Self-emulsifying pharmaceutical compositions, methods of making same and uses thereof

Abstract

The present invention provides a self-emulsifying pharmaceutical composition of Compound (I). In the present invention, Compound (I) is prepared as a self-emulsifying pharmaceutical composition, which greatly improves the solubility and oral bioavailability of the drug, stabilizes its physical properties, and can be formulated into various dosage forms such as oral liquids, capsules, and tablets, making it easier for patients to take. [Formula 1] TIFF2026505949000025.tif40170

Description

[Technical Field]

[0001] The present invention relates to the pharmaceutical field, in particular to a self-emulsifying pharmaceutical composition, its preparation method and use. [Background technology]

[0002] Compound (I) has the formula (I) below, and was first disclosed in CN104860885A:

[0003] [ka]

[0004] Compound (I) is a VEGFR / CSF1R dual-target inhibitor with excellent activity, inhibits vascular proliferation of tumor cells, and promotes tumor immunity, exerting antitumor effects. Compound (I) is useful for the manufacture of a medicament for the prevention and / or treatment of diseases associated with abnormal vascular proliferation, and / or as a VEGFR-2 inhibitor, and / or as a medicament for the treatment of diseases associated with the CSF1R kinase signaling pathway, and / or as a CSF1R kinase inhibitor. The disease associated with abnormal blood vessel proliferation is selected from lung cancer, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, kidney cancer, glioma (e.g., glioblastoma, astroglioma, medulloblastoma), melanoma, pancreatic cancer, head and neck cancer, bladder cancer, cervical cancer, bile duct cancer, nasopharyngeal cancer, thyroid cancer, tumors including osteosarcoma, synovial sarcoma, rhabdomyosarcoma, fibrosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastasis tumor, meningioma and lymphoma, rheumatoid arthritis, age-related macular degeneration and psoriasis. Summary of the Invention [Problem to be solved by the invention]

[0005] Compound (I) has poor solubility in water, and when formulated into oral dosage forms such as conventional oral liquids, tablets, and capsules, the oral drug utilization rate is low.

[0006] Emulsions are a commonly used dosage form for improving the absorption of fat-soluble drugs, but conventional emulsions are not very satisfactory due to their high loading, short shelf life, and poor storage stability.

[0007] The technical problem to be solved by the present invention is to provide a self-emulsifying pharmaceutical composition of compound (I), wherein the formulation prepared using said composition has higher drug solubility and oral bioavailability, and the emulsified drug has stable physical properties, and can be formulated into various dosage forms such as oral liquids, capsules, and tablets, making it easy for patients to take. [Means for solving the problem]

[0008] In order to solve the above problems, the present invention provides the following aspects.

[0009] In one aspect, the present invention provides a self-emulsifying pharmaceutical composition of Compound (I), comprising Compound (I), an oil phase, an emulsifier, and a co-emulsifier, wherein the weight ratio of Compound (I), oil phase, emulsifier, and co-emulsifier is 0.5-2:0-20:50-80:20-35, and Compound (I) is represented by Formula (I):

[0010] [ka]

[0011] In some embodiments of the present invention, the weight ratio of Compound (I), oil phase, emulsifier and co-emulsifier is 0.99-1.98:0-20:50-80:20-35.

[0012] In some embodiments of the present invention, the weight ratio of Compound (I), oil phase, emulsifier and co-emulsifier is 0.99:0-20:50-80:20-35.

[0013] In some embodiments of the present invention, the weight ratio of Compound (I), oil phase, emulsifier and co-emulsifier is 1.25:0-20:50-80:20-35.

[0014] In some embodiments of the present invention, the weight ratio of Compound (I), oil phase, emulsifier and co-emulsifier is 1.98:0-20:50-80:20-35.

[0015] In some embodiments of the present invention, the weight ratio of Compound (I), oil phase, emulsifier and co-emulsifier is 0.5-2:0-15:55-75:20-30, preferably 0.99-1.98:0-15:55-75:20-30, more preferably 0.99-1.98:0-15:55-75:24-30.

[0016] In some embodiments of the present invention, the weight ratio of Compound (I), oil phase, emulsifier and co-emulsifier is 0.5-2:10-20:50-65:20-30, preferably 0.99-1.98:10-15:55-65:25-30, more preferably 0.99-1.98:13-14:55-57:28-29.

[0017] In some embodiments of the present invention, the weight ratio of Compound (I), oil phase, emulsifier and co-emulsifier is 0.99:10-20:50-65:20-30, preferably 0.99:10-15:55-65:25-30, more preferably 0.99:13-14:55-57:28-29, and even more preferably 0.99:13.86:56.44:28.71.

[0018] In some embodiments of the present invention, the weight ratio of Compound (I), oil phase, emulsifier and co-emulsifier is 1.25:10-20:50-65:20-30, preferably 1.25:10-15:55-65:25-30, more preferably 1.25:13-14:55-57:28-29, and even more preferably 1.25:13.83:56.25:28.67.

[0019] In some embodiments of the present invention, the weight ratio of Compound (I), oil phase, emulsifier and co-emulsifier is 1.98:10-20:50-65:20-30, preferably 1.98:10-15:55-65:25-30, more preferably 1.98:13-14:55-57:28-29, and even more preferably 1.98:13.72:55.88:28.42.

[0020] In some embodiments of the present invention, the weight ratio of Compound (I), oil phase, emulsifier and co-emulsifier is 0.5-2:0:60-80:20-30, preferably 0.99-1.98:0:70-80:20-30, or 0.99-1.98:0:75-80:25-30, or 0.99-1.98:0:70-75:20-25, or 0.99-1.98:0:74-76:24-26.

[0021] In some embodiments of the present invention, the weight ratio of Compound (I), oil phase, emulsifier and co-emulsifier is 0.99:0:60-80:20-30, preferably 0.99:0:70-80:20-30, or 0.99:0:75-80:25-30, or 0.99:0:70-75:20-25, or 0.99:0:74-76:24-26, more preferably 0.99:0:74.26:24.75.

[0022] In some embodiments of the present invention, the concentration of Compound (I) is 5-21 mg / mL, preferably 5-20 mg / mL, more preferably 10-21 mg / mL, more preferably 10-20 mg / mL, and even more preferably 10 mg / mL, 10.5 mg / mL, 20 mg / mL, 20.99 mg / mL, 13.25 mg / mL, or 12.5 mg / mL.

[0023] In some embodiments of the present invention, the concentration of Compound (I) is 5-20 mg / g, preferably 9.9-19.8 mg / g, and more preferably 9.9 mg / g, 19.8 mg / g, or 12.5 mg / g.

[0024] The oil phase is one of the important adjuvants in self-emulsifying formulations. The oil phase must be safe and stable, capable of dissolving the prescribed amount of drug in a small amount, and easily emulsified by the emulsifier in the formulation. Using an oil phase with high drug solubility can increase the drug loading of the self-emulsifying system, and the oil carrier increases the drug transport rate through the lymphatic system, improving the drug's bioavailability.

[0025] In some embodiments of the present invention, the oil phase of the present invention is selected from medium chain triglycerides (MCT), glyceryl monooctanoate, glyceryl dioctanoate, glyceryl monooleate, glyceryl monolinoleate, corn oil, castor oil, sesame oil, peanut oil, olive oil, and the like, preferably medium chain triglycerides.

[0026] Nonionic surfactants with high HLB values ​​are generally used as emulsifiers in self-emulsifying formulations. Nonionic surfactants are less toxic than ionic surfactants and only cause reversible changes in the permeability of the gastrointestinal wall. Surfactants with high HLB values ​​must be highly hydrophilic to instantly form oil-in-water droplets and disperse the self-emulsifying liquid in aqueous solution, allowing for more rapid self-emulsification. Emulsifiers are amphiphilic and can dissolve relatively large amounts of hydrophobic drugs, preventing drug deposition in the gastrointestinal tract and prolonging the dissolution state of drug molecules, which is important for efficient absorption. When the surfactant content reaches a certain level, a self-emulsifying system is formed.

