Pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention provides a pharmaceutical composition as well as a preparation method and application thereof. The pharmaceutical composition comprises a compound of formula I. The pharmaceutical composition provided by the invention has high drug loading capacity, good uniformity and good stability, and can be used for preparing drugs for preventing and / or treating glaucoma or intraocular hypertension. # imgabs0 #

Description

A pharmaceutical composition and its preparation method and application Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a pharmaceutical composition, a preparation method and an application thereof. Background Art

[0002] Rho-associated kinase (ROCK), a serine / threonine protein kinase, is a downstream target of RHO and is widely expressed in the human body. ROCK is involved in the regulation of myosin light chain (MLC) and is suitable for the treatment of vasodilation. ROCK also acts on trabecular outflow tract cells, relaxing them and reducing aqueous humor outflow resistance. Recent studies have shown that ROCK inhibitors can also promote the repair of damaged corneal endothelial cells and prevent fibrosis, offering promising therapeutic applications.

[0003] Isoquinoline sulfonamide compounds are an important class of ROCK inhibitors. Both fasudil and K-115, currently on the market, are isoquinoline sulfonamide compounds (WO2006057397A1). Fasudil is a novel drug with a broad range of pharmacological effects. It is a RHO kinase inhibitor that dilates blood vessels by increasing the activity of myosin light chain phosphatase, reducing endothelial cell tension, improving brain microcirculation, and preventing or exacerbating brain steal. It also antagonizes inflammatory factors, protects neurons from apoptosis, and promotes neural regeneration. K-115 has a wide range of approved and potential applications, including glaucoma, elevated intraocular pressure, complications of diabetic retinopathy, age-related macular degeneration, corneal damage, and recovery after cataract and glaucoma surgery. It may also be further expanded to systemic medication.

[0004] WO2020253882A1 discloses an isoquinolinone derivative as a ROCK protein kinase inhibitor and its use in the preparation of a drug for glaucoma or ocular hypertension related to ROCK protein kinase inhibitors, and specifically discloses compound 63 in the specification.

[0005] This compound shows a better intraocular pressure-lowering effect than K-115, but due to its poor water solubility, it may bring many adverse effects in terms of drugability, such as: 1) reduced exposure to the compound, affecting the efficacy of the drug; 2) affecting the metabolism of the drug in the body; 3) the need to increase the dosage to achieve the drug effect, which will cause the drug to accumulate in the body or crystallize, increasing the risk of toxic side effects; 4) it is not easy to make oral or intravenous or other liquid preparations, resulting in increased investment in later research and development; especially in the field of ophthalmic preparations, the range of dosage forms available is narrow (mainly liquid preparations, gels, eye ointments, etc.), among which eye drops are the most ideal dosage form, but due to the poor water solubility of the compound, often only suspensions can be obtained, or the uniformity and stability indicators of the developed liquid preparations are difficult to meet the requirements, and there are disadvantages such as severe eye irritation and poor patient compliance, making them unsuitable for use as drugs for patients.

[0006] Therefore, in order to overcome the above-mentioned defects, it is very necessary to develop ophthalmic preparations that are suitable for drug formulation and have simple components, especially liquid preparations, to improve the solubility of the compound, the stability of the preparation and the compliance of the patient.

[0007] Summary of the Invention

[0008] In view of the shortcomings of the prior art, the present invention aims to provide a pharmaceutical composition and its preparation method and application. The pharmaceutical composition comprises a sulfate salt of an isoquinolinone derivative and has a higher drug loading capacity, better uniformity and stability.

[0009] In a first aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I:

[0010] In some embodiments of the present invention, the pharmaceutical composition comprises a compound of formula I and a pharmaceutically acceptable excipient, carrier and / or diluent.

[0011] In some embodiments of the present invention, the pharmaceutical composition comprises a compound of formula I and a solubilizing agent. In some embodiments of the present invention, the pharmaceutical composition comprises a compound of formula I and an osmotic pressure regulator. In some embodiments of the present invention, the pharmaceutical composition comprises a compound of formula I and an antibacterial agent.

[0012] In some embodiments of the present invention, the pharmaceutical composition comprises a compound of formula I, a solubilizer, an osmotic pressure regulator, and an antibacterial agent.

[0013] In the pharmaceutical composition, the mass ratio of the compound of formula I to the osmotic pressure regulator can be 1:(4.5-600), for example, 1:(10-500), 1:(20-400), 1:(30-350), etc.

[0014] In the pharmaceutical composition, the mass ratio of the compound of formula I to the solubilizer can be 1:(2-70), preferably 1:(2-50), for example 1:(2.5-40), 1:(5-40), 1:(10-40), etc.

[0015] In some embodiments of the present invention, the solubilizer is selected from one or more of Tween 80, polyoxyethylene 40 hydrogenated castor oil, polyethylene glycol 400, poloxamer 188, polyoxyethylene hydrogenated stearate, polyoxyethylene castor oil and derivatives thereof, such as one, two, three or four.

[0016] In some embodiments of the present invention, the solubilizer is polyoxyethylene hydrogenated castor oil.

[0017] In some embodiments of the present invention, the polyoxyethylene hydrogenated castor oil is selected from one or more of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 54 hydrogenated castor oil and polyoxyethylene 60 hydrogenated castor oil.

[0018] In some embodiments of the present invention, the solubilizing agent is Tween 80 and / or polyoxyethylene 40 hydrogenated castor oil.

[0019] In some embodiments of the present invention, the solubilizing agent is Tween 80 and polyoxyl 40 hydrogenated castor oil. In some embodiments, in the composition, the mass ratio of Tween 80 to polyoxyl 40 hydrogenated castor oil is 1:(0.1-30), for example, 1:(0.5-20), 1:(1-10), 1:(2-10), 1:(2-8), etc.

[0020] In some embodiments of the present invention, the osmotic pressure regulator is selected from one or more of sodium chloride, potassium chloride, mannitol, glycerol, propylene glycol, dextrose, boric acid, and borax, for example, one, two, three, or four. Preferably, the osmotic pressure regulator is sodium chloride and / or mannitol. More preferably, the osmotic pressure regulator is sodium chloride and mannitol.

