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WO2023280319A1 - 洛索洛芬钠在制备治疗干眼的药物中的应用 - Google Patents

洛索洛芬钠在制备治疗干眼的药物中的应用 Download PDF

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WO2023280319A1
WO2023280319A1 PCT/CN2022/104727 CN2022104727W WO2023280319A1 WO 2023280319 A1 WO2023280319 A1 WO 2023280319A1 CN 2022104727 W CN2022104727 W CN 2022104727W WO 2023280319 A1 WO2023280319 A1 WO 2023280319A1
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Prior art keywords
sodium
loxoprofen sodium
application
application according
dry eye
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PCT/CN2022/104727
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English (en)
French (fr)
Inventor
梁翅勇
王延东
于垂亮
李亮
薛亚萍
吴美容
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Guangzhou Ocusun Ophthalmic Biotechnology Co Ltd
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Guangzhou Ocusun Ophthalmic Biotechnology Co Ltd
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Priority to US18/577,696 priority Critical patent/US20240315995A1/en
Priority to AU2022305711A priority patent/AU2022305711A1/en
Priority to KR1020247004355A priority patent/KR20240035827A/ko
Priority to CN202280048739.2A priority patent/CN117615756A/zh
Priority to EP22837064.9A priority patent/EP4368180A1/en
Priority to JP2024500540A priority patent/JP2024524590A/ja
Publication of WO2023280319A1 publication Critical patent/WO2023280319A1/zh
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds

Definitions

  • the invention relates to the field of medicine, in particular to the application of loxoprofen sodium or a composition containing loxoprofen sodium in the preparation of medicines for preventing and/or treating dry eye.
  • Dry eye also known as keratoconjunctival sicca syndrome.
  • dry eye dry eye disease
  • DED dry eye disease
  • the occurrence of dry eye also includes many environmental factors, such as environmental pollution or excessive dryness of the environment, eye surgery and excessive use of eye medicines, excessive use of video terminals, and wearing of contact lenses can all lead to the occurrence of dry eye disease. Workers who often work outdoors are more prone to dry eye. Although many studies have been conducted on the pathogenesis of dry eye, the pathogenesis of dry eye has not been fully clarified.
  • Loxoprofen sodium is a non-steroidal anti-inflammatory drug, which is clinically used for anti-inflammatory analgesia, surgery, trauma and tooth extraction for rheumatoid arthritis, low back pain, frozen shoulder, neck, shoulder and wrist syndrome, etc. There is no report about loxoprofen sodium for treating dry eye.
  • the object of the present invention is to overcome the defects of the prior art, and provide a dry eye treatment medicine with good therapeutic effect and little irritation.
  • the present invention provides the use of loxoprofen sodium or a composition containing loxoprofen sodium in the preparation of a medicament for preventing and/or treating dry eye.
  • Loxoprofen sodium (chemical name: 2-[4-(2-oxocyclopentane-1-ylmethyl) phenyl] sodium propionate dihydrate) is a non-steroidal anti-inflammatory drug, its The mechanism of action is to inhibit the synthesis of prostaglandins, and the target is cyclooxygenase.
  • the compound is currently clinically used for anti-inflammatory and analgesic treatment of rheumatoid arthritis, low back pain, frozen shoulder, neck, shoulder and wrist syndrome, analgesia and anti-inflammation after surgery, trauma and tooth extraction, and acute upper respiratory inflammation. Antipyretic and analgesic etc.
  • loxoprofen sodium has the effect of promoting tear secretion, enhancing tear film stability and alleviating corneal epithelial cell damage, and can be used to prevent and/or treat dry eye, especially in relation to lacrimal gland dysfunction or tear secretion Dry eye associated with reduced tear film stability and/or corneal epithelial cell damage.
  • the present invention also provides the application of the loxoprofen sodium or the composition containing loxoprofen sodium in the preparation of medicines for treating lacrimal gland dysfunction or promoting tear secretion.
  • the present invention also provides the application of the loxoprofen sodium or the composition containing loxoprofen sodium in the preparation of medicine for enhancing tear film stability.
  • the present invention also provides the application of the loxoprofen sodium or the composition containing loxoprofen sodium in the preparation of medicaments for preventing and/or alleviating corneal epithelial cell damage.
  • the composition containing loxoprofen sodium further contains one or more of a thickener, a metal ion complexing agent, an osmotic pressure regulator, a pH regulator and a bacteriostatic agent.
