WO2023280318A1 - 一种含有洛索洛芬钠的组合物 - Google Patents

一种含有洛索洛芬钠的组合物 Download PDF

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WO2023280318A1
WO2023280318A1 PCT/CN2022/104726 CN2022104726W WO2023280318A1 WO 2023280318 A1 WO2023280318 A1 WO 2023280318A1 CN 2022104726 W CN2022104726 W CN 2022104726W WO 2023280318 A1 WO2023280318 A1 WO 2023280318A1
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sodium
composition according
composition
sodium hyaluronate
loxoprofen sodium
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PCT/CN2022/104726
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English (en)
French (fr)
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周胜安
于垂亮
王延东
冯锡明
李亚雄
吴美容
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广州润尔眼科生物科技有限公司
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Priority to KR1020247004304A priority Critical patent/KR20240032950A/ko
Priority to EP22837063.1A priority patent/EP4368179A1/en
Priority to AU2022306163A priority patent/AU2022306163A1/en
Priority to CN202280048738.8A priority patent/CN117956987A/zh
Publication of WO2023280318A1 publication Critical patent/WO2023280318A1/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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • 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 relates to the field of medicine, in particular to a composition containing loxoprofen sodium.
  • Non-steroidal anti-inflammatory drugs have anti-inflammatory, antipyretic, and analgesic effects, and have no disadvantages of glucocorticoids that easily cause more serious adverse reactions. They have become an important class of anti-inflammatory drugs in clinical ophthalmology. . Its eye drops are used for eye trauma, anti-inflammatory after laser surgery and cataract surgery, and inhibit miosis during operation, and have achieved good results.
  • 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.
  • the eye drops containing loxoprofen sodium may have poor chemical stability, especially the high content of ring-opening impurities in the case of long-term storage.
  • the purpose of the present invention is to overcome the defects of the prior art and provide a composition containing loxoprofen sodium with good stability and long shelf life.
  • the present invention provides a composition containing loxoprofen sodium, said composition comprising loxoprofen sodium, sodium hyaluronate and polysorbate 80; wherein, the molecular weight of said sodium hyaluronate is 0.8 ⁇ 10 6 ⁇ 1.6 ⁇ 10 6 .
  • the present invention creatively finds that the combination of sodium hyaluronate and polysorbate 80 with a specific molecular weight and loxoprofen sodium can significantly improve the chemical stability of loxoprofen sodium itself, thereby obtaining a composition with more stable quality .
  • the sodium hyaluronate (Sodium Hyaluronate) used in the present invention is the sodium salt form of hyaluronic acid (Hyaluronic Acid for short HA).
  • Hyaluronic acid is a homopolymer formed by repeated alternation of D-glucuronic acid and N-acetylglucosamine disaccharide units. Its weight-average molecular weight is generally 100,000 to 10 million Da.
  • Sodium hyaluronate currently used For preparations, such as viscoelastic agents for ophthalmic surgery, joint cavity injections for arthritis, postoperative anti-adhesion preparations, eye drops, etc. the average molecular weight of HA used is generally 500,000 to 5 million Da.
  • the present invention finds that the stability of loxoprofen sodium can be significantly improved by using sodium hyaluronate with a molecular weight in the range of 0.8 ⁇ 10 6 to 1.6 ⁇ 10 6 in combination with polysorbate 80.
  • the molecular weight of the sodium hyaluronate is 0.8 ⁇ 10 6 to 1.4 ⁇ 10 6 .
  • the molecular weight of the sodium hyaluronate may be 0.8 ⁇ 10 6 to 1.0 ⁇ 10 6 , or 1.0 ⁇ 10 6 to 1.2 ⁇ 10 6 , or 1.2 ⁇ 10 6 to 1.4 ⁇ 10 6 .
  • the molecular weight of sodium hyaluronate in the present invention refers to the weight average molecular weight (M w ), and the unit is Dalton (Da).
  • the mass ratio of loxoprofen sodium, sodium hyaluronate and polysorbate 80 is (1-4):(0.5-2):(0.1-1), preferably 1:(0.5 -1.5): (0.1-1), more preferably 1: (0.8-1.2): (0.2-0.5).