[0021] In some embodiments of the present invention, the antibacterial agent is selected from any combination of one or more of benzalkonium chloride, thimerosal, domiphene, chlorbutanol, parabens, and sorbic acid, preferably benzalkonium chloride.

[0022] In some embodiments of the present invention, the pharmaceutical composition comprises the following components: a compound of formula I, and one or more selected from Tween 80, polyoxyethylene 40 hydrogenated castor oil, sodium chloride, mannitol, and benzalkonium chloride.

[0023] In some embodiments of the present invention, the pharmaceutical composition comprises the following components: a compound of formula I, and one or more of polyoxyethylene hydrogenated castor oil, sodium chloride, mannitol, and benzalkonium chloride.

[0024] In some embodiments of the present invention, the pharmaceutical composition comprises the following components: a compound of formula I, and polyoxyethylene hydrogenated castor oil.

[0025] In some embodiments of the present invention, the pharmaceutical composition comprises the following components: a compound of formula I, polyoxyethylene hydrogenated castor oil, sodium chloride, mannitol and benzalkonium chloride.

[0026] In some embodiments of the present invention, the pharmaceutical composition comprises the following components: a compound of formula I, polyoxyethylene 40 hydrogenated castor oil, sodium chloride, mannitol, and benzalkonium chloride.

[0027] In some embodiments of the present invention, the pharmaceutical composition comprises the following components: a compound of formula I, Tween 80, and polyoxyethylene 40 hydrogenated castor oil.

[0028] In some embodiments of the present invention, the pharmaceutical composition comprises the following components: a compound of formula I, Tween 80, polyoxyethylene 40 hydrogenated castor oil, and sodium chloride.

[0029] In some embodiments of the present invention, the pharmaceutical composition comprises the following components: a compound of formula I, Tween 80, polyoxyethylene 40 hydrogenated castor oil, sodium chloride and benzalkonium chloride.

[0030] In some embodiments of the present invention, the pharmaceutical composition comprises the following components: a compound of formula I, Tween 80, polyoxyethylene 40 hydrogenated castor oil, sodium chloride and mannitol.

[0031] In some embodiments of the present invention, the pharmaceutical composition comprises the following components: a compound of formula I, Tween 80, polyoxyethylene 40 hydrogenated castor oil, sodium chloride, mannitol and benzalkonium chloride.

[0032] In some embodiments of the present invention, in the pharmaceutical composition, the weight proportions of the compound of formula I, the solubilizer, the osmotic pressure regulator, and the antibacterial agent are respectively:

[0033] In some embodiments of the present invention, in the pharmaceutical composition, the weight ratio of the solubilizer can be any value in the range of 2-70 parts, for example, it can be 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 8 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts or 70 parts.

[0034] In some embodiments of the present invention, in the pharmaceutical composition, the weight ratio of the osmotic pressure regulator can be any value in the range of 13-600 parts, for example, it can be 13 parts, 14 parts, 15 parts, 16 parts, 18 parts, 20 parts, 25 parts, parts, 30 parts, 40 parts, 50 parts, 60 parts, 70 parts, 80 parts, 90 parts, 100 parts, 120 parts, 150 parts, 180 parts, 200 parts, 250 parts, 300 parts, 350 parts, 400 parts, 450 parts, 500 parts, 550 parts or 600 parts.

[0035] In some embodiments of the present invention, in the pharmaceutical composition, the weight ratio of the antibacterial agent can be any value in the range of 0.05-3.2 parts, for example, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1 or 3.2 parts.

[0036] In some embodiments of the present invention, the pharmaceutical composition comprises the following components in parts by weight:

[0037] 1 part of the compound of formula I;

[0038] Tween 80 0.3-3.5 parts (e.g., 0.3 parts, 0.4 parts, 0.5 parts, 0.6 parts, 0.7 parts, 0.8 parts, 0.9 parts, 1 part, 1.1 parts, 1.2 parts, 1.3 parts, 1.4 parts, 1.5 parts, 1.6 parts, 1.7 parts, 1.8 parts, 1.9 parts, 2 parts, 2.1 parts, 2.2 parts, 2.3 parts, 2.4 parts, 2.5 parts, 2.6 parts, 2.7 parts, 2.8 parts, 2.9 parts, 3 parts, 3.2 parts, etc.); and

[0039] Polyoxyethylene hydrogenated castor oil, such as polyoxyethylene 40 hydrogenated castor oil 2-35 parts (e.g., 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, 21 parts, 22 parts, 23 parts, 24 parts, 25 parts, 26 parts, 27 parts, 28 parts, 29 parts, 30 parts, 32 parts, etc.).

[0040] In some embodiments of the present invention, the pharmaceutical composition comprises the following components in parts by weight:

[0041] 1 part of the compound of formula I;

[0042] Tween 80 0.3-3.5 parts (e.g., 0.4 parts, 0.5 parts, 0.6 parts, 0.7 parts, 0.8 parts, 0.9 parts, 1 part, 1.1 parts, 1.2 parts, 1.3 parts, 1.4 parts, 1.5 parts, 1.6 parts, 1.7 parts, 1.8 parts, 1.9 parts, 2 parts, 2.1 parts, 2.2 parts, 2.3 parts, 2.4 parts, 2.5 parts, 2.6 parts, 2.7 parts, 2.8 parts, 2.9 parts, 3 parts, 3.2 parts, etc.);

[0043] Polyoxyethylene hydrogenated castor oil, such as polyoxyethylene 40 hydrogenated castor oil 2-35 parts (e.g., 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, 21 parts, 22 parts, 23 parts, 24 parts, 25 parts, 26 parts, 27 parts, 28 parts, 29 parts, 30 parts, 32 parts, etc.);

[0044] 9-110 parts of sodium chloride (e.g., 9 parts, 10 parts, 13 parts, 15 parts, 18 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 50 parts, 60 parts, 70 parts, 80 parts, 90 parts, 100 parts or 107 parts, etc.); and

[0045] Mannitol 4-200 parts (e.g., 4 parts, 5 parts, 8 parts, 10 parts, 12 parts, 15 parts, 18 parts, 20 parts, 25 parts, 30 parts, 40 parts, 50 parts, 60 parts, 80 parts, 100 parts, 120 parts, 150 parts, 170 parts, 190 parts, 195 parts, etc.).

