水21.86g，加热至60℃，加入HP-β-CD搅拌溶解后，加入活性化合物式(IX)化合物并升温至70℃搅拌60min至完全溶解；将溶液转入500ml容量瓶中，用约200g纯化水少量多次冲洗烧杯，冲洗水一并转入容量瓶，加醋酸氯己定并振摇溶解后，依次加入无水磷酸氢二钠、磷酸二氢钠一水合物、氯化钠，振摇溶解并加纯化水定容至500ml，摇匀，根据质量体积比算得该溶液密度为1.0166g/ml。将溶液按照5ml/支灌封于5ml中硼硅玻璃安瓿，即得滴眼液。
将实施例93置于室内40瓦日光灯下约1.5m处放置，分别于0、2、4和6h取样检测样品性状、pH和有关物质，试验结果见表28。结果表明，实施例93在室内日光灯下约1.5m处放置6h基本保持稳定，生产中配液及灌装均可在室内正常光照下进行。
表27

表28
实施例94～96
称取10.00g纯化水置于50ml烧杯中并水浴加热至75℃，按照表29的处方量加入HP-β-CD，搅拌至溶解后，边搅拌边加入活性化合物式(IX)化合物直至溶解。将含有活性化合物的环糊精溶液加入到含有126ml纯化水的500ml烧杯中，并用纯化水多次冲洗50ml烧杯，冲洗液一并转入500ml烧杯中。醋酸氯己定加入500ml烧杯，搅拌至溶解后，依次加入氯化钠、磷酸二氢钠一水合物、无水磷酸氢二钠，搅拌至溶解后，加水至250ml，搅匀，先后过0.45μm、0.22μm混合滤膜，即得实施例94。
实施例94的pH为7.75。取实施例94溶液，分别用1mol/L HCl和5mol/L NaOH调节pH至6.96得实施例95；调节pH至8.54得实施例96。实施例94滴眼液分别经115℃灭菌30min，121℃灭菌15min和121℃灭菌30min，检测样品的性状、pH和有关物质，结果见表30。将实施例94、实施例95和实施例96滴眼液分别灌装于5ml安瓿瓶中，并置于60℃考察，分别于0、5、10天取样检测样品性状、含量和有关物质，试验结果见表31。
结果表明，实施例94经不同条件灭菌后有关物质明显增加。实施例94的热稳定性不佳，不可以耐受湿热灭菌。pH8.54的实施例96的样品稳定性最好。另外考虑到滴眼液的合理pH范围在6～8，实施例94滴眼液的pH更为合适。
表29

表30
表31
实施例97～98
称取10.00ml′纯化水置于50ml烧杯中并水浴加热至75℃，按照表32的处方量加入HP-β-CD，搅拌至溶解后，边搅拌边加入活性化合物直至溶解。将含有活性化合物式(IX)化合物的环糊精溶液加入到含有126ml纯化水的500ml烧杯中，并用纯化水多次冲洗50ml烧杯，冲洗液一并转入500ml烧杯中。醋酸氯己定加入500ml烧杯，搅拌至溶解后，依次加入氯化钠、磷酸二氢钠一水合物、无水磷酸氢二钠，搅拌至溶解后，加水至250ml，搅匀，先后过0.45μm、0.22μm混合滤膜，即得实施例97、实施例98。
测定实施例94、实施例97和实施例98的渗透压，结果见表33。实施例94、实施例97和实施例98的滴眼液处于接近等渗略微低渗的状态。
表32

