WO2021226738A1 - 包含仑伐替尼的分子水平的药物组合物及其制备方法和应用 - Google Patents

包含仑伐替尼的分子水平的药物组合物及其制备方法和应用 Download PDF

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WO2021226738A1
WO2021226738A1 PCT/CN2020/089324 CN2020089324W WO2021226738A1 WO 2021226738 A1 WO2021226738 A1 WO 2021226738A1 CN 2020089324 W CN2020089324 W CN 2020089324W WO 2021226738 A1 WO2021226738 A1 WO 2021226738A1
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lenvatinib
pharmaceutical composition
stabilizer
polymer carrier
active ingredient
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PCT/CN2020/089324
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English (en)
French (fr)
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贾慧娟
张加晏
何学敏
刘晓红
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北京睿创康泰医药研究院有限公司
天津睿创康泰生物技术有限公司
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Priority to PCT/CN2020/089324 priority Critical patent/WO2021226738A1/zh
Priority to CN202080099785.6A priority patent/CN115397416B/zh
Publication of WO2021226738A1 publication Critical patent/WO2021226738A1/zh

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    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition containing lenvatinib and a preparation method and application thereof, and particularly relates to a lenvatinib molecular level composition and a low-dose lenvatinib composition.
  • Patent WO 2002032872, WO 2004080462 discloses a quinoline derivative 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide (Lun Vatinib), has a strong angiogenesis inhibitory effect and c-Kit kinase inhibitory effect, and can be used clinically for the treatment of thyroid cancer, lung cancer, melanoma, pancreatic cancer, kidney cancer, liver cancer and other tumors.
  • Product name The dosage form is capsules, the specifications are 4mg, 10mg, and its clinical maximum daily dose is 24mg.
  • Patent CN110404079A also reported the following degradation pathways: 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide and its salts in strong acid and strong acid Under alkali, hydrolysis and oxidation conditions, especially under alkaline + damp heat conditions, 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxylic acid amide ( as shown in picture 2).
  • 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide is a genotoxic impurity, so its quality control limit is very low.
  • the control limit of genotoxic impurity B in the raw material is 60ppm, and the control limit in the preparation is 400ppm, which is far lower than the quality control limit of general impurities.
  • CN101001629 uses a compound containing (i) its 5% (W/W) aqueous solution or suspension with a pH of 8 or more, and/or (ii) silicic acid or its salt or their solvate.
  • CN102470133 uses magnesium carbonate or calcium carbonate as stabilizers and dissolution accelerators.
  • Patent CN106177965 contains (A) at least one compound selected from potassium carbonate and potassium bicarbonate, and (B) at least one compound selected from calcium hydrogen phosphate, calcium phosphate or calcium sulfate.
  • Patent CN106075456 and CN106551935 use calcium hydrogen phosphate to solve the stability and dissolution problems.
  • lenvatinib Compared with ordinary preparations, in lenvatinib solid dispersion preparations, lenvatinib will degrade quickly, and the commonly used stabilizers reported have no obvious effect on its degradation.
  • the genotoxic impurity B can be stored at 60°C for 10 days. Will greatly increase, exceeding the quality control limit (400ppm) of the formulation.
  • CN109044977A provides a solid dispersion of lenvatinib, including lenvatinib and a water-soluble carrier material; the combination of the lenvatinib and the water-soluble carrier material The mass ratio is 10:1 to 1:10.
  • WO2013105895A1 provides a pharmaceutical composition comprising at least one protein kinase inhibitor and at least one polymer stabilized and matrix-forming component stable, amorphous hybrid nanoparticles; wherein the composition optionally further comprises at least A pharmaceutically acceptable solubilizer.
  • the lenvatinib solid dispersion prepared according to the typical examples of patent CN109044977A and WO2013105895A1 was subjected to a dissolution test using a two-step dissolution method that simulates the physiological conditions of the human body. Compared with the dissolution, there is no improvement, and there is no report in the patent that the solid dispersion of lenvatinib is the same Comparative in vivo pharmacokinetics.
  • solid dispersion technology alone cannot obtain a better in vitro dissolution effect than the original development agent LENVIMA, which is converted to amorphous form of mesylate C with poor solubility through wet granulation, and can simulate the physiological conditions of the human body.
  • the dissolution behavior in the two-step dissolution medium is the same or no obvious improvement, and the above solid dispersion solution cannot achieve the expected effect in the organism.
  • the present invention provides a new lenvatinib with better stability.