  • the composition further contains one or more of a metal ion complexing agent, an osmotic pressure regulator, a pH regulator, a surfactant, and a bacteriostatic agent.
  • 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 preferably (1-4):(0.05-0.2), more preferably 1:(0.05-0.1).
  • the metal ion complexing agent is disodium edetate.
  • the composition containing loxoprofen sodium further contains at least an osmotic pressure regulator.
  • the dosage of the osmotic pressure regulator in the present invention is determined according to actual needs, and the osmotic pressure value of the final product can be adjusted to a level suitable for human use.
  • 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 (1-4):(0.05-0.2), more preferably 1:(0.05-0.1).
  • the bacteriostatic agent is selected from one or more of thimerosal, quaternary ammonium salts, dumiphene, chlorhexidine, chlorobutanol, parabens, and sorbic acid, preferably benzene ammonium chloride.
  • loxoprofen sodium, sodium hyaluronate, disodium edetate, sodium chloride, and polysorbate 80 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, polysorbate 80, and benzalkonium chloride.
  • the composition comprises the following components by weight:
  • the composition comprises the following components by weight:
  • the composition comprising loxoprofen sodium is in the form of an aqueous solution.
  • concentration of loxoprofen sodium in the aqueous solution is preferably 0.05-5 mg/mL, more preferably 1-2 mg/mL.
  • the composition containing loxoprofen sodium is a solution, such as eye drops.
  • the composition containing loxoprofen sodium is a gel, such as ophthalmic gel.
  • the composition containing loxoprofen sodium is an ointment, such as eye ointment.
  • the present invention provides a method for preparing the composition.
  • the preparation method of the composition comprises the following steps: preparing an aqueous solution of sodium hyaluronate, dissolving other components including loxoprofen sodium in water, mixing with the aqueous solution of sodium hyaluronate, and adding water to constant volume.
  • the composition contains loxoprofen sodium, sodium hyaluronate, polysorbate 80, metal ion chelating agent and osmotic pressure regulator, and the method for preparing the composition comprises the following steps:
  • solution I dissolving sodium hyaluronate with water to obtain solution I;
  • the temperature of water used for dissolving sodium hyaluronate is preferably below 40°C;
  • the composition contains loxoprofen sodium, sodium hyaluronate, polysorbate 80, metal ion chelating agent, osmotic pressure regulator and antibacterial agent, and the method for preparing the composition includes the following steps :
  • solution I dissolving sodium hyaluronate with water to obtain solution I;
  • the temperature of water used for dissolving sodium hyaluronate is preferably below 40°C;
  • the present invention provides the use of the composition described in the first aspect in the preparation of drugs for preventing or treating ophthalmic diseases.
  • the ophthalmic disease is inflammation, such as allergic conjunctivitis or uveitis.
  • the ophthalmic disease is dry eye, such as dry eye caused by lacrimal gland dysfunction, dry eye caused by decreased tear secretion, dry eye caused by poor tear film stability, or dry eye caused by corneal epithelial cell damage.
  • the ophthalmic disease is lacrimal gland dysfunction or manifests as decreased tear secretion.
  • the ophthalmic disorder is manifested by poor tear film stability.
  • the ophthalmic disease is local edema caused by corneal epithelial cell injury or eye injury.
  • the quality of loxoprofen sodium is calculated by C 15 H 17 NaO 3 .
  • the present embodiment provides an aqueous solution composition containing loxoprofen sodium, which consists of: 5 g of loxoprofen sodium, 5 g of sodium hyaluronate with a molecular weight of 0.972 ⁇ 10 6 , 0.5 g of disodium edetate, chlorine Add sodium chloride 42.5g, polysorbate 802.5g, benzalkonium chloride 0.5g, and water for injection to a total of 5L.
  • loxoprofen sodium which consists of: 5 g of loxoprofen sodium, 5 g of sodium hyaluronate with a molecular weight of 0.972 ⁇ 10 6 , 0.5 g of disodium edetate, chlorine Add sodium chloride 42.5g, polysorbate 802.5g, benzalkonium chloride 0.5g, and water for injection to a total of 5L.
