WO2024002147A1 - 喹啉衍生物或其盐环糊精包合物 - Google Patents

喹啉衍生物或其盐环糊精包合物 Download PDF

Info

Publication number
WO2024002147A1
WO2024002147A1 PCT/CN2023/103130 CN2023103130W WO2024002147A1 WO 2024002147 A1 WO2024002147 A1 WO 2024002147A1 CN 2023103130 W CN2023103130 W CN 2023103130W WO 2024002147 A1 WO2024002147 A1 WO 2024002147A1
Authority
WO
WIPO (PCT)
Prior art keywords
anlotinib
cyclodextrin
parts
inclusion compound
cyclodextrin inclusion
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2023/103130
Other languages
English (en)
French (fr)
Inventor
赵泽恺
谢华
苏佳
王茹
董平
何雄雄
鲁锡峰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Original Assignee
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chia Tai Tianqing Pharmaceutical Group Co Ltd filed Critical Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority to CN202380049144.3A priority Critical patent/CN119403575A/zh
Publication of WO2024002147A1 publication Critical patent/WO2024002147A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This application belongs to the field of pharmaceutical preparations.
  • This application relates to quinoline derivatives or their salt cyclodextrin inclusion compounds, and pharmaceutical compositions containing quinoline derivatives or their salt inclusion compounds.
  • this application relates to a Anlotinib cyclodextrin inclusion complex, preparation method, and pharmaceutical composition containing anlotinib cyclodextrin inclusion complex, and preparation method.
  • anlotinib a first-class new drug containing the compound of Formula I as the main drug ingredient, was successfully launched in China. It is the first approved third-line treatment drug for advanced non-small cell lung cancer in China. It is a multi-target receptor tyrosine kinase inhibitor that can inhibit the activity of vascular endothelial cell growth factor receptors (VEGFR1, VEGFR2/KDR and VEGFR3), stem cell factor receptors, platelet-derived growth factor receptors and other kinases. Inhibits VEGFR2-mediated downstream signal transduction, thereby inhibiting tumor angiogenesis.
  • VEGFR1 vascular endothelial cell growth factor receptors
  • Anlotinib hydrochloride shows good anti-tumor activity; it has good bioavailability in animals and humans. It is mainly distributed in the metabolic excretion system and endocrine system. It has extensive metabolism and is mainly excreted through feces; its main toxicity reaction is in teeth. , kidney, hepatobiliary system, blood system, etc. Anlotinib hydrochloride has shown good and broad therapeutic prospects in clinical anti-tumor treatment.
  • Cyclodextrins are enzyme-modified starch derivatives composed of grape sugar linked to ⁇ -1,4 glycosidic bonds.
  • a cyclic oligosaccharide composed of sugar units, usually containing 6 to 12 D-glucopyranose unit structures.
  • molecules that have been studied more and have important practical significance are molecules containing 6, 7, and 8 glucose units respectively, which are called ⁇ -cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin respectively.
  • ⁇ -cyclodextrin molecules that have been studied more and have important practical significance
  • molecules ⁇ -cyclodextrin, ⁇ -cyclodextrin and ⁇ -cyclodextrin respectively.
  • people have passed The structural modification of cyclodextrin is used to improve its physical and chemical properties, such as increasing water solubility, forming new chiral sites, and building supramolecular aggregates.
  • 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 by patients.
  • the pharmacokinetic data of commercially available anlotinib hydrochloride capsules show that there are individual differences in absorption. Specifically, the average maximum blood concentration (Cmax) of cancer patients and healthy people after taking anlotinib hydrochloride capsules There are significant differences in individual absorption and average drug time area under the curve (AUC 0-t ), and the variability rate is high.
  • this application provides an anlotinib cyclodextrin inclusion compound.
  • the present application provides a pharmaceutical composition comprising anlotinib cyclodextrin inclusion complex.
  • this application provides a method for preparing anlotinib cyclodextrin inclusion complex, and a method for preparing a pharmaceutical composition containing anlotinib cyclodextrin inclusion complex.
  • this application provides an anlotinib cyclodextrin inclusion complex and the use of a pharmaceutical composition containing anlotinib cyclodextrin inclusion complex in the preparation of drugs for treating cancer.
  • this application provides a method for treating cancer using anlotinib cyclodextrin inclusion complex and a pharmaceutical composition containing anlotinib cyclodextrin inclusion complex.
  • this application provides an anlotinib cyclodextrin inclusion compound, which contains: (a) anlotinib as the main drug ingredient; (b) cyclodextrin; the anlotinib
  • the main drug ingredient includes but is not limited to anlotinib or its pharmaceutically acceptable salt and/or its hydrate.
  • anlotinib cyclodextrin inclusion complex for preparing oral pharmaceutical preparations, which contains: (a) anlotinib as the main drug ingredient; (b) cyclodextrin Essence; the anlotinib as the main drug ingredient includes but is not limited to anlotinib or its pharmaceutically acceptable salts and/or its hydrates.
  • the application provides an anlotinib cyclodextrin inclusion complex containing:
  • anlotinib as the main drug ingredient includes but is not limited to anlotinib or its pharmaceutically acceptable salts and/or its hydrates.
  • the cyclodextrin is selected from alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin One or more of methyl- ⁇ -cyclodextrin and methyl- ⁇ -cyclodextrin; in some embodiments, the cyclodextrin is ⁇ -cyclodextrin; in some embodiments, the cyclodextrin is hydroxy Propyl-beta-cyclodextrin.
  • 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 The weight ratio of the anlotinib or its pharmaceutically acceptable salt and/or its hydrate to cyclodextrin is 1:11-1:18; in some embodiments, the anlotinib or The weight ratio of its pharmaceutically acceptable salt and/or its hydrate to cyclodextrin is 1:12-1:15.
  • the anlotinib cyclodextrin inclusion complex further contains a pH adjuster; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is >5; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is >6; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is >6.5; in some implementations In the scheme, the pH of the anlotinib cyclodextrin inclusion complex is >7.
  • the anlotinib cyclodextrin inclusion complex contains:
  • anlotinib as the main drug ingredient includes but is not limited to anlotinib or its pharmaceutically acceptable salts and/or its hydrates.
  • the anlotinib cyclodextrin inclusion complex contains:
  • anlotinib as the main drug ingredient includes but is not limited to anlotinib or its pharmaceutically acceptable salts and/or its hydrates.
  • the pharmaceutical composition contains 1.5-2.5 parts of the main drug ingredient, and the main drug ingredient is anlotinib or a pharmaceutically acceptable salt thereof and/or a hydrate thereof; in some cases In 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.
  • the pharmaceutical composition contains 18-38 parts of cyclodextrin, and the cyclodextrin is ⁇ -cyclodextrin.
  • the cyclodextrin is ⁇ -cyclodextrin.
  • the product contains 24-36 parts of cyclodextrin, which are ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and methyl- ⁇ -cyclodextrin.
  • the pharmaceutical composition contains 28.32-35.4 parts of cyclodextrin, and the cyclodextrin is ⁇ -cyclodextrin, hydroxyethyl- One or more of ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and methyl- ⁇ -cyclodextrin.
  • the anlotinib cyclodextrin inclusion complex is presented in a liquid form. In some embodiments, the anlotinib cyclodextrin inclusion complex is present in a solid form.
  • the anlotinib cyclodextrin inclusion complex further contains a pH adjuster; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is >5; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is >6; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is >6.5; in some implementations In the scheme, the pH of the anlotinib cyclodextrin inclusion complex is >7.
  • the anlotinib cyclodextrin inclusion compound liquid can be further dried to obtain a cyclodextrin inclusion compound solid; in some embodiments, the anlotinib cyclodextrin inclusion compound liquid can be further dried to obtain a cyclodextrin inclusion compound solid.
  • the liquid can be directly used to prepare pharmaceutical compositions containing the anlotinib cyclodextrin inclusion complex.
  • the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 1 ⁇ m ⁇ X50 ⁇ 15 ⁇ m and 5 ⁇ m ⁇ X90 ⁇ 30 ⁇ m.
  • the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 2 ⁇ m ⁇ X50 ⁇ 12 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 3 ⁇ m ⁇ X50 ⁇ 10 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 4 ⁇ m ⁇ X50 ⁇ 8 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 6 ⁇ m ⁇ X90 ⁇ 25 ⁇ m.
  • the particle size distribution of the solid anlotinib cyclodextrin inclusion complex satisfies 8 ⁇ m ⁇ X90 ⁇ 22 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 10 ⁇ m ⁇ X90 ⁇ 20 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion complex satisfies 2 ⁇ m ⁇ X50 ⁇ 12 ⁇ m and 6 ⁇ m ⁇ X90 ⁇ 25 ⁇ m.
  • the particle size distribution of the solid anlotinib cyclodextrin inclusion complex satisfies 3 ⁇ m ⁇ X50 ⁇ 10 ⁇ m and 8 ⁇ m ⁇ X90 ⁇ 22 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 4 ⁇ m ⁇ X50 ⁇ 8 ⁇ m and 10 ⁇ m ⁇ X90 ⁇ 20 ⁇ m.
  • the inclusion rate of the inclusion compound reaches more than 80%; in some embodiments, the inclusion rate of the inclusion compound reaches more than 85%; in some embodiments, the inclusion rate of the inclusion compound reaches more than 85%.
  • the inclusion rate of the inclusion compound reaches more than 90%; in some embodiments, the inclusion rate of the inclusion compound reaches more than 95%.
  • anlotinib cyclodextrin inclusion complex which contains: (i) anlotinib cyclodextrin inclusion complex; (ii) filler; (i) anlotinib cyclodextrin inclusion complex; iii) Disintegrant; (iv) Lubricant; (v) Other medicinal purposes as needed
  • the auxiliary material, wherein the anlotinib cyclodextrin inclusion complex contains (a) anlotinib as the main drug ingredient; (b) cyclodextrin.
  • the present application provides an oral solid pharmaceutical composition comprising anlotinib cyclodextrin inclusion complex, which contains: (i) anlotinib cyclodextrin inclusion complex; (ii) ) filler; (iii) disintegrant; (iv) lubricant; (v) other pharmaceutical excipients as needed, including anlotinib cyclodextrin inclusion complex containing (a) anlotinib As the main drug ingredient; (b) cyclodextrin.
  • anlotinib cyclodextrin inclusion complex which contains: (i) anlotinib cyclodextrin inclusion complex; (ii) ) filler; (iii) disintegrant; (iv) lubricant; (v) other pharmaceutical excipients as needed, including anlotinib cyclodextrin inclusion complex containing (a) anlotinib As the main drug ingredient; (b) cyclodextrin.
  • the application provides a pharmaceutical composition comprising anlotinib cyclodextrin inclusion complex, which contains:
  • anlotinib cyclodextrin inclusion complex contains:
  • anlotinib as the main drug ingredient includes but is not limited to anlotinib or its pharmaceutically acceptable salts and/or its hydrates.
  • 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.
  • the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, crospovidone, carboxymethyl starch sodium, hydroxypropyl cellulose, hydroxypropyl One or more of methylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, hydroxybutylmethylcellulose, ethylmethylcellulose, ethylhydroxyethylcellulose and methylcellulose ;
  • the disintegrant is one or more of hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch, and croscarmellose sodium; in some embodiments
  • the disintegrant is one or more of SSL model hydroxypropyl cellulose, SL model hydroxypropyl cellulose, and L model hydroxypropyl cellulose; in some embodiments, the disintegrant is The disintegrant is low-substituted hydroxypropyl cellulose; in some embodiments, the disintegrant is low-substituted
  • the lubricant is selected from magnesium stearate, stearic acid, micronized silica gel, colloidal silica, glyceryl behenate, talc, sodium stearyl fumarate, dodecane One or more of sodium sulfate, polyethylene glycol 4000, polyethylene glycol 6000, and hydrogenated castor oil.
  • the lubricant is magnesium stearate; in some embodiments, the lubricant is talc.
  • the cyclodextrin is selected from alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin One or more of methyl- ⁇ -cyclodextrin and methyl- ⁇ -cyclodextrin; in some embodiments, the cyclodextrin is ⁇ -cyclodextrin; in some embodiments, the cyclodextrin is hydroxy Propyl-beta-cyclodextrin.
  • 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 The weight ratio of the anlotinib or its pharmaceutically acceptable salt and/or its hydrate to cyclodextrin is 1:11-1:18; in some embodiments, the anlotinib or The weight ratio of its pharmaceutically acceptable salt and/or its hydrate to cyclodextrin is 1:12-1:15.
  • compositions containing anlotinib cyclodextrin inclusion complex may be further added to the above-mentioned pharmaceutical composition containing anlotinib cyclodextrin inclusion complex if necessary. one or more agents.
  • (v) 1-5 parts of a binder is further added to the above pharmaceutical composition containing anlotinib cyclodextrin inclusion complex, and the parts are by weight.
  • the binder is selected from one or more of hypromellose, hydroxypropyl cellulose, povidone, starch slurry, and sodium carboxymethylcellulose; in some embodiments In , the binder is hypromellose; in some embodiments, the binder is hypromellose E5.
  • the pharmaceutical composition contains:
  • the pharmaceutical composition contains:
  • the pharmaceutical composition contains 45-115 parts of filler, and the filler is selected from one or more of lactose, microcrystalline cellulose, mannitol, and sucrose; in some In specific embodiments, the pharmaceutical composition contains 50-105 parts of filler; in some specific embodiments, the pharmaceutical composition contains 55-100 parts of filler.
  • the pharmaceutical composition contains 3-15 parts of a disintegrant, and the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, and cross-linked polyvinylidene.
  • the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, and cross-linked polyvinylidene.
  • Vinyl pyrrolidone sodium carboxymethyl starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hydroxybutyl methyl cellulose, ethyl methyl cellulose, One or more of ethyl hydroxyethyl cellulose and methyl cellulose; in some specific embodiments, the pharmaceutical composition contains 4-13 parts of disintegrant.
  • the pharmaceutical composition contains 0.2-11 parts of lubricant, and the lubricant is magnesium stearate, stearic acid, micronized silica gel, colloidal silica, and behenic acid.
  • the lubricant is magnesium stearate, stearic acid, micronized silica gel, colloidal silica, and behenic acid.
  • the pharmaceutical composition contains 0.5-10 parts of lubricant.
  • the pharmaceutical composition contains 2-4 parts of a binder, and the binder is selected from the group consisting of hypromellose, hydroxypropyl cellulose, povidone, and starch slurry. , one or more sodium carboxymethylcellulose; in some embodiments, the binder is hydroxypropyl methylcellulose.
  • the pharmaceutical composition includes:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition includes:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition contains 1.5-2.5 parts of the main drug ingredient, and the main drug ingredient is anlotinib or a pharmaceutically acceptable salt thereof and/or a hydrate thereof; in some cases In 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.
  • the pharmaceutical composition contains 18-38 parts of cyclodextrin, and the cyclodextrin is ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -One or more of cyclodextrin and methyl- ⁇ -cyclodextrin; in some specific embodiments, the pharmaceutical composition contains 24-36 parts of cyclodextrin, and the cyclodextrin Be one or more of ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and methyl- ⁇ -cyclodextrin; in some specific embodiments, The pharmaceutical composition contains 28.32-35.4 parts of cyclodextrin, which is ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and methyl cyclodextrin; in
  • the anlotinib cyclodextrin inclusion complex is presented in a liquid form. In some embodiments, the anlotinib cyclodextrin inclusion complex is present in a solid form. In some embodiments, the pH of the anlotinib cyclodextrin inclusion complex liquid is >5.
  • the anlotinib cyclodextrin inclusion compound liquid can be further dried to obtain a cyclodextrin inclusion compound solid; in some embodiments, the anlotinib cyclodextrin inclusion compound liquid can be further dried to obtain a cyclodextrin inclusion compound solid.
  • the liquid can be directly used to prepare pharmaceutical compositions containing the anlotinib cyclodextrin inclusion complex.
  • the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 1 ⁇ m ⁇ X50 ⁇ 15 ⁇ m and 5 ⁇ m ⁇ X90 ⁇ 30 ⁇ m.
  • the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 2 ⁇ m ⁇ X50 ⁇ 12 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 3 ⁇ m ⁇ X50 ⁇ 10 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 4 ⁇ m ⁇ X50 ⁇ 8 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 6 ⁇ m ⁇ X90 ⁇ 25 ⁇ m.
  • the particle size distribution of the solid anlotinib cyclodextrin inclusion complex satisfies 8 ⁇ m ⁇ X90 ⁇ 22 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 10 ⁇ m ⁇ X90 ⁇ 20 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion complex satisfies 2 ⁇ m ⁇ X50 ⁇ 12 ⁇ m and 6 ⁇ m ⁇ X90 ⁇ 25 ⁇ m.
  • the particle size distribution of the solid anlotinib cyclodextrin inclusion complex satisfies 3 ⁇ m ⁇ X50 ⁇ 10 ⁇ m and 8 ⁇ m ⁇ X90 ⁇ 22 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 4 ⁇ m ⁇ X50 ⁇ 8 ⁇ m and 10 ⁇ m ⁇ X90 ⁇ 20 ⁇ m.