[0027] In some embodiments of the present invention, the emulsifier is selected from polyoxyethylene (40) hydrogenated castor oil (e.g., RH40, e.g., Cremophor® RH40 or Kolliphor® RH40), polyoxyethylene (35) castor oil (e.g., Kolliphor EL or Cremophor EL), vitamin E polyethylene glycol succinate (e.g., TPGS1000), polyethylene glycol 15-hydroxystearate (e.g., HS15, e.g., Kolliphor® HS15), linoleoyl polyoxyethylene (6) glyceride, caprylocaproyl polyethylene glycol glyceride (e.g., Labrasol® ALF), and the like, preferably polyoxyethylene (40) hydrogenated castor oil, vitamin E polyethylene glycol succinate, polyoxyethylene (35) castor oil, and more preferably polyoxyethylene (40) hydrogenated castor oil.

[0028] The co-emulsifier in a self-emulsifying formulation contributes to the formation of a uniform emulsion of the active ingredient and to maintaining the storage stability of the emulsion.

[0029] In some embodiments of the present invention, the co-emulsifier is selected from polyethylene glycol (PEG), diethylene glycol monoethyl ether (e.g., Transcutol HP), propylene glycol, glycerin, preferably polyethylene glycol 400 (PEG400), diethylene glycol monoethyl ether (e.g., Transcutol HP).

[0030] Furthermore, optionally, the self-emulsifying pharmaceutical composition of compound (I) of the present invention further comprises an antioxidant, and preferably, the weight ratio of compound (I) to antioxidant is 1:(0-0.5), preferably 1:(0-0.1), more preferably 1:(0-0.05), even more preferably 1:(0-0.03), even more preferably 0.99:0.02, 1:0.02 or 1:0. When the self-emulsifying pharmaceutical composition of compound (I) of the present invention comprises an antioxidant, the lower limit of the content of the antioxidant is not particularly limited, and for example, the weight ratio of compound (I) to antioxidant may be 1:0.0001, for example, 1:0.001. In one embodiment, the self-emulsifying pharmaceutical composition of compound (I) according to the present invention optionally further comprises an antioxidant, and preferably the weight ratio of compound (I) to the antioxidant is 1:(0 or 0.001-0.5), preferably 1:(0 or 0.001-0.1), more preferably 1:(0 or 0.001-0.05), even more preferably 1:(0 or 0.001-0.03), even more preferably 0.99:0.02, 1:0.02 or 1:0.

[0031] In the present invention, the total weight of the self-emulsifying pharmaceutical composition is 100 parts, and the weight ratio of each component in the pharmaceutical composition is expressed in parts by weight, which allows for an error range of, for example, ±5, or ±3, or ±2, or ±1, or ±0.5, or ±0.3, or ±0.2, or ±0.1, or ±0.05, or ±0.02, or ±0.01.

[0032] In some embodiments of the present invention, the total weight of the self-emulsifying pharmaceutical composition is 100.

[0033] When the self-emulsifying pharmaceutical composition of compound (I) of the present invention contains an antioxidant, the proportions of other adjuvants such as an oil phase, an emulsifier, or a co-emulsifier can be reduced accordingly. For example, based on the amount of compound (I) used, the amount of antioxidant is determined by the weight ratio of compound (I) to the antioxidant, and the amount of oil phase, emulsifier, and co-emulsifier is determined by the weight ratio of compound (I) to the oil phase, emulsifier, and co-emulsifier. Then, the amounts of compound (I), antioxidant, oil phase, emulsifier, and co-emulsifier used are standardized, and the total amount of each component is calculated as 100 based on the total weight. Alternatively, the amount of antioxidant used is determined based on the weight ratio of compound (I) to antioxidant per part by weight of compound (I), and the amounts of compound (I), oil phase, and emulsifier used are kept constant (or the amounts of compound (I), emulsifier, and emulsifier used are kept constant, or the amounts of compound (I), oil phase, and emulsifier used are kept constant), and the amount of antioxidant used is subtracted from the amount of emulsifier (or oil phase, or emulsifier used).

[0034] In some embodiments of the present invention, the antioxidant is selected from dibutylhydroxytoluene, butylhydroxyanisole, vitamin E, and propyl gallate, preferably dibutylhydroxytoluene and vitamin E, and more preferably dibutylhydroxytoluene.

[0035] The above-described embodiments of the present invention can be arbitrarily combined, and the combined embodiments also belong to the embodiments of the present invention.

[0036] In some embodiments of the present invention, the self-emulsifying pharmaceutical composition of Compound (I) can be formulated as a self-emulsifying formulation of Compound (I), wherein the self-emulsifying formulation is an oral liquid, a capsule, or a tablet, and the capsule is a soft capsule or a hard capsule.

[0037] In another aspect, the present invention further provides a method for preparing a self-emulsifying formulation of Compound (I), comprising adding self-emulsifying pharmaceutical composition adjuvants to a formulation tank and stirring uniformly with heating, further adding Compound (I), and continuing to heat and stir until dissolution is complete, thereby producing a self-emulsifying pharmaceutical composition of Compound (I), wherein the self-emulsifying pharmaceutical composition adjuvants include an oil phase, an emulsifier, a co-emulsifier, and an optional antioxidant.

[0038] The resulting self-emulsifying pharmaceutical composition is dispensed into oral liquid bottles or capsules, or the self-emulsifying pharmaceutical composition is prepared into granules or pellets by liquid solidification techniques and compressed into tablets or capsules to obtain a self-emulsifying formulation of Compound (I).

[0039] The temperature of the heating and stirring is 40-70°C.

[0040] The liquid solidification method may be a conventional method in the art, for example, by mixing and dispersing a self-emulsifying liquid with a non-volatile carrier such as microcrystalline cellulose, lactose, starch, or hypromellose, optionally adding nanosilica as an adsorbent to absorb the remaining liquid, preparing the mixture into granules or pellets, and finally adding a tableting aid such as croscarmellose sodium or magnesium stearate to compress the mixture into tablets or form capsules.

[0041] In yet another aspect, the present invention also provides use of the self-emulsifying formulation of Compound (I) as described above in the manufacture of a medicament for the prevention and / or treatment of a disease associated with abnormal vascular proliferation, and / or in the manufacture of a medicament as a VEGFR-2 inhibitor, and / or in the manufacture of a medicament for the treatment of a disease associated with the CSF1R kinase signaling pathway, and / or in the manufacture of a medicament as a CSF1R kinase inhibitor.

[0042] In some embodiments of the present invention, the disease associated with abnormal vascular proliferation is selected from tumors, rheumatoid arthritis, age-related macular degeneration, and psoriasis, and preferably the tumor is lung cancer, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, kidney cancer, glioma, melanoma, pancreatic cancer, head and neck cancer, bladder cancer, cervical cancer, bile duct cancer, nasopharyngeal cancer, thyroid cancer, osteosarcoma, synovium, rhabdomyosarcoma, fibromyosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastasis tumor, meningioma, and lymphoma. The glioma is preferably glioblastoma, astroglioma, or medulloblastoma.