  • the composition containing loxoprofen sodium also contains at least a thickener.
  • the mass ratio of loxoprofen sodium to the thickener is preferably 1:(0.5-1.5), more preferably 1:(0.8-1).
  • the thickener is selected from one or more of sodium hyaluronate, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, poloxamer, hypromellose, xanthan gum species, preferably sodium hyaluronate.
  • the composition containing loxoprofen sodium also contains at least a metal ion complexing agent.
  • the mass ratio of loxoprofen sodium to the metal ion complexing agent is 1:(0.02-0.5), more preferably 1:(0.08-0.2).
  • the metal ion complexing agent is disodium edetate.
  • the composition containing loxoprofen sodium further contains at least an osmotic pressure regulator.
  • the mass ratio of loxoprofen sodium to the osmotic pressure regulator is preferably 1:(2-18), more preferably 1:(4.5-10).
  • the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, glucose, and potassium chloride, preferably sodium chloride.
  • the composition containing loxoprofen sodium further contains at least a pH regulator.
  • the dosage of the pH regulator in the present invention is determined according to the actual demand, and the pH value of the final product can be adjusted to a level suitable for human body.
  • the pH regulator is selected from one or more of sodium hydroxide, hydrochloric acid, sodium citrate, citric acid, boric acid, and borax.
  • the composition containing loxoprofen sodium also contains at least a bacteriostat.
  • the mass ratio of loxoprofen sodium to the bacteriostatic agent is preferably 1: (0.2-0.5).
  • the bacteriostatic agent is selected from one or more of thimerosal, quaternary ammonium salts, dumiphene, chlorhexidine, chlorobutanol, parabens, and sorbic acid, preferably hydroxy phenethyl ester or benzalkonium chloride.
  • the composition comprises loxoprofen sodium, edetate disodium, and sodium chloride.
  • the composition comprises the following components in parts by weight:
  • the composition comprises the following components by weight:
  • loxoprofen sodium, sodium hyaluronate, edetate disodium, and sodium chloride are included in the composition.
  • the composition comprises the following components by weight:
  • the composition comprises the following components by weight:
  • the composition comprises loxoprofen sodium, sodium hyaluronate, disodium edetate, sodium chloride, and ethylparaben or benzalkonium chloride.
  • the composition comprises the following components by weight:
  • the composition comprises the following components by weight:
  • the composition containing loxoprofen sodium is an aqueous solution.
  • the concentration of loxoprofen sodium in the aqueous solution is preferably 0.05-5 mg/mL, more preferably 0.1-2 mg/mL.
  • the drug of the present invention is a solution, such as eye drops.
  • the medicament of the present invention is a gel, such as an ophthalmic gel.
  • the drug of the present invention is ointment, such as eye ointment.
  • Fig. 1 is the influence that the composition containing loxoprofen sodium has on alkali-burned rabbit ophthalmic fluorescein sodium score;
  • Fig. 2 is the effect of the composition containing loxoprofen sodium on the ophthalmic tiger bengal staining score of alkali-burned rabbits.
  • the present invention has prepared an aqueous solution composition containing loxoprofen sodium, the composition of which is shown in Table 1 below (the quality of loxoprofen sodium in Table 1 is calculated by C 15 H 17 NaO 3 ).
  • This embodiment also provides the preparation method of the above-mentioned composition 1, specifically:
  • compositions can be conventionally adjusted on the basis of the preparation method of composition 1 according to the difference in components to obtain their respective preparation methods.
  • aqueous solution composition can be directly processed into eye drops. After adding water for injection to the full amount, it can be filtered and sterilized through a 0.22 ⁇ m microporous membrane, and then repacked in an eye drop bottle in a sterile environment.
  • Embodiment 1 Effect on dry eye of New Zealand rabbits caused by alkali burn
  • Each New Zealand rabbit was anesthetized with 1% propofol injection intravenously (1.5ml/kg), and after the animal maintained stable anesthesia, it was topically anesthetized with 100 ⁇ l eye drops of 2% lidocaine hydrochloride injection.
  • the animals were maintained in the third stage of anesthesia, dip a piece of filter paper strip about 10mm ⁇ 5mm in 1mol/L NaOH solution and place it on the conjunctiva about 2mm above the limbus of the rabbit.
  • the conjunctival sac was rinsed repeatedly with % sodium chloride injection.
