WO2024060373A1 - 一种s-(+)-氟比洛芬盐及其制备方法、药物组合物和用途 - Google Patents

一种s-(+)-氟比洛芬盐及其制备方法、药物组合物和用途 Download PDF

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WO2024060373A1
WO2024060373A1 PCT/CN2022/131059 CN2022131059W WO2024060373A1 WO 2024060373 A1 WO2024060373 A1 WO 2024060373A1 CN 2022131059 W CN2022131059 W CN 2022131059W WO 2024060373 A1 WO2024060373 A1 WO 2024060373A1
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flurbiprofen
salt
pharmaceutical composition
salt derivative
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石江涛
付海舰
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南京知和医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to but is not limited to the field of medical technology, and in particular to a preparation method and use of salts, stereoisomers, hydrates and solvates formed from S(+)-flurbiprofen and basic amino acids.
  • Flurbiprofen is a non-steroidal anti-inflammatory drug commonly used in clinical practice. Since it was put on the market in 1977, it has been widely used in rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, deformed arthritis, ankylosing spondylitis, etc. , it can also be used for the symptomatic treatment of soft tissue diseases (such as sprains and strains) and mild and moderate pain (such as dysmenorrhea, post-operative pain, toothache, etc.). It mainly works by inhibiting COX (cyclooxygenase) and is the most powerful propionic acid non-steroidal anti-inflammatory drug currently known. The anti-inflammatory effect and analgesic effect of flurbiprofen are the same as those of aspirin respectively. 250 times and 50 times more effective and tolerable than similar ibuprofen, and less toxic.
  • COX cyclooxygenase
  • Flurbiprofen is a chiral drug with a chiral center in the molecule and a pair of S-type and R-type enantiomers.
  • its racemate is used clinically.
  • the anti-inflammatory activity of flurbiprofen mainly comes from its (S)-enantiomer, while the (R)-enantiomer lacks significant cyclooxygenase inhibitory activity ( Japanese Patent Application Laid-Open No. 8-119859); in addition, the gastrointestinal side effects of the racemate are greatly enhanced by the presence of the (R)-enantiomer.
  • Flurbiprofen is a white or off-white crystalline powder at room temperature. It has good solubility in methanol, ethanol, acetone or ether, can be dissolved in acetonitrile, and is almost insoluble in water. It has low solubility, strong fat solubility, and low bioavailability, and flurbiprofen is pH-dependent solubility. The solubility of salts is greatly affected by pH.
  • flurbiprofen-related preparations currently on the market mostly use different APIs, such as flurbiprofen axetil for injections, flurbiprofen sodium for eye drops, etc. Therefore, it is necessary to develop new flurbiprofen derivatives to improve drug efficacy and meet all relevant formulation form requirements.
  • the invention provides a salt of S(+)-flurbiprofen and basic amino acids and a preparation method and pharmaceutical composition thereof.
  • the water solubility of the derivatives prepared by salting S(+)-flurbiprofen with basic amino acids is significantly higher than that of the salts formed with other salt-forming agents such as tromethamine, and the salt compounds of the present invention It has stronger anti-inflammatory and analgesic effects; in addition, it was unexpectedly discovered that the derivative prepared by forming a salt between S(+)-flurbiprofen and basic amino acids in the present invention significantly reduces the gastrointestinal side effects; when used as eye drops, The compounds of the present invention have better anti-inflammatory effects and lower eye irritation.
  • the invention provides a preparation method, pharmaceutical composition and use of a derivative, stereoisomer, hydrate or solvate of S(+)-flurbiprofen and a basic amino acid formed into a salt.
  • the present invention provides an S(+)-flurbiprofen salt derivative, hydrate or solvate represented by formula (I);
  • R is selected from basic amino acids, including but not limited to the following structures: D-arginine, D-lysine, D-histidine, D-ornithine, L-arginine, L-lysine, L-histidine, L-ornithine.
  • S(+)-flurbiprofen salt derivative has the following structure:
  • the present invention provides a preparation method of the above-mentioned S(+)-flurbiprofen salt, and the preparation method includes the following steps:
  • Racemic flurbiprofen forms a salt with S-1-phenylethylamine, and is separated and decomposed to obtain pure S(+)-flurbiprofen;
  • step (1) React the pure S(+)-flurbiprofen obtained in step (1) with a basic amino acid to obtain an S(+)-flurbiprofen salt derivative.
  • the preparation method includes the following steps:
  • the solvent used in the process of forming a salt with S-1-phenylethylamine is methanol, ethanol, ethyl acetate, butyl acetate, isopropyl acetate, isopropyl ether, dichloro One or a combination of methane, chloroform, tetrahydrofuran, acetone, acetonitrile, 1,4-dioxane, toluene, and xylene.
  • the solvent used for recrystallization and purification is methanol, ethanol, ethyl acetate, butyl acetate, isopropyl acetate, isopropyl ether, dichloromethane, chloroform, tetrahydrofuran, acetone, One or a combination of acetonitrile, 1,4-dioxane, toluene, xylene, water.
  • the organic solvent used in the desalting process is one or a combination of methanol, ethanol, ethyl acetate, butyl acetate, isopropyl acetate, isopropyl ether, dichloromethane, chloroform, toluene and xylene.
  • step (2) S(+)-flurbiprofen reacts with basic amino acids to obtain S(+)-flurbiprofen salt derivatives
  • the solvents used in the process are methanol, ethanol, and isopropyl.
  • step (2) the molar ratio of S(+)-flurbiprofen used in the salt formation process and the basic amino acid reaction is 1:0.4 ⁇ 1:1.5.
  • the infrared spectrum of the compound of the present invention shows that the carbonyl stretching vibration peak moves to a low wave number after salt formation, which indicates that the compound has formed a salt.