[0043] The self-emulsifying formulation of the present invention may be in solid or liquid form. When diluted with water or gastrointestinal fluid for oral administration, it can form an oil-in-water emulsion or microemulsion by emulsification. The average particle size is typically greater than 0 and less than 250 nm, preferably greater than 0 and less than 100 nm, or 10-100 nm, more preferably greater than 0 and less than 50 nm, even more preferably 10-50 nm, and even more preferably 10-40 nm or 20-40 nm. The self-emulsifying formulation of the present invention can spontaneously form a microemulsion upon contact with gastric or intestinal fluid. Compound (I) is dissolved in the microemulsion. Therefore, the self-emulsifying formulation of the present invention can increase the solubility of the pharmaceutical compound (I) in the gastrointestinal tract. The medicinal compound (I) is present in these fine microemulsions and is rapidly dispersed throughout the gastrointestinal tract. The medicinal compound (I) is distributed between two phases, oil and water, and the large specific surface area of ​​the fine oil droplets significantly increases the membrane absorption of the medicinal compound (I), thereby improving the oral bioavailability of the medicinal compound (I).

[0044] The present invention provides the following technical solutions:

[0045] Technical proposal 1. A self-emulsifying pharmaceutical composition of compound (I), comprising compound (I), an oil phase, an emulsifier and a co-emulsifier, wherein the weight ratio of compound (I), oil phase, emulsifier and co-emulsifier is 0.5-2:0-20:50-80:20-35, preferably 0.99-1.98:0-20:50-80:20-35, more preferably 0.99:0-20:50-80:20-35, or 1.25:0-20:50-80:20-35, or 1.98:0-20:50-80:20-35; The structural formula of compound (I) is represented by the following formula (I).

[0046] [ka]

[0047] Technical proposal 2. The weight ratio of the compound (I), oil phase, emulsifier and co-emulsifier is 0.5-2:10-20:50-65:20-30; or 0.5-2:0:60-80:20-30, or 0.5-2:0-15:55-75:20-30, More preferably 0.99-1.98:0-15:55-75:20-30, or 0.99-1.98:0-15:55-75:24-30, or 0.99-1.98:10-15:55-65:25-30, or 0.99-1.98:13-14:55-57:28-29, or 0.99-1.98:0:70-80:20-30, or 0.99-1.98:0:75-80:25-30, or 0.99-1.98:0:70-75:20-25, or 0.99-1.98:0:74-76:24-26, More preferably 0.99:10-20:50-65:20-30, or 0.99:10-15:55-65:25-30, or 0.99:13-14:55-57:28-29, or 0.99:13.86:56.44:28.71, or 1.25:10-20:50-65:20-30, or 1.25:10-15:55-65:25-30, or 1.25:13-14:55-57:28-29, or 1.25:13.83:56.25:28.67, or 1.98:10-20:50-65:20-30, or 1.98:10-15:55-65:25-30, or 1.98:13-14:55-57:28-29, or 1.98:13.72:55.88:28.42, or 0.99:0:60-80:20-30, or 0.99:0:70-80:20-30, or 0.99:0:75-80:25-30, or 0.99:0:70-75:20-25, or 0.99:0:74-76:24-26, or The self-emulsifying pharmaceutical composition of compound (I) according to Technical Scheme 1, characterized in that the ratio is 0.99:0:74.26:24.75.

[0048] Technical solution 3: The concentration of the compound (I) is 5-20 mg / g, preferably 9.9-19.8 mg / g, more preferably 9.9 mg / g, 19.8 mg / g or 12.5 mg / g; or The self-emulsifying pharmaceutical composition of compound (I) according to any of the above technical solutions, characterized in that the concentration of compound (I) is 5-21 mg / mL, preferably 5-20 mg / mL, or 10-21 mg / mL, or 10-20 mg / mL, more preferably 10 mg / mL, 10.5 mg / mL, 20 mg / mL, 20.99 mg / mL, 13.25 mg / mL or 12.5 mg / mL.

[0049] Technical Scheme 4. A self-emulsifying pharmaceutical composition of compound (I) according to any of the above technical schemes, characterized in that the oil phase is selected from medium-chain triglycerides, glyceryl monooctanoate, glyceryl dioctanoate, glyceryl monooleate, glyceryl monolinoleate, corn oil, castor oil, sesame oil, peanut oil, and olive oil, preferably medium-chain triglycerides.

[0050] Technical Suggestion 5. A self-emulsifying pharmaceutical composition of Compound (I) according to any of the preceding technical suggestions, characterized in that the emulsifier is selected from polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (35) castor oil, vitamin E polyethylene glycol succinate, polyethylene glycol 15-hydroxystearate, linoleoyl polyoxyethylene (6) glyceride, and caprylocaproyl polyethylene glycol glyceride, preferably polyoxyethylene (40) hydrogenated castor oil, vitamin E polyethylene glycol succinate, and polyoxyethylene (35) castor oil, and more preferably polyoxyethylene (40) hydrogenated castor oil.

[0051] Technical Solution 6. A self-emulsifying pharmaceutical composition of compound (I) according to any of the above technical solutions, characterized in that the co-emulsifier is selected from polyethylene glycol, diethylene glycol monoethyl ether, propylene glycol, and glycerol, preferably polyethylene glycol 400 and diethylene glycol monoethyl ether.

[0052] Technical proposal 7. Optionally, an antioxidant is further included, and the weight ratio of the compound (I) to the antioxidant is preferably 1:(0-0.5), more preferably 1:(0-0.1), more preferably 1:(0-0.05), even more preferably 1:(0-0.03), even more preferably 0.99:0.02, 1:0.02 or 1:0; More preferably, the weight ratio of the compound (I) to the antioxidant is 1:(0 or 0.001-0.5), preferably 1:(0 or 0.001-0.1), more preferably 1:(0 or 0.001-0.05), even more preferably 1:(0 or 0.001-0.03), and even more preferably 0.99:0.02, 1:0.02 or 1:0.

[0053] Technical Scheme 8. The self-emulsifying pharmaceutical composition of compound (I) according to Technical Scheme 7, wherein the antioxidant is selected from dibutylhydroxytoluene, butylhydroxyanisole, vitamin E, and propyl gallate, preferably dibutylhydroxytoluene and vitamin E, and more preferably dibutylhydroxytoluene.

[0054] Technical Suggestion 9. The self-emulsifying pharmaceutical composition is composed of the compound (I), an oil phase, an emulsifier, and a co-emulsifier, and the weight ratio of the compound (I), the oil phase, the emulsifier, and the co-emulsifier is 0.5-2:10-20:50-65:20-30, preferably 0.99-1.98:10-15:55-65:25-30, more preferably 0.99-1.98:13-14:55-57:28-29, for example, 0.99:13-14:55-57:28-29, or 1.25:13-14:55-57:28-29, or 1.98:13-14:55-57:28-29, and even more preferably Preferably, the ratio is 0.99:13.86:56.44:28.71, or 1.25:13.83:56.25:28.67, or 1.98:13.72:55.88:28.42, wherein the oil phase is a medium chain triglyceride, the emulsifier is polyoxyethylene (40) hydrogenated castor oil, vitamin E polyethylene glycol succinate, polyethylene glycol 15-hydroxystearate or polyoxyethylene (35) castor oil, and the co-emulsifier is polyethylene glycol 400 or diethylene glycol monoethyl ether, or

[0055] the self-emulsifying pharmaceutical composition comprises the compound (I), an oil phase, an emulsifier, and a co-emulsifier, and the weight ratio of the compound (I), the oil phase, the emulsifier, and the co-emulsifier is 0.99-1.98:13-14:55-57:28-29, for example, 0.99:13-14:55-57:28-29, and preferably 0.99:13.86:56.44:28.71; the oil phase is a medium-chain triglyceride; the emulsifier is polyoxyethylene (40) hydrogenated castor oil; and the co-emulsifier is polyethylene glycol 400 or diethylene glycol monoethyl ether; or

[0056] the self-emulsifying pharmaceutical composition comprises the compound (I), an oil phase, an emulsifier and a co-emulsifier, and the weight ratio of the compound (I), the oil phase, the emulsifier and the co-emulsifier is 0.99-1.98:13-14:55-57:28-29, for example 0.99:13-14:55-57:28-29, preferably 0.99:13.86:56.44:28.71; the oil phase is a medium-chain triglyceride; the emulsifier is vitamin E polyethylene glycol succinate; and the co-emulsifier is polyethylene glycol 400 or diethylene glycol monoethyl ether; or