  • the tear secretion of New Zealand rabbits was measured by Schirmer I test. That is, clamp the phenol red cotton thread with ophthalmic tweezers, place it on the outer canthus of New Zealand rabbits, take it out after 60 seconds and measure the wet length of the phenol red cotton thread.
  • composition 1 has no significant difference in tear film breakup time on the first day (D1) after administration (P>0.05). However, the tear film break-up time was significantly prolonged on the fifth day (D5) and the ninth day (D9) after administration, and there was a statistical difference (P ⁇ 0.05 or 0.01).
  • composition 1 and Figure 2 The effects of the composition on the ophthalmic sodium fluorescein score and tiger bengal staining score of alkali-burned rabbits are shown in Figure 1 and Figure 2, respectively. Combined with the data in Figure 1, Figure 2 and Table 3 and Table 4, it can be seen that compared with the model control group, the composition 1 containing loxoprofen sodium has a significant reduction effect on ophthalmic scores on the fifth and ninth days after administration . It can be seen that the composition containing loxoprofen sodium can effectively relieve eye damage.
  • the composition containing loxoprofen sodium has a significant improvement effect on the dry eye model of rabbits caused by alkali burn, and its improvement effect is mainly manifested in enhancing tear film stability and increasing tear secretion. And relieve corneal epithelial cell damage (mainly manifested as reducing local ocular edema).
  • the composition containing loxoprofen sodium also has the effect of increasing goblet cells.
  • compositions 2-4 were tested in the same method in this example. Compositions 2-4 all had obvious improvement effects on the alkali burn-induced dry eye model in rabbits, and there was no significant difference from the effect of composition 1.
  • Embodiment 2 Effect on mouse conjunctival sicca syndrome
  • mice of the same species were taken and euthanized by cervical dislocation, the eyes were sterilized by conventional methods, the conjunctiva was taken out on the ultra-clean workbench, washed with normal saline containing 80,000/500mL gentamicin, and placed in a solution containing 80,000/500mL gentamicin.
  • 500mL gentamicin normal saline cut the conjunctiva into pieces and grind them into a homogenate in a homogenizer. Keep it at 4°C, crush it on an ultrasonic crusher for 1 hour, and then put it in a centrifuge for centrifugation (3000r/min, ⁇ 15min).
  • the supernatant was taken out, and the protein content was determined by the Coomassie brilliant blue method. Then the protein concentration was diluted to 100 ⁇ g/mL with 0.14MPBS. Add an equal volume of conjunctival antigen solution to complete Freund's adjuvant (FCA), and mix thoroughly to form an oil-in-water solution.
  • FCA complete Freund's adjuvant
  • Tear film breakup time (BUT): Use a micropipette to drop 1 ⁇ l into the conjunctival sac below the BALB/c mouse and observe the cornea with cobalt blue light under a slit lamp microscope. When the corneal green film appears black, it indicates tears. Membrane ruptured. Measure 3 times in a row and take the average value. The normal BUT is 10-15 seconds, less than 10 seconds is abnormal, repeat the measurement 3 times, and take the average value.
  • Composition 1 has a significant improvement effect on the mouse conjunctival sicca syndrome model, and its improvement effect is mainly manifested in increasing the secretion of tear fluid in mice and prolonging the tear film breakup time.
  • compositions 2-4 were tested by the same method in this example. Compositions 2-4 all had obvious improvement effects on the mouse conjunctival sicca syndrome model, and the effect was not significantly different from that of composition 1.
  • Embodiment 3 stimulating experiment
  • Pranoprofen eye drops commercially available, the manufacturer is Senju Pharmaceutical Co., Ltd. Fukusaki Plant;
  • Diclofenac sodium eye drops commercially available, the manufacturer is Zhengzhou Zhuofeng Pharmaceutical Co., Ltd.;
  • Loxoprofen sodium eye drops obtained by filtering composition 1 through a 0.22 ⁇ m microporous membrane.
  • compositions 2-4 were tested by the same method, and it was found that compositions 2-4 provided eye drops with less irritation.

