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WO2024199095A1 - Reproxalap nanomicelle composition, preparation method therefor, and use thereof - Google Patents

Reproxalap nanomicelle composition, preparation method therefor, and use thereof Download PDF

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Publication number
WO2024199095A1
WO2024199095A1 PCT/CN2024/083150 CN2024083150W WO2024199095A1 WO 2024199095 A1 WO2024199095 A1 WO 2024199095A1 CN 2024083150 W CN2024083150 W CN 2024083150W WO 2024199095 A1 WO2024199095 A1 WO 2024199095A1
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Prior art keywords
polyoxyethylene
units
castor oil
solubilizer
mixture
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PCT/CN2024/083150
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French (fr)
Chinese (zh)
Inventor
罗文卿
刘东红
李萌
牛国琴
赵骞
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JUMPCAN PHARMACEUTICAL GROUP Co Ltd
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JUMPCAN PHARMACEUTICAL GROUP Co Ltd
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Publication of WO2024199095A1 publication Critical patent/WO2024199095A1/en
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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 present invention belongs to the field of medical technology, and specifically relates to a novel nano-micelle composition for Reprosa, and a preparation method and application of the nano-micelle composition.
  • Dry eye or keratoconjunctivitis sicca
  • Tearatoconjunctivitis sicca is an abnormality in tear quality or quantity or dynamics caused by any reason. Its main feature is tear film homeostasis imbalance, which can cause discomfort in the affected eye and visual impairment. Its pathological mechanisms are mainly increased tear osmotic pressure, tear film instability, ocular surface damage, neurosensory abnormalities, and ocular surface inflammation. For a long time, the harm of dry eye has been ignored. With the change of people's lifestyle, the number of cases of dry eye has increased year by year. In my country, its prevalence rate is 10%-15%, and the prevalence rate in women is higher than that in men. The clinical symptoms of dry eye include blurred vision, dryness, photophobia, etc.
  • the treatment methods for dry eye can be mainly divided into general treatment (such as removing the cause, nutritional support, disease monitoring, etc.) and drug treatment (such as applying artificial tears or autologous serum, promoting tear secretion, reducing ocular surface inflammation, treating blepharitis, etc.).
  • Reproxalap (CAS: 916056-79-6, structure shown below), also known as ADX-102 or NS-2, is a small molecule reactive aldehyde inhibitor that treats eye diseases by binding and capturing pro-inflammatory reactive aldehyde species (RASP) in the eye. Reproxalap was developed by Aldeyra Therapeutics. The Phase III clinical trial for dry eye disease reached the primary endpoint and the FDA has submitted a new drug application (NDA) and has been accepted.
  • NDA new drug application
  • CN113056353A discloses a reproza eye drop for treating dry eye disease, which uses cyclodextrin (such as sulfobutyl ether- ⁇ -cyclodextrin or hydroxypropyl- ⁇ -cyclodextrin) to encapsulate and deliver the reproza molecule.
  • cyclodextrin such as sulfobutyl ether- ⁇ -cyclodextrin or hydroxypropyl- ⁇ -cyclodextrin
  • the technical problem to be solved by the present invention is to overcome the shortcomings of the existing Reprosa ophthalmic composition, such as low ocular surface permeability, short residence time, low bioavailability, multiple daily dosing times, short duration of drug efficacy and poor patient compliance.
  • the present invention provides a Reprosa nano-micelle composition, a preparation method and use thereof.
  • the present invention provides an ophthalmic solution composition
  • an ophthalmic solution composition comprising reproxaoroxat or a pharmaceutically acceptable salt thereof, a solubilizer, water, and optionally a stabilizer.
  • the ophthalmic solution composition is an ophthalmic micellar solution composition.
  • the ophthalmic solution composition is an ophthalmic nanomicelle solution composition.
  • the average particle size of the nanomicelles in the ophthalmic solution composition is 5-100 nm, preferably 5-80 nm, more preferably 10-65 nm, further preferably 10-30 nm, and most preferably 10-15 nm.
  • the acid addition salt is selected from one or more of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, glucarate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate.
  • the content of Reprosa is 0.05%-0.5%, preferably 0.15%-0.5%, more preferably 0.2%-0.45%, further preferably 0.25%-0.4%, further preferably 0.25%-0.35%, most preferably 0.25%-0.3%.
  • the content of Reprosa is 0.05%-0.5%, preferably 0.1%-0.5%, more preferably 0.1%-0.45%, further preferably 0.1-0.3%, and most preferably 0.15%-0.25%.
  • the solubilizing agent is a surfactant.
  • the solubilizing agent comprises a nonionic surfactant; preferably, the solubilizing agent is a nonionic surfactant.
  • the nonionic surfactant is a polyethylene glycol type nonionic surfactant.
  • the polyethylene glycol type nonionic surfactant comprises a polyoxyethylene castor oil derivative, wherein the polyoxyethylene castor oil derivative is selected from one or more of polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil, preferably one or more of polyoxyethylene castor oil having 30-40 polyoxyethylene units and polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units, more preferably one or more of polyoxyethylene castor oil having 30-40 polyoxyethylene units and polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units.
  • the present invention can be selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated ...
  • the vitamin E polyethylene glycol succinate is selected from one or more vitamin E polyethylene glycol succinates having a polyethylene glycol average molecular weight of 200-4000, preferably a polyethylene glycol average molecular weight of One or more of the vitamin E polyethylene glycol succinates with an average molecular weight of 500-1500, more preferably one or more of the vitamin E polyethylene glycol succinates with an average molecular weight of polyethylene glycol of 800-1200, and most preferably vitamin E polyethylene glycol succinate 1000.
  • the solubilizing agent comprises a polymer surfactant; preferably, the solubilizing agent is a polymer surfactant, preferably a biodegradable polymer surfactant.
  • the polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer is selected from one or more polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers obtained by copolymerization of 5%-20% polyethylene glycol 6000, 20%-40% vinyl acetate and 50%-70% vinyl caprolactam and having an average relative molecular weight of 50000-200000 g/mol, preferably one or more polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers obtained by copolymerization of 10%-15% polyethylene glycol 6000, 25%-35% vinyl acetate and 55%-60% vinyl caprolactam and having an average relative molecular weight of 90000-140000 g/mol, or preferably a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer with a
  • the solubilizing agent comprises one or more of polyoxyethylene castor oil derivatives, polyoxyethylene fatty acid esters, polyoxyethylene alkylphenol ethers, polyoxyethylene fatty alcohol ethers and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers; preferably, the solubilizing agent is selected from one or more of polyoxyethylene castor oil derivatives, polyoxyethylene fatty acid esters, polyoxyethylene alkylphenol ethers, polyoxyethylene fatty alcohol ethers and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers.
  • the solubilizer comprises polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units, preferably polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units, a mixture thereof with polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, or a mixture thereof with octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units.
  • the solubilizer comprises polyoxyethylene castor oil having 30-40 polyoxyethylene units, preferably polyoxyethylene castor oil having 30-40 polyoxyethylene units or a mixture thereof with a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer.
  • the solubilizing agent comprises vitamin E polyethylene glycol succinate with a polyethylene glycol molecular weight of 500-1500, preferably vitamin E polyethylene glycol succinate with a polyethylene glycol molecular weight of 500-1500.
  • the solubilizer comprises polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, preferably polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units or a mixture thereof with polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units.
  • the solubilizer comprises polyoxyethylene stearate having 30-50 polyoxyethylene units, preferably polyoxyethylene stearate having 30-50 polyoxyethylene units.
  • the solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, a mixture of polyoxyethylene castor oil having 30-40 polyoxyethylene units and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, a polyethylene glycol having an average molecular weight of 500-1500, Vitamin E polyethylene glycol succinate, one or more of polyoxyethylene stearate having 30-50 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, preferably a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units and one or more of polyoxyethylene hydroxystearate
  • the solubilizer is selected from one or more of a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40, and vitamin E polyethylene glycol succinate having a polyethylene glycol average molecular weight of 500-1500, preferably one or more of a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, more preferably
  • the solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units,
  • the invention can be selected from the group consisting of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 50-55, polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40, and vitamin E polyethylene glycol succinate having a polyethylene glycol average molecular weight of 800-1200, preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 35-45, polyoxyethylene hydrogenated castor oil having a polyoxyethylene
  • the solubilizer is selected from one or more of a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, preferably a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, or polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units;
  • the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate with 10-20 polyoxyethylene units
  • the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably
  • the solubilizer is selected from one or more of a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40 and polyoxyethylene 15 hydroxystearate, preferably a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40 or polyoxyethylene 15 hydroxystearate; wherein, when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, the weight percentage of polyoxyethylene 15 hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, the weight percentage of octylphenol polyoxyethylene ether 40 in the mixture is
  • the weight ratio of the reprozac or a pharmaceutically acceptable salt thereof to the solubilizer is 1:5-1:40, preferably 1:8-1:30, more preferably 1:10-1:20, and most preferably 1:10-1:15.
  • the content of the solubilizer is 1%-16%, preferably 2%-12%, more preferably 2.5%-10%, most preferably 3.75%-7.5%, based on the total weight of the composition.
  • the water content is 83%-98%, preferably 84%-98%, more preferably 86%-98%, most preferably 88%-98%, based on the total weight of the composition.
  • the water content is 83%-98%, preferably 87%-97%, more preferably 89%-97%, most preferably 91%-95%, based on the total weight of the composition.
  • the composition does not include a stabilizer; that is, the composition includes reprozac or a pharmaceutically acceptable salt thereof, a solubilizer, and water, but does not include a stabilizer.
  • the composition comprises a stabilizer; that is, the composition comprises reprozac or a pharmaceutically acceptable salt thereof, a solubilizer, water, and a stabilizer.
  • the stabilizer is a chain polyol containing 2 to 6 carbon atoms and at least 2 hydroxyl groups.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of solubilizer, 0-5% of stabilizer and 83%-98% of water.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0.5%-4% of a stabilizer, and 87%-97% of water.
  • the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or its pharmaceutically acceptable salt, 2.5%-10% of solubilizer, 0-3% of stabilizer and 89%-97% of water.
  • the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or its pharmaceutically acceptable salt, 3.75%-7.5% of solubilizer, 1%-3% of stabilizer and 91%-95% of water.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water.
  • the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer, and 84%-98% of water.
  • the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer, and 86%-98% of water.
  • the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer, and 88%-98% of water.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of polyoxyethylene castor oil derivatives, polyoxyethylene fatty acid esters, polyoxyethylene alkylphenol ethers, and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, vitamin E polyethylene glycol succinate, polyoxyethylene stearate, polyoxyethylene hydroxystearate, octylphenol polyoxyethylene ether, and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units, polyoxyethylene castor oil having 30-40 polyoxyethylene units, polyethylene glycol vitamin E succinate having an average molecular weight of 500-1500, polyoxyethylene stearate having 30-50 polyoxyethylene units, polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of solubilizer, 0-5% of stabilizer and 83%-98% water; wherein the solubilizer is selected from a mixture of polyoxyethylene castor oil having 30-40 polyoxyethylene units and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, polyoxyethylene stearate having 30-50 polyoxyethylene units, polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene polyoxyethylene
  • vitamin E polyethylene glycol succinates having an average molecular weight of 500-1500, preferably a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, and one or more of polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, more preferably a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units and octyldodecyl hydroxystearate having 30-50 polyoxyethylene units, and a mixture of polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units and octyldodecyl hydroxystearate having 30-50 polyoxyethylene units.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 35-45, and a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 10-20 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 10-20.
  • the present invention is a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 45 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 35-45, polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 50-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, and more preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, and polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 35-45.
  • solubilizing agent is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 35-45, polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 50-55, or polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20; wherein, when the solubilizing agent is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, the polyoxyethylene hydroxystearate accounts for The weight percentage of the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether with 35-45 polyoxyethylene units, the weight percentage
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 35-45, and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number
  • the invention relates to a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 35-45 or polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20; wherein, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 35-45, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer and 83%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and the weight ratio of the polyoxyethylene hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and the weight ratio of the polyoxyethylene hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and the weight ratio of the polyoxyethylene hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and the weight ratio of the polyoxyethylene hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer and 83%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and the weight ratio of the octylphenol polyoxyethylene ether to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and the weight ratio of the octylphenol polyoxyethylene ether to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and the weight ratio of the octylphenol polyoxyethylene ether to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and the weight ratio of the octylphenol polyoxyethylene ether to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0-5% of a stabilizer and 83%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0-5% of a stabilizer and 83%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0-5% of a stabilizer and 83%-98% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0.5%-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from polyoxyethylene 35 castor oil and a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, vitamin E polyethylene glycol succinate 1000, polyoxyethylene 15 hydroxystearate, polyoxyethylene 35 castor oil, polyoxyethylene 54 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil and polyoxyethylene 40 stearate; wherein, when the solubilizing agent is polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 When the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, vitamin E polyethylene glycol succinate 1000, polyoxyethylene 15 hydroxystearate, polyoxyethylene 35 castor oil, and polyoxyethylene 54 hydrogenated castor oil; wherein, when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, the weight percentage of the polyoxyethylene 15 hydroxystearate in the mixture is 0-80%, preferably 0-50%, and more preferably
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and polyoxyethylene 15 hydroxystearate; wherein, when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, the weight percentage of polyoxyethylene 15 hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene 40
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable, 1%-16% solubilizer, 0-5% stabilizer and 83%-98% water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0.5%-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable, 1%-16% of solubilizer, 0-5% of stabilizer and 83%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and the weight ratio of octylphenol polyoxyethylene ether 40 to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or its pharmaceutically acceptable salt, 2%-12% of solubilizer, 0-4% of stabilizer and 87%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and the octylphenol
  • the weight ratio of polyoxyethylene ether 40 to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%;
  • the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and the weight ratio of octylphenol polyoxyethylene ether 40 to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and the weight ratio of octylphenol polyoxyethylene ether 40 to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0-5% of a stabilizer and 83%-98% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable, 1%-16% solubilizer, 0-5% stabilizer and 83%-98% water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0.5%-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is selected from one or more of polyoxyethylene castor oil derivatives, polyoxyethylene fatty acid esters, polyoxyethylene alkylphenol ethers and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water;
  • the solubilizer is selected from one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, vitamin E polyethylene glycol succinate, polyoxyethylene stearate, polyoxyethylene hydroxystearate, octylphenol polyoxyethylene ether and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or its pharmaceutically acceptable salt, 1%-16% of solubilizer, 0.5%-3% of stabilizer and 83%-98% of water; wherein the solubilizer is selected from one or more of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units, polyoxyethylene castor oil having 30-40 polyoxyethylene units, polyethylene glycol vitamin E succinate having an average molecular weight of 500-1500, polyoxyethylene stearate having 30-50 polyoxyethylene units, polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from a mixture of polyoxyethylene castor oil having 30-40 polyoxyethylene units and a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octyl stearate having 30-50 polyoxyethylene units.
  • the solubilizer is selected from a mixture of polyoxyethylene castor oil having 30-40 polyoxyethylene units and a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer,
  • the solubilizing agent is a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 30-60 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40, and one or more of vitamin E polyethylene glycol succinate having a polyethylene glycol average molecular weight of 500-1500.
  • the solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having a
  • polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20 preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, more preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50,
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units.
  • oxyethylene hydroxystearate polyoxyethylene castor oil having 30-40 polyoxyethylene units, polyoxyethylene hydrogenated castor oil having 50-55 polyoxyethylene units, and vitamin E polyethylene glycol succinate having an average molecular weight of 800-1200, preferably a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, polyoxyethylene succinate having 50-55 polyoxyethylene units, One or more of hydrogenated castor oil and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, more preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 35-45, and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, and a
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and the weight ratio of the polyoxyethylene hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and the weight ratio of the polyoxyethylene hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer and 86%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and the weight ratio of the polyoxyethylene hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and the weight ratio of the polyoxyethylene hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and the weight ratio of the octylphenol polyoxyethylene ether to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and the weight ratio of the octylphenol polyoxyethylene ether to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer and 86%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and the weight ratio of the octylphenol polyoxyethylene ether to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and the weight ratio of the octylphenol polyoxyethylene ether to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer and 86%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer and 86%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer and 86%-98% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from polyoxyethylene 35 castor oil and a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, vitamin E polyethylene glycol succinate 1000, polyoxyethylene 15 hydroxystearate, polyoxyethylene 35 castor oil, polyoxyethylene 54 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil and polyoxyethylene 40 stearate; wherein, when the solubilizing agent is polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 When the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol poly
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, vitamin E polyethylene glycol succinate 1000, polyoxyethylene 15 hydroxystearate, polyoxyethylene 35 castor oil, and polyoxyethylene 54 hydrogenated castor oil; wherein, when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, the weight percentage of the polyoxyethylene 15 hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and polyoxyethylene 15 hydroxystearate; wherein, when the solubilizer is polyoxyethylene When the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, the weight percentage of polyoxyethylene 15 hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer and 86%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and the weight ratio of octylphenol polyoxyethylene ether 40 to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and the weight ratio of octylphenol polyoxyethylene ether 40 to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or its pharmaceutically acceptable salt, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer, and 86%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and the octylphenol polyoxyethylene ether 40 is ...
  • the weight ratio of phenol polyoxyethylene ether 40 to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%;
  • the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and the weight ratio of octylphenol polyoxyethylene ether 40 to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer and 86%-98% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer and 86%-98% of water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.
  • the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.
  • the composition optionally comprises other pharmaceutically acceptable excipients.
  • the composition does not contain other pharmaceutically acceptable excipients; specifically, the composition consists of reprozac or a pharmaceutically acceptable salt thereof, a solubilizer, water and an optional stabilizer.
  • the composition further comprises one or more other pharmaceutically acceptable excipients.
  • the other pharmaceutically acceptable excipients are selected from one or more of viscosity enhancers, antioxidants, pH adjusters, osmotic pressure regulators, wetting agents, mucoadhesive agents, penetration enhancers, preservatives, gelling agents, antibacterial agents and chelating agents, preferably one or more of viscosity enhancers, antioxidants, chelating agents, antibacterial agents, pH adjusters and osmotic pressure regulators.
  • the composition further comprises a viscosity enhancer; preferably, the viscosity enhancer is selected from one or more of carboxymethyl cellulose or its sodium salt, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, poloxamer, carbomer, xanthan gum, hyaluronic acid or its sodium salt, polyvinyl pyrrolidone, polycarbophil, gum, carrageenan, guar gum, tragacanth gum, agarose, polyethylene glycol, alginic acid or its sodium salt and hyaluronic acid or its sodium salt, preferably xanthan gum, sodium hyaluronate, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, carbomer, sodium carboxymethyl cellulose, poloxamer, seaweed One or more of sodium hyaluronate and sodium hyaluronate, more preferably one or more of xanthan gum
  • the content of the viscosity increasing agent is 0-5%, preferably 0-3%, more preferably 0.1%-3%, most preferably 0.2%-3%.
  • the composition further comprises an antioxidant; preferably, the antioxidant is selected from one or more of tocopherol or its succinate, ascorbic acid or its palmitate, butylated hydroxyanisole, 2,6-di-tert-butylated p-cresol and sodium thiosulfate, preferably one or more of tocopherol, butylated hydroxyanisole, 2,6-di-tert-butylated p-cresol and sodium thiosulfate, more preferably one or more of tocopherol and sodium thiosulfate.
  • the antioxidant is selected from one or more of tocopherol or its succinate, ascorbic acid or its palmitate, butylated hydroxyanisole, 2,6-di-tert-butylated p-cresol and sodium thiosulfate, preferably one or more of tocopherol, butylated hydroxyanisole, 2,6-di-tert-butylated p-cresol and sodium thiosul
  • the content of the antioxidant is 0-1%, preferably 0.05%-1%, more preferably 0.1%-1%, based on the total weight of the composition.
  • the composition further comprises a chelating agent; preferably, the chelating agent is selected from one or more of citric acid or its salts, glucuronic acid or its salts, hexametaphosphate, edetic acid or its salts and phosphonates, preferably edetic acid or edetic disodium.
  • a chelating agent is selected from one or more of citric acid or its salts, glucuronic acid or its salts, hexametaphosphate, edetic acid or its salts and phosphonates, preferably edetic acid or edetic disodium.
  • the chelating agent is present in an amount of 0-2%, preferably 0.01%-1%, more preferably 0.05%-0.5%, most preferably 0.1%-0.2%, based on the total weight of the composition.
  • the composition further comprises a pH regulator; preferably, the pH regulator is selected from one or more of inorganic or organic acids, bases and buffer salts, preferably buffer salts; wherein the acid is selected from one or more of hydrochloric acid, phosphoric acid, acetic acid, citric acid, lactic acid and boric acid; the base is selected from one or more of ethylenediamine, ethanolamine, basic amino acids, sodium hydroxide, calcium hydroxide, potassium hydroxide and aqueous ammonia solution; the buffer salt is selected from one or more of boric acid-borax buffer salt, citric acid-sodium citrate buffer salt, phosphate-sodium phosphate buffer salt and acetic acid-sodium acetate buffer salt, preferably one or more of phosphate-sodium phosphate buffer salt and boric acid-borax buffer salt.
  • the pH regulator is selected from one or more of inorganic or organic acids, bases and buffer salts, preferably buffer salts
  • the acid is selected from one or
  • the pH value of the composition is 5-9.5, preferably 6-9, more preferably 6-8.5, most preferably 6.5-8.
  • the composition further comprises an osmotic pressure regulator; preferably, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, glucose, sorbitol, polyethylene glycol, glycerol and propylene glycol, preferably one or more of sodium chloride, mannitol, sorbitol and glycerol.
  • the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, glucose, sorbitol, polyethylene glycol, glycerol and propylene glycol, preferably one or more of sodium chloride, mannitol, sorbitol and glycerol.
  • the content of the bacteriostatic agent is 0-5%, preferably 0-1%, more preferably 0.1%-0.5%, most preferably 0.2%-0.3%.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0-5% of propylene glycol, 83%-98% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of propylene glycol, 87%-97% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0.5%-4% of propylene glycol, 87%-97% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of propylene glycol, 89%-97% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of propylene glycol, 91%-95% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of solubilizer, 0-5% of propylene glycol, 83%-98% of water, 0-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of propylene glycol, 87%-97% of water, 0-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0.5%-4% of propylene glycol, 87%-97% of water, 0-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of propylene glycol, 89%-97% of water, 0-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of propylene glycol, 91%-95% of water, 0-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of solubilizer, 0-5% of propylene glycol, 83%-98% of water, 0.1%-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of propylene glycol, 87%-97% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0.5%-4% of propylene glycol, 87%-97% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of propylene glycol, 89%-97% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of propylene glycol, 91%-95% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of propylene glycol, 87%-97% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0.5%-4% of propylene glycol, 87%-97% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of propylene glycol, 89%-97% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of propylene glycol, 91%-95% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of propylene glycol, 83%-98% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of propylene glycol, 84%-98% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of propylene glycol, 86%-98% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of propylene glycol, 88%-98% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of propylene glycol, 84%-98% of water, 0.2%-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of propylene glycol, 88%-98% of water, 0.2%-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of propylene glycol, 83%-98% of water, 0-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of propylene glycol, 84%-98% of water, 0-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of propylene glycol, 86%-98% of water, 0-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of propylene glycol, 83%-98% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of propylene glycol, 84%-98% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of propylene glycol, 88%-98% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of propylene glycol, 83%-98% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of propylene glycol, 86%-98% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of propylene glycol, 88%-98% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the composition comprises a viscosity enhancer but does not comprise a stabilizer; that is, the composition comprises reproza or a pharmaceutically acceptable salt thereof, a solubilizer, water and a viscosity enhancer but does not comprise a stabilizer; preferably, the composition comprises reproza or a pharmaceutically acceptable salt thereof, a solubilizer, water, a viscosity enhancer, an optional antioxidant, an optional chelating agent, an optional osmotic pressure regulator and an optional pH regulator but does not comprise a stabilizer.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 83%-98% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 84%-98% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 86%-98% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 88%-98% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 83%-98% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 84%-98% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 86%-98% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 88%-98% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.
  • the present invention provides a method for preparing an ophthalmic solution composition (especially the ophthalmic solution composition described in the first aspect above), comprising the following steps:
  • step 2) adding the drug-containing solution obtained in step 1) into water and dispersing it evenly, filtering and sterilizing it to obtain an ophthalmic solution composition.
  • step 2) of the preparation method further comprises the following steps between the dispersion and filtration steps: adding a viscosity enhancer and dispersing uniformly again.
  • step 2) of the preparation method comprises the following steps: adding the drug-containing solution obtained in step 1) into water and dispersing uniformly, adding a viscosity enhancer, dispersing uniformly again, filtering and sterilizing, and obtaining an ophthalmic solution composition.
  • step 2) of the preparation method further comprises the following steps after the filtration step: adding a pre-sterilized (e.g., high temperature sterilized) aqueous solution of a viscosity enhancer, and dispersing evenly again.
  • step 2) of the preparation method comprises the following steps: adding the drug-containing solution obtained in step 1) into water and dispersing evenly, filtering and sterilizing, adding a pre-sterilized aqueous solution of a viscosity enhancer, and dispersing evenly again to obtain an ophthalmic solution composition.
  • the preparation method further comprises the following step before the mixing step of step 1) or before the dispersing step of step 2): adding an antioxidant.
  • the preparation method further comprises the following step before the mixing step of step 1) or before the dispersion step of step 2): adding an antibacterial agent.
  • the preparation method further comprises the following step before the dispersion step of step 2): adding a chelating agent.
  • step 2) of the preparation method further comprises the following step before the filtration step: using a pH adjuster (such as a buffer salt) to adjust the pH value of the redispersed material to a range that meets the requirements for ophthalmic use.
  • a pH adjuster such as a buffer salt
  • step 2) of the preparation method further comprises the following step before the filtering step: using an osmotic pressure regulator to adjust the re-dispersed material to an osmotic pressure value range that meets the requirements for ophthalmic use.
  • the mixing in step 1) of the preparation method is carried out under heating conditions, such as heating by a water bath, the water bath temperature is 0-90°C, preferably 30-60°C, more preferably 40-50°C.
  • step 1) of the preparation method is performed under stirring conditions.
  • the temperature of the water in step 2) of the preparation method is 0-50°C, preferably 20-40°C, more preferably 25-35°C.
  • the present invention provides use of an ophthalmic solution composition (particularly the ophthalmic solution composition described in the first aspect above) in the preparation of a medicament for preventing and/or treating ocular diseases or conditions associated with toxic aldehydes including pro-inflammatory reactive aldehyde substances (RASPs).
  • an ophthalmic solution composition particularly the ophthalmic solution composition described in the first aspect above
  • RASPs pro-inflammatory reactive aldehyde substances
  • the present invention provides an ophthalmic solution composition (particularly the ophthalmic solution composition described in the first aspect above), which is used to prevent and/or treat ocular diseases or conditions associated with toxic aldehydes including pro-inflammatory active aldehyde substances.
  • the present invention provides a method for preventing and/or treating ocular diseases or conditions associated with toxic aldehydes including pro-inflammatory active aldehydes, comprising the following steps: administering a preventively and/or therapeutically effective amount of an ophthalmic solution composition (particularly the ophthalmic solution composition described in the first aspect above) to an individual in need thereof.
  • the ocular disease or disorder is selected from one or more of corneal diseases, ocular diseases associated with excess toxic aldehydes, ocular rosacea, and other ocular diseases.
  • the corneal disease is selected from one or more of dry eye syndrome, cataracts, keratoconus, bullous and other types of corneal lesions and Fuch's corneal endothelial dystrophy.
  • the other ocular disease is selected from one or more of allergic conjunctivitis, ocular cicatricial pemphigoid, diseases associated with photorefractive keratectomy (PRK) healing or other corneal healing, and diseases associated with tear lipid degradation or tear gland dysfunction.
  • PRK photorefractive keratectomy
  • the ocular disease or condition is selected from one or more of dry eye syndrome, allergic conjunctivitis, and uveitis.
  • the ocular disease or disorder is dry eye syndrome.
  • Reprosa has very low solubility in water and poor chemical stability.
  • the topical ophthalmic preparations in the prior art are all short-acting, rapid-release products that need to be applied multiple times a day, resulting in poor medication compliance among patients.
  • the present invention creatively designs an ophthalmic nano-micelle solution composition of Reprosa.
  • the nano-micelle system can effectively encapsulate Reprosa molecules, improve its solubility and stability, enable the drug to penetrate the aqueous layer of the eye, more effectively penetrate into the cornea, increase the drug's adhesion and retention time in the eye, and achieve long-term and stable release of the drug while improving bioavailability.
  • the ophthalmic nano-micelle solution composition of the present invention has excellent chemical stability. After being stored under normal conditions (e.g., room temperature 25°C/60%RH) for at least 1 week, or at least 10 days, or at least 2 weeks, or at least 1 month, or at least 3 months, or at least 4 months, or at least 6 months, or at least 9 months, or at least 12 months, it contains only less than 1% impurities, or less than 0.8% impurities, or less than 0.5% impurities, or less than 0.2% impurities, or less than 0.1% impurities.
  • normal conditions e.g., room temperature 25°C/60%RH
  • the ophthalmic nano-micelle solution composition of the present invention has excellent physical stability. After being stored under normal conditions (e.g., room temperature 25°C/60%RH) for at least 1 week, or at least 10 days, or at least 2 weeks, or at least 1 month, or at least 3 months, or at least 4 months, or at least 6 months, or at least 9 months, or at least 12 months, the value of micelle particle size growth is ⁇ 50nm, or ⁇ 40nm, or ⁇ 30nm, or ⁇ 20nm.
  • normal conditions e.g., room temperature 25°C/60%RH
  • the value of micelle particle size growth is ⁇ 50nm, or ⁇ 40nm, or ⁇ 30nm, or ⁇ 20nm.
  • FIG1 shows the in vitro dissolution test results of the samples.
  • FIG2 shows the in vitro dissolution test results of the samples.
  • FIG3 shows a comparison of corneal sodium fluorescein staining scores in a rat dry eye model after 14 days of drug administration.
  • the term "micelles" used in the present invention refers to the thermodynamically stable colloidal aggregates formed by the self-assembly of surfactant molecules in an aqueous solution when the surfactant reaches a certain concentration.
  • Surfactants with adsorption capacity are dissolved in water at low concentrations. When the concentration reaches saturation, excess surfactant molecules begin to accumulate in the water. Since the hydrophobic part of the surfactant molecule has a low affinity for water, the hydrophobic part is The attraction is large, so the hydrophobic parts of many surfactant molecules attract each other and associate to form an inner core, and the hydrophilic groups face outward to form an outer layer, thus forming a multi-molecular complex.
  • micelles are composed of a lipophilic inner core and a hydrophilic outer shell, and have multiple functions.
  • the lipophilic inner core can be used to encapsulate hydrophobic drugs, greatly improving the solubility of poorly soluble drugs in water;
  • the hydrophilic outer shell can interact with biological components in the body, affecting pharmacokinetic behavior and drug distribution, and controlling drug delivery in the body.
  • micelles with an amphiphilic colloidal structure and a particle size range of usually 5 to 100 nm can be called “nano micelles.”
  • critical micelle concentration refers to the minimum concentration of surfactant molecules in a solvent that associates to form micelles.
  • the critical micelle concentration can be found in the literature (e.g., Mukerjee, P., Mysels, KJ, Critical Micelle Concentrations of Aqueous Surfactant Systems, NIST National Institute of Standards and Technology: Washington DC USA, 1971; Al-Soufi W., L.,Novo M.,A model for monomer and micellar concentrations in surfactant solutions:application to conductivity,NMR,diffusion,and surface tension data[J],J.Colloid Interface Sci.,2012,370:102-110;Lucas Sonia Freire, Jorge Bordello, Mercedes Novo, and Wajih Al-Soufi, Dye Exchange in Micellar Solutions.
  • the term "solubilizer” used in the present invention refers to a surfactant with solubilizing ability, under the action of which, the solubility of poorly soluble drugs in solvents can be increased and a solution can be formed.
  • the properties, HLB value, and dosage of the solubilizer are all direct factors affecting the solubilizing effect.
  • the term "surfactant” used in the present invention refers to a substance that can (significantly) reduce the surface tension of the target solution and can be oriented on the surface of the solution.
  • the molecular structure of the surfactant has two properties: one end is a hydrophilic group and the other end is a hydrophobic group; the hydrophilic group is usually a polar group, such as carboxylic acid, sulfonic acid, sulfuric acid, (substituted) amino group and its salt, hydroxyl group, amide group, ether bond, etc.; while the hydrophobic group is usually a non-polar hydrocarbon chain, such as a hydrocarbon chain with more than 8 carbon atoms.
  • surfactants can be divided into four categories: cationic surfactants, anionic surfactants, nonionic surfactants, and amphoteric surfactants.
  • nonionic surfactants will not dissociate in water and are usually low molecular weight.
  • the molecular structure includes hydrophilic groups and hydrophobic groups.
  • the hydrophilic group is selected from one or more of polyethylene glycol and polyols
  • the hydrophobic group is selected from one or more of fatty acids, fatty alcohols, phenols, and alkylphenols.
  • the hydrophilic group and the hydrophobic group are connected by ester bonds or ether bonds.
  • nonionic surfactants can be further divided into polyethylene glycol type (or polyoxyethylene type) and polyol type.
  • Polyoxyethylene nonionic surfactants can be obtained by reacting hydrophobic materials with ethylene oxide or polyethylene glycol, and can be roughly divided into the following types:
  • Polyoxyethylene fatty alcohol ether (or fatty alcohol polyoxyethylene ether, obtained by etherification of polyethylene glycol and fatty alcohol);
  • polyoxyethylene fatty acid esters or fatty acid polyoxyethylene esters, obtained by esterification of polyethylene glycol with fatty acids or their derivatives
  • Polyoxyethylene castor oil derivatives obtained by the reaction of glycerol, polyethylene glycol and castor oil or hydrogenated castor oil.
  • Polyoxyethylene castor oil derivatives include (but are not limited to) polyoxyethylene castor oil (such as polyoxyethylene 5 castor oil, polyoxyethylene 9 castor oil, polyoxyethylene 15 castor oil, polyoxyethylene 35 castor oil, polyoxyethylene 40 castor oil, polyoxyethylene 60 castor oil, polyoxyethylene 100 castor oil, etc.) and polyoxyethylene hydrogenated castor oil (such as polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 54 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil, polyoxyethylene 100 hydrogenated castor oil, etc.), preferably polyoxyethylene castor oil with 30-40 polyoxyethylene units (such as polyoxyethylene 35 castor oil) and polyoxyethylene hydrogenated castor oil with 30-60 polyoxyethylene units (such as polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 54 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil
  • the present invention relates to polyoxyethylene castor oils having 30 to 40 polyoxyethylene units (e.g., polyoxyethylene 35 castor oil) and polyoxyethylene hydrogen
  • Polyoxyethylene hydrogenated castor oils having 35 to 45 polyoxyethylene units e.g., polyoxyethylene 40 hydrogenated castor oil
  • polyoxyethylene hydrogenated castor oils having 50 to 55 polyoxyethylene units e.g., polyoxyethylene 54 hydrogenated castor oil
  • Polyoxyethylene hydrogenated castor oils having 35 to 45 polyoxyethylene units e.g., polyoxyethylene 40 hydrogenated castor oil
  • Polyoxyethylene 40 hydrogenated castor oil is most preferred.
  • Polyoxyethylene fatty acid esters include (but are not limited to) polyoxyethylene stearate (or polyoxyethylene stearate, obtained by esterifying polyethylene glycol with stearic acid), polyoxyethylene hydroxystearate (or polyoxyethylene hydroxystearate, obtained by esterifying polyethylene glycol with hydroxystearate) and vitamin E polyethylene glycol succinate (derived by esterifying D- ⁇ -tocopherol succinate with polyethylene glycol), wherein polyoxyethylene stearate includes (but is not limited to) polyoxyethylene stearate with a polyoxyethylene unit number of 2-50 Fatty acid esters (such as polyoxyethylene 2 stearate, polyoxyethylene 4 stearate, polyoxyethylene 6 stearate, polyoxyethylene 8 stearate, polyoxyethylene 12 stearate, polyoxyethylene 20 stearate, polyoxyethylene 30 stearate, polyoxyethylene 40 stearate, polyoxyethylene 50 stearate, etc.), especially polyoxyethylene stearate having 10-50 poly
  • polyoxyethylene stearate most preferably polyoxyethylene 40 stearate
  • polyoxyethylene hydroxystearate including (but not limited to) polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, preferably polyoxyethylene 15 hydroxystearate
  • vitamin E polyethylene glycol succinate including (but not limited to) vitamin E polyethylene glycol succinate with a polyethylene glycol average molecular weight of 200-4000 (such as vitamin E polyethylene glycol succinate 200, ...
  • Vitamin E polyethylene glycol succinate 1000 vitamin E polyethylene glycol succinate 1500, vitamin E polyethylene glycol succinate 2000, vitamin E polyethylene glycol succinate 4000, etc.
  • vitamin E polyethylene glycol succinate with an average molecular weight of 500-1500 more preferably vitamin E polyethylene glycol succinate with an average molecular weight of 800-1200, and most preferably vitamin E polyethylene glycol succinate 1000.
  • Polyoxyethylene alkylphenol ethers include (but are not limited to) nonylphenol polyoxyethylene ethers having 4-10 polyoxyethylene units (such as nonylphenol polyoxyethylene ether 4, nonylphenol polyoxyethylene ether 6, nonylphenol polyoxyethylene ether 7, nonylphenol polyoxyethylene ether 8, nonylphenol polyoxyethylene ether 10, etc.), octylphenol polyoxyethylene ethers having 13-50 polyoxyethylene units (such as octylphenol polyoxyethylene ether 13, octylphenol polyoxyethylene ether 15, octylphenol polyoxyethylene ether 20, octylphenol polyoxyethylene ether 30, octylphenol polyoxyethylene ether 40, octylphenol polyoxyethylene ether 50), dodecylphenol polyoxyethylene ether and dinonylphenol polyoxyethylene ether, preferably octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, more preferably octylphenol polyoxyethylene ether
  • polyoxyethylene unit number refers to the average degree of polymerization of the polyoxyethylene part (i.e., polyethylene glycol part) in the molecule.
  • polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40 means that the average degree of polymerization of the polyoxyethylene part in the defined polyoxyethylene castor oil is 30-40
  • polyoxyethylene 40 stearate means that the average degree of polymerization of the polyoxyethylene part in the defined polyoxyethylene stearate is 40.
  • the term "average molecular weight of polyethylene glycol” used in the present invention refers to the average molecular weight of the polyethylene glycol portion (i.e., the polyoxyethylene portion) in the defined molecule.
  • vitamin E polyethylene glycol succinate with an average molecular weight of 500-1500 means that the average molecular weight of the polyethylene glycol portion in the defined vitamin E polyethylene glycol succinate is 500-1500
  • vitamin E polyethylene glycol succinate 1000 means that the average molecular weight of the polyethylene glycol portion in the defined vitamin E polyethylene glycol succinate is 1000.
  • Polyol-type nonionic surfactants can be composed of a hydrophilic group combined with a hydrophobic group derived from fatty acids, and can be roughly divided into the following types:
  • Glycerol fatty acid esters or fatty acid glycerides
  • Sorbitan fatty acid esters or sorbitan fatty acid esters, Span
  • Pentaerythritol fatty acid esters or fatty acid pentaerythritol esters
  • Sucrose fatty acid esters (or sucrose fatty acid esters).
  • surfactants can be divided into low molecular surfactants and high molecular surfactants.
  • the molecular weight of the two is usually 1000 as the demarcation standard. Those with a molecular weight of more than 1000 (and mostly below 1000000) are considered high molecular surfactants, and those with a molecular weight of less than 1000 are considered low molecular surfactants.
  • High molecular surfactants are mostly polymerized from hydrophilic monomers and hydrophobic monomers, mostly block copolymers or graft copolymers, and are biodegradable. Their molecular structure includes hydrophilic groups and hydrophobic groups.
  • the hydrophilic group is selected from one or more of polyols (such as polyethylene glycol, polyvinyl alcohol, etc.), polysaccharides (such as dextran, chitosan, alginic acid, etc.), polyamides (such as polyvinyl caprolactam, polyisopropyl acrylamide, etc.), and the hydrophobic group is selected from one or more of polyesters (such as polyvinyl acetate, polycaprolactone, polyglycolide (or polyglycolic acid), polylactide (or polylactic acid), etc.), polyamino acids (such as polylysine, polyglutamic acid, polyaspartic acid, etc.).
  • polyols such as polyethylene glycol, polyvinyl alcohol, etc.
  • polysaccharides such as dextran, chitosan, alginic acid, etc.
  • polyamides such as polyvinyl caprolactam, polyisopropyl acrylamide, etc.
  • the high molecular surfactant with polyethylene glycol as the hydrophilic group can be a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, which is obtained by copolymerizing N-vinyl caprolactam, vinyl acetate and polyethylene glycol.
  • Examples thereof include (but are not limited to) a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer obtained by copolymerizing 5%-20%wt of polyethylene glycol 6000, 20%-40%wt of vinyl acetate and 50%-70%wt of vinyl caprolactam and having an average relative molecular weight of 50000-200000 g/mol, preferably a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer obtained by copolymerizing 10%-15%wt of polyethylene glycol 6000, 25%-35%wt of vinyl acetate and 55%-60%wt of vinyl caprolactam and having an average relative molecular weight of 90000-140000 g/mol, for example the term It refers to a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer sold by BASF of Germany and can be used as a pharmaceutical
  • the term "stabilizer” used in the present invention refers to a substance that can increase the physical stability of a specific preparation (such as the ophthalmic micelle solution composition of the present invention) (such as preventing micelle aggregation and/or micelle particle size growth to avoid sedimentation, etc.).
  • the stabilizer in the present invention can be a chain polyol containing 2-6 carbon atoms and at least 2 hydroxyl groups, and illustrative examples include (but are not limited to) propylene glycol (such as 1,2-propylene glycol), glycerol (i.e., glycerol), butylene glycol (such as 1,2-butylene glycol) and pentanediol (such as 1,2-pentanediol).
  • propylene glycol such as 1,2-propylene glycol
  • glycerol i.e., glycerol
  • butylene glycol such as 1,2-butylene glycol
  • pentanediol such as 1,2-pentanediol
  • viscosity enhancer used in the present invention refers to an excipient that can increase the viscosity of the composition of the present invention to a certain extent, and further enhance the sustained release effect of the active pharmaceutical ingredient (i.e., Reprosa or its pharmaceutically acceptable salt).
  • Exemplary viscosity enhancers include (but are not limited to) carboxymethyl cellulose or its sodium salt, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, poloxamer, carbomer, xanthan gum, hyaluronic acid or its sodium salt, polyvinyl pyrrolidone, polycarbophil, gum, carrageenan, guar gum, tragacanth gum, agarose, polyethylene glycol, alginic acid or its sodium salt, and hyaluronic acid or its sodium salt, etc.
  • chelating agent refers to an auxiliary material that can complex with metal ions to a certain extent to form a chelate, thereby reducing or controlling the concentration of metal ions in the composition of the present invention.
  • exemplary chelating agents include (but are not limited to) citric acid or its salts (such as sodium citrate), glucuronic acid or its salts (such as sodium glucuronic acid), hexametaphosphate (such as sodium hexametaphosphate, zinc hexametaphosphate, etc.), edetic acid or its salts (such as disodium edetate) and phosphonates.
  • pH regulator refers to an auxiliary material that can maintain or change the pH value of the composition of the present invention to a certain extent.
  • the pH regulator used in the present invention can be a conventional pH regulator in the art, including (but not limited to) inorganic or organic acids, bases and buffer salts.
  • osmotic pressure regulator refers to an excipient that can adjust the osmotic pressure of the composition of the present invention to a certain extent, so that it is equal to or close to the osmotic pressure of the body fluid of the subject's whole body and/or the local administration site.
  • exemplary osmotic pressure regulators include (but are not limited to) sodium chloride, mannitol, glucose, sorbitol, polyethylene glycol, glycerol and propylene glycol.
  • the numerical range expressed by "value A to value B" or “value A-value B” means a range including the endpoint values A and B.
  • “polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units” includes both polyoxyethylene hydroxystearate having 10 polyoxyethylene units and polyoxyethylene hydroxystearate having 20 polyoxyethylene units.
  • the chemical structure of "main impurity 1" is The chemical structure of "Main Impurity 2" is
  • Micelle particle size detection Take 1 mL of the test solution into the detection cell for particle size detection; the device used is Malvern's Zetasizer Pro nanoparticle size analyzer. "Z-Average” refers to the average particle size, which is measured using dynamic light scattering technology and is applicable to particles in dispersions or molecules in solutions.
  • In vitro dissolution test The dissolution and release rate determination method (basket method) of the Chinese Pharmacopoeia (2020 edition) was used for the test.
  • the original basket was replaced with a ready-to-use dialysis tube/dialysis bag (CE, molecular weight cutoff: 100KD); dissolution medium: artificial tears; dissolution medium volume: 1000mL; dissolution medium temperature: 34°C ⁇ 0.5°C; rotation speed: 100rpm; sampling time: 10min, 20min, 30min, 45min, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 16h, 20h and 24h.
  • the test was performed by HPLC, and the test method was the same as the content test method.
  • Reprosa ophthalmic solution (batch size 100g-200g): first weigh the prescribed amount of Reprosa, solubilizer and optional propylene glycol into a beaker according to the weight percentage recorded in Table 1-1, stir in a 45°C water bath until completely dissolved to obtain a drug-containing solution; then slowly add the drug-containing solution into water at about 30°C, and after it is completely dispersed, obtain the Reprosa ophthalmic solution.
  • Stability test Observe the properties of Reprosa ophthalmic solution with naked eyes, and test the relevant substances, API content and micelle particle size within 24 hours after preparation. The specific test results are shown in Table 1-2.
  • the Reprosa ophthalmic solutions of prescriptions 1.1-1.10 are all uniform micellar solutions, with an average micellar particle size of 10-65nm, most of which are 10-30nm, and some can even reach 10-15nm, and can form micellar solutions with uniform particle size.
  • the total amount of impurities of related substances can be controlled within an acceptable range of no more than 1.5%, and some can even reach less than 0.5%.
  • the total amount of impurities and the number of impurity peaks of prescriptions 1.2, 1.8 and 1.9 are higher than those of other prescriptions.
  • Reprosa ophthalmic solution (batch size 100 g-200 g) was prepared in the same manner as in Example 1. The prepared solution was subjected to physical and chemical stability tests, and the properties of the samples were observed after 0 days, 10 days of acceleration (40°C/75% RH) and 30 days of acceleration (40°C/75% RH), and the related substances, API content and micelle particle size of the samples were tested respectively. The specific test results are shown in Table 2-2.
  • Test results Prescriptions 2.1-2.6 were colorless clear liquids at 0 days, 10 days of acceleration, and 30 days of acceleration; the relevant substances could still be controlled within a range below about 0.5% after 30 days of acceleration, and the changes in API content and particle size fluctuations were all within controllable ranges.
  • the Reprosa ophthalmic solution (batch size 100g-200g) was prepared, and the preparation method was the same as in Example 1.
  • an intermediate liquid was obtained, on which a thickener was further added and stirred to disperse evenly, and the Reprosa ophthalmic solution (batch size 100g) was obtained.
  • the prepared micellar solution was subjected to a physical stability test, and the micellar particle size of the samples after 0 days, 10 days of acceleration (40°C/75%RH) and 30 days of acceleration (40°C/75%RH) was tested respectively.
  • the specific test results are shown in Table 3-2.
  • Test results The total amount of impurities and/or the number of impurity peaks of prescriptions 4.3 and 4.5 after 7 days at high temperature (60°C) were higher than those of other prescriptions, so the accelerated stability test was not conducted on the above two prescriptions.
  • the total amount of impurities of prescriptions 4.1, 4.2, 4.4 and 4.6 after 7 days at high temperature was controlled within the range of less than about 0.5%, and after 30 days of acceleration, it was still controlled within the range of less than 0.5%, and some even reached less than 0.2%.
  • Reprosa ophthalmic solutions of different concentrations were prepared with reference to prescriptions 5.1-5.5 in Table 5-1 and the preparation method in Example 4.
  • the prepared solutions were subjected to chemical stability tests, and the relevant substances of the samples were tested after 0 days, 10 days of acceleration (40°C/75% RH), and 30 days of acceleration (40°C/75% RH).
  • the specific test results are detailed in Table 5-2.
  • the in vitro sustained release effect of the ophthalmic nanomicelle solution of the present invention is significantly better than that of the cyclodextrin ophthalmic solution.
  • prescription 1.6 with prescription 6.1 and prescription 1.7 with prescription 6.2 it can be seen that the introduction of a viscosity enhancer into the prescription can further improve the in vitro sustained release effect of the ophthalmic nanomicelle solution of the present invention to a certain extent.
  • Example 6-2 In vitro dissolution test
  • Test results The in vitro sustained-release effects of the ophthalmic nano-micelle solutions of different concentrations and prescriptions of the present invention are significant.
  • Example 7 Prescription for adding antioxidants, chelating agents, pH regulators, osmotic pressure regulators and other auxiliary materials
  • antioxidants, chelating agents, pH regulators, osmotic pressure regulators are further selectively added and the corresponding ophthalmic nano-micelle solutions (batch size 100g-200g) are prepared by conventional preparation techniques commonly used in the art.
  • the prepared samples were tested for pH, osmotic pressure and particle size, and the test results all met the relevant quality requirements of Reprosa ophthalmic micelles (as shown in Table 7-2).
  • Preparation method (batch size 100g-200g): First weigh the prescribed amount of Reprosa (the excipient group does not contain Reprosa), solubilizer and propylene glycol into a beaker according to the weight percentage recorded in Prescriptions 5.2 and 5.3 in Table 5-1, and stir in a 45°C water bath until completely dissolved to obtain a drug-containing solution; then slowly add the drug-containing solution to half of the prescribed amount of water at about 30°C, and after it is completely dispersed, filter with a 0.22 ⁇ m filter membrane to obtain a sterile Reprosa ophthalmic solution 1); add CMC-Na to the remaining half of the water, stir until completely dissolved, and sterilize at high temperature at 121°C for 12 minutes to obtain a sterile CMC-Na concentrated solution 2); mix solution 1) and solution 2) under sterile conditions to obtain a Reprosa ophthalmic solution.
  • Reprosa the excipient group does not contain Reprosa
  • the corneas of rats in other experimental groups were continuously administered (20 ⁇ L each time, twice a day), and fluorescein sodium scoring was performed on the 0th, 1st, 3rd, 7th, and 14th days of administration to evaluate the degree of animal eye lesions, using the fluorescein sodium score as the standard.
  • CFS Corneal fluorescein sodium staining
  • Scoring criteria 0 points - no staining; 1 point - less than or equal to 30 punctate staining; 2 points - more than 30 punctate staining, but not diffuse; 3 points - severe diffuse staining, but no plaque staining; 4 points - plaque staining.
  • the corneal fluorescein sodium staining score of each group was averaged, and the values obtained by deducting the mean score of the blank control group on the corresponding administration day from the mean values of the model control group, positive control group, vehicle group, test substance 0.25% group, and test substance 0.15% group were entered into Table 8, and a graph was drawn based on the data in Table 8 to obtain Figure 3.

