A Reprosa nano-micelle composition and its preparation method and use

Abstract

The present invention belongs to the field of pharmaceutical technology and relates to a reproza nano-micelle composition, its preparation method, and use. Specifically, the reproza nano-micelle composition of the present invention comprises reproza or a pharmaceutically acceptable salt thereof, a solubilizer, water, and an optional stabilizer, and optionally further comprises other pharmaceutically acceptable excipients, such as a viscosity-increasing agent. The reproza nano-micelle composition of the present invention has a high encapsulation efficiency, is non-irritating to the eyes, and exhibits excellent sustained-release effects in both in vitro and in vivo pharmacodynamic tests.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and particularly relates to a novel nano-micelle composition for Reprosa, as well as a preparation method and use of the nano-micelle composition. Background Art

[0002] Dry eye, also known as keratoconjunctivitis sicca, is a condition characterized by abnormal tear quality, quantity, or dynamics caused by any reason. Disturbances in tear film homeostasis are its main characteristic, which can lead to eye discomfort and visual impairment. Its pathological mechanisms are mainly increased tear osmolarity, tear film instability, ocular surface damage, neurosensory abnormalities, and ocular surface inflammation. Clinical symptoms of dry eye include blurred vision, dryness, and photophobia. Severe cases may develop keratoconjunctival lesions, filamentous adhesions, corneal ulcers, and even blindness, seriously endangering the patient's eye health and affecting daily life and work (Chong Junci, Research Progress on the Pathogenesis and Surgical Treatment of Dry Eye [J], Chinese and Foreign Medical Research, 2022, 20(33):181-184). Currently, the treatments for dry eye can be mainly divided into general treatments (such as eliminating the cause, nutritional support, and disease monitoring) and drug treatments (such as applying artificial tears or autologous serum, promoting tear secretion, reducing ocular surface inflammation, and treating blepharitis).

[0003] 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 ocular diseases by binding to and capturing pro-inflammatory reactive aldehyde species (RASP) in the eye. Developed by Aldeyra Therapeutics, Reproxalap achieved its primary endpoint in a Phase III clinical trial for dry eye disease. A New Drug Application (NDA) has been submitted to and accepted by the FDA.

[0004]

[0005] CN113056353A discloses a reproza eye drop for treating dry eye disease. The reproza molecule is encapsulated and delivered using a cyclodextrin (such as sulfobutyl ether-β-cyclodextrin or hydroxypropyl-β-cyclodextrin). Phase 2b clinical trial results showed that 12 weeks of application of the eye drop resulted in statistically significant improvements in multiple signs and symptoms. However, the eye drop requires topical application four times daily to the patient's eye (especially in the initial or exacerbated stages of the disease), leading to poor patient compliance.

[0006] Therefore, there is an urgent need in the art to develop a long-acting reproza ophthalmic composition with sustained-release or controlled-release effects, which can enhance the drug's penetration in the eye, prolong the drug's retention time, and thereby promote drug absorption, increase bioavailability, reduce the number of dosing times, improve patient compliance, and enhance drug efficacy. Summary of the Invention

[0007] Problems to be solved by the invention

[0008] The technical problem to be solved by the present invention is to overcome the shortcomings of the existing reproza ophthalmic composition, such as low ocular surface permeability, short residence time, low bioavailability, high daily dosing frequency, short duration of efficacy, and poor patient compliance. To this end, the present invention provides a reproza nano-micelle composition, a preparation method, and use thereof.

[0009] Solutions for solving problems

[0010] In a first aspect, the present invention provides an ophthalmic solution composition comprising reprozac or a pharmaceutically acceptable salt thereof, a solubilizer, water, and optionally a stabilizer.

[0011] In one embodiment, the ophthalmic solution composition is an ophthalmic micellar solution composition.

[0012] In a specific embodiment, the ophthalmic solution composition is an ophthalmic nanomicelle solution composition.

[0013] In a more specific embodiment, the average particle size of the nanomicelles in the ophthalmic solution composition is 5-100 nm, preferably 5-80 nm, more preferably 10-65 nm, further preferably 10-30 nm, and most preferably 10-15 nm.

[0014] In one embodiment, the reprozac or a pharmaceutically acceptable salt thereof is reprozac or an acid addition salt of reprozac.

[0015] In a specific embodiment, the acid addition salt is selected from one or more of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, glucarate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate.

[0016] In one embodiment, based on the total weight of the composition, the content of reprozac 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%, and most preferably 0.25%-0.3%.

[0017] In one embodiment, based on the total weight of the composition, the content of Reprosa is 0.05%-0.5%, preferably 0.1%-0.5%, more preferably 0.1%-0.45%, further preferably 0.1-0.3%, and most preferably 0.15%-0.25%.

[0018] In one embodiment, the solubilizing agent is a surfactant.

[0019] In one embodiment, the solubilizing agent comprises a nonionic surfactant; preferably, the solubilizing agent is a nonionic surfactant.

[0020] In one embodiment, the nonionic surfactant is a polyethylene glycol type nonionic surfactant.

[0021] In a specific embodiment, the polyethylene glycol type nonionic surfactant is selected from one or more of polyoxyethylene castor oil derivatives, polyoxyethylene fatty acid esters and polyoxyethylene alkylphenol ethers.

[0022] In a more specific embodiment, the polyethylene glycol type nonionic surfactant comprises a polyoxyethylene castor oil derivative, wherein the polyoxyethylene castor oil derivative is selected from one or more of polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil, preferably one or more of polyoxyethylene castor oil having 30-40 polyoxyethylene units and polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units, more preferably one or more of polyoxyethylene castor oil having 30-40 polyoxyethylene units and polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units. The present invention can be selected from one or more of polyoxyethylene castor oils, further preferably one or more of polyoxyethylene castor oil having 30-40 polyoxyethylene units, polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units, and polyoxyethylene hydrogenated castor oil having 50-55 polyoxyethylene units, still further preferably one or more of polyoxyethylene castor oil having 30-40 polyoxyethylene units and polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units, most preferably polyoxyethylene 35 hydrogenated castor oil or polyoxyethylene 40 hydrogenated castor oil.

[0023] In a more specific embodiment, the polyethylene glycol type nonionic surfactant includes polyoxyethylene fatty acid ester, and the polyoxyethylene fatty acid ester is selected from one or more of polyoxyethylene stearate, polyoxyethylene hydroxystearate and vitamin E polyethylene glycol succinate.

[0024] In a further specific embodiment, the polyoxyethylene stearate is selected from one or more polyoxyethylene stearates having 10-50 polyoxyethylene units, preferably one or more polyoxyethylene stearates having 30-50 polyoxyethylene units, more preferably one or more polyoxyethylene stearates having 35-45 polyoxyethylene units, and most preferably polyoxyethylene 40 stearate.

[0025] In a further specific embodiment, the polyoxyethylene hydroxystearate is selected from one or more polyoxyethylene hydroxystearates having 10-20 polyoxyethylene units, preferably polyoxyethylene 15 hydroxystearate.

[0026] In a further specific embodiment, the vitamin E polyethylene glycol succinate is selected from one or more vitamin E polyethylene glycol succinates with an average polyethylene glycol molecular weight of 200-4000, preferably one or more vitamin E polyethylene glycol succinates with an average polyethylene glycol molecular weight of 500-1500, more preferably one or more vitamin E polyethylene glycol succinates with an average polyethylene glycol molecular weight of 800-1200, and most preferably vitamin E polyethylene glycol succinate 1000.

[0027] In a more specific embodiment, the polyethylene glycol type nonionic surfactant includes polyoxyethylene alkylphenol ether, and the polyoxyethylene alkylphenol ether is selected from one or more of nonylphenol polyoxyethylene ether with 4-10 polyoxyethylene units, octylphenol polyoxyethylene ether with 13-50 polyoxyethylene units, dodecylphenol polyoxyethylene ether and dinonylphenol polyoxyethylene ether, preferably octylphenol polyoxyethylene ether with 30-50 polyoxyethylene units, more preferably octylphenol polyoxyethylene ether with 35-45 polyoxyethylene units, and most preferably octylphenol polyoxyethylene ether 40.

[0028] In one embodiment, the solubilizing agent comprises a polymeric surfactant; preferably, the solubilizing agent is a polymeric surfactant, preferably a biodegradable polymeric surfactant.

[0029] In one embodiment, the polymer surfactant is a polymer surfactant having polyethylene glycol as a hydrophilic group.

[0030] In a specific embodiment, the polymer surfactant with polyethylene glycol as the hydrophilic group is a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer.

[0031] In a more specific embodiment, the polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer is selected from one or more polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers obtained by copolymerizing 5%-20% polyethylene glycol 6000, 20%-40% vinyl acetate and 50%-70% vinyl caprolactam and having an average relative molecular weight of 50,000-200,000 g / mol, preferably one or more polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers obtained by copolymerizing 10%-15% polyethylene glycol 6000, 25%-35% vinyl acetate and 55%-60% vinyl caprolactam and having an average relative molecular weight of 90,000-140,000 g / mol, or preferably a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer with a trade name Polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer.

[0032] In one embodiment, the solubilizer 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 solubilizer 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.

[0033] In a specific embodiment, the solubilizer is selected from one or more of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 30-60, polyoxyethylene castor oil with a polyoxyethylene unit number of 30-40, vitamin E polyethylene glycol succinate with a polyethylene glycol molecular weight of 500-1500, polyoxyethylene stearate with a polyoxyethylene unit number of 30-50, polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 30-50, and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer; preferably, the solubilizer is selected from polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-55, polyoxyethylene castor oil with a polyoxyethylene unit number of 30-40, vitamin E polyethylene glycol succinate with a polyethylene glycol molecular weight of 500-1500, polyoxyethylene One or more of polyoxyethylene hydroxystearate with a unit number of 10-20 and octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 30-50; more preferably, the solubilizer is selected from polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-55, polyoxyethylene castor oil with a polyoxyethylene unit number of 30-40, vitamin E polyethylene glycol succinate with a polyethylene glycol molecular weight of 800-1200, polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20 and octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 35-45; further preferably, the solubilizer is selected from one or more of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 54 hydrogenated castor oil, polyoxyethylene 35 castor oil, vitamin E polyethylene glycol succinate 1000, polyoxyethylene 15 hydroxystearate and octylphenol polyoxyethylene ether 40.

[0034] In a more specific embodiment, the solubilizer comprises polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units, preferably polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units, a mixture thereof with polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, or a mixture thereof with octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units.

[0035] In a more specific embodiment, the solubilizer comprises polyoxyethylene castor oil having 30-40 polyoxyethylene units, preferably polyoxyethylene castor oil having 30-40 polyoxyethylene units or a mixture thereof with a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer.

[0036] In a more specific embodiment, the solubilizing agent comprises vitamin E polyethylene glycol succinate with a polyethylene glycol molecular weight of 500-1500, preferably vitamin E polyethylene glycol succinate with a polyethylene glycol molecular weight of 500-1500.

[0037] In a more specific embodiment, the solubilizer comprises polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, preferably polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units or a mixture thereof with polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units.

[0038] In a more specific embodiment, the solubilizer comprises polyoxyethylene stearate having 30-50 polyoxyethylene units, preferably polyoxyethylene stearate having 30-50 polyoxyethylene units.