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Abstract

涉及一种洛索洛芬钠或含有洛索洛芬钠的组合物在制备预防和/或治疗干眼的药物中的应用。

Description

洛索洛芬钠在制备治疗干眼的药物中的应用
本申请要求申请日为2021年07月09日的中国专利申请202110780762.8的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及医药领域，具体涉及洛索洛芬钠或含有洛索洛芬钠的组合物在制备预防和/或治疗干眼的药物中的应用。
背景技术
干眼，又称为角结膜干燥综合征。国际泪膜和眼表协会TFOS(the Tear Film&Ocular Surface Society)在2015年举行的第二次工作组干眼病会议将干眼重新定义，即：干眼(dry eye disease，DED)是眼表的一种多因子疾病，特征是泪膜稳态的丧失并伴有眼表症状，主要为眼部干涩感、异物感、灼热感、经常会伴随眼部有粘稠分泌物，由于睡眠质量差，用眼过度加重，严重者甚至会影响视力和正常生活。
近些年来，干眼的发病率呈逐年上升的趋势，已经成为最普遍的眼科疾病之一。从世界范围来看，干眼发病率处在5.5％～33.7％，从发病率来看，女性高于男性，老年人高于青年人，亚洲人高于以及其他地区的人。国外的流行病学报道显示，在30～40岁人群中，干眼的患病率为20％；而70岁以上人群中，干眼的得病率高达36.1％，这些人群中女性的患病率依旧高于男性。
干眼的病因有很多，包括自身因素，如泪膜受损、泪腺功能障碍、睑板腺功能障碍、眼表蛋白表达异常、维生素A缺乏、性激素失调、神经调节异常等。许多系统性疾病也会引起干眼，如系统性红斑狼疮、糖尿病、干燥综合征、类风湿性关节炎、睡眠障碍、围绝经期综合征、甲状腺病、过敏性结膜炎等，干眼的发生还与年龄相关。另外，干眼的发生还包括很多环境因素，如环境污染或环境过度干燥，眼部手术及过度使用眼部药物，视频终端过度使用以及角膜接触镜的佩戴等因素都会导致干眼病的发生。经常从事户外工作的工作者会更容易出现干眼。虽然对干眼的发病因素进行了很多研究，但是干眼的发病机制并未完全明确。
洛索洛芬钠是一种非甾体抗炎药，临床上被用于类风湿性关节炎、腰痛、肩周炎、 颈肩腕综合症等的抗炎镇痛、手术、外伤后及拔牙后的镇痛消炎和急性上呼吸道炎症的解热镇痛等，目前还没有关于洛索洛芬钠治疗干眼的报道。
发明内容
本发明的目的在于克服现有技术的缺陷，提供一种治疗效果好且刺激性小的干眼治疗药物。
具体而言，本发明提供了洛索洛芬钠或含有洛索洛芬钠的组合物在制备用于预防和/或治疗干眼的药物中的应用。
洛索洛芬钠(化学名称：2-[4-(2-氧代环戊烷-1-基甲基)苯基]丙酸钠二水合物)是一种非甾体抗炎药，其作用机理为抑制前列腺素合成作用，作用靶点为环氧合酶。该化合物目前在临床上被用于类风湿性关节炎、腰痛、肩周炎、颈肩腕综合症等的抗炎镇痛、手术、外伤后及拔牙后的镇痛消炎和急性上呼吸道炎症的解热镇痛等。
本发明创造性地发现，洛索洛芬钠具有促进泪液分泌、增强泪膜稳定性以及缓解角膜上皮细胞损伤的功效，可以用于预防和/或治疗干眼，尤其是与泪腺功能障碍或泪液分泌减少、泪膜稳定性差和/或角膜上皮细胞损伤相关的干眼。
本发明同时提供了所述洛索洛芬钠或含有洛索洛芬钠的组合物在制备用于治疗泪腺功能障碍或促进泪液分泌的药物中的应用。
本发明同时提供了所述洛索洛芬钠或含有洛索洛芬钠的组合物在制备用于增强泪膜稳定性的药物中的应用。
本发明同时提供了所述洛索洛芬钠或含有洛索洛芬钠的组合物在制备用于预防和/或缓解角膜上皮细胞损伤的药物中的应用。
在一些实施方式中，所述含有洛索洛芬钠的组合物还含有增稠剂、金属离子络合剂、渗透压调节剂、pH调节剂和抑菌剂中的一种或多种。
在一些实施方式中，所述含有洛索洛芬钠的组合物至少还含有增稠剂。洛索洛芬钠与所述增稠剂的质量比优选为1：(0.5-1.5)，更优选为1：(0.8-1)。
在一些实施方式中，所述增稠剂选自玻璃酸钠、甲基纤维素、聚乙烯醇、聚乙烯吡咯烷酮、泊洛沙姆、羟丙甲纤维素、黄原胶中的一种或多种，优选为玻璃酸钠。
