Quinoline derivative or cyclodextrin inclusion compound of salt thereof

Abstract

The invention relates to an anlotinib cyclodextrin inclusion compound and a preparation method thereof, and a pharmaceutical composition containing the anlotinib cyclodextrin inclusion compound and a preparation method thereof. The anlotinib cyclodextrin inclusion compound and the pharmaceutical composition prepared from the anlotinib cyclodextrin inclusion compound can effectively reduce the variation rate of individual absorption difference and the variation rate of individual bioavailability, and are beneficial to improving the medication safety and reducing the medication maintenance cost.

Description

Quinoline derivative or its salt cyclodextrin inclusion complex

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of the Chinese patent application No. 202210755401.2 filed with the State Intellectual Property Office of China on June 29, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present application belongs to the field of pharmaceutical preparations. The present application relates to a cyclodextrin inclusion complex of a quinoline derivative or its salt, and a pharmaceutical composition comprising the inclusion complex of a quinoline derivative or its salt. Specifically, the present application relates to an anlotinib cyclodextrin inclusion complex, a preparation method, and a pharmaceutical composition comprising anlotinib cyclodextrin inclusion complex and a preparation method. Background Art

[0004] International patent application WO2008112407 discloses in Example 24 the compound 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine and its preparation method, the structural formula of which is shown in Formula I:

[0005] In May 2018, anlotinib, a new class of drug with a compound of Formula I as its main ingredient, was successfully launched in China. It is the first approved third-line treatment for advanced non-small cell lung cancer in China. It is a multi-target receptor tyrosine kinase inhibitor that inhibits the activity of kinases such as vascular endothelial growth factor receptors (VEGFR1, VEGFR2 / KDR, and VEGFR3), stem cell factor receptors, and platelet-derived growth factor receptors. It also inhibits VEGFR2-mediated downstream signaling, thereby suppressing tumor angiogenesis.

[0006] Anlotinib hydrochloride exhibits excellent anti-tumor activity and has good bioavailability in both animals and humans. It is primarily distributed in the metabolic and endocrine systems, undergoes extensive metabolism, and is primarily excreted through feces. Its primary toxicity is in the teeth, kidneys, hepatobiliary system, and blood system. Anlotinib hydrochloride demonstrates promising and broad therapeutic potential in clinical anti-tumor treatment.

[0007] Cyclodextrins (CDs) are enzymatically modified starch derivatives. They are cyclic oligosaccharides composed of glucose units linked by α-1,4-glycosidic bonds, typically containing 6 to 12 D-pyranose units. The most studied and practically significant molecules are those containing 6, 7, and 8 glucose units, known as α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, respectively. Furthermore, structural modifications of cyclodextrins are being explored to improve their physical and chemical properties, such as increasing water solubility, forming new chiral sites, and constructing supramolecular aggregates.

[0008] The purpose of the present invention is to find a pharmaceutical composition containing anlotinib that has small individual absorption differences, is safer and more effective, and is suitable for clinical use in patients.

[0009] Summary of the Invention

[0010] The pharmacokinetic data of the commercially available anlotinib hydrochloride capsules showed that there were individual differences in absorption. Specifically, the average maximum plasma concentration (Cmax) and the average area under the concentration-time curve (AUC) after taking anlotinib hydrochloride capsules were different between cancer patients and healthy people. 0-t ) There are significant differences in individual absorption and a high variation rate.

[0011] In addition, there are problems such as the accumulation of blood drug concentration after continuous administration of commercially available anlotinib capsules, which causes adverse reactions and forces patients to stop taking the medicine. Specifically, due to the long elimination half-life of anlotinib in the human body, after continuous administration, its blood drug concentration increases with the number of doses.

[0012] therefore:

[0013] In a first aspect, the present application provides an anlotinib cyclodextrin inclusion complex.

[0014] In a second aspect, the present application provides a pharmaceutical composition comprising anlotinib cyclodextrin inclusion complex.

[0015] In a third aspect, the present application provides a method for preparing anlotinib cyclodextrin inclusion complex, and a method for preparing a pharmaceutical composition comprising anlotinib cyclodextrin inclusion complex.

[0016] In a fourth aspect, the present application provides an anlotinib cyclodextrin inclusion complex and a pharmaceutical composition comprising the anlotinib cyclodextrin inclusion complex for use in preparing a drug for treating cancer.

[0017] In a fifth aspect, the present application provides a method for treating cancer using anlotinib cyclodextrin inclusion complex and a pharmaceutical composition comprising the anlotinib cyclodextrin inclusion complex.

[0018] Summary of the Invention

[0019] In the first aspect, the present application provides an anlotinib cyclodextrin inclusion compound, which contains: (a) anlotinib as a main drug component; (b) cyclodextrin; the anlotinib as the main drug component includes but is not limited to anlotinib or a pharmaceutically acceptable salt and / or hydrate thereof.

[0020] In some embodiments, the present application provides an anlotinib cyclodextrin inclusion complex for preparing an oral pharmaceutical preparation, which contains: (a) anlotinib as a main drug ingredient; (b) cyclodextrin; the anlotinib as the main drug ingredient includes but is not limited to anlotinib or a pharmaceutically acceptable salt and / or hydrate thereof.

[0021] In some embodiments, the present application provides an anlotinib cyclodextrin inclusion compound comprising:

[0022] (a) 1-3 parts of anlotinib as the main drug ingredient;

[0023] (b) 12-45 parts of cyclodextrin;

[0024] All parts are by weight, and the anlotinib as the main drug component includes but is not limited to anlotinib or its pharmaceutically acceptable salt and / or hydrate.

[0025] In some embodiments, the cyclodextrin is selected from one or more of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin; in some embodiments, the cyclodextrin is β-cyclodextrin; in some embodiments, the cyclodextrin is hydroxypropyl-β-cyclodextrin.

[0026] In some embodiments, the weight ratio of anlotinib or its pharmaceutically acceptable salt and / or its hydrate to cyclodextrin is 1:10-1:20; in some embodiments, the weight ratio of anlotinib or its pharmaceutically acceptable salt and / or its hydrate to cyclodextrin is 1:11-1:18; in some embodiments, the weight ratio of anlotinib or its pharmaceutically acceptable salt and / or its hydrate to cyclodextrin is 1:12-1:15.

[0027] In some embodiments, the anlotinib cyclodextrin inclusion complex further contains a pH regulator; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is greater than 5; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is greater than 6; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is greater than 6.5; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is greater than 7.

[0028] In some embodiments, the anlotinib cyclodextrin inclusion complex contains:

[0029] (a) 1.5-2.5 parts of anlotinib as the main drug ingredient;

[0030] (b) 18-38 parts of cyclodextrin;

[0031] All parts are by weight, and the anlotinib as the main drug component includes but is not limited to anlotinib or its pharmaceutically acceptable salt and / or hydrate.

[0032] In some embodiments, the anlotinib cyclodextrin inclusion complex contains:

[0033] (a) 2-2.4 parts of anlotinib as the main drug ingredient;

[0034] (b) 24-36 parts of cyclodextrin;

[0035] All parts are by weight, and the anlotinib as the main drug component includes but is not limited to anlotinib or its pharmaceutically acceptable salt and / or hydrate.

[0036] In some embodiments, the pharmaceutical composition contains 1.5-2.5 parts of the main drug ingredient, which is anlotinib or a pharmaceutically acceptable salt and / or hydrate thereof; in some specific embodiments, the pharmaceutical composition contains 2-2.4 parts of the main drug ingredient; in some specific embodiments, the pharmaceutical composition contains 2.36 parts of the main drug ingredient.

[0037] In some embodiments, the pharmaceutical composition contains 18-38 parts of cyclodextrin, and the cyclodextrin is one or more of β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin; in some specific embodiments, the pharmaceutical composition contains 24-36 parts of cyclodextrin, and the cyclodextrin is one or more of β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin; in some specific embodiments, the pharmaceutical composition contains 28.32-35.4 parts of cyclodextrin, and the cyclodextrin is one or more of β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin.

[0038] In some embodiments, the anlotinib cyclodextrin inclusion complex is presented in a liquid form. In some embodiments, the anlotinib cyclodextrin inclusion complex is presented in a solid form.

[0039] In some embodiments, the anlotinib cyclodextrin inclusion complex further contains a pH regulator; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is greater than 5; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is greater than 6; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is greater than 6.5; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is greater than 7.

[0040] In some embodiments, the anlotinib cyclodextrin inclusion complex liquid can be further dried to obtain a cyclodextrin inclusion complex solid; in some embodiments, the anlotinib cyclodextrin inclusion complex liquid can be directly used to prepare a pharmaceutical composition containing anlotinib cyclodextrin inclusion complex.

[0041] In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 1 μm≤X50≤15 μm, 5 μm≤X90≤30 μm.

[0042] In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 2μm≤X50≤12μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 3μm≤X50≤10μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 4μm≤X50≤8μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 6μm≤X90≤25μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 8μm≤X90≤22μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 10μm≤X90≤20μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 2μm≤X50≤12μm and 6μm≤X90≤25μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion compound solid satisfies 3 μm ≤ X50 ≤ 10 μm, 8 μm ≤ X90 ≤ 22 μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion compound solid satisfies 4 μm ≤ X50 ≤ 8 μm, 10 μm ≤ X90 ≤ 20 μm.