  • the inclusion rate of the inclusion compound reaches more than 80%; in some embodiments, the inclusion rate of The inclusion rate of the inclusion compound reaches more than 85%; in some embodiments, the inclusion rate of the inclusion compound reaches more than 90%; in some embodiments, the inclusion rate of the inclusion compound reaches above 95.
  • the pharmaceutical composition is a solid preparation, including tablets, capsules, powders, granules, dropping pills, pastes, powders, etc., preferably tablets and capsules; in some embodiments, tablets
  • the dosage form is coated tablets.
  • the pharmaceutical composition is a liquid preparation, including solution, suspension, emulsion, injection, infusion, and implant.
  • the present application provides a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof and/or a hydrate thereof as an active ingredient, and the daily dosage is sufficient to provide the required therapeutic effect.
  • the pharmaceutical composition contains 2 mg to 20 mg of anlotinib or a pharmaceutically acceptable salt thereof and/or a hydrate thereof; in some embodiments, the pharmaceutical composition Containing 4 mg to 18 mg of anlotinib or a pharmaceutically acceptable salt thereof and/or a hydrate thereof; in some embodiments, the pharmaceutical composition contains 6 mg to 16 mg of anlotinib or Its pharmaceutically acceptable salt and/or its hydrate; in some embodiments, the pharmaceutical composition contains 8 mg to 14 mg of anlotinib or its pharmaceutically acceptable salt and/or its hydrate In some embodiments, the pharmaceutical composition 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
  • the pharmaceutical composition is formulated as a pharmaceutical composition in unit dosage form.
  • the pharmaceutical composition in unit dosage form contains 2 mg to 20 mg of anlotinib or a pharmaceutically acceptable salt thereof and/or its hydrate; in some embodiments, the The pharmaceutical composition in unit dosage form contains 4 mg to 18 mg of anlotinib or a pharmaceutically acceptable salt thereof and/or its hydrate; in some embodiments, the pharmaceutical composition in unit dosage form Containing 6 mg to 16 mg of anlotinib or a pharmaceutically acceptable salt thereof and/or its hydrate; in some embodiments, the pharmaceutical composition in unit dosage form contains 8 mg to 14 mg of anlotinib.
  • the pharmaceutical composition in unit dosage 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 its pharmaceutical counterpart Acceptable salts and/or hydrates thereof.
  • the pharmaceutical composition in unit dosage form contains a capsule of 4 mg of anlotinib or a pharmaceutically acceptable salt thereof and/or a hydrate thereof; in some specific embodiments, the The pharmaceutical composition in unit dosage form contains a capsule of 6 mg of anlotinib or a pharmaceutically acceptable salt thereof and/or its hydrate; in some embodiments, the pharmaceutical composition in unit dosage form contains A capsule of 8 mg of anlotinib or a pharmaceutically acceptable salt thereof and/or a hydrate thereof; in some embodiments, the pharmaceutical composition in unit dosage form contains 10 mg of anlotinib or Capsules of pharmaceutically acceptable salts thereof and/or hydrates thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains a capsule of 12 mg of anlotinib or a pharmaceutically acceptable salt thereof and/or a hydrate thereof.
  • the pharmaceutical composition in unit dosage form contains a tablet of 4 mg of anlotinib or a pharmaceutically acceptable salt thereof and/or a hydrate thereof; in some specific embodiments, the The pharmaceutical composition in unit dosage form contains a tablet of 6 mg of anlotinib or a pharmaceutically acceptable salt thereof and/or a hydrate thereof; in some embodiments, the pharmaceutical composition in unit dosage form is A tablet containing 8 mg of anlotinib or a pharmaceutically acceptable salt thereof and/or a hydrate thereof; in some embodiments, the pharmaceutical composition in unit dosage form contains 10 mg of anlotinib. or tablets of pharmaceutically acceptable salts and/or hydrates thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains a tablet of 12 mg of anlotinib or a pharmaceutically acceptable salt thereof and/or a hydrate thereof.
  • Individual differences refer to individual differences in drug response. It is a common biological phenomenon that exists in normal and diseased human bodies. For example, when given a common dose, most people can produce the expected effect, but some people are ineffective, or even Toxic reactions occur, and this reaction that varies from person to person is called individual differences.
  • Individual differences in drugs are mainly related to individual differences in drug metabolism and pharmacodynamics, and there are many factors causing this difference. For example, differences in the gastrointestinal environment of different patients, patients' genetic factors, differences in organ function, and the impact of other diseases may all cause individual differences. Among them, those who are particularly sensitive to drugs are called hypersensitivity, and those who are otherwise called tolerance. Due to the existence of individual differences in drug effects, in clinical medication, it is sometimes necessary to select an appropriate dose according to the patient's condition and pay attention to the principle of individualized dose.
  • the plasma nortriptyline concentration produced by different individuals varies more than 30 times.
  • the plasma drug concentration produced after applying propranolol 3 times a day, 10 mg, 20 mg, 40 mg, and 80 mg each time, the plasma drug concentration of propranolol in different individuals can vary as much as 7 times.
  • the plasma drug concentrations produced by different doses overlap within a certain range, that is, some individuals can obtain the plasma drug concentrations produced by larger doses in other individuals by using smaller doses.
  • Individual differences in drug effects can also be manifested in pharmacodynamics, that is, the same drug plasma concentration or action site concentration produces different drug effects in different individuals.
  • Individual differences in pharmacodynamics can be manifested in the different doses of a drug that produce the same effect in different individuals, or in the different times it takes for the same dose to produce a response in different individuals.
  • plasma concentration monitoring of the drug can help individualize drug therapy. Since old age and liver and kidney disease can also affect the responsiveness of target organs such as the brain, when monitoring therapeutic drug concentrations, special attention should be paid to the possible changes in the effective concentration range of the drug in these patients.
  • the pharmacokinetic data of commercially available anlotinib hydrochloride capsules show that there is a problem of individual absorption differences. Specifically, the average maximum plasma concentration (Cmax) and The area under the average drug-time curve (AUC 0-t ) varies significantly among individuals, and the variation rate reaches about 50%. In clinical practice, if the individual differences in the main pharmacokinetic parameters are large (RSD>50%), it is necessary to adjust the dose or monitor the blood drug concentration when necessary.
  • the pharmaceutical composition containing anlotinib cyclodextrin inclusion complex and its preparation provided by this application can unexpectedly effectively reduce the variation rate of individual absorption differences, and can reduce the variation rate of individual bioavailability to 14.2%. -27.7%, a drop of 42% or more.
  • the variability in individual absorption differences is reduced even more in patients with gastrointestinal disease, liver damage, renal insufficiency, etc. This will help improve medication safety, reduce medication maintenance costs, and benefit more patients.
  • anlotinib has a long elimination half-life in the human body. After continuous administration of anlotinib, its blood concentration increases with the increase in the number of administrations. In other words, anlotinib hydrochloride has a long elimination half-life. When Tinib capsules are used continuously, the drug accumulates in the patient's body, and more adverse reactions occur.
  • anlotinib has a high bioavailability for the treatment of cancer.
  • the pharmaceutical composition provided by this application containing anlotinib cyclodextrin inclusion complex and its preparation can maintain the basic level of In the case of effective bioavailability (relative AUC reaches 88.4%), the blood drug concentration Cmax is effectively reduced by 26% while controlling the blood drug concentration, and the average blood drug concentration 24 hours after a single dose is even lower. Therefore, the pharmaceutical composition of the present application can maintain the oral bioavailability of the drug while reducing the blood concentration of the drug in the human body, so as to obtain better patient compliance and more reasonable dosage and dosage regimens. 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.
  • anlotinib hydrochloride capsules adopt a treatment cycle of 2 weeks of continuous medication and 1 week of drug withdrawal ("Continuous Er”). "stop") administration method. Under the two-stop administration method, the blood concentration of anlotinib in the patient's body reached the peak after the 14th day of administration. In the subsequent two cycles of observation, at doses of 10 and 12 mg/person per day, the plasma concentration of anlotinib was basically controlled below 100 ng/mL.
  • the anlotinib cyclodextrin inclusion complex and the pharmaceutical composition made from it provided in this application can provide a larger dosage, or tolerate a larger dosage after long-term continuous administration, and improve patient compliance.
  • this application provides a method for preparing anlotinib cyclodextrin inclusion complex, which is characterized in that anlotinib is used as the main drug ingredient and cyclodextrin, and an appropriate amount of solvent is added separately or successively, After mixing, anlotinib cyclodextrin inclusion complex liquid is obtained; in some embodiments, the liquid is dried to prepare anlotinib cyclodextrin inclusion complex solid.
  • This application also provides a method for preparing a pharmaceutical composition containing anlotinib cyclodextrin inclusion complex, which is characterized by:
  • the anlotinib cyclodextrin inclusion compound is added to other pharmaceutical excipients to prepare a pharmaceutical composition.
  • the pharmaceutical excipients include, but are not limited to, one or more of fillers, disintegrants, lubricants, binders, and flavoring agents.
  • an appropriate amount of solvent is added to the main drug ingredient and cyclodextrin separately or successively to prepare anlotinib cyclodextrin inclusion complex liquid.
  • other pharmaceutical excipients are added to the anlotinib cyclodextrin inclusion complex, and appropriate amounts of solvents are added separately or successively as needed to prepare anlotinib cyclodextrin inclusion complex. pharmaceutical compositions.
  • This application provides a method for preparing anlotinib cyclodextrin inclusion complex, which is characterized in that the method includes the following steps:
  • the cyclodextrin is selected from alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin One or more of methyl- ⁇ -cyclodextrin and methyl- ⁇ -cyclodextrin; in some embodiments, the cyclodextrin is ⁇ -cyclodextrin; in some embodiments, the cyclodextrin is hydroxy Propyl-beta-cyclodextrin.
  • step a 1.5-2.5 parts of anlotinib or its pharmaceutically acceptable salt and/or hydrate is added; in some embodiments, in step a, Add 2-2.4 parts of anlotinib or its pharmaceutically acceptable salt and/or its hydrate; in some embodiments, in step a, add anlotinib or its pharmaceutically acceptable salt and/or its hydrate 2.36 parts.
  • step a 18-38 parts of cyclodextrin are added, and the cyclodextrin is ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ - One or more of cyclodextrin and methyl- ⁇ -cyclodextrin; in some embodiments, in step a, 24-36 parts of cyclodextrin are added, and the cyclodextrin is ⁇ -cyclodextrin.
  • step a add 28.32-35.4 parts of cyclodextrin, the cyclodextrins are ⁇ -cyclodextrin, hydroxyethyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and methyl- ⁇ -cyclodextrin of one or more.
  • 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 The weight ratio of the anlotinib or its pharmaceutically acceptable salt and/or its hydrate to cyclodextrin is 1:11-1:18; in some embodiments, the anlotinib or The weight ratio of its pharmaceutically acceptable salt and/or its hydrate to cyclodextrin is 1:12-1:15.
  • the pH of the anlotinib cyclodextrin inclusion complex is >5; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is >6; in some In embodiments, the pH of the anlotinib cyclodextrin inclusion complex is >6.5; in some embodiments, the pH of the anlotinib cyclodextrin inclusion complex is >7.
  • step a the main drug ingredient and cyclodextrin are respectively dissolved in an appropriate amount of solvent and then mixed, or are simultaneously dissolved in an appropriate amount of solvent to prepare anlotinib cyclodextrin inclusion complex. liquid.
  • the solvent is selected from one of water and a solution with added pH adjuster.
  • the pH adjusting agent includes, but is not limited to, acid, base or buffer salt.
  • 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, etc.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
  • organic acids such as acetic acid, trifluoroacetic acid, propionic acid, etc.
  • caproic acid caproic acid, heptanoic acid, cyclopentane propionic 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, 1,2ethanedisulfonic acid, 2hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid , salicylic acid.
  • the base includes, but is not limited to, organic bases and inorganic bases.
  • Enumerable 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 bicarbonate (such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate), alkali metal hydroxide (such as sodium hydroxide, calcium hydroxide, Potassium hydroxide), metal alkoxides (such as sodium, lithium, potassium alkoxides, sodium tert-butoxide), sodium acetate and sodium hydride, the preferred bases are potassium
  • the buffer salt is made into a buffer with a pH>5, including but not limited to citric acid-disodium hydrogen phosphate buffer, ammonia-ammonium chloride buffer, acetic acid-sodium acetate buffer, Phosphate buffer.
  • the drying in step b includes but is not limited to spray drying, freeze drying, fluidized drying, preferably spray drying.
  • the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 1 ⁇ m ⁇ X50 ⁇ 15 ⁇ m and 5 ⁇ m ⁇ X90 ⁇ 30 ⁇ m.
  • the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 2 ⁇ m ⁇ X50 ⁇ 12 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 3 ⁇ m ⁇ X50 ⁇ 10 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 4 ⁇ m ⁇ X50 ⁇ 8 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 6 ⁇ m ⁇ X90 ⁇ 25 ⁇ m.
  • the particle size distribution of the solid anlotinib cyclodextrin inclusion complex satisfies 8 ⁇ m ⁇ X90 ⁇ 22 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 10 ⁇ m ⁇ X90 ⁇ 20 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion complex satisfies 2 ⁇ m ⁇ X50 ⁇ 12 ⁇ m and 6 ⁇ m ⁇ X90 ⁇ 25 ⁇ m.
  • the particle size distribution of the solid anlotinib cyclodextrin inclusion complex satisfies 3 ⁇ m ⁇ X50 ⁇ 10 ⁇ m and 8 ⁇ m ⁇ X90 ⁇ 22 ⁇ m. In some embodiments, the anlotinib cyclodextrin inclusion complex solid The particle size distribution satisfies 4 ⁇ m ⁇ X50 ⁇ 8 ⁇ m, 10 ⁇ m ⁇ X90 ⁇ 20 ⁇ m.
  • the inclusion rate of the inclusion compound reaches more than 80%; in some embodiments, the inclusion rate of the inclusion compound reaches more than 85%; in some embodiments, the inclusion rate of the inclusion compound reaches more than 85%.
  • the inclusion rate of the inclusion compound reaches more than 90%; in some embodiments, the inclusion rate of the inclusion compound reaches more than 95%.
  • This application also provides a method for preparing a pharmaceutical composition containing anlotinib cyclodextrin inclusion complex, which is characterized in that the method includes the following steps:
  • A Mix the anlotinib cyclodextrin inclusion compound with fillers, disintegrants, and lubricants, and add other pharmaceutical excipients if necessary, including but not limited to adhesives and flavoring agents to make an intermediate;
  • This application also provides a method for preparing a pharmaceutical composition containing anlotinib cyclodextrin inclusion complex, which is characterized in that the method includes the following steps:
  • This application also provides a method for preparing a pharmaceutical composition containing anlotinib cyclodextrin inclusion complex, which is characterized in that the method includes the following steps:
  • g Mix the preparation intermediate with fillers, disintegrants, and lubricants, and add other pharmaceutical excipients as necessary, including but not limited to binders and flavoring agents, to prepare a solid preparation suitable for oral administration.
  • the anlotinib cyclodextrin inclusion complex is presented in a liquid form. In some embodiments, the anlotinib cyclodextrin inclusion complex is present in a solid form.
  • the anlotinib cyclodextrin inclusion compound liquid can be further dried to obtain a cyclodextrin inclusion compound solid; in some embodiments, the anlotinib cyclodextrin inclusion compound liquid can be further dried to obtain a cyclodextrin inclusion compound solid.
  • the liquid can be directly used to prepare pharmaceutical compositions containing the anlotinib cyclodextrin inclusion complex.
  • the particle size distribution of the solid anlotinib cyclodextrin inclusion complex satisfies 1 ⁇ m ⁇ X50 ⁇ 15 ⁇ m, 5 ⁇ m ⁇ X90 ⁇ 30 ⁇ m.