[0039] In a specific embodiment, the solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, a mixture of polyoxyethylene castor oil having 30-40 polyoxyethylene units and polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, a polyethylene glycol having an average molecular weight of 500-1500, Vitamin E polyethylene glycol succinate, polyoxyethylene stearate with 30-50 polyoxyethylene units, and one or more polyoxyethylene hydroxystearate with 10-20 polyoxyethylene units, preferably a mixture of polyoxyethylene hydrogenated castor oil with 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether with 30-50 polyoxyethylene units, and one or more polyoxyethylene hydroxystearate with 10-20 polyoxyethylene units, more preferably a mixture of polyoxyethylene hydrogenated castor oil with 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether with 30-50 polyoxyethylene units. A mixture of polyoxyethylene ethers or polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20; wherein, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 30-60 and polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 30-60 and polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 3 When the solubilizer is a mixture of polyoxyethylene castor oil having 30-40 polyoxyethylene units and a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, the weight percentage of the polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer in the mixture is 0-50%, preferably 0-30%, more preferably 0-15%.

[0040] In a specific embodiment, the solubilizer is selected from one or more of a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40 and vitamin E polyethylene glycol succinate having a polyethylene glycol average molecular weight of 500-1500, preferably one or more of a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, more preferably wherein, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, or polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20; wherein, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%.

[0041] In a specific embodiment, the solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, polyoxyethylene hydrogenated castor oil having 50-55 polyoxyethylene units, polyoxyethylene hydroxystearic acid having 10-20 polyoxyethylene units, One or more of esters, polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40 and vitamin E polyethylene glycol succinate having a polyethylene glycol average molecular weight of 800-1200, preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 35-45, polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 50-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20 or More preferably, a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, polyoxyethylene hydrogenated castor oil having 50-55 polyoxyethylene units or polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; wherein, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, The weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%. When the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%.

[0042] In a specific embodiment, the solubilizer is selected from one or more of a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, preferably a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, or polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; Among them, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate with 10-20 polyoxyethylene units, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether with 35-45 polyoxyethylene units, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%.

[0043] In a specific embodiment, the solubilizer is selected from one or more of a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and polyoxyethylene 15 hydroxystearate, preferably a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40 or polyoxyethylene 15 hydroxystearate; wherein, when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, the weight percentage of polyoxyethylene 15 hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, the weight percentage of octylphenol polyoxyethylene ether 40 in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%.

[0044] In one embodiment, in the composition, the weight ratio of 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.

[0045] In one embodiment, the solubilizer is present in an amount of 1% to 16%, preferably 1% to 15%, more preferably 1% to 11%, and most preferably 1% to 9%, based on the total weight of the composition.

[0046] In one embodiment, the solubilizer is present in an amount of 1% to 16%, preferably 2% to 12%, more preferably 2.5% to 10%, and most preferably 3.75% to 7.5%, based on the total weight of the composition.

[0047] In one embodiment, the water content is 83%-98%, preferably 84%-98%, more preferably 86%-98%, most preferably 88%-98%, based on the total weight of the composition.

[0048] In one embodiment, the water content is 83%-98%, preferably 87%-97%, more preferably 89%-97%, most preferably 91%-95%, based on the total weight of the composition.

[0049] In one embodiment, the composition does not comprise a stabilizer; that is, the composition comprises reprozac or a pharmaceutically acceptable salt thereof, a solubilizer, and water, but does not comprise a stabilizer.

[0050] In one embodiment, the composition comprises a stabilizer; that is, the composition comprises reprozac or a pharmaceutically acceptable salt thereof, a solubilizer, water, and a stabilizer.

[0051] In a specific embodiment, the stabilizer is a chain polyol containing 2 to 6 carbon atoms and at least 2 hydroxyl groups.

[0052] In a more specific embodiment, the stabilizer is selected from one or more of propylene glycol, glycerol, butylene glycol and pentylene glycol, preferably one or more of propylene glycol and glycerol, more preferably propylene glycol.

[0053] In one embodiment, based on the total weight of the composition, the content of the stabilizer is 0-5%, preferably 0-4%, more preferably 0-3%, further preferably 0.5%-3%, most preferably 1%-3%.

[0054] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of reproxamar or a pharmaceutically acceptable salt thereof, 1%-16% of solubilizer, 0-5% of stabilizer and 83%-98% of water.

[0055] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: reprozac or a pharmaceutically acceptable salt thereof 0.2%-0.45%, solubilizer 2%-12%, stabilizer 0-4% and water 87%-97%.

[0056] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of reproxaparin or a pharmaceutically acceptable salt thereof, 2%-12% of solubilizer, 0.5%-4% of stabilizer and 87%-97% of water.

[0057] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of reproxaparin or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer, and 89%-97% of water.

[0058] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of reproxadin or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of solubilizer, 1%-3% of stabilizer and 91%-95% of water.

[0059] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of reprozac or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water.

[0060] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of reprozac or a pharmaceutically acceptable salt thereof, 1%-15% of solubilizer, 0.5%-3% of stabilizer and 84%-98% of water.

[0061] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of reprozac or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer, and 86%-98% of water.

[0062] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of reprozac or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of a stabilizer, and 88%-98% of water.

[0063] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of reproxadin 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 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.

[0064] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of reprozac 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 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.

[0065] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of reproxadin 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 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 polyethylene glycol 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.

[0066] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from a mixture of polyoxyethylene 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 a ... The present invention relates to a mixture of octylphenol polyoxyethylene ethers having a polyoxyethylene unit number of 30-50, polyoxyethylene stearate having a polyoxyethylene unit number of 30-50, polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, and one or more of vitamin E polyethylene glycol succinate having a polyethylene glycol average molecular weight of 500-1500, preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 30-60 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 30-60 and octylphenol polyoxyethylene ethers 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 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, or polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units; wherein, when the solubilizer is a mixture of polyoxyethylene castor oil having 30-40 polyoxyethylene units and a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, the polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer accounts for 0-50% by weight of the mixture, preferably 0-30%, and more preferably When the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

[0067] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reproza 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 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. A mixture of polyoxyethylene octylphenol polyoxyethylene ethers, polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40, and vitamin E polyethylene glycol succinate having a polyethylene glycol average molecular weight of 500-1500, preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, and One or more polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, more preferably a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 30-50, or polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20; wherein, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-55 and polyoxyethylene unit When the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 30-50, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

[0068] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or its pharmaceutically acceptable salt, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having 35-45 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 mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units. One or more of polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40, polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 50-55, 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 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 50-5 5 polyoxyethylene hydrogenated castor oil and polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, more preferably a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-45 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 solubilizer is a polyoxyethylene unit with a polyoxyethylene unit number of 35-45, the solubilizer is preferably a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 35-45. When the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit of 35-45 and polyoxyethylene octylphenol ether with a polyoxyethylene unit of 35-45, the weight percentage of the polyoxyethylene octylphenol ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

[0069] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is 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 polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units. The invention relates to a mixture of polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether with 35-45 polyoxyethylene units, or polyoxyethylene hydroxystearate with 10-20 polyoxyethylene units; wherein, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units and polyoxyethylene octylphenol polyoxyethylene ether with 35-45 polyoxyethylene units, the weight percentage of polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether with 35-45 polyoxyethylene units, the weight percentage of octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; and the stabilizer is propylene glycol.

[0070] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of reprozac 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 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%; and the stabilizer is propylene glycol.

[0071] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of reprozac 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%; and the stabilizer is propylene glycol.

[0072] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of reprozac 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%; and the stabilizer is propylene glycol.

[0073] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of reprozac 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%; and the stabilizer is propylene glycol.

[0074] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of reproxadin 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 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.

[0075] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of reprozac 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%; and the stabilizer is propylene glycol.

[0076] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of reprozac 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.

[0077] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of reprozac 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.

[0078] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.

[0079] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reproza or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-4% of a stabilizer, and 87%-97% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.

[0080] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reprosa or a pharmaceutically acceptable salt thereof, 2.5%-10% of a solubilizer, 0-3% of a stabilizer, and 89%-97% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.

[0081] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of Reproza 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.

[0082] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.

[0083] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reproza 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.

[0084] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reproza 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.

[0085] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of Reproza 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.

[0086] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of reproxadin 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 hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

[0087] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of reprozac 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 hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

[0088] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of reproxadin 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 hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

[0089] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of reprozac 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 hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

[0090] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of reproxadin 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 hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

[0091] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reproza 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 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 solubilizer is polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 When the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, the weight percentage of the octylphenol polyoxyethylene ether 40 in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

[0092] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from 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 5 4 hydrogenated castor oil; wherein, when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, the weight percentage of the polyoxyethylene 15 hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, the weight percentage of the octylphenol polyoxyethylene ether 40 in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

[0093] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and polyoxyethylene 15 hydroxystearate; wherein, when the When the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, the weight percentage of the polyoxyethylene 15 hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, the weight percentage of the octylphenol polyoxyethylene ether 40 in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

[0094] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable one thereof, 1%-16% of a solubilizer, 0-5% 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.

[0095] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of reprozac 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.

[0096] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of reprozac 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.

[0097] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of reprozac 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%; and the stabilizer is propylene glycol.

[0098] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of reprozac 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%; and the stabilizer is propylene glycol.

[0099] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is a 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.

[0100] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of reprozac 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 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.

[0101] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of reprozac 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.

[0102] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of reprozac 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.

[0103] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.

[0104] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reproza 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.

[0105] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reproza 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.

[0106] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of Reproza 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.

[0107] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.5% (or 0.05%-0.5%) of Reproza 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 15-hydroxystearate; and the stabilizer is propylene glycol.

[0108] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of Reproza 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.

[0109] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of reprozac 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.

[0110] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of Reproza 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.

[0111] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of reprozac 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.

[0112] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of reprozac 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.

[0113] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of reprozac 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 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.

[0114] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of reprozac 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 hydrogenated castor oil having 30-60 polyoxyethylene units, polyoxyethylene castor oil having 30-40 polyoxyethylene units, polyethylene glycol vitamin E polyethylene glycol 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.

[0115] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reproza 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 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 octyldodecyl hydroxystearate having 30-50 polyoxyethylene units, A mixture of phenol polyoxyethylene ethers, polyoxyethylene stearate having a polyoxyethylene unit number of 30-50, polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, and one or more of polyethylene glycol succinate having a polyethylene glycol average molecular weight of 500-1500, preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 30-60 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 30-60 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, more preferably wherein the solubilizing agent is a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 30-60 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 30-60 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, or polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20; wherein, when the solubilizing agent is a mixture of polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40 and a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer, the polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer accounts for 0-50% by weight of the mixture, preferably 0-30%, and more preferably 0- 15%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 30-60 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

[0116] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reproza 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 35-55 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units and octylphenol polyoxyethylene ether having 30-50 polyoxyethylene units, The present invention relates to a polyoxyethylene compound, a polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a polyoxyethylene castor oil having a polyoxyethylene unit number of 30-40, and a vitamin E polyethylene glycol succinate having a polyethylene glycol average molecular weight of 500-1500, preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 30-50, and 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. One or more polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, more preferably a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-55 and polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-55 and octylphenol polyoxyethylene ether with a polyoxyethylene unit number of 30-50, or polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20; wherein, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with a polyoxyethylene unit number of 35-55 and polyoxyethylene unit number of 1 When the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-55 polyoxyethylene units and octylphenol polyoxyethylene ether with 30-50 polyoxyethylene units, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%. When the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-55 polyoxyethylene units and octylphenol polyoxyethylene ether with 30-50 polyoxyethylene units, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%. The stabilizer is propylene glycol.