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Abstract

The present invention relates to the technical field of medicines, and relates to a reproxalap nanomicelle composition, a preparation method therefor, and a use thereof. Specifically, the reproxalap nanomicelle composition of the present invention comprises reproxalap or a pharmaceutically acceptable salt thereof, a solubilizer, water, and an optional stabilizer, and optionally further comprises other pharmaceutically acceptable adjuvants, such as a tackifier. The reproxalap nanomicelle composition of the present invention has high encapsulation rate, no irritation to eyes, and excellent sustained-release effect in in-vitro and in-vivo pharmacodynamic tests.

Description

一种瑞普洛莎纳米胶束组合物及其制备方法和用途A Reprosa nano-micelle composition and its preparation method and use

相关申请的引用Citation of Related Applications

本发明要求2023年3月24日在中国提交的、名称为“一种瑞普洛莎纳米胶束组合物及其制备方法和用途”、申请号为202310299034.4的发明专利申请和2024年2月23日在中国提交的、名称为“一种瑞普洛莎纳米胶束组合物及其制备方法和用途”、申请号为202410205630.6的发明专利申请的优先权，通过引用的方式将该专利申请的全部内容并入本文。The present invention claims priority to the invention patent application entitled “A Reprosa Nano-micelle Composition, Preparation Method and Use thereof” and application number 202310299034.4 filed in China on March 24, 2023 and the invention patent application entitled “A Reprosa Nano-micelle Composition, Preparation Method and Use thereof” and application number 202410205630.6 filed in China on February 23, 2024, and the entire contents of the patent applications are incorporated herein by reference.

技术领域Technical Field

本发明属于医药技术领域，具体涉及一种针对瑞普洛莎的新型纳米胶束组合物，以及该纳米胶束组合物的制备方法和用途。The present invention belongs to the field of medical technology, and specifically relates to a novel nano-micelle composition for Reprosa, and a preparation method and application of the nano-micelle composition.

背景技术Background Art

干眼症，或称角结膜干燥症，是任何原因造成的泪液质或量异常或者动力学异常，泪膜稳态失衡为其主要特征，可导致患眼不适、视力障碍，其病理机制主要为泪液渗透性增加、泪膜不稳定、眼表损伤、神经感觉异常及眼表炎症等。长久以来，干眼症的危害被忽略，随着人们生活方式的改变，干眼症的患病例数逐年增加，在我国其患病率为10％-15％，且女性患病率较男性更高。干眼症的临床症状包括视物模糊、干涩感、畏光等，病情严重者可出现角结膜病变、丝状物黏附、角膜溃疡等，甚至导致失明，严重危害患者眼部健康，影响日常生活及工作(崇君慈,干眼症发病机制及手术治疗研究进展[J],中外医学研究,2022,20(33):181-184)。目前，用于干眼症的治疗方法可主要分为一般治疗(如去除病因、营养支持、病情监测等)和药物治疗(如施用人工泪液或自体血清、促进泪液分泌、减轻眼表面炎症、治疗睑缘炎等)。Dry eye, or keratoconjunctivitis sicca, is an abnormality in tear quality or quantity or dynamics caused by any reason. Its main feature is tear film homeostasis imbalance, which can cause discomfort in the affected eye and visual impairment. Its pathological mechanisms are mainly increased tear osmotic pressure, tear film instability, ocular surface damage, neurosensory abnormalities, and ocular surface inflammation. For a long time, the harm of dry eye has been ignored. With the change of people's lifestyle, the number of cases of dry eye has increased year by year. In my country, its prevalence rate is 10%-15%, and the prevalence rate in women is higher than that in men. The clinical symptoms of dry eye include blurred vision, dryness, photophobia, etc. In severe cases, corneal and conjunctival lesions, filamentous adhesions, corneal ulcers, etc. may occur, and even blindness may occur, which seriously endangers the patient's eye health and affects daily life and work (Chong Junci, Research Progress on the Pathogenesis and Surgical Treatment of Dry Eye [J], Chinese and Foreign Medical Research, 2022, 20(33):181-184). Currently, the treatment methods for dry eye can be mainly divided into general treatment (such as removing the cause, nutritional support, disease monitoring, etc.) and drug treatment (such as applying artificial tears or autologous serum, promoting tear secretion, reducing ocular surface inflammation, treating blepharitis, etc.).

瑞普洛莎(Reproxalap，CAS:916056-79-6，结构如下所示)，或称ADX-102或NS-2，是一种小分子活性醛类抑制剂，通过结合和捕获眼部的促炎性活性醛类物质(Reactive aldehyde species，RASP)来治疗眼部疾病。瑞普洛莎由Aldeyra Therapeutics开发，针对干眼症的III期临床试验达到了主要终点，目前已向FDA递交新药上市申请(NDA)并获受理。
Reproxalap (CAS: 916056-79-6, structure shown below), also known as ADX-102 or NS-2, is a small molecule reactive aldehyde inhibitor that treats eye diseases by binding and capturing pro-inflammatory reactive aldehyde species (RASP) in the eye. Reproxalap was developed by Aldeyra Therapeutics. The Phase III clinical trial for dry eye disease reached the primary endpoint and the FDA has submitted a new drug application (NDA) and has been accepted.

CN113056353A公开了一种用于治疗干眼病的瑞普洛莎滴眼液，使用环糊精(如磺丁基醚-β-环糊精或羟丙基-β-环糊精)对瑞普洛莎分子进行包合和递送。2b期临床试验结果显示，施用该滴眼液12周导致多种征兆和症状的统计学显著改善，但该滴眼液需要向患者眼睛局部每天施用四次(尤其在疾病初始阶段或加重阶段)，患者依从性较差。CN113056353A discloses a reproza eye drop for treating dry eye disease, which uses cyclodextrin (such as sulfobutyl ether-β-cyclodextrin or hydroxypropyl-β-cyclodextrin) to encapsulate and deliver the reproza molecule. The results of the Phase 2b clinical trial showed that the application of the eye drop for 12 weeks resulted in statistically significant improvement in multiple signs and symptoms, but the eye drop needs to be applied topically to the patient's eyes four times a day (especially in the initial stage or aggravation stage of the disease), and patient compliance is poor.

因此，本领域亟需开发一种具有缓释或控释作用的、长效的瑞普洛莎眼用组合物，其可提高药物在眼部的渗透作用，延长药物滞留时间，达到促进药物吸收、提高生物利用度、减少给药次数、改善患者依从性、提高药效的作用。Therefore, there is an urgent need in the art to develop a long-acting reproza eye composition with sustained-release or controlled-release effect, which can enhance the penetration of the drug in the eye, prolong the drug retention time, and achieve the effects of promoting drug absorption, improving bioavailability, reducing the number of dosing times, improving patient compliance, and enhancing drug efficacy.

发明内容Summary of the invention

发明要解决的问题Problem that the invention aims to solve

本发明所要解决的技术问题是克服现有瑞普洛莎眼用组合物存在的眼表渗透性低、滞留时间短、生物利用度低、每日给药次数多、药效持续时间短以及患者依从性较差等缺点，为此，本发明提供了一种瑞普洛莎纳米胶束组合物及其制备方法和用途。 The technical problem to be solved by the present invention is to overcome the shortcomings of the existing Reprosa ophthalmic composition, such as low ocular surface permeability, short residence time, low bioavailability, multiple daily dosing times, short duration of drug efficacy and poor patient compliance. To this end, the present invention provides a Reprosa nano-micelle composition, a preparation method and use thereof.