表33
实施例99～102
按照表34处方比例，生产制备实施例99～102。
生产工艺：
浓溶液配制：将处方量注射用水加入烧杯中，将烧杯放至数控加热型磁力搅拌器上进行加热，控制水温为77℃±2℃，搅拌状态下少量多次加入HP-β-CD。
待HP-β-CD溶解完全后，保持搅拌状态，一次性加入处方量的活性化合物，控制溶液温度在77℃±2℃，搅拌至溶液完全澄清。
浓溶液稀释定容：称量7.5kg 20℃～25℃的注射用水至不锈钢桶中，开启搅拌机搅拌，将浓溶液加入至不锈钢桶中，取约少量20℃～25℃的注射用水，分4～6次润洗配制浓溶液的烧杯，润洗液全部转移至不锈钢桶，搅拌均匀。依次加入处方量氯化钠、磷酸二氢钠一水合物、无水磷酸氢二钠，搅拌溶解。用20℃～25℃的注射用水将溶液定容至15L，搅拌均匀。取样进行中间体性状、含量、pH值、渗透压检测。检测结果见表35。
过滤灌装：生产开始前对滤芯进行完整性测试，并对配液罐及吹灌封一体机及其物料输送管道进行冲洗及在线蒸汽灭菌，保持≥121℃纯蒸汽灭菌30min。调试设备后，开始进行过滤灌装。生产结束后对滤芯进行完整性测试。
冲裁：将所有冲裁后的产品进行检漏，再逐支检查并剔除不合格产品。
外包：对所有冲裁合格产品进行灯检，并剔除不合格品。并对检漏和灯检合格的冲裁产品进行枕式包装。并用真空恒温干燥箱对所有包装好的样品进行热封效果检测。从热封合格的成品中取样送检，进行成品性状、含量、pH值、渗透压检测。检测结果见表35。
结果表明，实施例99～102的处方比例及制备工艺可以生产出性状、含量、pH值、渗透压符合2020版药典规定的滴眼液及滴眼剂安慰剂。
表34
表35
实施例103
按照表36处方比例，称取磺丁基-β-环糊精(SBE-β-CD)溶解于磷酸盐缓冲液。将处方量式(IX)化合物溶解于0.15ml的二甲基亚砜后，再加入到磺丁基-β-环糊精(SBE-β-CD)磷酸盐缓冲液，并持续搅拌后得澄清溶液。
实施例103中磺丁基-β-环糊精的用量多，并且二甲基亚砜具有局部毒性作用和低的全身毒性，并不适合用于滴眼液。与辅料组成简单且未加入二甲基亚砜的实施例66、67相比，实施例103的稳定性差，安全性风险更高。
表36
实施例104化合物(IX)的制备
合成路线：
步骤1：化合物2的制备
将化合物1(30g，130.4mmol，1eq)，双联嚬哪醇硼酸酯(66.23g，260.80mmol，2eq)，[1，1-双(二苯基膦基)二茂铁]二氯化钯(II)二氯甲烷加合物(5.32g，6.52mmol，0.1eq)和乙酸钾(25.60g，260.80mmol，2eq)加入到甲苯(500mL)中，氮气置换3次，反应液在110℃搅拌15小时。反应完毕后，将反应液垫硅藻土过滤，滤液浓缩，残余物经柱层析(石油醚∶乙酸乙酯＝0至100∶6)纯化得到化合物2。1H NMR(400MHz，CDCl3)δ7.84(d，J＝8.0Hz，1H)，7.06(s，1H)，7.04(d，J＝8.0Hz，1H)，5.65(brs，2H)，3.87(s，3H)，1.35(s，12H)。
步骤2：化合物4的制备
将化合物3(100g，460.79mmol，1eq)溶于无水乙醇(1L)中后，加入浓硫酸(225.97g，2.30mol，122.81mL，5eq)和无水硫酸钠Na2SO4(65.45g，460.79mmol，46.75mL，1eq)，反应液在85℃搅拌反应48小时。反应完毕后，反应液冷却至室温。将饱和碳酸氢钠水溶液(1L)滴加到反应液中，有大量固体生成，过滤，滤饼用水(500mL)洗涤，所得固体经真空干燥得到化合物4。1H NMR(400MHz，CDCl3)δ8.10(d，J＝1.8Hz，1H)，7.26(s，1H)，4.47(q，J＝7.1Hz，2H)，1.46(t，J＝7.2Hz，3H)。
步骤3：化合物5的制备
将化合物4(70.00g，285.63mmol，1eq)溶于四氢呋喃(1L)，氮气保护下，冷却至-78℃，甲基锂(1.6M，892.59mL，5eq)缓慢滴加到反应液中，反应液在-78℃下搅拌3小时。反应完毕后，缓慢滴加水(100mL)淬灭反应，升至室温，加入饱和氯化铵水溶液(500mL)稀释，并用乙酸乙酯(500mL*3)萃取。有机相合并，用无水硫酸钠干燥，减压浓缩得到粗品。粗品用正庚烷(500mL)打浆，过滤，干燥得到化合物5。1H NMR(400MHz，CDCl3)δ7.86(d，J＝1.9Hz，1H)，6.98(d，J＝1.9Hz，1H)，4.57(br s，2H)，1.57(s，6H)。
步骤4：化合物6的制备
将化合物5(10g，43.27mmol，1eq)，化合物2(23.98g，86.55mmol，2eq)，[1，1-双(二苯基膦基)二茂铁]二氯化钯(II)二氯甲烷加合物(1.77g，2.16mmol，0.05eq)，碳酸铯(28.20g，86.55mmol，2eq)加入到二氧六环(300mL)和水(75mL)中，氮气置换3次，反应液在80℃搅拌5小时。反应完毕后，反应液浓缩，残余物经柱层析(石油醚∶四氢呋喃＝0至100∶40)得到粗品化合物6。将此粗品用四氢呋喃(4mL/g)加热至80℃，冷却重结晶，25℃搅拌15小时，过滤，滤饼干燥得到化合物6。1H NMR(400MHz，DMSO-d6)δ7.94(d，J＝2.0Hz，1H)，7.77(d，J＝8.0Hz，1H)，7.17(d，J＝2.0Hz，1H)，6.99(d，J＝1.6Hz，1H)，7.77-7.75(m，3H)，5.69(s，2H)，5.50(s，1H)，3.81(s，3H)，1.52(s，6H)。