[0117] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, and a polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units. One or more of oxyethylene hydroxystearate, polyoxyethylene castor oil having 30-40 polyoxyethylene units, polyoxyethylene hydrogenated castor oil having 50-55 polyoxyethylene units, and vitamin E polyethylene glycol succinate having an average molecular weight of 800-1200, preferably a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, polyoxyethylene succinate having 50-55 polyoxyethylene units, One or more of hydrogenated castor oil and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, more preferably a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20, a mixture of polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45 and octylphenol polyoxyethylene ether having a polyoxyethylene unit number of 35-45, polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 50-55 or polyoxyethylene hydroxystearate having a polyoxyethylene unit number of 10-20; wherein, when the solubilizer is polyoxyethylene hydrogenated castor oil having a polyoxyethylene unit number of 35-45, When the solubilizer is a mixture of oxyethylene hydrogenated castor oil and polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

[0118] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of a mixture of polyoxyethylene hydrogenated castor oil having 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 polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and polyoxyethylene hydroxystearate having 35-45 polyoxyethylene units. A mixture of polyoxyethylene hydrogenated castor oil and octylphenol polyoxyethylene ether with 35-45 polyoxyethylene units or polyoxyethylene hydroxystearate with 10-20 polyoxyethylene units; wherein, when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate with 10-20 polyoxyethylene units, the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether with 35-45 polyoxyethylene units, the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; and the stabilizer is propylene glycol.

[0119] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of reprozac 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%; and the stabilizer is propylene glycol.

[0120] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of reprozac 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%; and the stabilizer is propylene glycol.

[0121] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of reprozac 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%; and the stabilizer is propylene glycol.

[0122] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of reprozac 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%; and the stabilizer is propylene glycol.

[0123] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of reprozac 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%; and the stabilizer is propylene glycol.

[0124] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of reprozac 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%; and the stabilizer is propylene glycol.

[0125] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of reprozac 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%; and the stabilizer is propylene glycol.

[0126] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of reprozac 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%; and the stabilizer is propylene glycol.

[0127] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.

[0128] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reproza 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.

[0129] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer, and 86%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units; and the stabilizer is propylene glycol.

[0130] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reproza 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.

[0131] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reproza 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.

[0132] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reproza 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.

[0133] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-11% of a solubilizer, 0.5%-3% of a stabilizer, and 86%-98% of water; wherein the solubilizer is polyoxyethylene hydrogenated castor oil having 35-45 polyoxyethylene units; and the stabilizer is propylene glycol.

[0134] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reproza 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.

[0135] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of reprozac 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 hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

[0136] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of reprozac 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 hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

[0137] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of reprozac 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 hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

[0138] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of reprozac 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 hydroxystearate having 10-20 polyoxyethylene units; and the stabilizer is propylene glycol.

[0139] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reproza 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 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 solubilizer is polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 When the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, the weight percentage of the octylphenol polyoxyethylene ether 40 in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

[0140] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from 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. One or more of; wherein, when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, the weight percentage of the polyoxyethylene 15 hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, the weight percentage of the octylphenol polyoxyethylene ether 40 in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

[0141] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is selected from one or more of a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, and polyoxyethylene 15 hydroxystearate; wherein, when the solubilizer is polyoxyethylene When the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate, the weight percentage of the polyoxyethylene 15 hydroxystearate in the mixture is 0-80%, preferably 0-50%, more preferably 0-30%, and most preferably 0-10%; when the solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40, the weight percentage of the octylphenol polyoxyethylene ether 40 in the mixture is 0-20%, preferably 0-18%, more preferably 0-15%, and most preferably 0-5%; the stabilizer is propylene glycol.

[0142] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of reprozac 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.

[0143] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of reprozac 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.

[0144] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of reprozac 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.

[0145] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of reprozac 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.

[0146] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of reprozac 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%; and the stabilizer is propylene glycol.

[0147] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of reprozac 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%; and the stabilizer is propylene glycol.

[0148] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of reprozac 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 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.

[0149] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of reprozac 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.

[0150] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reprosa or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of a stabilizer, and 83%-98% of water; wherein the solubilizer is polyoxyethylene 40 hydrogenated castor oil; and the stabilizer is propylene glycol.

[0151] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of Reproza 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.

[0152] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of Reproza 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.

[0153] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of Reproza 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.

[0154] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of Reproza 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.

[0155] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of reprozac 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.

[0156] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of reprozac 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.

[0157] In a more specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of reprozac 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.

[0158] In one embodiment, the composition optionally comprises other pharmaceutically acceptable excipients.

[0159] In one embodiment, in addition to the above components, the composition does not contain other pharmaceutically acceptable excipients; specifically, the composition consists of reprozac or a pharmaceutically acceptable salt thereof, a solubilizer, water, and an optional stabilizer.

[0160] In one embodiment, in addition to the above components, the composition further comprises one or more other pharmaceutically acceptable excipients.

[0161] In a specific embodiment, the other pharmaceutically acceptable excipients are selected from one or more of viscosity enhancers, antioxidants, pH regulators, osmotic pressure regulators, wetting agents, mucoadhesives, penetration enhancers, preservatives, gelling agents, antibacterial agents and chelating agents, preferably one or more of viscosity enhancers, antioxidants, chelating agents, antibacterial agents, pH regulators and osmotic pressure regulators.

[0162] In a more specific embodiment, the composition further comprises a viscosity increasing agent; preferably, the viscosity increasing agent is selected from one or more of carboxymethyl cellulose or its sodium salt, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, poloxamer, carbomer, xanthan gum, hyaluronic acid or its sodium salt, polyvinyl pyrrolidone, polycarbophil, gum, carrageenan, guar gum, tragacanth gum, agarose, polyethylene glycol, alginic acid or its sodium salt and hyaluronic acid or its sodium salt, preferably one or more of xanthan gum, sodium hyaluronate, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, carbomer, sodium carboxymethyl cellulose, poloxamer, sodium alginate and sodium hyaluronate, more preferably one or more of xanthan gum, sodium hyaluronate, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, carbomer and sodium carboxymethyl cellulose, most preferably one or more of xanthan gum, sodium hyaluronate, hydroxypropyl methylcellulose and sodium carboxymethyl cellulose.

[0163] In one embodiment, the content of the viscosity increasing agent is 0-5%, preferably 0-3%, more preferably 0.1%-3%, most preferably 0.2%-3%, based on the total weight of the composition.

[0164] In a more specific embodiment, the composition further comprises an antioxidant; preferably, the antioxidant is selected from one or more of tocopherol or its succinate, ascorbic acid or its palmitate, butylated hydroxyanisole, 2,6-di-tert-butylated cresol and sodium thiosulfate, preferably one or more of tocopherol, butylated hydroxyanisole, 2,6-di-tert-butylated cresol and sodium thiosulfate, more preferably one or more of tocopherol and sodium thiosulfate.

[0165] In one embodiment, the content of the antioxidant is 0-1%, preferably 0.05%-1%, more preferably 0.1%-1%, based on the total weight of the composition.

[0166] In a more specific embodiment, the composition further comprises a chelating agent; preferably, the chelating agent is selected from one or more of citric acid or its salts, glucuronic acid or its salts, hexametaphosphate, edetic acid or its salts and phosphonates, preferably edetic acid or edetate disodium.

[0167] In one embodiment, the chelating agent is present in an amount of 0-2%, preferably 0.01%-1%, more preferably 0.05%-0.5%, and most preferably 0.1%-0.2%, based on the total weight of the composition.

[0168] In a more specific embodiment, the composition further comprises a pH regulator; preferably, the pH regulator is selected from one or more of inorganic or organic acids, bases and buffer salts, preferably buffer salts; wherein the acid is selected from one or more of hydrochloric acid, phosphoric acid, acetic acid, citric acid, lactic acid and boric acid; the base is selected from one or more of ethylenediamine, ethanolamine, basic amino acids, sodium hydroxide, calcium hydroxide, potassium hydroxide and 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.

[0169] In one embodiment, the pH of the composition is 5-9.5, preferably 6-9, more preferably 6-8.5, most preferably 6.5-8.

[0170] In a more specific embodiment, the composition further comprises an osmotic pressure regulator; preferably, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, glucose, sorbitol, polyethylene glycol, glycerol and propylene glycol, preferably one or more of sodium chloride, mannitol, sorbitol and glycerol.

[0171] In a more specific embodiment, the composition further comprises an antibacterial agent; preferably, the antibacterial agent is selected from one or more of benzyl alcohol, phenoxyethanol, sorbic acid or its salts, parahydroxybenzoates, chlorhexidine, benzalkonium chloride, benzalkonium bromide, chlorobutanol, benzoic acid or its salts, citric acid or its salts and ascorbic acid or its salts, preferably one or more of butyl parahydroxybenzoate, benzalkonium chloride, benzalkonium bromide, chlorhexidine, sorbic acid and chlorobutanol.

[0172] In one embodiment, the content of the bacteriostatic agent is 0-5%, preferably 0-1%, more preferably 0.1%-0.5%, most preferably 0.2%-0.3%, based on the total weight of the composition.

[0173] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: reproza or a pharmaceutically acceptable salt thereof 0.15%-0.5% (or 0.05%-0.5%), solubilizer 1%-16%, propylene glycol 0-5%, water 83%-98%, viscosity enhancer 0-5%, antioxidant 0-1%, chelating agent 0-2%, optional osmotic pressure regulator and optional pH regulator.

[0174] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of reprozac or a pharmaceutically acceptable salt thereof, 2%-12% of solubilizer, 0-4% of propylene glycol, 87%-97% of water, 0-5% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0175] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of reprozac or a pharmaceutically acceptable salt thereof, 2%-12% of solubilizer, 0.5%-4% of propylene glycol, 87%-97% of water, 0-5% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0176] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of reprozac or a pharmaceutically acceptable salt thereof, 2.5%-10% of solubilizer, 0-3% of propylene glycol, 89%-97% of water, 0-5% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0177] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of reprozac or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of solubilizer, 1%-3% of propylene glycol, 91%-95% of water, 0-5% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0178] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: reproza or a pharmaceutically acceptable salt thereof 0.15%-0.5% (or 0.05%-0.5%), solubilizer 1%-16%, propylene glycol 0-5%, water 83%-98%, viscosity enhancer 0-3%, antioxidant 0-1%, chelating agent 0-2%, optional osmotic pressure regulator and optional pH regulator.

[0179] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of reprozac or a pharmaceutically acceptable salt thereof, 2%-12% of solubilizer, 0-4% of propylene glycol, 87%-97% of water, 0-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0180] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of reprozac or a pharmaceutically acceptable salt thereof, 2%-12% of solubilizer, 0.5%-4% of propylene glycol, 87%-97% of water, 0-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0181] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of reprozac or a pharmaceutically acceptable salt thereof, 2.5%-10% of solubilizer, 0-3% of propylene glycol, 89%-97% of water, 0-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0182] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of reprozac or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of solubilizer, 1%-3% of propylene glycol, 91%-95% of water, 0-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0183] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: reproza or a pharmaceutically acceptable salt thereof 0.15%-0.5% (or 0.05%-0.5%), solubilizer 1%-16%, propylene glycol 0-5%, water 83%-98%, viscosity enhancer 0.1%-3%, antioxidant 0-1%, chelating agent 0-2%, optional osmotic pressure regulator and optional pH regulator.