  • the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 2 ⁇ m ⁇ X50 ⁇ 12 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 3 ⁇ m ⁇ X50 ⁇ 10 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 4 ⁇ m ⁇ X50 ⁇ 8 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 6 ⁇ m ⁇ X90 ⁇ 25 ⁇ m.
  • the particle size distribution of the solid anlotinib cyclodextrin inclusion complex satisfies 8 ⁇ m ⁇ X90 ⁇ 22 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 10 ⁇ m ⁇ X90 ⁇ 20 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion complex satisfies 2 ⁇ m ⁇ X50 ⁇ 12 ⁇ m and 6 ⁇ m ⁇ X90 ⁇ 25 ⁇ m.
  • the particle size distribution of the solid anlotinib cyclodextrin inclusion complex satisfies 3 ⁇ m ⁇ X50 ⁇ 10 ⁇ m and 8 ⁇ m ⁇ X90 ⁇ 22 ⁇ m. In some embodiments, the particle size distribution of the solid anlotinib cyclodextrin inclusion compound satisfies 4 ⁇ m ⁇ X50 ⁇ 8 ⁇ m and 10 ⁇ m ⁇ X90 ⁇ 20 ⁇ m.
  • the inclusion rate of the inclusion compound reaches more than 80%; in some embodiments, the inclusion rate of the inclusion compound reaches more than 85%; in some embodiments, the inclusion rate of the inclusion compound reaches more than 85%.
  • the inclusion rate of the inclusion compound reaches more than 90%; in some embodiments, the inclusion rate of the inclusion compound reaches more than 95%.
  • step A 25-40 parts of anlotinib cyclodextrin inclusion complex; (ii) 50-105 parts of filler are added to step A or step c or steps f and g. ; (iii) 4-13 parts of disintegrant; (iv) 0.5-10 parts of lubricant.
  • 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.
  • the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, crospovidone, carboxymethyl starch sodium, hydroxypropyl cellulose, hydroxypropyl One or more of methylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose, hydroxybutylmethylcellulose, ethylmethylcellulose, ethylhydroxyethylcellulose and methylcellulose ;
  • the disintegrant is hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch, cross-linked One or more of sodium carboxymethylcellulose;
  • the disintegrant is SSL type hydroxypropyl cellulose, SL type hydroxypropyl cellulose, L type hydroxypropyl cellulose One or more types of cellulose; in some embodiments, the disintegrant is low-substituted hydroxypropyl cellulose; in some embodiments, the disintegrant is low-substituted hydroxypropyl cellulose; in some embodiments, the disintegr
  • the lubricant is selected from magnesium stearate, stearic acid, micronized silica gel, colloidal silica, glyceryl behenate, talc, sodium stearyl fumarate, dodecane One or more of sodium sulfate, polyethylene glycol 4000, polyethylene glycol 6000, and hydrogenated castor oil.
  • the lubricant is magnesium stearate; in some embodiments, the lubricant is talc.
  • (v) 1-5 parts of adhesive is optionally added to step A or step c or steps f and g, and the number of parts is Weight scale.
  • the binder is selected from one or more of hypromellose, hydroxypropyl cellulose, povidone, starch slurry, and sodium carboxymethylcellulose; in some embodiments In , the binder is hypromellose; in some embodiments, the binder is hypromellose E5.
  • step A or step c or steps f and g 45-115 parts of filler are added to step A or step c or steps f and g, and the filler is selected from the group consisting of lactose, microcrystalline cellulose, mannitol, and sucrose. or more; in some specific embodiments, 50-105 parts of filler are added to the step A or step c or steps f and g; in some specific embodiments, the step A or step c or add 55-100 parts of filler in steps f and g.
  • step A 3-15 parts of disintegrating agent are added to step A, step c or step g, and the disintegrating agent is selected from the group consisting of crospovidone and croscarmellose sodium. , Cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose, hydroxybutyl methyl cellulose, ethyl methyl cellulose.
  • ethyl hydroxyethyl cellulose, ethyl hydroxyethyl cellulose and methyl cellulose 4-13 parts of disintegration are added to the step A or step c or step g. Antidote.
  • 0.2-11 parts of lubricant is added to step A, step c or step g.
  • the lubricant is magnesium stearate, stearic acid, micronized silica gel, and colloidal silica. , glyceryl behenate, talc, sodium stearyl fumarate, sodium lauryl sulfate, one or more of polyethylene glycol 4000, polyethylene glycol 6000, hydrogenated castor oil; in some specific
  • 0.5-10 parts of lubricant is added to step A, step c or step g.
  • 2-4 parts of a binder are added to step A, step c or step g, and the binder is selected from the group consisting of hypromellose, hydroxypropyl cellulose, polyvitamin One or more of ketone, starch slurry, sodium carboxymethylcellulose; in some embodiments, the binder is hydroxypropyl methylcellulose.
  • step A 13-48 parts of anlotinib cyclodextrin inclusion complex; (ii) 40-120 parts of manna are added to step A, step c or step g. Alcohol; (iii) 2-16 parts of hydroxypropyl cellulose; (iv) 0.1-3 parts of magnesium stearate.
  • step A 20-45 parts of anlotinib cyclodextrin inclusion complex;
  • step c 50-100 parts of manna are added to step A, step c or step g.
  • Alcohol iii) 3-12 parts of hydroxypropyl cellulose;
  • iv 0.5-2 parts of magnesium stearate.
  • step A 20-45 parts of anlotinib cyclodextrin inclusion complex
  • step c 50-100 parts of lactose are added to step A, step c or step g. and/or microcrystalline cellulose
  • step c 50-100 parts of lactose are added to step A, step c or step g. and/or microcrystalline cellulose
  • step c 50-100 parts of lactose are added to step A, step c or step g. and/or microcrystalline cellulose
  • step c 50-100 parts of lactose are added to step A, step c or step g. and/or microcrystalline cellulose
  • step c 50-100 parts of lactose are added to step A, step c or step g. and/or microcrystalline cellulose
  • step c 50-100 parts of lactose are added to step A, step c or step g. and/or microcrystalline cellulose
  • step c 50-100 parts of lactose are added to step A, step c
  • step A 13-48 parts of anlotinib cyclodextrin inclusion complex
  • step c 40-120 parts of lactose are added to step A, step c or step g. and/or microcrystalline cellulose
  • step c 40-120 parts of lactose are added to step A, step c or step g. and/or microcrystalline cellulose
  • step c 40-120 parts of lactose are added to step A, step c or step g. and/or microcrystalline cellulose
  • step c 40-120 parts of lactose are added to step A, step c or step g. and/or microcrystalline cellulose
  • step c 20-30 parts of croscarmellose sodium and/or sodium carboxymethyl starch
  • iv 0.1-3 parts of magnesium stearate
  • v 1 -5 parts of hydroxypropyl methylcellulose.
  • step A 20-45 parts of anlotinib cyclodextrin inclusion complex
  • step c 50-100 parts of lactose are added to step A, step c or step g. and/or microcrystalline cellulose
  • step c 50-100 parts of lactose are added to step A, step c or step g. and/or microcrystalline cellulose
  • step c 50-100 parts of lactose are added to step A, step c or step g. and/or microcrystalline cellulose
  • step c 50-100 parts of lactose are added to step A, step c or step g. and/or microcrystalline cellulose
  • step c 50-100 parts of lactose are added to step A, step c or step g. and/or microcrystalline cellulose
  • step c 50-100 parts of lactose are added to step A, step c or step g. and/or microcrystalline cellulose
  • step c 50-100 parts of lactose are added to step A, step c
  • step A 20-45 parts of anlotinib cyclodextrin inclusion complex;
  • step c 50-100 parts of manna are added to step A, step c or step g. alcohol;
  • step c 20-45 parts of anlotinib cyclodextrin inclusion complex;
  • 50-100 parts of manna are added to step A, step c or step g. alcohol;
  • step c 3-12 parts of crospovidone;
  • step stearic acid 0.5-2 parts of stearic acid.
  • the temperature range of step A, step c or step f is controlled to be 20-40°C. In some embodiments, the temperature range of step A, step c or step f is controlled to be 25-35°C.
  • the solid preparations include tablets, capsules, powders, granules, dropping pills, pastes, powders, etc., preferably tablets and capsules; in some embodiments, tablets are packaged coated tablets.
  • the intermediate of step B or step d or step g is dry granulated and compressed to obtain tablet cores or tablets; in some embodiments, the intermediate of step B, After wet granulation and tableting, tablet cores or tablets are produced; in some embodiments, the tablet cores or tablets are further coated to produce coated tablets.
  • step B or step d or step g is filled into a capsule shell to prepare capsules.
  • the inclusion complexes or intermediates and pharmaceutical compositions containing the main drug ingredients prepared by this application 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, has a certain hardness, and maintains good content uniformity and particle porosity uniformity.
  • the present application provides a use of anlotinib cyclodextrin inclusion complex and a pharmaceutical composition made thereof in the preparation of drugs 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 renal cell carcinoma, advanced gastric cancer, advanced esophageal squamous cell carcinoma, advanced liver cancer, Neuroendocrine tumors, primary bone tumors, nasopharyngeal carcinoma, etc.
  • the present application provides a method for treating cancer containing anlotinib cyclodextrin inclusion complex and a pharmaceutical composition made thereof.
  • compositions containing the anlotinib cyclodextrin inclusion complex and the preparation thereof can be administered through a variety of routes, including but not limited to routes selected from the following: oral, parenteral, intraperitoneal, intravenous, Intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intrafatty, intraarticular, intraperitoneal, and intrathecal.
  • routes including but not limited to routes selected from the following: oral, parenteral, intraperitoneal, intravenous, Intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intrafatty, intraarticular, intraperitoneal, and intrathecal.
  • routes selected from the following: oral, parenteral, intraperitoneal, intravenous, Intraarterial, transdermal, sub
  • anlotinib cyclodextrin inclusion complex and pharmaceutical compositions thereof may be determined based on the severity of the disease, response to the disease, any treatment-related toxicity, and the age and health status of the subject.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 3 mg to 30 mg.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 5 mg to 20 mg.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 8 mg to 16 mg.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 10 mg to 14 mg.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 8 mg. In a specific embodiment, anlotinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 10 mg. In a specific embodiment, anlotinib or a pharmaceutical agent thereof is administered An acceptable daily dose of salt is 12 mg. In this 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 is finally made. Each capsule contains 8 mg of anlotinib.
  • compositions containing the anlotinib cyclodextrin inclusion complex and the preparation thereof can be administered once or multiple times per day.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered once daily.
  • the oral solid formulation is administered once daily.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered as a continuous administration.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered in spaced doses.
  • the interval administration includes a administration period and a drug withdrawal period.
  • anlotinib or its pharmaceutically acceptable salt can be administered once or multiple times a day.
  • anlotinib or its pharmaceutically acceptable salt 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 the administration period, and then the withdrawal period. This can be repeated multiple times.
  • the ratio in days between the dosing period and the drug-free period is 2: (0.1-2), preferably 2:0.2-1.5, more preferably 2:0.4-1, even more preferably 2:0.5-1.
  • any reference to anlotinib refers to the compound of formula I.
  • Anlotinib may be administered in its free base form, as well as in the form of its salts, hydrates, and prodrugs that are converted in vivo to the free base form of anlotinib.
  • pharmaceutically acceptable salts of anlotinib within the scope of the present application can be produced from different organic and inorganic acids according to methods well known in the art.
  • 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 with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, etc.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
  • organic acids such as acetic acid, trifluoroacetic acid, propionic acid, etc.
  • 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, benzene Acid addition salts formed from sulfonic acid, p-chlorobenzenesulfonic acid, p-toluenesulfonic acid, 3-phenylpropionic acid, trimethylacetic acid, salicylic acid, etc.
  • anlotinib is administered as free base. In some embodiments, anlotinib is administered as the free base anhydrous form. In some embodiments, anlotinib is administered as free base monohydrate. In some embodiments, anlotinib hydrochloride is administered. In some embodiments, anlotinib monohydrochloride is administered. In some embodiments, anlotinib is administered as anlotinib dihydrochloride. In some embodiments, the crystalline form of anlotinib hydrochloride is administered. In specific embodiments, the crystalline form of anlotinib dihydrochloride is administered.
  • Unit dosage means a pharmaceutical composition packaged in a single package for convenience of administration, for example, "unit dosage form of a pharmaceutical composition” means each capsule. “The pharmaceutical composition in unit dosage form contains 100 mg of anlotinib” means that each final capsule contains 100 mg of anlotinib.
  • Patient or “subject” refers to a mammal, preferably a human.
  • Treatment means any administration of a therapeutically effective amount of a compound, and includes:
  • inclusion compound refers to a non-chemically bonded inclusion body formed by the structure of a drug molecule (guest molecule) being fully or partially included in the hole structure of another substance (host molecule) molecule.
  • inclusion compound refers to a solid or liquid based on an inclusion compound formed by enclosing anlotinib as the main drug ingredient in the hole structure of cyclodextrin molecules. According to the main molecular cavity geometry, inclusion complexes are divided into tubular, cage, and layered inclusion complexes.
  • “Lubricants” include but are not limited to substances used to reduce the friction between raw materials, excipients and equipment during the pharmaceutical preparation process, substances used as anti-sticking agents to prevent raw materials, excipients from adhering to the surface of equipment, and substances used as flow aids. A substance that reduces the friction between raw materials and auxiliary materials to improve the fluidity of powder.
  • X50 refers to the particle size with a particle size distribution of 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 distribution of 90% Particle size, that is, the volume content of particles smaller than this size accounts for 90% of all particles.
  • the instrument and its model HELOS-OASIS or a laser particle size analyzer with equivalent performance, HELOS-RODOS/T4.1.
  • Inclusion rate (%) content of the main drug ingredient after filtration/main ingredient before filtration. Medicinal ingredient content *100%.
  • the particle size distribution of the solid inclusion compound 1 prepared is: X50: 6.8 ⁇ m; X90: 15.7 ⁇ m.
  • HPC-SL hydroxypropylcellulose
  • the drug suspension is fluidized on the sucrose blank pill core to apply the drug to obtain drug-containing pellets.
  • the intermediate is filled into capsules to produce pellet capsules, or compressed to produce tablets.
  • the intermediate is filled into capsules or compressed to produce tablets.
  • the intermediate is filled into capsules or compressed to produce tablets.
  • the intermediate is filled into capsules or compressed to produce tablets.
  • a randomized, open-label, single-cycle, parallel fasting bioequivalence trial was carried out on 16 subjects, divided into 2 groups, with 8 people in each group.
  • the reference preparation was commercially available anlotinib hydrochloride capsules with a specification of 8 mg.
  • the test preparation is a capsule (4 mg, 2 capsules) containing anlotinib cyclodextrin inclusion complex prepared according to the inclusion complex 1 of Example 1 and prepared through the prescription 1 of Example 2.
  • Biological sample analysis Use a partially validated LC-MS/MS method to determine the concentration of anlotinib in plasma samples using EDTA-K2 as the anticoagulant, and calculate the relevant parameters C max , AUC 0-t , and C 24h .
  • Plasma sample collection time points 0h before dosing (within 60min) and 1, 2, 4, 5, 6, 8, 10, 12, 24, 48, 72, 120, 168, 336, 504, and 648h after dosing. Venous blood was collected at 17 time points.
  • a randomized, open, single-center, parallel fasting bioequivalence trial was conducted on 12 subjects, divided into 2 groups, with 6 people in each group.
  • the reference preparation was commercially available anlotinib hydrochloride capsules of 8 mg.
  • the test preparation was a tablet (8 mg, 1 tablet) containing anlotinib cyclodextrin inclusion complex prepared according to Example 8.
  • Biological sample analysis The partially validated LC-MS/MS method was used to determine the concentration of anlotinib in plasma samples using heparin sodium as the anticoagulant, and the relevant parameters Cmax, AUC 0-t , and C 24h were calculated.
  • Plasma sample collection time points 0h before dosing (within 60min) and 1, 2, 4, 5, 6, 8, 10, 12, 24, 48, 72, 120, 168, 336, 504, and 648h after dosing. Venous blood was collected at 17 time points.
  • Average relative bioavailability average relative bioavailability across all subjects.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Inorganic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种安罗替尼环糊精包合物、制备方法，以及包含安罗替尼环糊精包合物的药物组合物、制备方法。安罗替尼环糊精包合物及其制成的药物组合物可以有效降低个体吸收差异的变异率，降低个体生物利用度的变异率，有利于提高用药安全、降低用药维护成本。

