Self-emulsifying pharmaceutical composition, method for its production and its use

Abstract

FIELD: chemistry; pharmaceuticals.SUBSTANCE: self-emulsifying pharmaceutical composition of compound (I) inhibiting VEGFR / CSF1R, pharmaceutical composition of compound (I) inhibiting VEGFR / CSF1R, variants of a preparation containing the proposed composition, method for producing the preparation and use of the preparation in the production of a drug inhibiting VEGFR / CSF1R, as well as a method for the prevention and / or treatment of diseases associated with abnormal vascular proliferation using the said preparation. The self-emulsifying pharmaceutical composition contains: a compound (I) having the structure;an oil phase selected from medium chain triglycerides; an emulsifier selected from polyoxyl-40 hydrogenated castor oil, polyoxyl-35 castor oil, tocopherol polyethyleneglycol succinate and polyoxyl-15 hydroxystearate; an auxiliary emulsifier selected from polyethylene glycol and diethylene glycol monoethyl ether, wherein the weight ratio of these ingredients is 0.5–2:from more than 0 to 20:50–80:20–35, respectively.EFFECT: increase in the solubility of compound (I) and its oral bioavailability, as well as the stability of the composition and the possibility of its formulation in the form of various dosage forms (such as liquids for oral administration, capsules and tablets), which are convenient for patients to take.24 cl, 10 tbl, 13 ex

Description

[0001] Technical field

[0002] The present invention relates to the field of medicine, and in particular concerns a self-emulsifying pharmaceutical composition, a method for producing it and its use.

[0003] Prior Art

[0004] The compound (I) was first disclosed in CN104860885A, and its structural formula is as follows:

[0005] (I).

[0006] Compound (I) is a dual VEGFR / CSF1R inhibitor with excellent activity, which can suppress tumor cell angiogenesis and enhance tumor immunity to achieve antitumor effect. Compound (I) can be used to prepare drugs for the prevention and / or treatment of diseases associated with abnormal vascular proliferation, and / or drugs that are VEGFR-2 inhibitors, and / or drugs for the treatment of diseases associated with the CSF1R kinase signaling pathway, and / or drugs that are CSF1R kinase inhibitors.The disease associated with abnormal vascular proliferation is selected from tumor, rheumatoid arthritis, age-related macular degeneration and psoriasis; said tumor includes 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, cholangiocarcinoma, nasopharyngeal cancer, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, fibrosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastasis (metastatic brain cancer), meningioma and lymphadenoma.

[0007] Brief description of the invention

[0008] Technical tasks

[0009] Compound (I) has very low water solubility, which results in very low oral bioavailability of the drug when this compound is formulated into standard dosage forms such as oral liquids, tablets, capsules and other commonly known oral preparations.

[0010] An emulsion is a dosage form widely used to enhance the absorption of fat-soluble drugs. However, standard emulsions are not widely used due to their large volume, short shelf life, and poor taste.

[0011] The technical problem to be solved by the present invention is to develop a self-emulsifying pharmaceutical composition of compound (I), wherein a drug prepared with this self-emulsifying pharmaceutical composition has higher drug solubility and oral bioavailability, and the self-emulsifying pharmaceutical composition is stable and can be formulated into various dosage forms such as oral liquids, capsules and tablets, which are convenient for patients to take.

[0012] Technical solutions

[0013] In order to solve the above technical problem, the following technical solutions are described in the present invention:

[0014] On the one hand, the present invention describes a self-emulsifying pharmaceutical composition of compound (I), comprising: compound (I), an oil phase, an emulsifier and an auxiliary emulsifier, wherein the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier is 0.5-2:0-20:50-80:20-35, compound (I) has a structural formula corresponding to formula (I),

[0015] (I).

[0016] In some embodiments of the present invention, the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier is 0.99-1.98:0-20:50-80:20-35.

[0017] In some embodiments of the present invention, the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier is 0.99:0-20:50-80:20-35.

[0018] In some embodiments of the present invention, the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier is 1.25:0-20:50-80:20-35.

[0019] In some embodiments of the present invention, the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier is 1.98:0-20:50-80:20-35.

[0020] In some embodiments of the present invention, the weight ratio of compound (I): oil phase: emulsifier: auxiliary 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.

[0021] In some embodiments of the present invention, the weight ratio of compound (I): oil phase: emulsifier: auxiliary 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.

[0022] In some embodiments of the present invention, the weight ratio of compound (I): oil phase: emulsifier: auxiliary 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, even more preferably 0.99:13.86:56.44:28.71.

[0023] In some embodiments of the present invention, the weight ratio of compound (I): oil phase: emulsifier: auxiliary 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, even more preferably 1.25:13.83:56.25:28.67.

[0024] In some embodiments of the present invention, the weight ratio of compound (I): oil phase: emulsifier: auxiliary 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, even more preferably 1.98:13.72:55.88:28.42.

[0025] In some embodiments of the present invention, the weight ratio of compound (I): oil phase: emulsifier: auxiliary 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.

[0026] In some embodiments of the present invention, the weight ratio of compound (I): oil phase: emulsifier: auxiliary 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.

[0027] 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, 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.

[0028] In some embodiments of the present invention, 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.

[0029] The oil phase is one of the most important excipients in a self-emulsifying drug. Requirements for the oil phase include safety, stability, the ability to dissolve the required amount of drug in a relatively small amount, and the ability to be easily emulsified by the emulsifier present in the formulation. Using an oil phase with high drug solubility allows for increased drug loading in a self-emulsifying system; the oil carrier can increase the proportion of drug transport through the lymphatic system, thereby improving drug bioavailability.

[0030] In some embodiments of the present invention, the oil phase of the present invention is selected from the following: medium chain triglycerides (MCT), monocaprylin, dicaprylin, glyceryl monooleate, glyceryl monolinoleate, corn oil, castor oil, sesame oil, peanut oil, olive oil, and the like; preferably medium chain triglycerides.

[0031] A non-ionic surfactant with a high HLB value is commonly used as an emulsifier in self-emulsifying drugs. Non-ionic surfactants are less toxic than ionic surfactants and cause only reversible changes in gastrointestinal wall permeability. The high hydrophilicity of high HLB surfactants is necessary for the immediate formation of oil-in-water emulsion droplets and diffusion of the self-emulsifying liquid in an aqueous medium, accelerating the self-emulsification process. Emulsifiers are amphiphilic and can dissolve relatively large amounts of hydrophobic drugs, preventing drug deposition in the gastrointestinal tract and prolonging the solubility of drug molecules, which is essential for effective absorption.When the surfactant content reaches a certain level, it leads to the formation of a self-emulsifying system.

[0032] In some embodiments of the present invention, the emulsifier is selected from polyoxyl-40 hydrogenated castor oil (e.g., RH 40, such as Cremophor® RH 40 or Kolliphor® RH 40), polyoxyl-35 castor oil (e.g., Kolliphor EL or Cremophor EL), tocopherol polyethyleneglycol succinate (e.g., TPGS 1000), polyoxyl-15 hydroxystearate (e.g., HS 15, such as Kolliphor® HS 15), linoleoyl polyoxyl-6 glyceride, capryloyl caproyl polyoxyl glyceride (e.g., Labrasol® ALF), and the like; preferably from polyoxyl-40 hydrogenated castor oil, tocopherol polyethyleneglycol succinate, and polyoxyl-35 castor oil; more preferably from polyoxyl-40 hydrogenated castor oil.

[0033] The auxiliary emulsifier in the self-emulsifying drug helps the active ingredient form a uniform emulsion and maintain the stability of the emulsion during storage.

[0034] In some embodiments of the present invention, the auxiliary emulsifier is selected from polyethylene glycol (PEG), diethylene glycol monoethyl ether (e.g., Transcutol HP), propylene glycol, glycerol; preferably from polyethylene glycol 400 (PEG 400), diethylene glycol monoethyl ether (e.g., Transcutol HP).