步骤5：式(IX)化合物的制备
将化合物6(8.78g，29.14mmol，1eq)溶于四氢呋喃(80mL)中，氮气保护下冷却至0℃。将甲基溴化镁(3M，97.12mL，10eq)滴加到反应液中，0℃搅拌反应1小时。反应完毕后，缓慢加饱和氯化铵水溶液(400mL)淬灭反应，用乙酸乙酯(400mL*2)萃取，有机相减压浓缩，残余物经将此粗品用二氯甲烷(3mL/g)25℃纯化，过滤干燥得到产物，分子量301.40。1H NMR(400MHz，DMSO-d6)δ7.88(d，J＝1.8Hz，1H)，7.15-7.01(m，2H)，6.82(d，J＝1.6Hz，1H)，6.69(dd，J＝1.5，8.0Hz，1H)，5.59(br s，2H)，5.51(br s，2H)，5.44(s，1H)，5.23(s，1H)，1.51(d，J＝3.6Hz，12H)。称取11.9g上述产物加入到圆底烧瓶中，加入150mL的甲基叔丁基谜，将上述样品置于50℃搅拌12小时，再降温至25℃下搅拌4小时。过滤烘干，得到式(IX)化合物固体。进一步称取大约50mg上述式(IX)化合物加入到2.0mL玻璃小瓶中，加入适量的溶剂或溶剂混合物，使其成悬浊液。加入磁子后，将上述样品置于磁力加热搅拌器上(25℃/50℃)进行搅拌一周，离心后将所得的固体样品置于40℃真空干燥箱中，干燥过夜，得到式(IX)化合物。分子式C17H23N3O2·H2O，分子量319.40。
上述式(IX)化合物的XRPD图谱解析数据如表37所示，图谱如图1所示。式(IX)化合物的差示扫描量热曲线分别在101.7±3.0℃和158.7±3.0℃有一个吸热峰的起始点，如图2所示。其热重分析曲线在120.00℃±3.0℃时失重达5.477％，如图3所示。
表37式(IX)化合物的XRPD图谱解析数据
实施例105～107
按照表38处方比例，生产制备实施例105～107。
生产工艺：
浓溶液配制：将处方量注射用水加入烧杯中，将烧杯放至数控加热型磁力搅拌器上进行加热，控制水温为77℃±2℃，搅拌状态下少量多次加入HP-β-CD。
待HP-β-CD溶解完全后，保持搅拌状态，一次性加入处方量的活性化合物，控制溶液温度在77℃±2℃，搅拌至溶液完全澄清。
浓溶液稀释定容：称量7.5kg 20℃～25℃的注射用水至不锈钢桶中，开启搅拌机搅拌，将浓溶液加入至不锈钢桶中，取约少量20℃～25℃的注射用水，分4～6次润洗配制浓溶液的烧杯，润洗液全部转移至不锈钢桶，搅拌均匀。依次加入处方量氯化钠、磷酸二氢钠一水合物、无水磷酸氢二钠，搅拌溶解。用20℃～25℃的注射用水将溶液定容至15L，搅拌均匀。
过滤灌装：生产开始前对滤芯进行完整性测试，并对配液罐及吹灌封一体机及其物料输送管道进行冲洗及在线蒸汽灭菌，保持≥121℃纯蒸汽灭菌30min。调试设备后，开始进行过滤灌装。生产结束后对滤芯进行完整性测试。
冲裁：将所有冲裁后的产品进行检漏，再逐支检查并剔除不合格产品。
外包：对所有冲裁合格产品进行灯检，并剔除不合格品。并对检漏和灯检合格的冲裁产品进行枕式包装。并用真空恒温干燥箱对所有包装好的样品进行热封效果检测。
结果表明，实施例105～107的处方比例及制备工艺可以生产出质量可控，性质稳定的产品。
表38
实验例1：小鼠干眼症模型的影响试验研究
实验目的：
通过下肢皮下注射氢溴酸东莨菪碱溶液诱发C57BL/6小鼠干眼症模型来考察实施例105、实施例106、实施例107对该模型的治疗效果。
实验过程：
根据泪液分泌量将动物随机均衡分为5组，分别为阴性对照组(生理盐水，G1)、模型对照组(溶媒，实施例102，G2)、低浓度组(1mg/mL)(实施例105，G3)、中浓度组(2.5mg/mL)(实施例106，G4)、高浓度组(5mg/mL)(实施例107，G5)，每组8只动物，全部雌性。
各组动物均于D1双侧下肢皮下交替注射5mg/mL的氢溴酸东莨菪碱溶液，4次/日，0.1mL/次，每次间隔约3小时，连续12天(D12给药3次)，阴性对照组动物双侧下肢皮下注射等体积生理盐水，需避免同一个注射点连续多次注射。
各受试物组动物均于D1双眼滴眼给药，3μL/眼/次，4次/日，给药间隔约3小时，共给药12天(D12给药3次)，阴性对照组及模型对照组动物双眼滴眼给予等体积溶媒。分别于D7、D12第二次给药后约30min进行双眼泪液分泌量测定，于D7、D12第三次给药后约30min进行角膜荧光染色评分。于D12指标测定完毕后采用颈椎脱臼法对动物进行安乐死。
实验结果：
低浓度组(1mg/mL)、中浓度组(2.5mg/mL)、高浓度组(5mg/mL)对氢溴酸东莨菪碱溶液诱发的小鼠干眼症模型均具有良好的治疗作用，其主要改善干眼症模型小鼠的泪液分泌量和角膜损伤情况。综合泪液分泌量(表39、图4)及角膜荧光染色(表40、图5)评分结果判断，高浓度组(5mg/mL)治疗效果最优。
表39考察干眼症模型小鼠泪液分泌量的影响