用于解决问题的方案Solutions for solving problems

第一方面，本发明提供了一种眼用溶液组合物，其包含瑞普洛莎或其药学上可接受的盐、增溶剂、水和任选的稳定剂。In a first aspect, the present invention provides an ophthalmic solution composition comprising reproxaoroxat or a pharmaceutically acceptable salt thereof, a solubilizer, water, and optionally a stabilizer.

在一个实施方案中，所述眼用溶液组合物为眼用胶束溶液组合物。In one embodiment, the ophthalmic solution composition is an ophthalmic micellar solution composition.

在一个具体的实施方案中，所述眼用溶液组合物为眼用纳米胶束溶液组合物。In a specific embodiment, the ophthalmic solution composition is an ophthalmic nanomicelle solution composition.

在一个更具体的实施方案中，所述眼用溶液组合物中纳米胶束的平均粒径为5-100nm，优选5-80nm，更优选10-65nm，进一步优选10-30nm，最优选10-15nm。In a more specific embodiment, the average particle size of the nanomicelles in the ophthalmic solution composition is 5-100 nm, preferably 5-80 nm, more preferably 10-65 nm, further preferably 10-30 nm, and most preferably 10-15 nm.

在一个实施方案中，所述瑞普洛莎或其药学上可接受的盐为瑞普洛莎或瑞普洛莎的酸加成盐。In one embodiment, the reprozac or a pharmaceutically acceptable salt thereof is reprozac or an acid addition salt of reprozac.

在一个具体的实施方案中，所述酸加成盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乙酸盐、乳酸盐、水杨酸盐、柠檬酸盐、酒石酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、葡糖二酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐中的一种或多种。In a specific embodiment, the acid addition salt is selected from one or more of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, glucarate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate.

在一个实施方案中，以所述组合物的总重量计，所述瑞普洛莎的含量为0.05％-0.5％，优选0.15％-0.5％，更优选0.2％-0.45％，进一步优选0.25％-0.4％，更进一步优选0.25％-0.35％，最优选0.25％-0.3％。In one embodiment, based on the total weight of the composition, the content of Reprosa is 0.05%-0.5%, preferably 0.15%-0.5%, more preferably 0.2%-0.45%, further preferably 0.25%-0.4%, further preferably 0.25%-0.35%, most preferably 0.25%-0.3%.

在一个实施方案中，以所述组合物的总重量计，所述瑞普洛莎的含量为0.05％-0.5％，优选0.1％-0.5％，更优选0.1％-0.45％，进一步优选0.1-0.3％，最优选0.15％-0.25％。In one embodiment, based on the total weight of the composition, the content of Reprosa is 0.05%-0.5%, preferably 0.1%-0.5%, more preferably 0.1%-0.45%, further preferably 0.1-0.3%, and most preferably 0.15%-0.25%.

在一个实施方案中，所述增溶剂为表面活性剂。In one embodiment, the solubilizing agent is a surfactant.

在一个实施方案中，所述增溶剂包含非离子表面活性剂；优选地，所述增溶剂为非离子表面活性剂。In one embodiment, the solubilizing agent comprises a nonionic surfactant; preferably, the solubilizing agent is a nonionic surfactant.

在一个实施方案中，所述非离子表面活性剂为聚乙二醇型非离子表面活性剂。In one embodiment, the nonionic surfactant is a polyethylene glycol type nonionic surfactant.

在一个具体的实施方案中，所述聚乙二醇型非离子表面活性剂选自聚氧乙烯蓖麻油衍生物、聚氧乙烯脂肪酸酯和聚氧乙烯烷基酚醚中的一种或多种。In a specific embodiment, the polyethylene glycol type nonionic surfactant is selected from one or more of polyoxyethylene castor oil derivatives, polyoxyethylene fatty acid esters and polyoxyethylene alkylphenol ethers.

在一个更具体的实施方案中，所述聚乙二醇型非离子表面活性剂包括聚氧乙烯蓖麻油衍生物，所述聚氧乙烯蓖麻油衍生物选自聚氧乙烯蓖麻油和聚氧乙烯氢化蓖麻油中的一种或多种，优选聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油和聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油中的一种或多种，更优选聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油和聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油中的一种或多种，进一步优选聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油、聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油和聚氧乙烯单元数为50-55的聚氧乙烯氢化蓖麻油中的一种或多种，更进一步优选聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油和聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油中的一种或多种，最优选聚氧乙烯35氢化蓖麻油或聚氧乙烯40氢化蓖麻油。In a more specific embodiment, the polyethylene glycol type nonionic surfactant comprises a polyoxyethylene castor oil derivative, wherein the polyoxyethylene castor oil derivative is selected from one or more of polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil, preferably one or more of polyoxyethylene castor oil having 30-40 polyoxyethylene units and polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units, more preferably one or more of polyoxyethylene castor oil having 30-40 polyoxyethylene units and polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units. The present invention can be selected from the group consisting of polyoxyethylene castor oil, polyoxyethylene hydrogenated ...

在一个更具体的实施方案中，所述聚乙二醇型非离子表面活性剂包括聚氧乙烯脂肪酸酯，所述聚氧乙烯脂肪酸酯选自聚氧乙烯硬脂酸酯、聚氧乙烯羟基硬脂酸酯和维生素E聚乙二醇琥珀酸酯中一种或多种。In a more specific embodiment, the polyethylene glycol type nonionic surfactant includes polyoxyethylene fatty acid ester, and the polyoxyethylene fatty acid ester is selected from one or more of polyoxyethylene stearate, polyoxyethylene hydroxystearate and vitamin E polyethylene glycol succinate.

在一个进一步具体的实施方案中，所述聚氧乙烯硬脂酸酯选自聚氧乙烯单元数为10-50的聚氧乙烯硬脂酸酯中的一种或多种，优选聚氧乙烯单元数为30-50的聚氧乙烯硬脂酸酯中的一种或多种，更优选聚氧乙烯单元数为35-45的聚氧乙烯硬脂酸酯中的一种或多种，最优选聚氧乙烯40硬脂酸酯。In a further specific embodiment, the polyoxyethylene stearate is selected from one or more polyoxyethylene stearates having 10-50 polyoxyethylene units, preferably one or more polyoxyethylene stearates having 30-50 polyoxyethylene units, more preferably one or more polyoxyethylene stearates having 35-45 polyoxyethylene units, and most preferably polyoxyethylene 40 stearate.

在一个进一步具体的实施方案中，所述聚氧乙烯羟基硬脂酸酯选自聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种，优选聚氧乙烯15羟基硬脂酸酯。In a further specific embodiment, the polyoxyethylene hydroxystearate is selected from one or more polyoxyethylene hydroxystearates having 10-20 polyoxyethylene units, preferably polyoxyethylene 15 hydroxystearate.

在一个进一步具体的实施方案中，所述维生素E聚乙二醇琥珀酸酯选自聚乙二醇平均分子量为200-4000的维生素E聚乙二醇琥珀酸酯中的一种或多种，优选聚乙二醇平均分子量为 500-1500的维生素E聚乙二醇琥珀酸酯中的一种或多种，更优选聚乙二醇平均分子量为800-1200的维生素E聚乙二醇琥珀酸酯中的一种或多种，最优选维生素E聚乙二醇琥珀酸酯1000。In a further specific embodiment, the vitamin E polyethylene glycol succinate is selected from one or more vitamin E polyethylene glycol succinates having a polyethylene glycol average molecular weight of 200-4000, preferably a polyethylene glycol average molecular weight of One or more of the vitamin E polyethylene glycol succinates with an average molecular weight of 500-1500, more preferably one or more of the vitamin E polyethylene glycol succinates with an average molecular weight of polyethylene glycol of 800-1200, and most preferably vitamin E polyethylene glycol succinate 1000.

在一个更具体的实施方案中，所述聚乙二醇型非离子表面活性剂包括聚氧乙烯烷基酚醚，所述聚氧乙烯烷基酚醚选自聚氧乙烯单元数为4-10的壬基酚聚氧乙烯醚、聚氧乙烯单元数为13-50的辛基酚聚氧乙烯醚、十二烷基酚聚氧乙烯醚和二壬基酚聚氧乙烯醚中的一种或多种，优选聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚，更优选聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚，最优选辛基酚聚氧乙烯醚40。In a more specific embodiment, the polyethylene glycol type nonionic surfactant includes polyoxyethylene alkylphenol ether, which is selected from one or more of nonylphenol polyoxyethylene ether with a polyoxyethylene unit number of 4-10, octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 13-50, dodecylphenol polyoxyethylene ether and dinonylphenol polyoxyethylene ether, preferably octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 30-50, more preferably octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 35-45, and most preferably octylphenol polyoxyethylene ether 40.

在一个实施方案中，所述增溶剂包含高分子表面活性剂；优选地，所述增溶剂为高分子表面活性剂，优选生物可降解的高分子表面活性剂。In one embodiment, the solubilizing agent comprises a polymer surfactant; preferably, the solubilizing agent is a polymer surfactant, preferably a biodegradable polymer surfactant.

在一个实施方案中，所述高分子表面活性剂为以聚乙二醇为亲水基团的高分子表面活性剂。In one embodiment, the polymer surfactant is a polymer surfactant having polyethylene glycol as a hydrophilic group.

在一个具体的实施方案中，所述以聚乙二醇为亲水基团的高分子表面活性剂为聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物。In a specific embodiment, the polymer surfactant with polyethylene glycol as the hydrophilic group is a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer.

在一个更具体的实施方案中，所述聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物选自由5％-20％的聚乙二醇6000、20％-40％的乙酸乙烯酯和50％-70％的乙烯基己内酰胺共聚而得且平均相对分子量为50000-200000g/mol的聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物中的一种或多种，优选由10％-15％的聚乙二醇6000、25％-35％的乙酸乙烯酯和55％-60％的乙烯基己内酰胺共聚而得且平均相对分子量为90000-140000g/mol的聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物中的一种或多种，或者，优选商品名为的聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物。In a more specific embodiment, the polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer is selected from one or more polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers obtained by copolymerization of 5%-20% polyethylene glycol 6000, 20%-40% vinyl acetate and 50%-70% vinyl caprolactam and having an average relative molecular weight of 50000-200000 g/mol, preferably one or more polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers obtained by copolymerization of 10%-15% polyethylene glycol 6000, 25%-35% vinyl acetate and 55%-60% vinyl caprolactam and having an average relative molecular weight of 90000-140000 g/mol, or preferably a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer with a trade name Polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer.

在一个实施方案中，所述增溶剂包含聚氧乙烯蓖麻油衍生物、聚氧乙烯脂肪酸酯、聚氧乙烯烷基酚醚、聚氧乙烯脂肪醇醚和聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物中的一种或多种；优选地，所述增溶剂选自聚氧乙烯蓖麻油衍生物、聚氧乙烯脂肪酸酯、聚氧乙烯烷基酚醚、聚氧乙烯脂肪醇醚和聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物中的一种或多种。In one embodiment, the solubilizing agent comprises one or more of polyoxyethylene castor oil derivatives, polyoxyethylene fatty acid esters, polyoxyethylene alkylphenol ethers, polyoxyethylene fatty alcohol ethers and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers; preferably, the solubilizing agent is selected from one or more of polyoxyethylene castor oil derivatives, polyoxyethylene fatty acid esters, polyoxyethylene alkylphenol ethers, polyoxyethylene fatty alcohol ethers and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers.

在一个具体的实施方案中，所述增溶剂选自聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油、聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油、聚乙二醇分子量为500-1500的维生素E聚乙二醇琥珀酸酯、聚氧乙烯单元数为30-50的聚氧乙烯硬脂酸酯、聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯、聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚和聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物中的一种或多种；优选地，所述增溶剂选自聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油、聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油、聚乙二醇分子量为500-1500的维生素E聚乙二醇琥珀酸酯、聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯和聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚中的一种或多种；更优选地，所述增溶剂选自聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油、聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油、聚乙二醇分子量为800-1200的维生素E聚乙二醇琥珀酸酯、聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯和聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚中的一种或多种；进一步优选地，所述增溶剂选自聚氧乙烯40氢化蓖麻油、聚氧乙烯54氢化蓖麻油、聚氧乙烯35蓖麻油、维生素E聚乙二醇琥珀酸酯1000、聚氧乙烯15羟基硬脂酸酯和辛基酚聚氧乙烯醚40中的一种或多种。In a specific embodiment, the solubilizer is selected from one or more of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 30-60, polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40, vitamin E polyethylene glycol succinate having a polyethylene glycol molecular weight of 500-1500, polyoxyethylene stearate having a polyoxyethylene unit number of 30-50, polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer; preferably, the solubilizer is selected from polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55, polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40, vitamin E polyethylene glycol succinate having a polyethylene glycol molecular weight of 500-1500, polyoxyethylene One or more of polyoxyethylene hydroxystearate with a unit number of 10-20 and octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 30-50; more preferably, the solubilizer is selected from polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-55, polyoxyethylene castor oil with a polyoxyethylene unit number of 30-40, vitamin E polyethylene glycol succinate with a polyethylene glycol molecular weight of 800-1200, polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20 and octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 35-45; further preferably, the solubilizer is selected from polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 54 hydrogenated castor oil, polyoxyethylene 35 castor oil, vitamin E polyethylene glycol succinate 1000, polyoxyethylene 15 hydroxystearate and octylphenol polyoxyethylene ether 40.

在一个更具体的实施方案中，所述增溶剂包含聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油，优选为聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油、其与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物或其与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物。 In a more specific embodiment, the solubilizer comprises polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units, preferably polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units, a mixture thereof with polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, or a mixture thereof with octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units.

在一个更具体的实施方案中，所述增溶剂包含聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油，优选为聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油或其与聚乙二醇-聚乙烯乙酸酯-聚乙烯基己内酰胺接枝共聚物的混合物。In a more specific embodiment, the solubilizer comprises polyoxyethylene castor oil having 30-40 polyoxyethylene units, preferably polyoxyethylene castor oil having 30-40 polyoxyethylene units or a mixture thereof with a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer.

在一个更具体的实施方案中，所述增溶剂包含聚乙二醇分子量为500-1500的维生素E聚乙二醇琥珀酸酯，优选为聚乙二醇分子量为500-1500的维生素E聚乙二醇琥珀酸酯。In a more specific embodiment, the solubilizing agent comprises vitamin E polyethylene glycol succinate with a polyethylene glycol molecular weight of 500-1500, preferably vitamin E polyethylene glycol succinate with a polyethylene glycol molecular weight of 500-1500.

在一个更具体的实施方案中，所述增溶剂包含聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯，优选为聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯或其与聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油的混合物。In a more specific embodiment, the solubilizer comprises polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, preferably polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units or a mixture thereof with polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units.

在一个更具体的实施方案中，所述增溶剂包含聚氧乙烯单元数为30-50的聚氧乙烯硬脂酸酯，优选为聚氧乙烯单元数为30-50的聚氧乙烯硬脂酸酯。In a more specific embodiment, the solubilizer comprises polyoxyethylene stearate having 30-50 polyoxyethylene units, preferably polyoxyethylene stearate having 30-50 polyoxyethylene units.

在一个具体的实施方案中，所述增溶剂选自聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油与聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物的混合物、聚乙二醇平均分子量为500-1500的维生素E聚乙二醇琥珀酸酯、聚氧乙烯单元数为30-50的聚氧乙烯硬脂酸酯和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种，优选聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种，更优选聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物或聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；其中，当所述增溶剂为聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物时，所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；当所述增溶剂为聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物时，所述辛基酚聚氧乙烯醚占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；当所述增溶剂为聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油与聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物的混合物时，所述聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物占所述混合物的重量百分比为0-50％，优选0-30％，更优选0-15％。In a specific embodiment, the solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, a mixture of polyoxyethylene castor oil having 30-40 polyoxyethylene units and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, a polyethylene glycol having an average molecular weight of 500-1500, Vitamin E polyethylene glycol succinate, one or more of polyoxyethylene stearate having 30-50 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, preferably a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units and one or more of polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, more preferably a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units. A mixture of polyoxyethylene ethers or polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20; wherein, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 30-60 and polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 30-60 and polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 3 When the solubilizing agent is a mixture of octylphenol polyoxyethylene ether with 0-50 units of octylphenol polyoxyethylene ether, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; when the solubilizing agent is a mixture of polyoxyethylene castor oil with 30-40 polyoxyethylene units and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, the weight percentage of the polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer in the mixture is 0-50%, preferably 0-30%, and more preferably 0-15%.

在一个具体的实施方案中，所述增溶剂选自聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯、聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油和聚乙二醇平均分子量为500-1500的维生素E聚乙二醇琥珀酸酯中的一种或多种，优选聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种，更优选聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物或聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；其中，当所述增溶剂为聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物时，所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；当所述增溶剂为聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物时，所述辛基酚聚氧乙烯醚占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％。In a specific embodiment, the solubilizer is selected from one or more of a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40, and vitamin E polyethylene glycol succinate having a polyethylene glycol average molecular weight of 500-1500, preferably one or more of a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, more preferably wherein, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50 or polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20; wherein, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%.

在一个具体的实施方案中，所述增溶剂选自聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元 数为50-55的聚氧乙烯氢化蓖麻油、聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯、聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油和聚乙二醇平均分子量为800-1200的维生素E聚乙二醇琥珀酸酯中的一种或多种，优选聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为50-55的聚氧乙烯氢化蓖麻油和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种，更优选聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为50-55的聚氧乙烯氢化蓖麻油或聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；其中，当所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物时，所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；当所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物时，所述辛基酚聚氧乙烯醚占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％。In a specific embodiment, the solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, The invention can be selected from the group consisting of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 50-55, polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40, and vitamin E polyethylene glycol succinate having a polyethylene glycol average molecular weight of 800-1200, preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 35-45, polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 50-55, and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, more preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 35-45, polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 50-55, and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, wherein, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 35-45, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%.

在一个具体的实施方案中，所述增溶剂选自聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种，优选聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物或聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；其中，当所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物时，所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；当所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物时，所述辛基酚聚氧乙烯醚占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％。In a specific embodiment, the solubilizer is selected from one or more of a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, preferably a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, or polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; Among them, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate with 10-20 polyoxyethylene units, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether with 35-45 polyoxyethylene units, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%.

在一个具体的实施方案中，所述增溶剂选自聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物、聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物和聚氧乙烯15羟基硬脂酸酯中的一种或多种，优选聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物或聚氧乙烯15羟基硬脂酸酯；其中，当所述增溶剂为聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物时，所述聚氧乙烯15羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；当所述增溶剂为聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物时，所述辛基酚聚氧乙烯醚40占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％。In a specific embodiment, the solubilizer is selected from one or more of a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40 and polyoxyethylene 15 hydroxystearate, preferably a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40 or polyoxyethylene 15 hydroxystearate; wherein, when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, the weight percentage of polyoxyethylene 15 hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, the weight percentage of octylphenol polyoxyethylene ether 40 in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%.

在一个实施方案中，在所述组合物中，所述瑞普洛莎或其药学上可接受的盐与所述增溶剂的重量比为1:5-1:40，优选1:8-1:30，更优选1:10-1:20，最优选1:10-1:15。In one embodiment, in the composition, the weight ratio of the reprozac or a pharmaceutically acceptable salt thereof to the solubilizer is 1:5-1:40, preferably 1:8-1:30, more preferably 1:10-1:20, and most preferably 1:10-1:15.

在一个实施方案中，以所述组合物的总重量计，所述增溶剂的含量为1％-16％，优选1％-15％，更优选1％-11％，最优选1％-9％。In one embodiment, the content of the solubilizer is 1%-16%, preferably 1%-15%, more preferably 1%-11%, most preferably 1%-9%, based on the total weight of the composition.

在一个实施方案中，以所述组合物的总重量计，所述增溶剂的含量为1％-16％，优选2％-12％，更优选2.5％-10％，最优选3.75％-7.5％。In one embodiment, the content of the solubilizer is 1%-16%, preferably 2%-12%, more preferably 2.5%-10%, most preferably 3.75%-7.5%, based on the total weight of the composition.

在一个实施方案中，以所述组合物的总重量计，所述水的含量为83％-98％，优选84％-98％，更优选86％-98％，最优选88％-98％。In one embodiment, the water content is 83%-98%, preferably 84%-98%, more preferably 86%-98%, most preferably 88%-98%, based on the total weight of the composition.

在一个实施方案中，以所述组合物的总重量计，所述水的含量为83％-98％，优选87％-97％，更优选89％-97％，最优选91％-95％。In one embodiment, the water content is 83%-98%, preferably 87%-97%, more preferably 89%-97%, most preferably 91%-95%, based on the total weight of the composition.

在一个实施方案中，所述组合物不包含稳定剂；即，所述组合物包含瑞普洛莎或其药学上可接受的盐、增溶剂和水，但不包含稳定剂。 In one embodiment, the composition does not include a stabilizer; that is, the composition includes reprozac or a pharmaceutically acceptable salt thereof, a solubilizer, and water, but does not include a stabilizer.

在一个实施方案中，所述组合物包含稳定剂；即，所述组合物包含瑞普洛莎或其药学上可接受的盐、增溶剂、水和稳定剂。In one embodiment, the composition comprises a stabilizer; that is, the composition comprises reprozac or a pharmaceutically acceptable salt thereof, a solubilizer, water, and a stabilizer.

在一个具体的实施方案中，所述稳定剂为含有2-6个碳原子和至少2个羟基的链状多元醇。In a specific embodiment, the stabilizer is a chain polyol containing 2 to 6 carbon atoms and at least 2 hydroxyl groups.

在一个更具体的实施方案中，所述稳定剂选自丙二醇、甘油、丁二醇和戊二醇中的一种或多种，优选丙二醇和甘油中的一种或多种，更优选丙二醇。In a more specific embodiment, the stabilizer is selected from one or more of propylene glycol, glycerol, butylene glycol and pentylene glycol, preferably one or more of propylene glycol and glycerol, more preferably propylene glycol.