在一些实施方式中，所述含有洛索洛芬钠的组合物至少还含有金属离子络合剂。洛索洛芬钠与所述金属离子络合剂的质量比为1：(0.02-0.5)，更优选为1：(0.08-0.2)。
在一些实施方式中，所述金属离子络合剂为依地酸二钠。
在一些实施方式中，所述含有洛索洛芬钠的组合物至少还含有渗透压调节剂。洛索洛芬钠与所述渗透压调节剂的质量比优选为1：(2-18)，更优选为1：(4.5-10)。
在一些实施方式中，所述渗透压调节剂选自氯化钠、甘露醇、葡萄糖、氯化钾中的一种或多种，优选为氯化钠。
在一些实施方式中，所述含有洛索洛芬钠的组合物至少还含有pH调节剂。本发明中pH调节剂的用量依据实际需求而定，将最终产品的pH值调节至适合人体使用的水平即可。
在一些实施方式中，所述pH调节剂选自氢氧化钠、盐酸、枸缘酸钠、枸橼酸、硼酸、硼砂中的一种或多种。
在一些实施方式中，所述含有洛索洛芬钠的组合物中至少还含有抑菌剂。洛索洛芬钠与所述抑菌剂的质量比优选为1：(0.2-0.5)。
在一些实施方式中，所述抑菌剂选自硫柳汞、季铵盐类、杜米芬、洗必泰、三氯叔丁醇、尼泊金类、山梨酸中的一种或多种，优选为羟苯乙酯或苯扎氯铵。
在一些实施方式中，所述组合物包含洛索洛芬钠、依地酸二钠和氯化钠。
在一些实施方式中，所述组合物包含如下重量份的组分：
洛索洛芬钠                    1份；
依地酸二钠             0.02-0.5份；
氯化钠                     2-18份。
在一些实施方式中，所述组合物中包含如下重量份的组分：
洛索洛芬钠                    1份；
依地酸二钠             0.08-0.2份；
氯化钠                   4.5-10份。
在一些实施方式中，所述组合物中包含洛索洛芬钠、玻璃酸钠、依地酸二钠和氯化钠。
在一些实施方式中，所述组合物中包含如下重量份的组分：
Figure PCTCN2022104727-appb-000001
在一些实施方式中，所述组合物中包含如下重量份的组分：
Figure PCTCN2022104727-appb-000002
在一些实施方式中，所述组合物中包含洛索洛芬钠、玻璃酸钠、依地酸二钠、氯化钠以及羟苯乙酯或苯扎氯铵。
在一些实施方式中，所述组合物中包含如下重量份的组分：
Figure PCTCN2022104727-appb-000003
在一些实施方式中，所述组合物中包含如下重量份的组分：
Figure PCTCN2022104727-appb-000004
在一些实施方式中，所述含有洛索洛芬钠的组合物为水溶液。所述水溶液中洛索洛芬钠的浓度优选为0.05-5mg/mL，更优选为0.1-2mg/mL。
在一些实施方式中，本发明所述药物为溶液剂，如滴眼液。
在一些实施方式中，本发明所述药物为凝胶剂，如眼用凝胶。
在一些实施方式中，本发明所述药物为膏剂，如眼膏。
附图说明
图1为含有洛索洛芬钠的组合物对碱烧伤兔眼科荧光素钠评分的影响；
图2为含有洛索洛芬钠的组合物对碱烧伤兔眼科虎红染色评分的影响。
具体实施方式
以下实施例用于说明本发明，但不用来限制本发明的范围。
以下各实施例对洛索洛芬钠对干眼的治疗效果进行验证。
为了便于实验，本发明制备了含有洛索洛芬钠的水溶液组合物，组成如下表1所示(表1中的洛索洛芬钠的质量以C 15H 17NaO 3计)。
表1：组合物组成
Figure PCTCN2022104727-appb-000005
本实施例还提供了上述组合物1的制备方法，具体为：
(1)称取玻璃酸钠，取约1/2处方量注射用水，边搅拌边加入玻璃酸钠，溶胀3小时以上，使玻璃酸钠完全溶解；
(2)称取洛索洛芬钠，加入少量水使其溶解，加入氯化钠、依地酸二钠搅拌溶解；
(3)用少量注射用水溶解羟苯乙酯，煮沸使其完全溶解，再与已溶解好的玻璃酸钠、洛索洛芬钠、氯化钠和依地酸二钠溶液混合，加注射用水至全量。
其余组合物可依据组分的差异，在组合物1制备方法的基础上进行常规调整得到各自的制备方法。