[0057] the self-emulsifying pharmaceutical composition comprises the compound (I), an oil phase, an emulsifier, and a co-emulsifier, and the weight ratio of the compound (I), the oil phase, the emulsifier, and the co-emulsifier is 0.99-1.98:13-14:55-57:28-29, for example, 0.99:13-14:55-57:28-29, and preferably 0.99:13.86:56.44:28.71; the oil phase is a medium-chain triglyceride; the emulsifier is polyethylene glycol 15-hydroxystearate or polyoxyethylene (35) castor oil; and the co-emulsifier is polyethylene glycol 400; or

[0058] the self-emulsifying pharmaceutical composition comprises the compound (I), an oil phase, an emulsifier, and a co-emulsifier, wherein the weight ratio of the compound (I), the oil phase, the emulsifier, and the co-emulsifier is 0.99-1.98:13-14:55-57:28-29, for example, 1.25:13-14:55-57:28-29, and preferably 1.25:13.83:56.25:28.67; the oil phase is a medium-chain triglyceride; the emulsifier is polyoxyethylene (40) hydrogenated castor oil; and the co-emulsifier is polyethylene glycol 400; or

[0059] the self-emulsifying pharmaceutical composition comprises the compound (I), an oil phase, an emulsifier, and a co-emulsifier, and the weight ratio of the compound (I), the oil phase, the emulsifier, and the co-emulsifier is 0.99-1.98:13-14:55-57:28-29, for example, 0.99:13-14:55-57:28-29, or 1.98:13-14:55-57:28-29, preferably 0.99:13.86:56.44:28.71, or 1.98:13.72:55.88:28.42; the oil phase is a medium-chain triglyceride; the emulsifier is polyoxyethylene (40) hydrogenated castor oil; and the co-emulsifier is polyethylene glycol 400; or

[0060] The self-emulsifying pharmaceutical composition comprises the compound (I), an oil phase, an emulsifier, a co-emulsifier and an antioxidant, and the weight ratio of the compound (I), the oil phase, the emulsifier, the co-emulsifier and the antioxidant is 0.5-2:10-20:50-65:20-30:(more than 0 and not more than 0.5), preferably 0.99-1.98:10-15:55-65:25-30:(more than 0 and not more than 0.5), more preferably 0.99-1.98:10-15:55-61:27-29:(more than 0 and not more than 0.5), for example, 0.99:13-14:55-57:28-29:(0.01-0.03), or 0.99:10-12:59-61:26-28:( 0.4-0.5), more preferably 0.99:13.86:56.42:28.71:0.02, or 0.99:10.90:60.39:27.22:0.50, wherein the oil phase is a medium chain triglyceride, the emulsifier is polyoxyethylene (40) hydrogenated castor oil, vitamin E polyethylene glycol succinate, polyethylene glycol 15-hydroxystearate, or polyoxyethylene (35) castor oil, the co-emulsifier is polyethylene glycol 400 or diethylene glycol monoethyl ether, and the antioxidant is dibutylhydroxytoluene or vitamin E, or

[0061] the self-emulsifying pharmaceutical composition comprises the compound (I), an oil phase, an emulsifier, a co-emulsifier, and an antioxidant, and the weight ratio of the compound (I), the oil phase, the emulsifier, the co-emulsifier, and the antioxidant is 0.99-1.98:13-14:55-57:28-29:(more than 0 and not more than 0.05), for example, 0.99:13-14:55-57:28-29:(0.01-0.03), preferably 0.99:13.86:56.42:28.71:0.02; the oil phase is a medium-chain triglyceride; the emulsifier is polyoxyethylene (40) hydrogenated castor oil; the co-emulsifier is polyethylene glycol 400; and the antioxidant is dibutylhydroxytoluene; or

[0062] the self-emulsifying pharmaceutical composition comprises the compound (I), an oil phase, an emulsifier, a co-emulsifier and an antioxidant, and the weight ratio of the compound (I), the oil phase, the emulsifier, the co-emulsifier and the antioxidant is 0.99-1.98:10-12:59-61:26-28:(0.1-0.5), for example, 0.99:10-12:59-61:26-28:(0.4-0.5), preferably 0.99:10.90:60.39:27.22:0.50; the oil phase is a medium-chain triglyceride; the emulsifier is polyoxyethylene (40) hydrogenated castor oil; the co-emulsifier is diethylene glycol monoethyl ether; and the antioxidant is vitamin E; or

[0063] the self-emulsifying pharmaceutical composition comprises the compound (I), an emulsifier and a co-emulsifier, wherein the weight ratio of the compound (I), the emulsifier and the co-emulsifier is 0.99:60-80:20-30, for example, 0.99:70-80:20-30, or 0.99:75-80:25-30, or 0.99:70-75:20-25, or 0.99:74-76:24-26, or 0.99:74.26:24.75; the emulsifier is polyoxyethylene (40) hydrogenated castor oil, and the co-emulsifier is polyethylene glycol 400 or diethylene glycol monoethyl ether; A self-emulsifying pharmaceutical composition of compound (I) according to any of the above technical solutions.

[0064] Technical Scheme 10. A self-emulsifying pharmaceutical composition of compound (I) according to any of the technical solutions above, characterized in that the self-microemulsion obtained from the self-emulsifying pharmaceutical composition by dilution has an average size of more than 0 to 250 nm, preferably more than 0 to 100 nm or 10-100 nm, more preferably more than 0 to 50 nm, even more preferably 10-50 nm, even more preferably 10-40 nm or 20-40 nm; preferably, the diluent used for dilution is selected from water, hydrochloric acid buffer (pH=1.0), acetate buffer (pH=4.5) and phosphate buffer (pH=6.8); more preferably, the dilution ratio of the self-emulsifying pharmaceutical composition to the diluent is 1:(3-500), for example 1:(5-500).

[0065] Technical proposal 11. A self-emulsifying formulation prepared from the self-emulsifying pharmaceutical composition of compound (I) according to any of the above technical proposals, characterized in that the dosage form of the self-emulsifying formulation of compound (I) is an oral liquid, capsule or tablet, the capsule may be a soft capsule or a hard capsule, and preferably the dosage form of the self-emulsifying formulation of compound (I) is an oral liquid.

[0066] Technical proposal 12. It comprises adding a self-emulsifying pharmaceutical composition auxiliary to a preparation tank, stirring the mixture under heat, adding compound (I), and continuing to heat and stir until dissolution is complete, thereby preparing a self-emulsifying pharmaceutical composition of compound (I). The self-emulsifying pharmaceutical composition auxiliary comprises an oil phase, an emulsifier, a co-emulsifier, and an optional antioxidant, preferably, the heating and stirring temperature is 40-70°C; The method for producing a self-emulsifying formulation of compound (I) according to Technical Scheme 11, comprises dispensing the obtained self-emulsifying pharmaceutical composition into oral liquid bottles or capsules, or preparing the self-emulsifying pharmaceutical composition into granules or pellets by liquid solidification technology and compressing them into tablets or capsules to produce a self-emulsifying formulation of compound (I).