  • Present embodiment provides the preparation method of described composition simultaneously, specifically:
  • 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.
  • This example provides an aqueous solution composition containing loxoprofen sodium. Compared with Example 1, the only difference is that the molecular weight of sodium hyaluronate is 1.353 ⁇ 10 6 .
  • This example provides an aqueous solution composition containing loxoprofen sodium. Compared with Example 1, the only difference is that the dosage of loxoprofen sodium is 10 g, and the molecular weight of sodium hyaluronate is 0.878 ⁇ 10 6 .
  • This example provides an aqueous solution composition containing loxoprofen sodium. Compared with Example 3, the only difference is that the molecular weight of sodium hyaluronate is 1.276 ⁇ 10 6 .
  • Embodiment 5 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.
  • Scoring criteria for conjunctival fluorescence staining divide the conjunctiva into four quadrants, and each quadrant is divided into four grades according to the degree and area of staining: 0: no staining; 1: scattered punctate staining; 2: intensive punctate staining; 3 Divided into sheet staining, a total of 12 points (the left eye was not modeled, as a negative control eye).
  • 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.
  • Example 1 of the present invention has obvious improvement effect on the rabbit dry eye model caused by alkali burn. Eye damage local edema).
  • Embodiment 6 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 embodiment 1 (prepared into eye drops).
  • the eye drops provided by the embodiment of the present invention only the patient has ocular irritation symptoms, and it is less irritating tearing symptoms, other patients generally reflect that after use, the eyes have a strong sense of comfort, so it can be used for a long time More suitable for children with dry eye patients.
  • Example 1 and Example 4 were respectively accelerated for 6 months (40 ⁇ 2°C/RH 25% ⁇ 5%) and long-term for 24 months (25 ⁇ 2°C/RH 40% ⁇ 5%) to stabilize sex studies.
  • Impurity 1 in the following tables refers to:
  • Ring-opening impurities in the following tables refer to:
  • Example 1 and Example 4 of the present invention showed good stability in both the accelerated test and the long-term stability test, and the impurity content was low. And the present invention uses the same method to detect the composition provided by Example 2 and Example 3, and the stability is not significantly different from that of Example 1 and Example 4.
  • Loxoprofen sodium eye drops eye drops of different concentrations prepared according to Example 1;
  • Placebo no loxoprofen sodium was added in embodiment 1, and other ingredients were identical.
  • Single administration includes 0.025mg (concentration 0.5mg/ml), 0.05mg (concentration 1mg/ml), 0.1mg (concentration 2mg/ml), 0.2mg (concentration 4mg/mL) dosage, administration method 1 drop/time , 1 time/day; multiple administrations include 0.05mg, 0.1mg, 0.2mg doses, the administration method is 1 drop/time, 4 times/day.
  • the pharmacokinetic test data are shown in Table 5.