[0035] Further optionally, the self-emulsifying pharmaceutical composition of compound (I) according to the present invention further contains an antioxidant, preferably, the weight ratio of compound (I) to the antioxidant is 1:(0-0.5), preferably 1:(0-0.1), more preferably 1:(0-0.05), 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) according to the present invention contains an antioxidant, the lower limit of the amount of the antioxidant is not limited, for example, the weight ratio of compound (I) to the antioxidant may be 1:0.0001, such as 1:0.001. In one embodiment, the self-emulsifying pharmaceutical composition of compound (I) according to the present invention further optionally contains an antioxidant. Preferably, the weight ratio of compound (I) to 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), more preferably 1:(0 or 0.001-0.03), even more preferably 0.99:0.02, 1:0.02 or 1:0.

[0036] In the context of the present application, the total weight of the self-emulsifying pharmaceutical composition is taken as 100 parts; the weight ratio of the components in the pharmaceutical composition is calculated in parts by weight; the parts by weight have a certain error range, 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.

[0037] In some embodiments of the present invention, the total weight of the self-emulsifying pharmaceutical composition is 100.

[0038] When the self-emulsifying pharmaceutical composition of compound (I) according to the present invention contains an antioxidant, the proportion of other auxiliary substances such as an oil phase, an emulsifier, and an auxiliary emulsifier can be correspondingly reduced. For example, based on 1 part by weight of compound (I), the amount of the antioxidant is determined according to the weight ratio of compound (I) to the antioxidant, and the amounts of the oil phase, the emulsifier, and the auxiliary emulsifier are determined according to the weight ratios of compound (I) to the oil phase, to the emulsifier, and to the auxiliary emulsifier, and then the amount of compound (I), the amount of the antioxidant, and the amounts of the oil phase, the emulsifier, and the auxiliary emulsifier are normalized to calculate the amount of each component based on the total weight of 100;or alternatively, based on 1 part by weight of the compound (I), the amount of the antioxidant is determined according to the weight ratio of the compound (I) to the antioxidant, and then the amount of the antioxidant is subtracted from the amount of the emulsifier (or the oil phase; or the auxiliary emulsifier), while the amounts of the compound (I), the oil phase and the auxiliary emulsifier remain unchanged (or the amounts of the compound (I), the emulsifier and the auxiliary emulsifier remain unchanged; or the amount of the compound (I), the oil phase, and the emulsifier remain unchanged).;

[0039] In some embodiments of the present invention, the antioxidant is selected from butylated hydroxytoluene, butylated hydroxyanisole, vitamin E and propyl gallate; preferably from butylated hydroxytoluene and vitamin E, more preferably from butylated hydroxytoluene.

[0040] The embodiments of the present invention described above can be arbitrarily combined, and the embodiments obtained by such combination are also embodiments of the present invention.

[0041] In some embodiments of the present invention, the self-emulsifying pharmaceutical composition of compound (I) can be formulated into a self-emulsifying preparation of compound (I), the dosage form of the self-emulsifying preparation is an oral liquid, a capsule or a tablet, and the capsule may be a soft capsule or a hard capsule.

[0042] On the other hand, the present invention also describes a method for producing the above-mentioned self-emulsifying preparation of compound (I), which comprises: adding auxiliary substances of the self-emulsifying pharmaceutical composition to a liquid reactor, heating and stirring until uniform, adding compound (I) and continuing heating and stirring until complete dissolution to obtain a self-emulsifying pharmaceutical composition of compound (I), wherein the auxiliary substances of the self-emulsifying pharmaceutical composition include an oil phase, an emulsifier, an auxiliary emulsifier and, optionally, an antioxidant.

[0043] The obtained self-emulsifying pharmaceutical composition is packaged in vials for oral liquid or filled into capsules, or the self-emulsifying pharmaceutical composition is incorporated into granules or pellets by liquid-to-solid conversion technologies and pressed into tablets or capsules to obtain a self-emulsifying preparation of compound (I).

[0044] The heating and stirring temperature is 40-70°C.

[0045] The liquid-to-solid conversion technology can be carried out by standard methods known in the art, for example, a non-volatile carrier such as microcrystalline cellulose, lactose, starch and hypromellose is mixed and dispersed with a self-emulsifying liquid, and optionally nano-sized adsorbent silica gel is added to absorb the remaining liquid, to form granules or micropellets, which can then be compressed into tablets after adding tableting excipients such as sodium croscarmellose and magnesium stearate, or they can then be incorporated into capsules.

[0046] In another aspect, the present invention also describes the use of the above-described self-emulsifying preparation of compound (I) in the manufacture of a medicament for the prevention and / or treatment of diseases associated with abnormal vascular proliferation, and / or a medicament that is a VEGFR-2 inhibitor, and / or a medicament for the treatment of diseases associated with the CSF1R kinase signaling pathway, and / or a medicament that is a CSF1R kinase inhibitor.

[0047] In some embodiments of the present invention, the disease associated with abnormal vascular proliferation is selected from a tumor, rheumatoid arthritis, age-related macular degeneration and psoriasis; said tumor is preferably selected from 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, cholangiocarcinoma, nasopharyngeal cancer, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, fibrosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastases, meningioma and lymphadenoma. The glioma is preferably a glioblastoma, astroglioma, or medulloblastoma.

[0048] The self-emulsifying preparation of the present invention may be a solid or liquid dosage form. When diluted with water or diluted with gastrointestinal juice during oral administration, the preparation is emulsified to form an oil-in-water emulsion or a microemulsion, which generally has an average particle 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, more preferably 10-50 nm, even more preferably 10-40 nm or 20-40 nm. Upon contact with gastric juice or intestinal juice, the self-emulsifying preparation of the present invention can spontaneously form a microemulsion, and the compound (I) is dissolved in this microemulsion. Therefore, the self-emulsifying preparation of the present invention can increase the solubility of the compound (I) as a drug in the gastrointestinal tract.Compound (I) as a drug is contained in these small microemulsion droplets and rapidly disperses throughout the gastrointestinal tract. Compound (I) as a drug is distributed between the oil and aqueous phases, and transmembrane adsorption of Compound (I) as a drug is significantly enhanced due to the large specific surface area of ​​the small oil droplets, thereby improving the oral bioavailability of Compound (I).

[0049] The present invention describes the following technical solutions:

[0050] Embodiment 1. A self-emulsifying pharmaceutical composition of compound (I), comprising: Compound (I), an oil phase, an emulsifier and an auxiliary emulsifier, wherein the weight ratio of compound (I): oil phase: emulsifier: auxiliary 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;

[0051] Compound (I) has a structural formula corresponding to formula (I),

[0052] (I).

[0053] Option 2. A self-emulsifying pharmaceutical composition of compound (I) according to option 1, characterized in that the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier is

[0054] 0.5-2:10-20:50-65:20-30; or

[0055] 0.5-2:0:60-80:20-30; or

[0056] 0.5-2:0-15:55-75:20-30;

[0057] more preferable

[0058] 0.99-1.98:0-15:55-75:20-30; or

[0059] 0.99-1.98:0-15:55-75:24-30; or

[0060] 0.99-1.98:10-15:55-65:25-30; or

[0061] 0.99-1.98:13-14:55-57:28-29; or

[0062] 0.99-1.98:0:70-80:20-30; or

[0063] 0.99-1.98:0:75-80:25-30; or

[0064] 0.99-1.98:0:70-75:20-25; or

[0065] 0.99-1.98:0:74-76:24-26;

[0066] more preferable

[0067] 0.99:10-20:50-65:20-30; or

[0068] 0.99:10-15:55-65:25-30; or

[0069] 0.99:13-14:55-57:28-29; or

[0070] 0.99:13.86:56.44:28.71; or

[0071] 1.25:10-20:50-65:20-30; or

[0072] 1.25:10-15:55-65:25-30; or

[0073] 1.25:13-14:55-57:28-29; or

[0074] 1.25:13.83:56.25:28.67; or

[0075] 1.98:10-20:50-65:20-30; or

[0076] 1.98:10-15:55-65:25-30; or

[0077] 1.98:13-14:55-57:28-29; or

[0078] 1.98:13.72:55.88:28.42; or

[0079] 0.99:0:60-80:20-30; or

[0080] 0.99:0:70-80:20-30; or

[0081] 0.99:0:75-80:25-30; or

[0082] 0.99:0:70-75:20-25; or

[0083] 0.99:0:74-76:24-26; or

[0084] 0.99:0:74.26:24.75.