[0046] In some embodiments of the present invention, the pharmaceutical composition comprises the following components in parts by weight:

[0047] In some embodiments of the present invention, the pharmaceutical composition is in the form of a solution, suspension, emulsion, gel, micelle or any pharmaceutically applicable topical ophthalmic dosage form.

[0048] In some embodiments of the present invention, in the pharmaceutical composition, the content of the compound of formula I is 0.01-2 mg / mL, specifically, it can be any value in the range of 0.01-2 mg / mL, for example, it can be 0.01 mg / mL, 0.02 mg / mL, 0.05 mg / mL, 0.08 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.5 mg / mL, 0.8 mg / mL, 1 mg / mL, 1.2 mg / mL, 1.5 mg / mL, 1.8 mg / mL or 2 mg / mL, etc.; preferably, it is any value in the range of 0.05-1 mg / mL.

[0049] In some embodiments of the present invention, the crystalline form of the compound of formula I is crystalline form A or crystalline form B.

[0050] In some embodiments of the present invention, the crystalline form of the compound of formula I is crystalline form B.

[0051] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 6.33±0.20°, 10.62±0.20°, and 13.11±0.20°.

[0052] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 3.30±0.20°, 6.33±0.20°, 6.55°±0.20°, 10.62±0.20°, 12.57±0.20°, 13.11±0.20°.

[0053] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 3.30±0.20°, 6.33±0.20°, 10.62±0.20°, 12.57±0.20°, 13.11±0.20°, 17.85±0.20°, 18.51±0.20°, 20.99±0.20°.

[0054] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A has characteristic diffraction peaks at the following 2θ angles: 3.30±0.20°, 6.33±0.20°, 6.55±0.20°, 10.62±0.20°, 12.57±0.20°, 13.11±0.20°, 14.20±0.20°, 16.37±0.20°, 17.85±0.20°, 18.51±0.20°, 19.56±0.20°, 20.99±0.20°, 25.53±0.20°, 26.35±0.20°.

[0055] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 9.69±0.20°, 12.12±0.20°, 16.48±0.20°, 16.95±0.20°, 17.94±0.20°, 19.23±0.20°, 20.37±0.20°, 21.87±0.20°.

[0056] The present invention provides a crystalline form B of a compound of formula I, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 16.48±0.20°, 16.95±0.20°, and / or 21.87±0.20°, and / or 12.12±0.20°, and / or 17.94±0.20°, and / or 9.69±0.20°, and / or 20.37±0.20°, and / or 21.87±0.20°, and / or 4.80±0.20°, and / or 14.61±0.20°, and / or 19.23±0.20°, and / or 27.53±0.20°, and / or 28.72±0.20°, and / or 33.61±0.20°.

[0057] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2θ angles: 4.80±0.20°, 9.69±0.20°, 12.12±0.20°, 14.61±0.20°, 16.48±0.20°, 16.95±0.20°, 17.94±0.20°, 19.23±0.20°, 20.37±0.20°, 21.87±0.20°, 27.53±0.20°, 28.72±0.20°, and 33.61±0.20°.

[0058] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2θ angles: 4.80±0.20°, 9.69±0.20°, 12.12±0.20°, 16.48±0.20°, 16.95±0.20°, 17.94±0.20°, 19.23±0.20°, 20.37±0.20°, 21.87±0.20°.

[0059] In some embodiments of the present invention, the pH of the pharmaceutical composition is 4.0-6.0, specifically, any value within the range of 4.0-6.0, for example, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0.

[0060] In some preferred embodiments of the present invention, by selecting Tween 80 and / or polyoxyethylene 40 hydrogenated castor oil as solubilizers, and / or selecting sodium chloride and mannitol as osmotic pressure regulators for synergistic use, the solubility of the compound of formula I and the stability of the liquid preparation containing the compound are further improved, which helps to solve the defects of the compound of formula I caused by poor water solubility, such as low drug loading, poor preparation uniformity and stability, etc.

[0061] In a second aspect, the present invention provides a method for preparing the pharmaceutical composition according to the first aspect, comprising the following steps:

[0062] The compound of formula I is mixed with pharmaceutically acceptable excipients, carriers and / or diluents (such as solubilizers, osmotic pressure regulators and / or antibacterial agents) in corresponding parts by weight to obtain the pharmaceutical composition.

[0063] Preferably, the preparation method comprises: mixing the compound of formula I with a solubilizer, an osmotic pressure regulator and an antibacterial agent in corresponding parts by weight to obtain the pharmaceutical composition.

[0064] In some embodiments of the present invention, the preparation method comprises: uniformly mixing the compound of formula I, Tween 80, polyoxyethylene 40 hydrogenated castor oil, an optional osmotic pressure regulator, and an optional antibacterial agent in corresponding parts by weight to obtain the composition.

[0065] It should be noted that the term "optionally" as used herein refers to the presence or absence of a corresponding component. When a pharmaceutical composition contains a corresponding component, that component is used in the preparation method; when a pharmaceutical composition does not contain a corresponding component, that component is not used in the preparation method.

[0066] In some embodiments of the present invention, the preparation method comprises the following steps:

[0067] (1) dissolving the osmotic pressure regulator in water for injection to obtain solution I;

[0068] (2) uniformly mixing the solubilizing agent and the compound of formula I to obtain a mixture II;

[0069] (3) mixing the solution I and the mixture II and stirring them uniformly to obtain a solution III;

[0070] (4) dissolving the antibacterial agent in water for injection to obtain solution IV;

[0071] (5) The solution III and the solution IV are mixed, and the volume is adjusted to the full amount with water for injection, and the solution is sterilized by three-stage filtration using a microporous filter membrane to obtain the pharmaceutical composition.