[0184] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: reproza or a pharmaceutically acceptable salt thereof 0.2%-0.45%, solubilizer 2%-12%, propylene glycol 0-4%, water 87%-97%, viscosity enhancer 0.1%-3%, antioxidant 0-1%, chelating agent 0-2%, optional osmotic pressure regulator and optional pH regulator.

[0185] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of reprozac or a pharmaceutically acceptable salt thereof, 2%-12% of solubilizer, 0.5%-4% of propylene glycol, 87%-97% 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.

[0186] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of reprozac or a pharmaceutically acceptable salt thereof, 2.5%-10% of solubilizer, 0-3% of propylene glycol, 89%-97% 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.

[0187] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of reprozac or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of solubilizer, 1%-3% of propylene glycol, 91%-95% 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.

[0188] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: reproza or a pharmaceutically acceptable salt thereof 0.15%-0.5% (or 0.05%-0.5%), solubilizer 1%-16%, propylene glycol 0-5%, water 83%-98%, viscosity enhancer 0.2%-3%, antioxidant 0-1%, chelating agent 0-2%, optional osmotic pressure regulator and optional pH regulator.

[0189] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of reprozac or a pharmaceutically acceptable salt thereof, 2%-12% of solubilizer, 0-4% of propylene glycol, 87%-97% of water, 0.2%-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0190] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.2%-0.45% of reprozac or a pharmaceutically acceptable salt thereof, 2%-12% of solubilizer, 0.5%-4% of propylene glycol, 87%-97% of water, 0.2%-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0191] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.4% of reprozac or a pharmaceutically acceptable salt thereof, 2.5%-10% of solubilizer, 0-3% of propylene glycol, 89%-97% of water, 0.2%-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0192] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.25%-0.35% of reprozac or a pharmaceutically acceptable salt thereof, 3.75%-7.5% of solubilizer, 1%-3% of propylene glycol, 91%-95% of water, 0.2%-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0193] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: reproza or a pharmaceutically acceptable salt thereof 0.1%-0.5%, solubilizer 1%-16%, propylene glycol 0.5%-3%, water 83%-98%, viscosity enhancer 0-5%, antioxidant 0-1%, chelating agent 0-2%, optional osmotic pressure regulator and optional pH regulator.

[0194] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of reprozac or a pharmaceutically acceptable salt thereof, 1%-15% of solubilizer, 0.5%-3% of propylene glycol, 84%-98% of water, 0-5% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0195] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: reproza or a pharmaceutically acceptable salt thereof 0.1%-0.3%, solubilizer 1%-11%, propylene glycol 0.5%-3%, water 86%-98%, viscosity enhancer 0-5%, antioxidant 0-1%, chelating agent 0-2%, optional osmotic pressure regulator and optional pH regulator.

[0196] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of reprozac or a pharmaceutically acceptable salt thereof, 1%-9% of solubilizer, 0.5%-3% of propylene glycol, 88%-98% of water, 0-5% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0197] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of reprozac or a pharmaceutically acceptable salt thereof, 1%-16% of a solubilizer, 0.5%-3% of propylene glycol, 83%-98% of water, 0.2%-5% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

[0198] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of reprozac or a pharmaceutically acceptable salt thereof, 1%-15% of solubilizer, 0.5%-3% of propylene glycol, 84%-98% of water, 0.2%-5% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0199] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: reproza or a pharmaceutically acceptable salt thereof 0.1%-0.3%, solubilizer 1%-11%, propylene glycol 0.5%-3%, water 86%-98%, viscosity enhancer 0.2%-5%, antioxidant 0-1%, chelating agent 0-2%, optional osmotic pressure regulator and optional pH regulator.

[0200] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of reprozac or a pharmaceutically acceptable salt thereof, 1%-9% of solubilizer, 0.5%-3% of propylene glycol, 88%-98% of water, 0.2-5% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0201] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of reprozac 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.

[0202] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of reprozac or a pharmaceutically acceptable salt thereof, 1%-15% of solubilizer, 0.5%-3% of propylene glycol, 84%-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.

[0203] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: reproza or a pharmaceutically acceptable salt thereof 0.1%-0.3%, solubilizer 1%-11%, propylene glycol 0.5%-3%, water 86%-98%, viscosity enhancer 0-3%, antioxidant 0-1%, chelating agent 0-2%, optional osmotic pressure regulator and optional pH regulator.

[0204] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of reprozac or a pharmaceutically acceptable salt thereof, 1%-9% of a solubilizer, 0.5%-3% of propylene glycol, 88%-98% of water, 0-3% of a viscosity enhancer, 0-1% of an antioxidant, 0-2% of a chelating agent, an optional osmotic pressure regulator, and an optional pH regulator.

[0205] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of reprozac 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.

[0206] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of reprozac or a pharmaceutically acceptable salt thereof, 1%-15% of solubilizer, 0.5%-3% of propylene glycol, 84%-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.

[0207] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: reproza or a pharmaceutically acceptable salt thereof 0.1%-0.3%, solubilizer 1%-11%, propylene glycol 0.5%-3%, water 86%-98%, viscosity enhancer 0.1%-3%, antioxidant 0-1%, chelating agent 0-2%, optional osmotic pressure regulator and optional pH regulator.

[0208] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of reprozac or a pharmaceutically acceptable salt thereof, 1%-9% of solubilizer, 0.5%-3% of propylene glycol, 88%-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.

[0209] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: reproza or a pharmaceutically acceptable salt thereof 0.1%-0.5%, solubilizer 1%-16%, propylene glycol 0.5%-3%, water 83%-98%, viscosity enhancer 0.2%-3%, antioxidant 0-1%, chelating agent 0-2%, optional osmotic pressure regulator and optional pH regulator.

[0210] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of reprozac or a pharmaceutically acceptable salt thereof, 1%-15% of solubilizer, 0.5%-3% of propylene glycol, 84%-98% of water, 0.2%-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0211] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of reprozac 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.

[0212] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of reprozac 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.

[0213] In one embodiment, the composition contains a viscosity enhancer but does not contain a stabilizer; that is, the composition contains reproza or a pharmaceutically acceptable salt thereof, a solubilizer, water and a viscosity enhancer, but does not contain a stabilizer; preferably, the composition contains 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 contain a stabilizer.

[0214] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of reprozac or a pharmaceutically acceptable salt thereof, 1%-16% of solubilizer, 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.

[0215] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of reprozac or a pharmaceutically acceptable salt thereof, 1%-15% of solubilizer, 84%-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.

[0216] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of reprozac or a pharmaceutically acceptable salt thereof, 1%-11% of solubilizer, 86%-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.

[0217] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of reprozac or a pharmaceutically acceptable salt thereof, 1%-9% of solubilizer, 88%-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.

[0218] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of reprozac or a pharmaceutically acceptable salt thereof, 1%-16% of solubilizer, 83%-98% of water, 0.2%-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0219] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of reprozac or a pharmaceutically acceptable salt thereof, 1%-15% of solubilizer, 84%-98% of water, 0.2%-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0220] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.3% of reprozac or a pharmaceutically acceptable salt thereof, 1%-11% of solubilizer, 86%-98% of water, 0.2%-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0221] In a specific embodiment, based on the total weight of the composition, the weight percentages of the components are as follows: 0.15%-0.25% of reprozac or a pharmaceutically acceptable salt thereof, 1%-9% of solubilizer, 88%-98% of water, 0.2%-3% of viscosity enhancer, 0-1% of antioxidant, 0-2% of chelating agent, optional osmotic pressure regulator and optional pH regulator.

[0222] In a second aspect, the present invention provides a method for preparing an ophthalmic solution composition (particularly the ophthalmic solution composition described in the first aspect above), comprising the following steps:

[0223] 1) uniformly mixing Reprozac or a pharmaceutically acceptable salt thereof, a solubilizer, and an optional stabilizer to obtain a drug-containing solution;

[0224] 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.

[0225] In one embodiment, step 2) of the preparation method further comprises the following steps between the dispersion and filtration steps: adding a viscosity enhancer and redispersing the solution to obtain a uniform dispersion. In other words, step 2) of the preparation method comprises the following steps: adding the drug-containing solution obtained in step 1) to water and dispersing the solution to obtain a uniform dispersion; adding a viscosity enhancer; redispersing the solution to obtain a sterile filtration step to obtain an ophthalmic solution composition.

[0226] In one embodiment, step 2) of the preparation method further comprises, after the filtration step, the following step: adding a pre-sterilized (e.g., high-temperature sterilized) aqueous solution of a viscosity-increasing agent and redispersing the solution uniformly. In other words, step 2) of the preparation method comprises the following steps: adding the drug-containing solution obtained in step 1) to water and dispersing the solution uniformly, filtering and sterilizing the solution, adding a pre-sterilized aqueous solution of a viscosity-increasing agent, and redispersing the solution uniformly to obtain an ophthalmic solution composition.

[0227] In one embodiment, the preparation method further comprises the following step before the mixing step of step 1) or before the dispersing step of step 2): adding an antioxidant.

[0228] In one embodiment, the preparation method further comprises the following step before the mixing step of step 1) or before the dispersion step of step 2): adding an antibacterial agent.

[0229] In one embodiment, the preparation method further comprises the following step before the dispersion step in step 2): adding a chelating agent.

[0230] In one embodiment, step 2) of the preparation method further comprises the following step before the filtration step: using a pH regulator (such as buffer salt) to adjust the pH value of the redispersed material to a range that meets the requirements for ophthalmic use.

[0231] In one embodiment, step 2) of the preparation method further comprises the following step before the filtration step: using an osmotic pressure regulator to adjust the redispersed material to an osmotic pressure value range that meets ophthalmic requirements.

[0232] In a specific embodiment, the mixing in step 1) of the preparation method is carried out under heating conditions, for example, by heating in a water bath, the water bath temperature is 0-90°C, preferably 30-60°C, more preferably 40-50°C.

[0233] In a specific embodiment, the mixing in step 1) of the preparation method is performed under stirring conditions.

[0234] In a specific embodiment, the temperature of the water in step 2) of the preparation method is 0-50°C, preferably 20-40°C, more preferably 25-35°C.

[0235] In a third aspect, the present invention provides use of an ophthalmic solution composition (particularly the ophthalmic solution composition described in the first aspect) in the preparation of a medicament for preventing and / or treating ophthalmic diseases or conditions associated with toxic aldehydes including pro-inflammatory reactive aldehyde substances (RASPs).

[0236] In a fourth aspect, the present invention provides an ophthalmic solution composition (particularly the ophthalmic solution composition described in the first aspect above), which is used to prevent and / or treat ophthalmic diseases or conditions associated with toxic aldehydes including pro-inflammatory active aldehydes.

[0237] In a fifth aspect, the present invention provides a method for preventing and / or treating ocular diseases or conditions associated with toxic aldehydes, including pro-inflammatory reactive 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.

[0238] In one embodiment, the ocular disease or condition is selected from one or more of corneal diseases, ocular diseases associated with excess toxic aldehydes, ocular rosacea, and other ocular diseases.

[0239] In a specific embodiment, the corneal disease is selected from one or more of dry eye syndrome, cataracts, keratoconus, bullous and other types of keratopathy, and Fuch's endothelial corneal dystrophy.

[0240] In a specific embodiment, the eye disease associated with excessive toxic aldehydes is selected from one or more of uveitis, scleritis, and Sjogren-Larsson Syndrome.

[0241] In a specific embodiment, the other ocular disease is selected from one or more of allergic conjunctivitis, ocular cicatricial pemphigoid, diseases associated with photorefractive keratectomy (PRK) healing or other corneal healing, and diseases associated with tear lipid degradation or tear gland dysfunction.