[0043] In some embodiments, the inclusion rate of the inclusion complex reaches more than 80%; in some embodiments, the inclusion rate of the inclusion complex reaches more than 85%; in some embodiments, the inclusion rate of the inclusion complex reaches more than 90%; in some embodiments, the inclusion rate of the inclusion complex reaches more than 95%.

[0044] In a second aspect, the present application provides a pharmaceutical composition comprising anlotinib cyclodextrin inclusion complex, which contains: (i) anlotinib cyclodextrin inclusion complex; (ii) a filler; (iii) a disintegrant; (iv) a lubricant; and (v) other pharmaceutical excipients as needed, wherein the anlotinib cyclodextrin inclusion complex contains (a) anlotinib as the main drug ingredient; and (b) cyclodextrin.

[0045] In some embodiments, the present application provides an oral solid pharmaceutical composition comprising anlotinib cyclodextrin inclusion complex, which contains: (i) anlotinib cyclodextrin inclusion complex; (ii) a filler; (iii) a disintegrant; (iv) a lubricant; and (v) other pharmaceutical excipients as needed, wherein the anlotinib cyclodextrin inclusion complex contains (a) anlotinib as the main drug ingredient; and (b) cyclodextrin.

[0046] In some embodiments, the present application provides a pharmaceutical composition comprising anlotinib cyclodextrin inclusion complex, which contains:

[0047] (i) 13-48 parts of anlotinib cyclodextrin inclusion complex;

[0048] (ii) 40-120 parts of a filler;

[0049] (iii) 2-16 parts of a disintegrant;

[0050] (iv) 0.1-12 parts of a lubricant;

[0051] Among them, the anlotinib cyclodextrin inclusion compound contains:

[0052] (a) 1-3 parts of anlotinib as the main drug ingredient;

[0053] (b) 12-45 parts of cyclodextrin;

[0054] All parts are by weight, and the anlotinib as the main drug component includes but is not limited to anlotinib or its pharmaceutically acceptable salt and / or hydrate.

[0055] In some embodiments, the filler is selected from one or more of lactose, microcrystalline cellulose, pregelatinized starch, corn starch, mannitol, anhydrous calcium hydrogen phosphate, and sucrose; in some embodiments, the filler is one or more of lactose, microcrystalline cellulose, mannitol, and sucrose; in some embodiments, the filler is lactose and / or microcrystalline cellulose; in some embodiments, the filler is mannitol and / or microcrystalline cellulose; in some embodiments, the filler is mannitol; in some embodiments, the filler is sucrose; in some embodiments, the filler is sucrose powder or sucrose pellets; in some embodiments, the filler is sucrose pellets.

[0056] In some embodiments, the disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxybutyl methylcellulose, ethyl methyl cellulose, ethyl hydroxyethyl cellulose and methyl cellulose; in some embodiments, the disintegrant is one or more of hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose; in some embodiments, the disintegrant is one or more of SSL type hydroxypropyl cellulose, SL type hydroxypropyl cellulose, L type hydroxypropyl cellulose; in some embodiments, the disintegrant is low-substituted hydroxypropyl cellulose; in some embodiments, the disintegrant is low-substituted hydroxypropyl cellulose and / or cross-linked polyvinylpyrrolidone; in some embodiments, the disintegrant is sodium carboxymethyl starch and / or cross-linked sodium carboxymethyl cellulose.

[0057] In some embodiments, the lubricant is selected from one or more of magnesium stearate, stearic acid, micronized silica gel, colloidal silicon dioxide, glyceryl behenate, talc, sodium stearyl fumarate, sodium lauryl sulfate, polyethylene glycol 4000, polyethylene glycol 6000, and hydrogenated castor oil. In some embodiments, the lubricant is magnesium stearate; in some embodiments, the lubricant is talc.

[0058] In some embodiments, the cyclodextrin is selected from one or more of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin; in some embodiments, the cyclodextrin is β-cyclodextrin; in some embodiments, the cyclodextrin is hydroxypropyl-β-cyclodextrin.

[0059] In some embodiments, the weight ratio of anlotinib or its pharmaceutically acceptable salt and / or its hydrate to cyclodextrin is 1:10-1:20; in some embodiments, the weight ratio of anlotinib or its pharmaceutically acceptable salt and / or its hydrate to cyclodextrin is 1:11-1:18; in some embodiments, the weight ratio of anlotinib or its pharmaceutically acceptable salt and / or its hydrate to cyclodextrin is 1:12-1:15.

[0060] Depending on the dosage form and formulation process, other pharmaceutical excipients may be added to the above-mentioned pharmaceutical composition containing the anlotinib cyclodextrin inclusion complex as needed, including but not limited to one or more of a binder, a flavoring agent, and a colorant. In some embodiments, (v) 1-5 parts of a binder are further added to the above-mentioned pharmaceutical composition containing the anlotinib cyclodextrin inclusion complex, and the parts are calculated by weight. In some embodiments, the binder is selected from one or more of hypromellose, hydroxypropyl cellulose, povidone, starch slurry, and sodium carboxymethyl cellulose; in some embodiments, the binder is hypromellose; in some embodiments, the binder is hypromellose E5.

[0061] In some embodiments, the pharmaceutical composition comprises:

[0062] (i) 20-45 parts of anlotinib cyclodextrin inclusion complex;

[0063] (ii) 45-115 parts of a filler;

[0064] (iii) 3-15 parts of a disintegrant;

[0065] (iv) 0.2-11 parts of a lubricant; wherein all parts are by weight.

[0066] In some embodiments, the pharmaceutical composition comprises:

[0067] (i) 25-40 parts of anlotinib cyclodextrin inclusion complex;

[0068] (ii) 50-105 parts of a filler;

[0069] (iii) 4-13 parts of a disintegrant;

[0070] (iv) 0.5-10 parts of a lubricant; wherein all parts are by weight.

[0071] In some embodiments, the pharmaceutical composition contains 45-115 parts of a filler, and the filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, and sucrose; in some specific embodiments, the pharmaceutical composition contains 50-105 parts of a filler; in some specific embodiments, the pharmaceutical composition contains 55-100 parts of a filler.

[0072] In some embodiments, the pharmaceutical composition contains 3-15 parts of a disintegrant, and the disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxybutyl methylcellulose, ethyl methylcellulose, ethyl hydroxyethyl cellulose and methylcellulose; in some specific embodiments, the pharmaceutical composition contains 4-13 parts of a disintegrant.

[0073] In some embodiments, the pharmaceutical composition contains 0.2-11 parts of a lubricant, and the lubricant is one or more of magnesium stearate, stearic acid, micronized silica, colloidal silicon dioxide, glyceryl behenate, talc, sodium stearyl fumarate, sodium lauryl sulfate, polyethylene glycol 4000, polyethylene glycol 6000, and hydrogenated castor oil; in some specific embodiments, the pharmaceutical composition contains 0.5-10 parts of a lubricant.

[0074] In some embodiments, the pharmaceutical composition contains 2-4 parts of a binder, and the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, starch slurry, and sodium carboxymethyl cellulose; in some embodiments, the binder is hydroxypropyl methylcellulose.

[0075] In some embodiments of the present application, the pharmaceutical composition comprises:

[0076] (i) 13-48 parts of anlotinib cyclodextrin inclusion complex;

[0077] (ii) 40-120 parts of mannitol;

[0078] (iii) 2-16 parts of hydroxypropyl cellulose;

[0079] (iv) 0.1 to 3 parts of magnesium stearate; wherein all parts are by weight.

[0080] In some embodiments of the present application, the pharmaceutical composition comprises:

[0081] (i) 20-45 parts of anlotinib cyclodextrin inclusion complex;

[0082] (ii) 50-100 parts of mannitol;

[0083] (iii) 3-12 parts of hydroxypropyl cellulose;

[0084] (iv) 0.5-2 parts of magnesium stearate; wherein all parts are by weight.

[0085] In some embodiments of the present application, the pharmaceutical composition comprises:

[0086] (i) 13-48 parts of anlotinib cyclodextrin inclusion complex;

[0087] (ii) 40-120 parts of mannitol;

[0088] (iii) 2-16 parts of crospovidone;

[0089] (iv) 0.1 to 3 parts of stearic acid; wherein all parts are by weight.

[0090] In some embodiments of the present application, the pharmaceutical composition comprises:

[0091] (i) 20-45 parts of anlotinib cyclodextrin inclusion complex;

[0092] (ii) 50-100 parts of mannitol;

[0093] (iii) 3-12 parts of crospovidone;

[0094] (iv) 0.5-2 parts of stearic acid; wherein all parts are by weight.

[0095] In some embodiments of the present application, the pharmaceutical composition comprises:

[0096] (i) 13-48 parts of anlotinib cyclodextrin inclusion complex;

[0097] (ii) 40-120 parts of sucrose;

[0098] (iii) 2-16 parts of hydroxypropyl cellulose;

[0099] (iv) 3-12 parts of talc; wherein all parts are by weight.

[0100] In some embodiments of the present application, the pharmaceutical composition comprises:

[0101] (i) 20-45 parts of anlotinib cyclodextrin inclusion complex;

[0102] (ii) 50-110 parts of sucrose pellets;

[0103] (iii) 3-12 parts of hydroxypropyl cellulose;

[0104] (iv) 5-11 parts of talc; wherein all parts are by weight.