  • AUC 0-t area under the drug-time curve (0 to t hours)

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Abstract

一种含有洛索洛芬钠的组合物，所述组合物包含洛索洛芬钠、玻璃酸钠以及聚山梨酯80；其中，所述玻璃酸钠的分子量为0.8×10 6～1.6×10 6。所述组合物稳定性好，保质期长，便于使用。

Description

一种含有洛索洛芬钠的组合物
本申请要求申请日为2021年07月09日的中国专利申请202110780094.9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，具体涉及一种含有洛索洛芬钠的组合物。
背景技术
非甾体类抗炎药(NSAIDS)具有抗炎、解热、镇痛作用，并且无糖皮质激素类药物易导致较多严重不良反应的缺点，目前已经成为眼科临床中一类重要抗炎药。其滴眼液用于眼外伤，激光手术和白内障手术后的消炎及术中抑制缩瞳的作用，取得良好的效果。
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。
在实际应用中，含有洛索洛芬钠的滴眼液在长期放置的情况下，可能存在化学稳定性不好尤其是开环杂质含量偏高的情况。
发明内容
本发明的目的在于克服现有技术的缺陷，提供一种稳定性好、保质期长的含有洛索洛芬钠的组合物。
具体而言，本发明提供一种含有洛索洛芬钠的组合物，所述组合物包含洛索洛芬钠、玻璃酸钠以及聚山梨酯80；其中，所述玻璃酸钠的分子量为0.8×10 6～1.6×10 6。
本发明创造性地发现，将特定分子量的玻璃酸钠以及聚山梨酯80 与洛索洛芬钠合用，可以显著提高洛索洛芬钠本身的化学稳定性，从而可以获得质量更为稳定的组合物。
本发明采用的玻璃酸钠(Sodium Hyaluronate)为玻璃酸(Hyaluronic Acid简称HA)的钠盐形式。玻璃酸是由D-葡萄糖醛酸和N-乙酰葡萄糖胺双糖单位反复交替而形成的一种均聚物，其重均分子量一般为10万至1000万Da，目前临床上应用的玻璃酸钠制剂，如眼科手术用黏弹剂、治疗关节炎的关节腔注射液、术后防粘连制剂、滴眼液等，所用HA的平均分子量一般为50万至500万Da。本发明发现采用分子量在0.8×10 6～1.6×10 6范围内的玻璃酸钠，配合聚山梨酯80使用，可以使洛索洛芬钠的稳定性显著提高。
在一些实施方式中，所述玻璃酸钠的分子量为0.8×10 6～1.4×10 6。具体而言，本发明提供的组合物中，所述玻璃酸钠的分子量可以为0.8×10 6～1.0×10 6，或者为1.0×10 6～1.2×10 6，或者为1.2×10 6～1.4×10 6。本发明中玻璃酸钠的分子量是指重均分子量(M w)，单位是道尔顿(Da)。
在一些实施方式中，所述洛索洛芬钠、玻璃酸钠以及聚山梨酯80的质量比为(1-4)：(0.5-2)：(0.1-1)，优选为1：(0.5-1.5)：(0.1-1)，更优选为1：(0.8-1.2)：(0.2-0.5)。
在一些实施方式中，所述组合物中还含有金属离子络合剂、渗透压调节剂、pH调节剂、表面活性剂、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优选为(1-4)：(0.05-0.2)，更优选为1：(0.05-0.1)。
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。本发明中渗透压调节剂的用量依据实际需求而定，将最终产品的渗透压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(1-4)：(0.05-0.2)，更优选为1：(0.05-0.1)。
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，优选为苯扎氯铵。
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、氯化钠和聚山梨酯80。
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 PCTCN2022104726-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 PCTCN2022104726-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、聚山梨酯80和苯扎氯铵。