[0242] In one embodiment, the ocular disease or condition is selected from one or more of dry eye syndrome, allergic conjunctivitis, and uveitis.

[0243] In one embodiment, the ocular disease or disorder is dry eye syndrome.

[0244] Effects of the Invention

[0245] 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.

[0246] To this end, the present invention creatively designed a nano-micelle solution composition for Reprozac for ophthalmology. The nano-micelle system effectively encapsulates Reprozac molecules, improving their solubility and stability. This allows the drug to penetrate the aqueous layer of the eye and more effectively penetrate the cornea, increasing its adhesion and retention time in the eye. This improves bioavailability while achieving long-lasting, stable drug release.

[0247] First, the ophthalmic nanomicellar solution composition of the present invention has excellent chemical stability. After storage under conventional conditions (e.g., room temperature 25°C / 60% RH) for at least 1 week, or at least 10 days, or at least 2 weeks, or at least 1 month, or at least 3 months, or at least 4 months, or at least 6 months, or at least 9 months, or at least 12 months, it contains only less than 1% impurities, or less than 0.8% impurities, or less than 0.5% impurities, or less than 0.2% impurities, or less than 0.1% impurities. After storage under accelerated conditions (40°C / 75%RH) for at least 1 week, or at least 10 days, or at least 2 weeks, or at least 1 month, or at least 4 months, it contains only less than 1%, or less than 0.8%, or less than 0.5%, or less than 0.3%, or less than 0.2%, or less than 0.1% of a single impurity and / or, it contains only less than 1.5%, or less than 1.2%, or less than 1%, or less than 0.8%, or less than 0.5%, or less than 0.3%, or less than 0.2% of total impurities.

[0248] Secondly, the ophthalmic nanomicelle solution composition of the present invention has excellent physical stability. After storage under conventional 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 micelle particle size growth value is ≤50 nm, or ≤40 nm, or ≤30 nm, or ≤20 nm. After storage under accelerated conditions (40°C / 75% RH) for at least 1 week, or at least 10 days, or at least 2 weeks, or at least 1 month, or at least 4 months, the micelle particle size growth value is ≤50 nm, or ≤40 nm, or ≤30 nm, or ≤20 nm.

[0249] Finally, the ophthalmic nano-micelle solution composition of the present invention has a high encapsulation rate, is non-irritating to the eyes, and exhibits excellent sustained-release effects in both in vitro and in vivo pharmacodynamic tests. BRIEF DESCRIPTION OF THE DRAWINGS

[0250] Figure 1 Shown are the results of in vitro dissolution testing of the samples.

[0251] Figure 2 Shown are the results of in vitro dissolution testing of the samples.

[0252] Figure 3 The figure shows the comparison of corneal sodium fluorescein staining scores in a rat dry eye model after 14 days of drug administration. DETAILED DESCRIPTION

[0253] Definition of terms

[0254] Unless otherwise specified, the term "micelles" as used herein refers to the ordered, thermodynamically stable, colloidal aggregates formed by the self-assembly of surfactant molecules in aqueous solution when a certain concentration is reached. 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. Because the hydrophobic portions of surfactant molecules have a low affinity for water, while the hydrophobic portions have a strong attraction to each other, the hydrophobic portions of many surfactant molecules attract each other and associate to form an inner core, while the hydrophilic groups face outward to form an outer layer, thus forming a multimolecular complex. Structurally, micelles are composed of a lipophilic inner core and a hydrophilic outer shell, and have multiple functions. The lipophilic inner core can be used to encapsulate hydrophobic drugs, greatly improving the solubility of poorly soluble drugs in water; the hydrophilic outer shell can interact with biological components in the body, affecting pharmacokinetic behavior and drug distribution, and controlling drug delivery in the body. Among them, micelles with an amphiphilic colloidal structure and a particle size range of typically 5 to 100 nm are referred to as "nanomicelles."

[0255] Unless otherwise specified, the term "critical micelle concentration" (CMC) used in the present invention refers to the minimum concentration of surfactant molecules in a solvent at which they associate 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 formonomer and micellar concentrations in surfactant solutions:application toconductivity,NMR,diffusion,and surface tension data[J],J.Colloid InterfaceSci.,2012,370:102-110;Lucas The determination was carried out according to the relevant methods described in Sonia Freire, Jorge Bordello, Mercedes Novo, and Wajih Al-Soufi, Dye Exchange in Micellar Solutions. Quantitative Analysis of Bulk and Single Molecule Fluorescence Titrations[J], Soft Matter, 2013, 9: 10779-10790; Zhang Chunyan, Luo Jianxin, Pan Chunyue, Yu Guipeng, Determination of the critical micelle concentration of sodium dodecylbenzenesulfonate by spectroscopic method[J], Environmental Science and Technology, 2016, 39(08): 99-107, etc.

[0256] Unless otherwise specified, the term "solubilizer" as used herein refers to a surfactant with solubilizing properties. Its action can increase the solubility of poorly soluble drugs in a solvent, leading to the formation of a solution. The solubilizing effect is directly influenced by factors such as the solubilizer's properties, HLB value, and dosage.

[0257] Unless otherwise specified, the term "surfactant" as used herein refers to a substance that can (significantly) reduce the surface tension of a target solution by aligning itself on the surface of the solution. Surfactants have an amphiphilic molecular structure: a hydrophilic group at one end and a hydrophobic group at the other. The hydrophilic group is typically a polar group, such as carboxylic acid, sulfonic acid, sulfuric acid, (substituted) amino groups and their salts, hydroxyl groups, amide groups, and ether bonds; while the hydrophobic group is typically a non-polar hydrocarbon chain, such as one with eight or more carbon atoms.

[0258] Based on their structural type, surfactants can be divided into four categories: cationic surfactants, anionic surfactants, nonionic surfactants, and amphoteric surfactants. Nonionic surfactants do not dissociate in water and are typically low molecular weight. Their molecular structure includes a hydrophilic group and a hydrophobic group. The hydrophilic group is selected from one or more of polyethylene glycol and polyols, and the hydrophobic group is selected from one or more of fatty acids, fatty alcohols, phenols, and alkylphenols. The hydrophilic and hydrophobic groups are bound together by ester or ether bonds. Based on the structural type of the hydrophilic group, nonionic surfactants can be further divided into polyethylene glycol type (also known as polyoxyethylene type) and polyol type.

[0259] 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:

[0260] (1) Polyoxyethylene fatty alcohol ether (or fatty alcohol polyoxyethylene ether, obtained by etherification of polyethylene glycol and fatty alcohol);

[0261] (2) Polyoxyethylene fatty acyl alkanolamine ether (or fatty acyl alkanolamine polyoxyethylene ether, obtained by etherification of polyethylene glycol and fatty acyl alkanolamine);

[0262] (3) Polyoxyethylene alkylphenol ether (or alkylphenol polyoxyethylene ether, obtained by etherification of polyethylene glycol and alkylphenol);

[0263] (4) Polyoxyethylene fatty acid esters (or fatty acid polyoxyethylene esters, obtained by esterification of polyethylene glycol with fatty acids or their derivatives); and

[0264] (5) Polyoxyethylene castor oil derivatives (obtained by the reaction of glycerol, polyethylene glycol and castor oil or hydrogenated castor oil).

[0265] 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, etc.). Oil, polyoxyethylene 60 hydrogenated castor oil, etc.), more preferably polyoxyethylene castor oil with 30-40 polyoxyethylene units (such as polyoxyethylene 35 castor oil) and polyoxyethylene hydrogenated castor oil with 35-55 polyoxyethylene units (such as polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 54 hydrogenated castor oil, etc.), further preferably polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units (such as polyoxyethylene 40 hydrogenated castor oil) and polyoxyethylene hydrogenated castor oil with 50-55 polyoxyethylene units (such as polyoxyethylene 54 hydrogenated castor oil), still further preferably polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units (such as polyoxyethylene 40 hydrogenated castor oil), and most preferably polyoxyethylene 40 hydrogenated castor oil.

[0266] Polyoxyethylene fatty acid esters include (but are not limited to) polyoxyethylene stearate (or polyoxyethylene stearate, obtained by esterifying polyethylene glycol with stearic acid), polyoxyethylene hydroxystearate (or polyoxyethylene hydroxystearate, obtained by esterifying polyethylene glycol with hydroxystearate) and vitamin E polyethylene glycol succinate (derived by esterifying D-α-tocopherol succinate with polyethylene glycol), wherein polyoxyethylene stearate includes (but is not limited to) polyoxyethylene stearate with a polyoxyethylene unit number of 2-50. Fatty acid esters (such as polyoxyethylene 2 stearate, polyoxyethylene 4 stearate, polyoxyethylene 6 stearate, polyoxyethylene 8 stearate, polyoxyethylene 12 stearate, polyoxyethylene 20 stearate, polyoxyethylene 30 stearate, polyoxyethylene 40 stearate, polyoxyethylene 50 stearate, etc.), especially polyoxyethylene stearate with 10-50 polyoxyethylene units, preferably polyoxyethylene stearate with 30-50 polyoxyethylene units, more preferably polyoxyethylene stearate with 30-50 polyoxyethylene units 5-45 polyoxyethylene stearate, most preferably polyoxyethylene 40 stearate; polyoxyethylene hydroxystearate including (but not limited to) polyoxyethylene hydroxystearate with a polyoxyethylene unit number of 10-20, preferably polyoxyethylene 15 hydroxystearate; vitamin E polyethylene glycol succinate including (but not limited to) vitamin E polyethylene glycol succinate with an average molecular weight of polyethylene glycol of 200-4000 (such as vitamin E polyethylene glycol succinate 200, ... Vitamin E polyethylene glycol succinate 400, vitamin E polyethylene glycol succinate 1000, vitamin E polyethylene glycol succinate 1500, vitamin E polyethylene glycol succinate 2000, vitamin E polyethylene glycol succinate 4000, etc.), preferably vitamin E polyethylene glycol succinate with an average polyethylene glycol molecular weight of 500-1500, more preferably vitamin E polyethylene glycol succinate with an average polyethylene glycol molecular weight of 800-1200, and most preferably vitamin E polyethylene glycol succinate 1000.

[0267] Polyoxyethylene alkylphenol ethers include, but are not limited to, nonylphenol polyoxyethylene ethers having 4-10 polyoxyethylene units (e.g., 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 (e.g., 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. Octylphenol polyoxyethylene ethers having 30-50 polyoxyethylene units are preferred, octylphenol polyoxyethylene ethers having 35-45 polyoxyethylene units are more preferred, and octylphenol polyoxyethylene ether 40 is most preferred.

[0268] Unless otherwise specified, the term "number of polyoxyethylene units" as used herein refers to the average degree of polymerization of the polyoxyethylene moiety (i.e., polyethylene glycol moiety) in the molecule. For example, "polyoxyethylene castor oil having 30-40 polyoxyethylene units" means that the average degree of polymerization of the polyoxyethylene moiety in the defined polyoxyethylene castor oil is 30-40, and "polyoxyethylene 40 stearate" means that the average degree of polymerization of the polyoxyethylene moiety in the defined polyoxyethylene stearate is 40.

[0269] Unless otherwise indicated, the term "average molecular weight of polyethylene glycol" as used herein refers to the average molecular weight of the polyethylene glycol portion (i.e., the polyoxyethylene portion) in a defined molecule. For example, "tocopherol polyethylene glycol succinate having an average molecular weight of 500-1500" means that the average molecular weight of the polyethylene glycol portion of the defined vitamin E polyethylene glycol succinate is 500-1500, and "tocopherol polyethylene glycol succinate 1000" means that the average molecular weight of the polyethylene glycol portion of the defined vitamin E polyethylene glycol succinate is 1000.