[0105] In some embodiments of the present application, the pharmaceutical composition comprises:

[0106] (i) 13-48 parts of anlotinib cyclodextrin inclusion complex;

[0107] (ii) 40-120 parts of lactose and / or microcrystalline cellulose;

[0108] (iii) 2-16 parts of crospovidone and / or hydroxypropyl cellulose;

[0109] (iv) 0.1 to 3 parts of magnesium stearate; wherein all parts are by weight.

[0110] In some embodiments of the present application, the pharmaceutical composition comprises:

[0111] (i) 20-45 parts of anlotinib cyclodextrin inclusion complex;

[0112] (ii) 50-100 parts of lactose and / or microcrystalline cellulose;

[0113] (iii) 3-12 parts of crospovidone and / or hydroxypropyl cellulose;

[0114] (iv) 0.5-2 parts of magnesium stearate; wherein all parts are by weight.

[0115] In some embodiments of the present application, the pharmaceutical composition comprises:

[0116] (i) 13-48 parts of anlotinib cyclodextrin inclusion complex;

[0117] (ii) 40-120 parts of lactose and / or microcrystalline cellulose;

[0118] (iii) 2-16 parts of cross-linked sodium carboxymethyl cellulose and / or sodium carboxymethyl starch;

[0119] (iv) 0.1-3 parts of magnesium stearate;

[0120] (v) 1-5 parts of hydroxypropyl methylcellulose; wherein all parts are by weight.

[0121] In some embodiments of the present application, the pharmaceutical composition comprises:

[0122] (i) 20-45 parts of anlotinib cyclodextrin inclusion complex;

[0123] (ii) 50-100 parts of lactose and / or microcrystalline cellulose;

[0124] (iii) 3-12 parts of cross-linked sodium carboxymethyl cellulose and / or sodium carboxymethyl starch;

[0125] (iv) 0.5-2 parts of magnesium stearate;

[0126] (v) 2-4 parts of hydroxypropyl methylcellulose; wherein all parts are by weight.

[0127] In some embodiments, the pharmaceutical composition contains 1.5-2.5 parts of the main drug ingredient, which is anlotinib or a pharmaceutically acceptable salt and / or hydrate thereof; in some specific embodiments, the pharmaceutical composition contains 2-2.4 parts of the main drug ingredient; in some specific embodiments, the pharmaceutical composition contains 2.36 parts of the main drug ingredient.

[0128] In some embodiments, the pharmaceutical composition contains 18-38 parts of cyclodextrin, and the cyclodextrin is one or more of β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin; in some specific embodiments, the pharmaceutical composition contains 24-36 parts of cyclodextrin, and the cyclodextrin is one or more of β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin; in some specific embodiments, the pharmaceutical composition contains 28.32-35.4 parts of cyclodextrin, and the cyclodextrin is one or more of β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin.

[0129] In some embodiments, the anlotinib cyclodextrin inclusion complex is presented as a liquid. In some embodiments, the anlotinib cyclodextrin inclusion complex is presented as a solid. In some embodiments, the anlotinib cyclodextrin inclusion complex liquid has a pH greater than 5.

[0130] In some embodiments, the anlotinib cyclodextrin inclusion complex liquid can be further dried to obtain a cyclodextrin inclusion complex solid; in some embodiments, the anlotinib cyclodextrin inclusion complex liquid can be directly used to prepare a pharmaceutical composition containing anlotinib cyclodextrin inclusion complex.

[0131] In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 1 μm≤X50≤15 μm, 5 μm≤X90≤30 μm.

[0132] In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 2μm≤X50≤12μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 3μm≤X50≤10μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 4μm≤X50≤8μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 6μm≤X90≤25μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 8μm≤X90≤22μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 10μm≤X90≤20μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 2μm≤X50≤12μm and 6μm≤X90≤25μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion compound solid satisfies 3 μm ≤ X50 ≤ 10 μm, 8 μm ≤ X90 ≤ 22 μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion compound solid satisfies 4 μm ≤ X50 ≤ 8 μm, 10 μm ≤ X90 ≤ 20 μm.

[0133] In some embodiments, the inclusion rate of the inclusion complex reaches more than 80%; in some embodiments, the inclusion rate of the inclusion complex reaches more than 85%; in some embodiments, the inclusion rate of the inclusion complex reaches more than 90%; in some embodiments, the inclusion rate of the inclusion complex reaches more than 95%.

[0134] In some embodiments, the pharmaceutical composition is a solid preparation, including tablets, capsules, powders, granules, pills, pastes, powders, etc., preferably tablets and capsules; in some embodiments, the tablets are coated tablets.

[0135] In some embodiments, the pharmaceutical composition is a liquid preparation, including a solution, a suspension, an emulsion, an injection, an infusion, or an implant.

[0136] The pharmaceutical composition provided in the present application contains anlotinib or its pharmaceutically acceptable salt and / or its hydrate as an active ingredient, and the daily dose is sufficient to provide the desired therapeutic effect. In some embodiments, the pharmaceutical composition comprises 2 mg to 20 mg of anlotinib or a pharmaceutically acceptable salt and / or hydrate thereof; in some embodiments, the pharmaceutical composition comprises 4 mg to 18 mg of anlotinib or a pharmaceutically acceptable salt and / or hydrate thereof; in some embodiments, the pharmaceutical composition comprises 6 mg to 16 mg of anlotinib or a pharmaceutically acceptable salt and / or hydrate thereof; in some embodiments, the pharmaceutical composition comprises 8 mg to 14 mg of anlotinib or a pharmaceutically acceptable salt and / or hydrate thereof; in some embodiments, the pharmaceutical composition comprises 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg of anlotinib or a pharmaceutically acceptable salt and / or hydrate thereof.

[0137] In some embodiments, the pharmaceutical composition is formulated as a pharmaceutical composition in unit dose form. In some embodiments, the pharmaceutical composition in unit dose form contains 2 mg to 20 mg of anlotinib or a pharmaceutically acceptable salt and / or hydrate thereof; in some embodiments, the pharmaceutical composition in unit dose form contains 4 mg to 18 mg of anlotinib or a pharmaceutically acceptable salt and / or hydrate thereof; in some embodiments, the pharmaceutical composition in unit dose form contains 6 mg to 16 mg of anlotinib or a pharmaceutically acceptable salt and / or hydrate thereof; in some embodiments, the pharmaceutical composition in unit dose form contains 8 mg to 14 mg of anlotinib or a pharmaceutically acceptable salt and / or hydrate thereof; in some specific embodiments, the pharmaceutical composition in unit dose form contains 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg of anlotinib or a pharmaceutically acceptable salt and / or hydrate thereof.

[0138] In some specific embodiments, the pharmaceutical composition in unit dose form contains 4 mg of anlotinib or its pharmaceutically acceptable salt and / or its hydrate capsules; in some specific embodiments, the pharmaceutical composition in unit dose form contains 6 mg of anlotinib or its pharmaceutically acceptable salt and / or its hydrate capsules; in some specific embodiments, the pharmaceutical composition in unit dose form contains 8 mg of anlotinib or its pharmaceutically acceptable salt and / or its hydrate capsules; in some specific embodiments, the pharmaceutical composition in unit dose form contains 10 mg of anlotinib or its pharmaceutically acceptable salt and / or its hydrate capsules. In some specific embodiments, the pharmaceutical composition in unit dose form contains 12 mg of anlotinib or its pharmaceutically acceptable salt and / or its hydrate capsules.

[0139] In some specific embodiments, the pharmaceutical composition in unit dose form contains a tablet containing 4 mg of anlotinib or a pharmaceutically acceptable salt and / or a hydrate thereof; in some specific embodiments, the pharmaceutical composition in unit dose form contains a tablet containing 6 mg of anlotinib or a pharmaceutically acceptable salt and / or a hydrate thereof; in some specific embodiments, the pharmaceutical composition in unit dose form contains a tablet containing 8 mg of anlotinib or a pharmaceutically acceptable salt and / or a hydrate thereof; in some specific embodiments, the pharmaceutical composition in unit dose form contains a tablet containing 10 mg of anlotinib or a pharmaceutically acceptable salt and / or a hydrate thereof. In some specific embodiments, the pharmaceutical composition in unit dose form contains a tablet containing 12 mg of anlotinib or a pharmaceutically acceptable salt and / or a hydrate thereof.

[0140] Individual variability refers to individual differences in drug response, a common biological phenomenon that exists in both healthy and diseased humans. For example, while a typical dose may produce the expected effect in most individuals, some may experience ineffectiveness or even toxicity. This individual variation in response is considered individual variability. Individual variability in drug response is primarily related to individual differences in drug metabolism and pharmacodynamics, which are driven by numerous factors. For example, differences in the gastrointestinal environment, genetic factors, organ function, and the influence of other diseases can all contribute to individual variability. Particular sensitivity to a drug is called hypersensitivity, while the opposite is called tolerance. Due to individual variability in drug response, clinical medications sometimes require selecting an appropriate dose based on the patient's condition, adhering to the principle of individualized dosage.