[0085] Embodiment 3. A self-emulsifying pharmaceutical composition of compound (I) according to any one of the preceding embodiments, 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; or

[0086] 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.

[0087] Variant 4. A self-emulsifying pharmaceutical composition of compound (I) according to any of the preceding variants, characterized in that the oil phase is selected from medium-chain triglycerides, monocaprylin, dicaprylin, glyceryl monooleate, glyceryl monolinoleate, corn oil, castor oil, sesame oil, peanut oil, olive oil; preferably from medium-chain triglycerides.

[0088] Variant 5. A self-emulsifying pharmaceutical composition of compound (I) according to any of the preceding variants, characterized in that the emulsifier is selected from polyoxyl-40 hydrogenated castor oil, polyoxyl-35 castor oil, tocopherol polyethyleneglycol succinate, polyoxyl-15 hydroxystearate, linoleoyl polyoxyl-6 glyceride, capryloylcaproyl polyoxyl glyceride; preferably from polyoxyl-40 hydrogenated castor oil, tocopherol polyethyleneglycol succinate, polyoxyl-35 castor oil; more preferably from polyoxyl-40 hydrogenated castor oil.

[0089] Option 6. A self-emulsifying pharmaceutical composition of compound (I) according to any of the preceding options, characterized in that the auxiliary emulsifier is selected from polyethylene glycol, diethylene glycol monoethyl ether, propylene glycol, glycerol; preferably from polyethylene glycol 400, diethylene glycol monoethyl ether.

[0090] Embodiment 7. The self-emulsifying pharmaceutical composition of compound (I) according to any one of the preceding embodiments, characterized in that it further optionally contains an antioxidant, preferably, the weight ratio of compound (I) to the antioxidant is 1:(0-0.5), preferably 1:(0-0.1), more preferably 1:(0-0.05), more preferably 1:(0-0.03), even more preferably 0.99:0.02, 1:0.02 or 1:0;

[0091] 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), more preferably 1:(0 or 0.001-0.03), even more preferably 0.99:0.02, 1:0.02 or 1:0.

[0092] Variant 8. A self-emulsifying pharmaceutical composition of compound (I) according to variant 7, characterized in that the antioxidant is selected from butylated hydroxytoluene, butylated hydroxyanisole, vitamin E, propyl gallate; preferably from butylated hydroxytoluene, vitamin E, more preferably from butylated hydroxytoluene.

[0093] Embodiment 9. The self-emulsifying pharmaceutical composition of compound (I) according to embodiment 1, characterized in that the self-emulsifying pharmaceutical composition consists of compound (I), an oil phase, an emulsifier and an auxiliary emulsifier, wherein the weight ratio of compound (I): oil phase: emulsifier: auxiliary 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; more preferably, 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 medium chain triglycerides; the emulsifier is polyoxyl-40 hydrogenated castor oil, tocopherol polyethyleneglycol succinate, polyoxyl-15 hydroxystearate or polyoxyl-35 castor oil; the auxiliary emulsifier is polyethyleneglycol 400 or diethylene glycol monoethyl ether; or.

[0094] The self-emulsifying pharmaceutical composition is composed of a compound (I), an oil phase, an emulsifier and an auxiliary emulsifier, wherein the weight ratio of the compound (I): the oil phase: the emulsifier: the auxiliary emulsifier is 0.99-1.98:13-14:55-57:28-29, such as 0.99:13-14:55-57:28-29; preferably, 0.99:13.86:56.44:28.71; wherein the oil phase is medium chain triglycerides; the emulsifier is polyoxyl-40 hydrogenated castor oil; the auxiliary emulsifier is polyethylene glycol 400 or diethylene glycol monoethyl ether; or

[0095] The self-emulsifying pharmaceutical composition is composed of a compound (I), an oil phase, an emulsifier and an auxiliary emulsifier, wherein the weight ratio of the compound (I): oil phase: emulsifier: auxiliary emulsifier is 0.99-1.98:13-14:55-57:28-29, such as 0.99:13-14:55-57:28-29; preferably, 0.99:13.86:56.44:28.71; wherein the oil phase is medium chain triglycerides; the emulsifier is tocopherol polyethyleneglycol succinate; the auxiliary emulsifier is polyethyleneglycol 400 or diethylene glycol monoethyl ether; or

[0096] The self-emulsifying pharmaceutical composition is composed of a compound (I), an oil phase, an emulsifier and an auxiliary emulsifier, wherein the weight ratio of the compound (I): the oil phase: the emulsifier: the auxiliary emulsifier is 0.99-1.98:13-14:55-57:28-29, such as 0.99:13-14:55-57:28-29; preferably, 0.99:13.86:56.44:28.71; wherein the oil phase is medium chain triglycerides; the emulsifier is polyoxyl-15 hydroxystearate or polyoxyl-35 castor oil; the auxiliary emulsifier is polyethyleneglycol 400; or

[0097] The self-emulsifying pharmaceutical composition is composed of a compound (I), an oil phase, an emulsifier and an auxiliary emulsifier, wherein the weight ratio of the compound (I): the oil phase: the emulsifier: the auxiliary emulsifier is 0.99-1.98:13-14:55-57:28-29, such as 1.25:13-14:55-57:28-29, preferably 1.25:13.83:56.25:28.67; wherein the oil phase is medium chain triglycerides; the emulsifier is polyoxyl-40 hydrogenated castor oil; the auxiliary emulsifier is polyethyleneglycol 400; or

[0098] The self-emulsifying pharmaceutical composition is composed of a compound (I), an oil phase, an emulsifier and an auxiliary emulsifier, wherein the weight ratio of the compound (I): oil phase: emulsifier: auxiliary emulsifier is 0.99-1.98:13-14:55-57:28-29, such as 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; wherein the oil phase is medium chain triglycerides; the emulsifier is polyoxyl-40 hydrogenated castor oil; the auxiliary emulsifier is polyethyleneglycol 400; or

[0099] The self-emulsifying pharmaceutical composition is composed of a compound (I), an oil phase, an emulsifier, an auxiliary emulsifier and an antioxidant, wherein the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier: antioxidant is 0.5-2:10-20:50-65:20-30:(from greater than 0 to 0.5), preferably, 0.99-1.98:10-15:55-65:25-30:(from greater than 0 to 0.5), more preferably, 0.99-1.98:10-15:55-61:27-29:(from greater than 0 to 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 medium chain triglycerides; the emulsifier is polyoxyl-40 hydrogenated castor oil, tocopherol polyethyleneglycol succinate, polyoxyl-15 hydroxystearate or polyoxyl-35 castor oil; the auxiliary emulsifier is polyethyleneglycol 400 or diethylene glycol monoethyl ether; the antioxidant is butylated hydroxytoluene or vitamin E; or.

[0100] The self-emulsifying pharmaceutical composition is composed of a compound (I), an oil phase, an emulsifier, an auxiliary emulsifier and an antioxidant, wherein the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier: antioxidant is 0.99-1.98:13-14:55-57:28-29:(from greater than 0 to 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; wherein the oil phase is medium chain triglycerides; the emulsifier is polyoxyl-40 hydrogenated castor oil; the auxiliary emulsifier is polyethyleneglycol 400; the antioxidant is butylated hydroxytoluene; or

[0101] The self-emulsifying pharmaceutical composition is composed of a compound (I), an oil phase, an emulsifier, an auxiliary emulsifier and an antioxidant, wherein the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier: antioxidant is 0.99-1.98:10-12:59-61:26-28:(0.1-0.5), such as 0.99:10-12:59-61:26-28:(0.4-0.5), preferably 0.99:10.90:60.39:27.22:0.50; wherein the oil phase is medium chain triglycerides; the emulsifier is polyoxyl-40 hydrogenated castor oil; the auxiliary emulsifier is diethylene glycol monoethyl ether; the antioxidant is vitamin E; or

[0102] The self-emulsifying pharmaceutical composition consists of a compound (I), an emulsifier and an auxiliary emulsifier, wherein the weight ratio of the compound (I): emulsifier: auxiliary emulsifier is 0.99:60-80:20-30, such as 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; wherein the emulsifier is polyoxyl-40 hydrogenated castor oil; the auxiliary emulsifier is polyethylene glycol 400 or diethylene glycol monoethyl ether.