[0072] In a third aspect, the present invention provides use of the pharmaceutical composition described in the first aspect or the pharmaceutical composition prepared by the preparation method described in the second aspect in preparing a drug for preventing and / or treating glaucoma or ocular hypertension.

[0073] Compared with the prior art, the present invention has the following beneficial effects:

[0074] The compound of formula I of the present invention is in the form of sulfate, which has improved water solubility compared to its non-salt form, and the obtained composition has a higher drug loading capacity, better uniformity and stability.

[0075] In an embodiment of the present invention, by selecting Tween 80 and / or polyoxyethylene 40 hydrogenated castor oil as a solubilizing agent, the solubility of the compound of formula I and the stability of the pharmaceutical preparation containing the compound are further improved, thereby overcoming the defects of the compound of formula I, such as low drug loading, poor formulation uniformity and stability, caused by its poor water solubility. The resulting composition can completely dissolve the compound of formula I, and under long-term conditions of 12 months (25°C ± 2°C; RH 40% ± 5%, 5 ± 3°C) and accelerated conditions of 6 months (40°C ± 2°C; RH 25% ± 5%), the preparation remains colorless and clear, and the osmotic pressure, pH value, relative content of the compound of formula I, and the content of related substances are all relatively stable. DETAILED DESCRIPTION

[0076] The technical solution of the present invention is further described below by way of specific embodiments. It should be understood by those skilled in the art that the specific embodiments are merely to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0077] X-ray powder diffractometer (XRPD) method

[0078] Instrument model: PANalytical X'pert 3 X-ray powder diffractometer

[0079] Test method: Approximately 10 mg of sample was used for XRPD analysis.

[0080] The detailed XRPD parameters are as follows:

[0081] Radiation source: Cu, Cu,

[0082] Light tube voltage: 40kV, light tube current: 40mA

[0083] Scanning range: 3-40 degrees

[0084] Step width angle: 0.0263deg

[0085] Step length: 46.665 seconds

[0086] Synthesis of intermediates 1-4

[0087] first step

[0088] Toluene (24 L) was added to the reactor while maintaining the internal temperature at 25-35°C. Compound 1-4a (4000 g), sodium carbonate (6120 g), methylboronic acid (3465 g), 2-dicyclohexylphosphine-2',6'-dimethoxybiphenyl (98.66 g), and trisdibenzylideneacetone dipalladium (88.03 g) were added sequentially to the reactor with stirring. The reactor was purged with nitrogen three times. The internal temperature of the reactor was raised to 90°C, and the mixture was stirred at 90-100°C for 13 hours. Water (4 L) was added to the reactor to dissolve the solid. The reaction mixture was cooled to room temperature and filtered through celite. The filter cake was washed with methyl tert-butyl ether (4 L). The washings and filtrate were combined, and the pH was adjusted to 3 with concentrated hydrochloric acid (8 L). The mixture was allowed to stand for separation. The lower aqueous phase was extracted with methyl tert-butyl ether (5 L), the pH of the aqueous phase was adjusted to 9 with aqueous sodium hydroxide solution, the aqueous phase was extracted twice with ethyl acetate (12 L), and the combined organic phases were concentrated in vacuo until the weight no longer decreased to obtain compound 1-4b.

[0089] MS-ESI calculated value [M+H] + 144, measured value 144.

[0090] Step 2

[0091] Control the temperature inside the reactor below 30°C and slowly add concentrated sulfuric acid (13.36L) to a 50L reactor. Control the temperature inside the reactor below 50°C and slowly add compound 1-4b (2500g) to the reactor using a constant pressure dropping funnel. Control the temperature inside the reactor at -10 to 0°C and slowly add N-bromosuccinimide (3070.25g) to the reactor in batches. The reaction solution is stirred at -10 to 8°C for 13 hours. Control the temperature inside the reactor below 50°C and slowly pour the reaction solution into ice water (8L). Control the temperature inside the reactor below 50°C and slowly add aqueous sodium hydroxide solution to the reaction solution to adjust the pH to 9. Add ethyl acetate (10L) to the reaction solution and stir for 10 minutes. Filter the reaction solution and wash the filter cake with ethyl acetate (12.5L). Extract the aqueous phase with ethyl acetate (10L×3) and concentrate the combined organic phases under reduced pressure at 45°C. n-Heptane (10 L) was added to the concentrated residue for slurrying, and suction filtration was performed to obtain a brown-red solid, which was placed in a vacuum drying oven (40° C.) and dried to obtain compound 1-4c.

[0092] MS-ESI calculated value [M+H] + 222, 224, measured values ​​222, 224.

[0093] Step 3

[0094] To a 50 L reactor, add N,N-dimethylacetamide (10 L) and stir. Add 1-4c (1003.65 g). Slowly add sodium thiomethoxide (1276.97 g) in portions to the 50 L reactor, maintaining the internal temperature below 55°C. Stir the reaction mixture at 50°C for 30 minutes. Raise the reactor temperature to 120°C, where the internal temperature is 109°C, and stir for 12 hours. Adjust the reactor temperature to 50°C, lowering the reaction mixture temperature to 40-50°C. Filter the reaction mixture through celite and wash with ethyl acetate (10 L). Add water (10 L) to the filtrate, and extract the aqueous phase with ethyl acetate (5 L x 2). Adjust the pH of the aqueous phase to 7 with concentrated hydrochloric acid. Extract the aqueous phase with ethyl acetate (5 L x 2). Combine the organic phases, wash with water (10 L x 3), and concentrate under reduced pressure until the weight remains unchanged to yield compound 1-4d.

[0095] MS-ESI calculated value [M+H] + 176, measured value 176.

[0096] Step 4

[0097] Add dichloromethane (8L) to a clean 50L high and low temperature reactor and start stirring. Add compound 1-4d (1474.02g) to the reactor and adjust the oil bath temperature to control the temperature in the reactor at 0-10°C. Add concentrated hydrochloric acid (4.38L) slowly to the reactor in batches, and control the internal temperature at 5-15°C. After the concentrated hydrochloric acid is added dropwise, reduce the internal temperature of the reactor to -5°C. Add sodium hypochlorite aqueous solution (21.35L) slowly dropwise to the reactor in batches, and control the temperature at 0-10°C throughout the process. Filter the reaction solution, wash the filter cake with methyl tert-butyl ether (2L×2), and collect the filter cake. Place the collected filter cake in an oven and dry to obtain compound 1-4e.