[0270] Polyol-type nonionic surfactants are composed of a hydrophilic group combined with a hydrophobic group derived from fatty acids and can be roughly divided into the following types:

[0271] (1) Glycerol fatty acid esters (or fatty acid glycerides);

[0272] (2) Sorbitan fatty acid esters (also known as sorbitan fatty acid esters, Span);

[0273] (3) Pentaerythritol fatty acid esters (or pentaerythritol fatty acid esters); and

[0274] (4) Sucrose fatty acid esters (or sucrose fatty acid esters).

[0275] Surfactants can be divided into low-molecular-weight surfactants and high-molecular-weight surfactants based on their molecular weight. The molecular weight of 1000 is usually used as the dividing line between the two. Surfactants with a molecular weight of 1000 or above (and mostly below 1,000,000) are considered high-molecular-weight surfactants, while those with a molecular weight of less than 1000 are considered low-molecular-weight surfactants. High-molecular-weight surfactants are mostly polymerized from hydrophilic monomers and hydrophobic monomers. They are mostly block copolymers or graft copolymers and are biodegradable. Their molecular structure includes hydrophilic 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.), and polyamides (such as polyvinyl caprolactam, polyisopropylacrylamide, etc.). 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.), and polyamino acids (such as polylysine, polyglutamic acid, polyaspartic acid, etc.).

[0276] 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) polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers 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 50,000-200,000 g / mol, preferably polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymers 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 90,000-140,000 g / mol, for example the term It refers to a polyethylene glycol-polyvinyl acetate-polyvinyl caprolactam graft copolymer sold by BASF of Germany and can be used as a pharmaceutical excipient.

[0277] The present invention has no particular limitation on the water used therein. For example, it can be purified water, distilled water, deionized water, water for injection, or any combination thereof in any type and / or ratio.

[0278] Unless otherwise specified, the term "stabilizer" as used herein refers to a substance that can increase the physical stability of a particular formulation (e.g., the ophthalmic micellar solution composition of the present invention) (e.g., preventing micelle aggregation and / or micelle particle size growth, thereby preventing sedimentation, etc.). The stabilizer in the present invention can be a chain polyol containing 2-6 carbon atoms and at least 2 hydroxyl groups. Illustrative examples include (but are not limited to) propylene glycol (e.g., 1,2-propylene glycol), glycerol (i.e., glycerol), butylene glycol (e.g., 1,2-butylene glycol), and pentanediol (e.g., 1,2-pentanediol).

[0279] Unless otherwise indicated, the term "pharmaceutically acceptable excipient" as used in the present invention refers to a pharmaceutically acceptable material, composition or vehicle. These substances must be "pharmaceutically acceptable", that is, compatible with the other ingredients in the drug prescription, and must also be suitable for contact with human or animal organs and / or tissues without excessive toxicity, irritation, allergy, immunogenicity or other adverse conditions, and commensurate with a reasonable benefit / risk ratio. Exemplary pharmaceutically acceptable excipients include (but are not limited to) viscosity enhancers, antioxidants, chelating agents, antibacterial agents (or preservatives), pH regulators and osmotic pressure regulators, etc. Those skilled in the art will understand that the above-mentioned exemplary pharmaceutically acceptable excipients are not necessary for the composition, and one or more of them can be added according to actual needs, or no one can be added.

[0280] Unless otherwise specified, the term "viscosity enhancer" as used herein refers to an excipient that can increase the viscosity of the composition of the present invention to a certain extent, thereby further enhancing the sustained-release effect of the active pharmaceutical ingredient (i.e., Reprozac or its pharmaceutically acceptable salt). Exemplary viscosity enhancers include (but are not limited to) carboxymethylcellulose 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.

[0281] Unless otherwise specified, the term "antioxidant" (or antioxidant) as used herein refers to an excipient that can, to a certain extent, prevent oxidizing substances such as oxygen from causing adverse effects such as oxidation on the components of the compositions of the present invention. Exemplary antioxidants include (but are not limited to) tocopherol or its carboxylates (such as succinate), ascorbic acid or its carboxylates (such as palmitate), butylated hydroxyanisole, 2,6-di-tert-butyl-p-cresol, and sodium thiosulfate.

[0282] Unless otherwise indicated, the term "chelating agent" (or complexing agent) as used herein refers to an excipient that can complex with metal ions to form a chelate to a certain extent, 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), hexametaphosphates (such as sodium hexametaphosphate, zinc hexametaphosphate, etc.), edetic acid or its salts (such as disodium edetate), and phosphonates.

[0283] Unless otherwise specified, the term "pH adjuster" (or acidity adjuster) as used herein refers to an auxiliary material that can maintain or modify the pH value of the compositions of the present invention to a certain extent. The pH adjuster used herein can be any conventional pH adjuster in the art, including (but not limited to) inorganic or organic acids, bases, and buffer salts. Exemplary acidic pH adjusters include (but are not limited to) hydrochloric acid, phosphoric acid, acetic acid, citric acid, lactic acid, and boric acid; exemplary alkaline pH adjusters include (but are not limited to) ethylenediamine, ethanolamine, basic amino acids, sodium hydroxide, calcium hydroxide, potassium hydroxide, and aqueous ammonia solution; exemplary buffer salt pH adjusters include (but are not limited to) boric acid-borax buffer, citric acid-sodium citrate buffer, phosphoric acid-sodium phosphate buffer, and acetic acid-sodium acetate buffer. Those skilled in the art will appreciate that a pH adjuster can be optionally added as needed to adjust the pH value of the compositions of the present invention until the final pH value meets ophthalmic requirements. If the pH value of the compositions of the present invention already meets ophthalmic requirements without the addition of a pH adjuster, then the addition of a pH adjuster is unnecessary.

[0284] Unless otherwise specified, the term "osmotic pressure regulator" (or isotonic pressure regulator) as used herein refers to an excipient that can adjust the osmotic pressure of the compositions of the present invention to a certain extent, so that it is equal to or similar to the osmotic pressure of the body fluids of the subject systemically and / or at the site of administration. Exemplary osmotic pressure regulators include (but are not limited to) sodium chloride, mannitol, glucose, sorbitol, polyethylene glycol, glycerol, and propylene glycol. Those skilled in the art will appreciate that an osmotic pressure regulator can be optionally added as needed to adjust the osmotic pressure of the compositions of the present invention until the final osmotic pressure meets ophthalmic requirements. If the osmotic pressure of the compositions of the present invention already meets ophthalmic requirements without the addition of an osmotic pressure regulator, then the addition of an osmotic pressure regulator is unnecessary. Generally speaking, the osmotic pressure of tears is equivalent to that of serum, equivalent to the osmotic pressure of 0.9% sodium chloride (286 mOsm). The eye can tolerate an osmotic pressure range equivalent to 0.6%-1.5% sodium chloride (200-450 mOsm), with the optimal osmotic pressure range being 260-310 mOsm.

[0285] Unless otherwise specified, the term "bacteriostatic agent" (or preservative) as used herein refers to an excipient that can inhibit, to a certain extent, the activity of microorganisms in the compositions of the present invention, thereby preventing spoilage and deterioration. Exemplary bacteriostatic agents include (but are not limited to) benzyl alcohol, phenoxyethanol, sorbic acid or its salts (e.g., potassium sorbate), parabens (or parabens, such as methylparaben, ethylparaben, propylparaben, butylparaben, etc.), chlorhexidine (or chlorhexidine), benzalkonium chloride, benzalkonium bromide, chlorobutanol, benzoic acid or its salts (e.g., sodium benzoate), citric acid or its salts (e.g., sodium citrate), and ascorbic acid or its salts (e.g., sodium ascorbate).

[0286] Unless otherwise specified, in the present invention, a numerical range expressed as "value A to value B" or "value A - value B" means a range including the endpoint values A and B. For example, "polyoxyethylene hydroxystearate having 10 to 20 polyoxyethylene units" includes both polyoxyethylene hydroxystearate having 10 polyoxyethylene units and polyoxyethylene hydroxystearate having 20 polyoxyethylene units.

[0287] The present invention is further illustrated by the following specific examples, but it should not be construed that the present invention is limited to the scope of the examples. Experimental methods in the following examples, where no specific conditions are specified, were performed according to conventional methods and conditions, or according to the methods or conditions described or recommended in the product specifications.

[0288] The abbreviations of some technical terms involved in the present invention and the trade names, meanings and sources of some products are shown in the following table. Unless otherwise specified, all reagents and raw materials in the present invention are commercially available.

[0289]

[0290] In the embodiment of the present invention, the chemical structure of "main impurity 1" is The chemical structure of "Main Impurity 2" is

[0291] The detection equipment and / or detection method used in the embodiments of the present invention are as follows:

[0292] 1. Osmotic pressure test: Use a pipette to measure 50 μL of sample into a test tube, ensuring that the sample is free of bubbles. Perform osmotic pressure test on the sample according to the equipment usage instructions; the equipment used is Gonotec's OSMOMAT 3000 Freezing Point Osmometer.

[0293] 2. Micellar Particle Size Measurement: Particle size measurement is performed using a Malvern Zetasizer Pro nanoparticle size analyzer (1 mL of the test solution). "Z-Average" refers to the average particle size, measured using dynamic light scattering technology, and is applicable to particles in dispersions or molecules in solutions.

[0294] 3. Detection of related substances: prepare reference solution (1 μg / mL) and test solution (1 mg / mL) respectively; detect the samples by HPLC; chromatographic column: Waters Xbridge C8 (4.6*250 mm, 5 μm) LC-0228; column temperature: 35°C; flow rate: 1.0 mL / min; injection volume: 20 μL; detector and wavelength: DAD detector, 249 nm; mobile phase A: 10 mmol / L potassium dihydrogen phosphate solution; mobile phase B: methanol-acetonitrile (65:35, V / V); HPLC mobile phase elution gradient and running time: 55% A / 45% B→10% A / 90% B→55% A / 45% B, a total of 46 min.

[0295] 4. API content detection: Prepare reference solution (0.02 mg / mL) and test solution (0.02 mg / mL) separately; detect the samples by HPLC using the external standard method; chromatographic column: Welch Ultimate XB-C18 (4.6*250 mm, 5 μm) LC-0082; column temperature: 30°C; flow rate: 1.0 mL / min; injection volume: 10 μL; detector and wavelength: DAD detector, 249 nm; mobile phase: 80% acetonitrile / 20% water; isocratic elution; run time: 10 min.

[0296] 5. In vitro dissolution testing: The dissolution and release rate determination method (basket method) of the Chinese Pharmacopoeia (2020 edition) was used. The original basket was replaced with a ready-to-use dialysis tubing / dialysis bag (CE, molecular weight cut-off: 100 kD); dissolution medium: artificial tears; dissolution medium volume: 1000 mL; dissolution medium temperature: 34°C ± 0.5°C; rotation speed: 100 rpm; sampling time: 10 min, 20 min, 30 min, 45 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, 16 h, 20 h, and 24 h. Detection was performed by HPLC using the same method as the content determination method.

[0297] Example 1: Solubilizer Screening

[0298] Preparation of Reproza ophthalmic solution (batch size 100g-200g): First, weigh the prescribed amount of Reproza, solubilizer, and optional propylene glycol according to the weight percentages recorded in Table 1-1 into a beaker, and 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 approximately 30°C, and after it is completely dispersed, obtain the Reproza ophthalmic solution.