[0103] Embodiment 10. The self-emulsifying pharmaceutical composition of compound (I) according to any one of the preceding embodiments, characterized in that the self-emulsifying pharmaceutical composition is diluted to obtain a self-emulsifying microemulsion that has an average particle size of from greater than 0 to 250 nm, preferably from greater than 0 to 100 nm, or 10-100 nm, more preferably from greater than 0 to 50 nm, more preferably 10-50 nm, even more preferably 10-40 nm or 20-40 nm; preferably, the diluent for dilution can be selected from water, hydrochloric acid medium (pH = 1.0), acetate buffer (pH = 4.5) and phosphate buffer (pH = 6.8); more preferably, the degree of dilution, i.e. the ratio of self-emulsifying pharmaceutical composition to diluent is 1:(3-500), for example, 1:(5-500).

[0104] Variant 11. A self-emulsifying preparation of compound (I), which is obtained from a self-emulsifying pharmaceutical composition of compound (I) according to any of the preceding variants, characterized in that the dosage form of the self-emulsifying preparation of compound (I) is a liquid for oral administration, a capsule or a tablet, and the capsule can be a soft capsule or a hard capsule; preferably, the dosage form of the self-emulsifying preparation of compound (I) is a liquid for oral administration.

[0105] Embodiment 12. A method for producing a self-emulsifying preparation of compound (I) according to embodiment 11, which comprises: adding auxiliary substances of a self-emulsifying pharmaceutical composition to a liquid reactor, heating and stirring until homogeneous, adding compound (I) and continuing heating and stirring until completely dissolved to obtain a self-emulsifying pharmaceutical composition of compound (I), wherein the auxiliary substances of the self-emulsifying pharmaceutical composition include an oil phase, an emulsifier, an auxiliary emulsifier and, optionally, an antioxidant; preferably, the heating and stirring temperature is 40-70°C;

[0106] The obtained self-emulsifying pharmaceutical composition is packaged into vials for oral liquid or filled into capsules, or the self-emulsifying pharmaceutical composition is formulated into granules or pellets by liquid-to-solid conversion technologies and pressed into tablets or capsules to obtain a self-emulsifying preparation of compound (I)

[0107] Embodiment 13. Use of a self-emulsifying preparation of compound (I) according to embodiment 11 in the manufacture of a medicament for the prevention and / or treatment of diseases associated with abnormal vascular proliferation, and / or a medicament that is a VEGFR-2 inhibitor, and / or a medicament for the treatment of diseases associated with the CSF1R kinase signaling pathway, and / or a medicament that is a CSF1R kinase inhibitor;

[0108] Preferably, the disease associated with abnormal vascular proliferation is selected from tumor, rheumatoid arthritis, age-related macular degeneration and psoriasis;

[0109] more preferably, said tumor is preferably selected from 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, cholangiocarcinoma, nasopharyngeal cancer, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, fibrosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastasis, meningioma and lymphadenoma;

[0110] It is particularly preferable that said glioma is a glioblastoma, astroglioma, or medulloblastoma.

[0111] Embodiment 14. A self-emulsifying preparation of compound (I) according to embodiment 11 for use in 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;

[0112] Preferably, the disease associated with abnormal vascular proliferation is selected from tumor, rheumatoid arthritis, age-related macular degeneration and psoriasis;

[0113] more preferably, said tumor is preferably selected from 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, cholangiocarcinoma, nasopharyngeal cancer, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, fibrosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastasis, meningioma and lymphadenoma;

[0114] It is particularly preferable that said glioma is a glioblastoma, astroglioma, or medulloblastoma.

[0115] Embodiment 15. A method for the prevention and / or treatment of diseases associated with abnormal vascular proliferation and / or treatment of diseases associated with the CSF1R kinase signaling pathway, which comprises administering to a subject a therapeutically effective amount of a self-emulsifying preparation of compound (I) according to embodiment 11;

[0116] Preferably, the disease associated with abnormal vascular proliferation is selected from tumor, rheumatoid arthritis, age-related macular degeneration and psoriasis;

[0117] more preferably, said tumor is preferably selected from 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, cholangiocarcinoma, nasopharyngeal cancer, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, fibrosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastasis, meningioma and lymphadenoma;

[0118] It is particularly preferable that said glioma is a glioblastoma, astroglioma, or medulloblastoma.

[0119] The present invention provides the following advantages by incorporating the compound (I) into a self-emulsifying preparation:

[0120] (1) After oral administration, microemulsions can be rapidly formed, which improves the solubility and dissolution rate of the drug, and increases the penetration rate of the drug through the gastrointestinal mucosa, thereby greatly enhancing the oral bioavailability of the drug.

[0121] (2) The self-emulsifying preparation of compound (I) of the present invention is stable and convenient for long-term storage.

[0122] (3) The self-emulsifying pharmaceutical composition of compound (I) according to the present invention can be formulated into various dosage forms, such as oral liquids, capsules, and tablets. The dosage forms are easy to administer and convenient for patients to take, and are characterized by high compliance.

[0123] (4) The method for producing the self-emulsifying preparation of compound (I) of the present invention is simple and convenient for industrial scale production.

[0124] Detailed description of the invention

[0125] The present invention is further described below using specific examples. It should be understood that these examples are intended only to illustrate the present invention and in no way limit the scope of the present invention. Experimental methods for which specific conditions are not provided in the examples described below are generally carried out under generally known conditions or in accordance with the conditions recommended by the manufacturer.

[0126] The substances used in the examples include the following pharmaceutical grade excipients that meet the requirements of the Chinese Pharmacopoeia 2020 and / or the European Pharmacopoeia 11.0:

[0127] Polyoxyl-15 hydroxystearate Macrogol 15 hydroxystearate Source: BASF Specification: Pharmaceutical grade PH101 Microcrystalline cellulose PH101 Source: Asahi Kasei, Japan Specification: Pharmaceutical grade (Average particle size: 50 μm, Bulk density: 0.26-0.31 g / cm3) PH302 Microcrystalline cellulose PH-302 Source: Asahi Kasei, Japan Specification: Pharmaceutical grade (Average particle size: 90 μm, bulk density: 0.35-0.46 g / cm3) SDS Sodium Dodecyl Sulfate Source: Hunan ER-KANG Pharmaceutical Co Ltd Specification: Pharmaceutical Grade Tween 80 Polysorbate 80 Source: Nanjing Well Pharmaceutical Group Co Ltd Specification: Pharmaceutical Grade Butylated hydroxytoluene Source: Jiangxi A'er Fagaoke Pharmaceutical Industry Limited Company Specification: Pharmaceutical Grade Diethylene glycol monoethyl ether Source: Gattefossé Purity: >99.9% Specification: Pharmaceutical grade Mannitol Source: Roquette France PEARLITOL® 200 SD Content of the declared substance: 98.0-102.0% Specification: Pharmaceutical grade Crosscarmellose sodium Source: DuPont Specification: Pharmaceutical grade (not more than 2% does not pass through a 200 mesh sieve, and not more than 10% does not pass through a 325 mesh sieve, bulk density: 0.529 g / cm3) Polyoxyl-35 castor oil Source: BASF Specification: Pharmaceutical grade Polyoxyl-40 hydrogenated castor oil Source: BASF Specification: Pharmaceutical grade Polyethylene glycol 1500 Source: Liaoning Oxiranchem Inc. Specification: Pharmaceutical Grade Polyethylene glycol 400 PEG 400 Source: Nanjing Well Pharmaceutical Group Co Ltd Specification: Pharmaceutical Grade Isotonic solution Self-prepared, 0.90% sodium chloride by weight (for injection) + the rest is sterile water for injection Vitamin E Source: Zhejiang Medicine Co., Ltd. Specification: Pharmaceutical grade Tocopherol polyethylene glycol succinate Source: Jiangxi Lianlu Biotechnology Co., Ltd. Specification: Pharmaceutical grade Ethanol Source: Nanjing Chemical Reagent Co., Ltd. Specification: Pharmaceutical grade Ethyl acetate Source: Tianjin Kermel Chemical Reagent Co., Ltd. Specification: Analytical Grade Magnesium stearate Source: Liaoning Aoda Specification: Pharmaceutical Grade Oleic acid Source: Nanjing Well Pharmaceutical Group Co Ltd Specification: Pharmaceutical Grade Medium chain triglycerides (MCT) Medium Chain Triglycerides Source: Liaoning Shinsun Pharmaceutical Co., Ltd. Specification: Pharmaceutical Grade