[0141] Individual variability in drug action is primarily manifested in pharmacokinetics. This is the phenomenon where the same dose of a drug produces varying concentrations of active drug in plasma and at the site of action due to differences in absorption, distribution, metabolism, and excretion. This inter-individual variability can be substantial. For example, after oral administration of 25 mg three times daily to the antidepressant nortriptyline, plasma nortriptyline concentrations vary by more than 30-fold in different individuals. Plasma drug concentrations of propranolol produced by three-daily doses of 10 mg, 20 mg, 40 mg, and 80 mg can vary by as much as 7-fold. Furthermore, plasma drug concentrations produced by different doses overlap within a certain range, meaning that some individuals can achieve the same plasma drug concentrations with a smaller dose as those achieved with a larger dose in others.

[0142] Individual differences in drug action can also be manifested in pharmacodynamics, where the same drug concentration in plasma or at the site of action produces different effects in different individuals. Specifically, individual differences in pharmacodynamics can manifest as different doses required to produce the same effect in different individuals, or as different times required for the same dose to produce a response in different individuals.

[0143] Therefore, when determining treatment plans, both inter- and intra-individual pharmacokinetic variability must be considered. For some drugs, this variability can be substantial, even leading to multiple dose changes and potentially causing safety concerns. The extent of inter-individual variability in drug metabolism depends largely on the drug's pharmacokinetic characteristics, particularly its route of elimination. For drugs primarily excreted unchanged through the kidneys, inter-individual variability is smaller than for drugs inactivated by hepatic metabolism in individuals with normal renal function. Drugs primarily eliminated through metabolism and those with a high first-pass effect exhibit significant inter-individual variability in bioavailability. For drugs with slower biotransformation, inter-individual variability manifests primarily in clearance. In these situations, monitoring plasma drug concentrations can aid in individualizing drug therapy. Because aging and liver and kidney disease can also affect the responsiveness of target organs, such as the brain, monitoring therapeutic drug concentrations in these patients requires particular attention to the potential altered effective drug concentration range.

[0144] The pharmacokinetic data of the commercially available anlotinib hydrochloride capsules showed that there were individual differences in absorption, specifically in the average maximum plasma concentration (Cmax) and the average area under the concentration-time curve (AUC) of anlotinib hydrochloride capsules after taking cancer patients and healthy people. 0-t Individual absorption varies significantly, with a variation rate of approximately 50%. In clinical practice, large individual differences in key pharmacokinetic parameters (RSD > 50%) suggest the need for dose adjustment or blood drug concentration monitoring.

[0145] The anlotinib cyclodextrin inclusion complex provided herein and the pharmaceutical composition prepared therefrom unexpectedly effectively reduce the variability of individual absorption differences, reducing the variability of individual bioavailability to 14.2%-27.7%, a decrease of 42% or more. The reduction in variability of individual absorption differences is even greater for patients with gastrointestinal diseases, liver damage, and renal insufficiency. This improves medication safety, reduces medication maintenance costs, and benefits more patients.

[0146] In addition, according to pharmacokinetic studies, anlotinib has a long elimination half-life in the human body. After continuous administration of anlotinib, its blood concentration increases with the number of doses. That is to say, when anlotinib hydrochloride capsules are used continuously, the drug accumulates in the patient's body and more adverse reactions occur.

[0147] At present, commercially available anlotinib has a high bioavailability for the treatment of cancer. The pharmaceutical composition provided by this application, comprising anlotinib cyclodextrin inclusion compound and its preparation, can maintain substantially equivalent bioavailability (relative AUC reaches 88.4%) while controlling the effective reduction of blood drug concentration Cmax by 26%, and the average blood drug concentration 24 hours after a single dose is lower. Therefore, the pharmaceutical composition of the present application can maintain the oral bioavailability of the drug while reducing the blood drug concentration of the drug in the human body, so as to obtain better patient compliance and more reasonable dosage and administration regimen. For example, when the dosage and frequency of administration remain unchanged, the symptoms, frequency and occurrence of adverse reactions are alleviated. Specifically, the number of patients with adverse reactions such as bleeding and hypertension is reduced, and the symptoms are alleviated.

[0148] Furthermore, in order to better control the tolerance of the drug, it is necessary to control the concentration of the drug in the body. The currently commercially available anlotinib hydrochloride capsules adopt a dosage method of continuous medication for 2 weeks and stopping the medication for 1 week as a treatment cycle ("two consecutive and one stop"). Under the dosage method of two consecutive and one stop, the blood concentration of anlotinib in the patient's body reached a peak after the 14th day of administration. In the observation of the subsequent two cycles, the blood concentration of anlotinib was basically controlled below 100ng / mL at the dosage of 10 and 12mg / person-day. The anlotinib cyclodextrin inclusion compound provided by the present application and the pharmaceutical composition prepared therefrom can provide a larger dosage, or tolerate a larger dose for long-term continuous administration, thereby improving patient compliance.

[0149] In a third aspect, the present application provides a method for preparing anlotinib cyclodextrin inclusion complex, characterized in that anlotinib is used as the main drug component and cyclodextrin is added with appropriate amounts of solvents separately or successively, and the mixture is mixed to obtain anlotinib cyclodextrin inclusion complex liquid; in some embodiments, the liquid is dried to obtain anlotinib cyclodextrin inclusion complex solid.

[0150] The present application also provides a method for preparing a pharmaceutical composition comprising anlotinib cyclodextrin inclusion complex, characterized in that the anlotinib cyclodextrin inclusion complex is added to other pharmaceutical excipients to prepare the pharmaceutical composition. The pharmaceutical excipients include, but are not limited to, one or more of a filler, a disintegrant, a lubricant, a binder, and a flavoring agent.

[0151] In some embodiments, an appropriate amount of solvent is added to the main drug component and cyclodextrin separately or successively to prepare anlotinib cyclodextrin inclusion complex liquid. In some embodiments, other pharmaceutical excipients are added to the anlotinib cyclodextrin inclusion complex, and an appropriate amount of solvent is added separately or successively as needed to prepare a pharmaceutical composition containing anlotinib cyclodextrin inclusion complex.

[0152] The present application provides a method for preparing anlotinib cyclodextrin inclusion complex, characterized in that the method comprises the following steps:

[0153] a: Add anlotinib or its pharmaceutically acceptable salt and / or its hydrate, and cyclodextrin separately or successively to a solvent, stir to dissolve and clarify, and if necessary, add a pH adjuster to adjust the solution pH to > 5 to obtain an inclusion complex liquid;

[0154] b: Optionally, the inclusion compound liquid is dried to obtain an inclusion compound solid.

[0155] In some embodiments, the cyclodextrin is selected from one or more of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin; in some embodiments, the cyclodextrin is β-cyclodextrin; in some embodiments, the cyclodextrin is hydroxypropyl-β-cyclodextrin.

[0156] In some embodiments, in the step a, 1.5-2.5 parts of anlotinib or a pharmaceutically acceptable salt and / or a hydrate thereof are added; in some embodiments, in the step a, 2-2.4 parts of anlotinib or a pharmaceutically acceptable salt and / or a hydrate thereof are added; in some embodiments, in the step a, 2.36 parts of anlotinib or a pharmaceutically acceptable salt and / or a hydrate thereof are added.

[0157] In some embodiments, in the step a, 18-38 parts of cyclodextrin are added, and the cyclodextrin is one or more of β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin; in some embodiments, in the step a, 24-36 parts of cyclodextrin are added, and the cyclodextrin is one or more of β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin; in some embodiments, in the step a, 28.32-35.4 parts of cyclodextrin are added, and the cyclodextrin is one or more of β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin.

[0158] In some embodiments, the weight ratio of anlotinib or its pharmaceutically acceptable salt and / or its hydrate to cyclodextrin is 1:10-1:20; in some embodiments, the weight ratio of anlotinib or its pharmaceutically acceptable salt and / or its hydrate to cyclodextrin is 1:11-1:18; in some embodiments, the weight ratio of anlotinib or its pharmaceutically acceptable salt and / or its hydrate to cyclodextrin is 1:12-1:15.

[0159] In some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is greater than 5; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is greater than 6; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is greater than 6.5; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is greater than 7.

[0160] In some embodiments, in step a, the main drug component and cyclodextrin are dissolved in appropriate amounts of solvents respectively and then mixed, or are dissolved in appropriate amounts of solvents simultaneously to prepare anlotinib cyclodextrin inclusion complex liquid.

[0161] In some embodiments, the solvent is selected from water and a solution containing a pH adjuster.

[0162] In some embodiments, the pH adjuster includes but is not limited to an acid, a base, or a buffer salt.

[0163] In some embodiments, the acid includes but is not limited to acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, salicylic acid.

[0164] In some embodiments, the base includes but is not limited to organic bases and inorganic bases. Examples include but are not limited to isopropylamine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, N-methylpiperazine, N-methylpyridine, pyridine, DBU, DABCO, triethylamine, alkali metals (such as sodium, potassium, lithium), alkali metal carbonates (such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate), alkali metal bicarbonates (such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate), alkali metal hydroxides (such as sodium hydroxide, calcium hydroxide, potassium hydroxide), metal alkoxides (such as sodium, lithium, potassium alkoxide, sodium tert-butoxide), sodium acetate and sodium hydride. Preferred bases are potassium carbonate, sodium carbonate, sodium hydroxide, sodium acetate, triethylamine, N,N-diisopropylethylamine, and pyridine.