  • the preparation of the S(+)-flurbiprofen salt derivative is a preparation made by adding pharmaceutically required excipients to the S(+)-flurbiprofen salt derivative.
  • the dosage forms of the S(+)-flurbiprofen salt derivative include but are not limited to: tablets, capsules, powders, granules, pills, suspensions, syrups, dropping pills, ointments, and plasters. , Babu cream, patches, patches, films, injections, eye drops, or sprays.
  • the content range of the S(+)-flurbiprofen salt derivative is: 0.001% to 80% (W/W%).
  • S(+)-flurbiprofen salt derivative has obvious activity in inhibiting cyclooxygenase (COX).
  • S(+)-flurbiprofen salt derivatives and pharmaceutical compositions are used for rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, etc., and can also be used for soft tissue diseases such as sprains and strains. , as well as the use of mild to moderate pain, such as dysmenorrhea and post-operative pain, toothache, etc.
  • the S(+)-flurbiprofen salt derivative and the pharmaceutical composition are used for anti-inflammation after surgery, and for treating inflammatory reactions after laser trabeculoplasty and other anterior segment inflammations.
  • the derivative prepared by forming a salt between S(+)-flurbiprofen and basic amino acids has the characteristics of high water solubility
  • the derivative prepared by forming a salt between S(+)-flurbiprofen and basic amino acids has better anti-inflammatory and analgesic effects;
  • Figure 1 shows the effect of S(+)-flurbiprofen salt derivative on the mouse pain model caused by glacial acetic acid.
  • the number of twists in mice is small, indicating high analgesic activity.
  • Test method Weigh an appropriate amount of the test sample ground into fine powder, add a certain volume of water at 25°C ⁇ 2°C, shake vigorously for 30 seconds every 5 minutes, observe the dissolution within 30 minutes, if there is no visible Complete dissolution is considered when visible solute particles are visible.
  • Table 1 The test results are shown in Table 1 below:
  • DSC5008 >50 >6.7 >500 S(+)-Flurbiprofen tromethamine salt 7.5 --- >75 S(+)-Flurbiprofen ⁇ 0.1 --- ---
  • the solubility of ornithine salt increased by more than 6.7 times; the solubility of S-flurbiprofen-L-arginine salt and S-flurbiprofen-D-arginine salt increased by more than 2 times.
  • the S-flurbiprofen-L-lysine salt, S-flurbiprofen-L-histidine salt, and S-flurbiprofen-D of the present invention Increased solubility of ornithine and S-flurbiprofen-D-lysine, S-flurbiprofen-D-histidine, and S-flurbiprofen-D-ornithine More than 500 times; the solubility of S-flurbiprofen-L-arginine salt and S-flurbiprofen-D-arginine salt increases more than 150 times.
  • Each group uses a 1mL syringe to draw the solution to be injected (group 1 is sterile water for injection, and the remaining 4 groups of samples are dissolved in sterile water for injection, group 2 is an aqueous solution of DSC5003, group 3 is an aqueous solution of DSC5004, and group 4 is SDB-1 Aqueous solution, group 5 is SDB-3 aqueous solution) 0.2 ml, groups 2 to 5 are all administered in equimolar doses (calculated as flurbiprofen, the dose is 5 mg/kg), 2 ml on the left side of the midline of the animal's abdomen between the legs Insert the needle into the -3mm site, withdraw the needle after entering the abdominal cavity, and inject the solution under a vacuum state.
  • each mouse was intraperitoneally injected with 0.2 mL of 0.6% glacial acetic acid, and the time and time of each writhing reaction (abdominal contraction into an "S" shape, body twisting, hind limb extension and creeping, etc.) were recorded in detail. The number of writhing times of mice within 20 minutes. The results are shown in Figure 1.
  • mice with symptoms of eye irritation, corneal defects, and conjunctival damage should not be used for testing.
  • a total of 15 rabbits were randomly divided into 3 groups, with 5 rabbits in each group. All animals were administered the test product to the left eye (group A was administered racemic flurbiprofen sodium eye drops; group B was administered DSC5001 eye drops; group C was administered DSC5004 eye drops), and the right eye was administered Normal saline (negative control).
  • Each dose in each group was 50 ⁇ l, and the dose was accurately administered with a microsyringe. After each dose, the rabbit eyes were passively closed for 10 seconds.
  • each group was given medication once every 1 hour, for a total of 6 times.
  • 30 minutes after the 6th eye drop 50 ⁇ L of 10% capsicum tincture was accurately dripped into each eye with a microsyringe, and the drug eye drops were continued 30 minutes later, once every 2 hours, for a total of 4 times; then changed to once every 6 hours, for 68 hours.
  • the local eye reactions were observed at 6, 12, 24, 36, 48, 60, and 72 hours after the capsicum tincture eye drops.
  • the eye irritation reaction score standard in the technical guidelines for drug irritation, allergy and hemolysis research issued by CDE on May 13, 2014 was slightly modified with reference to the eye inflammation evaluation standard.
  • the secretions, cornea, iris, and anterior chamber fluid were scored separately, the average score was calculated, and statistical processing was performed. The results are shown in Table 5:
  • the mean ocular inflammation scores of each experimental group were significantly lower than those of the normal saline treatment group, indicating that the anti-inflammatory effect of the drugs in each experimental group was significantly better than that of normal saline.
  • the ocular inflammation scores of group B The ocular inflammation scores of group C and group C were significantly lower than those of group A, which shows that compared with flurbiprofen sodium eye drops, the compounds of the present invention DSC5001 eye drops and DSC5004 eye drops have better anti-ocular inflammation effects.