上述水溶液组合物可以直接加工成滴眼液，在加注射用水至全量的基础上，经0.22μm微孔滤膜过滤除菌，再用滴眼剂瓶在无菌环境中分装即可。
实施例1：对碱烧伤致新西兰兔干眼的影响
1、造模方法
每只新西兰兔采用1％的丙泊酚注射液静脉注射麻醉(1.5ml/kg)，待动物维持麻醉稳定后用2％的盐酸利多卡因注射液100μl滴眼表面麻醉。动物维持在麻醉第三期时，用1张约10mm×5mm大小的滤纸条蘸1mol/L的NaOH溶液后置于距兔角膜缘上方约2mm的睑结膜上，90s后立即用约50ml 0.9％氯化钠注射液反复冲洗结膜囊。
2、结膜荧光素染色
使用移液器在新西兰兔右眼结膜囊内滴入2μl的0.5％荧光素钠溶液，5s后用 0.9％氯化钠注射液冲洗多余的荧光素，在裂隙灯显微镜下，钴蓝色弥散光观察结膜染色情况。结膜荧光染色评分标准：将结膜分成四个象限，每个象限根据染色程度和面积分为四个等级：0分为无染色；1分为散在点状染色；2分为密集点状染色；3分为片状染色，共12分(左眼未造模，作为阴性对照眼)。
3、结膜虎红染色
使用移液器在新西兰兔右眼结膜囊内滴入2μl的1％虎红，5s后用0.9％氯化钠注射液冲洗多余的虎红，在裂隙灯显微镜下，绿光观察结膜染色情况。结膜虎红染色评分标准与结膜荧光染色标准一致。
4、泪液分泌量(双眼)
采用Schirmer I实验(Schirmer I test)测量新西兰兔泪液的分泌。即用眼科镊夹住酚红棉线，置于新西兰兔外眦部，60秒后取出测量酚红棉线湿润的长度。
5、泪膜破裂时间(双眼)
使用可调移液器在新西兰兔眼下睑结膜囊内滴入2μl的0.5％荧光素钠溶液，以恒定力手动眨眼数次后，以恒定力撑开兔眼，用裂隙灯显微镜，钴蓝光观察角膜，当角膜绿色薄膜出现黑区时，表示泪膜破裂。连续测3次，取其平均值，结果如表2所示。
表2：对碱烧伤兔泪膜破裂时间的影响
Figure PCTCN2022104727-appb-000006
Figure PCTCN2022104727-appb-000007
注：与阴性对照眼比，#表示P<0.05，##表示P<0.01；与模型对照组相比，*表示P<0.05，**表示P<0.01(阴性对照眼为左眼，模型对照组为给予等容积的0.9％氯化钠注射液)。
表2数据可以看出，组合物1在给药后第一天(D1)对泪膜破裂时间未见明显差异(P>0.05)。但在给药后第五天(D5)、第九天(D9)对泪膜破裂时间均明显延长，有统计学差异(P<0.05或0.01)。
表3：对碱烧伤兔眼科评分的影响
Figure PCTCN2022104727-appb-000008
Figure PCTCN2022104727-appb-000009
注：与模型对照组比，#表示P<0.05，##表示P<0.01(模型对照组为给予等容积的0.9％氯化钠注射液)。
表4：对碱烧伤兔眼科评分的影响
Figure PCTCN2022104727-appb-000010
Figure PCTCN2022104727-appb-000011
注：与模型对照组比，#表示P<0.05，##表示P<0.01(模型对照组为给予等容积的0.9％氯化钠注射液)。
组合物对碱烧伤兔眼科荧光素钠评分和虎红染色评分的影响分别如图1和图2所示。结合图1、图2以及表3和表4的数据可以看出，与模型对照组相比，含有洛索洛芬钠的组合物1在给药后第五、九天对眼科评分具有明显降低作用。可见，含有洛索洛芬钠的组合物可以有效地缓解眼损伤。
表5：对碱灼伤兔酚红棉线湿润长度的影响
Figure PCTCN2022104727-appb-000012
Figure PCTCN2022104727-appb-000013
注：与阴性对照眼比，#表示P<0.05，##表示P<0.01。(阴性对照眼为左眼)
从以上表2～表5的数据可知，含有洛索洛芬钠的组合物对碱烧伤致兔干眼模型具有明显的改善作用，其改善作用主要表现为增强泪膜稳定性、增加泪液分泌量以及缓解角膜上皮细胞损伤(主要表现为降低眼损伤局部水肿)。此外，通过病理研究报告研究得知，含有洛索洛芬钠的组合物还具有增加杯状细胞的效果。