[0165] In some embodiments, the buffer salt is prepared as a buffer with a pH>5, including but not limited to citrate-disodium hydrogen phosphate buffer, ammonia-ammonium chloride buffer, acetic acid-sodium acetate buffer, and phosphate buffer.

[0166] In some embodiments, the drying in step b includes but is not limited to spray drying, freeze drying, fluidized bed drying, preferably spray drying.

[0167] In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 1 μm≤X50≤15 μm, 5 μm≤X90≤30 μm.

[0168] In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 2μm≤X50≤12μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 3μm≤X50≤10μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 4μm≤X50≤8μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 6μm≤X90≤25μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 8μm≤X90≤22μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 10μm≤X90≤20μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 2μm≤X50≤12μm and 6μm≤X90≤25μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion compound solid satisfies 3 μm ≤ X50 ≤ 10 μm, 8 μm ≤ X90 ≤ 22 μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion compound solid satisfies 4 μm ≤ X50 ≤ 8 μm, 10 μm ≤ X90 ≤ 20 μm.

[0169] In some embodiments, the inclusion rate of the inclusion complex reaches more than 80%; in some embodiments, the inclusion rate of the inclusion complex reaches more than 85%; in some embodiments, the inclusion rate of the inclusion complex reaches more than 90%; in some embodiments, the inclusion rate of the inclusion complex reaches more than 95%.

[0170] The present application also provides a method for preparing a pharmaceutical composition comprising anlotinib cyclodextrin inclusion complex, characterized in that the method comprises the following steps:

[0171] A: Add anlotinib cyclodextrin inclusion complex to filler, disintegrant, lubricant, and mix, and optionally add other pharmaceutical excipients, including but not limited to adhesives and flavoring agents, to prepare an intermediate;

[0172] B: Prepare the intermediate into a solid preparation suitable for oral administration.

[0173] The present application also provides a method for preparing a pharmaceutical composition comprising anlotinib cyclodextrin inclusion complex, characterized in that the method comprises the following steps:

[0174] a: Add anlotinib or its pharmaceutically acceptable salt and / or its hydrate, and cyclodextrin separately or successively to a solvent, stir to dissolve and clarify, and if necessary, add a pH adjuster to adjust the solution pH to > 5 to obtain an inclusion complex liquid;

[0175] b: drying the inclusion compound liquid to obtain an inclusion compound solid;

[0176] c. Adding anlotinib cyclodextrin inclusion complex to filler, disintegrant, lubricant, and mixing, and optionally adding other pharmaceutical excipients, including but not limited to adhesives and flavoring agents, to prepare an intermediate;

[0177] d: Prepare the intermediate into a solid preparation suitable for oral administration.

[0178] The present application also provides a method for preparing a pharmaceutical composition comprising anlotinib cyclodextrin inclusion complex, characterized in that the method comprises the following steps:

[0179] e) Adding anlotinib or its pharmaceutically acceptable salt and / or its hydrate and cyclodextrin separately or successively to a solvent, stirring to dissolve and clarify, and adding a pH adjuster to adjust the solution pH to > 5 as needed to obtain an inclusion complex liquid;

[0180] f: adding the anlotinib cyclodextrin inclusion complex liquid to the filler to prepare a formulation intermediate;

[0181] g: The preparation intermediate is added to the filler, disintegrant, and lubricant and mixed, and other pharmaceutical excipients, including but not limited to adhesives and flavoring agents, are added as needed to prepare a solid preparation suitable for oral administration.

[0182] In some embodiments, the anlotinib cyclodextrin inclusion complex is presented in a liquid form. In some embodiments, the anlotinib cyclodextrin inclusion complex is presented in a solid form.

[0183] In some embodiments, the anlotinib cyclodextrin inclusion complex liquid can be further dried to obtain a cyclodextrin inclusion complex solid; in some embodiments, the anlotinib cyclodextrin inclusion complex liquid can be directly used to prepare a pharmaceutical composition containing anlotinib cyclodextrin inclusion complex.

[0184] In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 1 μm≤X50≤15 μm, 5 μm≤X90≤30 μm.

[0185] In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 2μm≤X50≤12μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 3μm≤X50≤10μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 4μm≤X50≤8μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 6μm≤X90≤25μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 8μm≤X90≤22μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 10μm≤X90≤20μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion complex solid satisfies 2μm≤X50≤12μm and 6μm≤X90≤25μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion compound solid satisfies 3 μm ≤ X50 ≤ 10 μm, 8 μm ≤ X90 ≤ 22 μm. In some embodiments, the particle size distribution of the anlotinib cyclodextrin inclusion compound solid satisfies 4 μm ≤ X50 ≤ 8 μm, 10 μm ≤ X90 ≤ 20 μm.

[0186] In some embodiments, the inclusion rate of the inclusion complex reaches more than 80%; in some embodiments, the inclusion rate of the inclusion complex reaches more than 85%; in some embodiments, the inclusion rate of the inclusion complex reaches more than 90%; in some embodiments, the inclusion rate of the inclusion complex reaches more than 95%.

[0187] In some embodiments, in step A or step c or steps f and g, (i) 13-48 parts of anlotinib cyclodextrin inclusion complex; (ii) 40-120 parts of filler; (iii) 2-16 parts of disintegrant; (iv) 0.1-12 parts of lubricant are added. In some embodiments, in step A or step c or steps f and g, (i) 20-45 parts of anlotinib cyclodextrin inclusion complex; (ii) 45-115 parts of filler; (iii) 3-15 parts of disintegrant; (iv) 0.2-11 parts of lubricant are added. In some embodiments, in step A or step c or steps f and g, (i) 25-40 parts of anlotinib cyclodextrin inclusion complex; (ii) 50-105 parts of filler; (iii) 4-13 parts of disintegrant; (iv) 0.5-10 parts of lubricant are added.

[0188] In some embodiments, the filler is selected from one or more of lactose, microcrystalline cellulose, pregelatinized starch, corn starch, mannitol, anhydrous calcium hydrogen phosphate, and sucrose; in some embodiments, the filler is one or more of lactose, microcrystalline cellulose, mannitol, and sucrose; in some embodiments, the filler is lactose and / or microcrystalline cellulose; in some embodiments, the filler is mannitol and / or microcrystalline cellulose; in some embodiments, the filler is mannitol; in some embodiments, the filler is sucrose; in some embodiments, the filler is sucrose powder or sucrose pellets; in some embodiments, the filler is sucrose pellets.

[0189] In some embodiments, the disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxybutyl methylcellulose, ethyl methyl cellulose, ethyl hydroxyethyl cellulose and methyl cellulose; in some embodiments, the disintegrant is one or more of hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose; in some embodiments, the disintegrant is one or more of SSL type hydroxypropyl cellulose, SL type hydroxypropyl cellulose, L type hydroxypropyl cellulose; in some embodiments, the disintegrant is low-substituted hydroxypropyl cellulose; in some embodiments, the disintegrant is low-substituted hydroxypropyl cellulose and / or cross-linked polyvinylpyrrolidone; in some embodiments, the disintegrant is sodium carboxymethyl starch and / or cross-linked sodium carboxymethyl cellulose.

[0190] In some embodiments, the lubricant is selected from one or more of magnesium stearate, stearic acid, micronized silica gel, colloidal silicon dioxide, glyceryl behenate, talc, sodium stearyl fumarate, sodium lauryl sulfate, polyethylene glycol 4000, polyethylene glycol 6000, and hydrogenated castor oil. In some embodiments, the lubricant is magnesium stearate; in some embodiments, the lubricant is talc.

[0191] Depending on the dosage form and formulation process, in some embodiments, (v) 1-5 parts by weight of a binder are optionally added to step A, step c, or steps f and g. In some embodiments, the binder is selected from one or more of hypromellose, hydroxypropyl cellulose, povidone, starch slurry, and sodium carboxymethyl cellulose; in some embodiments, the binder is hypromellose; and in some embodiments, the binder is hypromellose E5.

[0192] In some embodiments, 45-115 parts of a filler are added to step A or step c or steps f and g, and the filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, and sucrose; in some specific embodiments, 50-105 parts of a filler are added to step A or step c or steps f and g; in some specific embodiments, 55-100 parts of a filler are added to step A or step c or steps f and g.

[0193] In some embodiments, 3-15 parts of a disintegrant are added to step A or step c or step g, and the disintegrant is selected from one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxybutyl methylcellulose, ethyl methylcellulose, ethyl hydroxyethyl cellulose and methylcellulose; in some specific embodiments, 4-13 parts of a disintegrant are added to step A or step c or step g.

[0194] In some embodiments, 0.2-11 parts of a lubricant are added to step A or step c or step g, and the lubricant is one or more of magnesium stearate, stearic acid, micropowdered silica, colloidal silicon dioxide, glyceryl behenate, talc, sodium stearyl fumarate, sodium lauryl sulfate, polyethylene glycol 4000, polyethylene glycol 6000, and hydrogenated castor oil; in some specific embodiments, 0.5-10 parts of a lubricant are added to step A or step c or step g.

[0195] In some embodiments, 2-4 parts of a binder are added to step A, step c, or step g, and the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, starch slurry, and sodium carboxymethyl cellulose; in some embodiments, the binder is hydroxypropyl methylcellulose.