Description

喹啉衍生物或其盐环糊精包合物
相关申请的交叉引用
本申请要求于2022年06月29日向中国国家知识产权局提交的、申请号为202210755401.2的中国专利申请的优先权和权益，其内容通过引用整体并入本文中。
技术领域
本申请属于药物制剂领域，本申请涉及喹啉衍生物或其盐环糊精包合物，及包含喹啉衍生物或其盐包合物的药物组合物，具体而言，本申请涉及一种安罗替尼环糊精包合物、制备方法，以及包含安罗替尼环糊精包合物的药物组合物、制备方法。
背景技术
国际专利申请WO2008112407在实施例24中公开了化合物1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺及其制备方法，它的结构式如式Ⅰ所示：
2018年5月，以式I化合物为主药成分的一类新药安罗替尼成功在中国上市，为中国首个获批的晚期非小细胞肺癌三线治疗药物。它是一个多靶点的受体酪氨酸激酶抑制剂，能抑制血管内皮细胞生长因子受体(VEGFR1、VEGFR2/KDR和VEGFR3)、干细胞因子受体、血小板源生长因子受体等激酶活性，抑制VEGFR2介导的下游信号转导，从而抑制肿瘤新生血管生成。
盐酸安罗替尼表现出良好的抗肿瘤活性；在动物体内、人群体内的生物利用度均较好，主要分布于代谢排泄系统和内分泌系统，代谢广泛，主要通过粪便排泄；主要毒性反应于牙齿、肾脏、肝胆系统、血液系统等。盐酸安罗替尼在临床抗肿瘤治疗中展现了良好且广泛的治疗前景。
环糊精(cyclodextrins，简称CD)是酶改性的淀粉衍生物，由与α-1,4糖苷键连接的葡萄 糖单元组成的环状低聚糖，通常含有6～12个D-吡喃葡萄糖单元结构。其中研究得较多并且具有重要实际意义的是分别含有6、7、8个葡萄糖单元的分子，分别称为α-环糊精、β-环糊精和γ-环糊精，另外，人们通过对环糊精的结构修饰来改善其理化性质，达到如增加水溶性、形成新的手性位点、构筑超分子聚集体等目的。
本发明的目的在于寻找一种个体吸收差异小的、更安全、有效地适于患者临床使用的包含安罗替尼的药物组合物。
发明概况
针对市售的盐酸安罗替尼胶囊的药代动力学数据显示存在个体吸收差异的问题，具体来说，肿瘤患者和健康人群对于服用盐酸安罗替尼胶囊后平均最大血药浓度(Cmax)和平均药时曲线下面积(AUC0-t)个体吸收差异显著，变异率高。
以及，针对市售的安罗替尼胶囊连续给药后血药浓度蓄积引发不良反应导致患者被迫停药等问题，具体来说，由于安罗替尼在人体内消除半衰期长，采用连续给药后，其血药浓度随给药次数的增加而增加。
因此：
第一方面，本申请提供了一种安罗替尼环糊精包合物。
第二方面，本申请提供了一种包含安罗替尼环糊精包合物的药物组合物。
第三方面，本申请提供了一种安罗替尼环糊精包合物的制备方法，及包含安罗替尼环糊精包合物的药物组合物的制备方法。
第四方面，本申请提供了一种安罗替尼环糊精包合物及包含安罗替尼环糊精包合物的药物组合物在制备用于治疗癌症的药物中的用途。
第五方面，本申请提供了一种安罗替尼环糊精包合物及包含安罗替尼环糊精包合物的药物组合物在治疗癌症中的方法。
发明内容
第一方面，本申请提供了一种安罗替尼环糊精包合物，其含有：(a)安罗替尼作为主药成分；(b)环糊精；所述的安罗替尼作为主药成分包括但不限于安罗替尼或其药学上可接受的盐和/或其水合物。
在一些实施方案中，本申请提供了一种用于制备口服药物制剂的安罗替尼环糊精包合物，其含有：(a)安罗替尼作为主药成分；(b)环糊精；所述的安罗替尼作为主药成分包括但不限于安罗替尼或其药学上可接受的盐和/或其水合物。
在一些实施方案中，本申请提供了一种安罗替尼环糊精包合物，其含有：
(a)1-3份的安罗替尼作为主药成分；
(b)12-45份环糊精；
其中所有的份数以重量计，所述的安罗替尼作为主药成分包括但不限于安罗替尼或其药学上可接受的盐和/或其水合物。
在一些实施方案中，所述的环糊精选自α-环糊精、β-环糊精、γ-环糊精、羟乙基-β-环糊精、羟丙基-β-环糊精及甲基-β-环糊精的一种或者多种；在一些实施方案中，所述的环糊精为β-环糊精；在一些实施方案中，所述的环糊精为羟丙基-β-环糊精。
在一些实施方案中，所述的安罗替尼或其药学上可接受的盐和/或其水合物与环糊精的重量比为1:10-1:20；在一些实施方案中，所述的安罗替尼或其药学上可接受的盐和/或其水合物与环糊精的重量比为1:11-1:18；在一些实施方案中，所述的安罗替尼或其药学上可接受的盐和/或其水合物与环糊精的重量比为1:12-1:15。
在一些实施方案中，所述的安罗替尼环糊精包合物进一步含有pH调节剂；在一些实施方案中，所述的安罗替尼环糊精包合物的pH>5；在一些实施方案中，所述的安罗替尼环糊精包合物的pH>6；在一些实施方案中，所述的安罗替尼环糊精包合物的pH>6.5；在一些实施方案中，所述的安罗替尼环糊精包合物的pH>7。
在一些实施方案中，所述的安罗替尼环糊精包合物，其含有：
(a)1.5-2.5份的安罗替尼作为主药成分；
(b)18-38份环糊精；
其中所有的份数以重量计，所述的安罗替尼作为主药成分包括但不限于安罗替尼或其药学上可接受的盐和/或其水合物。
在一些实施方案中，所述的安罗替尼环糊精包合物，其含有：
(a)2-2.4份的安罗替尼作为主药成分；
(b)24-36份环糊精；
其中所有的份数以重量计，所述的安罗替尼作为主药成分包括但不限于安罗替尼或其药学上可接受的盐和/或其水合物。
在一些实施方案中，所述的药物组合物中含有1.5-2.5份的主药成分，所述主药成分为安罗替尼或其药学上可接受的盐和/或其水合物；在一些具体的实施方案中，所述的药物组合物中含有2-2.4份的主药成分；在一些具体的实施方案中，所述的药物组合物中含有2.36份的主药成分。
在一些实施方案中，所述的药物组合物中含有18-38份的环糊精，所述环糊精为β-环糊 精、羟乙基-β-环糊精、羟丙基-β-环糊精及甲基-β-环糊精的一种或者多种；在一些具体的实施方案中，所述的药物组合物中含有24-36份的环糊精，所述环糊精为β-环糊精、羟乙基-β-环糊精、羟丙基-β-环糊精及甲基-β-环糊精的一种或者多种；在一些具体的实施方案中，所述的药物组合物中含有28.32-35.4份的环糊精，所述环糊精为β-环糊精、羟乙基-β-环糊精、羟丙基-β-环糊精及甲基-β-环糊精的一种或者多种。
在一些实施方案中，所述的安罗替尼环糊精包合物以液体的方式呈现。在一些实施方案中，所述的安罗替尼环糊精包合物以固体的方式呈现。
在一些实施方案中，所述的安罗替尼环糊精包合物进一步含有pH调节剂；在一些实施方案中，所述的安罗替尼环糊精包合物的pH>5；在一些实施方案中，所述的安罗替尼环糊精包合物的pH>6；在一些实施方案中，所述的安罗替尼环糊精包合物的pH>6.5；在一些实施方案中，所述的安罗替尼环糊精包合物的pH>7。
在一些实施方案中，所述的安罗替尼环糊精包合物液体可以进一步干燥得到环糊精包合物固体；在一些实施方案中，所述的安罗替尼环糊精包合物液体可以直接用于制备包含安罗替尼环糊精包合物的药物组合物。
在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足1μm≤X50≤15μm，5μm≤X90≤30μm。
在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足2μm≤X50≤12μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足3μm≤X50≤10μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足4μm≤X50≤8μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足6μm≤X90≤25μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足8μm≤X90≤22μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足10μm≤X90≤20μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足2μm≤X50≤12μm，6μm≤X90≤25μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足3μm≤X50≤10μm，8μm≤X90≤22μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足4μm≤X50≤8μm，10μm≤X90≤20μm。
在一些实施方案中，所述的包合物的包合率达到80％以上；在一些实施方案中，所述的包合物的包合率达到85％以上；在一些实施方案中，所述的包合物的包合率达到90％以上；在一些实施方案中，所述的包合物的包合率达到95％以上。
第二方面，本申请提供了一种包含安罗替尼环糊精包合物的药物组合物，其含有：(i)安罗替尼环糊精包合物；(ii)填充剂；(iii)崩解剂；(iv)润滑剂；(v)视需要的其它药用 的辅料，其中，包含安罗替尼环糊精包合物含有(a)安罗替尼作为主药成分；(b)环糊精。
在一些实施方案中，本申请提供了一种包含安罗替尼环糊精包合物的口服的固体药物组合物，其含有：(i)安罗替尼环糊精包合物；(ii)填充剂；(iii)崩解剂；(iv)润滑剂；(v)视需要的其它药用的辅料，其中，包含安罗替尼环糊精包合物含有(a)安罗替尼作为主药成分；(b)环糊精。
在一些实施方案中，本申请提供了一种包含安罗替尼环糊精包合物的药物组合物，其含有：
(i)13-48份的安罗替尼环糊精包合物；
(ii)40-120份的填充剂；
(iii)2-16份的崩解剂；
(iv)0.1-12份的润滑剂；
其中，安罗替尼环糊精包合物，其含有：
(a)1-3份的安罗替尼作为主药成分；
(b)12-45份环糊精；
其中所有的份数以重量计，所述的安罗替尼作为主药成分包括但不限于安罗替尼或其药学上可接受的盐和/或其水合物。
在一些实施方案中，所述的填充剂选自乳糖、微晶纤维素、预胶化淀粉、玉米淀粉、甘露醇、无水磷酸氢钙、蔗糖的一种或多种；在一些实施方案中，所述的填充剂为乳糖、微晶纤维素、甘露醇、蔗糖的一种或多种；在一些实施方案中，所述的填充剂为乳糖和/或微晶纤维素；在一些实施方案中，所述的填充剂为甘露醇和/或微晶纤维素；在一些实施方案中，所述的填充剂为甘露醇；在一些实施方案中，所述的填充剂为蔗糖；在一些实施方案中，所述的填充剂为蔗糖糖粉或蔗糖丸芯；在一些实施方案中，所述的填充剂为蔗糖丸芯。
在一些实施方案中，所述的崩解剂选自交联聚维酮、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、羟丙基纤维素、羟丙基甲基纤维素、羟乙基甲基纤维素、羟乙基纤维素、羟丁基甲基纤维素、乙基甲基纤维素、乙基羟乙基纤维素和甲基纤维素中一种或多种；在一些实施方案中，所述的崩解剂为羟丙基纤维素、交联聚维酮、羧甲基淀粉钠、交联羧甲基纤维素钠中一种或多种；在一些实施方案中，所述的崩解剂为SSL型号的羟丙基纤维素、SL型号的羟丙基纤维素、L型号的羟丙基纤维素的一种或多种；在一些实施方案中，所述的崩解剂为低取代羟丙基纤维素；在一些实施方案中，所述的崩解剂为低取代羟丙基纤维素和/或交联聚维酮；在一些实施方案中，所述的崩解剂为羧甲基淀粉钠和/或交联羧甲基纤维素钠。
在一些实施方案中，所述的润滑剂选自硬脂酸镁、硬脂酸、微粉硅胶、胶态二氧化硅、山嵛酸甘油酯、滑石粉、硬脂富马酸钠、十二烷基硫酸钠、聚乙二醇4000、聚乙二醇6000、氢化蓖麻油的一种或多种。在一些实施方案中，所述的润滑剂为硬脂酸镁；在一些实施方案中，所述的润滑剂为滑石粉。
在一些实施方案中，所述的环糊精选自α-环糊精、β-环糊精、γ-环糊精、羟乙基-β-环糊精、羟丙基-β-环糊精及甲基-β-环糊精的一种或者多种；在一些实施方案中，所述的环糊精为β-环糊精；在一些实施方案中，所述的环糊精为羟丙基-β-环糊精。
在一些实施方案中，所述的安罗替尼或其药学上可接受的盐和/或其水合物与环糊精的重量比为1:10-1:20；在一些实施方案中，所述的安罗替尼或其药学上可接受的盐和/或其水合物与环糊精的重量比为1:11-1:18；在一些实施方案中，所述的安罗替尼或其药学上可接受的盐和/或其水合物与环糊精的重量比为1:12-1:15。
根据药物剂型、处方工艺的不同，视需要地在上述包含安罗替尼环糊精包合物的药物组合物中进一步加入其他药用辅料，包括但不限于粘合剂、矫味剂、着色剂的一种或多种。在一些实施方案中，在上述包含安罗替尼环糊精包合物的药物组合物中进一步加入(v)1-5份的粘合剂，其份数以重量计。在一些实施方案中，所述的粘合剂选自羟丙甲纤维素、羟丙基纤维素、聚维酮、淀粉浆、羧甲基纤维素钠的一种或多种；在一些实施方案中，所述的粘合剂为羟丙甲纤维素；在一些实施方案中，所述的粘合剂为羟丙甲纤维素E5。
在一些实施方案中，所述的药物组合物，其含有：
(i)20-45份的安罗替尼环糊精包合物；
(ii)45-115份的填充剂；
(iii)3-15份的崩解剂；
(iv)0.2-11份的润滑剂；其中所有的份数以重量计。
在一些实施方案中，所述的药物组合物，其含有：
(i)25-40份的安罗替尼环糊精包合物；
(ii)50-105份的填充剂；
(iii)4-13份的崩解剂；
(iv)0.5-10份的润滑剂；其中所有的份数以重量计。
在一些实施方案中，所述的药物组合物中，含有45-115份的填充剂，所述的填充剂选自乳糖、微晶纤维素、甘露醇、蔗糖的一种或多种；在一些具体的实施方案中，所述的药物组合物中含有50-105份的填充剂；在一些具体的实施方案中，所述的药物组合物中含有55-100份的填充剂。
在一些实施方案中，所述的药物组合物中，含有3-15份的崩解剂，所述的崩解剂选自交联聚维酮、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、羟丙基纤维素、羟丙基甲基纤维素、羟乙基甲基纤维素、羟乙基纤维素、羟丁基甲基纤维素、乙基甲基纤维素、乙基羟乙基纤维素和甲基纤维素中一种或多种；在一些具体的实施方案中，所述的药物组合物中含有4-13份的崩解剂。
在一些实施方案中，所述的药物组合物中，含有0.2-11份的润滑剂，所述的润滑剂为硬脂酸镁、硬脂酸、微粉硅胶、胶态二氧化硅、山嵛酸甘油酯、滑石粉、硬脂富马酸钠、十二烷基硫酸钠、聚乙二醇4000、聚乙二醇6000、氢化蓖麻油的一种或多种；在一些具体的实施方案中，所述的药物组合物中含有0.5-10份的润滑剂。
在一些实施方案中，所述的药物组合物中，含有2-4份的粘合剂，所述的粘合剂选自羟丙甲纤维素、羟丙基纤维素、聚维酮、淀粉浆、羧甲基纤维素钠的一种或多种；在一些实施方案中，所述的粘合剂为羟丙基甲基纤维素。
在本申请的一些实施方案中，所述的药物组合物包含：
(i)13-48份的安罗替尼环糊精包合物；
(ii)40-120份的甘露醇；
(iii)2-16份的羟丙基纤维素；
(iv)0.1-3份的硬脂酸镁；其中所有的份数以重量计。
在本申请的一些实施方案中，所述的药物组合物包含：
(i)20-45份的安罗替尼环糊精包合物；
(ii)50-100份的甘露醇；
(iii)3-12份的羟丙基纤维素；
(iv)0.5-2份的硬脂酸镁；其中所有的份数以重量计。
在本申请的一些实施方案中，所述的药物组合物包含：
(i)13-48份的安罗替尼环糊精包合物；
(ii)40-120份的甘露醇；
(iii)2-16份的交联聚维酮；
(iv)0.1-3份的硬脂酸；其中所有的份数以重量计。
在本申请的一些实施方案中，所述的药物组合物包含：
(i)20-45份的安罗替尼环糊精包合物；
(ii)50-100份的甘露醇；
(iii)3-12份的交联聚维酮；
(iv)0.5-2份的硬脂酸；其中所有的份数以重量计。
在本申请的一些实施方案中，所述的药物组合物包含：
(i)13-48份的安罗替尼环糊精包合物；
(ii)40-120份的蔗糖；
(iii)2-16份的羟丙基纤维素；
(iv)3-12份的滑石粉；其中所有的份数以重量计。
在本申请的一些实施方案中，所述的药物组合物包含：
(i)20-45份的安罗替尼环糊精包合物；
(ii)50-110份的蔗糖丸芯；
(iii)3-12份的羟丙基纤维素；
(iv)5-11份的滑石粉；其中所有的份数以重量计。
在本申请的一些实施方案中，所述的药物组合物包含：
(i)13-48份的安罗替尼环糊精包合物；
(ii)40-120份的乳糖和/或微晶纤维素；
(iii)2-16份的交联聚维酮和/或羟丙基纤维素；
(iv)0.1-3份的硬脂酸镁；其中所有的份数以重量计。
在本申请的一些实施方案中，所述的药物组合物包含：
(i)20-45份的安罗替尼环糊精包合物；
(ii)50-100份的乳糖和/或微晶纤维素；
(iii)3-12份的交联聚维酮和/或羟丙基纤维素；
(iv)0.5-2份的硬脂酸镁；其中所有的份数以重量计。
在本申请的一些实施方案中，所述的药物组合物包含：
(i)13-48份的安罗替尼环糊精包合物；
(ii)40-120份的乳糖和/或微晶纤维素；
(iii)2-16份的交联羧甲基纤维素钠和/或羧甲基淀粉钠；
(iv)0.1-3份的硬脂酸镁；
(v)1-5份的羟丙基甲基纤维素；其中所有的份数以重量计。
在本申请的一些实施方案中，所述的药物组合物包含：
(i)20-45份的安罗替尼环糊精包合物；
(ii)50-100份的乳糖和/或微晶纤维素；
(iii)3-12份的交联羧甲基纤维素钠和/或羧甲基淀粉钠；
(iv)0.5-2份的硬脂酸镁；
(v)2-4份的羟丙基甲基纤维素；其中所有的份数以重量计。
在一些实施方案中，所述的药物组合物中含有1.5-2.5份的主药成分，所述主药成分为安罗替尼或其药学上可接受的盐和/或其水合物；在一些具体的实施方案中，所述的药物组合物中含有2-2.4份的主药成分；在一些具体的实施方案中，所述的药物组合物中含有2.36份的主药成分。