[0128] Examples 1-5: Preparation of liquids for oral administration

[0129] Specification: 20ml (density about 1.06g / ml, also lower): 200mg / vial, 1000 vials per batch

[0130] Components Weight percent (%) Example 1 Example 2 Example 3 Example 4 Example 5 Compound (I) 0.99 0.99 0.99 0.99 0.99 Medium chain triglycerides 13.86 13.86 13.86 - - Polyoxyl-40 hydrogenated castor oil 56.42 56.44 56.44 74.26 74.26 Polyethylene glycol 400 28.71 28.71 - 24.75 - Diethylene glycol monoethyl ether - - 28.71 - 24.75 Butylated hydroxytoluene 0.020 - - - -

[0131] How to obtain:

[0132] According to the above compositions, polyoxyl-40 hydrogenated castor oil was melted in warm water at approximately 60°C until it became liquid. Medium-chain triglycerides, polyoxyl-40 hydrogenated castor oil, polyethyleneglycol 400 or diethylene glycol monoethyl ether, and butylated hydroxytoluene were added to a liquid reactor and uniformly stirred at 40-70°C. Compound (I) was added, and heating and stirring were continued at 40-70°C until the raw materials were completely dissolved, obtaining a self-emulsifying liquid, which was then filled into oral liquid vials according to the specifications.

[0133] Self-emulsifying liquid was collected and diluted according to the proportions of self-emulsifying liquid:water (volume ratio) = 1:3, 1:5, 1:20, and 1:500, and shaken for 1-2 minutes to obtain microemulsions. The particle size of the microemulsions was measured, and the average particle size was found to be in the range of 20-40 nm.

[0134] The self-emulsifying liquid was collected and diluted according to the proportions of self-emulsifying liquid:medium (volume ratio) = 1:5, 1:20, and 1:500, and shaken for 1-2 minutes to obtain microemulsions. The particle size of the microemulsion was measured, and the average particle size was in the range of 20-40 nm. The medium can be hydrochloric acid (pH = 1.0), acetate buffer (pH = 4.5), or phosphate buffer (pH = 6.8).

[0135] The medium was prepared according to the Technical Regulations for Dissolution Testing of Standard Solid Preparations for Oral Administration (China Food and Drug Administration, 2015).

[0136] Examples 6-7: Preparation of capsules

[0137] Specification: 15mg, 10000 capsules / batch

[0138] Components Weight percent (%) Example 6 Example 7 Compound (I) 0.99 1.98 Medium chain triglycerides 13.86 13.72 Polyoxyl-40 hydrogenated castor oil 56.44 55.88 Polyethylene glycol 400 28.71 28.42

[0139] How to obtain:

[0140] According to the above compositions, polyoxyl-40 hydrogenated castor oil was melted in warm water at approximately 60°C until liquid. Medium-chain triglycerides, polyoxyl-40 hydrogenated castor oil, and polyethyleneglycol 400 were added to a liquid reactor and uniformly stirred at 40-70°C. Compound (I) was added, and the mixture was heated and stirred until the raw materials were completely dissolved, obtaining a self-emulsifying liquid. The self-emulsifying liquid was filled into hypromellose capsules, and the capsules were then hermetically sealed by dissolving the hypromellose in an ethanol / water mixture.

[0141] Examples 8-12: Preparation of other liquids for oral administration

[0142] Specification: 20ml: 200mg / vial, 10 vials / lot

[0143] The following oral liquids were prepared according to the production methods of Examples 1 to 5.

[0144] Components Weight percent (%) Example 8 Example 9 Example 10 Example 11 Example 12 Compound (I) 0.99 0.99 0.99 0.99 0.99 Medium chain triglycerides 10.90 13.86 13.86 13.86 13.86 Polyoxyl-40 hydrogenated castor oil 60.39 - - - - Tocopherol polyethylene glycol succinate - 56.44 56.44 - - Polyoxyl-15 hydroxystearate - - - 56.44 - Polyoxyl-35 castor oil - - - - 56.44 Polyethylene glycol 400 - 28.71 - 28.71 28.71 Diethylene glycol monoethyl ether 27.22 - 28.71 - - Vitamin E 0.50 - - - -

[0145] Self-emulsifying liquid was collected and diluted according to the proportions of self-emulsifying liquid:water (volume ratio) = 1:3, 1:5, 1:20, and 1:500, and shaken for 1-2 minutes to obtain microemulsions. The particle size of the microemulsions was measured, and the average particle size was found to be in the range of 10-40 nm.

[0146] The self-emulsifying liquid was collected and diluted according to the proportions of self-emulsifying liquid:medium (volume ratio) = 1:5, 1:20, and 1:500, and shaken for 1-2 minutes to obtain microemulsions. The particle size of the microemulsion was measured, and the average particle size was in the range of 10-40 nm. The medium can be hydrochloric acid (pH = 1.0), acetate buffer (pH = 4.5), or phosphate buffer (pH = 6.8).

[0147] The medium was prepared according to the Technical Regulations for Dissolution Testing of Standard Oral Solid Preparations (China Food and Drug Administration, 2015).

[0148] Example 13: Preparation of liquid for oral administration

[0149] According to the method for producing the oral liquids of Examples 1 to 5, the oral liquid was prepared according to the following formulation and specification.

[0150] Specification: 2.0g: 25mg / vial, 1000 vials / lot

[0151] Component Weight percent (%) Compound (I) 1.25 Medium chain triglycerides 13.83 Polyoxyl-40 hydrogenated castor oil 56.25 Polyethylene glycol 400 28.67

[0152] The above oral liquid can also be packaged according to other specifications as needed, such as 1.2g:15mg / vial, or 1.6g:20mg / vial.

[0153] Self-emulsifying liquid was collected and diluted according to the proportions of self-emulsifying liquid:water (volume ratio) = 1:3, 1:5, 1:20, and 1:500, and shaken for 1-2 minutes to obtain microemulsions. The particle size of the microemulsions was measured, and the average particle size was found to be in the range of 20-40 nm.

[0154] The self-emulsifying liquid was collected and diluted according to the proportions of self-emulsifying liquid:medium (volume ratio) = 1:5, 1:20, and 1:500, and shaken for 1-2 minutes to obtain microemulsions. The particle size of the microemulsion was measured, and the average particle size was in the range of 20-40 nm. The medium can be hydrochloric acid (pH = 1.0), acetate buffer (pH = 4.5), or phosphate buffer (pH = 6.8).

[0155] The medium was prepared according to the Technical Regulations for Dissolution Testing of Standard Solid Preparations for Oral Administration (China Food and Drug Administration, 2015).

[0156] Comparative Example 1: Solubilization of API

[0157] Component Weight percent (%) Compound (I) 0.99 Ethanol: Tween 80: PEG 400: isotonic solution (2:5:20:73) 99.01

[0158] How to obtain:

[0159] Compound (I) was dissolved in a mixture of ethanol: Tween 80: PEG 400: isotonic solution (2:5:20:73).

[0160] Comparative Example 2: Standard Oral Solid Preparation

[0161] Component Weight percent (%) Compound (I) 15 Mannitol 200SD 74.5 PH302 10 SDS 0.5

[0162] How to obtain:

[0163] The components were weighed according to the formula. Compound (I) was ultradispersed and sieved through a 60-mesh sieve. The components were mixed until homogeneous using the equal-volume method, obtaining drug-containing granules with a drug content of 15 mg / 100 mg.