[0067] Technical Suggestion 13. Use of a self-emulsifying preparation of compound (I) according to Technical Suggestion 11 in the manufacture of a medicament for the prevention and / or treatment of diseases associated with abnormal vascular proliferation, and / or in the manufacture of a medicament as a VEGFR-2 inhibitor, and / or in the manufacture of a medicament for the treatment of diseases associated with the CSF1R kinase signaling pathway, and / or in the manufacture of a medicament as a CSF1R kinase inhibitor, Preferably, the disease associated with abnormal vascular proliferation is selected from tumors, rheumatoid arthritis, age-related macular degeneration, and psoriasis; More preferably, the tumor is selected from the group consisting of lung cancer, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, kidney cancer, glioma, melanoma, pancreatic cancer, head and neck cancer, bladder cancer, cervical cancer, bile duct cancer, nasopharyngeal cancer, thyroid cancer, osteosarcoma, synovium, rhabdomyosarcoma, fibromyosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastasis tumor, meningioma and lymphoma; Particularly preferred is the use wherein said glioma is a glioblastoma, an astroglioma or a medulloblastoma.

[0068] Technical proposal 14. A self-emulsifying formulation of compound (I) according to technical proposal 11 for the prevention and / or treatment of diseases associated with abnormal vascular proliferation and / or for the treatment of diseases associated with the CSF1R kinase signaling pathway, comprising: Preferably, the disease associated with abnormal vascular proliferation is selected from tumors, rheumatoid arthritis, age-related macular degeneration, and psoriasis; More preferably, the tumor is selected from the group consisting of lung cancer, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, kidney cancer, glioma, melanoma, pancreatic cancer, head and neck cancer, bladder cancer, cervical cancer, bile duct cancer, nasopharyngeal cancer, thyroid cancer, osteosarcoma, synovium, rhabdomyosarcoma, fibromyosarcoma, leiomyosarcoma, myeloma, glioma, brain metastasis tumor, meningioma and lymphoma; Particularly preferably, the glioma is a glioblastoma, an astroglioma, or a medulloblastoma.

[0069] Technical Scheme 15. A method for the prevention and / or treatment of diseases associated with abnormal vascular proliferation and / or for the treatment of diseases associated with the CSF1R kinase signaling pathway, comprising administering to a subject a therapeutically effective amount of a self-emulsifying formulation of compound (I) according to Technical Scheme 11, Preferably, the disease associated with abnormal vascular proliferation is selected from tumors, rheumatoid arthritis, age-related macular degeneration, and psoriasis; More preferably, the tumor is selected from the group consisting of lung cancer, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, kidney cancer, glioma, melanoma, pancreatic cancer, head and neck cancer, bladder cancer, cervical cancer, bile duct cancer, nasopharyngeal cancer, thyroid cancer, osteosarcoma, synovium, rhabdomyosarcoma, fibromyosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastasis tumor, meningioma and lymphoma; Particularly preferably, the glioma is a glioblastoma, an astroglioma, or a medulloblastoma.

[0070] The present invention provides the following beneficial effects by preparing Compound (I) as a self-emulsifying formulation:

[0071] (1) After oral administration, microemulsions are rapidly formed, improving the solubility and dissolution rate of the drug as well as its permeability through the gastrointestinal mucosa, thereby significantly improving the oral availability of the drug.

[0072] (2) The self-emulsifying formulation of compound (I) of the present invention has stable properties and is convenient for long-term storage.

[0073] (3) The self-emulsifying pharmaceutical composition of compound (I) of the present invention can be prepared into various dosage forms such as oral liquid, capsules, and tablets, which are convenient to use, easy for patients to take, and improve patient compliance.

[0074] (4) The method for producing the self-emulsifying formulation of compound (I) of the present invention is simple and convenient for industrial-scale production. DETAILED DESCRIPTION OF THE INVENTION

[0075] The present invention will be further described below with reference to specific examples. It should be understood that these examples are for illustrative purposes only and do not limit the scope of the present invention. In the following examples, experimental methods for which no specific conditions are described are performed according to standard conditions or conditions recommended by the manufacturer.

[0076] The materials used in the examples include the following pharmaceutical grade auxiliary substances, which comply with the provisions of the "Chinese Pharmacopoeia 2020" and / or "EUROPEAN PHARMACOPOEIA 11.0".

[0077] [Table 0-1]

[0078] [Table 0-2]

[0079] Examples 1-5: Preparation of oral liquid Specifications: 20 mL (density approximately 1.06 mg / mL, same below): 200 mg / bottle, 1000 bottles / batch

[0080] [Table 0-3]

[0081] Manufacturing method: According to the above recipe, polyoxyethylene (40) hydrogenated castor oil was melted in advance in warm water at about 60°C to a liquid state, and medium-chain triglyceride, polyoxyethylene (40) hydrogenated castor oil, polyethylene glycol 400 or diethylene glycol monoethyl ether, and dibutylhydroxytoluene were added to a formulation tank and stirred uniformly at 40-70°C. Compound (I) was then added, and the mixture was further heated and stirred at 40-70°C until the ingredients were completely dissolved, obtaining a self-emulsifying liquid, which was then dispensed into oral liquid bottles according to the above specifications.

[0082] The self-emulsifying liquid was collected and diluted with water (volume ratio) at 1:3, 1:5, 1:20, and 1:500, and then shaken for 1 to 2 minutes to obtain a self-emulsifying microemulsion. The particle size was measured, and the average particle size was 20 to 40 nm.

[0083] The self-emulsifying solution was collected and diluted with the self-emulsifying solution to the carrier (volume ratio) at 1:5, 1:20, and 1:500, and then shaken for 1-2 minutes to obtain a self-emulsifying microemulsion. The particle size was measured and found to be 20-40 nm. The carrier could also be hydrochloric acid buffer (pH=1.0), acetate buffer (pH=4.5), or phosphate buffer (pH=6.8).

[0084] The vehicle was prepared according to the “Guiding Principles of Dissolution Test Techniques for Ordinary Oral Solid Dosage Forms” ( State Food and Drug Administration, 2015 ).

[0085] Examples 6-7: Preparation of capsules Specification: 15mg, 10,000 tablets / lot

[0086] [Table 0-4]

[0087] Manufacturing method: According to the above recipe, polyoxyethylene (40) hydrogenated castor oil was dissolved in warm water at about 60°C to form a liquid, and then medium-chain triglyceride, polyoxyethylene (40) hydrogenated castor oil, and polyethylene glycol 400 were added to a blending tank and stirred uniformly at 40-70°C. Compound (I) was then added, and the mixture was heated and stirred until the ingredients were completely dissolved to obtain a self-emulsifying liquid. This was then filled into hypromellose capsules according to the above specifications, dissolved in ethanol-water hypromellose, and sealed.

[0088] Examples 8-12: Preparation of other oral liquids Specification: 20ml: 200mg / bottle, 10 bottles / lot

[0089] With reference to the manufacturing methods of Examples 1-5, oral liquid preparations were prepared according to the following formulation.

[0090] [Table 0-5]

[0091] The self-emulsifying liquid was collected and diluted with water (volume ratio) at 1:3, 1:5, 1:20, and 1:500, and then shaken for 1 to 2 minutes to obtain a microemulsion. The particle size was measured, and the average particle size was 10 to 40 nm.

[0092] The self-emulsifying liquid was collected and diluted with a volume ratio of 1:5, 1:20, or 1:500 of the solvent, and shaken for 1-2 minutes to obtain a microemulsion. The particle size was measured and found to be 10-40 nm. The solvent could also be a hydrochloric acid buffer (pH = 1.0), acetate buffer (pH = 4.5), or phosphate buffer (pH = 6.8).

[0093] The vehicle was prepared according to the “Guiding Principles of Dissolution Test Techniques for Ordinary Oral Solid Dosage Forms” ( State Food and Drug Administration, 2015 ).

[0094] Example 13: Preparation of oral liquid Oral liquid preparations were prepared according to the following recipes and specifications, with reference to the manufacturing methods of the oral liquid preparations in Examples 1-5. Specification: 2.0g: 25mg / bottle, 1000 bottles / lot

[0095] [Table 0-6]

[0096] Furthermore, the oral liquid preparation can also be dispensed into other specifications, such as 1.2 g: 15 mg / bottle, or 1.6 g: 20 mg / bottle, if necessary.