在一些实施方案中，所述的药物组合物中含有18-38份的环糊精，所述环糊精为β-环糊精、羟乙基-β-环糊精、羟丙基-β-环糊精及甲基-β-环糊精的一种或者多种；在一些具体的实施方案中，所述的药物组合物中含有24-36份的环糊精，所述环糊精为β-环糊精、羟乙基-β-环糊精、羟丙基-β-环糊精及甲基-β-环糊精的一种或者多种；在一些具体的实施方案中，所述的药物组合物中含有28.32-35.4份的环糊精，所述环糊精为β-环糊精、羟乙基-β-环糊精、羟丙基-β-环糊精及甲基-β-环糊精的一种或者多种。
在一些实施方案中，所述的安罗替尼环糊精包合物以液体的方式呈现。在一些实施方案中，所述的安罗替尼环糊精包合物以固体的方式呈现。在一些实施方案中，所述的安罗替尼环糊精包合物液体的pH＞5。
在一些实施方案中，所述的安罗替尼环糊精包合物液体可以进一步干燥得到环糊精包合物固体；在一些实施方案中，所述的安罗替尼环糊精包合物液体可以直接用于制备包含安罗替尼环糊精包合物的药物组合物。
在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足1μm≤X50≤15μm，5μm≤X90≤30μm。
在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足2μm≤X50≤12μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足3μm≤X50≤10μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足4μm≤X50≤8μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足6μm≤X90≤25μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足8μm≤X90≤22μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足10μm≤X90≤20μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足2μm≤X50≤12μm，6μm≤X90≤25μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足3μm≤X50≤10μm，8μm≤X90≤22μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足4μm≤X50≤8μm，10μm≤X90≤20μm。
在一些实施方案中，所述的包合物的包合率达到80％以上；在一些实施方案中，所述的 包合物的包合率达到85％以上；在一些实施方案中，所述的包合物的包合率达到90％以上；在一些实施方案中，所述的包合物的包合率达到95％以上。
在一些实施方案中，所述药物组合物是固体制剂，包括片剂、胶囊剂、粉剂、颗粒剂、滴丸、糊剂、散剂等，优选片剂和胶囊剂；在一些实施方案中，片剂为包衣片剂。
在一些实施方案中，所述药物组合物是液体制剂，包括溶液剂、混悬剂、乳剂、注射剂、输液剂、植入剂。
本申请提供的含有的安罗替尼或其药学上可接受的盐和/或其水合物作为活性成分的药物组合物，每日剂量足以提供所需的治疗效果。在一些实施方案中，所述的药物组合物包含2毫克至20毫克的安罗替尼或其药学上可接受的盐和/或其水合物；在一些实施方案中，所述的药物组合物包含4毫克至18毫克的安罗替尼或其药学上可接受的盐和/或其水合物；在一些实施方案中，所述的药物组合物包含6毫克至16毫克的安罗替尼或其药学上可接受的盐和/或其水合物；在一些实施方案中，所述的药物组合物包含8毫克至14毫克的安罗替尼或其药学上可接受的盐和/或其水合物；在一些实施方案中，所述的药物组合物包含2毫克、3毫克、4毫克、5毫克、6毫克、7毫克、8毫克、9毫克、10毫克、11毫克、12毫克、13毫克、14毫克、15毫克、16毫克、17毫克、18毫克、19毫克、20毫克的安罗替尼或其药学上可接受的盐和/或其水合物。
在一些实施方案中，所述药物组合物配制成单位剂量形式的药物组合物。在一些实施方案中，所述的单位剂量形式的药物组合物含有2毫克至20毫克的安罗替尼或其药学上可接受的盐和/或其水合物；在一些实施方案中，所述的单位剂量形式的药物组合物含有4毫克至18毫克的安罗替尼或其药学上可接受的盐和/或其水合物；在一些实施方案中，所述的单位剂量形式的药物组合物含有6毫克至16毫克的安罗替尼或其药学上可接受的盐和/或其水合物；在一些实施方案中，所述的单位剂量形式的药物组合物含有8毫克至14毫克的安罗替尼或其药学上可接受的盐和/或其水合物；在一些特定的实施方案中，该单位剂量形式的药物组合物含有2毫克、3毫克、4毫克、5毫克、6毫克、7毫克、8毫克、9毫克、10毫克、11毫克、12毫克、13毫克、14毫克、15毫克、16毫克、17毫克、18毫克、19毫克、20毫克的安罗替尼或其药学上可接受的盐和/或其水合物。
在一些具体实施方案中，所述的单位剂量形式的药物组合物含4mg的安罗替尼或其药学上可接受的盐和/或其水合物的胶囊；在一些具体实施方案中，所述的单位剂量形式的药物组合物含6mg的安罗替尼或其药学上可接受的盐和/或其水合物的胶囊；在一些具体实施方案中，所述的单位剂量形式的药物组合物含8mg的安罗替尼或其药学上可接受的盐和/或其水合物的胶囊；在一些具体实施方案中，所述的单位剂量形式的药物组合物含10mg的安罗替尼或 其药学上可接受的盐和/或其水合物的胶囊。在一些具体实施方案中，所述的单位剂量形式的药物组合物含12mg的安罗替尼或其药学上可接受的盐和/或其水合物的胶囊。
在一些具体实施方案中，所述的单位剂量形式的药物组合物含4mg的安罗替尼或其药学上可接受的盐和/或其水合物的片剂；在一些具体实施方案中，所述的单位剂量形式的药物组合物含6mg的安罗替尼或其药学上可接受的盐和/或其水合物的片剂；在一些具体实施方案中，所述的单位剂量形式的药物组合物含8mg的安罗替尼或其药学上可接受的盐和/或其水合物的片剂；在一些具体实施方案中，所述的单位剂量形式的药物组合物含10mg的安罗替尼或其药学上可接受的盐和/或其水合物的片剂。在一些具体实施方案中，所述的单位剂量形式的药物组合物含12mg的安罗替尼或其药学上可接受的盐和/或其水合物的片剂。
个体差异是指药物反应的个体差异，是存在于正常和患病的人体中的一种普通的生物现象，如给予常用剂量时，多数人可产生预期的效用，但某些人却无效，甚至出现毒性反应，这种因人而异的反应即为个体差异。药物个体差异主要是与药物代谢及药效动力学的个体差异有关，而造成这一差异的因素很多。例如，不同患者的胃肠道环境的差异、患者的遗传因素、器官功能差异、其他疾病的影响都有可能造成个体差异。其中对药物特别敏感的称高敏性，反之称耐受性。由于药物作用个体差异的存在，所以在临床用药，有时需要根据患者情况，选择适当剂量，注意剂量个体化的原则。
药物作用的个体差异主要体现在是药代动力学方面，即相同剂量的药物在不同个体内由于吸收、分布、代谢和排泄等过程不同而在血浆内和作用部位产生不同的活性药物浓度。个体之间的这种差异可以很大，例如抗抑郁药去甲替林在口服25mg一天3次后，在不同个体所产生的血浆去甲替林的浓度相差30余倍。应用普萘洛尔每日3次，每次10mg、20mg、40mg、80mg后产生的血浆药物浓度，不同个体的普萘洛尔血浆药物浓度差异可大到7倍。而且，不同剂量产生的血浆药物浓度在一定范围内出现重叠，即某些个体用较小剂量可获得另一些个体较大剂量产生的血浆药物浓度。
药物作用的个体差异也可以表现在药效动力学方面，即相同的药物血浆浓度或作用部位浓度在不同个体产生不同的药物效应。药效动力学个体差异具体可表现在药物在不同个体产生同一效应的剂量不一，也可表现在同一剂量在不同个体产生反应的时间不同。
因此，在确定治疗方案时，必须考虑个体间和个体内的药代动力学差异，某些药物在不同个体的这种差异很大，甚至导致剂量成倍改变，导致用药安全问题。药物代谢的个体差异大小在很大程度上取决于药物的药代动力学特征，特别是药物的消除途径。主要经肾脏以原形药排泄的药物，在肾功能正常的个体间，差异比以肝代谢而灭活的药物小。在体内主要经代谢消除的药物和有很高的首过效应的药物，生物利用度的个体差异大。生物转化较慢的药 物，个体差异主要表现在清除率方面。在这些情况下，对药物进行血浆浓度监测有助于药物治疗个体化。由于老年和肝肾疾病也能影响诸如大脑等靶器官的反应性，在进行治疗药物浓度监测时，尤其要注意这类患者的药物有效浓度范围可能改变。
市售的盐酸安罗替尼胶囊的药代动力学数据显示存在个体吸收差异的问题，具体表现在，肿瘤患者和健康人群对于服用盐酸安罗替尼胶囊后平均最大血药浓度(Cmax)和平均药时曲线下面积(AUC0-t)个体吸收差异显著，变异率达到50％左右。在临床中，主要药代动参数的个体差异较大者(RSD＞50％)，提示必要时需作剂量调整或进行血药浓度监测。
本申请提供的包含安罗替尼环糊精包合物及其制成的药物组合物，出乎意料地可以有效降低个体吸收差异的变异率，可以降低个体生物利用度的变异率至14.2％-27.7％，下降了42％甚至更多。对于胃肠道疾病、肝损伤、肾功能不全等患者的个体吸收差异的变异率降低更多。这有利于提高用药安全、降低用药维护成本，惠及更多患者。
另外，根据药代动力学研究，安罗替尼在人体内消除半衰期长，采用连续给药安罗替尼后，其血药浓度随给药次数的增加而增加，也就是说，盐酸安罗替尼胶囊在连续用药情况下，患者体内药物存在蓄积，同时发生的不良反应更多。
目前，市售安罗替尼用于治疗癌症已经有较高的生物利用度，本申请提供的包含安罗替尼环糊精包合物及其制成的药物组合物，能够在维持基本等效的生物利用度(相对AUC达到88.4％)的情况下，同时控制血药浓度Cmax的有效降低26％，单次给药后24h的血药浓度平均值更低。因而，本申请的药物组合物可以维持药物口服生物利用度的同时降低药品在人体的血药浓度，以获得患者依从性更好、更合理的给药剂量和给药方案。例如，在给药剂量、频次不变的情况下，不良反应症状、频次、发生情况有所缓解，具体来说，例如发生出血、高血压等不良反应的患者人数减少、症状减轻。
进一步地，为了更好地控制药物的耐受性，需要控制药物在体内的浓度，目前市售的盐酸安罗替尼胶囊采用连续用药2周，停药1周为一个治疗周期(“连二停一”)的给药方式。连二停一的给药方式下患者体内安罗替尼血药浓度在给药第14天后达到峰值。在后续两个周期的观察中，10及12mg/人天给药剂量下，安罗替尼的血药浓度基本都控制在100ng/mL以下。本申请提供的安罗替尼环糊精包合物及其制成的药物组合物可以提供更大的给药剂量，或是长期连续给药耐受更大的剂量，改善患者依从性。
第三方面，本申请提供了一种安罗替尼环糊精包合物的制备方法，其特征在于，将安罗替尼作为主药成分和环糊精，分别或先后加入适量的溶剂，混合后得到安罗替尼环糊精包合物液体；在一些实施方案中，所述液体经过干燥制备得到安罗替尼环糊精包合物固体。
本申请还提供了一种包含安罗替尼环糊精包合物的药物组合物的制备方法，其特征在于， 将安罗替尼环糊精包合物加入其它药用的辅料，制备得到药物组合物。其中药用的辅料包括但不限于填充剂、崩解剂、润滑剂、粘合剂、矫味剂的一种或多种。
在一些实施方案中，在所述主药成分和环糊精中，分别或先后加入适量的溶剂，以制备安罗替尼环糊精包合物液体。在一些实施方案中，在所述安罗替尼环糊精包合物中加入其它药用的辅料，视需要分别或先后加入适量的溶剂，以制备包含安罗替尼环糊精包合物的药物组合物。
本申请提供了一种安罗替尼环糊精包合物的制备方法，其特征在于，该方法包括以下步骤：
a：将安罗替尼或其药学上可接受的盐和/或其水合物、环糊精，分别或先后加入到溶剂中，搅拌溶解澄清，视需要，加入pH调节剂调节溶液pH＞5，得到包合物液体；
b：可选地，将包合物液体干燥得到包合物固体。
在一些实施方案中，所述的环糊精选自α-环糊精、β-环糊精、γ-环糊精、羟乙基-β-环糊精、羟丙基-β-环糊精及甲基-β-环糊精的一种或者多种；在一些实施方案中，所述的环糊精为β-环糊精；在一些实施方案中，所述的环糊精为羟丙基-β-环糊精。
在一些实施方案中，所述的步骤a中，加入安罗替尼或其药学上可接受的盐和/或其水合物1.5-2.5份；在一些实施方案中，所述的步骤a中，加入安罗替尼或其药学上可接受的盐和/或其水合物2-2.4份；在一些实施方案中，所述的步骤a中，加入安罗替尼或其药学上可接受的盐和/或其水合物2.36份。
在一些实施方案中，所述的步骤a中，加入环糊精18-38份，所述环糊精为β-环糊精、羟乙基-β-环糊精、羟丙基-β-环糊精及甲基-β-环糊精的一种或者多种；在一些实施方案中，所述的步骤a中，加入环糊精24-36份，所述环糊精为β-环糊精、羟乙基-β-环糊精、羟丙基-β-环糊精及甲基-β-环糊精的一种或者多种；在一些实施方案中，所述的步骤a中，加入环糊精28.32-35.4份，所述环糊精为β-环糊精、羟乙基-β-环糊精、羟丙基-β-环糊精及甲基-β-环糊精的一种或者多种。
在一些实施方案中，所述的安罗替尼或其药学上可接受的盐和/或其水合物与环糊精的重量比为1:10-1:20；在一些实施方案中，所述的安罗替尼或其药学上可接受的盐和/或其水合物与环糊精的重量比为1:11-1:18；在一些实施方案中，所述的安罗替尼或其药学上可接受的盐和/或其水合物与环糊精的重量比为1:12-1:15。
在一些实施方案中，所述的安罗替尼环糊精包合物的pH＞5；在一些实施方案中，所述的安罗替尼环糊精包合物的pH>6；在一些实施方案中，所述的安罗替尼环糊精包合物的pH>6.5；在一些实施方案中，所述的安罗替尼环糊精包合物的pH>7。
在一些实施方案中，所述的步骤a中，主药成分和环糊精分别溶解于适量的溶剂中后混合，或同时溶解于适量的溶剂中，制备得到安罗替尼环糊精包合物液体。
在一些实施方案中，所述的溶剂选自水、加入pH调节剂的溶液的一种。
在一些实施方案中，所述的pH调节剂包括但不限于酸、碱或缓冲盐。
在一些实施方案中，所述的酸包括但不限于与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等形成的酸加成盐；或者与有机酸如乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2乙二磺酸、2羟基乙磺酸、苯磺酸、对氯苯磺酸、对甲苯磺酸、3苯基丙酸、三甲基乙酸、水杨酸。
在一些实施方案中，所述的碱包括但不限于有机碱和无机碱，可列举的实例包括但不限于异丙胺、二异丙胺、二异丙基乙胺、N-甲基吗啉、N-甲基哌啶、N-甲基哌嗪、N-甲基吡啶、吡啶、DBU、DABCO、三乙胺、碱金属(如钠、钾、锂)、碱金属碳酸盐(如碳酸钠、碳酸钾、碳酸铯、碳酸锂)、碱金属碳酸氢盐(如碳酸氢钠、碳酸氢钾、碳酸氢锂、铯碳酸氢盐)、碱金属氢氧化物(如氢氧化钠、氢氧化钙、氢氧化钾)、金属醇盐(如钠、锂、钾的醇盐，叔丁醇钠)、醋酸钠和氢化钠，优选的碱为碳酸钾、碳酸钠、氢氧化钠、醋酸钠、三乙胺、N,N-二异丙基乙胺、吡啶。
在一些实施方案中，所述的缓冲盐制成pH＞5的缓冲液，包括但不限于枸橼酸-磷酸氢二钠缓冲液、氨-氯化铵缓冲液、醋酸-醋酸钠缓冲液、磷酸盐缓冲液。
在一些实施方案中，所述的步骤b中的干燥，包括但不限于喷雾干燥，冷冻干燥、流化干燥，优选为喷雾干燥。
在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足1μm≤X50≤15μm，5μm≤X90≤30μm。
在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足2μm≤X50≤12μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足3μm≤X50≤10μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足4μm≤X50≤8μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足6μm≤X90≤25μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足8μm≤X90≤22μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足10μm≤X90≤20μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足2μm≤X50≤12μm，6μm≤X90≤25μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足3μm≤X50≤10μm，8μm≤X90≤22μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体 的粒径分布满足4μm≤X50≤8μm，10μm≤X90≤20μm。
在一些实施方案中，所述的包合物的包合率达到80％以上；在一些实施方案中，所述的包合物的包合率达到85％以上；在一些实施方案中，所述的包合物的包合率达到90％以上；在一些实施方案中，所述的包合物的包合率达到95％以上。
本申请还提供了一种包含安罗替尼环糊精包合物的药物组合物的制备方法，其特征在于，该方法包括以下步骤：
A：将安罗替尼环糊精包合物加入填充剂、崩解剂、润滑剂混合，视需要加入其他药用辅料，包括但不限于粘合剂、矫味剂，制成中间体；
B：将中间体制备适用口服的固体制剂。
本申请还提供了一种包含安罗替尼环糊精包合物的药物组合物的制备方法，其特征在于，该方法包括以下步骤：
a：将安罗替尼或其药学上可接受的盐和/或其水合物、环糊精，分别或先后加入到溶剂中，搅拌溶解澄清，视需要，加入pH调节剂调节溶液pH＞5，得到包合物液体；
b：将包合物液体干燥得到包合物固体；
c：将安罗替尼环糊精包合物加入填充剂、崩解剂、润滑剂混合，视需要加入其他药用辅料，包括但不限于粘合剂、矫味剂，制成中间体；
d：将中间体制备适用口服的固体制剂。
本申请还提供了一种包含安罗替尼环糊精包合物的药物组合物的制备方法，其特征在于，该方法包括以下步骤：
e：将安罗替尼或其药学上可接受的盐和/或其水合物、环糊精，分别或先后加入到溶剂中，搅拌溶解澄清，视需要，加入pH调节剂调节溶液pH＞5，得到包合物液体；