  • the above two eye drops of the present invention have better anti-ocular inflammation effects.
  • a total of 15 adult male rabbits were randomly divided into 3 groups, with 5 rabbits in each group.
  • the left and right self-contrast method of the same body was used. All animals in each group were given blank solvent (physiological saline) in the right eye, group A was given DSC5001 eye drops in the left eye, group B was given DSC5004 eye drops in the left eye, and group C was given DSC5004 eye drops in the left eye.
  • SDB-1 eye drops within 24 hours before the test, use a magnifying glass and fluorescein dye to examine both eyes of each animal, and record the conjunctival blood vessels, corneal transparency, and eye secretions. Animals with symptoms of eye irritation, corneal defects, and conjunctival damage should not be used for testing.
  • Single eye irritation test During the experiment, 0.05 ml of the test substance was dropped into the left eye of each animal, and the solvent was added to the right eye as a blank control. Then the eyelids were gently closed for about 10 seconds. During the observation process, fluorescein staining was performed. The sodium fluorescein solution was dropped on the cornea and rinsed with sterile saline after 1-5 minutes. If there is a lesion, a yellow-green fluorescent ring will immediately appear around it. The eyes were examined before administration and 1, 2, 4, 24, 48 and 72 hours after administration. In the single-dose rabbit eye irritation experiment, no irritation was observed in all groups.
  • test substance The number of times the test substance should be administered per day should be the same as the clinical medication frequency, 3 times/day, and the test substance should be administered continuously for 2 weeks, with the daily administration time being fixed. Eye examinations, including corneal fluorescein staining, were performed before daily dosing and 1, 2, 4, 24, 48, and 72 hours after the last dose. If no irritation symptoms are seen within 72 hours.
  • Example 11 Experiment on the effect of S(+)-flurbiprofen salt on body weight and gastrointestinal function in rats