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 PCTCN2022104726-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 PCTCN2022104726-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性溶液的形式。所述水性溶液中洛索洛芬钠的浓度优选为0.05-5mg/mL，更优选为1-2mg/mL。
在一些实施方式中，所述含有洛索洛芬钠的组合物为溶液剂，如滴眼液。
在一些实施方式中，所述含有洛索洛芬钠的组合物为凝胶剂，如眼用凝胶。
在一些实施方式中，所述含有洛索洛芬钠的组合物为膏剂，如眼膏。
第二方面，本发明提供所述组合物的制备方法。
具体而言，所述组合物的制备方法包括如下步骤：配制玻璃酸钠 水溶液，将包含洛索洛芬钠在内的其它成分用水溶解后与所述玻璃酸钠水溶液混合，加水定容。
本发明提供的制备过程中，全程保持搅拌状态为宜，以确保玻璃酸钠完全溶解，溶液澄清。
在一些实施方式中，所述组合物中含有洛索洛芬钠、玻璃酸钠、聚山梨酯80、金属离子螯合剂和渗透压调节剂，制备该组合物的方法包括如下步骤：
(1)用水溶解玻璃酸钠，得溶液I；溶解玻璃酸钠所用水的温度优选为40℃以下；
(2)用水溶解洛索洛芬钠，再加入金属离子螯合剂和渗透压调节剂，得溶液II；
(3)将溶液II加入到溶液I中，得溶液III；
(4)用水溶解聚山梨酯80，将所得溶液加入溶液III中；
(5)加水定容至全量。
在一些实施方式中，所述组合物中含有洛索洛芬钠、玻璃酸钠、聚山梨酯80、金属离子螯合剂、渗透压调节剂和抑菌剂，制备该组合物的方法包括如下步骤：
(1)用水溶解玻璃酸钠，得溶液I；溶解玻璃酸钠所用水的温度优选为40℃以下；
(2)用水溶解洛索洛芬钠，再加入金属离子螯合剂、渗透压调节剂，得溶液II；
(3)将溶液II加入到溶液I中，得溶液III；
(4)用水分别溶解聚山梨酯80和抑菌剂，将所得的两种溶液加入溶液III中；
(5)加水定容至全量。
第三方面，本发明提供了第一方面所述的组合物在制备预防或治疗眼科疾病药物中的应用。
在一些实施方式中，所述眼科疾病为炎症，如过敏性结膜炎或葡萄膜炎。
在一些实施方式中，所述眼科疾病为干眼，如由泪腺功能障碍引起的干眼、泪液分泌减少引起的干眼、泪膜稳定性差引起的干眼或角膜上皮细胞损伤引起的干眼。
在一些实施方式中，所述眼科疾病为泪腺功能障碍或表现为泪液分泌减少。
在一些实施方式中，所述眼科疾病表现为泪膜稳定性差。
在一些实施方式中，所述眼科疾病为角膜上皮细胞损伤或眼损伤引起的局部水肿。
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。
以下各实施例中，洛索洛芬钠的质量以C 15H 17NaO 3计。
实施例1
本实施例提供了一种含有洛索洛芬钠的水溶液组合物，其组成为：洛索洛芬钠5g，分子量为0.972×10 6的玻璃酸钠5g，依地酸二钠0.5g，氯化钠42.5g，聚山梨酯802.5g，苯扎氯铵0.5g，注射用水加至总量为5L。
本实施例同时提供了所述组合物的制备方法，具体为：
(1)称取玻璃酸钠，取约60％处方量注射用水(40℃以下)，边搅拌边分散加入玻璃酸钠，得溶液I；
(2)称取洛索洛芬钠，加入少量水使溶解，加入氯化钠、依地酸二钠搅拌至溶解，得溶液II，将溶液II加入到溶液I中，得溶液III，并持续搅拌；
(3)称取聚山梨酯80，加入少量注射用水，搅拌溶解后加入到溶液III中；
(4)用10％处方量的注射用水溶解苯扎氯铵，并加入到溶液III 中，继续搅拌至溶液澄清；
(5)加注射用水定容至全量。
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2
本实施例提供了一种含有洛索洛芬钠的水溶液组合物，与实施例1相比，区别仅在于：玻璃酸钠的分子量为1.353×10 6。
实施例3
本实施例提供了一种含有洛索洛芬钠的水溶液组合物，与实施例1相比，区别仅在于：洛索洛芬钠的用量为10g，玻璃酸钠的分子量为0.878×10 6。
实施例4
本实施例提供了一种含有洛索洛芬钠的水溶液组合物，与实施例3相比，区别仅在于：玻璃酸钠的分子量为1.276×10 6。
实施例5：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。
本发明实施例1提供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)。