f：将安罗替尼环糊精包合物液体加入填充剂，制成制剂中间体；
g：将制剂中间体加入填充剂、崩解剂、润滑剂混合，视需要加入其他药用辅料，包括但不限于粘合剂、矫味剂，制成适用口服的固体制剂。
在一些实施方案中，所述的安罗替尼环糊精包合物以液体的方式呈现。在一些实施方案中，所述的安罗替尼环糊精包合物以固体的方式呈现。
在一些实施方案中，所述的安罗替尼环糊精包合物液体可以进一步干燥得到环糊精包合物固体；在一些实施方案中，所述的安罗替尼环糊精包合物液体可以直接用于制备包含安罗替尼环糊精包合物的药物组合物。
在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足1μm≤X50≤15μm， 5μm≤X90≤30μm。
在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足2μm≤X50≤12μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足3μm≤X50≤10μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足4μm≤X50≤8μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足6μm≤X90≤25μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足8μm≤X90≤22μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足10μm≤X90≤20μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足2μm≤X50≤12μm，6μm≤X90≤25μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足3μm≤X50≤10μm，8μm≤X90≤22μm。在一些实施方案中，所述的安罗替尼环糊精包合物固体的粒径分布满足4μm≤X50≤8μm，10μm≤X90≤20μm。
在一些实施方案中，所述的包合物的包合率达到80％以上；在一些实施方案中，所述的包合物的包合率达到85％以上；在一些实施方案中，所述的包合物的包合率达到90％以上；在一些实施方案中，所述的包合物的包合率达到95％以上。
在一些实施方案中，所述的步骤A或步骤c或步骤f和g中加入(i)13-48份的安罗替尼环糊精包合物；(ii)40-120份的填充剂；(iii)2-16份的崩解剂；(iv)0.1-12份的润滑剂。在一些实施方案中，所述的步骤A或步骤c或步骤f和g中加入(i)20-45份的安罗替尼环糊精包合物；(ii)45-115份的填充剂；(iii)3-15份的崩解剂；(iv)0.2-11份的润滑剂。在一些实施方案中，所述的步骤A或步骤c或步骤f和g中加入(i)25-40份的安罗替尼环糊精包合物；(ii)50-105份的填充剂；(iii)4-13份的崩解剂；(iv)0.5-10份的润滑剂。
在一些实施方案中，所述的填充剂选自乳糖、微晶纤维素、预胶化淀粉、玉米淀粉、甘露醇、无水磷酸氢钙、蔗糖的一种或多种；在一些实施方案中，所述的填充剂为乳糖、微晶纤维素、甘露醇、蔗糖的一种或多种；在一些实施方案中，所述的填充剂为乳糖和/或微晶纤维素；在一些实施方案中，所述的填充剂为甘露醇和/或微晶纤维素；在一些实施方案中，所述的填充剂为甘露醇；在一些实施方案中，所述的填充剂为蔗糖；在一些实施方案中，所述的填充剂为蔗糖糖粉或蔗糖丸芯；在一些实施方案中，所述的填充剂为蔗糖丸芯。
在一些实施方案中，所述的崩解剂选自交联聚维酮、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、羟丙基纤维素、羟丙基甲基纤维素、羟乙基甲基纤维素、羟乙基纤维素、羟丁基甲基纤维素、乙基甲基纤维素、乙基羟乙基纤维素和甲基纤维素中一种或多种；在一些实施方案中，所述的崩解剂为羟丙基纤维素、交联聚维酮、羧甲基淀粉钠、交联 羧甲基纤维素钠中一种或多种；在一些实施方案中，所述的崩解剂为SSL型号的羟丙基纤维素、SL型号的羟丙基纤维素、L型号的羟丙基纤维素的一种或多种；在一些实施方案中，所述的崩解剂为低取代羟丙基纤维素；在一些实施方案中，所述的崩解剂为低取代羟丙基纤维素和/或交联聚维酮；在一些实施方案中，所述的崩解剂为羧甲基淀粉钠和/或交联羧甲基纤维素钠。
在一些实施方案中，所述的润滑剂选自硬脂酸镁、硬脂酸、微粉硅胶、胶态二氧化硅、山嵛酸甘油酯、滑石粉、硬脂富马酸钠、十二烷基硫酸钠、聚乙二醇4000、聚乙二醇6000、氢化蓖麻油的一种或多种。在一些实施方案中，所述的润滑剂为硬脂酸镁；在一些实施方案中，所述的润滑剂为滑石粉。
根据药物剂型、处方工艺的不同，在一些实施方案中，视需要地在所述的步骤A或步骤c或步骤f和g中加入(v)1-5份的粘合剂，其份数以重量计。在一些实施方案中，所述的粘合剂选自羟丙甲纤维素、羟丙基纤维素、聚维酮、淀粉浆、羧甲基纤维素钠的一种或多种；在一些实施方案中，所述的粘合剂为羟丙甲纤维素；在一些实施方案中，所述的粘合剂为羟丙甲纤维素E5。
在一些实施方案中，所述的步骤A或步骤c或步骤f和g中加入45-115份的填充剂，所述的填充剂选自乳糖、微晶纤维素、甘露醇、蔗糖的一种或多种；在一些具体的实施方案中，所述的步骤A或步骤c或步骤f和g中加入50-105份的填充剂；在一些具体的实施方案中，所述的步骤A或步骤c或步骤f和g中加入55-100份的填充剂。
在一些实施方案中，所述的步骤A或步骤c或步骤g中加入3-15份的崩解剂，所述的崩解剂选自交联聚维酮、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、羟丙基纤维素、羟丙基甲基纤维素、羟乙基甲基纤维素、羟乙基纤维素、羟丁基甲基纤维素、乙基甲基纤维素、乙基羟乙基纤维素和甲基纤维素中一种或多种；在一些具体的实施方案中，所述的步骤A或步骤c或步骤g中加入4-13份的崩解剂。
在一些实施方案中，所述的步骤A或步骤c或步骤g中加入0.2-11份的润滑剂，所述的润滑剂为硬脂酸镁、硬脂酸、微粉硅胶、胶态二氧化硅、山嵛酸甘油酯、滑石粉、硬脂富马酸钠、十二烷基硫酸钠、聚乙二醇4000、聚乙二醇6000、氢化蓖麻油的一种或多种；在一些具体的实施方案中，所述的步骤A或步骤c或步骤g中加入0.5-10份的润滑剂。
在一些实施方案中，所述的步骤A或步骤c或步骤g中加入2-4份的粘合剂，所述的粘合剂选自羟丙甲纤维素、羟丙基纤维素、聚维酮、淀粉浆、羧甲基纤维素钠的一种或多种；在一些实施方案中，所述的粘合剂为羟丙基甲基纤维素。
在本申请的一些实施方案中，所述的步骤A或步骤c或步骤g中加入(i)13-48份的安罗替尼环糊精包合物；(ii)40-120份的甘露醇；(iii)2-16份的羟丙基纤维素；(iv)0.1-3份的硬脂酸镁。
在本申请的一些实施方案中，所述的步骤A或步骤c或步骤g中加入(i)20-45份的安罗替尼环糊精包合物；(ii)50-100份的甘露醇；(iii)3-12份的羟丙基纤维素；(iv)0.5-2份的硬脂酸镁。
在本申请的一些实施方案中，所述的步骤A或步骤c或步骤g中加入(i)13-48份的安罗替尼环糊精包合物；(ii)40-120份的蔗糖；(iii)2-16份的羟丙基纤维素；(iv)3-12份的滑石粉。
在本申请的一些实施方案中，所述的步骤A或步骤c或步骤g中加入(i)20-45份的安罗替尼环糊精包合物；(ii)50-110份的蔗糖丸芯；(iii)3-12份的羟丙基纤维素；(iv)5-11份的滑石粉。
在本申请的一些实施方案中，所述的步骤A或步骤c或步骤g中加入(i)13-48份的安罗替尼环糊精包合物；(ii)40-120份的乳糖和/或微晶纤维素；(iii)2-16份的交联聚维酮和/或羟丙基纤维素；(iv)0.1-3份的硬脂酸镁。
在本申请的一些实施方案中，所述的步骤A或步骤c或步骤g中加入(i)20-45份的安罗替尼环糊精包合物；(ii)50-100份的乳糖和/或微晶纤维素；(iii)3-12份的交联聚维酮和/或羟丙基纤维素；(iv)0.5-2份的硬脂酸镁。
在本申请的一些实施方案中，所述的步骤A或步骤c或步骤g中加入(i)13-48份的安罗替尼环糊精包合物；(ii)40-120份的乳糖和/或微晶纤维素；(iii)2-16份的交联羧甲基纤维素钠和/或羧甲基淀粉钠；(iv)0.1-3份的硬脂酸镁；(v)1-5份的羟丙基甲基纤维素。
在本申请的一些实施方案中，所述的步骤A或步骤c或步骤g中加入(i)20-45份的安罗替尼环糊精包合物；(ii)50-100份的乳糖和/或微晶纤维素；(iii)3-12份的交联羧甲基纤维素钠和/或羧甲基淀粉钠；(iv)0.5-2份的硬脂酸镁；(v)2-4份的羟丙基甲基纤维素。
在本申请的一些实施方案中，所述的步骤A或步骤c或步骤g中加入(i)13-48份的安罗替尼环糊精包合物；(ii)40-120份的甘露醇；(iii)2-16份的交联聚维酮；(iv)0.1-3份的硬脂酸。
在本申请的一些实施方案中，所述的步骤A或步骤c或步骤g中加入(i)20-45份的安罗替尼环糊精包合物；(ii)50-100份的甘露醇；(iii)3-12份的交联聚维酮；(iv)0.5-2份的硬脂酸。
在一些实施方案中，所述的步骤A、步骤c或步骤f控制物料温度范围为20～40℃。在一些实施方案中，所述的步骤A、步骤c或步骤f控制物料温度范围为25～35℃。
在一些实施方案中，所述的固体制剂，包括片剂、胶囊剂、粉剂、颗粒剂、滴丸、糊剂、散剂等，优选片剂和胶囊剂；在一些实施方案中，片剂为包衣片剂。
在一些实施方案中，所述的步骤B或步骤d或步骤g的中间体，经过干法制粒，压片制得片芯或者片剂；在一些实施方案中，所述的步骤B中间体，经过湿法制粒，压片制得片芯或者片剂；在一些实施方案中，所述片芯或者片剂进一步包衣制得包衣片剂。
在一些实施方案中，所述的步骤B或步骤d或步骤g的中间体，填充入胶囊壳中制得胶囊剂。
本申请制备得到的包合物或者含有主药成分的中间体、药物组合物，均具有良好的粉体学性质、流动性、溶出性质，并且安全和稳定，干法制粒的处方工艺连续性好，使得中间产品具有良好的性状，具有一定硬度，以及含量均匀度、颗粒孔隙率的均一性保持良好。
第四方面，本申请提供了一种包含安罗替尼环糊精包合物及其制成的药物组合物在制备用于治疗癌症的药物中的用途。所述的癌症包括但不限非小细胞肺癌、小细胞肺癌甲状腺髓样癌、分化型甲状腺癌、软组织肉瘤、晚期结直肠癌、透明肾细胞癌、晚期胃癌、晚期食管鳞癌、晚期肝癌、神经内分泌瘤、骨原发肿瘤、鼻咽癌等。
第五方面，本申请提供了一种包含安罗替尼环糊精包合物及其制成的药物组合物在治疗癌症中的方法。
包含安罗替尼环糊精包合物及其制成的药物组合物可通过多种途径给药，该途径包括但不限于选自以下的途径：口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、吸入、阴道、眼内、局部、皮下、脂肪内、关节内、腹膜内和鞘内。在一个特定的实施方案中，通过口服给药。
给予包含安罗替尼环糊精包合物及其制成的药物组合物的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、受试者的年龄和健康状态来确定。在一些实施方案中，给予安罗替尼或其药学上可接受的盐的日剂量为3毫克至30毫克。在一些实施方案中，给予安罗替尼或其药学上可接受的盐的日剂量为5毫克至20毫克。在一些实施方案中，给予安罗替尼或其药学上可接受的盐的日剂量为8毫克至16毫克。在一些实施方案中，给予安罗替尼或其药学上可接受的盐的日剂量为10毫克至14毫克。在一个特定的实施方案中，给予安罗替尼或其药学上可接受的盐的日剂量为8毫克。在一个特定的实施方案中，给予安罗替尼或其药学上可接受的盐的日剂量为10毫克。在一个特定的实施方案中，给予安罗替尼或其药学上 可接受的盐的日剂量为12毫克。在本申请中，例如，对于片剂或胶囊剂而言，“以单位剂量为基础含有8mg的安罗替尼或其药学上可接受的盐”意味着最终制成的每片片剂或每颗胶囊剂中含有8mg的安罗替尼。
包含安罗替尼环糊精包合物及其制成的药物组合物可以每日施用一次或多次。在一些实施方案中，每天一次给予安罗替尼或其药学上可接受的盐。在一个实施方案中，以口服固体制剂每天给药一次。
上述治疗方法中，给药的方法可根据药物的活性、毒性以及受试者的耐受性等来综合确定。优选地，以连续给药的方式给予安罗替尼或其药学上可接受的盐。在一些实施方案中，以间隔给药的方式给予安罗替尼或其药学上可接受的盐。所述的间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予安罗替尼或其药学上可接受的盐。例如在给药期内每天给予安罗替尼或其药学上可接受的盐，然后停药期内停止给药一段时间，接着给药期，然后停药期，如此可以反复进行多次。其中，给药期和停药期的以天数计的比值为2:(0.1～2)，优选2:0.2～1.5，较优选2:0.4～1，更优选2:0.5～1。
安罗替尼或其药学上可接受的盐
式I化合物的化学名为1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺，其具有如下的结构式：
本申请中，凡是涉及安罗替尼，均是指式I化合物。
安罗替尼可以以它的游离碱形式给药，也可以以其盐、水合物和前药的形式给药，该前药在体内转换成安罗替尼的游离碱形式。例如，安罗替尼药学上可接受的盐在本申请的范围内可按照本领域公知的方法由不同的有机酸和无机酸产生。
本申请中，所述的可药用盐包括但不限于与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等形成的酸加成盐；或者与有机酸如乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2乙二磺酸、2羟基乙磺酸、苯 磺酸、对氯苯磺酸、对甲苯磺酸、3苯基丙酸、三甲基乙酸、水杨酸等形成的酸加成盐。
在一些实施方案中，以安罗替尼游离碱的形式给药。在一些实施方案中，以安罗替尼游离碱无水物的形式给药。在一些实施方案中，以安罗替尼游离碱一水合物的形式给药。在一些实施方案中，以安罗替尼盐酸盐的形式给药。在一些实施方案中，以安罗替尼一盐酸盐的形式给药。在一些实施方案中，以安罗替尼二盐酸盐的形式给药。在一些实施方案中，以安罗替尼盐酸盐的晶体形式给药。在特定的实施方案中，以安罗替尼二盐酸盐的晶体形式给药。
除非另有说明，为本申请的目的，本说明书和权利要求书中所用的下列术语应具有下述含义。
“单位剂量(unit dosage或unit dose)”是指为了服用的方便，包装在单个包装中的药物组合物，例如，“单位剂量形式的药物组合物”意味着每颗胶囊。“单位剂量形式的药物组合物含有100mg的安罗替尼”意味着最终制成的每颗胶囊剂中含有100mg的安罗替尼。
“患者”或“受试者”是指哺乳动物，优选人。
“治疗”意指治疗上有效量的化合物的任何施用，并且包括：
(1)抑制正经历或显示出所述疾病的病理学或症状学的人体中的该疾病(即，阻滞所述病理学和/或症状学的进一步发展)，或
(2)改善正经历或显示出所述疾病的病理学或症状学的人体中的该疾病(即逆转所述病理学和/或症状学)。
“包合物”指一种药物分子(客分子)结构被全部或部分包含入另一种物质(主分子)分子的空穴结构内形成的非化学键包合体。在本申请中“包合物”指以安罗替尼作为主药成分被包嵌于环糊精分子的空穴结构内形成的包合体为主的固体或者液体。根据主分子空穴几何形状，包合物分为管型、笼型、和层状包合物。
“润滑剂”包括但不限于在药物制剂过程中，用于降低原料、辅料与设备之间摩擦力的物质、作为抗粘剂的防止原料、辅料粘着与设备表面的物质、作为助流剂的降低原料、辅料之间摩擦力从而改善粉末流动性的物质。
本申请所述的“X50”是指颗粒粒径分布为50％的粒径，即小于此粒径的颗粒体积含量占全部颗粒的50％；“X90”是指颗粒粒径分布为90％的粒径，即小于此粒径的颗粒体积含量占全部颗粒的90％。
附图说明
图1实施例8参比制剂与受试制剂的血药浓度-时间曲线
具体实施方式
下面结合具体实施例，进一步阐述本申请。应理解，这些实施例仅用于说明本申请而不用于限制本申请的保护范围。
采集数据所用的仪器及方法：
采用激光法测定物料的粒径分布，仪器及其型号：新帕泰克HELOS-OASIS或性能相当的激光粒度仪，HELOS-RODOS/T4.1。
采用过滤法测定包合率，将所得包合物液体过0.22微米滤膜后，采用液相色谱法测定过滤前后的含量变化，包合率(％)＝过滤后主药成分含量/过滤前主药成分含量*100％。
实施例1环糊精包合物的制备
包合物1处方
制备过程：
取处方量羟丙基-β-环糊精(HP-β-CD)和盐酸安罗替尼，加水搅拌溶解澄清，得包合物液体，包合率达到95％，将溶液经喷雾干燥制备得到包合物固体。
所制备得到包合物1固体的粒径分布为：X50：6.8μm；X90：15.7μm。
包合物2处方
制备过程：
取处方量羟丙基-β-环糊精(HP-β-CD)，加水搅拌溶解澄清，加入盐酸安罗替尼，再加入有机/无机碱调节pH＞5，得包合物液体，包合率达到96％，将溶液经喷雾干燥制备得到包合物固体。
包合物3处方
制备过程：
取处方量羟丙基-β-环糊精(HP-β-CD)和盐酸安罗替尼，加pH＞5的缓冲液，搅拌溶解澄清，控制终点pH＞5，得包合物液体，包合率达到94％，将溶液经喷雾干燥制备得到包合物固体。
包合物4处方
制备过程：
取处方量羟丙基-β-环糊精(HP-β-CD)和盐酸安罗替尼，加pH＞5的缓冲液，搅拌溶解澄清，控制终点pH＞5，得包合物液体，包合率达到95％，将溶液经喷雾干燥制备得到包合物固体。
包合物5处方
制备过程：
取处方量羟丙基-β-环糊精(HP-β-CD)和盐酸安罗替尼，加水搅拌溶解澄清，得包合物液体，包合率达到96％，将溶液经喷雾干燥制备得到包合物固体。
包合物6处方
制备过程：
取处方量羟丙基-β-环糊精(HP-β-CD)和安罗替尼碱基，加pH＜3的酸性溶液，搅拌溶解澄清，再用pH＞5的碱性溶液调节pH，控制终点pH＞5，得包合液体，包合率达到95％，将溶液经喷雾干燥制备得到包合物固体。
实施例2
处方1