[0097] The self-emulsifying liquid was collected and diluted with water (volume ratio) at 1:3, 1:5, 1:20, and 1:500, and then shaken for 1 to 2 minutes to obtain a microemulsion. The particle size was measured, and the average particle size was 20 to 40 nm.

[0098] The self-emulsifying liquid was collected and diluted with a volume ratio of 1:5, 1:20, or 1:500 of the solvent, and shaken for 1-2 minutes to obtain a microemulsion. The particle size was measured and found to be 20-40 nm. The solvent could also be a hydrochloric acid buffer (pH = 1.0), acetate buffer (pH = 4.5), or phosphate buffer (pH = 6.8).

[0099] The vehicle was prepared according to the “Guiding Principles of Dissolution Test Techniques for Ordinary Oral Solid Dosage Forms” ( State Food and Drug Administration, 2015 ).

[0100] Comparative Example 1: Solubilization of Drug Substance

[0101] [Table 0-7]

[0102] Manufacturing method: Compound (I) was dissolved in ethanol:Tween 80:PEG 400:physiological saline (2:5:20:73).

[0103] Comparative Example 2: Conventional oral solid preparation

[0104] [Table 0-8]

[0105] Manufacturing method: Each ingredient was weighed according to the recipe, and Compound (I) was air-pulverized, then passed through a 60-mesh sieve and mixed uniformly by the equal weight method to prepare drug-containing granules containing the drug at 15 mg / 100 mg.

[0106] Comparative Example 3:

[0107] [Table 0-9]

[0108] Manufacturing method: Compound (I) was dissolved in a 1:1 mixture of ethanol and ethyl acetate, dissolved by ultrasonic heating, and filtered through a 0.45 μm organic filter to prepare a drug solution. Polyoxyethylene (40) hydrogenated castor oil was first melted in warm water at approximately 60°C. The oil phase and other adjuvants were mixed uniformly to the above ratio, and the drug solution was added. The mixture was stirred at room temperature for 30 minutes, and the organic solvent was evaporated under reduced pressure in a 65°C water bath to obtain a pale yellow oily liquid containing the drug. The resulting liquid was then filled into oral liquid bottles.

[0109] Test Example 1: Stability test (1) The oral liquid preparations obtained in Examples 1-5, 8-9, 13 and Comparative Example 3 and the liquid capsule preparations obtained in Examples 6-7 were left at high temperatures of 40°C and 60°C for 10 days, and the test results were as follows.

[0110] [Table 1]

[0111] The experimental results showed that the formulations of Examples 1-9 and 13 did not show any significant changes in content or properties after being left at high temperatures of 40°C and 60°C for 10 days during storage for stability, indicating that the product quality was stable. The formulation of Comparative Example 3 showed a significant change in quality, with the content decreasing by more than 5% after being left at high temperatures of 40°C and 60°C for 10 days. Furthermore, the formulation of Comparative Example 3 changed from a clear yellow to a pink liquid during storage.

[0112] (2) The formulation of Example 1 was left at 2 to 8°C and the stability was examined. The results were as follows:

[0113] [Table 2]

[0114] The experimental results showed that the properties and content of the preparation of Example 1 did not change significantly even when left at 2 to 8°C for 24 months, and even for 36 months, and that the quality was stable.

[0115] (3) The formulation of Example 13 was left to stand at 2 to 8°C, 30°C ± 2°C / 65% RH ± 5% RH, and 40°C ± 2°C / 75% RH ± 5% RH to examine its stability. The results were as follows:

[0116] [Table 3]

[0117] [Table 4]

[0118] [Table 5]

[0119] The experimental results showed that even when the formulation of Example 13 was left under conditions of 2 to 8°C, 30°C ± 2°C / 65% RH ± 5% RH, and 40°C ± 2°C / 75% RH ± 5% RH, there were no significant changes in properties and content, and the quality was stable.

[0120] Test Example 2: Pharmacokinetic test of the formulations of Examples 1-5 and 13 In the following test examples, if the test formulation is an oral liquid, the oral liquid is taken to a specified volume, then diluted with approximately 3 to 5 times the volume of water, shaken or stirred until the liquid becomes clear, and prepared for administration to the subject. If the test formulation is a capsule, it is administered to the subject with the same amount of water as used for the dilution.

[0121] (1) Pharmacokinetics test of the formulations of Examples 1-5 The test formulation was intragastrically administered to 20 male Sprague Dawley rats (SD rats) (5 groups, 4 rats per group) at a dose of 15 mg / kg. 0.2 mL of blood was collected from each test animal via the orbit at 0 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The blood was centrifuged at 4°C and 3000 g to obtain plasma. The concentration of Compound (I) in the rat plasma was measured by LC-MS / MS. Pharmacokinetic parameters were calculated based on the blood drug concentration data using Phoenix WinNonlin 8.0 non-compartmental analysis. The results were as follows:

[0122] [Table 6]

[0123] In the table above, AUC 0-t In the above, t refers to the end time (24 h).

[0124] (2) Pharmacokinetics test of the formulation of Example 13 A pharmacokinetic test was carried out on the formulation of Example 13 using Sprague Dawley male rats (SD rats, 4 rats) with reference to the pharmacokinetic test on the formulations of Examples 1-5. The results are as follows.

[0125] [Table 7]

[0126] In the table above, AUC 0-t In the above, t refers to the end time (24 h).

[0127] Test Example 3: Pharmacokinetic test of the formulations of Examples 2 and 6-7 The test formulation was orally administered to Beagle dogs at 15 mg / dose (18 dogs, 6 dogs / group). For each test animal, 2 mL of blood was collected from the forelimb vein at 0 h, 0.15 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h after administration. The blood was centrifuged at 3000 g at 4°C to obtain plasma. The concentration of Compound (I) in rat plasma was measured by LC-MS / MS. Pharmacokinetic parameters were calculated based on the blood drug concentration data using Phoenix WinNonlin 8.0 non-compartmental analysis. The results were as follows:

[0128] [Table 8]

[0129] In the table above, AUC 0-t In the above, t refers to the end time (24 h).

[0130] Test Example 4: Pharmacokinetics test of comparative example Nine male Sprague Dawley rats (SD rats) (3 groups, 3 rats / group) were intragastrically administered with the test formulations or drug substances of Comparative Examples 1-3 at a dose of 10 mg / kg, and in Comparative Example 2, the test formulations were prepared with 0.5% CMC-Na. For each test animal, 0.2 mL of blood was collected via the orbit at 0 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration, and centrifuged at 3000 g at 4°C to obtain plasma. The concentration of Compound (I) in the rat plasma was measured by LC-MS / MS. Based on the blood drug concentration data, the pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.0 non-compartmental analysis, and the following were obtained:

[0131] [Table 9]

[0132] In the table above, AUC 0-t In the above, t refers to the end time (24 h).

[0133] Test Example 5: Pharmacokinetics test in humans A phase Ia clinical trial was conducted in patients with solid tumors using the formulation of Example 1. During the single-dose period, 3 mL of whole blood was collected before administration and 30 min ± 2 min, 1 h ± 5 min, 2 h ± 5 min, 4 h ± 5 min, 8 h ± 10 min, 12 h ± 10 min, 24 h ± 10 min, 48 h ± 15 min, and 72 h ± 30 min after administration. The blood was centrifuged to obtain plasma. Drug concentrations in human plasma were measured using a validated LC-MS / MS method, and pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.3 noncompartmental analysis.