[0098] MS-ESI calculated value [M+H] + 242, measured value 242.

[0099] Step 5

[0100] Add dichloromethane (10 L) to a 50 L reactor, start stirring, control the internal temperature at 0-10°C, and weigh 1-4e (1462.35 g) and add it to the reactor. Control the internal temperature at 0-10°C, weigh N,N-diisopropylethylamine (934.63 g) and slowly add it dropwise to the reaction solution. Control the internal temperature at 0-10°C, and weigh 1-4f (1230.24 g) and slowly add it to the reaction solution in batches. After the addition is complete, raise the temperature to 10-20°C and continue stirring for 0.5 hours. Wash the organic phase with saturated ammonium chloride aqueous solution (3 L x 3), and extract the combined saturated ammonium chloride aqueous solution with dichloromethane (3 L). Separate the organic phases and concentrate under reduced pressure until the weight remains unchanged, then dry them in a vacuum drying oven to obtain compound 1-4g.

[0101] MS-ESI calculated value [M+H] + 392, measured value 392.

[0102] Step 6

[0103] 3.1L of anhydrous dichloromethane is added to a clean 5L three-necked flask, opened and stirred. Weighed 1-4g (451.34g) is added to the reaction flask. After the solid dissolves, the reaction flask is put into an ice-water bath so that the temperature in the reaction system is reduced to 0 ℃. Weighed meta-chloroperbenzoic acid (429.81g) is slowly added to the 5L reaction flask in batches, and the whole process maintains the temperature at 0-10 ℃. After meta-chloroperbenzoic acid has added, the ice-water bath of the reaction flask is removed and replaced with an oil bath so that the temperature in the reaction flask is stabilized at 20-25 ℃, stirred for 12 hours. The reaction flask is put into an ice-water bath and stirred for 1 hour, filtered, and the filter cake is rinsed with dichloromethane (400mL×2). The filtrate is dripped with 10% sodium thiosulfate aqueous solution at 25-30 ℃ until the starch potassium iodide test paper does not turn blue. Saturated sodium bicarbonate aqueous solution is dripped in the system to pH=7. The organic phase was retained and the aqueous phase was extracted once more with 3 L of dichloromethane. The organic phases were combined. The organic phase was washed with 1% aqueous sodium bicarbonate (4 L x 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting solid was oven-dried to yield compound 1-4h.

[0104] MS-ESI calculated value [M+H] + 408, measured value 408.

[0105] Step 7

[0106] To a 5L three-necked flask, add 1-4h (301.42g) and tetrahydrofuran (1.5L). Stir thoroughly. Add triethylamine (206mL) dropwise at an internal temperature of 10-20°C and stir thoroughly. Add trifluoroacetic anhydride (206mL) dropwise at an internal temperature of 20-30°C and react at 20-30°C for 0.5 hour. Add water (1.5L) to the reaction solution and stir thoroughly, until the solution becomes turbid. Add solid sodium hydroxide (600g) at an internal temperature of 40-50°C and stir for 0.5 hour. A large amount of solid precipitates. Add 1.5L of methyl tert-butyl ether and stir for 0.5 hour. The reaction solution is separated, and the upper organic phase is filtered to obtain a solid. The solid is slurried with methyl tert-butyl ether / ethyl acetate (4.4L, 10:1), and the slurry is filtered to obtain a white solid. The white solid is oven-dried to obtain the crude product of 1-4 (371.52g). Tetrahydrofuran (7 L) was added to a 50 L reactor, the internal temperature was controlled at 20-25 ° C, and the crude compound 1-4 (1713.19 g, combined from other batches) was added and stirred at an internal temperature of 20-25 ° C for 0.5 hours. 8.6 L of water was added, stirred at 20-25 ° C for 0.5 hours, solid sodium hydroxide (800 g) was added, and stirred at an internal temperature of 20-25 ° C for 0.5 hours. Methyl tert-butyl ether (8.6 L) was added and stirred at an internal temperature of 20-25 ° C for 0.5 hours. The liquid was separated, the upper organic phase was filtered, and the solid obtained from the filtration was retained. The solid was placed in an oven and dried to constant weight to obtain compound 1-4.

[0107] MS-ESI calculated value [M+H] + 408, measured value 408.

[0108] Preparation of Crystalline Form A of Compound I

[0109] first step

[0110] Start stirring and nitrogen protection, and add dichloromethane (8.6L), water (8.6L), and starting material compound 1-1 (575.34g) to the reactor in sequence. Control the internal temperature of the reactor to 10-15°C, and add sodium bicarbonate (1289.36g), tetrabutylammonium hydrogen sulfate (133.87g), and starting material compound 1-2 (760.25g) to the reactor in sequence. Control the internal temperature of the reactor to 10-15°C and stir for 2 hours. The reaction solution is allowed to stand and separate, and the organic phase is concentrated under reduced pressure until no distillate flows out. Transfer the concentrate to a three-necked flask and control the internal temperature to 60-70°C. After stirring for 12 hours, cool naturally to room temperature. The crude product is quickly filtered through silica gel and rinsed with dichloromethane until no product residue is left. The eluate was concentrated under reduced pressure to about 1.2 L, washed with 1% aqueous sodium bicarbonate solution (3 L), and the organic phase was dried over anhydrous sodium sulfate (500 g). After filtration, the organic phase was concentrated under reduced pressure until no fraction flowed out, to obtain intermediate 1-3 which was used directly in the next step without purification.

[0111] MS-ESI calculated value [M+H] + 199, measured value 199.

[0112] 1 H NMR (400MHz, CD3Cl) δ7.81-7.79 (d, J = 8Hz, 1H), 7.01-6.95 (m, 2H), 5.84 (s, 2H), 2.52 (s, 3H), 2.27 (s, 3H) ppm.