[0299] Stability test: Observe the properties of the Reprosa ophthalmic solution with the naked eye, and test the relevant substances, API content and micelle particle size within 24 hours after preparation. Specific test results are shown in Table 1-2.

[0300] Results: Reprosa ophthalmic solutions in formulations 1.1-1.10 were uniform micellar solutions, with average micelle diameters ranging from 10-65 nm, with the majority ranging from 10-30 nm and some even reaching 10-15 nm. All solutions formed micellar solutions with uniform particle size. In terms of chemical stability, the total amount of impurities of related substances was controlled within the acceptable range of no more than 1.5%, with some even reaching below 0.5%. Formulations 1.2, 1.8, and 1.9 exhibited higher total impurities and impurity peak counts than the other formulations.

[0301] Table 1-1 Prescription composition of solubilizer screening test

[0302]

[0303] Table 1-2 Stability data of solubilizer screening test

[0304]

[0305] Example 2: Solubilizer dosage range examination

[0306] Reprosa ophthalmic solution (batch size 100 g-200 g) was prepared according to prescriptions 2.1-2.6 in Table 2-1, using the same preparation method as in Example 1. The prepared solution was subjected to physical and chemical stability testing. The properties of the samples were observed after 0 days, 10 days of accelerated storage (40°C / 75% RH), and 30 days of accelerated storage (40°C / 75% RH). The samples were also tested for related substances, API content, and micelle particle size. The specific test results are shown in Table 2-2.

[0307] Test results: Prescriptions 2.1-2.6 were colorless, clear liquids at 0 days, 10 days, and 30 days of acceleration; the content of related substances could still be controlled below about 0.5% after 30 days of acceleration, and the changes in API content and particle size fluctuations were all within controllable ranges.

[0308] Table 2-1 Prescription composition of solubilizer dosage range test

[0309] serial number 2.1 2.2 2.3 2.4 2.5 2.6 Reprosa 0.25％ 0.25％ 0.25％ 0.25％ 0.25％ 0.25％ RH40 2.00％ 7.50％ / / 1.90％ 7.12％ HS15 / / 2.00％ 7.50％ / / OP40 / / / / 0.10％ 0.38％ Propylene glycol 1.50％ 1.50％ 1.50％ 1.50％ / 3.00％ purified water 96.25％ 90.75％ 96.25％ 90.75％ 97.75％ 89.25％

[0310] Table 2-2 Stability data of the solubilizer dosage range test

[0311]

[0312] Example 3: Examination of the range of dosage of the stabilizer propylene glycol

[0313] Reproza ophthalmic solution (batch size 100 g-200 g) was prepared with reference to prescriptions 3.1-3.7 in Table 3-1, using the same preparation method as in Example 1. An intermediate solution was obtained by referring to prescription 3.8 in Table 3-1 and the preparation method in Example 1. A thickener was further added to the intermediate solution and stirred to obtain a uniform dispersion, thereby obtaining Reproza ophthalmic solution (batch size 100 g). The prepared micellar solution was subjected to physical stability testing, and the micelle particle size of the samples was measured after 0 days, 10 days of accelerated storage (40°C / 75% RH), and 30 days of accelerated storage (40°C / 75% RH). The specific test results are shown in Table 3-2.

[0314] Test results: When HS15 was used as the solubilizer, the particle size of formulation 3.1, which did not contain propylene glycol, increased slightly after 10 days of acceleration, but was not significant. However, it showed a significant increase after 30 days of acceleration. Otherwise, the micelle particle size of the remaining formulations remained stable under accelerated conditions.

[0315] Table 3-1 Prescription composition of the stabilizer propylene glycol dosage range test

[0316] serial number 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 Reprosa 0.25％ 0.25％ 0.25％ 0.25％ 0.25％ 0.25％ 0.25％ 0.25％ RH40 / / / 3.75％ 5.00％ 3.75％ / / HS15 3.75％ 3.75％ 3.75％ / / / 2.00％ 3.75％ Propylene glycol / 1.00％ 3.00％ / 2.00％ 3.00％ 0.50％ / purified water 96.00％ 95.00％ 93.00％ 96.00％ 92.75％ 93.00％ 97.25％ 95.50％ CMC-Na / / / / / / / 0.50％

[0317] Table 3-2 Stability data of the test on the dosage range of stabilizer propylene glycol

[0318]

[0319] Example 4: Screening of viscosity enhancers

[0320] Referring to prescriptions 4.1-4.6 in Table 4-1 and the preparation method in Example 1, an intermediate solution was obtained. A viscosity enhancer was further added and stirred to achieve uniform dispersion, resulting in Dereprosa ophthalmic solution (batch size 100g-200g). The resulting solution was subjected to chemical stability testing, with the relevant substances detected after 0 day, 7 days at high temperature (60°C), 10 days at accelerated temperature (40°C / 75% RH), and 30 days at accelerated temperature (40°C / 75% RH). The specific test results are shown in Table 4-2.

[0321] Test results: After 7 days of high temperature (60°C), the total amount of impurities and / or the number of impurity peaks in Formulations 4.3 and 4.5 were higher than those in other formulations. Therefore, subsequent accelerated stability testing was not conducted on these two formulations. For Formulations 4.1, 4.2, 4.4, and 4.6, the total amount of impurities was controlled below approximately 0.5% after 7 days of high temperature. This level was also maintained after 30 days of accelerated testing, with some even reaching levels below 0.2%.

[0322] Table 4-1 Prescription composition of viscosity enhancer screening test

[0323] serial number 4.1 4.2 4.3 4.4 4.5 4.6 Reprosa 0.25％ 0.25％ 0.25％ 0.25％ 0.25％ 0.25％ RH40 3.75％ 3.75％ 3.75％ 3.75％ 3.75％ 3.75％ Propylene glycol 1.50％ 1.50％ 1.50％ 1.50％ 1.50％ 1.50％ purified water 94.30％ 94.20％ 91.50％ 94.10％ 94.00％ 94.00％ Xanthan gum 0.20％ / / / / / Sodium hyaluronate / 0.30％ / / / / PVP / / 3.00％ / / / HPMC / / / 0.40％ / / Carbomer / / / / 0.50％ / CMC-Na / / / / / 0.50％

[0324] Table 4-2 Stability data of viscosity enhancer screening test

[0325]

[0326] Note: ND means not detected; N / A means not detected.

[0327] Example 5: Screening of API concentration

[0328] Reprosa ophthalmic solutions of varying concentrations (batch sizes of 100 g to 200 g) were prepared by referring to prescriptions 5.1 to 5.5 in Table 5-1 and the preparation method described in Example 4. Chemical stability tests were performed on the prepared solutions, with samples tested for related substances after 0 days, 10 days of accelerated storage (40°C / 75% RH), and 30 days of accelerated storage (40°C / 75% RH). Detailed test results are shown in Table 5-2.

[0329] Test results: The total impurity content of prescriptions 5.1, 5.2, 5.3, 5.4 and 5.5 was controlled below 0.2% after 10 days of acceleration, and was still controlled below 0.3% after 30 days of acceleration, and some even reached below 0.15%.

[0330] Table 5-1 Prescription composition of API concentration screening test

[0331] serial number 5.1 5.2 5.3 5.4 5.5 Reprosa 0.10％ 0.15％ 0.25％ 0.35％ 0.45％ HS15 2.00％ 2.25％ 3.75％ 5.25％ 11.25％ Propylene glycol 2.00％ 1.50％ 1.50％ 1.50％ 3.00％ purified water 95.60％ 95.50％ 93.90％ 92.40％ 84.90％ Xanthan gum 0.30％ / / / / Sodium hyaluronate / / / / 0.40％ HPMC / / / 0.50％ / CMC-Na / 0.60％ 0.60％ / /

[0332] Table 5-2 Stability data of API concentration screening test

[0333]

[0334] Note: ND means not detected.

[0335] Example 6-1: In vitro dissolution test

[0336] According to the prescriptions 6.1-6.3 in Table 6-1, Reprosa ophthalmic solution (batch size 100g-200g) was prepared and its in vitro dissolution behavior was examined. The preparation method was referred to Example 4; wherein, the comparative example cyclodextrin ophthalmic solution was prepared with reference to the examples in paragraphs

[0068] to

[0075] of the specification of CN113056353A as a comparative example for the in vitro dissolution experiment. At the same time, the in vitro dissolution behavior of prescriptions 1.4, 1.6 and 1.7 was examined, and the results are shown in Table 6-2 and Figure 1 shown.

[0337] Test results: The in vitro sustained-release effect of the ophthalmic nanomicellar solution of the present invention was significantly superior to that of the cyclodextrin ophthalmic solution. Furthermore, a comparison of Formulation 1.6 with Formulation 6.1, and Formulation 1.7 with Formulation 6.2, respectively, showed that the introduction of a viscosity-increasing agent into the formulation can further enhance the in vitro sustained-release effect of the ophthalmic nanomicellar solution of the present invention to a certain extent.

[0338] Table 6-1 In vitro dissolution test sample formulation

[0339] serial number 6.1 6.2 6.3 Comparative Example Reprosa 0.25％ 0.25％ 0.25％ 0.25％ SBECD / / / 7.00％ RH40 3.75％ / 1.88％ / HS15 / 3.75％ 1.88％ / Propylene glycol 1.50％ 1.50％ 1.50％ / Xanthan gum 0.10％ / / / CMC-Na / 0.50％ / / purified water 94.40％ 94.00％ 94.50％ / Phosphate buffer / / / 92.75％

[0340] Table 6-2 In vitro dissolution data

[0341]

[0342] Example 6-2: In vitro dissolution test

[0343] The in vitro dissolution behavior of the formulations 5.1, 5.2, 5.4 and 5.5 in Example 5 was examined, and the results are shown in Table 6-3 and Figure 2 shown.

[0344] Test results: The in vitro sustained-release effects of the ophthalmic nanomicelle solutions of the present invention with different concentrations and prescriptions are significant.

[0345] Table 6-3 In vitro dissolution data

[0346]

[0347] Example 7: Prescriptions for adding antioxidants, chelating agents, pH regulators, osmotic pressure regulators and other excipients

[0348] According to the formulations 7.1-7.9 in Table 7-1, and with reference to the preparation methods of the above examples, antioxidants, chelating agents, pH adjusters, and osmotic pressure regulators were further selectively added, and the corresponding ophthalmic nanomicelle solutions (batch size 100g-200g) were prepared using conventional formulation 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 for Reprosa ophthalmic micelles (as shown in Table 7-2).

[0349] Table 7-1 Prescription composition of other related preparation examples

[0350]

[0351] Note:

[0352] 1) qs refers to appropriate amount;

[0353] 2) Phosphate buffer: per 100 g, contains 0.4719 g sodium dihydrogen phosphate monohydrate, 0.4711 g anhydrous disodium hydrogen phosphate, and the remainder is purified water;

[0354] 3) Borate buffer: Each 100g contains 1.0992g of boric acid, 0.1880g of borax, and the rest is purified water.

[0355] Table 7-2 Basic property tests of other relevant preparation examples

[0356]

[0357] Example 8: In vivo animal efficacy experiment

[0358] Experimental samples: Prescription 5.2 of Example 5 of the present invention (0.15% test substance group), Prescription 5.3 of Example 5 (0.25% test substance group), Excipient 5.3 of Example 5 (Excipient group), Comparative Example of Prescription 6-1 (Positive Control Group).