[0134] The results of the experiment showed that after a single oral dose of 15-30 mg was administered to subjects, the drug was absorbed relatively rapidly and the T max The median time was 2.00-2.01 h, after which the drug concentration in plasma gradually disappeared. 1 / 2 The mean apparent volume of distribution (Vz / F) and clearance (CL / F) were 27.2-30.9 h, 187-189 L, and 4.39-5.06 L / h, respectively. Overall, the in vivo exposure of the drug increased with increasing dose, with mean C max The mean blood concentration-time area under the curve (AUC last and AUC inf ) were 2680-5910 h*ng / mL and 3300-7420 h*ng / mL, respectively. Over the dose range of 15-30 mg, the drug exhibited a substantially linear pharmacokinetic profile in vivo.

[0135] [Table 10]

[0136] It should be noted that the above is only a preferred embodiment of the present invention. It is understood by those skilled in the art that modifications and variations may be made without departing from the principles of the present invention, and such modifications and variations should be considered to fall within the protection scope of the present invention.

Claims

1. A self-emulsifying pharmaceutical composition of compound (I), comprising compound (I), an oil phase, an emulsifier and a co-emulsifier, wherein the weight ratio of compound (I), oil phase, emulsifier and co-emulsifier is 0.5-2:0-20:50-80:20-35, preferably 0.99-1.98:0-20:50-80:20-35, more preferably 0.99:0-20:50-80:20-35, or 1.25:0-20:50-80:20-35, or 1.98:0-20:50-80:20-35, and the structural formula of compound (I) is represented by the following formula (I): 【Chemistry 1】

2. The weight ratio of the compound (I), the oil phase, the emulsifier and the co-emulsifier is 0.5-2: 10-20: 50-65: 20-30, or 0.5-2:0:60-80:20-30, or 0.5-2: 0-15: 55-75: 20-30, More preferably 0.99-1.98: 0-15: 55-75: 20-30, or 0.99-1.98: 0-15: 55-75: 24-30, or 0.99-1.98: 10-15: 55-65: 25-30, or 0.99-1.98: 13-14: 55-57: 28-29, or 0.99-1.98:0:70-80:20-30, or 0.99-1.98:0:75-80:25-30, or 0.99-1.98:0:70-75:20-25, or 0.99-1.98:0:74-76:24-26, More preferably 0.99: 10-20: 50-65: 20-30, or 0.99: 10-15: 55-65: 25-30, or 0.99: 13-14: 55-57: 28-29, or 1.25: 10-20: 50-65: 20-30, or 1.25: 10-15: 55-65: 25-30, or 1.25:13-14:55-57:28-29, or 1.98: 10-20: 50-65: 20-30, or 1.98: 10-15: 55-65: 25-30, or 1.98:13-14:55-57:28-29, or 0.99:0:60-80:20-30, or 0.99:0:70-80:20-30, or 0.99:0:75-80:25-30, or 0.99:0:70-75:20-25, or 2. The self-emulsifying pharmaceutical composition of compound (I) according to claim 1, characterized in that the ratio is 0.99:0:74-76:24-26.

3. 10. The self-emulsifying pharmaceutical composition of compound (I) according to any one of the preceding claims, characterized in that the concentration of compound (I) is 5-20 mg / g, preferably 9.9-19.8 mg / g, more preferably 9.9 mg / g, 19.8 mg / g or 12.5 mg / g.

4. 10. A self-emulsifying pharmaceutical composition of compound (I) according to any one of the preceding claims, characterized in that the oil phase is selected from medium chain triglycerides, glyceryl monooctanoate, glyceryl dioctanoate, glyceryl monooleate, glyceryl monolinoleate, corn oil, castor oil, sesame oil, peanut oil, olive oil, preferably medium chain triglycerides.

5. 10. The self-emulsifying pharmaceutical composition of compound (I) according to any one of the preceding claims, characterized in that the emulsifier is selected from polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (35) castor oil, vitamin E polyethylene glycol succinate, polyethylene glycol 15-hydroxystearate, linoleoyl polyoxyethylene (6) glyceride, caprylocaproyl polyethylene glycol glyceride, preferably polyoxyethylene (40) hydrogenated castor oil, vitamin E polyethylene glycol succinate, polyoxyethylene (35) castor oil, more preferably polyoxyethylene (40) hydrogenated castor oil.

6. 10. The self-emulsifying pharmaceutical composition of compound (I) according to any one of the preceding claims, characterized in that the co-emulsifier is selected from polyethylene glycol, diethylene glycol monoethyl ether, propylene glycol, glycerol, preferably polyethylene glycol 400, diethylene glycol monoethyl ether.

7. 10. A self-emulsifying pharmaceutical composition of compound (I) according to any one of the preceding claims, optionally comprising an antioxidant, preferably characterized in that the weight ratio of compound (I) to antioxidant is 1:0-0.5, preferably 1:0-0.1, more preferably 1:0-0.05, even more preferably 1:0-0.03, even more preferably 1:0.02, 0.99:0.02 or 1:

0.

8. The self-emulsifying pharmaceutical composition of compound (I) according to claim 7, characterized in that the antioxidant is selected from dibutylhydroxytoluene, butylhydroxyanisole, vitamin E and propyl gallate, preferably dibutylhydroxytoluene and vitamin E, more preferably dibutylhydroxytoluene.