[0113] Step 2

[0114] Add 2-methyltetrahydrofuran (9702 mL) to a reactor, start stirring, and maintain the internal temperature at 10-20°C. Then, add Intermediate 1-4 (1078.26 g), cesium carbonate (1017.63 g), and Intermediate 1-3 (631.71 g) in sequence. Raise the internal temperature of the reactor to 57-63°C and stir for 2 hours and 40 minutes before stopping the reaction. Lower the internal temperature of the reactor to 15-25°C, add water (10.78 L), stir, and allow to stand to separate. The resulting aqueous phase is extracted twice with 2-methyltetrahydrofuran (5390 mL x 2). The combined organic phases are concentrated under reduced pressure to approximately 2.2 L. Add acetone (1078 mL) and n-heptane (2156 mL) to the concentrate and continue concentrating until no more fractions flow out, yielding a loose solid. The internal temperature was controlled at 10-30°C, and the solid was slurried and stirred three times with a mixed solvent (11.0495 L, acetone:n-heptane = 1:40), filtered, and rinsed with n-heptane (1078 mL). The filter cake was dried under reduced pressure in vacuo to a constant weight to obtain Intermediate 1-5.

[0115] MS-ESI calculated value [M+H] +570, measured value 570.

[0116] 1 H NMR(400MHz,CD3Cl)δ8.86-8.78(m,1H),8.13-8.04(m,1H),7.93-7.86(m,1H),7.5 8-7.49(m,1H),7.39-7.32(m,1H),7.09-6.99(m,2H),6.14(s,2H),4.86-4.76(m,1H ),4.42-4.30(m,1H),3.73-3.61(m,2H),3.57-3.47(m,1H),3.46-3.37(m,1H),2.7 6-2.67(m,3H),2.59(s,3H),2.39-2.29(m,4H),2.09-1.97(m,1H),1.46(s,9H)ppm.

[0117] Step 3

[0118] Control the internal temperature at 20-30°C and add anhydrous tetrahydrofuran (4.24 L) and concentrated sulfuric acid (712.43 g) to a 5L three-necked flask in sequence, stir evenly and set aside. Control the internal temperature at 20-30°C and add intermediate 1-5 (1062.15 g) and tetrahydrofuran (4.24 L) to a reactor in sequence, stir evenly and then add the pre-prepared sulfuric acid tetrahydrofuran solution dropwise to the system. Then control the internal temperature of the reaction at 35-45°C and stir for 4 hours. A large amount of white precipitate will gradually precipitate in the system. Methyl tert-butyl ether (8.48 L) was slowly added to the reactor, the internal temperature was controlled at 20-30°C, and the mixture was stirred for 0.5 hours. The filtered solid was then slurried in a mixed solvent (methyl tert-butyl ether / tetrahydrofuran = 10.6 L / 10.6 L) and methyl tert-butyl ether (21.2 L) at 20-30°C for 0.5 hours, and then slurried in water five times (21.2 L x 5) until the filtrate pH reached approximately 7. The internal temperature was controlled at 20-30°C, and the solid was slurried in methyl tert-butyl ether (15.9 L) and a mixed solvent (methyl tert-butyl ether / tetrahydrofuran = 10.6 L / 5.3 L) in sequence, followed by filtration, rinsing, and vacuum drying at below 45°C to obtain the crystalline form A of the compound of formula I. Ion chromatography analysis revealed a sulfate content of 9.17%, indicating that the compound of formula (II) contained 0.5 sulfate.

[0119] MS-ESI calculated value [M+H] + 470, measured value 470. 1H NMR(400MHz, DMSO-d6)δ8.64-8.58(m,1H),8.26(d,J=8Hz,1H),7.74-7.62( m,3H),7.16-7.11(m,1H),7.11-7.05(m,1H),6.08(s,2H),3.94-3.89(m,1H) ,3.70-3.55(m,2H),3.55-3.44(m,1H),3.43-3.27(m,1H),2.59(s,3H),2.4 8-2.45(m,3H),2.35-2.29(m,1H),2.29-2.24(m,3H),2.16-1.90(m,1H)ppm.

[0120] The X-ray powder diffraction pattern analysis data of the crystalline form A of the compound of formula I is shown in Table 1.

[0121] Table 1 X-ray powder diffraction pattern analysis data of the crystal form A of the compound of formula I

[0122] Preparation of Form B of Compound I

[0123] An appropriate amount of Form A of Compound I was weighed into a sample vial. A certain volume of the solvent listed in Table 2 was added to prepare suspensions or solutions in different single solvents. After stirring the suspension at 50°C for 3 hours, the sample was filtered and the filtered solid was placed in a vacuum drying oven and vacuum-dried at 45°C to remove residual solvent, yielding Form B of Compound I. The preparation conditions for Form B of Compound I are shown in Table 2 below. The X-ray powder diffraction pattern analysis data for Form B of Compound I is shown in Table 3.

[0124] Table 2 Preparation of Form B of Compound I

[0125] Table 3 X-ray powder diffraction pattern analysis data of the crystal form B of the compound of formula I

[0126] Study on the Hygroscopicity of Form B of Compound I

[0127] Experimental Materials:

[0128] SMS DVS intrinsic dynamic gas adsorption instrument.

[0129] Experimental methods:

[0130] 10-15 mg of the crystalline form B of the compound of formula I was placed in a DVS sample tray for testing.

[0131] Experimental conclusion:

[0132] The weight gain of the crystalline form B of the compound of formula I at 25° C. and 80% RH was 0.736%, indicating slight hygroscopicity.

[0133] Study on solid stability of crystal form B of compound I

[0134] The crystalline Form B of the compound of Formula I was stored at 40°C / 75% relative humidity (sealed in a double-layer LDPE bag, then heat-sealed in an aluminum foil bag) for 6 months and at 25°C / 60% RH (sealed in a double-layer LDPE bag, then heat-sealed in an aluminum foil bag) for 12 months. The crystalline form was tested at each sampling point to determine the sample's crystalline stability. The results of the solid-state stability study of the crystalline Form B of the compound of Formula I are shown in Table 4.