本实施例采用同样的方法对组合物2～4进行了检测，组合物2～4对于碱烧伤致兔 干眼模型均具有明显的改善作用，且与组合物1的效果没有明显差异。
实施例2：对小鼠结膜干燥综合症的影响
1、抗原制备方法
取同种小鼠，用颈椎脱臼法安乐死，常规方法眼周消毒，在超净工作台上整取出结膜，用含8万/500mL庆大霉素的生理盐水洗净，放于含8万/500mL庆大霉素的生理盐水中，将结膜剪成碎片，在匀浆器中碾成匀浆。保持4℃，在超声破碎机上破碎1h再放于离心机离心(3000r/min，×15min)。取出上清液，考马斯亮蓝法测定蛋白含量。然后再用0.14MPBS将蛋白浓度稀释至100μg/mL。在完全弗氏佐剂(FCA)中加入等体积的结膜抗原溶液，充分混匀成油包水溶液。
2、实验方法
将上述油包水溶液多点注射于鼠背部皮下、四肢腋下淋巴结和足垫，总量为0.5mL。具体而言：
(1)泪膜破裂时间(BUT)：使用微量加液器在BALB/c小鼠下方结膜囊内滴入1μl用裂隙灯显微镜的钴蓝光观察角膜，当角膜绿色薄膜出现黑区时，表示泪膜破裂。连续测3次，取其平均值。正常BUT为10～15秒，少于10秒为异常，重复测量3次，取平均值。
(2)BALB/c小鼠的泪液分泌实验：采用Schirmer I实验(Schirmer I test)测量BALB/c小鼠泪液的分泌量。即用眼科镊夹住酚红棉线，置于BALB/c小鼠外眦部，60秒后取出测量酚红棉线湿润的长度。
(3)统计分析方法：所有数据均输入EXCEL进行统计分析，各组计量数据均计算
Figure PCTCN2022104727-appb-000014
各实验组进行组间比较之前先进行组间方差分析(F-test)，当组间方差齐同时，组间比较采用Student-T检验(非配对的T检验)进行统计，组间方差不齐时，采用校正的Student-T检验进行统计分析。
表6：对小鼠结膜干燥综合征模型泪膜破裂时间的影响
Figure PCTCN2022104727-appb-000015
Figure PCTCN2022104727-appb-000016
注：与空白对照组比，#表示P<0.05，##表示P<0.01；与模型对照组比，#表示P<0.05，##表示P<0.01。
表7：对小鼠结膜干燥综合征模型酚红棉线湿润长度的影响
Figure PCTCN2022104727-appb-000017
Figure PCTCN2022104727-appb-000018
注：与空白对照组比，#表示P<0.05，##表示P<0.01；与模型对照组比，#表示P<0.05，##表示P<0.01。
根据表6、表7的实验数据可知，组合物1对小鼠结膜干燥综合症模型具有明显的改善作用，其改善作用主要表现为增加小鼠泪液的分泌量以及延长泪膜破裂时间。
本实施例采用同样的方法对组合物2～4进行了检测，组合物2～4对于小鼠结膜干燥综合症模型均具有明显的改善作用，且与组合物1的效果没有明显差异。
实施例3：刺激性实验
1、滴眼液来源：
普拉洛芬滴眼液：市售，厂家为Senju Pharmaceutical Co.，Ltd.Fukusaki Plant；
双氯芬酸钠滴眼液：市售，厂家为郑州卓峰制药有限公司；
洛索洛芬钠滴眼液：组合物1经0.22μm微孔滤膜过滤后所得。
2、实验操作：每组各选择20名干眼患者，随机双盲使用三种滴眼液，来对比浓度均为0.1％的普拉洛芬、双氯芬酸钠、洛索洛芬钠滴眼液对于患者眼部的刺激性症状。眼部刺激症状包括有如烧灼感、刺痛感或者流泪等症状。统计结果如表8所示。
表8：刺激性对比实验记录
Figure PCTCN2022104727-appb-000019
根据初步统计的结果，有40％的双氯芬酸钠滴眼液组出现了至少1种眼部刺激症状；20％的普拉洛芬滴眼液组出现了至少1种眼部刺激症状；而洛索洛芬钠滴眼液使用组，仅有一例患者出现眼部刺激症状，而且是刺激性比较小的流泪症状，其他患者普遍反映使用之后，眼部舒适感强，因此可以长期使用，同时也比较适合应用于儿童干眼患者。
本实施例采用同样的方法对组合物2～4进行了检测，发现组合物2～4提供滴眼液刺激性都比较小。