在一个实施方案中，以所述组合物的总重量计，所述稳定剂的含量为0-5％，优选0-4％，更优选0-3％，进一步优选0.5％-3％，最优选1％-3％。In one embodiment, based on the total weight of the composition, the content of the stabilizer is 0-5%, preferably 0-4%, more preferably 0-3%, further preferably 0.5%-3%, most preferably 1%-3%.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of solubilizer, 0-5% of stabilizer and 83%-98% of water.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、稳定剂0-4％和水87％-97％。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of a stabilizer, and 87%-97% of water.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、稳定剂0.5％-4％和水87％-97％。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0.5%-4% of a stabilizer, and 87%-97% of water.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.4％、增溶剂2.5％-10％、稳定剂0-3％和水89％-97％。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or its pharmaceutically acceptable salt, 2.5%-10% of solubilizer, 0-3% of stabilizer and 89%-97% of water.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.35％、增溶剂3.75％-7.5％、稳定剂1％-3％和水91％-95％。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or its pharmaceutically acceptable salt, 3.75%-7.5% of solubilizer, 1%-3% of stabilizer and 91%-95% of water.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、稳定剂0.5％-3％和水84％-98％。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer, and 84%-98% of water.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、稳定剂0.5％-3％和水86％-98％。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer, and 86%-98% of water.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、稳定剂0.5％-3％和水88％-98％。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer, and 88%-98% of water.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂选自聚氧乙烯蓖麻油衍生物、聚氧乙烯脂肪酸酯、聚氧乙烯烷基酚醚和聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物中的一种或多种；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of polyoxyethylene castor oil derivatives, polyoxyethylene fatty acid esters, polyoxyethylene alkylphenol ethers, and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂选自聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、维生素E聚乙二醇琥珀酸酯、聚氧乙烯硬脂酸酯、聚氧乙烯羟基硬脂酸酯、辛基酚聚氧乙烯醚和聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物中的一种或多种；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, vitamin E polyethylene glycol succinate, polyoxyethylene stearate, polyoxyethylene hydroxystearate, octylphenol polyoxyethylene ether, and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂选自聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油、聚氧乙烯单元数为30-40聚氧乙烯蓖麻油、聚乙二醇平均分子量为500-1500的维生素E聚乙二醇琥珀酸酯、聚氧乙烯单元数为30-50的聚氧乙烯硬脂酸酯、聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯、聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚和聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物中的一种或多种；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units, polyoxyethylene castor oil having 30-40 polyoxyethylene units, polyethylene glycol vitamin E succinate having an average molecular weight of 500-1500, polyoxyethylene stearate having 30-50 polyoxyethylene units, polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％ 和水83％-98％；其中，所述增溶剂选自聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油与聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物的混合物、聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为30-50的聚氧乙烯硬脂酸酯、聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯和聚乙二醇平均分子量为500-1500的维生素E聚乙二醇琥珀酸酯中的一种或多种，优选聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种，更优选聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物或聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；其中，当所述增溶剂为聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油与聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物的混合物时，所述聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物占所述混合物的重量百分比为0-50％，优选0-30％，更优选0-15％；当所述增溶剂为聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物时，所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；当所述增溶剂为聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物时，所述辛基酚聚氧乙烯醚占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of solubilizer, 0-5% of stabilizer and 83%-98% water; wherein the solubilizer is selected from a mixture of polyoxyethylene castor oil having 30-40 polyoxyethylene units and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, polyoxyethylene stearate having 30-50 polyoxyethylene units, polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units. One or more of vitamin E polyethylene glycol succinates having an average molecular weight of 500-1500, preferably a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, and one or more of polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, more preferably a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units. A mixture of polyoxyethylene hydrogenated castor oil with 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether with 30-50 polyoxyethylene units, or polyoxyethylene hydroxystearate with 10-20 polyoxyethylene units; wherein, when the solubilizer is a mixture of polyoxyethylene castor oil with 30-40 polyoxyethylene units and a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, the polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer accounts for 0-50% by weight of the mixture, preferably 0-30%, and more preferably 0-15%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether with 30-50 polyoxyethylene units, or polyoxyethylene hydroxystearate with 10-20 polyoxyethylene units. When the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 0-60 polyoxyethylene units and polyoxyethylene hydroxystearate with 10-20 polyoxyethylene units, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether with 30-50 polyoxyethylene units, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂选自聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯、聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油和聚乙二醇平均分子量为500-1500的维生素E聚乙二醇琥珀酸酯中的一种或多种，优选聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种，更优选聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物或聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；其中，当所述增溶剂为聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物时，所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；当所述增溶剂为聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物时，所述辛基酚聚氧乙烯醚占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units and octyldodecyl hydroxystearate having 30-50 polyoxyethylene units, and a mixture of polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units and octyldodecyl hydroxystearate having 30-50 polyoxyethylene units. The invention relates to a mixture of polyoxyethylene octylphenol polyoxyethylene ethers, polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40, and vitamin E polyethylene glycol succinate having a polyethylene glycol average molecular weight of 500-1500, preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, and One or more polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, more preferably a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 30-50, or polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20; wherein, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-55 and polyoxyethylene unit When the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 30-50, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂选自聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为10- 20的聚氧乙烯羟基硬脂酸酯、聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油、聚氧乙烯单元数为50-55的聚氧乙烯氢化蓖麻油和聚乙二醇平均分子量为800-1200的维生素E聚乙二醇琥珀酸酯中的一种或多种，优选聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为50-55的聚氧乙烯氢化蓖麻油和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种，更优选聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为50-55的聚氧乙烯氢化蓖麻油或聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；其中，当所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物时，所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；当所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物时，所述辛基酚聚氧乙烯醚占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 35-45, and a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 10-20 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 10-20. The invention can be selected from the group consisting of polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 20, polyoxyethylene castor oil with a polyoxyethylene unit number of 30-40, polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 50-55, and vitamin E polyethylene glycol succinate with a polyethylene glycol average molecular weight of 800-1200, preferably a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-45 and vitamin E polyethylene glycol succinate with a polyoxyethylene unit number of 10-20, and a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-45 and vitamin E polyethylene glycol succinate with a polyoxyethylene unit number of 10-20. The present invention is a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 45 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 35-45, polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 50-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, and more preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, and polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 35-45. wherein the solubilizing agent is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 35-45, polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 50-55, or polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20; wherein, when the solubilizing agent is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, the polyoxyethylene hydroxystearate accounts for The weight percentage of the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether with 35-45 polyoxyethylene units, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂选自聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种，优选聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物或聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；其中，当所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物时，所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；当所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物时，所述辛基酚聚氧乙烯醚占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 35-45, and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, and a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20. The invention relates to a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 35-45 or polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20; wherein, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 35-45, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物，并且所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer and 83%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and the weight ratio of the polyoxyethylene hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、稳定剂0-4％和水87％-97％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物，并且所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and the weight ratio of the polyoxyethylene hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.4％、增溶剂2.5％-10％、稳定剂0-3％和水89％-97％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物，并且所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；所述稳定剂为丙二醇。 In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and the weight ratio of the polyoxyethylene hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.35％、增溶剂3.75％-7.5％、稳定剂1％-3％和水91％-95％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物，并且所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and the weight ratio of the polyoxyethylene hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物，并且所述辛基酚聚氧乙烯醚占所述混合物的重量比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer and 83%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and the weight ratio of the octylphenol polyoxyethylene ether to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、稳定剂0-4％和水87％-97％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物，并且所述辛基酚聚氧乙烯醚占所述混合物的重量比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and the weight ratio of the octylphenol polyoxyethylene ether to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.4％、增溶剂2.5％-10％、稳定剂0-3％和水89％-97％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物，并且所述辛基酚聚氧乙烯醚占所述混合物的重量比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and the weight ratio of the octylphenol polyoxyethylene ether to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.35％、增溶剂3.75％-7.5％、稳定剂1％-3％和水91％-95％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物，并且所述辛基酚聚氧乙烯醚占所述混合物的重量比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and the weight ratio of the octylphenol polyoxyethylene ether to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0-5% of a stabilizer and 83%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、稳定剂0-4％和水87％-97％；其中，所述增溶剂为聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.4％、增溶剂2.5％-10％、稳定剂0-3％和水89％-97％；其中，所述增溶剂为聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.35％、增溶剂3.75％-7.5％、稳定剂1％-3％和水91％-95％；其中，所述增溶剂为聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油；所述稳定剂为丙二醇。 In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0-5% of a stabilizer and 83%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、稳定剂0-4％和水87％-97％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.4％、增溶剂2.5％-10％、稳定剂0-3％和水89％-97％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.35％、增溶剂3.75％-7.5％、稳定剂1％-3％和水91％-95％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂为聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0-5% of a stabilizer and 83%-98% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、稳定剂0-4％和水87％-97％；其中，所述增溶剂为聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.4％、增溶剂2.5％-10％、稳定剂0-3％和水89％-97％；其中，所述增溶剂为聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.35％、增溶剂3.75％-7.5％、稳定剂1％-3％和水91％-95％；其中，所述增溶剂为聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、稳定剂0.5％-4％和水87％-97％；其中，所述增溶剂为聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0.5%-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂选自聚氧乙烯35蓖麻油与的混合物、聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物、聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物、维生素E聚乙二醇琥珀酸酯1000、聚氧乙烯15羟基硬脂酸酯、聚氧乙烯35蓖麻油、聚氧乙烯54氢化蓖麻油、聚氧乙烯60氢化蓖麻油和聚氧乙烯40硬脂酸酯中的一种或多种；其中，当所述增溶剂为聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物时，所述聚氧乙烯15羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；当所述增溶剂为聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物时，所述辛基酚聚氧乙烯醚40占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from polyoxyethylene 35 castor oil and a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, vitamin E polyethylene glycol succinate 1000, polyoxyethylene 15 hydroxystearate, polyoxyethylene 35 castor oil, polyoxyethylene 54 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil and polyoxyethylene 40 stearate; wherein, when the solubilizing agent is polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 When the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, the weight percentage of the octylphenol polyoxyethylene ether 40 in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂选自聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物、聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物、维生素E聚乙二醇琥珀酸酯1000、聚氧乙烯15羟基硬脂酸酯、聚氧乙烯35蓖麻油和聚氧乙烯54氢化蓖麻油中的一种或多种；其中，当所述增溶剂为聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物时，所述聚氧乙烯15羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0- 30％，最优选0-10％；当所述增溶剂为聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物时，所述辛基酚聚氧乙烯醚40占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, vitamin E polyethylene glycol succinate 1000, polyoxyethylene 15 hydroxystearate, polyoxyethylene 35 castor oil, and polyoxyethylene 54 hydrogenated castor oil; wherein, when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, the weight percentage of the polyoxyethylene 15 hydroxystearate in the mixture is 0-80%, preferably 0-50%, and more preferably 0- 30%, most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, the weight percentage of octylphenol polyoxyethylene ether 40 in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂选自聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物、聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物和聚氧乙烯15羟基硬脂酸酯中的一种或多种；其中，当所述增溶剂为聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物时，所述聚氧乙烯15羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；当所述增溶剂为聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物时，所述辛基酚聚氧乙烯醚40占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and polyoxyethylene 15 hydroxystearate; wherein, when the When the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, the weight percentage of polyoxyethylene 15 hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, the weight percentage of octylphenol polyoxyethylene ether 40 in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物，并且所述聚氧乙烯15羟基硬脂酸酯占所述混合物的重量比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable, 1%-16% solubilizer, 0-5% stabilizer and 83%-98% water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、稳定剂0-4％和水87％-97％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物，并且所述聚氧乙烯15羟基硬脂酸酯占所述混合物的重量比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、稳定剂0.5％-4％和水87％-97％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物，并且所述聚氧乙烯15羟基硬脂酸酯占所述混合物的重量比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0.5%-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.4％、增溶剂2.5％-10％、稳定剂0-3％和水89％-97％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物，并且所述聚氧乙烯15羟基硬脂酸酯占所述混合物的重量比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.35％、增溶剂3.75％-7.5％、稳定剂1％-3％和水91％-95％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物，并且所述聚氧乙烯15羟基硬脂酸酯占所述混合物的重量比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物，并且所述辛基酚聚氧乙烯醚40占所述混合物的重量比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable, 1%-16% of solubilizer, 0-5% of stabilizer and 83%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and the weight ratio of octylphenol polyoxyethylene ether 40 to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、稳定剂0-4％和水87％-97％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物，并且所述辛基酚 聚氧乙烯醚40占所述混合物的重量比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or its pharmaceutically acceptable salt, 2%-12% of solubilizer, 0-4% of stabilizer and 87%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and the octylphenol The weight ratio of polyoxyethylene ether 40 to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.4％、增溶剂2.5％-10％、稳定剂0-3％和水89％-97％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物，并且所述辛基酚聚氧乙烯醚40占所述混合物的重量比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and the weight ratio of octylphenol polyoxyethylene ether 40 to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.35％、增溶剂3.75％-7.5％、稳定剂1％-3％和水91％-95％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物，并且所述辛基酚聚氧乙烯醚40占所述混合物的重量比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and the weight ratio of octylphenol polyoxyethylene ether 40 to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0-5% of a stabilizer and 83%-98% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、稳定剂0-4％和水87％-97％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.4％、增溶剂2.5％-10％、稳定剂0-3％和水89％-97％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.35％、增溶剂3.75％-7.5％、稳定剂1％-3％和水91％-95％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、稳定剂0-5％和水83％-98％；其中，所述增溶剂为聚氧乙烯15羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable, 1%-16% solubilizer, 0-5% stabilizer and 83%-98% water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、稳定剂0-4％和水87％-97％；其中，所述增溶剂为聚氧乙烯15羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、稳定剂0.5％-4％和水87％-97％；其中，所述增溶剂为聚氧乙烯15羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0.5%-4% of a stabilizer and 87%-97% of water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.4％、增溶剂2.5％-10％、稳定剂0-3％和水89％-97％；其中，所述增溶剂为聚氧乙烯15羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer and 89%-97% of water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.35％、增溶剂3.75％-7.5％、稳定剂1％-3％和水91％-95％；其中，所述增溶剂为聚氧乙烯15羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of a stabilizer and 91%-95% of water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂选自聚氧乙烯蓖麻油衍生物、聚氧乙烯脂肪酸酯、聚氧乙烯烷基酚醚和聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物中的一种或多种；所述稳定剂为丙二醇。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is selected from one or more of polyoxyethylene castor oil derivatives, polyoxyethylene fatty acid esters, polyoxyethylene alkylphenol ethers and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers; and the stabilizer is propylene glycol.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其 中，所述增溶剂选自聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、维生素E聚乙二醇琥珀酸酯、聚氧乙烯硬脂酸酯、聚氧乙烯羟基硬脂酸酯、辛基酚聚氧乙烯醚和聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物中的一种或多种；所述稳定剂为丙二醇。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; In the invention, the solubilizer is selected from one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, vitamin E polyethylene glycol succinate, polyoxyethylene stearate, polyoxyethylene hydroxystearate, octylphenol polyoxyethylene ether and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer; and the stabilizer is propylene glycol.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂选自聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油、聚氧乙烯单元数为30-40聚氧乙烯蓖麻油、聚乙二醇平均分子量为500-1500的维生素E聚乙二醇琥珀酸酯、聚氧乙烯单元数为30-50的聚氧乙烯硬脂酸酯、聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯、聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚和聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物中的一种或多种；所述稳定剂为丙二醇。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or its pharmaceutically acceptable salt, 1%-16% of solubilizer, 0.5%-3% of stabilizer and 83%-98% of water; wherein the solubilizer is selected from one or more of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units, polyoxyethylene castor oil having 30-40 polyoxyethylene units, polyethylene glycol vitamin E succinate having an average molecular weight of 500-1500, polyoxyethylene stearate having 30-50 polyoxyethylene units, polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer; the stabilizer is propylene glycol.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂选自聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油与聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物的混合物、聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为30-50的聚氧乙烯硬脂酸酯、聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯和聚乙二醇平均分子量为500-1500的维生素E聚乙二醇琥珀酸酯中的一种或多种，优选聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种，更优选聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物或聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；其中，当所述增溶剂为聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油与聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物的混合物时，所述聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物占所述混合物的重量百分比为0-50％，优选0-30％，更优选0-15％；当所述增溶剂为聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物时，所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；当所述增溶剂为聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物时，所述辛基酚聚氧乙烯醚占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from a mixture of polyoxyethylene castor oil having 30-40 polyoxyethylene units and a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octyl stearate having 30-50 polyoxyethylene units. A mixture of phenol polyoxyethylene ethers, polyoxyethylene stearate having a polyoxyethylene unit number of 30-50, polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, and one or more of vitamin E polyethylene glycol succinate having a polyethylene glycol average molecular weight of 500-1500, preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 30-60 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 30-60 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, more preferably polyoxyethylene unit The solubilizing agent is a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 30-60 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 30-60 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, or polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20; wherein, when the solubilizing agent is a mixture of polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40 and a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, the polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer accounts for 0-50% by weight of the mixture, preferably 0-30%, and more preferably 0- 15%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂选自聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯、聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油和聚乙二醇平均分子量为500-1500的维生素E聚乙二醇琥珀酸酯中的一种或多种，优选聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种，更优选聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物或聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；其中，当所述增溶剂为聚氧乙烯单元数为 35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物时，所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；当所述增溶剂为聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物时，所述辛基酚聚氧乙烯醚占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40, and one or more of vitamin E polyethylene glycol succinate having a polyethylene glycol average molecular weight of 500-1500. , preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, more preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, or polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20; wherein, when the solubilizing agent is a polyoxyethylene unit number of When the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 30-50, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂选自聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯、聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油、聚氧乙烯单元数为50-55的聚氧乙烯氢化蓖麻油和聚乙二醇平均分子量为800-1200的维生素E聚乙二醇琥珀酸酯中的一种或多种，优选聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为50-55的聚氧乙烯氢化蓖麻油和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种，更优选聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为50-55的聚氧乙烯氢化蓖麻油或聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；其中，当所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物时，所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；当所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物时，所述辛基酚聚氧乙烯醚占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units. One or more of oxyethylene hydroxystearate, polyoxyethylene castor oil having 30-40 polyoxyethylene units, polyoxyethylene hydrogenated castor oil having 50-55 polyoxyethylene units, and vitamin E polyethylene glycol succinate having an average molecular weight of 800-1200, preferably a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, polyoxyethylene succinate having 50-55 polyoxyethylene units, One or more of hydrogenated castor oil and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, more preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 35-45, polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 50-55 or polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20; wherein, when the solubilizing agent is polyoxyethylene having a polyoxyethylene unit number of 35-45 When the solubilizer is a mixture of oxyethylene hydrogenated castor oil and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂选自聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种，优选聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物或聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；其中，当所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物时，所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；当所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物时，所述辛基酚聚氧乙烯醚占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 35-45, and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, and a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20. A mixture of polyoxyethylene hydrogenated castor oil and octylphenol polyoxyethylene ether with 35-45 polyoxyethylene units or polyoxyethylene hydroxystearate with 10-20 polyoxyethylene units; wherein, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate with 10-20 polyoxyethylene units, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether with 35-45 polyoxyethylene units, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物，并且所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；所述稳定剂为丙二醇。 In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and the weight ratio of the polyoxyethylene hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、稳定剂0.5％-3％和水84％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物，并且所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and the weight ratio of the polyoxyethylene hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、稳定剂0.5％-3％和水86％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物，并且所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer and 86%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and the weight ratio of the polyoxyethylene hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、稳定剂0.5％-3％和水88％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物，并且所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and the weight ratio of the polyoxyethylene hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物，并且所述辛基酚聚氧乙烯醚占所述混合物的重量比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and the weight ratio of the octylphenol polyoxyethylene ether to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、稳定剂0.5％-3％和水84％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物，并且所述辛基酚聚氧乙烯醚占所述混合物的重量比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and the weight ratio of the octylphenol polyoxyethylene ether to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、稳定剂0.5％-3％和水86％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物，并且所述辛基酚聚氧乙烯醚占所述混合物的重量比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer and 86%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and the weight ratio of the octylphenol polyoxyethylene ether to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、稳定剂0.5％-3％和水88％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物，并且所述辛基酚聚氧乙烯醚占所述混合物的重量比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and the weight ratio of the octylphenol polyoxyethylene ether to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、稳定剂0.5％-3％和水84％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、稳定剂0.5％-3％和水86％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油；所述稳定剂为丙二醇。 In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer and 86%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、稳定剂0.5％-3％和水88％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、稳定剂0.5％-3％和水84％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、稳定剂0.5％-3％和水86％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer and 86%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、稳定剂0.5％-3％和水88％-98％；其中，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂为聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、稳定剂0.5％-3％和水84％-98％；其中，所述增溶剂为聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、稳定剂0.5％-3％和水86％-98％；其中，所述增溶剂为聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer and 86%-98% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、稳定剂0.5％-3％和水88％-98％；其中，所述增溶剂为聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂选自聚氧乙烯35蓖麻油与的混合物、聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物、聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物、维生素E聚乙二醇琥珀酸酯1000、聚氧乙烯15羟基硬脂酸酯、聚氧乙烯35蓖麻油、聚氧乙烯54氢化蓖麻油、聚氧乙烯60氢化蓖麻油和聚氧乙烯40硬脂酸酯中的一种或多种；其中，当所述增溶剂为聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物时，所述聚氧乙烯15羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；当所述增溶剂为聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物时，所述辛基酚聚氧乙烯醚40占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from polyoxyethylene 35 castor oil and a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, vitamin E polyethylene glycol succinate 1000, polyoxyethylene 15 hydroxystearate, polyoxyethylene 35 castor oil, polyoxyethylene 54 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil and polyoxyethylene 40 stearate; wherein, when the solubilizing agent is polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 When the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, the weight percentage of the octylphenol polyoxyethylene ether 40 in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂选自聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物、聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物、维生素E聚乙二醇琥珀酸酯1000、聚氧乙烯15羟基硬脂酸酯、聚氧乙烯35蓖麻油和聚氧乙烯54氢化蓖麻油中的一种或多种；其中，当所述增溶剂为聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物时，所述聚氧乙烯15羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0- 10％；当所述增溶剂为聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物时，所述辛基酚聚氧乙烯醚40占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, vitamin E polyethylene glycol succinate 1000, polyoxyethylene 15 hydroxystearate, polyoxyethylene 35 castor oil, and polyoxyethylene 54 hydrogenated castor oil; wherein, when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, the weight percentage of the polyoxyethylene 15 hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0- 10%; when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, the weight percentage of octylphenol polyoxyethylene ether 40 in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂选自聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物、聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物和聚氧乙烯15羟基硬脂酸酯中的一种或多种；其中，当所述增溶剂为聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物时，所述聚氧乙烯15羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；当所述增溶剂为聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物时，所述辛基酚聚氧乙烯醚40占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and polyoxyethylene 15 hydroxystearate; wherein, when the solubilizer is polyoxyethylene When the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, the weight percentage of polyoxyethylene 15 hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, the weight percentage of octylphenol polyoxyethylene ether 40 in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物，并且所述聚氧乙烯15羟基硬脂酸酯占所述混合物的重量比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、稳定剂0.5％-3％和水84％-98％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物，并且所述聚氧乙烯15羟基硬脂酸酯占所述混合物的重量比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、稳定剂0.5％-3％和水86％-98％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物，并且所述聚氧乙烯15羟基硬脂酸酯占所述混合物的重量比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer and 86%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、稳定剂0.5％-3％和水88％-98％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物，并且所述聚氧乙烯15羟基硬脂酸酯占所述混合物的重量比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, and the weight ratio of the polyoxyethylene 15 hydroxystearate to the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物，并且所述辛基酚聚氧乙烯醚40占所述混合物的重量比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and the weight ratio of octylphenol polyoxyethylene ether 40 to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、稳定剂0.5％-3％和水84％-98％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物，并且所述辛基酚聚氧乙烯醚40占所述混合物的重量比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and the weight ratio of octylphenol polyoxyethylene ether 40 to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、稳定剂0.5％-3％和水86％-98％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物，并且所述辛基 酚聚氧乙烯醚40占所述混合物的重量比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or its pharmaceutically acceptable salt, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer, and 86%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and the octylphenol polyoxyethylene ether 40 is ... The weight ratio of phenol polyoxyethylene ether 40 to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、稳定剂0.5％-3％和水88％-98％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物，并且所述辛基酚聚氧乙烯醚40占所述混合物的重量比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and the weight ratio of octylphenol polyoxyethylene ether 40 to the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、稳定剂0.5％-3％和水84％-98％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、稳定剂0.5％-3％和水86％-98％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer and 86%-98% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、稳定剂0.5％-3％和水88％-98％；其中，所述增溶剂为聚氧乙烯40氢化蓖麻油；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％；其中，所述增溶剂为聚氧乙烯15羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer and 83%-98% of water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、稳定剂0.5％-3％和水84％-98％；其中，所述增溶剂为聚氧乙烯15羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer and 84%-98% of water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、稳定剂0.5％-3％和水86％-98％；；其中，所述增溶剂为聚氧乙烯15羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer and 86%-98% of water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.

在一个更具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、稳定剂0.5％-3％和水88％-98％；其中，所述增溶剂为聚氧乙烯15羟基硬脂酸酯；所述稳定剂为丙二醇。In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer and 88%-98% of water; wherein the solubilizer is polyoxyethylene 15-hydroxystearate; and the stabilizer is propylene glycol.

在一个实施方案中，所述组合物任选地包含其他药学上可接受的辅料。In one embodiment, the composition optionally comprises other pharmaceutically acceptable excipients.

在一个实施方案中，除上述组分外，所述组合物不包含其他药学上可接受的辅料；具体地，所述组合物由瑞普洛莎或其药学上可接受的盐、增溶剂、水和任选的稳定剂组成。In one embodiment, in addition to the above components, the composition does not contain other pharmaceutically acceptable excipients; specifically, the composition consists of reprozac or a pharmaceutically acceptable salt thereof, a solubilizer, water and an optional stabilizer.

在一个实施方案中，除上述组分外，所述组合物还包含一种或多种其他药学上可接受的辅料。In one embodiment, in addition to the above components, the composition further comprises one or more other pharmaceutically acceptable excipients.

在一个具体的实施方案中，所述其他药学上可接受的辅料选自增黏剂、抗氧剂、pH调节剂、渗透压调节剂、润湿剂、粘膜粘附剂、促透剂、防腐剂、胶凝剂、抑菌剂和螯合剂中的一种或多种，优选增黏剂、抗氧剂、螯合剂、抑菌剂、pH调节剂和渗透压调节剂的一种或多种。In a specific embodiment, the other pharmaceutically acceptable excipients are selected from one or more of viscosity enhancers, antioxidants, pH adjusters, osmotic pressure regulators, wetting agents, mucoadhesive agents, penetration enhancers, preservatives, gelling agents, antibacterial agents and chelating agents, preferably one or more of viscosity enhancers, antioxidants, chelating agents, antibacterial agents, pH adjusters and osmotic pressure regulators.

在一个更具体的实施方案中，所述组合物还包含增黏剂；优选地，所述增黏剂选自羧甲基纤维素或其钠盐、羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素、泊洛沙姆、卡波姆、黄原胶、玻璃酸或其钠盐、聚乙烯吡咯烷酮、聚卡波菲、树胶、卡拉胶、瓜尔胶、黄芪胶、琼脂糖、聚乙二醇、海藻酸或其钠盐和透明质酸或其钠盐中的一种或多种，优选黄原胶、玻璃酸钠、聚乙烯吡咯烷酮、羟丙基甲基纤维素、卡波姆、羧甲基纤维素钠、泊洛沙姆、海藻 酸钠和透明质酸钠中的一种或几种，更优选黄原胶、玻璃酸钠、聚乙烯吡咯烷酮、羟丙基甲基纤维素、卡波姆和羧甲基纤维素钠中的一种或多种，最优选黄原胶、玻璃酸钠、羟丙基甲基纤维素和羧甲基纤维素钠中的一种或多种。In a more specific embodiment, the composition further comprises a viscosity enhancer; preferably, the viscosity enhancer is selected from one or more of carboxymethyl cellulose or its sodium salt, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, poloxamer, carbomer, xanthan gum, hyaluronic acid or its sodium salt, polyvinyl pyrrolidone, polycarbophil, gum, carrageenan, guar gum, tragacanth gum, agarose, polyethylene glycol, alginic acid or its sodium salt and hyaluronic acid or its sodium salt, preferably xanthan gum, sodium hyaluronate, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, carbomer, sodium carboxymethyl cellulose, poloxamer, seaweed One or more of sodium hyaluronate and sodium hyaluronate, more preferably one or more of xanthan gum, sodium hyaluronate, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, carbomer and sodium carboxymethylcellulose, most preferably one or more of xanthan gum, sodium hyaluronate, hydroxypropyl methylcellulose and sodium carboxymethylcellulose.

在一个实施方案中，以所述组合物的总重量计，所述增黏剂的含量为0-5％，优选0-3％，更优选0.1％-3％，最优选0.2％-3％。In one embodiment, based on the total weight of the composition, the content of the viscosity increasing agent is 0-5%, preferably 0-3%, more preferably 0.1%-3%, most preferably 0.2%-3%.

在一个更具体的实施方案中，所述组合物还包含抗氧剂；优选地，所述抗氧剂选自生育酚或其琥珀酸酯、抗坏血酸或其棕榈酸酯、丁基羟基茴香醚、2,6-二叔丁基对甲酚和硫代硫酸钠中的一种或多种，优选生育酚、丁基羟基茴香醚、2,6-二叔丁基对甲酚和硫代硫酸钠中的一种或多种，更优选生育酚和硫代硫酸钠中的一种或多种。In a more specific embodiment, the composition further comprises an antioxidant; preferably, the antioxidant is selected from one or more of tocopherol or its succinate, ascorbic acid or its palmitate, butylated hydroxyanisole, 2,6-di-tert-butylated p-cresol and sodium thiosulfate, preferably one or more of tocopherol, butylated hydroxyanisole, 2,6-di-tert-butylated p-cresol and sodium thiosulfate, more preferably one or more of tocopherol and sodium thiosulfate.

在一个实施方案中，以所述组合物的总重量计，所述抗氧剂的含量为0-1％，优选0.05％-1％，更优选0.1％-1％。In one embodiment, the content of the antioxidant is 0-1%, preferably 0.05%-1%, more preferably 0.1%-1%, based on the total weight of the composition.

在一个更具体的实施方案中，所述组合物还包含螯合剂；优选地，所述螯合剂选自柠檬酸或其盐、葡萄糖醛酸或其盐、六偏磷酸盐、依地酸或其盐和膦酸盐中的一种或多种，优选依地酸或依地酸二钠。In a more specific embodiment, the composition further comprises a chelating agent; preferably, the chelating agent is selected from one or more of citric acid or its salts, glucuronic acid or its salts, hexametaphosphate, edetic acid or its salts and phosphonates, preferably edetic acid or edetic disodium.

在一个实施方案中，以所述组合物的总重量计，所述螯合剂的含量为0-2％，优选0.01％-1％，更优选0.05％-0.5％，最优选0.1％-0.2％。In one embodiment, the chelating agent is present in an amount of 0-2%, preferably 0.01%-1%, more preferably 0.05%-0.5%, most preferably 0.1%-0.2%, based on the total weight of the composition.

在一个更具体的实施方案中，所述组合物还包含pH调节剂；优选地，所述pH调节剂选自无机或有机的酸、碱和缓冲盐中的一种或多种，优选缓冲盐；其中，所述酸选自盐酸、磷酸、醋酸、柠檬酸、乳酸和硼酸中的一种或多种；所述碱选自乙二胺、乙醇胺、碱性氨基酸、氢氧化钠、氢氧化钙、氢氧化钾和氨水溶液中的一种或多种；所述缓冲盐选自硼酸-硼砂缓冲盐、柠檬酸-柠檬酸钠缓冲盐、磷酸-磷酸钠缓冲盐和醋酸-醋酸钠缓冲盐中的一种或多种，优选磷酸-磷酸钠缓冲盐和硼酸-硼砂缓冲盐中的一种或多种。In a more specific embodiment, the composition further comprises a pH regulator; preferably, the pH regulator is selected from one or more of inorganic or organic acids, bases and buffer salts, preferably buffer salts; wherein the acid is selected from one or more of hydrochloric acid, phosphoric acid, acetic acid, citric acid, lactic acid and boric acid; the base is selected from one or more of ethylenediamine, ethanolamine, basic amino acids, sodium hydroxide, calcium hydroxide, potassium hydroxide and aqueous ammonia solution; the buffer salt is selected from one or more of boric acid-borax buffer salt, citric acid-sodium citrate buffer salt, phosphate-sodium phosphate buffer salt and acetic acid-sodium acetate buffer salt, preferably one or more of phosphate-sodium phosphate buffer salt and boric acid-borax buffer salt.

在一个实施方案中，所述组合物的pH值为5-9.5，优选6-9，更优选6-8.5，最优选6.5-8。In one embodiment, the pH value of the composition is 5-9.5, preferably 6-9, more preferably 6-8.5, most preferably 6.5-8.

在一个更具体的实施方案中，所述组合物还包含渗透压调节剂；优选地，所述渗透压调节剂选自氯化钠、甘露醇、葡萄糖、山梨醇、聚乙二醇、甘油和丙二醇中的一种或多种，优选氯化钠、甘露醇、山梨醇和甘油中的一种或多种。In a more specific embodiment, the composition further comprises an osmotic pressure regulator; preferably, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, glucose, sorbitol, polyethylene glycol, glycerol and propylene glycol, preferably one or more of sodium chloride, mannitol, sorbitol and glycerol.

在一个更具体的实施方案中，所述组合物还包含抑菌剂；优选地，所述抑菌剂选自苯甲醇、苯氧乙醇、山梨酸或其盐、对羟基苯甲酸酯、洗必泰、苯扎氯铵、苯扎溴铵、三氯叔丁醇、苯甲酸或其盐、柠檬酸或其盐和抗坏血酸或其盐中的一种或多种，优选对羟基苯甲酸丁酯、苯扎氯铵、苯扎溴铵、洗必泰、山梨酸和三氯叔丁醇中的一种或多种。In a more specific embodiment, the composition further comprises an antibacterial agent; preferably, the antibacterial agent is selected from one or more of benzyl alcohol, phenoxyethanol, sorbic acid or its salts, parabens, chlorhexidine, benzalkonium chloride, benzalkonium bromide, chlorobutanol, benzoic acid or its salts, citric acid or its salts and ascorbic acid or its salts, preferably one or more of butyl paraben, benzalkonium chloride, benzalkonium bromide, chlorhexidine, sorbic acid and chlorobutanol.