制备过程：
1)取处方量的实施例1制备得到的安罗替尼环糊精包合物1-6其中一种。
2)在包合物中加入甘露醇，低取代羟丙甲纤维素和硬脂酸镁，进行混合，得到中间体粉末。
3)中间体填充胶囊，或者压片制得片剂。
实施例3
处方2
1)取处方量的实施例1制备得到的安罗替尼环糊精包合物1-6其中一种。
2)在纯化水中加入包合物、羟丙纤维素(HPC-SL)，搅拌溶解澄清，在搅拌条件下加入滑石粉，搅拌使均匀分散，得到药物混悬液。
3)在流化床中，将药物混悬液在蔗糖空白丸芯上进行混悬液流化上药，得到含药微丸。
4)中间体填充胶囊，制得微丸胶囊，或者压片制得片剂。
实施例4
处方3
制备过程：
1)取处方量的实施例1制备得到的安罗替尼环糊精包合物1-6其中一种。
2)在包合物中加入微晶纤维素、甘露醇、低取代羟丙基纤维素混合，干法制粒。
3)将2)得到的药物颗粒加入交联聚维酮和硬脂酸镁，进行混合，得到中间体。
4)中间体填充胶囊，或者压片制得片剂。
实施例5
处方4
制备过程：
1)取处方量的实施例1制备得到的安罗替尼环糊精包合物1-6其中一种。
2)将羟丙甲纤维素加纯化水溶解，配制成粘合剂溶液。
3)流化床中加入包合物、交联羧甲基纤维素钠、微晶纤维素、乳糖，流化状态下喷入粘合剂溶液制粒并干燥。
4)将3)得到的药物颗粒加入羧甲基淀粉钠和硬脂酸镁，进行混合，得到中间体。
5)中间体填充胶囊，或者压片制得片剂。
实施例6
处方5
制备过程：
1)取处方量的实施例1制备得到的安罗替尼环糊精包合物1-6其中一种。
2)在包合物中加入甘露醇，低取代羟丙甲纤维素和硬脂酸镁，进行混合，得到中间体。
3)中间体填充胶囊，或者压片制得片剂。
实施例7
处方6
制备过程：
1)取处方量的实施例1制备得到的安罗替尼环糊精包合物1-6其中一种。
2)将羟丙甲纤维素加纯化水溶解，配制成粘合剂溶液。
3)流化床中加入包合物、交联羧甲基纤维素钠、微晶纤维素、乳糖，流化状态下喷入粘合剂溶液制粒并干燥。
4)将3)得到的药物颗粒加入羧甲基淀粉钠和硬脂酸镁，进行混合，得到中间体。
5)中间体填充胶囊，或者压片制得片剂。
实施例8
处方7
制备过程：
1)盐酸安罗替尼、羟丙基-β-环糊精依次加入纯化水1中搅拌至溶解，配制成药液，缓 慢滴加pH＞5的氢氧化钠溶液，调节pH至7.0以上，得到安罗替尼环糊精包合物液体。
2)流化床中加入甘露醇1，控制参数使物料温度范围：25～35℃。喷入药液一步制粒，干燥，过筛整粒。
3)加入硬脂酸、交联聚维酮、甘露醇2，进行混合，压片。
4)纯化水3中加入薄膜包衣预混剂，剪切，过筛，对片剂进行包衣。
实施例9人体药代动力学研究
16例受试者，随机、开放、单周期、平行空腹状态下生物等效性试验，分为2组，每组8人，其中参比制剂为8mg规格市售盐酸安罗替尼胶囊，受试制剂为按照实施例1制成的包合物1通过实施例2处方1制备得到的包含安罗替尼环糊精包合物的胶囊(4mg，2粒)。
生物样本分析：采用经部分验证的LC-MS/MS法测定以EDTA-K2为抗凝剂的血浆样本中安罗替尼的浓度，并进行相关参数Cmax、AUC0-t、C24h的计算。
血浆样本采集时间点：给药前0h(60min内)及给药后1、2、4、5、6、8、10、12、24、48、72、120、168、336、504、648h共17个时间点采集静脉血。
参比制剂与受试制剂的药动学参数统计见表1，血药浓度-时间关系曲线见附图1。
表1
实施例10人体药代动力学研究
12例受试者，随机、开放、单中心、平行空腹状态下生物等效性试验，分为2组，每组6人，其中参比制剂为8mg规格市售盐酸安罗替尼胶囊，受试制剂为按照实施例8制成的包含安罗替尼环糊精包合物的片剂(8mg，1粒)。
生物样本分析：采用经部分验证的LC-MS/MS法测定以肝素钠为抗凝剂的血浆样本中安罗替尼的浓度，并进行相关参数Cmax、AUC0-t、C24h的计算。
血浆样本采集时间点：给药前0h(60min内)及给药后1、2、4、5、6、8、10、12、24、48、72、120、168、336、504、648h共17个时间点采集静脉血。
参比制剂与受试制剂的药动学参数统计见表2。
表2
注：相对生物利用度：AUC0-t(受试制剂)*100％/AUC0-t(参比制剂)；
平均相对生物利用度：所有受试者相对生物利用度的平均值。
实施例11原辅料相容性研究
将原料药安罗替尼与羟丙基-β-环糊精制备成包合物后，选择固体制剂辅料与包合物按不同比例混合，分装于西林瓶中，分别在高湿(40℃，75％RH)条件下敞口放置，和高温(60℃)条件下轧盖密封放置，在第10，30天取样，考察有关物质变化情况。研究包合物与常用辅料的相容性，详见表3。
表3

