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WO2024199095A1 - Composition de nanomicelle de reproxalap, son procédé de préparation et son utilisation - Google Patents

Composition de nanomicelle de reproxalap, son procédé de préparation et son utilisation 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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English (en)
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/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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

La présente invention concerne le domaine technique des médicaments, et concerne une composition de nanomicelle de reproxalap, son procédé de préparation et son utilisation. Spécifiquement, la composition de nanomicelle de reproxalap selon la présente invention comprend du reproxalap ou un sel pharmaceutiquement acceptable de celui-ci, un solubilisant, de l'eau et un stabilisant facultatif, et comprend en outre éventuellement d'autres adjuvants pharmaceutiquement acceptables, tels qu'un tackifiant. La composition de nanomicelle de reproxalap selon la présente invention présente un taux d'encapsulation élevé, ne provoque aucune irritation des yeux, et a un excellent effet de libération prolongée dans des tests pharmacodynamiques in vitro et in vivo.
PCT/CN2024/083150 2023-03-24 2024-03-22 Composition de nanomicelle de reproxalap, son procédé de préparation et son utilisation Pending WO2024199095A1 (fr)

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CN113056353A (zh) * 2018-09-25 2021-06-29 奥尔德拉医疗公司 用于治疗干眼病的调配物
WO2021248031A1 (fr) * 2020-06-04 2021-12-09 Aldeyra Therapeutics, Inc. Biomarqueurs de la sécheresse oculaire et leur utilisation pour le traitement
CN115697336A (zh) * 2020-05-13 2023-02-03 奥尔德拉医疗公司 药物制剂及其用途

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US20200038392A1 (en) * 2018-08-03 2020-02-06 Aldeyra Therapeutics, Inc. Topical compositions and methods of preparation and use
CN113056353A (zh) * 2018-09-25 2021-06-29 奥尔德拉医疗公司 用于治疗干眼病的调配物
CN115697336A (zh) * 2020-05-13 2023-02-03 奥尔德拉医疗公司 药物制剂及其用途
WO2021248031A1 (fr) * 2020-06-04 2021-12-09 Aldeyra Therapeutics, Inc. Biomarqueurs de la sécheresse oculaire et leur utilisation pour le traitement

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