在一个实施方案中，以所述组合物的总重量计，所述抑菌剂的含量为0-5％，优选0-1％，更优选0.1％-0.5％，最优选0.2％-0.3％。In one embodiment, based on the total weight of the composition, the content of the bacteriostatic agent is 0-5%, preferably 0-1%, more preferably 0.1%-0.5%, most preferably 0.2%-0.3%.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、丙二醇0-5％、水83％-98％、增黏剂0-5％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0-5% of propylene glycol, 83%-98% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、丙二醇0-4％、水87％-97％、增黏剂0-5％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of propylene glycol, 87%-97% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、丙二醇0.5％-4％、水87％-97％、增黏剂0-5％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0.5%-4% of propylene glycol, 87%-97% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.4％、增溶剂2.5％-10％、丙二醇0-3％、水89％-97％、增黏剂0-5％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。 In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of propylene glycol, 89%-97% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.35％、增溶剂3.75％-7.5％、丙二醇1％-3％、水91％-95％、增黏剂0-5％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of propylene glycol, 91%-95% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、丙二醇0-5％、水83％-98％、增黏剂0-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of solubilizer, 0-5% of propylene glycol, 83%-98% of water, 0-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、丙二醇0-4％、水87％-97％、增黏剂0-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of propylene glycol, 87%-97% of water, 0-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、丙二醇0.5％-4％、水87％-97％、增黏剂0-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0.5%-4% of propylene glycol, 87%-97% of water, 0-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.4％、增溶剂2.5％-10％、丙二醇0-3％、水89％-97％、增黏剂0-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of propylene glycol, 89%-97% of water, 0-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.35％、增溶剂3.75％-7.5％、丙二醇1％-3％、水91％-95％、增黏剂0-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of propylene glycol, 91%-95% of water, 0-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、丙二醇0-5％、水83％-98％、增黏剂0.1％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of solubilizer, 0-5% of propylene glycol, 83%-98% of water, 0.1%-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、丙二醇0-4％、水87％-97％、增黏剂0.1％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of propylene glycol, 87%-97% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、丙二醇0.5％-4％、水87％-97％、增黏剂0.1％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0.5%-4% of propylene glycol, 87%-97% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.4％、增溶剂2.5％-10％、丙二醇0-3％、水89％-97％、增黏剂0.1％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of propylene glycol, 89%-97% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.35％、增溶剂3.75％-7.5％、丙二醇1％-3％、水91％-95％、增黏剂0.1％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of propylene glycol, 91%-95% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.5％(或0.05％-0.5％)、增溶剂1％-16％、丙二醇0-5％、水83％-98％、增黏剂0.2％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of solubilizer, 0-5% of propylene glycol, 83%-98% of water, 0.2%-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、丙二醇0-4％、水87％-97％、增黏剂0.2％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of propylene glycol, 87%-97% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.2％-0.45％、增溶剂2％-12％、丙二醇0.5％-4％、水87％-97％、增黏剂0.2％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。 In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0.5%-4% of propylene glycol, 87%-97% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.4％、增溶剂2.5％-10％、丙二醇0-3％、水89％-97％、增黏剂0.2％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of propylene glycol, 89%-97% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.25％-0.35％、增溶剂3.75％-7.5％、丙二醇1％-3％、水91％-95％、增黏剂0.2％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of Reprosa or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of a solubilizer, 1%-3% of propylene glycol, 91%-95% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、丙二醇0.5％-3％、水83％-98％、增黏剂0-5％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of propylene glycol, 83%-98% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、丙二醇0.5％-3％、水84％-98％、增黏剂0-5％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of propylene glycol, 84%-98% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、丙二醇0.5％-3％、水86％-98％、增黏剂0-5％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of propylene glycol, 86%-98% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、丙二醇0.5％-3％、水88％-98％、增黏剂0-5％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of propylene glycol, 88%-98% of water, 0-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、丙二醇0.5％-3％、水83％-98％、增黏剂0.2％-5％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of propylene glycol, 83%-98% of water, 0.2%-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、丙二醇0.5％-3％、水84％-98％、增黏剂0.2％-5％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of propylene glycol, 84%-98% of water, 0.2%-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、丙二醇0.5％-3％、水86％-98％、增黏剂0.2％-5％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of propylene glycol, 86%-98% of water, 0.2%-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、丙二醇0.5％-3％、水88％-98％、增黏剂0.2-5％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of propylene glycol, 88%-98% of water, 0.2%-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、丙二醇0.5％-3％、水83％-98％、增黏剂0-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of propylene glycol, 83%-98% of water, 0-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、丙二醇0.5％-3％、水84％-98％、增黏剂0-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of propylene glycol, 84%-98% of water, 0-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、丙二醇0.5％-3％、水86％-98％、增黏剂0-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of propylene glycol, 86%-98% of water, 0-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、丙二醇0.5％-3％、水88％-98％、增黏剂0-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of propylene glycol, 88%-98% of water, 0-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、丙二醇0.5％-3％、水83％-98％、增黏剂0.1％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。 In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of propylene glycol, 83%-98% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、丙二醇0.5％-3％、水84％-98％、增黏剂0.1％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of propylene glycol, 84%-98% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、丙二醇0.5％-3％、水86％-98％、增黏剂0.1％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of propylene glycol, 86%-98% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、丙二醇0.5％-3％、水88％-98％、增黏剂0.1％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of propylene glycol, 88%-98% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、丙二醇0.5％-3％、水83％-98％、增黏剂0.2％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of propylene glycol, 83%-98% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、丙二醇0.5％-3％、水84％-98％、增黏剂0.2％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of propylene glycol, 84%-98% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、丙二醇0.5％-3％、水86％-98％、增黏剂0.2％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of propylene glycol, 86%-98% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、丙二醇0.5％-3％、水88％-98％、增黏剂0.2％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of propylene glycol, 88%-98% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个实施方案中，所述组合物包含增黏剂，但不包含稳定剂；即，所述组合物包含瑞普洛莎或其药学上可接受的盐、增溶剂、水和增黏剂，但不包含稳定剂；优选地，所述组合物包含瑞普洛莎或其药学上可接受的盐、增溶剂、水、增黏剂、任选的抗氧剂、任选的螯合剂、任选的渗透压调节剂和任选的pH调节剂，但不包含稳定剂。In one embodiment, the composition comprises a viscosity enhancer but does not comprise a stabilizer; that is, the composition comprises reproza or a pharmaceutically acceptable salt thereof, a solubilizer, water and a viscosity enhancer but does not comprise a stabilizer; preferably, the composition comprises reproza or a pharmaceutically acceptable salt thereof, a solubilizer, water, a viscosity enhancer, an optional antioxidant, an optional chelating agent, an optional osmotic pressure regulator and an optional pH regulator but does not comprise a stabilizer.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、水83％-98％、增黏剂0.1％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 83%-98% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、水84％-98％、增黏剂0.1％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 84%-98% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、水86％-98％、增黏剂0.1％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 86%-98% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、水88％-98％、增黏剂0.1％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 88%-98% of water, 0.1%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、水83％-98％、增黏剂0.2％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 83%-98% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、水84％-98％、增黏剂0.2％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。 In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 84%-98% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、水86％-98％、增黏剂0.2％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 86%-98% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

在一个具体的实施方案中，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、水88％-98％、增黏剂0.2％-3％、抗氧剂0-1％、螯合剂0-2％、任选的渗透压调节剂和任选的pH调节剂。In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 88%-98% of water, 0.2%-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

第二方面，本发明提供了一种眼用溶液组合物(特别是上述第一方面所描述的眼用溶液组合物)的制备方法，其包括以下步骤：In a second aspect, the present invention provides a method for preparing an ophthalmic solution composition (especially the ophthalmic solution composition described in the first aspect above), comprising the following steps:

1)将瑞普洛莎或其药学上可接受的盐、增溶剂和任选的稳定剂混合均匀，得到含药溶液；1) mixing Reprosa or its pharmaceutically acceptable salt, a solubilizer and an optional stabilizer uniformly to obtain a drug-containing solution;

2)将步骤1)中得到的含药溶液加入水中分散均匀，过滤除菌，得到眼用溶液组合物。2) adding the drug-containing solution obtained in step 1) into water and dispersing it evenly, filtering and sterilizing it to obtain an ophthalmic solution composition.

在一个实施方案中，所述制备方法的步骤2)在分散和过滤两个环节之间进一步包括下列步骤：加入增黏剂，再次分散均匀。换言之，所述制备方法的步骤2)包括下列步骤：将步骤1)中得到的含药溶液加入水中分散均匀，加入增黏剂，再次分散均匀，过滤除菌，得到眼用溶液组合物。In one embodiment, step 2) of the preparation method further comprises the following steps between the dispersion and filtration steps: adding a viscosity enhancer and dispersing uniformly again. In other words, step 2) of the preparation method comprises the following steps: adding the drug-containing solution obtained in step 1) into water and dispersing uniformly, adding a viscosity enhancer, dispersing uniformly again, filtering and sterilizing, and obtaining an ophthalmic solution composition.

在一个实施方案中，所述制备方法的步骤2)在过滤环节之后进一步包括下列步骤：加入预先灭菌(例如高温灭菌)的增黏剂水溶液，再次分散均匀。换言之，所述制备方法的步骤2)包括下列步骤：将步骤1)中得到的含药溶液加入水中分散均匀，过滤除菌，加入预先灭菌的增黏剂水溶液，再次分散均匀，得到眼用溶液组合物。In one embodiment, step 2) of the preparation method further comprises the following steps after the filtration step: adding a pre-sterilized (e.g., high temperature sterilized) aqueous solution of a viscosity enhancer, and dispersing evenly again. In other words, step 2) of the preparation method comprises the following steps: adding the drug-containing solution obtained in step 1) into water and dispersing evenly, filtering and sterilizing, adding a pre-sterilized aqueous solution of a viscosity enhancer, and dispersing evenly again to obtain an ophthalmic solution composition.

在一个实施方案中，所述制备方法在步骤1)的混合环节之前或者在步骤2)的分散环节之前进一步包括下列步骤：加入抗氧剂。In one embodiment, the preparation method further comprises the following step before the mixing step of step 1) or before the dispersing step of step 2): adding an antioxidant.

在一个实施方案中，所述制备方法在步骤1)的混合环节之前或者在步骤2)的分散环节之前进一步包括下列步骤：加入抑菌剂。In one embodiment, the preparation method further comprises the following step before the mixing step of step 1) or before the dispersion step of step 2): adding an antibacterial agent.

在一个实施方案中，所述制备方法在步骤2)的分散环节之前进一步包括下列步骤：加入螯合剂。In one embodiment, the preparation method further comprises the following step before the dispersion step of step 2): adding a chelating agent.

在一个实施方案中，所述制备方法的步骤2)在过滤环节之前进一步包括下列步骤：采用pH调节剂(例如缓冲盐)将再次分散均匀后的物料调节至符合眼用要求的pH值范围当中。In one embodiment, step 2) of the preparation method further comprises the following step before the filtration step: using a pH adjuster (such as a buffer salt) to adjust the pH value of the redispersed material to a range that meets the requirements for ophthalmic use.

在一个实施方案中，所述制备方法的步骤2)在过滤环节之前进一步包括下列步骤：采用渗透压调节剂将再次分散均匀后的物料调节至符合眼用要求的渗透压值范围当中。In one embodiment, step 2) of the preparation method further comprises the following step before the filtering step: using an osmotic pressure regulator to adjust the re-dispersed material to an osmotic pressure value range that meets the requirements for ophthalmic use.

在一个具体的实施方案中，所述制备方法的步骤1)中的所述混合在加热条件下进行，例如通过水浴加热，水浴温度为0-90℃，优选30-60℃，更优选40-50℃。In a specific embodiment, the mixing in step 1) of the preparation method is carried out under heating conditions, such as heating by a water bath, the water bath temperature is 0-90°C, preferably 30-60°C, more preferably 40-50°C.

在一个具体的实施方案中，所述制备方法的步骤1)中的所述混合在搅拌条件下进行。In a specific embodiment, the mixing in step 1) of the preparation method is performed under stirring conditions.

在一个具体的实施方案中，所述制备方法的步骤2)中的所述水的温度为0-50℃，优选20-40℃，更优选25-35℃。In a specific embodiment, the temperature of the water in step 2) of the preparation method is 0-50°C, preferably 20-40°C, more preferably 25-35°C.

第三方面，本发明提供了眼用溶液组合物(特别是上述第一方面所描述的眼用溶液组合物)在制备用于预防和/或治疗与包括促炎性活性醛类物质(RASP)在内的毒性醛有关的眼部疾病或病症的药物中的用途。In a third aspect, the present invention provides use of an ophthalmic solution composition (particularly the ophthalmic solution composition described in the first aspect above) in the preparation of a medicament for preventing and/or treating ocular diseases or conditions associated with toxic aldehydes including pro-inflammatory reactive aldehyde substances (RASPs).

第四方面，本发明提供了眼用溶液组合物(特别是上述第一方面所描述的眼用溶液组合物)，其用于预防和/或治疗与包括促炎性活性醛类物质在内的毒性醛有关的眼部疾病或病症。In a fourth aspect, the present invention provides an ophthalmic solution composition (particularly the ophthalmic solution composition described in the first aspect above), which is used to prevent and/or treat ocular diseases or conditions associated with toxic aldehydes including pro-inflammatory active aldehyde substances.

第五方面，本发明提供了一种用于预防和/或治疗与包括促炎性活性醛类物质在内的毒性醛有关的眼部疾病或病症的方法，其包括下列步骤：将预防和/或治疗有效量的眼用溶液组合物(特别是上述第一方面所描述的眼用溶液组合物)施用于对其有需要的个体。In a fifth aspect, the present invention provides a method for preventing and/or treating ocular diseases or conditions associated with toxic aldehydes including pro-inflammatory active aldehydes, comprising the following steps: administering a preventively and/or therapeutically effective amount of an ophthalmic solution composition (particularly the ophthalmic solution composition described in the first aspect above) to an individual in need thereof.

在一个实施方案中，所述眼部疾病或病症选自角膜疾病、与过量毒性醛有关的眼部疾病、眼部红斑痤疮和其他眼部疾病中的一种或多种。 In one embodiment, the ocular disease or disorder is selected from one or more of corneal diseases, ocular diseases associated with excess toxic aldehydes, ocular rosacea, and other ocular diseases.

在一个具体的实施方案中，所述角膜疾病选自干眼综合征、白内障、圆锥形角膜、大疱性和其它类型角膜病变和富克氏(Fuch’s)角膜内皮营养不良中的一种或多种。In a specific embodiment, the corneal disease is selected from one or more of dry eye syndrome, cataracts, keratoconus, bullous and other types of corneal lesions and Fuch's corneal endothelial dystrophy.

在一个具体的实施方案中，所述与过量毒性醛有关的眼部疾病选自葡萄膜炎、巩膜炎和眼部史-约综合征(Sjogren-Larsson Syndrome)中的一种或多种。In a specific embodiment, the eye disease associated with excessive toxic aldehydes is selected from one or more of uveitis, scleritis and Sjogren-Larsson Syndrome.

在一个具体的实施方案中，所述其他眼部疾病选自过敏性结膜炎、眼部瘢痕性类天疱疮、与屈光性角膜切除术(PRK)愈合或其它角膜愈合相关的疾病和与泪脂质降解或泪腺功能障碍相关的疾病中的一种或多种。In a specific embodiment, the other ocular disease is selected from one or more of allergic conjunctivitis, ocular cicatricial pemphigoid, diseases associated with photorefractive keratectomy (PRK) healing or other corneal healing, and diseases associated with tear lipid degradation or tear gland dysfunction.

在一个实施方案中，所述眼部疾病或病症选自干眼综合征、过敏性结膜炎和葡萄膜炎中的一种或多种。In one embodiment, the ocular disease or condition is selected from one or more of dry eye syndrome, allergic conjunctivitis, and uveitis.

在一个实施方案中，所述眼部疾病或病症为干眼综合征。In one embodiment, the ocular disease or disorder is dry eye syndrome.

发明的效果Effects of the Invention

瑞普洛莎在水中的溶解度很低，化学稳定性较差，现有技术中的眼用局部制剂均为短效、速释产品，需要每日施用多次，使得患者用药依从性差。Reprosa has very low solubility in water and poor chemical stability. The topical ophthalmic preparations in the prior art are all short-acting, rapid-release products that need to be applied multiple times a day, resulting in poor medication compliance among patients.

为此，本发明创造性地设计了瑞普洛莎的眼用纳米胶束溶液组合物。采用纳米胶束体系可以有效包载瑞普洛莎分子，改善其溶解度和稳定性，使药物可以穿透眼睛的水层，更有效地渗透到角膜中，增加药物在眼部的粘附性和滞留时间，在提高生物利用度的同时，实现药物的长效、平稳释放。To this end, the present invention creatively designs an ophthalmic nano-micelle solution composition of Reprosa. The nano-micelle system can effectively encapsulate Reprosa molecules, improve its solubility and stability, enable the drug to penetrate the aqueous layer of the eye, more effectively penetrate into the cornea, increase the drug's adhesion and retention time in the eye, and achieve long-term and stable release of the drug while improving bioavailability.

首先，本发明的眼用纳米胶束溶液组合物具有优异的化学稳定性。在常规条件(例如室温25℃/60％RH)储存至少1周、或至少10天、或至少2周、或至少1个月、或至少3个月、或至少4个月、或至少6个月、或至少9个月、或至少12个月之后，仅含有小于1％的杂质、或小于0.8％的杂质、或小于0.5％的杂质、或小于0.2％的杂质、或小于0.1％的杂质。在加速条件(40℃/75％RH)下储存至少1周、或至少10天、或至少2周、或至少1个月、或至少4个月之后，仅含有小于1％、或小于0.8％、或小于0.5％、或小于0.3％、或小于0.2％、或小于0.1％的单个杂质，和/或，仅含有小于1.5％、或小于1.2％、或小于1％、或小于0.8％、或小于0.5％、或小于0.3％、或小于0.2％的总杂质。First, the ophthalmic nano-micelle solution composition of the present invention has excellent chemical stability. After being stored under normal conditions (e.g., room temperature 25°C/60%RH) for at least 1 week, or at least 10 days, or at least 2 weeks, or at least 1 month, or at least 3 months, or at least 4 months, or at least 6 months, or at least 9 months, or at least 12 months, it contains only less than 1% impurities, or less than 0.8% impurities, or less than 0.5% impurities, or less than 0.2% impurities, or less than 0.1% impurities. After storage under accelerated conditions (40°C/75%RH) for at least 1 week, or at least 10 days, or at least 2 weeks, or at least 1 month, or at least 4 months, it contains only less than 1%, or less than 0.8%, or less than 0.5%, or less than 0.3%, or less than 0.2%, or less than 0.1% of a single impurity, and/or, it contains only less than 1.5%, or less than 1.2%, or less than 1%, or less than 0.8%, or less than 0.5%, or less than 0.3%, or less than 0.2% of total impurities.

其次，本发明的眼用纳米胶束溶液组合物具有优异的物理稳定性。在常规条件(例如室温25℃/60％RH)储存至少1周、或至少10天、或至少2周、或至少1个月、或至少3个月、或至少4个月、或至少6个月、或至少9个月、或至少12个月之后，胶束粒径增长的值≤50nm、或≤40nm、或≤30nm、或≤20nm。在加速条件(40℃/75％RH)下储存至少1周、或至少10天、或至少2周、或至少1个月、或至少4个月之后，胶束粒径增长的值≤50nm、或≤40nm、或≤30nm、或≤20nm。Secondly, the ophthalmic nano-micelle solution composition of the present invention has excellent physical stability. After being stored under normal conditions (e.g., room temperature 25°C/60%RH) for at least 1 week, or at least 10 days, or at least 2 weeks, or at least 1 month, or at least 3 months, or at least 4 months, or at least 6 months, or at least 9 months, or at least 12 months, the value of micelle particle size growth is ≤50nm, or ≤40nm, or ≤30nm, or ≤20nm. After being stored under accelerated conditions (40°C/75%RH) for at least 1 week, or at least 10 days, or at least 2 weeks, or at least 1 month, or at least 4 months, the value of micelle particle size growth is ≤50nm, or ≤40nm, or ≤30nm, or ≤20nm.

最后，本发明的眼用纳米胶束溶液组合物具有较高的包封率，对眼部无刺激性，并且在体外和体内药效学试验中均表现出优异的缓释效果。Finally, the ophthalmic nano-micelle solution composition of the present invention has a high encapsulation rate, is non-irritating to the eyes, and exhibits excellent sustained-release effects in both in vitro and in vivo pharmacodynamic tests.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1示出了样品的体外溶出测试结果。FIG1 shows the in vitro dissolution test results of the samples.

图2示出了样品的体外溶出检测结果。FIG2 shows the in vitro dissolution test results of the samples.

图3示出了大鼠干眼症模型给药14天的角膜荧光素钠染色评分对比。FIG3 shows a comparison of corneal sodium fluorescein staining scores in a rat dry eye model after 14 days of drug administration.

具体实施方式DETAILED DESCRIPTION

术语定义Definition of terms

除非另有说明，本发明所用的术语“胶束”(Micelles)是指在水溶液中，当表面活性剂达到一定浓度时，分子自组装形成的有序排列的热力学稳定胶状团聚集体，或称“胶团”。具有吸附能力的表面活性剂在水中以低浓度溶解，当其浓度达到饱和状态时，过剩的表面活性剂分子开始在水中累积。由于表面活性分子的疏水部分与水的亲和力较小，而疏水部分之间的 吸引力较大，因此许多表面活性剂分子的疏水部分相互吸引并缔合形成内核，亲水基团朝外形成外层，从而形成了多分子复合物。从结构上讲，胶束由亲脂性内核和亲水性外壳组成，具有多重功能，亲脂性内核可用于包载疏水性药物，极大地改善难溶性药物在水中的溶解性；亲水性外壳则能与体内生物成分相互作用，影响药代动力学行为和药物分布，控制药物在体内的递送。其中，具有两亲性胶体结构，且粒径范围通常为5至100nm的胶束可称为“纳米胶束”。Unless otherwise specified, the term "micelles" used in the present invention refers to the thermodynamically stable colloidal aggregates formed by the self-assembly of surfactant molecules in an aqueous solution when the surfactant reaches a certain concentration. Surfactants with adsorption capacity are dissolved in water at low concentrations. When the concentration reaches saturation, excess surfactant molecules begin to accumulate in the water. Since the hydrophobic part of the surfactant molecule has a low affinity for water, the hydrophobic part is The attraction is large, so the hydrophobic parts of many surfactant molecules attract each other and associate to form an inner core, and the hydrophilic groups face outward to form an outer layer, thus forming a multi-molecular complex. Structurally, micelles are composed of a lipophilic inner core and a hydrophilic outer shell, and have multiple functions. The lipophilic inner core can be used to encapsulate hydrophobic drugs, greatly improving the solubility of poorly soluble drugs in water; the hydrophilic outer shell can interact with biological components in the body, affecting pharmacokinetic behavior and drug distribution, and controlling drug delivery in the body. Among them, micelles with an amphiphilic colloidal structure and a particle size range of usually 5 to 100 nm can be called "nano micelles."

除非另有说明，本发明所用的术语“临界胶束浓度”(critical micelle concentration，CMC)是指表面活性剂分子在溶剂中缔合形成胶束的最低浓度。临界胶束浓度可参照文献(如Mukerjee,P.,Mysels,K.J.,Critical Micelle Concentrations of Aqueous Surfactant Systems,NIST National Institute of Standards and Technology:Washington D.C.USA,1971；Al-Soufi W.,L.,Novo M.,A model for monomer and micellar concentrations in surfactant solutions:application to conductivity,NMR,diffusion,and surface tension data[J],J.Colloid Interface Sci.,2012,370:102-110；LucasSonia Freire,Jorge Bordello,Mercedes Novo,and Wajih Al-Soufi,Dye Exchange in Micellar Solutions.Quantitative Analysis of Bulk and Single Molecule Fluorescence Titrations[J],Soft Matter,2013,9:10779-10790；张春燕,罗建新,潘春跃,喻桂朋,光谱法测定十二烷基苯磺酸钠临界胶束浓度[J],环境科学与技术,2016,39(08):99-107等)中记载的相关方法进行测定。Unless otherwise specified, the term "critical micelle concentration" (CMC) used in the present invention refers to the minimum concentration of surfactant molecules in a solvent that associates to form micelles. The critical micelle concentration can be found in the literature (e.g., Mukerjee, P., Mysels, KJ, Critical Micelle Concentrations of Aqueous Surfactant Systems, NIST National Institute of Standards and Technology: Washington DC USA, 1971; Al-Soufi W., L.,Novo M.,A model for monomer and micellar concentrations in surfactant solutions:application to conductivity,NMR,diffusion,and surface tension data[J],J.Colloid Interface Sci.,2012,370:102-110;Lucas Sonia Freire, Jorge Bordello, Mercedes Novo, and Wajih Al-Soufi, Dye Exchange in Micellar Solutions. Quantitative Analysis of Bulk and Single Molecule Fluorescence Titrations [J], Soft Matter, 2013, 9: 10779-10790; Zhang Chunyan, Luo Jianxin, Pan Chunyue, Yu Guipeng, Determination of the critical micelle concentration of sodium dodecylbenzenesulfonate by spectroscopic method [J], Environmental Science and Technology, 2016, 39 (08): 99-107, etc.) were used for determination.

除非另有说明，本发明所用的术语“增溶剂”是指具有增溶能力的表面活性剂，难溶性药物在其作用下，可以增加药物在溶剂中的溶解度，并形成溶液。增溶剂的性质、HLB值、用量等都是影响增溶效果的直接因素。Unless otherwise specified, the term "solubilizer" used in the present invention refers to a surfactant with solubilizing ability, under the action of which, the solubility of poorly soluble drugs in solvents can be increased and a solution can be formed. The properties, HLB value, and dosage of the solubilizer are all direct factors affecting the solubilizing effect.

除非另有说明，本发明所用的术语“表面活性剂”是指能够(显著)降低目标溶液表面张力的物质，其能够在溶液表面定向排列。表面活性剂的分子结构具有两性：一端为亲水基团，另一端为疏水基团；亲水基团通常为极性基团，如羧酸、磺酸、硫酸、(取代)氨基及其盐、羟基、酰胺基、醚键等；而疏水基团通常为非极性烃链，如8个碳原子以上的烃链。Unless otherwise specified, the term "surfactant" used in the present invention refers to a substance that can (significantly) reduce the surface tension of the target solution and can be oriented on the surface of the solution. The molecular structure of the surfactant has two properties: one end is a hydrophilic group and the other end is a hydrophobic group; the hydrophilic group is usually a polar group, such as carboxylic acid, sulfonic acid, sulfuric acid, (substituted) amino group and its salt, hydroxyl group, amide group, ether bond, etc.; while the hydrophobic group is usually a non-polar hydrocarbon chain, such as a hydrocarbon chain with more than 8 carbon atoms.

按照结构类型划分，表面活性剂可分为阳离子表面活性剂、阴离子表面活性剂、非离子表面活性剂、两性表面活性剂四大类，其中非离子表面活性剂在水中不会解离，且通常为低分子量，分子结构包括亲水基团和疏水基团，亲水基团选自聚乙二醇、多元醇中的一种或多种，疏水基团选自脂肪酸、脂肪醇、酚、烷基酚中的一种或多种，亲水基团和疏水基团之间通过酯键或醚键结合。按照亲水基团的结构类型划分，非离子表面活性剂可进一步分为聚乙二醇型(或称聚氧乙烯型)和多元醇型。According to the structural type, surfactants can be divided into four categories: cationic surfactants, anionic surfactants, nonionic surfactants, and amphoteric surfactants. Among them, nonionic surfactants will not dissociate in water and are usually low molecular weight. The molecular structure includes hydrophilic groups and hydrophobic groups. The hydrophilic group is selected from one or more of polyethylene glycol and polyols, and the hydrophobic group is selected from one or more of fatty acids, fatty alcohols, phenols, and alkylphenols. The hydrophilic group and the hydrophobic group are connected by ester bonds or ether bonds. According to the structural type of the hydrophilic group, nonionic surfactants can be further divided into polyethylene glycol type (or polyoxyethylene type) and polyol type.

聚氧乙烯型非离子表面活性剂可由疏水性材料与环氧乙烷或聚乙二醇反应而得，大体可分为以下类型：Polyoxyethylene nonionic surfactants can be obtained by reacting hydrophobic materials with ethylene oxide or polyethylene glycol, and can be roughly divided into the following types:

(1)聚氧乙烯脂肪醇醚(或称脂肪醇聚氧乙烯醚，由聚乙二醇与脂肪醇醚化而得)；(1) Polyoxyethylene fatty alcohol ether (or fatty alcohol polyoxyethylene ether, obtained by etherification of polyethylene glycol and fatty alcohol);

(2)聚氧乙烯脂肪酰烷醇胺醚(或称脂肪酰烷醇胺聚氧乙烯醚，由聚乙二醇与脂肪酰烷醇胺醚化而得)；(2) Polyoxyethylene fatty acyl alkanolamine ether (or fatty acyl alkanolamine polyoxyethylene ether, obtained by etherification of polyethylene glycol and fatty acyl alkanolamine);

(3)聚氧乙烯烷基酚醚(或称烷基酚聚氧乙烯醚，由聚乙二醇与烷基酚醚化而得)；(3) Polyoxyethylene alkylphenol ether (or alkylphenol polyoxyethylene ether, obtained by etherification of polyethylene glycol and alkylphenol);

(4)聚氧乙烯脂肪酸酯(或称脂肪酸聚氧乙烯酯，由聚乙二醇与脂肪酸或其衍生物酯化而得)；以及(4) polyoxyethylene fatty acid esters (or fatty acid polyoxyethylene esters, obtained by esterification of polyethylene glycol with fatty acids or their derivatives); and

(5)聚氧乙烯蓖麻油衍生物(由甘油、聚乙二醇与蓖麻油或氢化蓖麻油反应而得)。(5) Polyoxyethylene castor oil derivatives (obtained by the reaction of glycerol, polyethylene glycol and castor oil or hydrogenated castor oil).