注：与D0比较，#P＜0.05；##P＜0.01；与G1组比较，*P＜0.05；**P＜0.01；与G2组比较，&P＜0.05；
&&P＜0.01。
表40考察干眼症模型小鼠角膜荧光染色评分的影响

注：与D0比较，#P＜0.05；##P＜0.01；与G1组比较，*P＜0.05；**P＜0.01；与G2组比较，&P＜0.05；
&&P＜0.01。
实验结论：
实施例105、实施例106、实施例107可以对氢溴酸东莨菪碱溶液诱发的小鼠干眼症模型均具有良好的治疗作用，其主要改善干眼症模型小鼠的泪液分泌量和角膜损伤情况。
实验例2：大鼠高渗干眼症模型的影响试验研究
实验目的：
通过高渗氯化钠溶液滴眼诱发SD大鼠干眼症模型来考察实施例105、实施例107对该模型的治疗效果。
实验过程：
选择适应性观察合格的雌性SD大鼠20只，对动物进行双眼角膜荧光染色评分及泪液分泌量测定，剔除角膜有问题荧光染色异常及双眼泪液分泌量差异较大的动物。选用双眼泪液分泌量差异显著的动物进行分组，根据动物双眼泪液分泌量均值将动物随机均衡分为3组，分别为模型对照组(实施例102，G1)、低浓度组(1mg/mL)(实施例105，G2)、高浓度组(5mg/mL)(实施例107，G3)，每组4例动物，8只眼，分组当天记为D0。
各组动物均于D1造模，使用移液器吸取20μL氯化钠溶液(渗透压为500mOsmol/L)滴入动物双眼结膜囊，5次/日，20μL/次，每次间隔约为2h，连续21天，滴入后被动闭合动物眼睑约90s。
各组动物均于D1滴眼给药，10μL/眼/次，4次/日，给药间隔约3小时，共给药21天，给药期间每周称重1次。于D0、D14、D21对动物进行双眼角膜荧光染色评分、泪液分泌量测定和泪膜破裂时间测定。
实验结果：
低浓度组(1mg/mL)、高浓度组(5mg/mL)相对模型对照组可增加干眼症模型大鼠泪液分泌量，降低角膜荧光染色评分，改善泪膜破裂时间。具体结果见表41、42、43和图6、7和8。
表41干眼症模型大鼠泪液分泌量的影响