实施例6：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：实施例1(制备成滴眼液)。
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。
本发明实施例1提供的滴眼液，仅有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。
实施例7：稳定性研究
将实施例1、实施例4所制得的组合物分别进行加速6月(40±2℃/RH 25％±5％)及长期24月(25±2℃/RH 40％±5％)稳定性研究。
以下各表格中杂质1是指：
Figure PCTCN2022104726-appb-000005
以下各表格中开环杂质是指：
Figure PCTCN2022104726-appb-000006
表1：实施例1的组合物加速稳定性有关物质检测结果
  限度要求 0月 1月 2月 3月 6月
杂质1 ≤1.0％ 未检出 未检出 未检出 未检出 未检出
开环杂质 ≤1.0％ 0.0128％ 0.0137％ 0.0125％ 0.0162％ 0.0157％
总杂 ≤2.0％ 0.0579％ 0.0546％ 0.0536％ 0.0465％ 0.0640％
表2：实施例4的组合物加速稳定性有关物质检测结果
  限度要求 0月 1月 2月 3月 6月
杂质1 ≤1.0％ 未检出 未检出 未检出 未检出 未检出
开环杂质 ≤1.0％ 0.0143％ 0.0137％ 0.0128％ 0.0171％ 0.0174％
总杂 ≤2.0％ 0.0520％ 0.0555％ 0.0489％ 0.0476％ 0.0586％
表3：实施例1的组合物长期稳定性有关物质检测结果
  限度要求 0月 3月 6月 9月 12月 18月 24月
杂质1 ≤1.0％ 未检出 未检出 未检出 未检出 未检出 未检出 未检出
开环杂质 ≤1.0％ 0.0128％ 0.0193％ 0.0153％ 0.0170％ 0.0167％ 0.0156％ 0.0273％
总杂 ≤2.0％ 0.0579％ 0.0473％ 0.0491％ 0.0670％ 0.0725％ 0.0553 0.0760％
表4：实施例4的组合物长期稳定性有关物质检测结果
  限度要求 0月 3月 6月 9月 12月 18月 24月
杂质1 ≤1.0％ 未检出 未检出 未检出 未检出 未检出 未检出 未检出
开环杂质 ≤1.0％ 0.0143％ 0.0167％ 0.0163％ 0.0159％ 0.0159％ 0.0240％ 0.0284％
总杂 ≤2.0％ 0.0520％ 0.0539％ 0.0566％ 0.0639％ 0.0652％ 0.0781％ 0.0716％
由以上结果可知，本发明实施例1及实施例4提供的组合物在加速实验和长期稳定性实验中都表现出了较好的稳定性，杂质含量低。且本发明采用相同的方法对实施例2及实施例3提供的组合物进行了检测，稳定性与实施例1和实施例4无显著性差异。
实施例8 I期临床安全性研究
1、滴眼液来源：
洛索洛芬钠滴眼液：按照实施例1制备所得不同浓度的滴眼液；
安慰剂：实施例1中未加洛索洛芬钠，其他成分相同。
2、研究方法：采用单中心、随机、双盲、单次和多次给药剂量递增设计，探索洛索洛芬钠滴眼液的安全性、耐受性和药代动力学特征。单次给药包括0.025mg(浓度0.5mg/ml)、0.05mg(浓度1mg/ml)、0.1mg(浓度2mg/ml)、0.2mg(浓度4mg/mL)剂量，给药方法1滴/次，1次/日；多次给药包括0.05mg、0.1mg、0.2mg剂量，给药方法1滴/次，4次/日。药代动力学试验数据见表5。
表5：I期临床洛索洛芬药代动力学参数
Figure PCTCN2022104726-appb-000007
注：C max：达峰浓度
AUC 0-t：药时曲线下面积(0到t小时)
T max：达峰浓度时间
结论：临床I期试验结果为单次给药后除滴眼液滴眼带来的局部不良反应外，未发生全身不良反应。多次给药后除发生眼睛不适不良反应外，无论是试验药物还是安慰剂均未发生全身不良反应。结合表5的药代动力学结果可知，洛索洛芬钠滴眼液在给药后快速进入循环系统，但系统暴露量较低，并且全身不良反应在未经干预情况下能很快恢复至基线水平，表明洛索洛芬钠滴眼液全身安全性良好。
另外，根据单次及多次给药试验眼部安全性检查结果，洛索洛芬钠滴眼液给药后眼压、视力均未受到影响，标准眼科检查和彩色眼底照相结果也均较基线无明显变化，眼部耐受性观察发现滴眼带来的眼睛不适和眼刺激总体发生率不高，并且在未经干预情况下能很快恢复正常，总体结果表明洛索洛芬钠滴眼液眼部安全性良好，且在本试验设定的最大剂量下耐受性良好。