聚氧乙烯蓖麻油衍生物包括(但不限于)聚氧乙烯蓖麻油(如聚氧乙烯5蓖麻油、聚氧乙烯9蓖麻油、聚氧乙烯15蓖麻油、聚氧乙烯35蓖麻油、聚氧乙烯40蓖麻油、聚氧乙烯60蓖麻油、聚氧乙烯100蓖麻油等)和聚氧乙烯氢化蓖麻油(如聚氧乙烯40氢化蓖麻油、聚氧乙烯54氢化蓖麻油、聚氧乙烯60氢化蓖麻油、聚氧乙烯100氢化蓖麻油等)，优选聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油(如聚氧乙烯35蓖麻油)和聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油(如聚氧乙烯40氢化蓖麻油、聚氧乙烯54氢化蓖麻油、聚氧乙烯60氢化蓖麻油 等)，更优选聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油(如聚氧乙烯35蓖麻油)和聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油(如聚氧乙烯40氢化蓖麻油、聚氧乙烯54氢化蓖麻油等)，进一步优选聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油(如聚氧乙烯40氢化蓖麻油)和聚氧乙烯单元数为50-55的聚氧乙烯氢化蓖麻油(如聚氧乙烯54氢化蓖麻油)，更进一步优选聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油(如聚氧乙烯40氢化蓖麻油)，最优选聚氧乙烯40氢化蓖麻油。Polyoxyethylene castor oil derivatives include (but are not limited to) polyoxyethylene castor oil (such as polyoxyethylene 5 castor oil, polyoxyethylene 9 castor oil, polyoxyethylene 15 castor oil, polyoxyethylene 35 castor oil, polyoxyethylene 40 castor oil, polyoxyethylene 60 castor oil, polyoxyethylene 100 castor oil, etc.) and polyoxyethylene hydrogenated castor oil (such as polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 54 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil, polyoxyethylene 100 hydrogenated castor oil, etc.), preferably polyoxyethylene castor oil with 30-40 polyoxyethylene units (such as polyoxyethylene 35 castor oil) and polyoxyethylene hydrogenated castor oil with 30-60 polyoxyethylene units (such as polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 54 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil The present invention relates to polyoxyethylene castor oils having 30 to 40 polyoxyethylene units (e.g., polyoxyethylene 35 castor oil) and polyoxyethylene hydrogenated castor oils having 35 to 55 polyoxyethylene units (e.g., polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 54 hydrogenated castor oil, etc.). Polyoxyethylene hydrogenated castor oils having 35 to 45 polyoxyethylene units (e.g., polyoxyethylene 40 hydrogenated castor oil) and polyoxyethylene hydrogenated castor oils having 50 to 55 polyoxyethylene units (e.g., polyoxyethylene 54 hydrogenated castor oil) are further preferred. Polyoxyethylene hydrogenated castor oils having 35 to 45 polyoxyethylene units (e.g., polyoxyethylene 40 hydrogenated castor oil) are further preferred. Polyoxyethylene 40 hydrogenated castor oil is most preferred.

聚氧乙烯脂肪酸酯包括(但不限于)聚氧乙烯硬脂酸酯(或称硬脂酸聚氧乙烯酯，由聚乙二醇与硬脂酸酯化而得)、聚氧乙烯羟基硬脂酸酯(或称羟基硬脂酸聚氧乙烯酯，由聚乙二醇与羟基硬脂酸酯化而得)和维生素E聚乙二醇琥珀酸酯(由D-α-生育酚琥珀酸酯与聚乙二醇酯化而得)，其中聚氧乙烯硬脂酸酯包括(但不限于)聚氧乙烯单元数为2-50的聚氧乙烯硬脂酸酯(如聚氧乙烯2硬脂酸酯、聚氧乙烯4硬脂酸酯、聚氧乙烯6硬脂酸酯、聚氧乙烯8硬脂酸酯、聚氧乙烯12硬脂酸酯、聚氧乙烯20硬脂酸酯、聚氧乙烯30硬脂酸酯、聚氧乙烯40硬脂酸酯、聚氧乙烯50硬脂酸酯等)，特别是聚氧乙烯单元数为10-50的聚氧乙烯硬脂酸酯，优选聚氧乙烯单元数为30-50的聚氧乙烯硬脂酸酯，更优选聚氧乙烯单元数为35-45的聚氧乙烯硬脂酸酯，最优选聚氧乙烯40硬脂酸酯；聚氧乙烯羟基硬脂酸酯包括(但不限于)聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯，优选聚氧乙烯15羟基硬脂酸酯；维生素E聚乙二醇琥珀酸酯包括(但不限于)聚乙二醇平均分子量为200-4000的维生素E聚乙二醇琥珀酸酯(如维生素E聚乙二醇琥珀酸酯200、维生素E聚乙二醇琥珀酸酯400、维生素E聚乙二醇琥珀酸酯1000、维生素E聚乙二醇琥珀酸酯1500、维生素E聚乙二醇琥珀酸酯2000、维生素E聚乙二醇琥珀酸酯4000等)，优选聚乙二醇平均分子量为500-1500的维生素E聚乙二醇琥珀酸酯，更优选聚乙二醇平均分子量为800-1200的维生素E聚乙二醇琥珀酸酯，最优选维生素E聚乙二醇琥珀酸酯1000。Polyoxyethylene fatty acid esters include (but are not limited to) polyoxyethylene stearate (or polyoxyethylene stearate, obtained by esterifying polyethylene glycol with stearic acid), polyoxyethylene hydroxystearate (or polyoxyethylene hydroxystearate, obtained by esterifying polyethylene glycol with hydroxystearate) and vitamin E polyethylene glycol succinate (derived by esterifying D-α-tocopherol succinate with polyethylene glycol), wherein polyoxyethylene stearate includes (but is not limited to) polyoxyethylene stearate with a polyoxyethylene unit number of 2-50 Fatty acid esters (such as polyoxyethylene 2 stearate, polyoxyethylene 4 stearate, polyoxyethylene 6 stearate, polyoxyethylene 8 stearate, polyoxyethylene 12 stearate, polyoxyethylene 20 stearate, polyoxyethylene 30 stearate, polyoxyethylene 40 stearate, polyoxyethylene 50 stearate, etc.), especially polyoxyethylene stearate having 10-50 polyoxyethylene units, preferably polyoxyethylene stearate having 30-50 polyoxyethylene units, more preferably polyoxyethylene stearate having 30-50 polyoxyethylene units. 5-45 polyoxyethylene stearate, most preferably polyoxyethylene 40 stearate; polyoxyethylene hydroxystearate including (but not limited to) polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, preferably polyoxyethylene 15 hydroxystearate; vitamin E polyethylene glycol succinate including (but not limited to) vitamin E polyethylene glycol succinate with a polyethylene glycol average molecular weight of 200-4000 (such as vitamin E polyethylene glycol succinate 200, ... Acid 400, vitamin E polyethylene glycol succinate 1000, vitamin E polyethylene glycol succinate 1500, vitamin E polyethylene glycol succinate 2000, vitamin E polyethylene glycol succinate 4000, etc.), preferably vitamin E polyethylene glycol succinate with an average molecular weight of 500-1500, more preferably vitamin E polyethylene glycol succinate with an average molecular weight of 800-1200, and most preferably vitamin E polyethylene glycol succinate 1000.

聚氧乙烯烷基酚醚包括(但不限于)聚氧乙烯单元数为4-10的壬基酚聚氧乙烯醚(如壬基酚聚氧乙烯醚4、壬基酚聚氧乙烯醚6、壬基酚聚氧乙烯醚7、壬基酚聚氧乙烯醚8、壬基酚聚氧乙烯醚10等)、聚氧乙烯单元数为13-50的辛基酚聚氧乙烯醚(如辛基酚聚氧乙烯醚13、辛基酚聚氧乙烯醚15、辛基酚聚氧乙烯醚20、辛基酚聚氧乙烯醚30、辛基酚聚氧乙烯醚40、辛基酚聚氧乙烯醚50)、十二烷基酚聚氧乙烯醚和二壬基酚聚氧乙烯醚，优选聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚，更优选聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚，最优选辛基酚聚氧乙烯醚40。Polyoxyethylene alkylphenol ethers include (but are not limited to) nonylphenol polyoxyethylene ethers having 4-10 polyoxyethylene units (such as nonylphenol polyoxyethylene ether 4, nonylphenol polyoxyethylene ether 6, nonylphenol polyoxyethylene ether 7, nonylphenol polyoxyethylene ether 8, nonylphenol polyoxyethylene ether 10, etc.), octylphenol polyoxyethylene ethers having 13-50 polyoxyethylene units (such as octylphenol polyoxyethylene ether 13, octylphenol polyoxyethylene ether 15, octylphenol polyoxyethylene ether 20, octylphenol polyoxyethylene ether 30, octylphenol polyoxyethylene ether 40, octylphenol polyoxyethylene ether 50), dodecylphenol polyoxyethylene ether and dinonylphenol polyoxyethylene ether, preferably octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, more preferably octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and most preferably octylphenol polyoxyethylene ether 40.

除非另有说明，本发明所用的术语“聚氧乙烯单元数”是指分子中聚氧乙烯部分(即聚乙二醇部分)的平均聚合度。例如，“聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油”是指所定义的聚氧乙烯蓖麻油中聚氧乙烯部分的平均聚合度为30-40，“聚氧乙烯40硬脂酸酯”是指所定义的聚氧乙烯硬脂酸酯中聚氧乙烯部分的平均聚合度为40。Unless otherwise specified, the term "polyoxyethylene unit number" used in the present invention refers to the average degree of polymerization of the polyoxyethylene part (i.e., polyethylene glycol part) in the molecule. For example, "polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40" means that the average degree of polymerization of the polyoxyethylene part in the defined polyoxyethylene castor oil is 30-40, and "polyoxyethylene 40 stearate" means that the average degree of polymerization of the polyoxyethylene part in the defined polyoxyethylene stearate is 40.

除非另有说明，本发明所用的术语“聚乙二醇平均分子量”是指所定义的分子中聚乙二醇部分(即聚氧乙烯部分)的平均分子量。例如，“聚乙二醇平均分子量为500-1500的维生素E聚乙二醇琥珀酸酯”是指所定义的维生素E聚乙二醇琥珀酸酯中聚乙二醇部分的平均分子量为500-1500，“维生素E聚乙二醇琥珀酸酯1000”是指所定义的维生素E聚乙二醇琥珀酸酯中聚乙二醇部分的平均分子量为1000。Unless otherwise specified, the term "average molecular weight of polyethylene glycol" used in the present invention refers to the average molecular weight of the polyethylene glycol portion (i.e., the polyoxyethylene portion) in the defined molecule. For example, "vitamin E polyethylene glycol succinate with an average molecular weight of 500-1500" means that the average molecular weight of the polyethylene glycol portion in the defined vitamin E polyethylene glycol succinate is 500-1500, and "vitamin E polyethylene glycol succinate 1000" means that the average molecular weight of the polyethylene glycol portion in the defined vitamin E polyethylene glycol succinate is 1000.

多元醇型非离子表面活性剂可由亲水基团与衍生自脂肪酸的疏水基团结合而成，大体可分为以下类型：Polyol-type nonionic surfactants can be composed of a hydrophilic group combined with a hydrophobic group derived from fatty acids, and can be roughly divided into the following types:

(1)甘油脂肪酸酯(或称脂肪酸甘油酯)；(1) Glycerol fatty acid esters (or fatty acid glycerides);

(2)失水山梨醇脂肪酸酯(或称脂肪酸失水山梨醇酯、司盘)；(2) Sorbitan fatty acid esters (or sorbitan fatty acid esters, Span);

(3)季戊四醇脂肪酸酯(或称脂肪酸季戊四醇酯)；以及(3) Pentaerythritol fatty acid esters (or fatty acid pentaerythritol esters); and

(4)蔗糖脂肪酸酯(或称脂肪酸蔗糖酯)。 (4) Sucrose fatty acid esters (or sucrose fatty acid esters).

按照分子量大小划分，表面活性剂可分为低分子表面活性剂和高分子表面活性剂，二者通常以分子量1000作为划界标准，达到1000以上(且多在1000000以下)可视为高分子表面活性剂，不到1000则视为低分子量表面活性剂。高分子表面活性剂多由亲水性单体与疏水性单体聚合而成，多为嵌段共聚物或接枝共聚物，并且可以生物降解，其分子结构包括亲水基团和疏水基团，亲水基团选自聚醇(如聚乙二醇、聚乙烯醇等)、多糖(如葡聚糖、壳聚糖、海藻酸等)、聚酰胺(如聚乙烯基己内酰胺、聚异丙基丙烯酰胺等)中的一种或多种，疏水基团选自聚酯(如聚乙酸乙烯酯、聚己内酯、聚乙交酯(或称聚乙醇酸)、聚丙交酯(或称聚乳酸)等)、聚氨基酸(如聚赖氨酸、聚谷氨酸、聚天冬氨酸等)中的一种或多种。According to the molecular weight, surfactants can be divided into low molecular surfactants and high molecular surfactants. The molecular weight of the two is usually 1000 as the demarcation standard. Those with a molecular weight of more than 1000 (and mostly below 1000000) are considered high molecular surfactants, and those with a molecular weight of less than 1000 are considered low molecular surfactants. High molecular surfactants are mostly polymerized from hydrophilic monomers and hydrophobic monomers, mostly block copolymers or graft copolymers, and are biodegradable. Their molecular structure includes hydrophilic groups and hydrophobic groups. The hydrophilic group is selected from one or more of polyols (such as polyethylene glycol, polyvinyl alcohol, etc.), polysaccharides (such as dextran, chitosan, alginic acid, etc.), polyamides (such as polyvinyl caprolactam, polyisopropyl acrylamide, etc.), and the hydrophobic group is selected from one or more of polyesters (such as polyvinyl acetate, polycaprolactone, polyglycolide (or polyglycolic acid), polylactide (or polylactic acid), etc.), polyamino acids (such as polylysine, polyglutamic acid, polyaspartic acid, etc.).

以聚乙二醇为亲水基团的高分子表面活性剂可以为聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物，其由N-乙烯基己内酰胺、乙酸乙烯酯与聚乙二醇共聚而得，其实例包括(但不限于)由5％-20％wt的聚乙二醇6000、20％-40％wt的乙酸乙烯酯和50％-70％wt的乙烯基己内酰胺共聚而得且平均相对分子量为50000-200000g/mol的聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物，优选由10％-15％wt的聚乙二醇6000、25％-35％wt的乙酸乙烯酯和55％-60％wt的乙烯基己内酰胺共聚而得且平均相对分子量为90000-140000g/mol的聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物，例如术语是指由德国巴斯夫公司出售的、可用作药用辅料的聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物。The high molecular surfactant with polyethylene glycol as the hydrophilic group can be a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, which is obtained by copolymerizing N-vinyl caprolactam, vinyl acetate and polyethylene glycol. Examples thereof include (but are not limited to) a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer obtained by copolymerizing 5%-20%wt of polyethylene glycol 6000, 20%-40%wt of vinyl acetate and 50%-70%wt of vinyl caprolactam and having an average relative molecular weight of 50000-200000 g/mol, preferably a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer obtained by copolymerizing 10%-15%wt of polyethylene glycol 6000, 25%-35%wt of vinyl acetate and 55%-60%wt of vinyl caprolactam and having an average relative molecular weight of 90000-140000 g/mol, for example the term It refers to a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer sold by BASF of Germany and can be used as a pharmaceutical excipient.

本发明对于其中所使用的水没有特殊限制，例如，可以是纯化水、蒸馏水、去离子水、注射用水或其任意种类和/或比例的组合。The present invention has no particular limitation on the water used therein, and the water may be, for example, purified water, distilled water, deionized water, water for injection, or any combination of their types and/or proportions.

除非另有说明，本发明所用的术语“稳定剂”是指可以增加特定制剂(如本发明的眼用胶束溶液组合物)的物理稳定性(如防止胶束聚集和/或胶束粒径增长从而避免沉降等)的物质。本发明中的稳定剂可以为含有2-6个碳原子并且至少含有2个羟基的链状多元醇，示例性的实例包括(但不限于)丙二醇(例如1,2-丙二醇)、甘油(即丙三醇)、丁二醇(例如1,2-丁二醇)和戊二醇(例如1,2-戊二醇)等。Unless otherwise specified, the term "stabilizer" used in the present invention refers to a substance that can increase the physical stability of a specific preparation (such as the ophthalmic micelle solution composition of the present invention) (such as preventing micelle aggregation and/or micelle particle size growth to avoid sedimentation, etc.). The stabilizer in the present invention can be a chain polyol containing 2-6 carbon atoms and at least 2 hydroxyl groups, and illustrative examples include (but are not limited to) propylene glycol (such as 1,2-propylene glycol), glycerol (i.e., glycerol), butylene glycol (such as 1,2-butylene glycol) and pentanediol (such as 1,2-pentanediol).

除非另有说明，本发明所用的术语“药学上可接受的辅料”是指药学上可接受的材料、组合物或媒介物。这些物质必须是“药学上可接受的”，即与药物处方中的其他成分相容，还必须适于与人类或动物的器官和/或组织接触，而无过度的毒性、刺激性、过敏性、免疫原性或其他不良情况，且与合理的利益/风险比相称。示例性的药学上可接受的辅料包括(但不限于)增黏剂、抗氧剂、螯合剂、抑菌剂(或防腐剂)、pH调节剂和渗透压调节剂等。本领域技术人员能够理解，上述示例性的药学上可接受的辅料并非所述组合物所必需，可以根据实际需要选择加入其中的一种或多种，也可以选择不加入任何一种。Unless otherwise indicated, the term "pharmaceutically acceptable excipient" used in the present invention refers to a pharmaceutically acceptable material, composition or vehicle. These substances must be "pharmaceutically acceptable", that is, compatible with other ingredients in the drug prescription, and must also be suitable for contact with human or animal organs and/or tissues without excessive toxicity, irritation, allergy, immunogenicity or other adverse conditions, and commensurate with a reasonable benefit/risk ratio. Exemplary pharmaceutically acceptable excipients include (but are not limited to) viscosity enhancers, antioxidants, chelating agents, antibacterial agents (or preservatives), pH regulators and osmotic pressure regulators, etc. Those skilled in the art will understand that the above-mentioned exemplary pharmaceutically acceptable excipients are not necessary for the composition, and one or more of them can be selected according to actual needs, or none of them can be selected.

除非另有说明，本发明所用的术语“增黏剂”是指可以在一定程度上增加本发明组合物的粘度，进一步提升药物活性成分(即瑞普洛莎或其药学上可接受的盐)缓释效果的辅料。示例性的增黏剂包括(但不限于)羧甲基纤维素或其钠盐、羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素、泊洛沙姆、卡波姆、黄原胶、玻璃酸或其钠盐、聚乙烯吡咯烷酮、聚卡波菲、树胶、卡拉胶、瓜尔胶、黄芪胶、琼脂糖、聚乙二醇、海藻酸或其钠盐和透明质酸或其钠盐等。Unless otherwise specified, the term "viscosity enhancer" used in the present invention refers to an excipient that can increase the viscosity of the composition of the present invention to a certain extent, and further enhance the sustained release effect of the active pharmaceutical ingredient (i.e., Reprosa or its pharmaceutically acceptable salt). Exemplary viscosity enhancers include (but are not limited to) carboxymethyl cellulose or its sodium salt, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, poloxamer, carbomer, xanthan gum, hyaluronic acid or its sodium salt, polyvinyl pyrrolidone, polycarbophil, gum, carrageenan, guar gum, tragacanth gum, agarose, polyethylene glycol, alginic acid or its sodium salt, and hyaluronic acid or its sodium salt, etc.

除非另有说明，本发明所用的术语“抗氧剂”(或称抗氧化剂)是指可以在一定程度上阻止氧气等具有氧化性的物质对本发明组合物中的组分造成氧化等不良影响的辅料。示例性的抗氧剂包括(但不限于)生育酚或其羧酸酯(如琥珀酸酯等)、抗坏血酸或其羧酸酯(如棕榈酸酯等)、丁基羟基茴香醚、2,6-二叔丁基对甲酚和硫代硫酸钠等。Unless otherwise specified, the term "antioxidant" (or antioxidant) used in the present invention refers to an auxiliary material that can prevent oxygen and other oxidizing substances from causing adverse effects such as oxidation on the components in the composition of the present invention to a certain extent. Exemplary antioxidants include (but are not limited to) tocopherol or its carboxylic acid esters (such as succinate, etc.), ascorbic acid or its carboxylic acid esters (such as palmitate, etc.), butylated hydroxyanisole, 2,6-di-tert-butyl-p-cresol and sodium thiosulfate, etc.

除非另有说明，本发明所用的术语“螯合剂”(或称络合剂)是指可以在一定程度上与金属离子络合而形成螯合物，从而降低或控制本发明组合物中的金属离子浓度的辅料。示例性的螯合剂包括(但不限于)柠檬酸或其盐(如柠檬酸钠)、葡萄糖醛酸或其盐(如葡萄糖醛酸钠)、六偏磷酸盐(如六偏磷酸钠、六偏磷酸锌等)、依地酸或其盐(如依地酸二钠)和膦酸盐。 Unless otherwise specified, the term "chelating agent" (or complexing agent) used in the present invention refers to an auxiliary material that can complex with metal ions to a certain extent to form a chelate, thereby reducing or controlling the concentration of metal ions in the composition of the present invention. Exemplary chelating agents include (but are not limited to) citric acid or its salts (such as sodium citrate), glucuronic acid or its salts (such as sodium glucuronic acid), hexametaphosphate (such as sodium hexametaphosphate, zinc hexametaphosphate, etc.), edetic acid or its salts (such as disodium edetate) and phosphonates.

除非另有说明，本发明所用的术语“pH调节剂”(或称酸度调节剂)是指可以在一定程度上维持或改变本发明组合物的pH值的辅料。本发明所用的pH调节剂可以为本领域常规的pH调节剂，包括(但不限于)无机或有机的酸、碱和缓冲盐。示例性的酸型pH调节剂包括(但不限于)盐酸、磷酸、醋酸、柠檬酸、乳酸和硼酸等，示例性的碱性pH调节剂包括(但不限于)乙二胺、乙醇胺、碱性氨基酸、氢氧化钠、氢氧化钙、氢氧化钾和氨水溶液等；示例性的缓冲盐型pH调节剂包括(但不限于)硼酸-硼砂缓冲盐、柠檬酸-柠檬酸钠缓冲盐、磷酸-磷酸钠缓冲盐和醋酸-醋酸钠缓冲盐等。本领域技术人员能够理解，可以根据需要任选加入pH调节剂对本发明组合物的pH值进行调节，直至最终pH值符合眼用要求。当在不加入pH调节剂的情况下，若本发明组合物的pH值已经符合眼用要求，则无需加入pH调节剂。Unless otherwise specified, the term "pH regulator" (or acidity regulator) used in the present invention refers to an auxiliary material that can maintain or change the pH value of the composition of the present invention to a certain extent. The pH regulator used in the present invention can be a conventional pH regulator in the art, including (but not limited to) inorganic or organic acids, bases and buffer salts. Exemplary acidic pH regulators include (but not limited to) hydrochloric acid, phosphoric acid, acetic acid, citric acid, lactic acid and boric acid, etc., and exemplary alkaline pH regulators include (but not limited to) ethylenediamine, ethanolamine, basic amino acids, sodium hydroxide, calcium hydroxide, potassium hydroxide and ammonia solution, etc.; Exemplary buffer salt-type pH regulators include (but not limited to) boric acid-borax buffer salt, citric acid-sodium citrate buffer salt, phosphoric acid-sodium phosphate buffer salt and acetic acid-sodium acetate buffer salt. It can be understood by those skilled in the art that the pH value of the composition of the present invention can be adjusted by optionally adding a pH regulator as needed until the final pH value meets the requirements for ophthalmic use. When the pH value of the composition of the present invention meets the requirements for ophthalmic use without adding a pH regulator, there is no need to add a pH regulator.

除非另有说明，本发明所用的术语“渗透压调节剂”(或称等渗调节剂)是指可以在一定程度上调节本发明组合物的渗透压，使之与受试者全身和/或给药局部的体液渗透压相等或相近的辅料。示例性的渗透压调节剂包括(但不限于)氯化钠、甘露醇、葡萄糖、山梨醇、聚乙二醇、甘油和丙二醇等。本领域技术人员能够理解，可以根据需要任选加入渗透压调节剂对本发明组合物的渗透压值进行调节，直至最终渗透压值符合眼用要求。当在不加入渗透压调节剂的情况下，若本发明组合物的渗透压值已经符合眼用要求，则无需加入渗透压调节剂。通常而言，泪液的渗透压与血清相等，相当于0.9％氯化钠(286mOsm)的渗透压，眼睛可耐受相当于0.6％-1.5％氯化钠的渗透压范围(200-450mOsm)，最佳渗透压范围为260-310mOsm。Unless otherwise specified, the term "osmotic pressure regulator" (or isotonic regulator) used in the present invention refers to an excipient that can adjust the osmotic pressure of the composition of the present invention to a certain extent, so that it is equal to or close to the osmotic pressure of the body fluid of the subject's whole body and/or the local administration site. Exemplary osmotic pressure regulators include (but are not limited to) sodium chloride, mannitol, glucose, sorbitol, polyethylene glycol, glycerol and propylene glycol. It will be understood by those skilled in the art that an osmotic pressure regulator can be optionally added as needed to adjust the osmotic pressure value of the composition of the present invention until the final osmotic pressure value meets the ophthalmic requirements. When no osmotic pressure regulator is added, if the osmotic pressure value of the composition of the present invention already meets the ophthalmic requirements, there is no need to add an osmotic pressure regulator. Generally speaking, the osmotic pressure of tears is equal to that of serum, which is equivalent to the osmotic pressure of 0.9% sodium chloride (286mOsm). The eye can tolerate an osmotic pressure range equivalent to 0.6%-1.5% sodium chloride (200-450mOsm), and the optimal osmotic pressure range is 260-310mOsm.

除非另有说明，本发明所用的术语“抑菌剂”(或称防腐剂)是指可以在一定程度上抑制本发明组合物中的微生物活动，防止腐败变质的辅料。示例性的抑菌剂包括(但不限于)苯甲醇、苯氧乙醇、山梨酸或其盐(如山梨酸钾)、对羟基苯甲酸酯(或称尼泊金酯，如羟苯甲酯、羟苯乙酯、羟苯丙酯、羟苯丁酯等)、洗必泰(或称氯己定)、苯扎氯铵、苯扎溴铵、三氯叔丁醇、苯甲酸或其盐(如苯甲酸钠)、柠檬酸或其盐(如柠檬酸钠)和抗坏血酸或其盐(如抗坏血酸钠)等。Unless otherwise specified, the term "bacteriostatic agent" (or preservative) used in the present invention refers to an auxiliary material that can inhibit the activity of microorganisms in the composition of the present invention to a certain extent and prevent spoilage. Exemplary antibacterial agents include (but are not limited to) benzyl alcohol, phenoxyethanol, sorbic acid or its salts (such as potassium sorbate), parabens (or parabens, such as methylparaben, ethylparaben, propylparaben, butylparaben, etc.), chlorhexidine (or chlorhexidine), benzalkonium chloride, benzalkonium bromide, chlorobutanol, benzoic acid or its salts (such as sodium benzoate), citric acid or its salts (such as sodium citrate), and ascorbic acid or its salts (such as sodium ascorbate).

除非另有说明，在本发明中，使用“数值A～数值B”或“数值A-数值B”表示的数值范围是指包含端点数值A、B的范围。例如，“聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯”既包括聚氧乙烯单元数为10的聚氧乙烯羟基硬脂酸酯，也包括聚氧乙烯单元数为20的聚氧乙烯羟基硬脂酸酯。Unless otherwise specified, in the present invention, the numerical range expressed by "value A to value B" or "value A-value B" means a range including the endpoint values A and B. For example, "polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units" includes both polyoxyethylene hydroxystearate having 10 polyoxyethylene units and polyoxyethylene hydroxystearate having 20 polyoxyethylene units.

下面通过具体实施例来进一步说明本发明，但并不应理解为将本发明限制在所述实施例的范围当中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书中记载或推荐的方法或条件进行。The present invention is further described below by specific examples, but it should not be understood that the present invention is limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or according to the methods or conditions recorded or recommended in the product instructions.

本发明中涉及的部分技术术语的缩写以及部分商品的商品名、含义及来源如下表所示。除非另有说明，本发明中的所有试剂、原料均为市售可得。
The abbreviations of some technical terms involved in the present invention and the trade names, meanings and sources of some commodities are shown in the following table. Unless otherwise specified, all reagents and raw materials in the present invention are commercially available.

本发明的实施例中，“主要杂质1”的化学结构为“主要杂质2”的化学结构为 In the embodiment of the present invention, the chemical structure of "main impurity 1" is The chemical structure of "Main Impurity 2" is

本发明的实施例中采用的检测设备和/或检测方法如下：The detection device and/or detection method used in the embodiments of the present invention are as follows:

1.渗透压检测：用移液枪量取50μL样品至测试管中，确保样品无气泡，按照设备使用流程对样品进行渗透压检测；使用设备为Gonotec的OSMOMAT 3000冰点渗透压仪。1. Osmotic pressure test: Use a pipette to measure 50 μL of sample into a test tube, ensure that there are no bubbles in the sample, and perform osmotic pressure test on the sample according to the equipment usage process; the equipment used is Gonotec's OSMOMAT 3000 Freezing Point Osmometer.

2.胶束粒径检测：取1mL待测液至检测池中，进行粒径检测；使用设备为Malvern的Zetasizer Pro纳米粒度仪。“Z-Average”是指粒径平均值，利用动态光散射技术而测得，适用于分散体中的颗粒或溶液中的分子。2. Micelle particle size detection: Take 1 mL of the test solution into the detection cell for particle size detection; the device used is Malvern's Zetasizer Pro nanoparticle size analyzer. "Z-Average" refers to the average particle size, which is measured using dynamic light scattering technology and is applicable to particles in dispersions or molecules in solutions.