  • mice After 3 days of adaptive feeding, 40 SD rats (180-220 g) were randomly divided into 4 groups, with 10 rats in each group. Groups 1 to 3 were administered 0.4 ml of test product suspension (S-flurbiprofen, DSC5004, SBD-2, respectively suspended with 1% methylcellulose aqueous solution) by intragastric administration, and the three samples were equimolar. The dosage was 7.2 mg/kg based on flurbiprofen. Group 4 was the vehicle group, and the same volume of methylcellulose aqueous solution was administered by gavage. Each group was administered drug or vehicle once a day for 30 consecutive days, and were weighed on the 15th and 30th days respectively, and then compared with the weight of each group on the first day and analyzed to evaluate the weight change. The results are shown in Table 7.

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Abstract

(+)-氟比洛芬盐衍生物，如下式（I）所示的化合物以及其制备方法、药物组合物和用途。

Description

一种S-(+)-氟比洛芬盐及其制备方法、药物组合物和用途 技术领域
本发明涉及但不限于医药技术领域，尤其涉及一种由S(+)-氟比洛芬与碱性氨基酸形成的盐、立体异构体、水合物及溶剂化物的制备方法与用途。
背景技术
氟比洛芬是临床上常用的非甾体抗炎类药物，自1977年投放市场以来，广泛用于风湿性关节炎、类风湿关节炎、骨关节炎、变形关节炎、强直性脊柱炎等，也可用于软组织病(如扭伤及劳损)以及轻、中度疼痛(如痛经和手术后疼痛、牙痛等)的对症治疗。主要通过抑制COX(环氧化酶)起作用，是目前已知的丙酸类非甾体抗炎药中作用最强的一种，氟比洛芬抗炎效果和镇痛效果分别为阿司匹林的250倍和50倍，药效和耐受性比同类布洛芬更强，且毒性低。
氟比洛芬是手性药物，分子中存在手性中心，具有S型和R型一对对映体。目前临床应用的是它的外消旋体，然而氟比洛芬的消炎活性主要来自其(S)-对映体，而(R)-对映体则缺乏显著的环氧合酶抑制活性(日本专利特开平8-119859)；此外，外消旋体的胃肠道副作用由于(R)-对映体的存在而大大加强。关于镇痛活性，文献(Experientia 1991，47(3)，257-261.)显示R (-)-氟比洛芬异构体通过作用于细胞激酶而发挥镇痛药效，效果与S构型相当。专利(WO2010001103、WO2015145163、US3959364A、CN201680057083.5)报道了S(+)-氟比洛芬拆分和合成的方法。
氟比洛芬在常温下为白色或类白色结晶性粉末。在甲醇、乙醇、丙酮或乙醚中溶解性较好，在乙腈中可以溶解，几乎不溶于水，其溶解度小，脂溶性较强，生物利用度低，且氟比洛芬是pH依赖型溶解型的盐类，其溶解度受pH影响较大。此外因其理化性质所限，目前上市的氟比洛芬相关的制剂多采用不同的API，如注射剂用氟比洛芬酯、滴眼液用氟比洛芬钠等，因此，有必要开发新的氟比洛芬衍生物来提高药物药效效果，并满足所有相关的制剂形式需求。
发明内容
本发明提供了一种S(+)-氟比洛芬与碱性氨基酸的盐及其制备方法、药物组合物。
本发明中S(+)-氟比洛芬与碱性氨基酸成盐制备的衍生物的水溶性显著高于与氨丁三醇等其它成盐剂所形成的盐，而且本发明的盐类化合物具有更强的抗炎及镇痛效果；另外，意外地发现本发明中S(+)-氟比洛芬与碱性氨基酸成盐制备的衍生物胃肠道副作用明显降低；滴眼使用时，本发明化合物具有更好的抗炎效果和更低的眼部刺激性。
本发明提供了一种S(+)-氟比洛芬与碱性氨基酸成盐后的衍生物、立体异 构体、水合物、或其溶剂化物的制备方法、药物组合物和用途。
一方面，本发明提供了一种如式(I)所示的S(+)-氟比洛芬盐衍生物、水合物或溶剂化物；
Figure PCTCN2022131059-appb-000001
式(I)中，其中，
R选自碱性氨基酸，包括但不限于下列结构：D-精氨酸、D-赖氨酸、D-组氨酸、D-鸟氨酸、L-精氨酸、L-赖氨酸、L-组氨酸、L-鸟氨酸。
进一步地，所述的S(+)-氟比洛芬盐衍生物具有如下结构：
Figure PCTCN2022131059-appb-000002
另一方面，本发明提供了上述的S(+)-氟比洛芬盐的制备方法，所述的制备方法包括如下步骤：
(1)外消旋的氟比洛芬与S-1-苯基乙胺成盐，进行拆分、经解盐得S(+)-氟比洛芬纯品；
(2)将步骤(1)得到的S(+)-氟比洛芬纯品与碱性氨基酸反应，得到S(+)-氟比洛芬盐衍生物。
在上述实施方案中，所述的制备方法包括如下步骤：
(1)将外消旋的氟比洛芬溶解于有机溶剂1中，回流状态下滴加S-1-苯基乙胺的有机溶剂2溶液成盐，通过降温、析晶、重结晶提纯、解盐得S(+)-氟比洛芬纯品；
(2)将得到的S(+)-氟比洛芬纯品在回流状态下与碱性氨基酸反应得S(+)-氟比洛芬盐衍生物。
进一步地，步骤(1)中，与S-1-苯基乙胺成盐过程中所使用的溶剂为甲醇、乙醇、乙酸乙酯、乙酸丁酯、乙酸异丙酯、异丙醚、二氯甲烷、三氯甲烷、四氢呋喃、丙酮、乙腈、1，4-二氧六环、甲苯、二甲苯中的一种或者几种的组合。