[0164] Comparative example 3:

[0165] Component Quantity Weight percent (%) Compound (I) 60 mg 1.02 Medium chain triglycerides 1 ml 15.63 Polyoxyl-40 hydrogenated castor oil 1.5 ml 26.10 Diethylene glycol monoethyl ether 2.5 ml 42.01 Oleic acid 1 ml 15.24 Ethanol: ethyl acetate (1:1) 15-20 ml -

[0166] How to obtain:

[0167] Compound (I) was dissolved in a 1:1 mixture of ethanol and ethyl acetate, heated, and treated in an ultrasonic bath until completely dissolved. The resulting solution was filtered through a 0.45 μm organic filter membrane to obtain a drug solution, which was reserved for subsequent use. Polyoxyl-40 hydrogenated castor oil was pre-melted in warm water at approximately 60°C until liquid. The oil phase was then mixed until homogeneous with other excipients according to the proportions specified above. The drug solution was added to the mixture and stirred at room temperature for 30 minutes to ensure complete homogeneity. The organic solvent was then removed using a rotary evaporator under reduced pressure in a 65°C water bath, yielding a light yellow oily liquid containing the drug. The resulting liquid was poured into vials for oral liquid.

[0168] Test 1: Stability test

[0169] (1) The oral liquids obtained in Examples 1-5, 8-9 and 13 and Comparative Example 3, and the liquid capsules obtained in Examples 6-7 were stored at an elevated temperature of 40°C and 60°C for 10 days. The following test results were obtained:

[0170] Table 1: Comparison of the drugs of Examples 1-9 and 13 and Comparative Example 3 in the storage stability test

[0171] Group Requirements for the content in the storage stability test Day 0 Test at elevated temperature of 40°C Test at elevated temperature of 60°C Day 5 Day 10 Day 30 Day 5 Day 10 Example 1 Significant changes in the quality of the drug include: the content differs from the starting value by 5% or more 102.6% 102.1% 102.1% 101.3% 101.1% 103.3% Example 2 101.6% 100.8% 102.3% 101.5% 101.2% 100.3% Example 3 99.8% 100.5% 99.8% 98.9% 98.7% 96.9% Example 4 100.8% 99.8% 97.6% 98.8% 99.6% 98.2% Example 5 100.5% 98.2% 99.1% 97.8% 98.6% 97.8% Example 6 100.9% 100.3% 99.6% 98.1% 99.7% 99.2% Example 7 99.6% 100.2% 98.2% 97.9% 99.0% 98.2% Example 8 100.3% 98.6% 97.2% 96.2% 97.5% 96.0% Example 9 100.5% 99.8% 98.5% 97.2% 99.6% 98.3% Example 13 101.5% n.d. n.d. 100.9% 100.9% 99.2% Comparative Example 3 100.0% 98.6% 93.1% n.d. 90.7% 89.3%

[0172] n.d. = no data

[0173] The test results showed that during the storage stability test, no significant changes in the content and appearance were observed for the products in Examples 1–9 and 13 after storage at elevated temperatures of 40°C and 60°C for 10 days, indicating product stability. The content of the product in Comparative Example 3 decreased by 5% or more after storage at elevated temperatures of 40°C and 60°C for 10 days, and the product experienced significant changes in quality. Furthermore, the product in Comparative Example 3 changed its appearance from a clear yellow liquid to a pink liquid during the stability test.

[0174] (2) The drug from Example 1 was stored at 2-8°C to test its stability. The results are shown below:

[0175] Table 2: Changes in appearance and content of the preparation from Example 1 upon storage at 2-8°C

[0176] Characteristic Controlled parameters Time (months) 0 3 6 9 12 18 24 36 Appearance An oily liquid from white to yellow in color; after heating in a water bath it turns into a clear yellow solution Meets the requirements Content (%) 90.0%-110.0%, and during the storage stability test, the content differs from the original value by less than 5% 103.2 101.4 102.0 103.4 102.1 102.7 101.3 103.5

[0177] The test results showed that there was no significant change in the content and appearance of the drug in Example 1 after storing at 2-8°C for 24 months or even 36 months, indicating the stability of the product's characteristics.

[0178] (3) The drug of Example 13 was stored at 2-8°C, 30°C±2°C / 65%RH±5%RH, and 40°C±2°C / 75%RH±5%RH, respectively, for stability evaluation. The results obtained are shown below:

[0179] Table 3: Changes in appearance and content of the preparation from Example 13 upon storage at 2-8°C

[0180] Characteristic Controlled parameters Time (months) 0 3 6 Appearance A yellow-green to yellow pasty semi-solid or liquid; when diluted with water it becomes a clear liquid with slight opalescence. Meets the requirements Meets the requirements Meets the requirements Content 90.0%-110.0%, and during the storage stability test, the content differs from the original value by less than 5% 102.3% 100.0% 99.5%

[0181] Table 4: Changes in appearance and content of the preparation of Example 13 when stored at 30°C±2°C / 65%RH±5%RH

[0182] Characteristic Controlled parameters Time (months) 0 3 6 Appearance A yellow-green to yellow pasty semi-solid or liquid; when diluted with water it becomes a clear liquid with slight opalescence. Meets the requirements Meets the requirements Meets the requirements Content 90.0%-110.0%, and during the storage stability test, the content differs from the original value by less than 5% 102.3% 101.9% 100.2%

[0183] Table 5: Changes in appearance and content of the preparation of Example 13 when stored at 40°C±2°C / 75%RH±5%RH

[0184] Characteristic Controlled parameters Time (months) 0 3 6 Appearance A yellow-green to yellow pasty semi-solid or liquid; when diluted with water it becomes a clear liquid with slight opalescence. Meets the requirements Meets the requirements Meets the requirements Content 90.0%-110.0%, and during the storage stability test, the content differs from the original value by less than 5% 102.3% 101.4% 99.8%

[0185] The test results showed that there was no significant change in the content and appearance of the product in Example 13 after storage at 2-8°C, 30°C±2°C / 65%RH±5%RH and 40°C±2°C / 75%RH±5%RH, indicating the stability of the product characteristics.

[0186] Test 2: Pharmacokinetic study of drugs from Examples 1-5 and 13

[0187] In the tests described below, when the test drug was an oral liquid, the oral liquid was taken out in a certain volume, then diluted with 3-5 times the volume of water, shaken or stirred until the liquid became clear, and then administered to the subject; when the test drug was a capsule, the capsule was administered to the subject with the same volume of water used for dilution.

[0188] (1) Pharmacokinetic study of the drugs in Examples 1-5

[0189] Twenty male Sprague Dawley rats (SD rats) (5 groups of 4 rats per group) were administered the test drug at a dosage of 15 mg / kg via gavage. Blood samples (0.2 ml) were collected through a puncture from each experimental animal at 0 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. Plasma was separated by centrifugation at 4 °C and 3000 × g. The concentration of compound (I) in rat plasma was determined by LC-MS / MS. The pharmacokinetic parameters were calculated using a non-compartmental model in Phoenix WinNonlin 8.0 software based on the drug concentration in plasma. The following results were obtained:

[0190] Table 6: Results of the pharmacokinetic study of the drugs from Examples 1-5 in rats

[0191] Group Pharmacokinetic parameters (n=4) Tmax Cmax AUC0-t AUC0-∞ h ng / ml h*ng / ml h*ng / ml Example 1 2.00 1665 11776 11828 Example 2 2.00 1758 12853 12898 Example 3 1.75 1463 11590 11630 Example 4 2.50 1758 12427 12480 Example 5 2.00 1800 11875 11931

[0192] Above in the table, t in AUC 0-t means the end point of time (24 h).

[0193] (2) Pharmacokinetic study of the drug from Example 13

[0194] According to the pharmacokinetic study method of Examples 1-5, the pharmacokinetic study of the drug from Example 13 was conducted using male Sprague Dawley rats (4 SD rats). The results obtained are presented below:

[0195] Table 7: Results of the pharmacokinetic study of the drug from Example 13 in rats

[0196] Group Pharmacokinetic parameters (n=4) Tmax Cmax AUC0-t AUC0-∞ h ng / ml h*ng / ml h*ng / ml Example 13 2.00 2485 13832 14123

[0197] Above in the table, t in AUC 0-t means the end point of time (24 h).