[0359] Preparation method (batch size 100g-200g): First, weigh the prescribed amount of reproza (the excipient group does not contain reproza), solubilizer and propylene glycol according to the weight percentages recorded in prescriptions 5.2 and 5.3 in Table 5-1 into a beaker, 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 using a 0.22μm filter membrane to obtain a sterile reproza 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 the reproza ophthalmic solution.

[0360] Experimental method: One day before modeling, the Wistar male rats that met the standard were randomly divided into six groups according to their body weight, namely blank control group, model control group, positive control group (prescription comparison of Example 6-1), test substance 0.15% group (prescription 5.2), test substance 0.25% group (prescription 5.3) and vehicle group (prescription 5.3 vehicle), with 10 rats in each group. Except for the blank control group, 100 μL of scopolamine hydrobromide (concentration of 6 mg / mL) was injected subcutaneously into the hind limbs of the rats alternately, 4 times a day; at the same time, the rats were placed in a ventilation device and blown continuously for 12 hours a day for 10 consecutive days to construct a dry eye model. After modeling, except for the blank control group and the model control group, the corneas of the rats in the other experimental groups were continuously administered (20 μL each time, twice a day). Fluorescein sodium scoring examinations were performed on the 0th, 1st, 3rd, 7th, and 14th days of administration to evaluate the degree of eye lesions in the animals, using the fluorescein sodium score as the standard.

[0361] Corneal fluorescein sodium staining (CFS) scoring: 1 μL of liquid fluorescein sodium (1% w / v) was instilled into the conjunctival sac and closed. After 90 seconds, corneal epithelial fluorescein sodium staining was graded using a slit lamp microscope under cobalt blue light. The cornea was divided into four equal quadrants and scored separately. All scores were summed to obtain a total score.

[0362] 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 patchy staining; 4 points - patchy staining.

[0363] Experimental results:

[0364] Table 8 Corneal fluorescein sodium staining scoring data

[0365]

[0366] 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 .

[0367] like Figure 3 As shown, the experimental results of the test substance 0.15% group and the test substance 0.25% group using prescriptions 5.2 and 5.3 of Example 5 of the present invention, respectively, showed a certain dose-effect trend; the efficacy of the positive control group entered a plateau period after the 7th day, while the test substance 0.15% group and the test substance 0.25% group both showed a continuous downward trend over time, reflecting a longer-lasting and better pharmacodynamic effect, and their pharmacodynamics were better than those of the positive control group.

Claims

1. An ophthalmic solution composition comprising reprozac or a pharmaceutically acceptable salt thereof, a solubilizer, water, and optionally a stabilizer; The solubilizing agent is selected from one or more of polyoxyethylene hydrogenated castor oil having 35-55 polyoxyethylene units, polyoxyethylene castor oil having 30-40 polyoxyethylene units, vitamin E polyethylene glycol succinate having a polyethylene glycol molecular weight of 800-1200, polyoxyethylene hydroxystearate having 10-20 polyoxyethylene units, and octylphenol polyoxyethylene ether having 35-45 polyoxyethylene units; The stabilizer is propylene glycol; Based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.5% of reprozac or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-5% of a stabilizer, and 83%-98% of water.

2. The ophthalmic solution composition according to claim 1, characterized in that Based on the total weight of the composition, the weight percentages of the components are as follows: 0.1%-0.45% of reproxaparin or a pharmaceutically acceptable salt thereof, 2%-12% of a solubilizer, 0-3% of a stabilizer, and 84%-98% of water.

3. The ophthalmic solution composition according to claim 1 or 2, characterized in that The ophthalmic solution composition is an ophthalmic nanomicelle solution composition, wherein the average particle size of the nanomicelles is 5-100 nm.

4. The ophthalmic solution composition according to claim 3, characterized in that The ophthalmic solution composition is an ophthalmic nanomicelle solution composition, wherein the average particle size of the nanomicelles is 5-80 nm.

5. The ophthalmic solution composition according to claim 1, characterized in that Based on the total weight of the composition, the content of Reprosa is 0.1%-0.45%.

6. The ophthalmic solution composition according to claim 1 or 2, characterized in that: Based on the total weight of the composition, the content of Reprosa is 0.1%-0.3%.

7. The ophthalmic solution composition according to claim 1 or 2, characterized in that: Based on the total weight of the composition, the content of Reprosa is 0.15%-0.25%.

8. The ophthalmic solution composition according to claim 1 or 2, characterized in that: The solubilizer is selected from one or more of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 54 hydrogenated castor oil, polyoxyethylene 35 castor oil, vitamin E polyethylene glycol succinate 1000, polyoxyethylene 15 hydroxystearate and octylphenol polyoxyethylene ether 40.

9. The ophthalmic solution composition according to claim 2, characterized in that: The solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-55 polyoxyethylene units and polyoxyethylene hydroxystearate with 10-20 polyoxyethylene units, and the weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-80%.

10. The ophthalmic solution composition according to claim 9, characterized in that The weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-50%.

11. The ophthalmic solution composition according to claim 9, characterized in that: The weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-30%.

12. The ophthalmic solution composition according to claim 9, characterized in that The weight percentage of the polyoxyethylene hydroxystearate in the mixture is 0-10%.

13. The ophthalmic solution composition according to any one of claims 9 to 12, characterized in that: The solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units and polyoxyethylene hydroxystearate with 10-20 polyoxyethylene units.

14. The ophthalmic solution composition according to any one of claims 9 to 12, characterized in that: The solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 15 hydroxystearate.

15. The ophthalmic solution composition according to claim 2, characterized in that: The solubilizer is a mixture of polyoxyethylene hydrogenated castor oil with 35-45 polyoxyethylene units and octylphenol polyoxyethylene ether with 35-45 polyoxyethylene units, and the weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-20%.

16. The ophthalmic solution composition according to claim 15, characterized in that The weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-18%.

17. The ophthalmic solution composition according to claim 15, characterized in that: The weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-15%.

18. The ophthalmic solution composition according to claim 15, characterized in that The weight percentage of the octylphenol polyoxyethylene ether in the mixture is 0-5%.

19. The ophthalmic solution composition according to any one of claims 15 to 18, characterized in that The solubilizer is a mixture of polyoxyethylene 40 hydrogenated castor oil and octylphenol polyoxyethylene ether 40.

20. The ophthalmic solution composition according to claim 1 or 2, characterized in that: The solubilizer is polyoxyethylene castor oil having 30-40 polyoxyethylene units.

21. The ophthalmic solution composition according to claim 20, characterized in that: The solubilizing agent is polyoxyethylene 35 castor oil.

22. The ophthalmic solution composition according to claim 1 or 2, characterized in that: The solubilizer is vitamin E polyethylene glycol succinate with an average molecular weight of polyethylene glycol of 800-1200.

23. The ophthalmic solution composition according to claim 22, characterized in that The solubilizer is vitamin E polyethylene glycol succinate 1000.

24. The ophthalmic solution composition according to claim 1 or 2, characterized in that: The solubilizer is polyoxyethylene hydrogenated castor oil with 50-55 polyoxyethylene units.

25. The ophthalmic solution composition according to claim 24, characterized in that The solubilizer is polyoxyethylene 54 hydrogenated castor oil.

26. The ophthalmic solution composition according to claim 1 or 2, characterized in that: The solubilizer is polyoxyethylene hydroxystearate with 10-20 polyoxyethylene units.

27. The ophthalmic solution composition according to claim 26, characterized in that The solubilizer is polyoxyethylene 15 hydroxystearate.

28. The ophthalmic solution composition according to claim 1, characterized in that Based on the total weight of the composition, the content of the solubilizer is 2.5%-10%.

29. The ophthalmic solution composition according to claim 1 or 2, characterized in that: Based on the total weight of the composition, the content of the solubilizer is 3.75%-7.5%.

30. The ophthalmic solution composition according to claim 1, wherein The water content is 84%-98% based on the total weight of the composition.

31. The ophthalmic solution composition according to claim 1 or 2, characterized in that: The water content is 86%-98% based on the total weight of the composition.

32. The ophthalmic solution composition according to claim 1 or 2, characterized in that: Based on the total weight of the composition, the water content is 88%-98%.

33. The ophthalmic solution composition according to claim 1, characterized in that The content of the stabilizer is 0-4% based on the total weight of the composition.

34. The ophthalmic solution composition according to claim 1, characterized in that The content of the stabilizer is 0-3% based on the total weight of the composition.

35. The ophthalmic solution composition according to claim 1 or 2, characterized in that: Based on the total weight of the composition, the content of the stabilizer is 0.5%-3%.

36. The ophthalmic solution composition according to claim 1 or 2, characterized in that The composition further comprises one or more other pharmaceutically acceptable excipients; The other pharmaceutically acceptable excipients are selected from one or more of a viscosity enhancer, an antioxidant, a chelating agent, an antibacterial agent, a pH regulator, and an osmotic pressure regulator.

37. The ophthalmic solution composition according to claim 36, characterized in that The viscosity increasing agent is selected from one or more of xanthan gum, sodium hyaluronate, hydroxypropyl methylcellulose and sodium carboxymethyl cellulose; Based on the total weight of the composition, the content of the viscosity enhancer is 0.1%-3%.

38. The ophthalmic solution composition according to claim 36, wherein The antioxidant is selected from one or more of tocopherol or its succinate, ascorbic acid or its palmitate, butylated hydroxyanisole, 2,6-di-tert-butylated cresol and sodium thiosulfate; The content of the antioxidant is 0-1% based on the total weight of the composition.

39. The ophthalmic solution composition according to claim 38, characterized in that The antioxidant is selected from one or more of tocopherol and sodium thiosulfate; Based on the total weight of the composition, the content of the antioxidant is 0.05%-1%.

40. The ophthalmic solution composition according to claim 36, wherein 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; The content of the chelating agent is 0-2% based on the total weight of the composition.

41. The ophthalmic solution composition according to claim 40, characterized in that The chelating agent is edetic acid or edetate disodium; The content of the chelating agent is 0.01%-1% based on the total weight of the composition.

42. The ophthalmic solution composition according to claim 36, wherein The pH regulator is selected from one or more of inorganic or organic acids, bases and buffer salts; wherein the acid is selected from one or more of hydrochloric acid, phosphoric acid, acetic acid, citric acid, lactic acid and boric acid; the base is selected from one or more of ethylenediamine, ethanolamine, basic amino acids, sodium hydroxide, calcium hydroxide, potassium hydroxide and ammonia solution; the buffer salt is selected from one or more of boric acid-borax buffer salt, citric acid-sodium citrate buffer salt, phosphoric acid-sodium phosphate buffer salt and acetic acid-sodium acetate buffer salt; The pH value of the composition is 5-9.

5.

43. The ophthalmic solution composition according to claim 42, characterized in that The pH regulator is selected from one or more of phosphoric acid-sodium phosphate buffer salt and boric acid-borax buffer salt; The pH value of the composition is 6.5-8.

44. The ophthalmic solution composition according to claim 36, characterized in that The osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, glucose, sorbitol, polyethylene glycol, glycerol and propylene glycol.

45. Use of the ophthalmic solution composition according to any one of claims 1 to 44 in the preparation of a medicament for preventing and / or treating ophthalmic diseases or conditions associated with toxic aldehydes including pro-inflammatory reactive aldehydes, wherein the ophthalmic diseases or conditions are selected from one or more of dry eye syndrome, allergic conjunctivitis and uveitis.

46. The use according to claim 45, characterized in that The ocular disease or disorder is dry eye syndrome.

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