进一步地，步骤(1)中，重结晶纯化所使用的溶剂为甲醇、乙醇、乙酸乙酯、乙酸丁酯、乙酸异丙酯、异丙醚、二氯甲烷、三氯甲烷、四氢呋喃、丙酮、乙腈、1，4-二氧六环、甲苯、二甲苯、水中的一种或者几种的组合。
进一步地，步骤(1)中，解盐过程所使用的有机溶剂为甲醇、乙醇、乙酸乙 酯、乙酸丁酯、乙酸异丙酯、异丙醚、二氯甲烷、三氯甲烷、甲苯、二甲苯中的一种或者几种的组合。
进一步地，步骤(2)中，S(+)-氟比洛芬与碱性氨基酸反应得S(+)-氟比洛芬盐衍生物，过程中所使用的溶剂为甲醇、乙醇、异丙醇、叔丁醇、丙酮、乙腈、乙酸乙酯、乙酸丁酯、乙酸异丙酯、异丙醚、二氯甲烷、1-氯丁烷三氯甲烷、四氢呋喃、甲苯、二甲苯、水中的一种或者几种的组合。
进一步地，步骤(2)中，成盐过程中所使用的S(+)-氟比洛芬与碱性氨基酸反应的摩尔比为1∶0.4～1∶1.5。
本发明化合物红外光谱显示成盐后羰基伸缩振动峰向低波数移动，这表明化合物已成盐。
进一步地，所述S(+)-氟比洛芬盐衍生物，其制剂为S(+)-氟比洛芬盐衍生物加入药学上所需的辅料做成的制剂。
进一步地，所述的S(+)-氟比洛芬盐衍生物制剂剂型包括但不限于：片剂、胶囊、散剂、颗粒剂、丸剂、混悬剂、糖浆剂、滴丸、软膏、硬膏、巴布膏、贴片、贴剂、膜剂、注射液、滴眼液、或喷雾剂。
进一步地，所述的S(+)-氟比洛芬盐衍生物制剂中，S(+)-氟比洛芬盐衍生物的含量范围为：0.001％～80％(W/W％)。
进一步地，所述的S(+)-氟比洛芬盐衍生物具有明显的抑制环氧合酶(Cyclooxygenase，COX)的活性。
进一步地，所述的S(+)-氟比洛芬盐衍生物及药物组合物用于类风湿性关节炎、骨关节炎、强直性脊椎炎等，也可用于软组织病，如扭伤及劳损，以及轻度至中度疼痛，如痛经和手术后疼痛、牙痛等的用途。
进一步地，所述S(+)-氟比洛芬盐衍生物及药物组合物用于在术后抗炎，治疗激光小梁成形术后的炎症反应和其他眼前段炎症。预防和治疗白内障人工晶状体植入术后的黄斑囊样水肿。也用于治疗巨乳头性结膜炎。抑制内眼手术中的瞳孔缩小等方面的用途。
本发明中S(+)-氟比洛芬与碱性氨基酸成盐制备的衍生物具有高水溶性的特点；
本发明中S(+)-氟比洛芬与碱性氨基酸成盐制备的衍生物具有更好的抗炎及镇痛效果；
另外，意外地发现本发明中S(+)-氟比洛芬与碱性氨基酸成盐制备的衍生物胃肠道副作用明显降低；滴眼使用时，本发明化合物具有更好的抗炎效果和更低的眼部刺激性。
附图说明
图1表示S(+)-氟比洛芬盐衍生物对冰醋酸所致的小鼠疼痛模型的效果，以小鼠扭体次数计，扭体次数少，说明镇痛活性高。
具体实施方式：
下面具体实施例中如无特殊说明，采用的制备与精制方法均为本领域的 常规方法：
实施例一：S(+)-氟比洛芬异构体的拆分
Figure PCTCN2022131059-appb-000003
步骤1：S-氟比洛芬/S-1-苯基乙胺盐的制备
将(RS)-氟比洛芬(3.0kg)装入20L的夹套玻璃反应器中。加入甲醇(2.0L)和甲苯(8.0L)。加热混合物以溶解固体。将S-1-苯基乙胺(1.49kg)溶于甲苯(3L)中，并在60℃下搅拌约30分钟将溶液加到20L反应器中。将混合物逐渐冷却至0℃至5℃以引起结晶。滤出晶体，用甲苯(3L)洗涤，并在55℃的真空烘箱中干燥，得S-氟比洛芬/S-1-苯基乙胺盐粗品(2.8kg)，收率62.4％。
将S-氟比洛芬/S-1-苯基乙胺盐(2.8kg)粗品加入20L夹套玻璃反应器中。加入甲苯(12.0L)和甲醇(2.5L)，搅拌混合物并加热至60℃以溶解固体。将该溶液逐渐冷却至0℃至5℃以引起结晶。滤出晶体，用甲苯(4L)洗涤，并在55℃的真空烘箱中干燥，得S-氟比洛芬/S-1-苯乙胺盐精制品(2.05kg)，精制收率73.2％。
步骤2：S-氟比洛芬的制备
将S-氟比洛芬/S-1-苯基乙胺盐精制品(1.2kg)加入到10L带夹套的玻璃反应瓶中。在搅拌下加入甲苯(4L)。加入水(1.0L)和浓盐酸(0.5L)，并将混合物在60℃下搅拌。分离出下部水层，并保留上部有机层。重复盐酸 洗涤，然后用水洗涤甲苯溶液。加入另外的甲苯(0.7L)，然后蒸出甲苯(2.0L)以确保溶液不含水。将该甲苯溶液逐渐冷却至-10℃以引起结晶。滤出晶体，用正庚烷(1.0L)洗涤并在40℃的真空烘箱中干燥，得S-氟比洛芬(0.6kg)，收率74.8％。总收率34.2％(以氟比洛芬计)。纯度：99.2％。以甲醇为溶剂，比旋度
Figure PCTCN2022131059-appb-000004
1H-NMR(300MHz，CDCl 3)δ7.45-7.56(m，2H)，7.29-7.47(m，4H)，7.12-7.26(m，2H)，3.75-3.84(m，1H)，1.38-1.59(d，3H)。
实施例二：S(+)-氟比洛芬L-精氨酸盐(DSC5001)的制备
Figure PCTCN2022131059-appb-000005
取S(+)-氟比洛芬(2.44g，10.0mmol)加入至25.0mL乙醇与水混合溶剂中(20∶1，V/V)，向其中加入L-精氨酸(化合物1，1.91g，11.0mmol)，加热至回流全溶，继续回流2.0h，冷却析晶，有白色固体析出，降为室温后过滤，所得滤饼用乙醇淋洗(5.0mL×2)，所得固体于50℃下真空干燥12h得1.46g产物DSC5001，收率：35％，纯度：98.7％。 1H-NMR(400MHz，H 2O)δ7.36-7.45(m，2H)，7.29-7.33(m，4H)，7.04-7.09(m，2H)，3.53-3.63(m，2H)，3.02-3.07(m，2H)，1.72-1.79(m，2H)，1.44-1.60(m，2H)，1.30-1.32(d，3H)。