3.有关物质检测：分别配制对照品溶液(1μg/mL)和供试品溶液(1mg/mL)；对样品通过HPLC进行检测；色谱柱：Waters Xbridge C8(4.6*250mm,5μm)LC-0228；柱温：35℃；流速：1.0mL/min；进样量：20μL；检测器及波长：DAD检测器，249nm；流动相A：10mmol/L磷酸二氢钾溶液；流动相B：甲醇-乙腈(65:35,V/V)；HPLC流动相洗脱梯度及运行时间：55％A/45％B→10％A/90％B→55％A/45％B，共46min。3. Detection of related substances: prepare reference solution (1 μg/mL) and test solution (1 mg/mL) respectively; detect the samples by HPLC; chromatographic column: Waters Xbridge C8 (4.6*250mm, 5μm) LC-0228; column temperature: 35℃; flow rate: 1.0mL/min; injection volume: 20μL; detector and wavelength: DAD detector, 249nm; mobile phase A: 10mmol/L potassium dihydrogen phosphate solution; mobile phase B: methanol-acetonitrile (65:35, V/V); HPLC mobile phase elution gradient and running time: 55%A/45%B→10%A/90%B→55%A/45%B, 46min in total.

4.API含量检测：分别配制对照品溶液(0.02mg/mL)和供试品溶液(0.02mg/mL)；外标法对样品通过HPLC进行检测；色谱柱：Welch Ultimate XB-C18(4.6*250mm,5μm)LC-0082；柱温：30℃；流速：1.0mL/min；进样量：10μL；检测器及波长：DAD检测器，249nm；流动相：乙腈80％/水20％；等度洗脱；运行时间：10min。4. API content detection: prepare reference solution (0.02 mg/mL) and test solution (0.02 mg/mL) respectively; detect the samples by HPLC using the external standard method; chromatographic column: Welch Ultimate XB-C18 (4.6*250 mm, 5 μm) LC-0082; column temperature: 30°C; flow rate: 1.0 mL/min; injection volume: 10 μL; detector and wavelength: DAD detector, 249 nm; mobile phase: acetonitrile 80%/water 20%; isocratic elution; running time: 10 min.

5.体外溶出检测：采用《中国药典》(2020年版)溶出度与释放度测定法(篮法)检测，将原有的篮体替换为即用型透析管/透析袋(CE，截留分子量：100KD)；溶出介质：人工泪液；溶出介质体积：1000mL；溶出介质温度：34℃±0.5℃；转速：100rpm；取样时间：10min、20min、30min、45min、1h、2h、3h、4h、6h、8h、12h、16h、20h和24h。通过HPLC进行检测，检测方法同含量检测方法。5. In vitro dissolution test: The dissolution and release rate determination method (basket method) of the Chinese Pharmacopoeia (2020 edition) was used for the test. The original basket was replaced with a ready-to-use dialysis tube/dialysis bag (CE, molecular weight cutoff: 100KD); dissolution medium: artificial tears; dissolution medium volume: 1000mL; dissolution medium temperature: 34℃±0.5℃; rotation speed: 100rpm; sampling time: 10min, 20min, 30min, 45min, 1h, 2h, 3h, 4h, 6h, 8h, 12h, 16h, 20h and 24h. The test was performed by HPLC, and the test method was the same as the content test method.

实施例1：增溶剂筛选 Example 1: Solubilizer Screening

瑞普洛莎眼用溶液的配制(批量100g-200g)：先按照表1-1中记载的重量百分比称取处方量的瑞普洛莎、增溶剂以及任选的丙二醇至烧杯中，于45℃水浴中搅拌至完全溶解，得到含药溶液；再将含药溶液缓慢加入到约30℃水中，待完全分散均匀后，得到瑞普洛莎眼用溶液。Preparation of Reprosa ophthalmic solution (batch size 100g-200g): first weigh the prescribed amount of Reprosa, solubilizer and optional propylene glycol into a beaker according to the weight percentage recorded in Table 1-1, stir in a 45°C water bath until completely dissolved to obtain a drug-containing solution; then slowly add the drug-containing solution into water at about 30°C, and after it is completely dispersed, obtain the Reprosa ophthalmic solution.

稳定性检测：肉眼观察瑞普洛莎眼用溶液性状，并在配制完毕后24h内进行有关物质、API含量和胶束粒径的检测，具体检测结果见表1-2。Stability test: Observe the properties of Reprosa ophthalmic solution with naked eyes, and test the relevant substances, API content and micelle particle size within 24 hours after preparation. The specific test results are shown in Table 1-2.

结果分析：处方1.1-1.10的瑞普洛莎眼用溶液均为均一胶束溶液，胶束平均粒径为10-65nm，绝大多数为10-30nm，部分甚至可达10-15nm，且均能形成粒度均一的胶束溶液。在化学稳定性方面，有关物质的杂质总量均能控制在不超过1.5％的可接受范围内，部分甚至可达0.5％以下，其中处方1.2、1.8和1.9的杂质总量和杂峰个数比其它处方高。Result analysis: The Reprosa ophthalmic solutions of prescriptions 1.1-1.10 are all uniform micellar solutions, with an average micellar particle size of 10-65nm, most of which are 10-30nm, and some can even reach 10-15nm, and can form micellar solutions with uniform particle size. In terms of chemical stability, the total amount of impurities of related substances can be controlled within an acceptable range of no more than 1.5%, and some can even reach less than 0.5%. Among them, the total amount of impurities and the number of impurity peaks of prescriptions 1.2, 1.8 and 1.9 are higher than those of other prescriptions.

表1-1增溶剂筛选试验的处方组成
Table 1-1 Prescription composition of solubilizer screening test

表1-2增溶剂筛选试验的稳定性数据
Table 1-2 Stability data of solubilizer screening test

实施例2：增溶剂用量范围考查Example 2: Solubilizer dosage range examination

按照表2-1中的处方2.1-2.6制备瑞普洛莎眼用溶液(批量100g-200g)，制备方法同实施例1。对制备得到的溶液进行物理和化学稳定性检测，观察0天、加速10天(40℃/75％RH)和加速30天(40℃/75％RH)后样品的性状，并分别检测样品的有关物质、API含量以及胶束粒径，具体检测结果见表2-2。According to the prescriptions 2.1-2.6 in Table 2-1, Reprosa ophthalmic solution (batch size 100 g-200 g) was prepared in the same manner as in Example 1. The prepared solution was subjected to physical and chemical stability tests, and the properties of the samples were observed after 0 days, 10 days of acceleration (40°C/75% RH) and 30 days of acceleration (40°C/75% RH), and the related substances, API content and micelle particle size of the samples were tested respectively. The specific test results are shown in Table 2-2.

检测结果：处方2.1-2.6在0天、加速10天和加速30天后均为无色澄明液体；有关物质在加速30天后仍能控制在低于约0.5％的范围内，API含量变化和粒径波动均在可控范围内。Test results: Prescriptions 2.1-2.6 were colorless clear liquids at 0 days, 10 days of acceleration, and 30 days of acceleration; the relevant substances could still be controlled within a range below about 0.5% after 30 days of acceleration, and the changes in API content and particle size fluctuations were all within controllable ranges.

表2-1增溶剂用量范围考查试验的处方组成
Table 2-1 Prescription composition of the solubilizer dosage range test

表2-2增溶剂用量范围考查试验的稳定性数据
Table 2-2 Stability data of the solubilizer dosage range test

实施例3：稳定剂丙二醇用量范围考查Example 3: Examination of the range of dosage of the stabilizer propylene glycol

参照表3-1中的处方3.1-3.7制备瑞普洛莎眼用溶液(批量100g-200g)，制备方法同实施例1。参照表3-1中的处方3.8以及实施例1中的制备方法，得到中间料液，在此基础上，进一步加入增黏剂并搅拌，分散均匀，即得瑞普洛莎眼用溶液(批量100g)。对制备得到的胶束溶液进行物理稳定性检测，分别检测0天、加速10天(40℃/75％RH)和加速30天(40℃/75％RH)后样品的胶束粒径，具体检测结果见表3-2。Referring to the prescriptions 3.1-3.7 in Table 3-1, the Reprosa ophthalmic solution (batch size 100g-200g) was prepared, and the preparation method was the same as in Example 1. Referring to the prescription 3.8 in Table 3-1 and the preparation method in Example 1, an intermediate liquid was obtained, on which a thickener was further added and stirred to disperse evenly, and the Reprosa ophthalmic solution (batch size 100g) was obtained. The prepared micellar solution was subjected to a physical stability test, and the micellar particle size of the samples after 0 days, 10 days of acceleration (40°C/75%RH) and 30 days of acceleration (40°C/75%RH) was tested respectively. The specific test results are shown in Table 3-2.

检测结果：当增溶剂为HS15时，未加入丙二醇的处方3.1在加速10天后粒径虽略有增长，但并不显著，而在加速30天后呈现出粒径增长。除此以外，其余处方的胶束粒径在加速条件下均能保持稳定。 Test results: When the solubilizer is HS15, the particle size of the formulation 3.1 without propylene glycol increases slightly after 10 days of acceleration, but it is not significant, and it increases after 30 days of acceleration. In addition, the micelle particle size of the other formulations can remain stable under accelerated conditions.

表3-1稳定剂丙二醇用量范围考查试验的处方组成
Table 3-1 Prescription composition of the stabilizer propylene glycol dosage range test

表3-2稳定剂丙二醇用量范围考查试验的稳定性数据
Table 3-2 Stability data of the test on the dosage range of stabilizer propylene glycol

实施例4：增黏剂的筛选Example 4: Screening of viscosity increasing agents

参照表4-1中的处方4.1-4.6以及实施例1中的制备方法，得到中间料液，在此基础上，进一步加入增黏剂并搅拌，分散均匀，即得瑞普洛莎眼用溶液(批量100g-200g)。对制备得到的溶液进行化学稳定性检测，分别检测0天、高温7天(60℃)、加速10天(40℃/75％RH)、加速30天(40℃/75％RH)后样品的有关物质，具体检测结果详见表4-2。Referring to the prescriptions 4.1-4.6 in Table 4-1 and the preparation method in Example 1, an intermediate liquid was obtained, on which a thickener was further added and stirred to disperse evenly, namely, Reprosa ophthalmic solution (batch size 100g-200g). The prepared solution was subjected to a chemical stability test, and the relevant substances of the samples were tested after 0 day, 7 days at high temperature (60°C), 10 days at acceleration (40°C/75%RH), and 30 days at acceleration (40°C/75%RH). The specific test results are shown in Table 4-2.

检测结果：处方4.3和4.5在高温7天(60℃)后的杂质总量和/或杂峰个数比其它处方偏高，因此后续未对上述两个处方进行加速稳定性试验。处方4.1、4.2、4.4和4.6在高温7天后的杂质总量均控制在低于约0.5％的范围内，并且在加速30天后仍能控制在低于0.5％的范围内，部分甚至可达0.2％以下。Test results: The total amount of impurities and/or the number of impurity peaks of prescriptions 4.3 and 4.5 after 7 days at high temperature (60°C) were higher than those of other prescriptions, so the accelerated stability test was not conducted on the above two prescriptions. The total amount of impurities of prescriptions 4.1, 4.2, 4.4 and 4.6 after 7 days at high temperature was controlled within the range of less than about 0.5%, and after 30 days of acceleration, it was still controlled within the range of less than 0.5%, and some even reached less than 0.2%.

表4-1增黏剂筛选试验的处方组成
Table 4-1 Prescription composition of viscosity enhancer screening test

表4-2增黏剂筛选试验的稳定性数据

注：N.D.指未检出；N/A指未检测。Table 4-2 Stability data of viscosity enhancer screening test

Note: ND means not detected; N/A means not detected.

实施例5：API浓度的筛选Example 5: Screening of API concentration

参照表5-1中的处方5.1-5.5以及实施例4中的制备方法制得不同浓度的瑞普洛莎眼用溶液(批量100g-200g)。对制备得到的溶液进行化学稳定性检测，分别检测0天、加速10天(40℃/75％RH)、加速30天(40℃/75％RH)后样品的有关物质，具体检测结果详见表5-2。Reprosa ophthalmic solutions of different concentrations (batch size 100 g-200 g) were prepared with reference to prescriptions 5.1-5.5 in Table 5-1 and the preparation method in Example 4. The prepared solutions were subjected to chemical stability tests, and the relevant substances of the samples were tested after 0 days, 10 days of acceleration (40°C/75% RH), and 30 days of acceleration (40°C/75% RH). The specific test results are detailed in Table 5-2.

检测结果：处方5.1、5.2、5.3、5.4和5.5在加速10天后的杂质总量均控制在低于0.2％的范围内，并且在加速30天后仍能控制在低于0.3％的范围内，部分甚至可达0.15％以下。Test results: The total amount of impurities in prescriptions 5.1, 5.2, 5.3, 5.4 and 5.5 were controlled below 0.2% after 10 days of acceleration, and were still controlled below 0.3% after 30 days of acceleration, and some could even reach below 0.15%.

表5-1API浓度筛选试验的处方组成
Table 5-1 Prescription composition of API concentration screening test

表5-2 API浓度筛选试验的稳定性数据

注：N.D.指未检出。Table 5-2 Stability data of API concentration screening test

Note: ND means not detected.

实施例6-1：体外溶出测试Example 6-1: In vitro dissolution test

按照表6-1中的处方6.1-6.3制备瑞普洛莎眼用溶液(批量100g-200g)，并考查其体外溶出行为，制备方法参考实施例4；其中，对比例的环糊精眼用溶液参考CN113056353A说明书[0068]至[0075]段实施例制备，作为体外溶出实验的对比例。同时，考查处方1.4、1.6和1.7的体外溶出行为，其结果如表6-2及图1所示。According to the prescriptions 6.1-6.3 in Table 6-1, Reprosa ophthalmic solution (batch size 100g-200g) was prepared, and its in vitro dissolution behavior was examined. The preparation method was referred to Example 4; wherein the comparative example cyclodextrin ophthalmic solution was prepared with reference to the examples in paragraphs [0068] to [0075] of the CN113056353A specification as a comparative example for the in vitro dissolution experiment. At the same time, the in vitro dissolution behavior of prescriptions 1.4, 1.6 and 1.7 was examined, and the results are shown in Table 6-2 and Figure 1.

检测结果：本发明的眼用纳米胶束溶液的体外缓释效果显著优于环糊精眼用溶液。另外，通过分别比较处方1.6和处方6.1以及处方1.7和处方6.2可知，向处方中引入增黏剂可以在一定程度上进一步提高本发明的眼用纳米胶束溶液的体外缓释效果。Test results: The in vitro sustained release effect of the ophthalmic nanomicelle solution of the present invention is significantly better than that of the cyclodextrin ophthalmic solution. In addition, by comparing prescription 1.6 with prescription 6.1 and prescription 1.7 with prescription 6.2, it can be seen that the introduction of a viscosity enhancer into the prescription can further improve the in vitro sustained release effect of the ophthalmic nanomicelle solution of the present invention to a certain extent.

表6-1体外溶出测试样品处方
Table 6-1 In vitro dissolution test sample formulation

表6-2体外溶出数据
Table 6-2 In vitro dissolution data

实施例6-2：体外溶出测试Example 6-2: In vitro dissolution test

考查实施例5中处方5.1、5.2、5.4和5.5的体外溶出行为，其结果如表6-3及图2所示。The in vitro dissolution behavior of formulations 5.1, 5.2, 5.4 and 5.5 in Example 5 was examined, and the results are shown in Table 6-3 and Figure 2.

检测结果：本发明不同浓度及处方的眼用纳米胶束溶液的体外缓释效果显著。Test results: The in vitro sustained-release effects of the ophthalmic nano-micelle solutions of different concentrations and prescriptions of the present invention are significant.

表6-3体外溶出数据
Table 6-3 In vitro dissolution data

实施例7：添加抗氧剂、螯合剂、pH调节剂、渗透压调节剂等辅料的处方Example 7: Prescription for adding antioxidants, chelating agents, pH regulators, osmotic pressure regulators and other auxiliary materials

按照表7-1中的处方7.1-7.9，参考上述实施例的制备方法，进一步选择性加入抗氧剂、螯合剂、pH调节剂、渗透压调节剂并通过本领域通用的常规制剂技术制备得到相应的眼用纳米胶束溶液(批量100g-200g)。对制备得到的样品进行pH、渗透压和粒径检测，检测结果均满足瑞普洛莎眼用胶束相关质量要求(如表7-2所示)。 According to the prescriptions 7.1-7.9 in Table 7-1, with reference to the preparation method of the above embodiment, antioxidants, chelating agents, pH regulators, osmotic pressure regulators are further selectively added and the corresponding ophthalmic nano-micelle solutions (batch size 100g-200g) are prepared by conventional preparation techniques commonly used in the art. The prepared samples were tested for pH, osmotic pressure and particle size, and the test results all met the relevant quality requirements of Reprosa ophthalmic micelles (as shown in Table 7-2).

表7-1其他相关制备例的处方组成

注：
1)q.s.指适量；
2)磷酸盐缓冲液：每100g含磷酸二氢钠一水合物0.4719g，无水磷酸氢二钠0.4711g，其余
为纯化水；
3)硼酸盐缓冲液：每100g含硼酸1.0992g，硼砂0.1880g，其余为纯化水。Table 7-1 Prescription composition of other related preparation examples

Note:
1) qs means appropriate amount;
2) Phosphate buffer: each 100 g contains 0.4719 g of sodium dihydrogen phosphate monohydrate, 0.4711 g of anhydrous disodium hydrogen phosphate, and the rest is purified water;
3) Borate buffer: Each 100 g contains 1.0992 g of boric acid, 0.1880 g of borax, and the rest is purified water.

表7-2其他相关制备例的基本性质检测
Table 7-2 Basic property tests of other relevant preparation examples

实施例8：动物体内药效实验Example 8: Animal in vivo efficacy experiment

实验样品：本发明实施例5处方5.2(受试物0.15％组)、实施例5处方5.3(受试物0.25％组)、实施例5处方5.3赋形剂(赋形剂组)、实施例6-1处方对比例(阳性对照组)。Experimental samples: Prescription 5.2 of Example 5 of the present invention (0.15% group of the test substance), Prescription 5.3 of Example 5 (0.25% group of the test substance), Excipient 5.3 of Example 5 (Excipient group), and Comparative Example 6-1 Prescription (positive control group).

制备方法(批量100g-200g)：先按照表5-1中处方5.2、5.3记载的重量百分比称取处方量的瑞普洛莎(赋形剂组不含瑞普洛莎)、增溶剂以及丙二醇至烧杯中，于45℃水浴中搅拌至完全溶解，得到含药溶液；再将含药溶液缓慢加入到约30℃处方量一半水中，待完全分散均匀后，使用0.22μm滤膜过滤，得到无菌瑞普洛莎眼用溶液1)；将CMC-Na加入到剩余一半水中搅拌至完全溶解，并高温121℃灭菌12min，得到灭菌CMC-Na浓溶液2)；将溶液1)与溶液2)在无菌条件下混合，即得瑞普洛莎眼用溶液。Preparation method (batch size 100g-200g): First weigh the prescribed amount of Reprosa (the excipient group does not contain Reprosa), solubilizer and propylene glycol into a beaker according to the weight percentage recorded in Prescriptions 5.2 and 5.3 in Table 5-1, and stir in a 45°C water bath until completely dissolved to obtain a drug-containing solution; then slowly add the drug-containing solution to half of the prescribed amount of water at about 30°C, and after it is completely dispersed, filter with a 0.22μm filter membrane to obtain a sterile Reprosa ophthalmic solution 1); add CMC-Na to the remaining half of the water, stir until completely dissolved, and sterilize at high temperature at 121°C for 12 minutes to obtain a sterile CMC-Na concentrated solution 2); mix solution 1) and solution 2) under sterile conditions to obtain a Reprosa ophthalmic solution.

实验方法：建模前一日，依据动物体重，将达标的Wistar雄性大鼠随机分成六组，分别为空白对照组、模型对照组、阳性对照组(实施例6-1处方对比例)、受试物0.15％组(处方5.2)、受试物0.25％组(处方5.3)和赋形剂组(处方5.3赋形剂)，每组10只。除空白对照组外，在大鼠后肢交替皮下注射100μL氢溴酸东莨菪碱(浓度为6mg/mL)，每天4次； 同时，将大鼠置于通风装置中，每天连续吹风12h，连续10日，以构建干眼症模型。造模后，除空白对照组和模型对照组外，对其他试验组大鼠角膜持续给药(每次20μL，一日2次)，分别于给药第0、1、3、7、14天进行荧光素钠评分检查，评价动物眼部病变程度，以荧光素钠的评分为标准。Experimental method: One day before modeling, the Wistar male rats that met the standard were randomly divided into six groups according to the animal weight, namely blank control group, model control group, positive control group (prescription comparison ratio of Example 6-1), test substance 0.15% group (prescription 5.2), test substance 0.25% group (prescription 5.3) and excipient group (prescription 5.3 excipient), with 10 rats in each group. Except for the blank control group, 100 μL of scopolamine hydrobromide (concentration of 6 mg/mL) was injected subcutaneously in the hind limbs of the rats alternately, 4 times a day; At the same time, the rats were placed in a ventilation device and blown for 12 hours every day for 10 consecutive days to construct a dry eye model. After modeling, except for the blank control group and the model control group, the corneas of rats in other experimental groups were continuously administered (20 μL each time, twice a day), and fluorescein sodium scoring was performed on the 0th, 1st, 3rd, 7th, and 14th days of administration to evaluate the degree of animal eye lesions, using the fluorescein sodium score as the standard.

角膜荧光素钠染色(CFS)评分：将1μL液态荧光素钠(1％w/v)滴至结膜囊并闭合，90s后使用裂隙灯显微镜在钴蓝光下进行角膜上皮荧光素钠染色分级。将角膜平均分成4个象限并分别评分，将所有分值相加后，得到总分值。Corneal fluorescein sodium staining (CFS) scoring: 1 μL of liquid fluorescein sodium (1% w/v) was dropped into the conjunctival sac and closed. After 90 seconds, corneal epithelial fluorescein sodium staining was graded under cobalt blue light using a slit lamp microscope. The cornea was divided into 4 quadrants and scored separately. All scores were added together to obtain the total score.

评分标准：0分-无染色；1分-点状着色少于或等于30个；2分-点状着色多于30个，但不弥散；3分-严重的弥散染色，但无斑块状染色；4分-有斑块状染色。Scoring criteria: 0 points - no staining; 1 point - less than or equal to 30 punctate staining; 2 points - more than 30 punctate staining, but not diffuse; 3 points - severe diffuse staining, but no plaque staining; 4 points - plaque staining.

实验结果：Experimental results:

表8角膜荧光素钠染色评分数据
Table 8 Corneal fluorescein sodium staining scoring data

将每组角膜荧光素钠染色评分取均值，以模型对照组、阳性对照组、赋形剂组、受试物0.25％组、受试物0.15％组均值各自扣除相应给药日空白对照组评分均值后所得数值，录入表8，并依据表8数据作图，得到图3。The corneal fluorescein sodium staining score of each group was averaged, and the values obtained by deducting the mean score of the blank control group on the corresponding administration day from the mean values of the model control group, positive control group, vehicle group, test substance 0.25% group, and test substance 0.15% group were entered into Table 8, and a graph was drawn based on the data in Table 8 to obtain Figure 3.

如图3所示，分别利用本发明实施例5处方5.2和5.3的受试物0.15％组与受试物0.25％组的实验结果显示出一定的量效趋势；阳性对照组的药效在第7天之后进入平台期，而受试物0.15％组和受试物0.25％组则随着时间推移均呈现出持续下降的趋势，体现出更长久、更佳的药效作用，并且其药效均优于阳性对照组。 As shown in FIG3 , the experimental results of the test substance 0.15% group and the test substance 0.25% group using prescriptions 5.2 and 5.3 of Example 5 of the present invention, respectively, showed a certain dose-effect trend; the efficacy of the positive control group entered a plateau phase after the 7th day, while the test substance 0.15% group and the test substance 0.25% group both showed a continuous downward trend over time, reflecting a longer-lasting and better pharmacodynamic effect, and their efficacy was better than that of the positive control group.

Claims (26)