[0196] In some embodiments of the present application, in step A, step c, or step g, (i) 13-48 parts of anlotinib cyclodextrin inclusion complex; (ii) 40-120 parts of mannitol; (iii) 2-16 parts of hydroxypropyl cellulose; and (iv) 0.1-3 parts of magnesium stearate are added.

[0197] In some embodiments of the present application, in step A, step c, or step g, (i) 20-45 parts of anlotinib cyclodextrin inclusion complex; (ii) 50-100 parts of mannitol; (iii) 3-12 parts of hydroxypropyl cellulose; and (iv) 0.5-2 parts of magnesium stearate are added.

[0198] In some embodiments of the present application, in step A, step c, or step g, (i) 13-48 parts of anlotinib cyclodextrin inclusion complex; (ii) 40-120 parts of sucrose; (iii) 2-16 parts of hydroxypropyl cellulose; and (iv) 3-12 parts of talc are added.

[0199] In some embodiments of the present application, in step A, step c, or step g, (i) 20-45 parts of anlotinib cyclodextrin inclusion complex; (ii) 50-110 parts of sucrose pellet cores; (iii) 3-12 parts of hydroxypropyl cellulose; and (iv) 5-11 parts of talc are added.

[0200] In some embodiments of the present application, in step A, step c, or step g, (i) 13-48 parts of anlotinib cyclodextrin inclusion complex; (ii) 40-120 parts of lactose and / or microcrystalline cellulose; (iii) 2-16 parts of cross-linked polyvinylpyrrolidone and / or hydroxypropyl cellulose; and (iv) 0.1-3 parts of magnesium stearate are added.

[0201] In some embodiments of the present application, in step A, step c, or step g, (i) 20-45 parts of anlotinib cyclodextrin inclusion complex; (ii) 50-100 parts of lactose and / or microcrystalline cellulose; (iii) 3-12 parts of cross-linked polyvinylpyrrolidone and / or hydroxypropyl cellulose; and (iv) 0.5-2 parts of magnesium stearate are added.

[0202] In some embodiments of the present application, in step A, step c, or step g, (i) 13-48 parts of anlotinib cyclodextrin inclusion complex; (ii) 40-120 parts of lactose and / or microcrystalline cellulose; (iii) 2-16 parts of cross-linked sodium carboxymethyl cellulose and / or sodium carboxymethyl starch; (iv) 0.1-3 parts of magnesium stearate; and (v) 1-5 parts of hydroxypropyl methylcellulose are added.

[0203] In some embodiments of the present application, in step A, step c, or step g, (i) 20-45 parts of anlotinib cyclodextrin inclusion complex; (ii) 50-100 parts of lactose and / or microcrystalline cellulose; (iii) 3-12 parts of cross-linked sodium carboxymethyl cellulose and / or sodium carboxymethyl starch; (iv) 0.5-2 parts of magnesium stearate; and (v) 2-4 parts of hydroxypropyl methylcellulose are added.

[0204] In some embodiments of the present application, in step A, step c, or step g, (i) 13-48 parts of anlotinib cyclodextrin inclusion complex; (ii) 40-120 parts of mannitol; (iii) 2-16 parts of cross-linked polyvinylpyrrolidone; and (iv) 0.1-3 parts of stearic acid are added.

[0205] In some embodiments of the present application, in step A, step c, or step g, (i) 20-45 parts of anlotinib cyclodextrin inclusion complex; (ii) 50-100 parts of mannitol; (iii) 3-12 parts of cross-linked polyvinylpyrrolidone; and (iv) 0.5-2 parts of stearic acid are added.

[0206] In some embodiments, the temperature of the material in step A, step c or step f is controlled to be in the range of 20 to 40° C. In some embodiments, the temperature of the material in step A, step c or step f is controlled to be in the range of 25 to 35° C.

[0207] In some embodiments, the solid preparation includes tablets, capsules, powders, granules, pellets, pastes, powders, etc., preferably tablets and capsules; in some embodiments, the tablets are coated tablets.

[0208] In some embodiments, the intermediate of step B or step d or step g is subjected to dry granulation and tablet compression to obtain a core tablet or tablet; in some embodiments, the intermediate of step B is subjected to wet granulation and tablet compression to obtain a core tablet or tablet; in some embodiments, the core tablet or tablet is further coated to obtain a coated tablet.

[0209] In some embodiments, the intermediate of step B, step d, or step g is filled into capsule shells to prepare capsules.

[0210] The inclusion compound or intermediate containing the main drug component and the pharmaceutical composition prepared in the present application all have good powder properties, fluidity, and dissolution properties, and are safe and stable. The dry granulation prescription process has good continuity, so that the intermediate product has good properties, a certain hardness, and good content uniformity and uniformity of particle porosity.

[0211] In a fourth aspect, the present application provides a use of anlotinib cyclodextrin inclusion complex and a pharmaceutical composition prepared therefrom in the preparation of a drug for treating cancer. The cancers include but are not limited to non-small cell lung cancer, small cell lung cancer, medullary thyroid cancer, differentiated thyroid cancer, soft tissue sarcoma, advanced colorectal cancer, clear cell renal carcinoma, advanced gastric cancer, advanced esophageal squamous cell carcinoma, advanced liver cancer, neuroendocrine tumors, primary bone tumors, nasopharyngeal carcinoma, etc.

[0212] In a fifth aspect, the present application provides a method for treating cancer using anlotinib cyclodextrin inclusion complex and a pharmaceutical composition prepared therefrom.

[0213] The anlotinib cyclodextrin inclusion compound and the pharmaceutical composition prepared therefrom can be administered by a variety of routes, including but not limited to routes selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intrafatty, intraarticular, intraperitoneal, and intrathecal. In a specific embodiment, the administration is by oral administration.

[0214] The amount of anlotinib cyclodextrin inclusion complex and the pharmaceutical composition prepared therefrom administered can be determined based on the severity of the disease, the response to the disease, any treatment-related toxicity, the age and health status of the subject. In some embodiments, the daily dose of anlotinib or a pharmaceutically acceptable salt thereof is 3 mg to 30 mg. In some embodiments, the daily dose of anlotinib or a pharmaceutically acceptable salt thereof is 5 mg to 20 mg. In some embodiments, the daily dose of anlotinib or a pharmaceutically acceptable salt thereof is 8 mg to 16 mg. In some embodiments, the daily dose of anlotinib or a pharmaceutically acceptable salt thereof is 10 mg to 14 mg. In a specific embodiment, the daily dose of anlotinib or a pharmaceutically acceptable salt thereof is 8 mg. In a specific embodiment, the daily dose of anlotinib or a pharmaceutically acceptable salt thereof is 10 mg. In a specific embodiment, the daily dose of anlotinib or a pharmaceutically acceptable salt thereof is 12 mg. In the present application, for example, for tablets or capsules, “containing 8 mg of anlotinib or a pharmaceutically acceptable salt thereof on a unit dose basis” means that each tablet or capsule finally manufactured contains 8 mg of anlotinib.

[0215] The pharmaceutical composition comprising anlotinib cyclodextrin inclusion complex and the pharmaceutical composition prepared therefrom can be administered once or more daily. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered once daily. In one embodiment, anlotinib or a pharmaceutically acceptable salt thereof is administered once daily as an oral solid formulation.

[0216] In the above-mentioned treatment methods, the method of administration can be comprehensively determined based on the activity, toxicity and tolerance of the subject of the drug. Preferably, anlotinib or a pharmaceutically acceptable salt thereof is administered in a continuous administration manner. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered in an intermittent administration manner. The intermittent administration includes an administration period and a withdrawal period, and anlotinib or a pharmaceutically acceptable salt thereof can be administered once or more per day during the administration period. For example, anlotinib or a pharmaceutically acceptable salt thereof is administered every day during the administration period, and then the administration is stopped for a period of time during the withdrawal period, followed by an administration period, and then a withdrawal period, and this can be repeated multiple times. Among them, the ratio of the administration period to the withdrawal period in days is 2:(0.1-2), preferably 2:0.2-1.5, more preferably 2:0.4-1, and more preferably 2:0.5-1.

[0217] Anlotinib or its pharmaceutically acceptable salt

[0218] The chemical name of the compound of formula I is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine, which has the following structural formula:

[0219] In this application, all references to anlotinib refer to the compound of formula I.

[0220] Anlotinib can be administered in its free base form, or in the form of its salts, hydrates, and prodrugs, which are converted into the free base form of anlotinib in vivo. For example, pharmaceutically acceptable salts of anlotinib can be produced from various organic and inorganic acids according to methods known in the art within the scope of this application.

[0221] In the present application, the pharmaceutically acceptable salts include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, salicylic acid, etc.

[0222] In some embodiments, anlotinib is administered as free base. In some embodiments, anlotinib is administered as anhydrous free base. In some embodiments, anlotinib is administered as free base monohydrate. In some embodiments, anlotinib is administered as hydrochloride. In some embodiments, anlotinib is administered as monohydrochloride. In some embodiments, anlotinib is administered as dihydrochloride. In some embodiments, anlotinib is administered as crystalline anlotinib hydrochloride. In a specific embodiment, anlotinib is administered as crystalline anlotinib dihydrochloride.

[0223] For the purposes of this application, unless otherwise stated, the following terms used in the specification and claims shall have the following meanings.