[0198] Test 3: Pharmacokinetic study of drugs from Examples 2 and 6-7

[0199] The test drug was orally administered to Beagle dogs at a dosage of 15 mg / dog (18 dogs, 6 dogs per group). Blood samples (2 ml) were collected from the forelimb vein of each experimental animal 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. Plasma was obtained by centrifugation at 4 °C and 3000 × g. The concentration of compound (I) in the blood plasma of dogs was determined by LC-MS / MS. The pharmacokinetic parameters were calculated using a non-compartmental model in Phoenix WinNonlin 8.0 software based on the drug concentration in plasma. The following results were obtained:

[0200] Table 8: Pharmacokinetic results of Examples 2, 6, and 7 in beagle dogs

[0201] Group Pharmacokinetic parameters (n=6) Tmax Cmax AUC0-t AUC0-∞ h ng / ml h*ng / ml h*ng / ml Example 2 1 (0.5, 2) 124±25 (20.2) 413±96 (23.1) 424±95 (22.4) Example 6 1 (1, 2) 186±75 (40.6) 611±353 (57.7) 616±354 (57.5) Example 7 1 (1, 2) 165±96 (58.3) 546±387 (70.9) 552±388 (70.3) Note: Tmax: median (maximum value, minimum value); Cmax, AUC0-t, AUC0-∞: Mean±SD(RSD)

[0202] Above in the table, t in AUC 0-t means the end point of time (24 h).

[0203] Test 4: Pharmacokinetic Study of Comparative Example

[0204] Nine male Sprague Dawley rats (SD rats) (3 groups, 3 rats per group) were administered the test drug or the API in Comparative Examples 1 to 3 (where Comparative Example 2 contained 0.5% CMC-Na) at a dosage of 10 mg / kg via gavage. Blood samples (0.2 ml) were collected through a puncture from each experimental animal at 0 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. Plasma was separated by centrifugation at 4 °C and 3000 × g. The concentration of compound (I) in rat plasma was determined by LC-MS / MS. The pharmacokinetic parameters were calculated according to the non-compartmental model in Phoenix WinNonlin 8.0 software based on the drug concentration data in plasma. The following results were obtained:

[0205] Table 9: Pharmacokinetic results of Comparative Examples 1-3 (n=3) in rats

[0206] Group Tmax (h) Cmax (ng / ml) AUC0-t (h*ng / ml) AUC0-∞ (h*ng / ml) Comparative Example 1 2.00 357 1356 1386 Comparative Example 2 4.00 26.0 130 144 Comparative Example 3 2.67 902 6299 6313

[0207] Above in the table, t in AUC0-t means the end point of time (24 h).

[0208] Test 5: Human Pharmacokinetic Study

[0209] Phase Ia clinical trials were conducted in patients with solid tumors using the drug in Example 1. Under single-dose conditions, 3 mL of whole blood were collected before administration, at 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, and the plasma was separated by centrifugation. The drug concentration in human plasma was determined using a validated LC-MS / MS method, and the pharmacokinetic parameters were calculated using a non-compartmental model using Phoenix WinNonlin 8.3 software.

[0210] The results of the study showed that after a single oral administration of 15-30 mg, the drugs were rapidly absorbed in subjects, the median time T максfor the drug in plasma was 2.00-2.01 h, and then the drug concentration in plasma slowly decreased. The average values ​​of t 1 / 2 , the apparent volume of distribution (Vz / F) and the elimination rate (CL / F) of the drug in the different dosage groups were 27.2-30.9 h, 187-189 L and 4.39-5.06 L / h, respectively. In general, the amount of drug in the systemic circulation increased with increasing administered dose, with the mean C values макс were 156-301 ng / ml, and the mean area under the plasma drug concentration-time curve (AUC last and AUC inf ) were 2680-5910 h*ng / ml and 3300-7420 h*ng / ml, respectively. In the dosage range of 15-30 mg, the drug demonstrated virtually linear pharmacokinetic characteristics in vivo.

[0211] Table 10: Summary of key pharmacokinetic characteristics after single oral administration to subjects

[0212] Pharmacokinetic characteristics (units) Dosage in a group 15 mg (N=14) 30 mg (N=5) Cmax (ng / ml) Average (%CV) 156 (20.0) 301 (18.5) Tmax (h) Median (Min, Max) 2.01 (0.48, 4.05) 2.00 (1.97, 2.05) AUClast (h*ng / ml) Average (%CV) 2680 (27.7) 5910 (28.7) AUCinf (h*ng / ml) Average (%CV) 3300 (33.0) 7420 (37.6) t1 / 2 (h) Average (%CV) 27.2 (22.2) 30.9 (19.9) CL / F (l / h) Average (%CV) 5.06 (35.7) 4.39 (26.9) Vz / F (l) Average (%CV) 187 (21.0) 189 (18.7)

[0213] The above descriptions represent only preferred embodiments of the present invention. It should be noted that those skilled in the art can make changes and modifications without departing from the spirit and scope of the present invention. Such changes and modifications are also within the scope of the present invention.

Claims

1. A self-emulsifying pharmaceutical composition of compound (I) that inhibits VEGFR / CSF1R, comprising: compound (I), an oil phase, an emulsifier and an auxiliary emulsifier, wherein the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier is 0.5-2:from more than 0 to 20:50-80:20-35; compound (I) has a structural formula corresponding to formula (I) (I), the oil phase is selected from medium chain triglycerides; the emulsifier is selected from polyoxyl-40 hydrogenated castor oil, polyoxyl-35 castor oil, tocopherol polyethyleneglycol succinate and polyoxyl-15 hydroxystearate; the auxiliary emulsifier is selected from polyethylene glycol and diethylene glycol monoethyl ether.

2. A self-emulsifying pharmaceutical composition according to claim 1, characterized in that the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier is 0.99-1.98:from more than 0 to 20:50-80:20-35; or 0.99:from more than 0 to 20:50-80:20-35; or 1.25:from more than 0 to 20:50-80:20-35; or 1.98:from more than 0 to 20:50-80:20-35; or 0.5-2:10-20:50-65:20-30; or 0.5-2: from more than 0 to 15:55-75:20-30; more preferable 0.99-1.98:from more than 0 to 15:55-75:20-30; or 0.99-1.98: from more than 0 to 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 more preferable 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.

3. A self-emulsifying pharmaceutical composition according to claim 1 or 2, 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. A self-emulsifying pharmaceutical composition according to any one of claims 1 or 2, characterized in that the emulsifier is selected from polyoxyl-40 hydrogenated castor oil, tocopherol polyethyleneglycol succinate, polyoxyl-35 castor oil; preferably from polyoxyl-40 hydrogenated castor oil.

5. A self-emulsifying pharmaceutical composition according to claim 1 or 2, characterized in that the auxiliary emulsifier is selected from polyethylene glycol 400 or diethylene glycol monoethyl ether.

6. A self-emulsifying pharmaceutical composition according to any one of claims 1 or 2, characterized in that it additionally contains an antioxidant, preferably the weight ratio of compound (I) to the antioxidant is 1:from more than 0 to 0.5, preferably 1:from more than 0 to 0.1, more preferably 1:from more than 0 to 0.05, more preferably 1:from more than 0 to 0.03, even more preferably 1:0.02 or 0.99:0.

02.

7. A self-emulsifying pharmaceutical composition according to claim 6, characterized in that the antioxidant is selected from butylated hydroxytoluene, butylated hydroxyanisole, vitamin E, propyl gallate; preferably from butylated hydroxytoluene, vitamin E, more preferably from butylated hydroxytoluene.