实施例三：S(+)-氟比洛芬L-赖氨酸盐(DSC5003)的制备
Figure PCTCN2022131059-appb-000006
取S(+)-氟比洛芬(2.44g，10.0mmol)加入至25.0mL乙醇与水混合溶剂中(4∶1，V/V)，向其中加入L-赖氨酸(化合物3，1.62g，11.0mmol)，加热至回流全溶，继续回流2.0h，冷却析晶，有白色固体析出，降为室温后过滤，所得滤饼用水淋洗(5.0mL×2)，所得固体于50℃下真空干燥12h得2.47g产物DSC5003，收率：63％，纯度：98.4％。 1H-NMR(400MHz，H 2O)δ7.49(m，2H)，7.35-7.42(m，4H)，7.12(m，2H)，3.59-3.64(m，2H)，2.91(m，2H)，1.79(m，2H)，1.60-1.62(m，2H)，1.30-1.40(m，5H)。
实施例四：S(+)-氟比洛芬D-组氨酸盐(DSC5006)的制备
Figure PCTCN2022131059-appb-000007
取S(+)-氟比洛芬(2.44g，10.0mmol)加入至100mL无水乙醇中，向其中加入D-组氨酸(化合物6，1.70g，11.0mmol)，加热至回流全溶，继续回流5.0h，冷却析晶，有白色固体析出，降为室温后过滤，所得滤饼用无水乙醇淋洗(5.0mL×2)，所得固体于50℃下真空干燥12h得1.56g产物DSC5006。收率：39％。纯度：98.1％。 1H-NMR(400MHz，H 2O)δ7.59(s，1H)，7.35-7.41(m，2H)，7.24-7.30(m，4H)，7.07-7.09(m，2H)，6.87(s，1H)，3.79-3.82(m，2H)，2.97-3.01(m，2H)，1.33-1.34(d，3H)。
实施例五：S(+)-氟比洛芬D-鸟氨酸盐(DSC5008)的制备
Figure PCTCN2022131059-appb-000008
S(+)-氟比洛芬(2.44g，10.0mmol)加入至20.0mL乙醇与水混合溶剂中(4∶1，V/V)，向其中加入鸟氨酸(化合物8，1.45g，11.0mmol)，加热至回流全溶，继续回流2.0h，冷却析晶，有白色固体析出，降为室温后过滤，所得滤饼用无水乙醇淋洗(5.0mL×2)，所得固体于50℃下真空干燥12h得2.67g产物DSC5008。收率：71％。纯度：98.5％。 1H-NMR(400MHz，H 2O)δ7.44-7.54(m，2H)，7.32-7.42(m，4H)，7.09-7.17(m，2H)，3.52-3.58(m，2H)，2.70-2.73(m，2H)，1.64-1.90(m，2H)，1.28-1.32(m，5H)。
按照与上述实施例同样的方法，使用市售化合物或由市售化合物适当合成的中间体化合物，合成了下列实施例化合物。
Figure PCTCN2022131059-appb-000009
Figure PCTCN2022131059-appb-000010
对比例一：S(+)-氟比洛芬氨丁三醇盐(SDB-1)的制备
Figure PCTCN2022131059-appb-000011
S(+)-氟比洛芬(2.44g，10mmol)和1-氯丁烷(25mL)的溶液加热至70℃，溶解后，滴加氨丁三醇(化合物9，1.21g，10mmol)、甲醇(10mL)和1-氯丁烷(25mL)的混合溶液。搅拌2h后，冷却结晶。抽滤，将其在50℃减压干燥过夜得到1.5g白色固体产物SDB-1，收率：41％。 1H-NMR(400MHz，H 2O)δ7.39-7.42(m，2H)，7.28-7.33(m，2H)，7.20-7.26(m，2H)，7.07-7.14(m，2H)，3.54-3.68(m，7H)，1.34-1.36(d，3H)。
对比例二：S(+)-氟比洛芬哌嗪盐(SDB-2)的制备
Figure PCTCN2022131059-appb-000012
取S(+)-氟比洛芬(2.44g，10.0mmol)加入至50mL无水乙醇中，向其中加入哌嗪(化合物14，0.86g，10.0mmol)，加热至回流全溶，继续回流5.0h，冷却析晶，有白色固体析出，降为室温后过滤，所得滤饼用无水乙醇淋洗，所得固体于50℃下真空干燥12h得1.75g产物SDB-2，收率：53％。纯度： 98.5％。 1H-NMR(400MHz，H 2O)δ7.35-7.40(m，2H)，7.27-7.30(m，2H)，7.20-7.24(m，2H)，7.09-7.17(m，2H)，5.57(q，1H)，3.38-3.46(m，4H)，3.24-3.33(m，4H)，1.43(d，3H)。
对比例三：RS-氟比洛芬-L-赖氨酸盐(SDB-3)的合成
完全按照DSC5003的合成方法，以外消旋的氟比洛芬(RS-氟比洛芬)为原料，合成RS-氟比洛芬-L-赖氨酸盐(SDB-3)。
实施例六：S(+)-氟比洛芬盐衍生物在水中的溶解度测试
根据中国药典2020版凡例溶解度测定方法测试S-(+)-普拉洛芬盐衍生物在水中的溶解度：
试验法：称取研成细粉的供试品适量，于25℃±2℃下加入一定容量的水中，每隔5分钟强力振摇30秒钟，观察30分钟内的溶解情况，如无目视可见的溶质颗粒时，即视为完全溶解。测试结果如下表1中：
表1：S(+)-氟比洛芬盐衍生物在水中的溶解度
名称 溶解度 倍数1＊ 倍数2 ＊＊
DSC5001 15.2 2 ＞152
DSC5002 15.6 2 ＞156
DSC5003 ＞50 ＞6.7 ＞500
DSC5004 ＞50 ＞6.7 ＞500
DSC5005 ＞50 ＞6.7 ＞500
DSC5006 ＞50 ＞6.7 ＞500