注*：包合物的0天总杂质为0.20％。
结果表明，填充剂如甘露醇、微晶纤维素、无水磷酸氢钙，崩解剂如低取代羟丙纤维素交联聚维酮与固体分散体配伍稳定性良好；润滑剂与固体分散体配伍稳定性均良好。

Claims (13)

  1. 一种安罗替尼环糊精包合物，其含有：(a)安罗替尼作为主药成分；(b)环糊精；所述的安罗替尼作为主药成分包括安罗替尼或其药学上可接受的盐和/或其水合物。
  2. 根据权利要求1所述的包合物，其含有：
    (a)1-3份的安罗替尼作为主药成分；
    (b)12-45份环糊精；
    其中所有的份数以重量计。
  3. 根据权利要求1或2所述的包合物，其中，环糊精选自α-环糊精、β-环糊精、γ-环糊精、羟乙基-β-环糊精、羟丙基-β-环糊精及甲基-β-环糊精的一种或者多种，优选为β-环糊精，更优选为羟丙基-β-环糊精。
  4. 根据权利要求1-3任意一项所述的包合物，其中，安罗替尼或其药学上可接受的盐和/或其水合物与环糊精的重量比为1:10-1:20，优选为1:11-1:18，更优选为1:12-1:15。
  5. 根据权利要求1-4任意一项所述的包合物，其中，安罗替尼环糊精包合物为液体或固体。
  6. 根据权利要求5所述的包合物，其中安罗替尼环糊精包合物固体的粒径分布满足1μm≤X50≤15μm，5μm≤X90≤30μm。
  7. 根据权利要求1-6任意一项所述的包合物，其特征在于包合率达到80％以上，优选包合率达到85％以上，更优选包合率达到90％以上，进一步优选包合率达到95％以上。
  8. 一种包含安罗替尼环糊精包合物的药物组合物，其含有：(i)安罗替尼环糊精包合物；(ii)填充剂；(iii)崩解剂；(iv)润滑剂；(v)视需要的其它药用的辅料。
  9. 根据权利要求8所述的药物组合物，其中：
    填充剂选自乳糖、微晶纤维素、预胶化淀粉、玉米淀粉、甘露醇、无水磷酸氢钙、蔗糖的一种或多种，优选为乳糖、微晶纤维素、甘露醇、蔗糖的一种或多种；
    崩解剂选自交联聚维酮、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、羧甲基淀粉钠、羟丙基纤维素、羟丙基甲基纤维素、羟乙基甲基纤维素、羟乙基纤维素、羟丁基甲基纤维素、乙基甲基纤维素、羟乙基甲基纤维素、乙基羟乙基纤维素和甲基纤维素中一种或多种，优选为羟丙基纤维素、交联聚维酮、羧甲基淀粉钠、交联羧甲基纤维素钠中一种或多种；
    润滑剂选自硬脂酸镁、硬脂酸、微粉硅胶、滑石粉、胶态二氧化硅、山嵛酸甘油酯、硬脂富马酸钠、十二烷基硫酸钠、聚乙二醇4000、聚乙二醇6000、氢化蓖麻油的一种或多种，优选为硬脂酸镁和/或滑石粉。
  10. 根据权利要求8或9所述的药物组合物，其含有：
    (i)13-48份的安罗替尼环糊精包合物；
    (ii)40-120份的填充剂；
    (iii)2-16份的崩解剂；
    (iv)0.1-12份的润滑剂；
    其中，安罗替尼环糊精包合物，其含有：
    (a)1-3份的安罗替尼作为主药成分；
    (b)12-45份环糊精；
    其中所有的份数以重量计，所述的安罗替尼作为主药成分包括安罗替尼或其药学上可接受的盐和/或其水合物。
  11. 根据权利要求1-7任意一项所述的包合物的制备方法，其特征在于，包括：将安罗替尼作为主药成分和环糊精，分别或先后加入适量的溶剂，混合后得到包合物液体，经过干燥制备得到安罗替尼环糊精包合物固体；或者，包括以下步骤：
    a：将安罗替尼或其药学上可接受的盐和/或其水合物、环糊精，分别或先后加入到溶剂中，搅拌溶解澄清，视需要，加入pH调节剂调节液体pH＞5，得到包合物液体；
    b：可选地，将包合物液体干燥得到包合物固体。
  12. 根据权利要求8-10任意一项所述的药物组合物的制备方法，其特征在于，包括以下步骤：
    A：将权利要求1-7任意一项所述的包合物加入填充剂、崩解剂、润滑剂混合，视需要加入其他药用辅料，所述其他药用辅料包括粘合剂、矫味剂，制成中间体；
    B：将中间体制备适用口服的固体制剂；
    或者，包括以下步骤：
    a：将安罗替尼或其药学上可接受的盐和/或其水合物、环糊精，分别或先后加入到溶剂中，搅拌溶解澄清，视需要，加入pH调节剂调节液体pH＞5，得到包合物液体；
    b：将包合物液体干燥得到包合物固体；
    c：将安罗替尼环糊精包合物加入填充剂、崩解剂、润滑剂混合，视需要加入其他药用辅料，所述其他药用辅料包括粘合剂、矫味剂，制成中间体；
    d：将中间体制备适用口服的固体制剂；
    或者，包括以下步骤：
    e：将安罗替尼或其药学上可接受的盐和/或其水合物、环糊精，分别或先后加入到溶剂中，搅拌溶解澄清，视需要，加入pH调节剂调节溶液pH＞5，得到包合物液体；
    f：将安罗替尼环糊精包合物液体与填充剂混合，制成制剂中间体；
    g：将制剂中间体与填充剂、崩解剂、和/或润滑剂混合，视需要加入其他药用辅料，所 述其他药用辅料包括粘合剂、矫味剂，制成适用口服的固体制剂。
  13. 根据权利要求1-7任意一项所述的包合物或权利要求8-10任意一项所述的药物组合物在制备用于治疗癌症的药物中的用途。
PCT/CN2023/103130 2022-06-29 2023-06-28 喹啉衍生物或其盐环糊精包合物 Ceased WO2024002147A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202380049144.3A CN119403575A (zh) 2022-06-29 2023-06-28 喹啉衍生物或其盐环糊精包合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210755401.2 2022-06-29
CN202210755401 2022-06-29

Publications (1)

Publication Number Publication Date
WO2024002147A1 true WO2024002147A1 (zh) 2024-01-04

Family

ID=89383030

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/103130 Ceased WO2024002147A1 (zh) 2022-06-29 2023-06-28 喹啉衍生物或其盐环糊精包合物

Country Status (2)

Country Link
CN (1) CN119403575A (zh)
WO (1) WO2024002147A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190262267A1 (en) * 2014-05-26 2019-08-29 Songyuan Chen Pharmaceutical solution having a toxicity-reducing effect for antitumor drugs, and pharmaceutical composition comprising same
US20190365737A1 (en) * 2016-09-13 2019-12-05 Kyowa Hakko Kirin Co., Ltd. Pharmaceutical composition
CN112076192A (zh) * 2014-06-06 2020-12-15 正大天晴药业集团股份有限公司 包含喹啉衍生物或其盐的药物组合物及其制备方法
WO2022003037A1 (en) * 2020-06-30 2022-01-06 Oculis SA Preparation of solid cyclodextrin complexes for ophthalmic active pharmaceutical ingredient delivery

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190262267A1 (en) * 2014-05-26 2019-08-29 Songyuan Chen Pharmaceutical solution having a toxicity-reducing effect for antitumor drugs, and pharmaceutical composition comprising same
CN112076192A (zh) * 2014-06-06 2020-12-15 正大天晴药业集团股份有限公司 包含喹啉衍生物或其盐的药物组合物及其制备方法
US20190365737A1 (en) * 2016-09-13 2019-12-05 Kyowa Hakko Kirin Co., Ltd. Pharmaceutical composition
WO2022003037A1 (en) * 2020-06-30 2022-01-06 Oculis SA Preparation of solid cyclodextrin complexes for ophthalmic active pharmaceutical ingredient delivery

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Pharmaceutics", 30 April 2000, CHINA ACADEMY OF PHARMACEUTICAL SCIENCE AND TECHNOLOGY PRESS, CN, ISBN: 7-5067-2243-7, article BI, DIANZHOU: "Inclusion Technology", pages: 42 - 44, XP009552342 *

Also Published As

Publication number Publication date
CN119403575A (zh) 2025-02-07

Similar Documents

Publication Publication Date Title
JP2005526738A (ja) 低溶解度の薬物を経口投与するための投与剤形
KR20210147082A (ko) 디메틸푸마레이트를 포함하는 일일 저용량 투여용 약제학적 조성물
BR112015015758B1 (pt) Dispersão sólida, formulação sólida de dose unitária, preparação farmacêutica e uso de uma dispersão sólida
TW200930712A (en) The amorphous of a heterocyclic compound, the solid dispersoid consisting it, the preparation, and the process for preparing thereof
CN102633777B (zh) 达比加群酯2-酮戊二酸盐及其制备方法和应用
BR112021013869A2 (pt) Inibidor de atr cinase bay1895344 para uso no tratamento de uma doença hiper-proliferativa
CN103304539A (zh) 达比加群酯苹果酸盐及其制备方法和应用
US11517569B2 (en) Vilazodone inclusion complexes, compositions and preparation thereof
BR112021018452B1 (pt) Comprimido de revestimento entérico e seu método de preparação
ES2414384T3 (es) Composición de liberación modificada que comprende ranolazina
CN101747305A (zh) 硝克柳胺化合物五种晶型、其制法和其药物组合物与用途
CA3186141A1 (en) Acalabrutinib maleate dosage forms
WO2024002147A1 (zh) 喹啉衍生物或其盐环糊精包合物
BRPI0513938B1 (pt) composição farmacêutica contendo drospirenona e etinilestradiol
CN111757737B (zh) 用于治疗三阴性乳腺癌的喹啉衍生物
CN120022270A (zh) 一种吲哚布芬缓释制剂及其制备方法和应用
JP2020510625A (ja) セレコキシブを含有する医薬組成物
JPWO2019230937A1 (ja) 溶出性に優れた経口固形製剤
US20250064798A1 (en) Vilazodone composition, pharmaceutical preparation thereof, preparation therefor, and use thereof
CN103622931A (zh) 卡维地洛包合物渗透泵型控释制剂及其制备方法
CN118715005A (zh) 药物配制品
CN113730350A (zh) 一种磷酸二酯酶4抑制剂组合物
PT1586310E (pt) Processo para a preparação de adsorvatos de valsartan na forma de pó solto
CN113924145A (zh) 痛风或高尿酸血症的治疗药
TWI746418B (zh) 包含1-[6-(嗎啉-4-基)嘧啶-4-基]-4-(1h-1,2,3-三唑-1-基)-1h-吡唑-5-醇鈉之醫藥劑型

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23830321

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202380049144.3

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: DE

WWP Wipo information: published in national office

Ref document number: 202380049144.3

Country of ref document: CN

122 Ep: pct application non-entry in european phase

Ref document number: 23830321

Country of ref document: EP

Kind code of ref document: A1