注：与G1组比较，*P＜0.05；**P＜0.01。
表42干眼症模型大鼠角膜荧光染色评分的影响

注：与G1组比较，*P＜0.05；**P＜0.01。
表43泪膜破裂时间

注：与G1组比较，*P＜0.05；**P＜0.01
实验结论：
低浓度组(1mg/mL)、高浓度组(5mg/mL)可以对高渗氯化钠溶液诱发的大鼠干眼症模型具有良好的治疗作用，主要表现为连续滴眼给药约2周后可明显改善干眼症模型大鼠的泪液分泌量、角膜损伤情况以及泪膜稳定性。
实验例3：考察在新西兰兔眼部的药代动力学研究
选择适应性观察合格的6只新西兰兔，分为2组，每组3只，分别为0.5h采样组和2h采样组，各组动物于左眼滴眼给药，给予5mg/mL(实施例107)，各试验组给药体积均为100μl/眼，分别于给药后0.5h和2h采集各组动物的血浆、角膜组织、结膜组织、视网膜组织样品，采用LC-MS法对生物样品中活性成分的浓度进行测定，具体结果见表44、表45。
表44活性成分在各生物样品中的浓度
表45活性成分在各眼部组织与血浆中的浓度比
实验结果表明，给予实施例107眼部给药后，活性成分在眼表组织角膜与结膜中有较高浓度分布，有利于眼表疾病的治疗；活性成分在眼底组织视网膜中的分布浓度较低，引发眼底不良反应的风险较小。因此，实施例107的药动学性质，有利于眼表疾病的治疗。
实验例4：对豚草花粉诱导小鼠过敏性结膜炎模型的影响试验研究
实验目的：
通过采用豚草花粉足垫皮下注射致敏和滴眼局部激发的方法制备过敏性结膜炎小鼠模型。检测小鼠眼部临床症状，眼部观察评分，病理HE，评价低浓度组(1mg/mL)(实施例105)、中浓度组(2.5mg/mL)(实施例106)、高浓度组(5mg/mL)(实施例107)对过敏性结膜炎小鼠的治疗作用。
实验过程：
1.1动物
健康的BALB/c小鼠，5-7周龄，50只，雌雄各半
1.2主要试剂配置
1.2.1造模致敏药物(豚草花粉跗关节注射液)的配制：称22.3mg豚草花粉溶于7.25ml的明矾佐剂；
1.2.2造模激发药物(豚草花粉滴眼液)的配制：称取168mg豚草花粉溶于1.12ml PBS中；称取189mg豚草花粉溶于1.26ml PBS(磷酸盐缓冲液)中；称取144mg豚草花粉溶于0.96ml PBS中.
1.2.3受试物
低浓度组(1mg/mL)(实施例105)、中浓度组(2.5mg/mL)(实施例106)、高浓度组(5mg/mL)(实施例107)，空白组(实施例102)。
1.3动物分组、造模和模型验证
(1)空白组(实施例102)(溶媒处理：4次/只/d，单次剂量：20μL，滴眼给药，连续4d)(N＝10)
(2)过敏性结膜炎模型组(本实验中又称模型组)(溶媒处理，4次/只/d，单次剂量：20μl，滴眼给药，连续4d)(N＝10)
(3)低浓度组(1mg/mL)组(低浓度组(1mg/mL)处理，4次/只/d，单次剂量：20μL，滴眼给药，连续4d)(N＝10)
(4)中浓度组(2.5mg/mL)组(中浓度组(2.5mg/mL)处理，4次/只/d，单次剂量：20μL，滴眼给药，连续4d)(N＝10)
(5)高浓度组(5mg/mL)组(高浓度组(5mg/mL)处理，4次/只/d，单次剂量：20μL，滴眼给药，连续4d)(N＝10)
造模：第0天时，在小鼠足垫皮下注射豚草花粉跗关节致敏注射液，65μL/只；第10-13天，豚草花粉滴眼液滴至模型组小鼠右眼进行激发，10μL/只/次，每天1次，连续4天。
1.4动物给药
于每次滴眼激发后30min开始进行药物干预治疗，每天4次，连续4d。空白组、模型组给予等量溶媒处理；供试药物治疗组给予相应剂量的化合物处理；给药按照剂量20μL/只，分为两次，10μL/次，间隔1min，4次/只/d，连续4d。
1.5检测指标
1.5.1临床症状评估
末次激发后30min内，显微镜下观察小鼠眼部临床症状，眼部观察评分：观察眼部的过敏反应，包括结膜水肿、结膜充血，根据严重程度(包括无、轻度、中度和重度)评分分别记为0-3分。结膜水肿评分标准：轻度局限性的结膜水肿为1分；弥散水肿、穹窿部受累为2分；结膜水肿致结膜囊浅窄为3分。结膜充血评分标准：轻度弥散的血管充血为1分；弥散充血、近穹窿部明显为2分；充血伴结膜下出血3分。
1.5.2 HE染色
实验流程：切取动物右眼连带眼睑组织，先将样品置于4％多聚甲醛常温固定4小时，取出组织流水冲洗数小时，经70％、80％、90％各级乙醇溶液脱水后再用纯酒精和二甲苯等量混合的溶液处理15min，再经二甲苯溶液透化两次，每次各15min，至样品透明为止。放入二甲苯和石蜡各半的混合液15min，再放入石蜡I、石蜡II各透蜡60min。石蜡包埋后，将样品按照预先选择的切面方向进行切片。将石蜡切片进行烤片、脱蜡和水化。将水化后的切片放入苏木精水溶液中染色3min，盐酸乙醇分化液分化15s，稍水洗，返蓝液返蓝15s，流水冲洗，伊红染色3min，流水冲洗，脱水，透明，封片，镜检。
1.6统计学分析
实验数据利用GraphPad Prism 5和IBM SPSS Statistics 19.0软件对各组进行样本单因素(One-wayANOVA)统计学分析(*p＜0.05，**p＜0.01)。
实验结果：
2.1药物对小鼠眼部临床症状的影响
在结膜水肿和结膜充血中，与空白组相比，模型组评分明显升高；与模型组比较，低浓度组(1mg/mL)、中浓度组(2.5mg/mL)、高浓度组(5mg/mL)能显著性降低评分(p＜0.05或p＜0.01)，改善结膜水肿和结膜充血情况。以上结果提示，低、中、高浓度组对豚草花粉诱导的过敏性结膜炎小鼠有改善结膜水肿和结膜充血的作用。具体试验结果见图9、10。
表45：低浓度组、中浓度组、高浓度组过敏性结膜炎小鼠临床症状评分
(均值±SEM)

注：与模型组比较，*p＜0.05，**p＜0.01。
2.2药物对过敏性结膜炎小鼠组织病理的影响
病理结果显示：空白组眼结膜完整，未见明显损伤现象，个别样本可见血管充血，伴有少量炎性细胞浸润；模型组可见眼结膜不同程度的增厚或变薄现象，结膜上皮细胞排列紊乱，炎性细胞浸润明显，结膜下未见明显毛细血管增生及充血现象。低浓度(1mg/mL)组结膜结构较为完整，可见部分样本少量炎性细胞浸润及充血现象；中浓度(2.5mg/mL)组中可见结膜上皮细胞脱落结，亦可见结膜增厚，仍存在少量炎性细胞浸润及充血现象；高浓度(5mg/mL)组部分样本结膜上皮细胞排列不规则，有变薄现象，可见少量炎性细胞浸润及充血样本；以上结果提示低、中、高浓度组可以改善过敏性结膜炎小鼠的结膜结构异常和炎症细胞浸润。试验结果见图11所示。
实验结论：低、中、高浓度组可以对豚草花粉诱导小鼠过敏性结膜炎模型具有良好的治疗作用，其主要改善过敏性结膜炎小鼠的结膜水肿和结膜充血，减少结膜结构异常和炎症细胞浸润。

Claims (40)