DSC5007 ＞50 ＞6.7 ＞500
DSC5008 ＞50 ＞6.7 ＞500
S(+)-氟比洛芬氨丁三醇盐 7.5 --- ＞75
S(+)-氟比洛芬 ＜0.1 --- ---
＊倍数1为相对于S(+)-氟比洛芬氨丁三醇盐；
＊＊倍数2为相对于S(+)-氟比洛芬
结果显示，本发明中S(+)-氟比洛芬氨基酸盐的溶解度远大于S(+)-氟比洛芬和S(+)-氟比洛芬氨丁三醇盐的溶解度。
其中，与S-氟比洛芬氨丁三醇盐的溶解度相比，本发明S-氟比洛芬-L-赖氨酸盐、S-氟比洛芬-L-组氨酸盐、S-氟比洛芬-D-鸟氨酸盐及S-氟比洛芬-D-赖氨酸盐、S-氟比洛芬-D-组氨酸盐、S-氟比洛芬-D-鸟氨酸盐的溶解度增加超过6.7倍；S-氟比洛芬-L-精氨酸盐和S-氟比洛芬-D-精氨酸盐的溶解度增加大于2倍。
与S-氟比洛芬的溶解度相比，本发明S-氟比洛芬-L-赖氨酸盐、S-氟比洛芬-L-组氨酸盐、S-氟比洛芬-D-鸟氨酸盐及S-氟比洛芬-D-赖氨酸盐、S-氟比洛芬-D-组氨酸盐、S-氟比洛芬-D-鸟氨酸盐的溶解度增加超过500倍；S-氟比洛芬-L-精氨酸盐和S-氟比洛芬-D-精氨酸盐的溶解度增加大于150倍。
实施例七：S(+)-氟比洛芬盐镇痛药效实验
取30只18-22g SPF级雌性KM小鼠(厂家：斯贝福(北京)生物技术有限公司；许可证号码：SCXK(京)2019-0010)，随机分成5组，每组6只动物。每组分别用1mL注射器吸取待注射溶液(组1为无菌注射用水，其余 4组样品用无菌注射用水溶解，其中组2为DSC5003的水溶液，组3为DSC5004水溶液，组4为SDB-1水溶液，组5为SDB-3水溶液)0.2ml，组2～组5均为等摩尔给药(以氟比洛芬计，剂量为5mg/kg)，在两腿之间动物腹中线左部2-3mm部位进针，针头进入腹腔后进行回抽，确认是真空的状态下进行溶液注射。于末次给药30min后，每鼠腹腔注射0.6％冰醋酸0.2mL，详细记录各鼠出现每一次扭体反应(腹部收缩成″S″形、身体扭曲、后肢伸展及蠕行等)的时间及20min内小鼠的扭体次数。结果如图1所示。
从图1可以看出各供试品组的扭体次数均小于溶媒组，其中，DSC5003组和DSC5004组的扭体次数要小于SDB-3组，意外的发现DSC5003组和DSC5004组的扭体次数小于SDB-1组。这说明本发明化合物DSC5003和DSC5004的镇痛活性要高于对比例化合物SDB-3(消旋氟比洛芬-L-赖氨酸盐)，也高于对比例化合物SDB-1(S-氟比洛芬氨丁三醇盐)。
实施例八：S(+)-氟比洛芬盐滴眼剂的制备
取生理盐水约900ml，控温在25±2℃，加入S(+)-氟比洛芬盐(以氟比洛芬计0.3g)，搅拌至溶解，加入生理盐水至1000ml，精滤，检查澄明度合格后，无菌分装，即得滴眼用样品溶液，规格为0.03％。按照该方法制备得到DSC5001滴眼液、DSC5004滴眼液、氟比洛芬钠滴眼液、SDB-1滴眼液。在每次使用前均应用0.22微米的微孔滤膜过滤。
实施例九：S(+)-氟比洛芬盐衍生物滴眼剂药效学试验
SPF级日本大耳白家兔，雄性，体重2.0-2.2kg。动物合格证编号：SCXK(辽)2020-0001。动物及饲料购自辽宁长生生物技术有限公司，标准兔饲养笼饲养，1只/笼。温度25℃±2℃，自由摄食及饮水。适应性饲养3天后用于实验。采用同体左右侧自身对比法。试验前24小时内采用放大镜与荧光素染料对每只动物的双眼进行检查，记录眼结膜血管、角膜透明度及眼分泌物等情况。有眼睛刺激症状、角膜缺陷和结膜损伤的动物不能用于试验。共15只家兔，随机分为3组，每组5只。所有动物左眼给药供试品(组A给药为消旋氟比洛芬钠滴眼液；组B给药为DSC5001滴眼液；组C给药为DSC5004滴眼液)，右眼给予生理盐水(阴性对照)。各组每次给药量均为50μl，微量注射器精确给药，每次给药后使兔眼被动闭合10s。
实验开始后，各组每1h给药一次，共6次。第6次滴眼后30min后，各眼用微量注射器准确滴入质量分数10％辣椒酊50μL，30min后继续药物滴眼，每2小时一次，共滴4次；然后改为6h一次，连续68h。于辣椒酊滴眼后第6、12、24、36、48、60、72h观察眼局部反应情况，参照眼部炎症评判标准CDE于2014年5月13日发布的药物刺激性、过敏性和溶血性研究技术指导原则中眼刺激反应分值标准的内容稍作修改，对分泌物、角膜、虹膜、前房液分别评分，算出平均分值，并进行统计学处理。结果见表5：
表5：S(+)-氟比洛芬盐滴眼剂药效学试验结果
Figure PCTCN2022131059-appb-000013
实验各组眼炎症评分均值均明显低于生理盐水治疗组，表明各实验组药物的消炎作用明显优于生理盐水。在辣椒酊滴眼致炎后的6-24小时内，组A、组B和组C的眼部炎症评分差异不大，但在辣椒酊滴眼致炎后的36-72小时内，组B和组C眼部炎症评分显著低于组A，这表明：与氟比洛芬钠滴眼液相比，本发明化合物DSC5001滴眼液和DSC5004滴眼液的抗眼部炎症的效果更好，尤其在眼部致炎24小时后，本发明的上述两种滴眼液的抗眼部炎症的效果更好。
实施例十：S(+)-氟比洛芬盐眼刺激性实验
SPF级日本大耳白家兔，雄性，体重2.0-2.2kg。动物合格证编号：SCXK(辽)2020-0001。动物及饲料购自辽宁长生生物技术有限公司，标准兔饲养笼饲养，1只/笼。温度25±2℃，自由摄食及饮水。适应性饲养3天后用于实验。采用同体左右侧自身对比法。试验前24小时内采用放大镜与荧光素染料对每只动物的双眼进行检查，记录眼结膜血管、角膜透明度及眼分泌物等情况。 有眼睛刺激症状、角膜缺陷和结膜损伤的动物不能用于试验。