[0135] Table 4 Experimental results of solid stability study of compound B of formula I

[0136] Conclusion: Form B of the compound of formula I has good stability under both accelerated and long-term tests.

[0137] In the embodiment of the present invention, the content of the compound of formula I was detected using a high performance liquid detector (Agilent 1260PDA / UV detector), and the chromatographic conditions are shown in Table 5 below.

[0138] Table 5

[0139] In the following examples, unless otherwise specified, the compound of formula I was tested using the crystal form B of compound of formula I.

[0140] Example 1 Solubility test of Compound I, Form B, see Table 6.

[0141] Table 6

[0142] It can be seen from the above experiments that although the water solubility of the compound of formula I is improved compared with the non-salt form, other excipients need to be added to meet the requirements of eye drop preparation.

[0143] Example 2

[0144] In this example, the compound of formula I and a solubilizer were dissolved in water to prepare different formulations to investigate the effects of different solubilizers on the solubility of the compound of formula I. The specific formulation components and experimental results are shown in Table 7 below.

[0145] Table 7

[0146] The experimental results in Table 7 show that in the presence of a certain amount of Tween 80 and / or polyoxyethylene 40 hydrogenated castor oil (Formulations 4, 5, and 7), the compound of Formula I can not only be completely dissolved, but also will not precipitate after long-term storage, indicating that the obtained formulation has good stability.

[0147] Example 3

[0148] In this example, Tween 80 and polyoxyethylene 40 hydrogenated castor oil were used as solubilizers, and an osmotic pressure regulator was further added to prepare different prescriptions to investigate the compatibility of the osmotic pressure regulator and the solubilizer. The specific prescription ingredients and experimental results are shown in Table 8 below:

[0149] Table 8

[0150] It can be seen from the experimental results in Table 8 that in the presence of a certain osmotic pressure regulator, the solubility and formulation stability of the compound of Formula I can be greatly improved by changing the ratio of the solubilizer.

[0151] Example 4

[0152] In this example, Tween 80 and polyoxyethylene 40 hydrogenated castor oil were used as solubilizers, sodium chloride was used as an osmotic pressure regulator, and an antibacterial agent was further added to prepare different prescriptions to investigate the compatibility between the raw and auxiliary materials. The specific prescription ingredients and experimental results are shown in Table 9 below:

[0153] Table 9

[0154] The content test result refers to the percentage of the detected content of the compound of formula I in the prescription to the labeled content.

[0155] From the experimental results in Table 9, it can be seen that the compatibility of raw materials and auxiliary materials is very good after adding osmotic pressure regulators (such as sodium chloride) and / or antibacterial agents.

[0156] Example 5

[0157] This example provides several preparations comprising the compound of formula I, and the specific formulation ingredients are shown in Table 10 below:

[0158] Table 10

[0159] The preparation method of the above-mentioned prescription preparation is as follows:

[0160] (1) Dissolve sodium chloride in approximately 10% water for injection and stir until completely dissolved to obtain Solution I;

[0161] (2) Dissolve mannitol in approximately 10% water for injection and stir until completely dissolved to obtain Solution II;

[0162] (3) Weigh the prescribed amount of the compound of formula I, add the prescribed amount of Tween 80 and polyoxyethylene 40 hydrogenated castor oil, stir to mix thoroughly, then add solution I and solution II separately while stirring, and stir thoroughly with a high-speed blender to obtain solution III;

[0163] (4) Weigh the prescribed amount of benzalkonium chloride, add approximately 10% water for injection, and stir to dissolve to obtain Solution IV;

[0164] (5) Solution III and Solution IV were mixed and diluted to full volume with cold sterile water for injection, and sterilized by three-stage filtration using 0.22 μm and 0.45 μm microporous filter membranes;

[0165] (6) After the intermediate product is tested and qualified, it is packaged. The test results are shown in Table 11 below.

[0166] Table 11

[0167] Note: Complying with regulations means complying with the requirements of visible foreign matter in ophthalmic preparations in the Chinese Pharmacopoeia.

[0168] The relative content of the compound of formula I refers to the percentage of the detected content of the compound of formula I in the prescription to the labeled content.

[0169] The test results in Table 11 show that the properties, pH value, osmotic pressure, related substances, benzalkonium chloride and the content of the compound of formula I of prescriptions 19 to 23 are relatively stable, and the preparation process is simple to operate and suitable for industrial production.

[0170] Long-term stability test of formulation 20 in Example 5

[0171] 5 mL of prescription 20 was sealed in a low-density polyethylene medicinal eye drop bottle. The properties, pH value, osmotic pressure, visible foreign matter, related substances and other indicators of the prescription were examined at a temperature of 25°C ± 2°C and a relative humidity of 40% ± 5% at 0, 3, 6, 9 and 12 months to see whether they met the requirements. The test results are shown in Table 12 below.

[0172] Table 12

[0173] “ / ” means not detected

[0174] From the 12-month long-term stability test results in Table 12, it can be seen that Formulation 20 remains a colorless, clear liquid at 25°C ± 2°C and a relative humidity of 40% ± 5%. There are no significant changes in osmotic pressure, pH value, relative content of the compound of Formula I, or content of related substances, demonstrating good stability.

[0175] Example 6

[0176] This embodiment provides several preparations comprising the compound of formula I. The excipients in the preparation prescription are polyoxyethylene 40 hydrogenated castor oil, mannitol, sodium chloride, benzalkonium chloride and water for injection.

[0177] The specific prescription ingredients are shown in Table 13 below.

[0178] Table 13

[0179] The preparation method of the above-mentioned prescription preparation is as follows:

[0180] (1) Dissolve sodium chloride in approximately 10% water for injection and stir until completely dissolved to obtain Solution I;

[0181] (2) Dissolve mannitol in approximately 10% water for injection and stir until completely dissolved to obtain Solution II;

[0182] (3) Weighing the prescribed amount of the compound of formula I, adding the prescribed amount of polyoxyethylene 40 hydrogenated castor oil, stirring to mix thoroughly, then adding solution I and solution II separately while stirring, and stirring thoroughly with a high-speed stirrer to obtain solution III;

[0183] (4) Weigh the prescribed amount of benzalkonium chloride, add approximately 10% water for injection, and stir to dissolve to obtain Solution IV;

[0184] (5) Solution III and Solution IV were mixed and diluted to full volume with cold sterile water for injection, and sterilized by three-stage filtration using 0.22 μm and 0.45 μm microporous filter membranes;

[0185] (6) Take the intermediate product and repack it after it passes the test.