虽然，上文中已经用一般性说明、具体实施方式及试验，对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。

Claims (18)

  1. 洛索洛芬钠或含有洛索洛芬钠的组合物在制备用于预防和/或治疗干眼的药物中的应用。
  2. 根据权利要求1所述的应用，其特征在于，所述干眼是由泪腺功能障碍或泪液分泌减少、泪膜稳定性差和/或角膜上皮细胞损伤引起的。
  3. 根据权利要求1所述的应用，其特征在于，所述药物是通过促进泪液分泌、增强泪膜稳定性和/或缓解角膜上皮细胞损伤实现对干眼的预防和/或治疗。
  4. 洛索洛芬钠或含有洛索洛芬钠的组合物在制备用于治疗泪腺功能障碍或促进泪液分泌的药物中的应用。
  5. 洛索洛芬钠或含有洛索洛芬钠的组合物在制备用于增强泪膜稳定性的药物中的应用。
  6. 洛索洛芬钠或含有洛索洛芬钠的组合物在制备用于预防和/或缓解角膜上皮细胞损伤的药物中的应用。
  7. 根据权利要求1～6任意一项所述的应用，其特征在于，所述组合物中除洛索洛芬钠之外，还包含增稠剂、金属离子络合剂、渗透压调节剂、pH调节剂和抑菌剂中的一种或多种。
  8. 根据权利要求7所述的应用，其特征在于，所述增稠剂选自玻璃酸钠、甲基纤维素、聚乙烯醇、聚乙烯吡咯烷酮、泊洛沙姆、羟丙甲纤维素、黄原胶中的一种或多种；和/或，
    所述金属离子络合剂选用依地酸二钠；和/或，
    所述渗透压调节剂选自氯化钠、甘露醇、葡萄糖、氯化钾中的一种或多种；和/或，
    所述pH调节剂选自氢氧化钠、盐酸、枸缘酸钠、枸橼酸、硼酸、硼砂中的一种或多种；和/或，
    所述抑菌剂选自硫柳汞、季铵盐类、杜米芬、洗必泰、三氯叔丁醇、尼泊金类、山梨酸的一种或多种。
  9. 根据权利要求8所述的应用，其特征在于，所述组合物包含洛索洛芬钠、依地酸二钠和氯化钠。
  10. 根据权利要求9所述的应用，其特征在于，所述组合物包含如下重量份的组分：
    洛索洛芬钠                    1份；
    依地酸二钠             0.02-0.5份；
    氯化钠                     2-18份。
  11. 根据权利要求8所述的应用，其特征在于，所述组合物包含洛索洛芬钠、玻璃酸钠、依地酸二钠和氯化钠。
  12. 根据权利要求11所述的应用，其特征在于，所述组合物包含如下重量份的组分：
    Figure PCTCN2022104727-appb-100001
  13. 根据权利要求8所述的应用，其特征在于，所述组合物包含洛索洛芬钠、玻璃酸钠、依地酸二钠、氯化钠以及羟苯乙酯或苯扎氯铵。
  14. 根据权利要求13所述的应用，其特征在于，所述组合物包含如下重量份的组分：
    Figure PCTCN2022104727-appb-100002
  15. 根据权利要求1～14任意一项所述的应用，其特征在于，所述含有洛索洛芬钠的组合物为水性溶液的形式。
  16. 根据权利要求15所述的应用，其特征在于，所述水性溶液中洛索洛芬钠的浓度为0.05-5mg/mL。
  17. 根据权利要求16所述的应用，其特征在于，所述水性溶液中洛索洛芬钠的浓度为0.1-2mg/mL。
  18. 根据权利要求1～17任意一项所述的应用，其特征在于，所述药物为溶液剂、凝胶剂或膏剂。
PCT/CN2022/104727 2021-07-09 2022-07-08 洛索洛芬钠在制备治疗干眼的药物中的应用 Ceased WO2023280319A1 (zh)

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KR1020247004355A KR20240035827A (ko) 2021-07-09 2022-07-08 안구건조증 치료를 위한 약물의 제조에 있어서의 록소프로펜나트륨의 용도
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