  • a pharmaceutical composition at the molecular level is to provide a lower dose composition that can take 40%-50% of the original marketed product LENVIMA to achieve the same efficacy as the original marketed product LENVIMA, significantly reducing Side effects related to the administered dose;
  • Another object of the present invention is to provide a pharmaceutical composition at the molecular level of lenvatinib, which has lower intra- and inter-individual variability in the organism, and reduces the exposure of the drug in the plasma.
  • the nephrotoxicity and neurotoxicity caused by a sudden increase in the dose or the ineffectiveness caused by a sudden decrease in plasma exposure have improved the safety of patients' medication.
  • the present invention provides a pharmaceutical composition comprising a molecular level composition of lenvatinib, the molecular level composition of lenvatinib containing:
  • Active ingredient lenvatinib or a pharmaceutically acceptable salt or solvate thereof
  • the genotoxic impurity B is less than 400 ppm.
  • the pharmacokinetic AUC 0-t of the pharmaceutical composition is compared with that of the original research agent Improved by at least 40%.
  • the specific dose or specification can be reduced by more than 40%.
  • the pharmacokinetic AUC 0-t of the pharmaceutical composition is compared with that of the original research agent Reduced variability, preferably CV ⁇ 30%.
  • the stabilizer is selected from at least one of tromethamine, meglumine, or sodium lauryl sulfate.
  • the polymer carrier is selected from hypromellose, hypromellose, copovidone, hypromellose phthalate, povidone, hydroxypropyl acetate At least one of propylmethyl cellulose succinate, hydroxyethyl cellulose, and acrylic resin.
  • the polymer carrier is selected from hypromellose, copovidone, hypromellose phthalate, hypromellose acetate succinate, acrylic acid At least one of resin and povidone.
  • the pharmaceutically acceptable salt thereof is selected from the hydrochloride, hydrobromide, p-toluenesulfonate, methanesulfonate, sulfate or ethyl ester of lenvatinib. At least one of the sulfonates, preferably lenvatinib mesylate.
  • the solvate of lenvatinib or a pharmaceutically acceptable salt thereof is hydrate, dimethyl sulfoxide or acetate.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:(0.05 ⁇ 0.75):(0.5 ⁇ 10), preferably 1:(0.05 ⁇ 0.6):(1 ⁇ 5), more preferably 1:(0.1 ⁇ 0.6):(1 ⁇ 3).
  • the pharmaceutical composition includes the following solutions:
  • the stabilizer is tromethamine, and the polymer carrier is hypromellose acetate succinate;
  • the active ingredient is lenvatinib and/or lenvatinib mesylate, preferably lenvatinib;
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:(0.05 ⁇ 0.75):(0.5 ⁇ 10), preferably 1:(0.05 ⁇ 0.4):(1 ⁇ 5), more preferably 1: (0.075 ⁇ 0.3):(1 ⁇ 2), more preferably 1:(0.1 ⁇ 0.3):(1 ⁇ 2);
  • the stabilizer is meglumine, and the polymer carrier is hypromellose acetate succinate;
  • the active ingredient is lenvatinib and/or lenvatinib mesylate, preferably lenvatinib;
  • the weight ratio of the active ingredient, stabilizer and polymer carrier is 1:(0.05 ⁇ 0.75):(0.5 ⁇ 10), preferably 1:(0.05 ⁇ 0.4):(1 ⁇ 5), more preferably 1:(0.05 ⁇ 0.4):(1 ⁇ 5) (0.075 ⁇ 0.3):(1 ⁇ 2), more preferably 1:(0.1 ⁇ 0.3):(1 ⁇ 2);
  • the stabilizer is sodium lauryl sulfate, and the polymer carrier is hypromellose;
  • the active ingredient is lenvatinib and/or lenvatinib mesylate, preferably lenvatinib;
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:(0.075-0.5):(1-5), preferably 1:(0.15-0.5):(1-3), more preferably 1: (0.15 ⁇ 0.25): (1 ⁇ 2);
  • the stabilizer is sodium lauryl sulfate, and the polymer carrier is copovidone;
  • the active ingredient is lenvatinib and/or lenvatinib mesylate, preferably lenvatinib;
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:(0.1 ⁇ 0.75):(1 ⁇ 5), preferably 1:(0.4 ⁇ 0.75):(2 ⁇ 3), more preferably 1: (0.4 ⁇ 0.6): (2 ⁇ 3);
  • the stabilizer is sodium lauryl sulfate
  • the polymer carrier is a copolymer of ethyl acrylate-methyl methacrylate and trimethylaminoethyl methacrylate chloride
  • the active ingredient is lenvatinib and/or lenvatinib mesylate, preferably lenvatinib;
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:(0.1 ⁇ 0.5):(1 ⁇ 5), preferably 1:(0.2 ⁇ 0.5):(2 ⁇ 3), more preferably 1:(0.2 ⁇ 0.5):(2 ⁇ 3) (0.2 ⁇ 0.3): 3.