[0186] Long-term stability test of Formulation 26

[0187] 5 mL of prescription 26 was sealed in a low-density polyethylene medicinal eye drop bottle. The properties, pH value, osmotic pressure, visible foreign matter, related substances and other indicators of the prescription were examined at a temperature of 25°C ± 2°C and a relative humidity of 40% ± 5% at 0, 1, 2, 3, and 6 months to determine whether they met the requirements. The test results are shown in Table 14 below.

[0188] Table 14

[0189] Although the present invention has been described in detail above using general explanations, specific embodiments, and experiments, it will be apparent to those skilled in the art that modifications and improvements may be made based on the present invention. Therefore, such modifications and improvements, which do not depart from the spirit of the present invention, are intended to be within the scope of protection claimed herein.

Claims

1. A pharmaceutical composition comprising a compound of formula I, 2. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition further comprises: one or more of a solubilizer, an osmotic pressure regulator, and an antibacterial agent; Preferably, the pharmaceutical composition further comprises a solubilizer and an osmotic pressure regulator.

3. The pharmaceutical composition according to claim 2, characterized in that The solubilizing agent is selected from one or more of Tween 80, polyoxyethylene hydrogenated castor oil, polyethylene glycol 400, poloxamer 188, polyoxyethylene hydrogenated stearate, polyoxyethylene castor oil and derivatives thereof, Preferably, the solubilizer is polyoxyethylene hydrogenated castor oil; Preferably, the polyoxyethylene hydrogenated castor oil is selected from one or more of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 54 hydrogenated castor oil and polyoxyethylene 60 hydrogenated castor oil; Preferably, the solubilizing agent is Tween 80 and / or polyoxyethylene 40 hydrogenated castor oil, Preferably, the solubilizing agent is Tween 80 and polyoxyethylene 40 hydrogenated castor oil; The osmotic pressure regulator is selected from one or more of sodium chloride, potassium chloride, mannitol, glycerol, propylene glycol, dextrose, boric acid and borax, preferably sodium chloride and / or mannitol, more preferably sodium chloride and mannitol; The antibacterial agent is selected from one or more of benzalkonium chloride, thimerosal, domiphene, chlorhexidine, chlorobutanol, parabens, and sorbic acid, preferably benzalkonium chloride.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The pharmaceutical composition comprises a compound of formula I, Tween 80 and polyoxyethylene 40 hydrogenated castor oil; Alternatively, the pharmaceutical composition comprises a compound of formula I and polyoxyethylene 40 hydrogenated castor oil; Alternatively, the pharmaceutical composition comprises a compound of formula I, polyoxyethylene 40 hydrogenated castor oil, sodium chloride, mannitol and benzalkonium chloride; Alternatively, the pharmaceutical composition comprises a compound of formula I, Tween 80, polyoxyethylene 40 hydrogenated castor oil and sodium chloride; Alternatively, the pharmaceutical composition comprises a compound of formula I, Tween 80, polyoxyethylene 40 hydrogenated castor oil, sodium chloride and benzalkonium chloride; Alternatively, the pharmaceutical composition comprises a compound of formula I, Tween 80, polyoxyethylene 40 hydrogenated castor oil, sodium chloride and mannitol; Alternatively, the pharmaceutical composition comprises the compound of formula I, Tween 80, polyoxyethylene 40 hydrogenated castor oil, sodium chloride, mannitol and benzalkonium chloride.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that The pharmaceutical composition comprises the following components in parts by weight:

6. The pharmaceutical composition according to any one of claims 2 to 4, characterized in that The pharmaceutical composition comprises the following components in parts by weight: 1 part of the compound of formula I; Tween 80 0.3-3.5 parts; 2-35 parts of polyoxyethylene 40 hydrogenated castor oil; Alternatively, the pharmaceutical composition comprises the following components in parts by weight: Alternatively, the pharmaceutical composition comprises the following components in parts by weight: Alternatively, the pharmaceutical composition comprises the following components in parts by weight: Alternatively, the pharmaceutical composition comprises the following components in parts by weight: Alternatively, the pharmaceutical composition comprises the following components in parts by weight: Alternatively, the pharmaceutical composition comprises the following components in parts by weight:

7. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that The dosage form of the pharmaceutical composition is a solution, suspension, emulsion, micelle or gel; Preferably, the content of the compound of formula I in the pharmaceutical composition is 0.01-2 mg / mL, preferably 0.05-1 mg / mL; Preferably, the crystalline form of the compound of formula I is crystalline form A or crystalline form B; Preferably, the pH of the pharmaceutical composition is 4.0-6.

0.

8. A method for preparing the pharmaceutical composition according to any one of claims 1 to 7, characterized in that: The preparation method comprises the following steps: The compound of formula I is mixed with a solubilizer, an osmotic pressure regulator and / or an antibacterial agent in corresponding parts by weight to obtain the pharmaceutical composition.

9. The preparation method according to claim 8, characterized in that The preparation method comprises the following steps: (1) dissolving the osmotic pressure regulator in water for injection to obtain solution I; (2) uniformly mixing the solubilizing agent and the compound of formula I to obtain a mixture II; (3) mixing the solution I and the mixture II and stirring them uniformly to obtain a solution III; (4) dissolving the antibacterial agent in water for injection to obtain solution IV; (5) The solution III and the solution IV are mixed, and the volume is adjusted to the full amount with water for injection, and the solution is sterilized by three-stage filtration using a microporous filter membrane to obtain the pharmaceutical composition.

10. Use of the pharmaceutical composition according to any one of claims 1 to 7 or the pharmaceutical composition prepared by the preparation method according to claim 8 or 9 in the preparation of a medicament for preventing and / or treating glaucoma or ocular hypertension.

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