8. The self-emulsifying pharmaceutical composition according to claim 1, characterized in that the self-emulsifying pharmaceutical composition consists of a compound (I), an oil phase, an emulsifier and an auxiliary emulsifier, wherein the weight ratio of compound (I): oil phase: emulsifier: auxiliary 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 medium chain triglycerides; the emulsifier is polyoxyl-40 hydrogenated castor oil, tocopherol polyethyleneglycol succinate, polyoxyl-15 hydroxystearate or polyoxyl-35 castor oil; the auxiliary emulsifier is polyethyleneglycol 400 or diethylene glycol monoethyl ether; or the self-emulsifying pharmaceutical composition comprises compound (I), an oil phase, an emulsifier and an auxiliary emulsifier, wherein the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier is 0.99-1.98:13-14:55-57:28-29, for example 0.99:13-14:55-57:28-29; wherein the oil phase is medium chain triglycerides; the emulsifier is polyoxyl-40 hydrogenated castor oil; the auxiliary emulsifier is polyethyleneglycol 400 or diethylene glycol monoethyl ether; or the self-emulsifying pharmaceutical composition comprises compound (I), an oil phase, an emulsifier and an auxiliary emulsifier, wherein the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier is 0.99-1.98:13-14:55-57:28-29, for example 0.99:13-14:55-57:28-29; wherein the oil phase is medium chain triglycerides; the emulsifier is tocopherol polyethyleneglycol succinate; the auxiliary emulsifier is polyethyleneglycol 400 or diethylene glycol monoethyl ether; or the self-emulsifying pharmaceutical composition comprises compound (I), an oil phase, an emulsifier and an auxiliary emulsifier, wherein the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier is 0.99-1.98:13-14:55-57:28-29, for example 0.99:13-14:55-57:28-29; wherein the oil phase is medium chain triglycerides; the emulsifier is polyoxyl-15 hydroxystearate or polyoxyl-35 castor oil; the auxiliary emulsifier is polyethyleneglycol 400; or the self-emulsifying pharmaceutical composition comprises compound (I), an oil phase, an emulsifier and an auxiliary emulsifier, wherein the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier is 0.99-1.98:13-14:55-57:28-29, for example 1.25:13-14:55-57:28-29; wherein the oil phase is medium chain triglycerides; the emulsifier is polyoxyl-40 hydrogenated castor oil; the auxiliary emulsifier is polyethyleneglycol 400; or the self-emulsifying pharmaceutical composition comprises compound (I), an oil phase, an emulsifier and an auxiliary emulsifier, wherein the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier is 0.99-1.98:13-14:55-57:28-29, such as 0.99:13-14:55-57:28-29 or 1.98:13-14:55-57:28-29; wherein the oil phase is medium chain triglycerides; the emulsifier is polyoxyl-40 hydrogenated castor oil; the auxiliary emulsifier is polyethyleneglycol 400; or the self-emulsifying pharmaceutical composition consists of a compound (I), an oil phase, an emulsifier, an auxiliary emulsifier and an antioxidant, wherein the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier: antioxidant is 0.5-2:10-20:50-65:20-30:from greater than 0 to 0.5, preferably 0.99-1.98:10-15:55-65:25-30:from greater than 0 to 0.5, more preferably 0.99-1.98:10-15:55-61:27-29:from greater than 0 to 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 medium chain triglycerides; the emulsifier is polyoxyl-40 hydrogenated castor oil, tocopherol polyethyleneglycol succinate, polyoxyl-15 hydroxystearate or polyoxyl-35 castor oil; the auxiliary emulsifier is polyethyleneglycol 400 or diethylene glycol monoethyl ether; the antioxidant is butylated hydroxytoluene or vitamin E; or the self-emulsifying pharmaceutical composition comprises compound (I), an oil phase, an emulsifier, an auxiliary emulsifier and an antioxidant, wherein the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier: antioxidant is 0.99-1.98:13-14:55-57:28-29:from greater than 0 to 0.05, for example 0.99:13-14:55-57:28-29:0.01-0.03; wherein the oil phase is medium chain triglycerides; the emulsifier is polyoxyl-40 hydrogenated castor oil; the auxiliary emulsifier is polyethyleneglycol 400; the antioxidant is butylated hydroxytoluene; or The self-emulsifying pharmaceutical composition consists of a compound (I), an oil phase, an emulsifier, an auxiliary emulsifier and an antioxidant, wherein the weight ratio of compound (I): oil phase: emulsifier: auxiliary emulsifier: 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; wherein the oil phase is medium-chain triglycerides; the emulsifier is polyoxyl-40 hydrogenated castor oil; the auxiliary emulsifier is diethylene glycol monoethyl ether; the antioxidant is vitamin E.

9. A preparation of compound (I) that inhibits VEGFR / CSF1R, which contains a self-emulsifying pharmaceutical composition according to any one of claims 1-8, where the dosage form of the drug is an oral liquid, capsule or tablet.

10. The preparation according to claim 9, wherein the capsule may be a soft capsule or a hard capsule.

11. The drug according to claim 9, wherein the dosage form of the drug is a liquid for oral administration.

12. A method for producing a preparation according to any one of paragraphs 9-11, which comprises: adding auxiliary substances of a self-emulsifying pharmaceutical composition to a liquid reactor, heating and mixing until homogeneity, adding compound (I) and continuing heating and mixing until complete dissolution to obtain a self-emulsifying pharmaceutical composition, where the auxiliary substances include an oil phase, an emulsifier and an auxiliary emulsifier; The resulting self-emulsifying pharmaceutical composition is packaged in vials for oral liquid or filled into capsules, or the self-emulsifying pharmaceutical composition is incorporated into granules or pellets using liquid-to-solid conversion technologies and pressed into tablets or capsules to obtain a VEGFR / CSF1R inhibiting drug.

13. The method according to claim 12, wherein the auxiliary substances additionally include an antioxidant.

14. The method according to claim 12 or 13, wherein the heating and stirring temperature is 40-70°C.

15. A pharmaceutical composition of compound (I) that inhibits VEGFR / CSF1R, wherein compound (I) has a structural formula corresponding to formula (I) (I); the said pharmaceutical composition consists of compound (I), an emulsifier and an auxiliary emulsifier, the emulsifier is polyoxyl-40 hydrogenated castor oil; the auxiliary emulsifier is selected from polyethylene glycol 400 and diethylene glycol monoethyl ether, where the weight ratio of compound (I): emulsifier: auxiliary emulsifier is 0.5-2:60-80:20-30.

16. The pharmaceutical composition according to claim 15, wherein the weight ratio of compound (I): emulsifier: auxiliary emulsifier is 0.99-1.98:70-80:20-30; or 0.99-1.98:75-80:25-30; or 0.99-1.98:70-75:20-25; or 0.99-1.98:74-76:24-26; preferably 0.99:60-80:20-30, or 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.

17. A preparation of compound (I) that inhibits VEGFR / CSF1R, comprising a pharmaceutical composition according to claim 15 or 16, where the dosage form of the drug is an oral liquid, capsule or tablet.

18. The preparation according to claim 17, wherein the capsule may be a soft capsule or a hard capsule.

19. The drug according to claim 17, wherein the dosage form of the drug is a liquid for oral administration.

20. Use of the drug according to any of paragraphs 9-11 and 17-19 in the manufacture of a VEGFR / CSF1R inhibiting drug, wherein said drug is intended for the prevention and / or treatment of diseases associated with abnormal vascular proliferation and / or inhibition of VEGFR-2 and / or treatment of diseases associated with the CSF1R kinase signaling pathway and / or inhibition of CSF1R kinase.

21. The use according to claim 20, wherein the disease associated with abnormal vascular proliferation is selected from a tumor, rheumatoid arthritis, age-related macular degeneration and psoriasis; preferably, said tumor is selected from 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, cholangiocarcinoma, nasopharyngeal cancer, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, fibrosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastases, meningioma and lymphadenoma; particularly preferably, said glioma is a glioblastoma, astroglioma or medulloblastoma.

22. A method for the prevention and / or treatment of diseases associated with abnormal vascular proliferation, which comprises administering to a subject a therapeutically effective amount of a drug according to any one of paragraphs 9-11 and 17-19.

23. The method of claim 22, wherein the disease associated with abnormal vascular proliferation is selected from a tumor, rheumatoid arthritis, age-related macular degeneration, and psoriasis; preferably, said tumor is selected from 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, cholangiocarcinoma, nasopharyngeal cancer, thyroid cancer, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, fibrosarcoma, leiomyosarcoma, myeloma, brain glioma, brain metastases, meningioma and lymphadenoma; particularly preferably, said glioma is a glioblastoma, astroglioma or medulloblastoma.

24. The method of claim 22, wherein the disease associated with abnormal vascular proliferation is a disease associated with the CSF1R kinase signaling pathway.

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