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 (25)

  1. 一种含有洛索洛芬钠的组合物，其特征在于，所述组合物包含洛索洛芬钠、玻璃酸钠以及聚山梨酯80；其中，所述玻璃酸钠的分子量为0.8×10 6～1.6×10 6。
  2. 根据权利要求1所述的组合物，其特征在于，所述玻璃酸钠的分子量为0.8×10 6～1.4×10 6。
  3. 根据权利要求2所述的组合物，其特征在于，所述玻璃酸钠的分子量为0.8×10 6～1.0×10 6、1.0×10 6～1.2×10 6或1.2×10 6～1.4×10 6。
  4. 根据权利要求1所述的组合物，其特征在于，所述洛索洛芬钠、玻璃酸钠以及聚山梨酯80的质量比为(1-4)：(0.5-2)：(0.1-1)。
  5. 根据权利要求4所述的组合物，其特征在于，所述洛索洛芬钠、玻璃酸钠以及聚山梨酯80的质量比为1：(0.5-1.5)：(0.1-1)。
  6. 根据权利要求4所述的组合物，其特征在于，所述洛索洛芬钠、玻璃酸钠以及聚山梨酯80的质量比为为1：(0.8-1.2)：(0.2-0.5)。
  7. 根据权利要求1～3任意一项所述的组合物，其特征在于，所述组合物中还包含金属离子络合剂、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所述的组合物，其特征在于，
    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所述的组合物，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、氯化钠和聚山梨酯80。
  10. 根据权利要求9所述的组合物，其特征在于，所述组合物包含如下重量份的组分：
    Figure PCTCN2022104726-appb-100001
  11. 根据权利要求10所述的组合物，其特征在于，所述组合物包含如下重量份的组分：
    Figure PCTCN2022104726-appb-100002
  12. 根据权利要求9所述的组合物，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、聚山梨酯80和苯扎氯铵。
  13. 根据权利要求12所述的组合物，其特征在于，所述组合物包含如下重量份的组分：
    Figure PCTCN2022104726-appb-100003
  14. 根据权利要求13所述的组合物，其特征在于，所述组合物包含如下重量份的组分：
    Figure PCTCN2022104726-appb-100004
  15. 根据权利要求1～14任意一项所述的组合物，其特征在于，所述组合物为水性溶液的形式。
  16. 根据权利要求15所述的组合物，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所述的组合物，其特征在于，所述水性溶液中洛索洛芬钠的浓度为1-2mg/mL。
  18. 根据权利要求1～14任意一项所述的组合物，其特征在于，所述组合物为溶液剂、凝胶剂或膏剂。
  19. 权利要求1～18任意一项所述组合物的制备方法，其特征在于，包括如下步骤：配制玻璃酸钠水溶液，将包含洛索洛芬钠在内的其它成分用水溶解后与所述玻璃酸钠水溶液混合，加水定容。
  20. 根据权利要求19所述的制备方法，其特征在于，所述的溶解玻璃酸钠所用水的温度为40℃以下，和/或，制备过程中保持搅拌状态。
  21. 权利要求1～18任意一项所述组合物在制备预防或治疗眼科疾病药物中的应用。
  22. 根据权利要求21所述的应用，其特征在于，所述的眼科疾病为炎症。
  23. 根据权利要求22所述的应用，其特征在于，所述的眼科疾病为过敏性结膜炎或葡萄膜炎。
  24. 根据权利要求21所述的应用，其特征在于，所述的眼科疾病 为干眼。
  25. 根据权利要求24所述的应用，其特征在于，所述眼科疾病为由泪腺功能障碍引起的干眼、泪液分泌减少引起的干眼、泪膜稳定性差引起的干眼或角膜上皮细胞损伤引起的干眼；或者，
    所述眼科疾病为泪腺功能障碍或表现为泪液分泌减少；或者，
    所述眼科疾病为泪膜稳定性差；或者，
    所述眼科疾病为角膜上皮细胞损伤或眼损伤引起的局部水肿。
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