成年雄性家兔共15只，随机分成3组，每组5只。采用同体左右侧自身对比法，所有各组动物右眼给予空白溶剂(生理盐水)，组A左眼给药DSC5001滴眼液、组B左眼给药DSC5004滴眼液、组C左眼给药SDB-1滴眼液；试验前24小时内采用放大镜与荧光素染料对每只动物的双眼进行检查，记录眼结膜血管、角膜透明度及眼分泌物等情况。有眼睛刺激症状、角膜缺陷和结膜损伤的动物不能用于试验。
单次眼刺激实验：实验时每只动物左眼睛滴入0.05ml受试物，右侧眼睛加入溶媒作为空白对照。然后轻合眼睑约10秒。在观察过程中进行荧光素染色检查，将荧光素钠溶液滴于角膜，1-5分钟后以灭菌生理盐水冲洗。如有病变则周围立即会出现一黄绿色荧光环。给药前以及给药后1、2、4、24、48和72小时对眼部进行检查，在单次给药的兔眼刺激性实验中，所有各组均未观察到刺激性。
多次眼刺激实验：每天给受试物的次数应与临床用药频率相同，3次/天，连续给受试物2周，其中每天给药时间固定。每天给药前以及最后一次给药后1、2、4、24、48和72小时对眼部进行检查，包括角膜荧光素染色检查。如果在72小时未见任何刺激症状。
按照CDE于2014年5月13日发布的药物刺激性、过敏性和溶血性研究技术指导原则中眼刺激反应分值标准进行评价。结果如表6所示。
表6：S(+)-氟比洛芬盐多次给药眼刺激性实验结果
Figure PCTCN2022131059-appb-000014
由表6可以明显看出，组C的得分明显高于空白对照组(组D)和两个供试品组(组A和组B)，这表明，与SDB-1滴眼液相比，DSC5001滴眼液和DSC5004滴眼液的眼刺激性明显更低的眼刺激性。
实施例十一：S(+)-氟比洛芬盐对大鼠体重及胃肠道功能的影响实验
40只SD大鼠(180～220g)适应性饲养3天后，随机分成4组，每组10只。组1～组3分别灌胃给予供试品混悬液(S-氟比洛芬、DSC5004、SBD-2，分别用1％的甲基纤维素水溶液混悬)0.4ml，三个样品等摩尔给药，以氟比洛芬计7.2mg/kg，组4为溶媒组，灌胃给予同体积的甲基纤维素水溶液。各组每天给药或给溶媒1次，连续给药30天，分别在第15天和第30天称重，然后与各组第1天体重对照分析，评估体重变化量。结果如表7所示。
表7：S(+)-氟比洛芬盐长期给药后大鼠体重变化量(单位：g)
分组 15天动物数 15天体重变化量 30天动物数 30天体重变化量
S-氟比洛芬 10 7.5±5.8 10 12.9±6.1
DSC5004组 10 11.3±6.3 10 18.7±5.5
SBD-2组 10 6.8±5.2 10 13.3±5.7
溶媒组 10 14.7±6.2 10 20.1±6.6
从上表可以看出，给药30天后，所以动物均存活。相比于溶媒组，其它各组动物体重的增加量均有所降低，其中，S-氟比洛芬组和SDB-2组的体重增加幅度小于DSC5004组，这说明S-氟比洛芬和SDB-2可使大鼠体重增加明显下降，因此可判断对大鼠胃肠道功能的影响较大，而DSC5004对大鼠体重增加影响较小，因此判断其对大鼠胃肠道功能的影响相对较小。
本申请描述了多个实施例，但是该描述是示例性的，而不是限制性的，并且对于本领域的普通技术人员来说显而易见的是，在本申请所描述的实施例包含的范围内可以有更多的实施例和实现方案。

Claims (9)

  1. 一种如(I)所示的S(+)-氟比洛芬盐衍生物、水合物、或溶剂化物：
    Figure PCTCN2022131059-appb-100001
    式(I)中，
    R选自碱性氨基酸，包括但不限于下列结构：D-精氨酸、D-赖氨酸、D-组氨酸、D-鸟氨酸、L-精氨酸、L-赖氨酸、L-组氨酸、L-鸟氨酸。
  2. 根据权利要求1所述S(+)-氟比洛芬盐衍生物，选自下列化合物：
    Figure PCTCN2022131059-appb-100002
  3. 一种药物组合物，其包含权利要求1-2中任一项所述S(+)-氟比洛芬盐 衍生物、水合物、或溶剂化物以及药学上所需的辅料。
  4. 根据权利要求书3所述的药物组合物，其中S(+)-氟比洛芬盐衍生物的含量范围为：0.001％～80％(W/W)。
  5. 根据权利要求书3或4所述的药物组合物，其中，所述药物组合物的的制剂剂型包括但不限于片剂、胶囊、散剂、颗粒剂、丸剂、混悬剂、糖浆剂、滴丸、软膏、硬膏、巴布膏、贴片、贴剂、膜剂、注射液、滴眼液、或喷雾剂的剂型形式。
  6. 权利要求1～2中任一项所述的S(+)-氟比洛芬盐衍生物作为抑制环氧合酶(Cyclooxygenase，COX)的用途。
  7. 权利要求1～2中任一项所述的S(+)-氟比洛芬盐衍生物、立体异构体、溶剂化物、或其药学上可接受盐，或者权利要求3～5中任一项所述的药物组合物在制备解热、镇痛、和/或抗炎药物中的应用。
  8. 权利要求1～2中任一项所述的S(+)-氟比洛芬盐衍生物、立体异构体、溶剂化物、或其药学上可接受盐，或者权利要求3～5中任一项所述的药物组合物在制备治疗下列疾病药物中的用途，所述疾病为类风湿性关节炎、骨关节炎、强直性脊椎炎等，也可用于软组织病，如扭伤及劳损，以及轻度至中度疼痛，如痛经和手术后疼痛、牙痛等。
  9. 权利要求1～2中任一项所述的S(+)-氟比洛芬盐衍生物、溶剂化物、或其药学上可接受盐，或者权利要求3～5中任一项所述的药物组合物在制备治 疗下列疾病药物中的用途，其中，所述疾病为术后抗炎，治疗激光小梁成形术后的炎症反应和其他眼前段炎症；预防和治疗白内障人工晶状体植入术后的黄斑囊样水肿；也用于治疗巨乳头性结膜炎；抑制内眼手术中的瞳孔缩小。
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