  1. 一种含有吡啶苯基类化合物的眼用制剂，其特征在于，所述眼用制剂包括活性成分吡啶苯基类化合物及辅料，其中，
    所述辅料包括促溶剂、pH调节剂、渗透压调节剂，或它们中两种或两种以上组合，
    所述活性成分吡啶苯基类化合物包括式(II)通式化合物、其异构体或其药学上可接受的盐；
    其中，
    所述选自单键或双键；
    T1、T2、T3和T4分别独立地选自N、C或CR1；
    T5选自C、CR5或C＝O；
    T6选自C、CR6或N；
    T7选自N或CR7；
    当T5选自C＝O，T6选自N时，所述选自单键；
    L选自单键、-O-、-S-、-NR2-或-(CR3R4)n-；
    R1选自H、F、Cl、Br、I、OH或NH2；
    R2选自H、任选被1、2或3个Ra取代的C1-3烷基；
    R3和R4分别独立地选自H、F、Cl、Br、I、OH、NH2、CN或任选被1、2或3个Rb取代的C1-3烷基；
    R5、R6和R7分别独立地选自H、F、Cl、Br或I；
    n选自1、2或3；
    Ra和Rb分别独立地选自H、F、Cl、Br、I、OH、NH2、CN或CH3。
  2. 根据权利要求1所述的眼用制剂，其特征在于，所述式(II)通式化合物、其异构体或其药学上可接受的盐，其中，所述R2选自H、CH3或CH2CH3，所述CH3和CH2CH3任选被1、2或3个Ra取代。
  3. 根据权利要求2所述的眼用制剂，其特征在于，所述式(II)通式化合物、其异构体或其药学上可接受的盐，其中，所述R2选自H、CH3或CH2CH3。
  4. 根据权利要求1～3任意一项所述的眼用制剂，其特征在于，所述式(II)通式化合物、其异构体或其药学上可接受的盐，其中，所述R3、R4分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、CH3或CH2CH3，所述CH3或CH2CH3任选地被1、2或3个Rb取代。
  5. 根据权利要求4所述的眼用制剂，其特征在于，所述式(II)通式化合物、其异构体或其药学上可接受的盐，其中，R3和R4分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、CH3或CH2CH3。
  6. 根据权利要求5所述的眼用制剂，其特征在于，所述式(II)通式化合物、其异构体或其药学上可接受的盐，其中，L选自单键、-O-、-S-、-NH-、-(CH2)2-或-CH2-。
  7. 根据权利要求1～6任意一项所述的眼用制剂，其特征在于，所述式(II)通式化合物、其异构体或其药学上可接受的盐，其选自：
    其中，
    T3、T4分别独立地选自N或CR1；
    R1和L如权利要求1～6任意一项所定义。
  8. 根据权利要求7所述的眼用制剂，其特征在于，所述式(II)通式化合物、其异构体或其药学上可接受的盐，其选自