9. The self-emulsifying pharmaceutical composition comprises the compound (I), an oil phase, an emulsifier and a co-emulsifier, and the weight ratio of the compound (I), the oil phase, the emulsifier and the co-emulsifier is 0.5-2:10-20:50-65:20-30, preferably 0.99-1.98:10-15:55-65:25-30, more preferably 0.99-1.98:13-14:55-57:28-29, for example 0.99:13-14:55-57:28-29, or 1.25:13-14: 55-57:28-29, or 1.98:13-14:55-57:28-29, wherein the oil phase is a medium chain triglyceride, the emulsifier is polyoxyethylene (40) hydrogenated castor oil, vitamin E polyethylene glycol succinate, polyethylene glycol 15-hydroxystearate, or polyoxyethylene (35) castor oil, and the co-emulsifier is polyethylene glycol 400 or diethylene glycol monoethyl ether, or the self-emulsifying pharmaceutical composition comprises the compound (I), an oil phase, an emulsifier and a co-emulsifier, the weight ratio of the compound (I), the oil phase, the emulsifier and the co-emulsifier being 0.99-1.98:13-14:55-57:28-29, for example 0.99:13-14:55-57:28-29, the oil phase being a medium-chain triglyceride, the emulsifier being polyoxyethylene (40) hydrogenated castor oil, and the co-emulsifier being polyethylene glycol 400 or diethylene glycol monoethyl ether, or The self-emulsifying pharmaceutical composition comprises the compound (I), an oil phase, an emulsifier and a co-emulsifier, and the weight ratio of the compound (I), the oil phase, the emulsifier and the co-emulsifier is 0.99-1.98:13-14:55-57:28-29, for example 0.99:13-14:55-57:28-29, the oil phase is a medium-chain triglyceride, the emulsifier is vitamin E polyethylene glycol succinate, and the co-emulsifier is polyethylene glycol 400 or diethylene glycol monoethyl ether, or the self-emulsifying pharmaceutical composition comprises the compound (I), an oil phase, an emulsifier and a co-emulsifier, wherein the weight ratio of the compound (I), the oil phase, the emulsifier and the co-emulsifier is 0.99-1.98:13-14:55-57:28-29, for example 0.99:13-14:55-57:28-29, the oil phase is a medium-chain triglyceride, the emulsifier is polyethylene glycol 15-hydroxystearate or polyoxyethylene (35) castor oil, and the co-emulsifier is polyethylene glycol 400; or the self-emulsifying pharmaceutical composition comprises the compound (I), an oil phase, an emulsifier, and a co-emulsifier, and the weight ratio of the compound (I), the oil phase, the emulsifier, and the co-emulsifier is 0.99-1.98:13-14:55-57:28-29, for example, 1.25:13-14:55-57:28-29; the oil phase is a medium-chain triglyceride; the emulsifier is polyoxyethylene (40) hydrogenated castor oil; and the co-emulsifier is polyethylene glycol 400; or the self-emulsifying pharmaceutical composition comprises the compound (I), an oil phase, an emulsifier, and a co-emulsifier, and the weight ratio of the compound (I), the oil phase, the emulsifier, and the co-emulsifier is 0.99-1.98:13-14:55-57:28-29, for example, 0.99:13-14:55-57:28-29 or 1.98:13-14:55-57:28-29; the oil phase is a medium-chain triglyceride; the emulsifier is polyoxyethylene (40) hydrogenated castor oil; and the co-emulsifier is polyethylene glycol 400; or The self-emulsifying pharmaceutical composition comprises the compound (I), an oil phase, an emulsifier, a co-emulsifier and an antioxidant, and the weight ratio of the compound (I), the oil phase, the emulsifier, the co-emulsifier and the antioxidant is 0.5-2:10-20:50-65:20-30:(more than 0 and not more than 0.5), preferably 0.99-1.98:10-15:55-65:25-30:(more than 0 and not more than 0.5), more preferably 0.99-1.98:10-15:55-61:27-29:(more than 0 and not more than 0.5), for example 0.99:13-14:55-57:28-29:(0.01- 0.03), or 0.99:10-12:59-61:26-28:(0.4-0.5), wherein the oil phase is a medium chain triglyceride, the emulsifier is polyoxyethylene (40) hydrogenated castor oil, vitamin E polyethylene glycol succinate, polyethylene glycol 15-hydroxystearate, or polyoxyethylene (35) castor oil, the co-emulsifier is polyethylene glycol 400 or diethylene glycol monoethyl ether, and the antioxidant is dibutylhydroxytoluene or vitamin E, or The self-emulsifying pharmaceutical composition comprises compound (I), an oil phase, an emulsifier, a co-emulsifier, and an antioxidant, and the weight ratio of compound (I), oil phase, emulsifier, co-emulsifier, and antioxidant is 0.99-1.98:13-14:55-57:28-29:(more than 0 and not more than 0.05), for example, 0.99:13-14:55-57:28-29:(0.01-0.03), the oil phase is a medium-chain triglyceride, the emulsifier is polyoxyethylene (40) hydrogenated castor oil, the co-emulsifier is polyethylene glycol 400, and the antioxidant is dibutylhydroxytoluene, or the self-emulsifying pharmaceutical composition comprises compound (I), an oil phase, an emulsifier, a co-emulsifier and an antioxidant, wherein the weight ratio of compound (I), oil phase, emulsifier, co-emulsifier and antioxidant is 0.99-1.98:10-12:59-61:26-28:(0.1-0.5), for example 0.99:10-12:59-61:26-28:(0.4-0.5), the oil phase is a medium-chain triglyceride, the emulsifier is polyoxyethylene (40) hydrogenated castor oil, the co-emulsifier is diethylene glycol monoethyl ether and the antioxidant is vitamin E, or the self-emulsifying pharmaceutical composition comprises the compound (I), an emulsifier, and a co-emulsifier, and the weight ratio of the compound (I), the emulsifier, and the co-emulsifier is 0.99:60-80:20-30, for example, 0.99:70-80:20-30, or 0.99:75-80:25-30, or 0.99:70-75:20-25, or 0.99:74-76:24-26; the emulsifier is polyoxyethylene (40) hydrogenated castor oil, and the co-emulsifier is polyethylene glycol 400 or diethylene glycol monoethyl ether; A self-emulsifying pharmaceutical composition of compound (I) according to claim 1.

10. 10. A self-emulsifying pharmaceutical composition of compound (I) according to any of the preceding claims, characterized in that the self-microemulsions obtained from said self-emulsifying pharmaceutical composition upon dilution have an average size of more than 0 to 250 nm, preferably 10-100 nm.

11. A self-emulsifying formulation prepared from the self-emulsifying pharmaceutical composition of compound (I) according to any of the preceding claims, characterized in that the dosage form of the self-emulsifying formulation of compound (I) is an oral liquid, a capsule or a tablet, the capsule may be a soft capsule or a hard capsule, and preferably the dosage form of the self-emulsifying formulation of compound (I) is an oral liquid.

12. a method for producing a self-emulsifying pharmaceutical composition of compound (I), comprising adding a self-emulsifying pharmaceutical composition adjuvant to a formulation tank and stirring the mixture uniformly under heating, adding compound (I), and continuing to heat and stir until dissolution is complete, wherein the self-emulsifying pharmaceutical composition adjuvant comprises an oil phase, an emulsifier, a co-emulsifier, and an optional antioxidant; and preferably, the heating and stirring temperature is 40-70°C; The method for preparing the self-emulsifying formulation of compound (I) according to claim 11, wherein the obtained self-emulsifying pharmaceutical composition is dispensed into oral liquid bottles or capsules, or the obtained self-emulsifying pharmaceutical composition is prepared into granules or pellets by liquid solidification technology and compressed into tablets or capsules to prepare the self-emulsifying formulation of compound (I).

13. 12. Use of a self-emulsifying formulation of compound (I) according to claim 11 for the manufacture of a medicament for the prevention and / or treatment of a disease associated with abnormal vascular proliferation, and / or for the manufacture of a medicament as a VEGFR-2 inhibitor, and / or for the manufacture of a medicament for the treatment of a disease associated with the CSF1R kinase signaling pathway, and / or for the manufacture of a medicament as a CSF1R kinase inhibitor, Preferably, the disease associated with abnormal vascular proliferation is selected from tumors, rheumatoid arthritis, age-related macular degeneration, and psoriasis; More preferably, the tumor is selected from the group consisting of lung cancer, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, kidney cancer, glioma, melanoma, pancreatic cancer, head and neck cancer, bladder cancer, cervical cancer, bile duct cancer, nasopharyngeal cancer, thyroid cancer, osteosarcoma, synovium, rhabdomyosarcoma, fibromyosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastasis tumor, meningioma and lymphoma; Particularly preferred is the use wherein said glioma is a glioblastoma, an astroglioma or a medulloblastoma.

14. 12. A self-emulsifying formulation of compound (I) according to claim 11 for the prevention and / or treatment of diseases associated with abnormal vascular proliferation and / or for the treatment of diseases associated with the CSF1R kinase signaling pathway, comprising: Preferably, the disease associated with abnormal vascular proliferation is selected from tumors, rheumatoid arthritis, age-related macular degeneration, and psoriasis; More preferably, the tumor is selected from the group consisting of lung cancer, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, kidney cancer, glioma, melanoma, pancreatic cancer, head and neck cancer, bladder cancer, cervical cancer, bile duct cancer, nasopharyngeal cancer, thyroid cancer, osteosarcoma, synovium, rhabdomyosarcoma, fibromyosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastasis tumor, meningioma and lymphoma; Particularly preferably, the glioma is a glioblastoma, an astroglioma, or a medulloblastoma.

15. A method for the prevention and / or treatment of diseases associated with abnormal vascular proliferation and / or for the treatment of diseases associated with the CSF1R kinase signaling pathway, comprising administering to a subject a therapeutically effective amount of a self-emulsifying formulation of compound (I) according to claim 11, Preferably, the disease associated with abnormal vascular proliferation is selected from tumors, rheumatoid arthritis, age-related macular degeneration, and psoriasis; More preferably, the tumor is selected from the group consisting of lung cancer, breast cancer, colorectal cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, ovarian cancer, kidney cancer, glioma, melanoma, pancreatic cancer, head and neck cancer, bladder cancer, cervical cancer, bile duct cancer, nasopharyngeal cancer, thyroid cancer, osteosarcoma, synovium, rhabdomyosarcoma, fibromyosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastasis tumor, meningioma and lymphoma; Particularly preferably, the glioma is a glioblastoma, an astroglioma, or a medulloblastoma.

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