[0224] "Unit dosage" or "unit dose" refers to a pharmaceutical composition packaged in a single package for the convenience of administration. For example, "a pharmaceutical composition in unit dosage form" means each capsule. "A pharmaceutical composition in unit dosage form contains 100 mg of anlotinib" means that each capsule finally prepared contains 100 mg of anlotinib.

[0225] "Patient" or "subject" refers to a mammal, preferably a human.

[0226] "Treatment" means any administration of a therapeutically effective amount of a compound, and includes:

[0227] (1) inhibiting the disease in a human being who is experiencing or exhibiting the pathology or symptomology of the disease (i.e., arresting further development of the pathology and / or symptomology), or

[0228] (2) Ameliorating a disease in a human who is experiencing or exhibiting the pathology or symptomology of the disease (i.e., reversing the pathology and / or symptomology).

[0229] "Inclusion complex" refers to a non-chemically bonded inclusion complex formed by the structure of a drug molecule (guest molecule) being fully or partially contained within the cavity structure of another substance (host molecule). In this application, "inclusion complex" refers to a solid or liquid complex formed by anlotinib as the main drug component being embedded in the cavity structure of a cyclodextrin molecule. Based on the geometry of the host molecule cavity, inclusion complexes are divided into tubular, cage-type, and lamellar inclusion complexes.

[0230] "Lubricants" include but are not limited to substances used to reduce the friction between raw materials, excipients and equipment during the drug preparation process, substances used as anti-adhesives to prevent raw materials and excipients from adhering to the surface of equipment, and substances used as glidants to reduce the friction between raw materials and excipients to improve powder flowability.

[0231] The "X50" mentioned in this application refers to the particle size at which the particle size distribution is 50%, that is, the volume content of particles smaller than this particle size accounts for 50% of all particles; "X90" refers to the particle size at which the particle size distribution is 90%, that is, the volume content of particles smaller than this particle size accounts for 90% of all particles. BRIEF DESCRIPTION OF THE DRAWINGS

[0232] Figure 1 Blood concentration-time curves of the reference preparation and the test preparation in Example 8 DETAILED DESCRIPTION

[0233] The present application will be further described below with reference to specific examples. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of protection of the present application.

[0234] Instruments and methods used to collect data:

[0235] The particle size distribution of the material is determined by the laser method. The instrument and its model are: Sympatec HELOS-OASIS or laser particle size analyzer with equivalent performance, HELOS-RODOS / T4.1.

[0236] The inclusion rate was determined by filtration. The resulting inclusion complex liquid was filtered through a 0.22-μm filter membrane and the change in content before and after filtration was determined by liquid chromatography. The inclusion rate (%) = content of the main drug component after filtration / content of the main drug component before filtration * 100%.

[0237] Example 1 Preparation of cyclodextrin inclusion compound

[0238] Inclusion compound 1 prescription

[0239] Preparation process:

[0240] Take the prescribed amount of hydroxypropyl-β-cyclodextrin (HP-β-CD) and anlotinib hydrochloride, add water, stir and dissolve to clarify, and obtain an inclusion compound liquid with an inclusion rate of 95%. The solution is spray-dried to prepare an inclusion compound solid.

[0241] The particle size distribution of the prepared inclusion compound 1 solid is: X50: 6.8 μm; X90: 15.7 μm.

[0242] Inclusion compound 2 prescription

[0243] Preparation process:

[0244] Take the prescribed amount of hydroxypropyl-β-cyclodextrin (HP-β-CD), add water, stir and dissolve to clarify, add anlotinib hydrochloride, and then add organic / inorganic base to adjust the pH to >5 to obtain an inclusion compound liquid with an inclusion rate of 96%. The solution is spray-dried to prepare an inclusion compound solid.

[0245] Inclusion compound 3 prescription

[0246] Preparation process:

[0247] Take the prescribed amount of hydroxypropyl-β-cyclodextrin (HP-β-CD) and anlotinib hydrochloride, add a buffer solution with a pH value greater than 5, stir to dissolve and clarify, control the end point pH value greater than 5, and obtain an inclusion compound liquid with an inclusion rate of 94%. The solution is spray-dried to prepare an inclusion compound solid.

[0248] Inclusion compound 4 prescription

[0249] Preparation process:

[0250] Take the prescribed amount of hydroxypropyl-β-cyclodextrin (HP-β-CD) and anlotinib hydrochloride, add a buffer solution with a pH value greater than 5, stir to dissolve and clarify, control the end point pH value greater than 5, and obtain an inclusion compound liquid with an inclusion rate of 95%. The solution is spray-dried to prepare an inclusion compound solid.

[0251] Inclusion compound 5 prescription

[0252] Preparation process:

[0253] Take the prescribed amount of hydroxypropyl-β-cyclodextrin (HP-β-CD) and anlotinib hydrochloride, add water, stir and dissolve to clarify, and obtain an inclusion compound liquid with an inclusion rate of 96%. The solution is spray-dried to prepare an inclusion compound solid.

[0254] Inclusion compound 6 prescription

[0255] Preparation process:

[0256] Take the prescribed amount of hydroxypropyl-β-cyclodextrin (HP-β-CD) and anlotinib base, add an acidic solution with a pH of less than 3, stir to dissolve and clarify, then adjust the pH with an alkaline solution with a pH of more than 5, control the end point pH to be more than 5, obtain an inclusion liquid, and the inclusion rate reaches 95%. The solution is spray-dried to prepare an inclusion compound solid.

[0257] Example 2

[0258] Prescription 1

[0259] Preparation process:

[0260] 1) Take one of the anlotinib cyclodextrin inclusion compounds 1-6 prepared in Example 1 according to the prescribed amount.

[0261] 2) adding mannitol, low-substituted hypromellose and magnesium stearate to the inclusion compound and mixing them to obtain an intermediate powder.

[0262] 3) The intermediate is filled into capsules or compressed into tablets.

[0263] Example 3

[0264] Prescription 2

[0265] 1) Take one of the anlotinib cyclodextrin inclusion compounds 1-6 prepared in Example 1 according to the prescribed amount.

[0266] 2) Add the inclusion compound and hydroxypropyl cellulose (HPC-SL) to purified water, stir to dissolve and clarify, add talc powder under stirring, stir to evenly disperse, and obtain a drug suspension.

[0267] 3) In a fluidized bed, the drug suspension is fluidized onto the sucrose blank pellet cores to obtain drug-containing pellets.

[0268] 4) The intermediate is filled into capsules to produce micropellet capsules, or compressed into tablets to produce tablets.

[0269] Example 4

[0270] Prescription 3

[0271] Preparation process:

[0272] 1) Take one of the anlotinib cyclodextrin inclusion compounds 1-6 prepared in Example 1 according to the prescribed amount.

[0273] 2) Add microcrystalline cellulose, mannitol and low-substituted hydroxypropyl cellulose to the inclusion compound, mix, and dry granulate.

[0274] 3) The drug particles obtained in 2) are added with cross-linked polyvinylpyrrolidone and magnesium stearate, and the mixture is mixed to obtain an intermediate.

[0275] 4) The intermediate is filled into capsules or compressed into tablets.

[0276] Example 5

[0277] Prescription 4

[0278] Preparation process:

[0279] 1) Take one of the anlotinib cyclodextrin inclusion compounds 1-6 prepared in Example 1 according to the prescribed amount.

[0280] 2) Dissolve the hydropropyl methylcellulose in purified water to prepare a binder solution.

[0281] 3) Add the inclusion compound, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and lactose into the fluidized bed, spray the binder solution into the granulation under the fluidized state and dry.

[0282] 4) adding sodium carboxymethyl starch and magnesium stearate to the drug granules obtained in 3) and mixing them to obtain an intermediate.

[0283] 5) The intermediate is filled into capsules or compressed into tablets.

[0284] Example 6

[0285] Prescription 5

[0286] Preparation process:

[0287] 1) Take one of the anlotinib cyclodextrin inclusion compounds 1-6 prepared in Example 1 according to the prescribed amount.

[0288] 2) adding mannitol, low-substituted hypromellose and magnesium stearate to the inclusion compound and mixing them to obtain an intermediate.

[0289] 3) The intermediate is filled into capsules or compressed into tablets.

[0290] Example 7

[0291] Prescription 6

[0292] Preparation process:

[0293] 1) Take one of the anlotinib cyclodextrin inclusion compounds 1-6 prepared in Example 1 according to the prescribed amount.

[0294] 2) Dissolve the hydropropyl methylcellulose in purified water to prepare a binder solution.

[0295] 3) Add the inclusion compound, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose and lactose into the fluidized bed, spray the binder solution into the granulation under the fluidized state and dry.

[0296] 4) adding sodium carboxymethyl starch and magnesium stearate to the drug granules obtained in 3) and mixing them to obtain an intermediate.

[0297] 5) The intermediate is filled into capsules or compressed into tablets.

[0298] Example 8

[0299] Prescription 7

[0300] Preparation process:

[0301] 1) Anlotinib hydrochloride and hydroxypropyl-β-cyclodextrin were sequentially added to purified water 1 and stirred until dissolved to prepare a drug solution, and a sodium hydroxide solution with a pH greater than 5 was slowly added dropwise to adjust the pH to above 7.0 to obtain anlotinib cyclodextrin inclusion complex liquid.

[0302] 2) Add mannitol 1 to the fluidized bed and control the parameters so that the material temperature ranges from 25 to 35° C. Spray the liquid into the fluidized bed for one-step granulation, dry it, and sieve the granules.