    其中，
    R1和L如权利要求7所定义。
  9. 根据权利要求8所述的眼用制剂，其特征在于，所述式(II)通式化合物、其异构体或其药学上可接受的盐，其选自：
  10. 根据权利要求1所述的眼用制剂，其特征在于，所述辅料还包括抑菌剂、抗氧剂、冻干溶剂、或它们中的两种或两种以上组合。
  11. 根据权利要求10所述的眼用制剂，其特征在于，所述抗氧剂选自丁基羟基茴香醚、或维生素E，或它们组合。
  12. 根据权利要求10所述的眼用制剂，其特征在于，所述抑菌剂选自苯扎氯铵、醋酸氯已定、醋酸苯汞，或它们中的两种或两种以上的组合。
  13. 根据权利要求1～12任一所述的眼用制剂，其特征在于，所述促溶剂选自甲基化-β-环糊精、羟丙基-β-环糊精、羟丙基-γ-环糊精、磺丁基-β-环糊精、泊洛沙姆407、吐温80、聚维酮、聚乙二醇、丙二醇、丙三醇，或它们中的两种或两种以上的组合。
  14. 根据权利要求1～12任一所述的眼用制剂，其特征在于，所述pH调节剂选自磷酸二氢钠一水合物、无水磷酸氢二钠、硼砂、硼酸、枸橼酸二水合物、盐酸、氢氧化钠，或它们中的两种或两种以上的组合。
  15. 根据权利要求1～12任一所述的眼用制剂，其特征在于，所述渗透压调节剂选自氯化钠、硼酸、硼砂、葡萄糖、甘露醇，或它们中的两种或两种以上的组合。
  16. 根据权利要求1～15任一所述的眼用制剂，其特征在于，所述眼用制剂包括吡啶苯基类化合物、一种或多种促溶剂、一种或多种pH调节剂、一种或多种渗透压调节剂、一种或多种抑菌剂、一种或多种抗氧剂，其中所述吡啶苯基类化合物包括式(III)、式(IV)、式(V)、式(VI)、式(VII)或式(VIII)化合物、其异构体或其药学上可接受的盐；
  17. 根据权利要求16所述的眼用制剂，其特征在于，所述式(III)化合物还包括式(III)的一水合物(式IX化合物)、其异构体或其药学上可接受的盐
  18. 根据权利要求1～17所述的眼用制剂，其特征在于，所述活性成分的含量为0.05～0.6％w/v，优选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、或0.55％w/v。
  19. 根据权利要求17所述的眼用制剂，其特征在于，所述促溶剂选自甲基化-β-环糊精、羟丙基-β-环糊精、羟丙基-γ-环糊精、磺丁基-β-环糊精、泊洛沙姆407、吐温80、聚维酮、聚乙二醇、丙二醇、丙三醇，或它们中的两种或两种以上的组合。
  20. 据权利要求19所述的眼用制剂，其特征在于，所述促溶剂的含量为0.2％～15％w/v，优选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、或9.9％w/v。
  21. 根据权利要求19所述的眼用制剂，其特征在于，所述羟丙基-β-环糊精的含量为0.5％w/v～12％w/v，优选0.7％w/v～10％w/v，更优选1％w/v～8％w/v，最优选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、或8％w/v。
  22. 根据权利要求18所述的眼用制剂，其特征在于，所述磺丁基-β-环糊精的含量为4％～13％，优选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、或12.5％w/v。
  23. 根据权利要求17所述的眼用制剂，其特征在于，所述pH调节剂的含量为0.12～20％w/v，优选0.2％w/v、0.25％w/v、0.3％w/v、0.35％w/v、0.4％w/v、0.47％w/v、0.5％w/v、0.6％w/v、0.7％w/v、0.8％w/v、0.81％w/v、0.9％w/v、1％w/v、2％w/v、3％w/v、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、或20％w/v。
  24. 根据权利要求21所述的眼用制剂，其特征在于，所述pH调节剂选自磷酸二氢钠一水合物、无水磷酸氢二钠，或它们两种的组合。
  25. 根据权利要求23所述的眼用制剂，其特征在于，所述磷酸二氢钠一水合物的含量为0.1％w/v～0.5％w/v，优选0.12％w/v～0.45％w/v，更优选0.15％w/v、0.2％w/v、0.25％w/v、0.3％w/v、0.35％w/v、或0.4％w/v。
  26. 根据权利要求22所述的眼用制剂，其特征在于，所述无水磷酸氢二钠的含量为0.3％w/v～1％w/v，优选0.4％w/v～0.9％w/v，更优选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、或0.81％w/v。
  27. 根据权利要求17所述的眼用制剂，其特征在于，所述渗透压调节剂的含量为0.1％～1％w/v，优选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、或0.95％w/v。
  28. 根据权利要求17所述的眼用制剂，其特征在于，所述渗透压调节剂选自氯化钠。
  29. 根据权利要求28所述的眼用制剂，其特征在于，所述氯化钠的含量为0.2％w/v～0.8％w/v，优选0.25％w/v～0.7％w/v，更优选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、或0.65％w/v。
  30. 根据权利要求17所述的眼用制剂，其特征在于，所述抑菌剂的含量为0.001％w/v～0.02％w/v，优选0.002％w/v～0.018％w/v，进一步优选0.003％w/v～0.016％w/v，最优选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、或0.015％w/v。
  31. 根据权利要求17所述的眼用制剂，其特征在于，所述抑菌剂选自苯扎氯铵、或醋酸氯已定。
  32. 根据权利要求31所述的眼用制剂，其特征在于，所述苯扎氯铵的含量为0.001％w/v～0.02％w/v，优选0.002％w/v～0.018％w/v，进一步优选0.003％w/v～0.016％w/v，最优选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、或0.015％w/v。
  33. 根据权利要求31所述的眼用制剂，其特征在于，所述醋酸氯已定的含量为0.001％w/v～0.02％w/v，优选0.002％w/v～0.018％w/v，进一步优选0.003％w/v～0.016％w/v，最优选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、或0.015％w/v。
  34. 根据权利要求17所述的眼用制剂，其特征在于，所述抗氧剂的含量为0.1％～0.8％w/v，优选0.2％w/v、0.3％w/v、0.4％w/v、0.5％w/v、0.6％w/v、或0.7％w/v。
  35. 根据权利要求17所述的眼用制剂，其特征在于，所述眼用制剂包括：
    式(IX)化合物及其异构体或其药学上可接受的盐，优选其含量为0.1％w/v～0.5％w/v；
    羟丙基-β-环糊精，优选其含量为0.7％w/v～3.5％w/v，优选1.75％w/v、3.5％w/v、或0.7％w/v；
    无水磷酸氢二钠，优选其含量为0.81％w/v；
    磷酸二氢钠一水合物，优选其含量为0.12％w/v；
    氯化钠，含量为0.25％w/v～0.45％w/v，优选0.27％w/v、0.36％w/v、0.4％w/v和；
    醋酸氯已定，优选其含量为0.01％w/v。
  36. 根据权利要求1～35所述的眼用制剂，其特征在于，所述眼用制剂的pH值范围为5.0～9.0，优选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、或8.9。
  37. 根据权利要求10所述的眼用制剂，其特征在于，所述冻干溶剂选自95％乙醇、叔丁醇、异丙醇、或乙腈。
  38. 根据权利要求1～37任一所述的眼用制剂的制备方法，所述制备方法采用旋蒸工艺、浓配稀释法、或冷冻干燥法。
  39. 根据权利要求1～37任一所述的眼用制剂，所述制剂为液体制剂，优选为滴眼液、洗眼剂或眼内注射溶液；眼用半固体制剂，优选为眼膏剂、眼用乳膏剂、眼用凝胶剂；或眼用固体制剂，优选为眼膜剂、眼丸剂、或眼内插入剂。
  40. 根据权利要求1～37任一所述的眼用制剂在制备治疗眼科疾病的药物中的用途，所述眼科疾病优选干眼症、过敏性结膜炎、黄斑变性、白内障、角膜圆锥、大疱性角膜病变、Fuch角膜内皮营养不良、眼部疤痕性类天疱疮、睑板腺功能障碍、葡萄膜炎、巩膜炎、Stevens-Johnson综合征、眼红斑痤疮、或综合征。
PCT/CN2023/133814 2022-11-26 2023-11-24 一种含有吡啶苯基类化合物的眼用制剂及其制备方法和应用 WO2024109905A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2023387378A AU2023387378A1 (en) 2022-11-26 2023-11-24 Ophthalmic formulation comprising pyridine phenyl compound, preparation method therefor, and use thereof
CN202380070800.8A CN119997941A (zh) 2022-11-26 2023-11-24 一种含有吡啶苯基类化合物的眼用制剂及其制备方法和应用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211479343 2022-11-26
CN202211479343.1 2022-11-26