一种眼用溶液组合物，其包含瑞普洛莎或其药学上可接受的盐、增溶剂、水和任选的稳定剂；An ophthalmic solution composition comprising Reprosa or a pharmaceutically acceptable salt thereof, a solubilizer, water and optionally a stabilizer; 所述增溶剂选自聚氧乙烯蓖麻油衍生物、聚氧乙烯脂肪酸酯、聚氧乙烯烷基酚醚、聚氧乙烯脂肪醇醚和聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物中的一种或多种；The solubilizing agent is selected from one or more of polyoxyethylene castor oil derivatives, polyoxyethylene fatty acid esters, polyoxyethylene alkylphenol ethers, polyoxyethylene fatty alcohol ethers, and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers; 所述稳定剂为含有2-6个碳原子和至少2个羟基的链状多元醇。The stabilizer is a chain polyol containing 2 to 6 carbon atoms and at least 2 hydroxyl groups. 根据权利要求1所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to claim 1, characterized in that 所述眼用溶液组合物为眼用纳米胶束溶液组合物，其中纳米胶束的平均粒径为5-100nm，优选5-80nm，更优选10-65nm，最优选10-30nm。The ophthalmic solution composition is an ophthalmic nanomicelle solution composition, wherein the average particle size of the nanomicelles is 5-100 nm, preferably 5-80 nm, more preferably 10-65 nm, and most preferably 10-30 nm. 根据权利要求1或2所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to claim 1 or 2, characterized in that 以所述组合物的总重量计，所述瑞普洛莎的含量为0.05％-0.5％，优选0.1％-0.5％，更优选0.1％-0.45％，进一步优选0.1％-0.3％，最优选0.15％-0.25％。Based on the total weight of the composition, the content of Reprosa is 0.05%-0.5%, preferably 0.1%-0.5%, more preferably 0.1%-0.45%, further preferably 0.1%-0.3%, and most preferably 0.15%-0.25%. 根据权利要求1至3中任一项所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to any one of claims 1 to 3, characterized in that 所述增溶剂选自聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、聚氧乙烯硬脂酸酯、聚氧乙烯羟基硬脂酸酯、维生素E聚乙二醇琥珀酸酯、聚氧乙烯烷基酚醚和聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物中的一种或多种；The solubilizing agent is selected from one or more of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene stearate, polyoxyethylene hydroxystearate, vitamin E polyethylene glycol succinate, polyoxyethylene alkylphenol ether and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer; 其中，in, 所述聚氧乙烯蓖麻油选自聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油中的一种或多种，优选聚氧乙烯35蓖麻油；The polyoxyethylene castor oil is selected from one or more polyoxyethylene castor oils having 30 to 40 polyoxyethylene units, preferably polyoxyethylene 35 castor oil; 所述聚氧乙烯氢化蓖麻油选自聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油中的一种或多种，优选聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油中的一种或多种，更优选聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油和聚氧乙烯单元数为50-55的聚氧乙烯氢化蓖麻油中的一种或多种，进一步优选聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油中的一种或多种，最优选聚氧乙烯40氢化蓖麻油；The polyoxyethylene hydrogenated castor oil is selected from one or more polyoxyethylene hydrogenated castor oils having 30-60 polyoxyethylene units, preferably one or more polyoxyethylene hydrogenated castor oils having 35-55 polyoxyethylene units, more preferably one or more polyoxyethylene hydrogenated castor oils having 35-45 polyoxyethylene units and polyoxyethylene hydrogenated castor oils having 50-55 polyoxyethylene units, further preferably one or more polyoxyethylene hydrogenated castor oils having 35-45 polyoxyethylene units, and most preferably polyoxyethylene 40 hydrogenated castor oil; 所述聚氧乙烯硬脂酸酯选自聚氧乙烯单元数为10-50的聚氧乙烯硬脂酸酯中的一种或多种，优选聚氧乙烯单元数为30-50的聚氧乙烯硬脂酸酯中的一种或多种，更优选聚氧乙烯单元数为35-45的聚氧乙烯硬脂酸酯中的一种或多种，进一步优选聚氧乙烯40硬脂酸酯；The polyoxyethylene stearate is selected from one or more polyoxyethylene stearates having a polyoxyethylene unit number of 10-50, preferably one or more polyoxyethylene stearates having a polyoxyethylene unit number of 30-50, more preferably one or more polyoxyethylene stearates having a polyoxyethylene unit number of 35-45, and further preferably polyoxyethylene 40 stearate; 所述聚氧乙烯羟基硬脂酸酯选自聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种，优选聚氧乙烯15羟基硬脂酸酯；The polyoxyethylene hydroxystearate is selected from one or more polyoxyethylene hydroxystearates having 10 to 20 polyoxyethylene units, preferably polyoxyethylene 15 hydroxystearate; 所述维生素E聚乙二醇琥珀酸酯选自聚乙二醇平均分子量为200-4000的维生素E聚乙二醇琥珀酸酯中的一种或多种，优选聚乙二醇平均分子量为500-1500的维生素E聚乙二醇琥珀酸酯中的一种或多种，更优选聚乙二醇平均分子量为800-1200的维生素E聚乙二醇琥珀酸酯中的一种或多种，进一步优选维生素E聚乙二醇琥珀酸酯1000；The vitamin E polyethylene glycol succinate is selected from one or more vitamin E polyethylene glycol succinates with a polyethylene glycol average molecular weight of 200-4000, preferably one or more vitamin E polyethylene glycol succinates with a polyethylene glycol average molecular weight of 500-1500, more preferably one or more vitamin E polyethylene glycol succinates with a polyethylene glycol average molecular weight of 800-1200, and further preferably vitamin E polyethylene glycol succinate 1000; 所述聚氧乙烯烷基酚醚选自聚氧乙烯单元数为13-50的辛基酚聚氧乙烯醚中的一种或多种，优选聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚中的一种或多种，更优选聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚中的一种或多种，进一步优选辛基酚聚氧乙烯醚40；The polyoxyethylene alkylphenol ether is selected from one or more octylphenol polyoxyethylene ethers having 13-50 polyoxyethylene units, preferably one or more octylphenol polyoxyethylene ethers having 30-50 polyoxyethylene units, more preferably one or more octylphenol polyoxyethylene ethers having 35-45 polyoxyethylene units, and further preferably octylphenol polyoxyethylene ether 40; 所述聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物选自由5％-20％的聚乙二醇6000、20％-40％的乙酸乙烯酯和50％-70％的乙烯基己内酰胺共聚而得且平均相对分子量为50000-200000g/mol的聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物中的一种或多种，优选由10％-15％的聚乙二醇6000、25％-35％的乙酸乙烯酯和55％-60％的乙烯基己内酰胺共聚而得且平均相对分子量为90000-140000g/mol的聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物中的一种或多种，或者，优选商品名为的聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物。 The polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer is selected from one or more polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers obtained by copolymerization of 5%-20% polyethylene glycol 6000, 20%-40% vinyl acetate and 50%-70% vinyl caprolactam and having an average relative molecular weight of 50000-200000 g/mol, preferably one or more polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers obtained by copolymerization of 10%-15% polyethylene glycol 6000, 25%-35% vinyl acetate and 55%-60% vinyl caprolactam and having an average relative molecular weight of 90000-140000 g/mol, or preferably a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer with a trade name Polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer. 根据权利要求1至3中任一项所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to any one of claims 1 to 3, characterized in that 所述增溶剂选自聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油、聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油、聚乙二醇分子量为500-1500的维生素E聚乙二醇琥珀酸酯、聚氧乙烯单元数为30-50的聚氧乙烯硬脂酸酯、聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯、聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚和聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物中的一种或多种；The solubilizing agent is selected from one or more of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units, polyoxyethylene castor oil having 30-40 polyoxyethylene units, vitamin E polyethylene glycol succinate having a polyethylene glycol molecular weight of 500-1500, polyoxyethylene stearate having 30-50 polyoxyethylene units, polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer; 优选地，所述增溶剂选自聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油、聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油、聚乙二醇分子量为500-1500的维生素E聚乙二醇琥珀酸酯、聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯和聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚中的一种或多种；Preferably, the solubilizer is selected from one or more of polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units, polyoxyethylene castor oil having 30-40 polyoxyethylene units, vitamin E polyethylene glycol succinate having a polyethylene glycol molecular weight of 500-1500, polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units; 更优选地，所述增溶剂选自聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油、聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油、聚乙二醇分子量为800-1200的维生素E聚乙二醇琥珀酸酯、聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯和聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚中的一种或多种；More preferably, the solubilizer is selected from one or more of polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units, polyoxyethylene castor oil having 30-40 polyoxyethylene units, vitamin E polyethylene glycol succinate having a polyethylene glycol molecular weight of 800-1200, polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units; 进一步优选地，所述增溶剂选自聚氧乙烯40氢化蓖麻油、聚氧乙烯54氢化蓖麻油、聚氧乙烯35蓖麻油、维生素E聚乙二醇琥珀酸酯1000、聚氧乙烯15羟基硬脂酸酯和辛基酚聚氧乙烯醚40中的一种或多种。Further preferably, the solubilizer is selected from one or more of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 54 hydrogenated castor oil, polyoxyethylene 35 castor oil, vitamin E polyethylene glycol succinate 1000, polyoxyethylene 15 hydroxystearate and octylphenol polyoxyethylene ether 40. 根据权利要求5所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to claim 5, characterized in that 所述增溶剂选自聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油与聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物的混合物、聚乙二醇平均分子量为500-1500的维生素E聚乙二醇琥珀酸酯、聚氧乙烯单元数为30-50的聚氧乙烯硬脂酸酯和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种；The solubilizing agent is selected from the group consisting of a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, a mixture of polyoxyethylene castor oil having 30-40 polyoxyethylene units and a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, vitamin E polyethylene glycol succinate having an average molecular weight of 500-1500, polyoxyethylene stearate having 30-50 polyoxyethylene units, and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units. 优选地，所述增溶剂选自聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种；Preferably, the solubilizer is selected from one or more of a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; 更优选地，所述增溶剂为聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物或聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；More preferably, the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, or polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; 其中，in, 当所述增溶剂为聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物时，所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；When the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; 当所述增溶剂为聚氧乙烯单元数为30-60的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物时，所述辛基酚聚氧乙烯醚占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％；When the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; 当所述增溶剂为聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油与聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物的混合物时，所述聚乙二醇-聚乙酸乙烯酯-聚乙烯基己内酰胺接枝共聚物占所述混合物的重量百分比为0-50％，优选0-30％，更优选0-15％。When the solubilizer is a mixture of polyoxyethylene castor oil having 30-40 polyoxyethylene units and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, the weight percentage of the polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer in the mixture is 0-50%, preferably 0-30%, and more preferably 0-15%. 根据权利要求5所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to claim 5, characterized in that 所述增溶剂选自聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧 乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯、聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油和聚乙二醇平均分子量为500-1500的维生素E聚乙二醇琥珀酸酯中的一种或多种；The solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, One or more of a mixture of octylphenol polyoxyethylene ethers having 30-50 ethylene units, polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, polyoxyethylene castor oil having 30-40 polyoxyethylene units, and vitamin E polyethylene glycol succinate having a polyethylene glycol average molecular weight of 500-1500; 优选地，所述增溶剂选自聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种；Preferably, the solubilizer is selected from one or more of a mixture of polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; 更优选地，所述增溶剂为聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物或聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；More preferably, the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units or polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; 其中，in, 当所述增溶剂为聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物时，所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；When the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; 当所述增溶剂为聚氧乙烯单元数为35-55的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为30-50的辛基酚聚氧乙烯醚的混合物时，所述辛基酚聚氧乙烯醚占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％。When the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%. 根据权利要求5所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to claim 5, characterized in that 所述增溶剂选自聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为50-55的聚氧乙烯氢化蓖麻油、聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯、聚氧乙烯单元数为30-40的聚氧乙烯蓖麻油和聚乙二醇平均分子量为800-1200的维生素E聚乙二醇琥珀酸酯中的一种或多种；The solubilizing agent is selected from one or more of a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, polyoxyethylene hydrogenated castor oil having 50-55 polyoxyethylene units, polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, polyoxyethylene castor oil having 30-40 polyoxyethylene units, and vitamin E polyethylene glycol succinate having a polyethylene glycol average molecular weight of 800-1200; 优选地，所述增溶剂选自聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为50-55的聚氧乙烯氢化蓖麻油和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种；Preferably, the solubilizer is selected from one or more of a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, polyoxyethylene hydrogenated castor oil having 50-55 polyoxyethylene units, and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; 更优选地，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物、聚氧乙烯单元数为50-55的聚氧乙烯氢化蓖麻油或聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；More preferably, the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, polyoxyethylene hydrogenated castor oil having 50-55 polyoxyethylene units, or polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; 其中，in, 当所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物时，所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；When the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; 当所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物时，所述辛基酚聚氧乙烯醚占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％。When the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%. 根据权利要求5所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to claim 5, characterized in that 所述增溶剂选自聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物、聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物和聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯中的一种或多种；The solubilizing agent is selected from one or more of a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; 优选地，所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物或聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯；Preferably, the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units or polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; 其中， in, 当所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为10-20的聚氧乙烯羟基硬脂酸酯的混合物时，所述聚氧乙烯羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；When the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; 当所述增溶剂为聚氧乙烯单元数为35-45的聚氧乙烯氢化蓖麻油与聚氧乙烯单元数为35-45的辛基酚聚氧乙烯醚的混合物时，所述辛基酚聚氧乙烯醚占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％。When the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%. 根据权利要求5所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to claim 5, characterized in that 所述增溶剂选自聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物、聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物和聚氧乙烯15羟基硬脂酸酯中的一种或多种；The solubilizing agent is selected from one or more of a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and polyoxyethylene 15 hydroxystearate; 优选地，所述增溶剂为聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物或聚氧乙烯15羟基硬脂酸酯；Preferably, the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40 or polyoxyethylene 15 hydroxystearate; 其中，in, 当所述增溶剂为聚氧乙烯40氢化蓖麻油与聚氧乙烯15羟基硬脂酸酯的混合物时，所述聚氧乙烯15羟基硬脂酸酯占所述混合物的重量百分比为0-80％，优选0-50％，更优选0-30％，最优选0-10％；When the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, the weight percentage of the polyoxyethylene 15 hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; 当所述增溶剂为聚氧乙烯40氢化蓖麻油与辛基酚聚氧乙烯醚40的混合物时，所述辛基酚聚氧乙烯醚40占所述混合物的重量百分比为0-20％，优选0-18％，更优选0-15％，最优选0-5％。When the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, the weight percentage of octylphenol polyoxyethylene ether 40 in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%. 根据权利要求1至10中任一项所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to any one of claims 1 to 10, characterized in that 在所述组合物中，所述瑞普洛莎或其药学上可接受的盐与所述增溶剂的重量比为1:5-1:40，优选1:8-1:30，更优选1:10-1:20，最优选1:10-1:15。In the composition, the weight ratio of the reprozac or its pharmaceutically acceptable salt to the solubilizer is 1:5-1:40, preferably 1:8-1:30, more preferably 1:10-1:20, and most preferably 1:10-1:15. 根据权利要求1至11中任一项所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to any one of claims 1 to 11, characterized in that 以所述组合物的总重量计，所述增溶剂的含量为1％-16％，优选1％-15％，更优选1％-11％，最优选1％-9％。Based on the total weight of the composition, the content of the solubilizer is 1%-16%, preferably 1%-15%, more preferably 1%-11%, most preferably 1%-9%. 根据权利要求1至12中任一项所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to any one of claims 1 to 12, characterized in that 以所述组合物的总重量计，所述水的含量为83％-98％，优选84％-98％，更优选86％-98％，最优选88％-98％。Based on the total weight of the composition, the water content is 83%-98%, preferably 84%-98%, more preferably 86%-98%, most preferably 88%-98%. 根据权利要求1至13中任一项所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to any one of claims 1 to 13, characterized in that 所述稳定剂选自丙二醇、甘油、丁二醇和戊二醇中的一种或多种，优选丙二醇和甘油中的一种或多种，更优选丙二醇。The stabilizer is selected from one or more of propylene glycol, glycerol, butylene glycol and pentylene glycol, preferably one or more of propylene glycol and glycerol, more preferably propylene glycol. 根据权利要求14所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to claim 14, characterized in that 以所述组合物的总重量计，所述稳定剂的含量为0-5％，优选0-4％，更优选0-3％，最优选0.5％-3％。Based on the total weight of the composition, the content of the stabilizer is 0-5%, preferably 0-4%, more preferably 0-3%, most preferably 0.5%-3%. 根据权利要求1至15中任一项所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to any one of claims 1 to 15, characterized in that 以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.05％-0.5％、增溶剂1％-16％、稳定剂0-5％和水83％-98％；Based on the total weight of the composition, the weight percentages of the components are as follows: 0.05%-0.5% of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; 优选地，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.5％、增溶剂1％-16％、稳定剂0.5％-3％和水83％-98％； Preferably, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; 更优选地，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.45％、增溶剂1％-15％、稳定剂0.5％-3％和水84％-98％；More preferably, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-15% of a solubilizer, 0.5%-3% of a stabilizer, and 84%-98% of water; 进一步优选地，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.1％-0.3％、增溶剂1％-11％、稳定剂0.5％-3％和水86％-98％；Further preferably, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer, and 86%-98% of water; 最优选地，以所述组合物的总重量计，各组分的重量百分比如下：瑞普洛莎或其药学上可接受的盐0.15％-0.25％、增溶剂1％-9％、稳定剂0.5％-3％和水88％-98％。Most preferably, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reprosa or its pharmaceutically acceptable salt, 1%-9% of solubilizer, 0.5%-3% of stabilizer and 88%-98% of water. 根据权利要求1至16中任一项所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to any one of claims 1 to 16, characterized in that 所述组合物还包含一种或多种其他药学上可接受的辅料；The composition further comprises one or more other pharmaceutically acceptable excipients; 优选地，所述其他药学上可接受的辅料选自增黏剂、抗氧剂、pH调节剂、渗透压调节剂、润湿剂、粘膜粘附剂、促透剂、防腐剂、胶凝剂、抑菌剂和螯合剂中的一种或多种，优选增黏剂、抗氧剂、螯合剂、抑菌剂、pH调节剂和渗透压调节剂的一种或多种。Preferably, the other pharmaceutically acceptable excipients are selected from one or more of viscosity enhancers, antioxidants, pH adjusters, osmotic pressure regulators, wetting agents, mucoadhesive agents, penetration enhancers, preservatives, gelling agents, antibacterial agents and chelating agents, preferably one or more of viscosity enhancers, antioxidants, chelating agents, antibacterial agents, pH adjusters and osmotic pressure regulators. 根据权利要求17所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to claim 17, characterized in that 所述组合物还包含增黏剂；The composition further comprises a viscosity increasing agent; 优选地，所述增黏剂选自羧甲基纤维素或其钠盐、羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素、泊洛沙姆、卡波姆、黄原胶、玻璃酸或其钠盐、聚乙烯吡咯烷酮、聚卡波菲、树胶、卡拉胶、瓜尔胶、黄芪胶、琼脂糖、聚乙二醇、海藻酸或其钠盐和透明质酸或其钠盐中的一种或多种，优选黄原胶、玻璃酸钠、聚乙烯吡咯烷酮、羟丙基甲基纤维素、卡波姆、羧甲基纤维素钠、泊洛沙姆、海藻酸钠和透明质酸钠中的一种或几种，更优选黄原胶、玻璃酸钠、聚乙烯吡咯烷酮、羟丙基甲基纤维素、卡波姆和羧甲基纤维素钠中的一种或多种，最优选黄原胶、玻璃酸钠、羟丙基甲基纤维素和羧甲基纤维素钠中的一种或多种；Preferably, the viscosity increasing agent is selected from one or more of carboxymethyl cellulose or its sodium salt, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, poloxamer, carbomer, xanthan gum, hyaluronic acid or its sodium salt, polyvinyl pyrrolidone, polycarbophil, gum, carrageenan, guar gum, tragacanth gum, agarose, polyethylene glycol, alginic acid or its sodium salt and hyaluronic acid or its sodium salt, preferably one or more of xanthan gum, sodium hyaluronate, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, carbomer, sodium carboxymethyl cellulose, poloxamer, sodium alginate and sodium hyaluronate, more preferably one or more of xanthan gum, sodium hyaluronate, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, carbomer and sodium carboxymethyl cellulose, most preferably one or more of xanthan gum, sodium hyaluronate, hydroxypropyl methylcellulose and sodium carboxymethyl cellulose; 和/或，and/or, 优选地，以所述组合物的总重量计，所述增黏剂的含量为0-5％，优选0-3％，更优选0.1％-3％。Preferably, based on the total weight of the composition, the content of the viscosity enhancer is 0-5%, preferably 0-3%, more preferably 0.1%-3%. 根据权利要求17或18所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to claim 17 or 18, characterized in that 所述组合物还包含抗氧剂；The composition further comprises an antioxidant; 优选地，所述抗氧剂选自生育酚或其琥珀酸酯、抗坏血酸或其棕榈酸酯、丁基羟基茴香醚、2,6-二叔丁基对甲酚和硫代硫酸钠中的一种或多种，优选生育酚、丁基羟基茴香醚、2,6-二叔丁基对甲酚和硫代硫酸钠中的一种或多种，更优选生育酚和硫代硫酸钠中的一种或多种；Preferably, the antioxidant is selected from one or more of tocopherol or its succinate, ascorbic acid or its palmitate, butylated hydroxyanisole, 2,6-di-tert-butylated cresol and sodium thiosulfate, preferably one or more of tocopherol, butylated hydroxyanisole, 2,6-di-tert-butylated cresol and sodium thiosulfate, more preferably one or more of tocopherol and sodium thiosulfate; 和/或，and/or, 优选地，以所述组合物的总重量计，所述抗氧剂的含量为0-1％，优选0.05％-1％，更优选0.1％-1％。Preferably, based on the total weight of the composition, the content of the antioxidant is 0-1%, preferably 0.05%-1%, more preferably 0.1%-1%. 根据权利要求17至19中任一项所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to any one of claims 17 to 19, characterized in that 所述组合物还包含螯合剂；The composition further comprises a chelating agent; 优选地，所述螯合剂选自柠檬酸或其盐、葡萄糖醛酸或其盐、六偏磷酸盐、依地酸或其盐和膦酸盐中的一种或多种，优选依地酸或依地酸二钠；Preferably, the chelating agent is selected from one or more of citric acid or its salts, glucuronic acid or its salts, hexametaphosphate, edetic acid or its salts and phosphonates, preferably edetic acid or edetic acid disodium; 和/或，and/or, 优选地，以所述组合物的总重量计，所述螯合剂的含量为0-2％，优选0.01％-1％，更优选0.05％-0.5％，最优选0.1％-0.2％。Preferably, based on the total weight of the composition, the chelating agent is present in an amount of 0-2%, preferably 0.01%-1%, more preferably 0.05%-0.5%, most preferably 0.1%-0.2%. 根据权利要求17至20中任一项所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to any one of claims 17 to 20, characterized in that 所述组合物还包含pH调节剂； The composition further comprises a pH adjuster; 优选地，所述pH调节剂选自无机或有机的酸、碱和缓冲盐中的一种或多种，优选缓冲盐；其中，所述酸选自盐酸、磷酸、醋酸、柠檬酸、乳酸和硼酸中的一种或多种；所述碱选自乙二胺、乙醇胺、碱性氨基酸、氢氧化钠、氢氧化钙、氢氧化钾和氨水溶液中的一种或多种；所述缓冲盐选自硼酸-硼砂缓冲盐、柠檬酸-柠檬酸钠缓冲盐、磷酸-磷酸钠缓冲盐和醋酸-醋酸钠缓冲盐中的一种或多种，优选磷酸-磷酸钠缓冲盐和硼酸-硼砂缓冲盐中的一种或多种；Preferably, the pH regulator is selected from one or more of inorganic or organic acids, bases and buffer salts, preferably buffer salts; wherein the acid is selected from one or more of hydrochloric acid, phosphoric acid, acetic acid, citric acid, lactic acid and boric acid; the base is selected from one or more of ethylenediamine, ethanolamine, basic amino acids, sodium hydroxide, calcium hydroxide, potassium hydroxide and ammonia solution; the buffer salt is selected from one or more of boric acid-borax buffer salt, citric acid-sodium citrate buffer salt, phosphoric acid-sodium phosphate buffer salt and acetic acid-sodium acetate buffer salt, preferably one or more of phosphoric acid-sodium phosphate buffer salt and boric acid-borax buffer salt; 和/或，and/or, 优选地，所述组合物的pH值为5-9.5，优选6-9，更优选6-8.5，最优选6.5-8。Preferably, the pH value of the composition is 5-9.5, preferably 6-9, more preferably 6-8.5, most preferably 6.5-8. 根据权利要求17至21中任一项所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to any one of claims 17 to 21, characterized in that 所述组合物还包含渗透压调节剂；The composition further comprises an osmotic pressure regulator; 优选地，所述渗透压调节剂选自氯化钠、甘露醇、葡萄糖、山梨醇、聚乙二醇、甘油和丙二醇中的一种或多种，优选氯化钠、甘露醇、山梨醇和甘油中的一种或多种。Preferably, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, glucose, sorbitol, polyethylene glycol, glycerol and propylene glycol, preferably one or more of sodium chloride, mannitol, sorbitol and glycerol. 根据权利要求17至22中任一项所述的眼用溶液组合物，其特征在于，The ophthalmic solution composition according to any one of claims 17 to 22, characterized in that 所述组合物还包含抑菌剂；The composition further comprises a bacteriostatic agent; 优选地，所述抑菌剂选自苯甲醇、苯氧乙醇、山梨酸或其盐、对羟基苯甲酸酯、洗必泰、苯扎氯铵、苯扎溴铵、三氯叔丁醇、苯甲酸或其盐、柠檬酸或其盐和抗坏血酸或其盐中的一种或多种，优选对羟基苯甲酸丁酯、苯扎氯铵、苯扎溴铵、洗必泰、山梨酸和三氯叔丁醇中的一种或多种；Preferably, the antibacterial agent is selected from one or more of benzyl alcohol, phenoxyethanol, sorbic acid or its salt, paraben, chlorhexidine, benzalkonium chloride, benzalkonium bromide, chlorobutanol, benzoic acid or its salt, citric acid or its salt and ascorbic acid or its salt, preferably one or more of butyl paraben, benzalkonium chloride, benzalkonium bromide, chlorhexidine, sorbic acid and chlorobutanol; 和/或，and/or, 优选地，以所述组合物的总重量计，所述抑菌剂的含量为0-5％，优选0-1％，更优选0.1％-0.5％，最优选0.2％-0.3％。Preferably, based on the total weight of the composition, the content of the bacteriostatic agent is 0-5%, preferably 0-1%, more preferably 0.1%-0.5%, most preferably 0.2%-0.3%. 根据权利要求1至23中任一项所述的眼用溶液组合物在制备用于预防和/或治疗与包括促炎性活性醛类物质在内的毒性醛有关的眼部疾病或病症的药物中的用途；Use of the ophthalmic solution composition according to any one of claims 1 to 23 in the preparation of a medicament for preventing and/or treating ocular diseases or conditions associated with toxic aldehydes including pro-inflammatory active aldehydes; 优选地，所述眼部疾病或病症选自角膜疾病、与过量毒性醛有关的眼部疾病、眼部红斑痤疮和其他眼部疾病中的一种或多种；Preferably, the eye disease or condition is selected from one or more of corneal diseases, eye diseases associated with excessive toxic aldehydes, ocular rosacea and other eye diseases; 更优选地，所述角膜疾病选自干眼综合征、白内障、圆锥形角膜、大疱性和其它类型角膜病变和富克氏角膜内皮营养不良中的一种或多种；More preferably, the corneal disease is selected from one or more of dry eye syndrome, cataract, keratoconus, bullous and other types of corneal lesions and Fuchs' corneal endothelial dystrophy; 更优选地，所述与过量毒性醛有关的眼部疾病选自葡萄膜炎、巩膜炎和眼部史-约综合征中的一种或多种；More preferably, the eye disease associated with excessive toxic aldehydes is selected from one or more of uveitis, scleritis and ocular Johns-Johnson syndrome; 更优选地，所述其他眼部疾病选自过敏性结膜炎、眼部瘢痕性类天疱疮、与屈光性角膜切除术愈合或其它角膜愈合相关的疾病和与泪脂质降解或泪腺功能障碍相关的疾病中的一种或多种；More preferably, the other ocular diseases are selected from one or more of allergic conjunctivitis, ocular cicatricial pemphigoid, diseases related to photorefractive keratectomy healing or other corneal healing, and diseases related to tear lipid degradation or tear gland dysfunction; 进一步优选地，所述眼部疾病或病症选自干眼综合征、过敏性结膜炎和葡萄膜炎中的一种或多种；Further preferably, the eye disease or condition is selected from one or more of dry eye syndrome, allergic conjunctivitis and uveitis; 更进一步优选地，所述眼部疾病或病症为干眼综合征。Still more preferably, the eye disease or disorder is dry eye syndrome. 根据权利要求1至23中任一项所述的眼用溶液组合物，其用于预防和/或治疗与包括促炎性活性醛类物质在内的毒性醛有关的眼部疾病或病症；An ophthalmic solution composition according to any one of claims 1 to 23, for use in preventing and/or treating ocular diseases or conditions associated with toxic aldehydes including pro-inflammatory active aldehydes; 优选地，所述眼部疾病或病症选自角膜疾病、与过量毒性醛有关的眼部疾病、眼部红斑痤疮和其他眼部疾病中的一种或多种；Preferably, the eye disease or condition is selected from one or more of corneal diseases, eye diseases associated with excessive toxic aldehydes, ocular rosacea and other eye diseases; 更优选地，所述角膜疾病选自干眼综合征、白内障、圆锥形角膜、大疱性和其它类型角膜病变和富克氏角膜内皮营养不良中的一种或多种； More preferably, the corneal disease is selected from one or more of dry eye syndrome, cataract, keratoconus, bullous and other types of corneal lesions and Fuchs' corneal endothelial dystrophy; 更优选地，所述与过量毒性醛有关的眼部疾病选自葡萄膜炎、巩膜炎和眼部史-约综合征中的一种或多种；More preferably, the eye disease associated with excessive toxic aldehydes is selected from one or more of uveitis, scleritis and ocular Johns-Johnson syndrome; 更优选地，所述其他眼部疾病选自过敏性结膜炎、眼部瘢痕性类天疱疮、与屈光性角膜切除术愈合或其它角膜愈合相关的疾病和与泪脂质降解或泪腺功能障碍相关的疾病中的一种或多种；More preferably, the other ocular diseases are selected from one or more of allergic conjunctivitis, ocular cicatricial pemphigoid, diseases related to photorefractive keratectomy healing or other corneal healing, and diseases related to tear lipid degradation or tear gland dysfunction; 进一步优选地，所述眼部疾病或病症选自干眼综合征、过敏性结膜炎和葡萄膜炎中的一种或多种；Further preferably, the eye disease or condition is selected from one or more of dry eye syndrome, allergic conjunctivitis and uveitis; 更进一步优选地，所述眼部疾病或病症为干眼综合征。Still more preferably, the eye disease or disorder is dry eye syndrome. 一种用于预防和/或治疗与包括促炎性活性醛类物质在内的毒性醛有关的眼部疾病或病症的方法，其包括下列步骤：将预防和/或治疗有效量的根据权利要求1至23中任一项所述的眼用溶液组合物施用于对其有需要的个体；A method for preventing and/or treating ocular diseases or conditions associated with toxic aldehydes including pro-inflammatory reactive aldehydes, comprising the steps of: administering a preventively and/or therapeutically effective amount of an ophthalmic solution composition according to any one of claims 1 to 23 to an individual in need thereof; 优选地，所述眼部疾病或病症选自角膜疾病、与过量毒性醛有关的眼部疾病、眼部红斑痤疮和其他眼部疾病中的一种或多种；Preferably, the eye disease or condition is selected from one or more of corneal diseases, eye diseases associated with excessive toxic aldehydes, ocular rosacea and other eye diseases; 更优选地，所述角膜疾病选自干眼综合征、白内障、圆锥形角膜、大疱性和其它类型角膜病变和富克氏角膜内皮营养不良中的一种或多种；More preferably, the corneal disease is selected from one or more of dry eye syndrome, cataract, keratoconus, bullous and other types of corneal lesions and Fuchs' corneal endothelial dystrophy; 更优选地，所述与过量毒性醛有关的眼部疾病选自葡萄膜炎、巩膜炎和眼部史-约综合征中的一种或多种；More preferably, the eye disease associated with excessive toxic aldehydes is selected from one or more of uveitis, scleritis and ocular Johns-Johnson syndrome; 更优选地，所述其他眼部疾病选自过敏性结膜炎、眼部瘢痕性类天疱疮、与屈光性角膜切除术愈合或其它角膜愈合相关的疾病和与泪脂质降解或泪腺功能障碍相关的疾病中的一种或多种；More preferably, the other ocular diseases are selected from one or more of allergic conjunctivitis, ocular cicatricial pemphigoid, diseases related to photorefractive keratectomy healing or other corneal healing, and diseases related to tear lipid degradation or tear gland dysfunction; 进一步优选地，所述眼部疾病或病症选自干眼综合征、过敏性结膜炎和葡萄膜炎中的一种或多种；Further preferably, the eye disease or condition is selected from one or more of dry eye syndrome, allergic conjunctivitis and uveitis; 更进一步优选地，所述眼部疾病或病症为干眼综合征。 Still more preferably, the eye disease or disorder is dry eye syndrome.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200038392A1 (en) * 2018-08-03 2020-02-06 Aldeyra Therapeutics, Inc. Topical compositions and methods of preparation and use
CN113056353A (en) * 2018-09-25 2021-06-29 奥尔德拉医疗公司 Formulation for treating dry eye
WO2021248031A1 (en) * 2020-06-04 2021-12-09 Aldeyra Therapeutics, Inc. Dry eye disease biomarkers and their use for treatment
CN115697336A (en) * 2020-05-13 2023-02-03 奥尔德拉医疗公司 Pharmaceutical preparation and use thereof

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Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200038392A1 (en) * 2018-08-03 2020-02-06 Aldeyra Therapeutics, Inc. Topical compositions and methods of preparation and use
CN113056353A (en) * 2018-09-25 2021-06-29 奥尔德拉医疗公司 Formulation for treating dry eye
CN115697336A (en) * 2020-05-13 2023-02-03 奥尔德拉医疗公司 Pharmaceutical preparation and use thereof
WO2021248031A1 (en) * 2020-06-04 2021-12-09 Aldeyra Therapeutics, Inc. Dry eye disease biomarkers and their use for treatment

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