[0303] 3) Add stearic acid, cross-linked polyvinylpyrrolidone and mannitol 2, mix, and compress into tablets.

[0304] 4) Add film coating premix to purified water 3, shear, sieve, and coat the tablets.

[0305] Example 9 Human Pharmacokinetic Study

[0306] A randomized, open, single-cycle, parallel bioequivalence study was conducted in the fasting state on 16 subjects, divided into 2 groups, with 8 subjects in each group. The reference preparation was anlotinib hydrochloride capsules with a strength of 8 mg, and the test preparation was anlotinib cyclodextrin inclusion compound capsules (4 mg, 2 capsules) prepared by the inclusion compound 1 prepared in Example 1 and the prescription 1 in Example 2.

[0307] Biological sample analysis: The concentration of anlotinib in plasma samples treated with EDTA-K2 as anticoagulant was determined using a partially validated LC-MS / MS method, and the relevant parameters C max , AUC 0-t 、C 24h Calculation.

[0308] Plasma sample collection time points: venous blood was collected at 17 time points, including 0 h (within 60 min) before administration and 1, 2, 4, 5, 6, 8, 10, 12, 24, 48, 72, 120, 168, 336, 504, and 648 h after administration.

[0309] The pharmacokinetic parameters of the reference preparation and the test preparation are shown in Table 1, and the blood drug concentration-time relationship curve is shown in Figure 1.

[0310] Table 1

[0311] Example 10 Human Pharmacokinetic Study

[0312] A randomized, open, single-center, parallel bioequivalence study was conducted in the fasting state on 12 subjects, divided into 2 groups, with 6 subjects in each group. The reference preparation was anlotinib hydrochloride capsules with a strength of 8 mg, and the test preparation was a tablet containing anlotinib cyclodextrin inclusion complex prepared according to Example 8 (8 mg, 1 tablet).

[0313] Biological sample analysis: The concentration of anlotinib in plasma samples with heparin sodium as anticoagulant was determined by a partially validated LC-MS / MS method, and the relevant parameters Cmax, AUC 0-t 、C 24h Calculation.

[0314] Plasma sample collection time points: venous blood was collected at 17 time points, including 0 h (within 60 min) before administration and 1, 2, 4, 5, 6, 8, 10, 12, 24, 48, 72, 120, 168, 336, 504, and 648 h after administration.

[0315] The pharmacokinetic parameters of the reference preparation and the test preparation are shown in Table 2.

[0316] Table 2

[0317] Note: Relative bioavailability: AUC0-t (test preparation) * 100% / AUC0-t (reference preparation);

[0318] Mean relative bioavailability: the average of the relative bioavailability of all subjects.

[0319] Example 11 Compatibility study of raw materials and auxiliary materials

[0320] After preparing an inclusion complex with the API anlotinib and hydroxypropyl-β-cyclodextrin, the inclusion complex was mixed with selected solid formulation excipients in varying proportions. The inclusion complex was then packaged in vials and stored either openly at high humidity (40°C, 75% RH) or sealed with a crimp cap at high temperature (60°C). Samples were collected on days 10 and 30 to examine changes in related substances. The compatibility of the inclusion complex with commonly used excipients was investigated, as detailed in Table 3.

[0321] Table 3 Note*: The total impurities of the inclusion compound on day 0 are 0.20%.

[0322] The results showed that fillers such as mannitol, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and disintegrants such as low-substituted hydroxypropyl cellulose cross-linked polyvinylpyrrolidone had good compatibility with solid dispersions; lubricants also had good compatibility with solid dispersions.

Claims

1. An anlotinib cyclodextrin inclusion complex, comprising: (a) anlotinib as a main drug component; (b) cyclodextrin; the anlotinib as the main drug component comprises anlotinib or a pharmaceutically acceptable salt and / or a hydrate thereof.

2. The inclusion compound according to claim 1, comprising: (a) 1-3 parts of anlotinib as the main drug ingredient; (b) 12-45 parts of cyclodextrin; All parts therein are by weight.

3. The inclusion compound according to claim 1 or 2, wherein The cyclodextrin is selected from one or more of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin, preferably β-cyclodextrin, more preferably hydroxypropyl-β-cyclodextrin.

4. The inclusion compound according to any one of claims 1 to 3, wherein The weight ratio of anlotinib or its pharmaceutically acceptable salt and / or its hydrate to cyclodextrin is 1:10-1:20, preferably 1:11-1:18, and more preferably 1:12-1:

15.

5. The inclusion compound according to any one of claims 1 to 4, wherein The anlotinib cyclodextrin inclusion complex is liquid or solid.

6. The inclusion compound according to claim 5, wherein the particle size distribution of the anlotinib cyclodextrin inclusion compound solid satisfies 1 μm≤X50≤15 μm, 5 μm≤X90≤30 μm.

7. The inclusion compound according to any one of claims 1 to 6, characterized in that The inclusion rate is 80% or more, preferably 85% or more, more preferably 90% or more, and even more preferably 95% or more.

8. A pharmaceutical composition comprising anlotinib cyclodextrin inclusion complex, comprising: (i) anlotinib cyclodextrin inclusion complex; (ii) a filler; (iii) a disintegrant; (iv) a lubricant; and (v) other pharmaceutical excipients as needed.

9. The pharmaceutical composition according to claim 8, wherein: The filler is selected from one or more of lactose, microcrystalline cellulose, pregelatinized starch, corn starch, mannitol, anhydrous calcium hydrogen phosphate, and sucrose, preferably one or more of lactose, microcrystalline cellulose, mannitol, and sucrose; The disintegrant is selected from one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxybutyl methylcellulose, ethyl methylcellulose, hydroxyethyl methylcellulose, ethyl hydroxyethyl cellulose and methylcellulose, preferably one or more of hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch and cross-linked sodium carboxymethyl cellulose; The lubricant is selected from one or more of magnesium stearate, stearic acid, micropowdered silica, talc, colloidal silicon dioxide, glyceryl behenate, sodium stearyl fumarate, sodium lauryl sulfate, polyethylene glycol 4000, polyethylene glycol 6000, and hydrogenated castor oil, preferably magnesium stearate and / or talc.

10. The pharmaceutical composition according to claim 8 or 9, comprising: (i) 13-48 parts of anlotinib cyclodextrin inclusion complex; (ii) 40-120 parts of a filler; (iii) 2-16 parts of a disintegrant; (iv) 0.1-12 parts of a lubricant; in, Anlotinib cyclodextrin inclusion complex, which contains: (a) 1-3 parts of anlotinib as the main drug ingredient; (b) 12-45 parts of cyclodextrin; All parts are by weight, and the anlotinib as the main drug component includes anlotinib or a pharmaceutically acceptable salt and / or hydrate thereof.

11. The method for preparing the inclusion compound according to any one of claims 1 to 7, characterized in that: include: Anlotinib is used as the main drug component and cyclodextrin is added with appropriate amounts of solvents separately or successively, mixed to obtain an inclusion compound liquid, and dried to obtain anlotinib cyclodextrin inclusion compound solid; or, the method includes the following steps: a: Add anlotinib or its pharmaceutically acceptable salt and / or its hydrate, and cyclodextrin separately or successively to a solvent, stir to dissolve and clarify, and if necessary, add a pH adjuster to adjust the liquid pH to > 5 to obtain an inclusion complex liquid; b: Optionally, the inclusion compound liquid is dried to obtain an inclusion compound solid.

12. The method for preparing the pharmaceutical composition according to any one of claims 8 to 10, characterized in that: The following steps are involved: A: The inclusion compound according to any one of claims 1 to 7 is added to a filler, a disintegrant, and a lubricant, and other pharmaceutical excipients are added as needed, wherein the other pharmaceutical excipients include a binder and a flavoring agent to prepare an intermediate; B: preparing the intermediate into a solid dosage form suitable for oral administration; Alternatively, include the following steps: a: Add anlotinib or its pharmaceutically acceptable salt and / or its hydrate, and cyclodextrin separately or successively to a solvent, stir to dissolve and clarify, and if necessary, add a pH adjuster to adjust the liquid pH to > 5 to obtain an inclusion complex liquid; b: drying the inclusion compound liquid to obtain an inclusion compound solid; c. Adding anlotinib cyclodextrin inclusion compound to filler, disintegrant, lubricant, and mixing, and optionally adding other pharmaceutical excipients, including adhesives and flavoring agents, to prepare an intermediate; d: preparing the intermediate into a solid preparation suitable for oral administration; Alternatively, include the following steps: e) Adding anlotinib or its pharmaceutically acceptable salt and / or its hydrate and cyclodextrin separately or successively to a solvent, stirring to dissolve and clarify, and adding a pH adjuster to adjust the solution pH to > 5 as needed to obtain an inclusion complex liquid; f: mixing the anlotinib cyclodextrin inclusion complex liquid with the filler to prepare a formulation intermediate; g: Mix the preparation intermediate with filler, disintegrant, and / or lubricant, and add other pharmaceutical excipients as needed. The other pharmaceutical excipients include adhesives and flavoring agents, which are used to make solid preparations suitable for oral administration.

13. Use of the inclusion compound according to any one of claims 1 to 7 or the pharmaceutical composition according to any one of claims 8 to 10 in the preparation of a medicament for treating cancer.

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