Publications (1)

Publication Number Publication Date
WO2024109905A1 true WO2024109905A1 (zh) 2024-05-30

Family

ID=91195189

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/133814 WO2024109905A1 (zh) 2022-11-26 2023-11-24 一种含有吡啶苯基类化合物的眼用制剂及其制备方法和应用

Country Status (3)

Country Link
CN (1) CN119997941A (zh)
AU (1) AU2023387378A1 (zh)
WO (1) WO2024109905A1 (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108135907A (zh) * 2015-08-21 2018-06-08 奥尔德拉医疗公司 氘化化合物和其用途
CN108135867A (zh) * 2015-08-21 2018-06-08 奥尔德拉医疗公司 醛结合物和其用途
WO2020125659A1 (zh) 2018-12-18 2020-06-25 南京明德新药研发有限公司 用于视网膜疾病的化合物
CN111356451A (zh) * 2017-10-10 2020-06-30 奥尔德拉医疗公司 炎性病症的治疗
WO2022063325A1 (zh) * 2020-09-28 2022-03-31 南京明德新药研发有限公司 吡啶苯基类化合物的晶型及其制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108135907A (zh) * 2015-08-21 2018-06-08 奥尔德拉医疗公司 氘化化合物和其用途
CN108135867A (zh) * 2015-08-21 2018-06-08 奥尔德拉医疗公司 醛结合物和其用途
CN111356451A (zh) * 2017-10-10 2020-06-30 奥尔德拉医疗公司 炎性病症的治疗
WO2020125659A1 (zh) 2018-12-18 2020-06-25 南京明德新药研发有限公司 用于视网膜疾病的化合物
WO2022063325A1 (zh) * 2020-09-28 2022-03-31 南京明德新药研发有限公司 吡啶苯基类化合物的晶型及其制备方法

Also Published As

Publication number Publication date
AU2023387378A1 (en) 2025-06-19
CN119997941A (zh) 2025-05-13

Similar Documents

Publication Publication Date Title
DK2614838T3 (en) Diquafosol and hyaluronic acid or salts thereof for the treatment of dry eyes
US20070110812A1 (en) Ophthalmic composition for dry eye therapy
ES2972099T3 (es) Formulación oftálmica
JP2024037806A (ja) ４－（７－ヒドロキシ－２－イソプロピル－４－オキソ－４ｈ－キナゾリン－３－イル）－ベンゾニトリルの製剤
US20140256696A1 (en) Steroid conjugates
BR112020014265A2 (pt) Composições oftálmicas de uma vez ao dia de compostos de benzimidazol
AU2014239222A1 (en) Ophthalmic formulations
WO2023213182A1 (zh) 一种卡瑞斯汀的盐及其用途
US20220162170A1 (en) Crystalline forms of 4-(7-hydroxy-2-isopropyl-4-oxo-4h-quinazolin-3-yl)-benzonitrile and formulations thereof
WO2024109905A1 (zh) 一种含有吡啶苯基类化合物的眼用制剂及其制备方法和应用
CN111349036B (zh) 一种格隆溴铵的替代物及其制备方法和医药用途
US20240166691A1 (en) Prodrugs and compositions for ophthalmology applications
WO2017166888A1 (zh) 一种滴眼液及其制备方法与应用
CN114392235B (zh) 盐酸西替利嗪眼用脂质体、原位凝胶及其制备方法
US20230286924A1 (en) Crystalline forms of 4-(7-hydroxy-2-isopropyl-4-oxo-4h-quinazolin-3-yl)-benzonitrile and formulations thereof
JP2020536922A (ja) 眼疾患を治療するためのアザビシクロ及びジアゼピン誘導体
AU2022306163A1 (en) Composition containing loxoprofen sodium
CN118406048B (zh) 氘代乙酰克里定药物及用途
AU2021433515B2 (en) Prodrug of celecoxib, preparation method therefor and application thereof
CN107915752B (zh) 一种治疗白内障的药物及其制备方法
PT1927353E (pt) Medicamento para doenças corneais
TW202330510A (zh) 對老花眼等之治療或預防有用之含硫化合物
CN118765279A (zh) 治疗年龄相关性眼部疾病的化合物、组合物和方法
CN119235779A (zh) 一种包含芳基丙酸类化合物的滴眼液
AU2023346366A1 (en) Crystalline polymorph forms of a trpv1 antagonist and formulations thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23893994

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: AU2023387378

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2023387378

Country of ref document: AU

Date of ref document: 20231124

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2023893994

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2023893994

Country of ref document: EP

Effective date: 20250626