  • the stabilizer is sodium lauryl sulfate, and the polymer carrier is povidone;
  • the active ingredient is lenvatinib and/or lenvatinib mesylate, preferably lenvatinib;
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:(0.05 ⁇ 0.75):(1 ⁇ 10), preferably 1:(0.2 ⁇ 0.5):(2 ⁇ 3), more preferably 1: (0.2 ⁇ 0.3): 3.
  • the pharmaceutical composition further contains pharmaceutically acceptable excipients selected from fillers, disintegrants, binders, lubricants, and flavoring agents , At least one of the suspending agents.
  • the dosage form of the pharmaceutical composition is a capsule, a tablet, a granule, a suspension, preferably a capsule, a tablet, and more preferably a tablet.
  • the present invention also provides a co-solvent for dissolving lenvatinib or a pharmaceutically acceptable salt or solvate thereof, the co-solvent comprising methyl halide and alcohols.
  • the alcohols are preferably methanol and/or ethanol.
  • the halogenated methane is preferably dichloromethane.
  • the ratio of the halogenated methane to the alcohol is 10:2-10:10, preferably 10:2-10:5, more preferably 10:3-10:5.
  • the latent solvent includes the following solutions:
  • the latent solvent includes dichloromethane and methanol
  • the ratio of dichloromethane to methanol is 10:2-10:10, preferably 10:3-10:5;
  • the latent solvent includes dichloromethane and ethanol
  • the ratio of dichloromethane and ethanol is 10:3-10:10, preferably 10:4-10:5.
  • the present invention also provides a method for improving the solubility of lenvatinib or a pharmaceutically acceptable salt or solvate thereof, using the cosolvent.
  • the present invention also provides a method for preparing a molecular level composition of lenvatinib, which includes dissolving the active ingredient, stabilizer and polymer carrier in an organic solvent, spray drying, and obtaining a solid Dispersant.
  • the organic solvent is the latent solvent.
  • the present invention also provides the application of the pharmaceutical composition or the molecular level composition of lenvatinib prepared by the preparation method in the preparation of a medicine for treating or preventing cancer/tumor.
  • the cancer/tumor is thyroid cancer, renal cell carcinoma, liver cancer, gastric cancer or lung cancer.
  • the present invention also provides a method for treating or preventing cancer/tumor, using the pharmaceutical composition or the molecular level composition of lenvatinib prepared by the preparation method.
  • the cancer/tumor is thyroid cancer, renal cell carcinoma, liver cancer, stomach cancer or lung cancer.
  • the present invention provides a new lenvatinib molecular level composition with better stability, which can obviously improve the bioavailability in the body.
  • the present invention also provides a method for treating or preventing cancer/tumor, using the pharmaceutical composition or the molecular level composition of lenvatinib prepared by the preparation method.
  • Figure 1 shows the decomposition mechanism of lenvatinib or its salt into a pharmaceutical composition when it is decomposed under humidified and heated storage conditions
  • Figure 2 shows the degradation pathway of lenvatinib
  • FIG. 3 shows the DSC of the compound of formula (I): 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide;
  • FIG. 4 shows the TGA of the compound of formula (I): 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide;
  • Figure 5 shows the compound of formula (I): XRPD of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide;
  • Figure 6 shows the IR of a compound of formula (I): 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide;
  • Figure 7 shows the DSC chart of the sample of Comparative Example 1. It can be seen from the figure that the peak of lenvatinib at 234°C disappeared, suggesting the formation of a molecular-level composition
  • Figure 8 shows the DSC chart of the sample of Comparative Example 3. It can be seen from the figure that the peak of lenvatinib at 234°C disappeared, suggesting the formation of a molecular-level composition
  • Figure 9 shows the DSC chart of the sample of Comparative Example 4. It can be seen from the figure that the peak of lenvatinib at 234°C disappeared, suggesting the formation of a molecular-level composition
  • Figure 10 shows the DSC chart of the physical mixture of lenvatinib, HPMCAS and tromethamine
  • Figure 11 shows the DSC chart of the sample of Example 8. It can be seen from the figure that the peak of lenvatinib at 234°C disappeared, suggesting the formation of a molecular-level composition
  • Figure 12 shows the DSC chart of the sample of Example 14. It can be seen from the figure that the peak of lenvatinib at 234°C disappeared, suggesting the formation of a molecular-level composition
  • Figure 13 shows the DSC chart of the physical mixture of Lenvatinib, HPMC K15M, and SDS;
  • Figure 14 shows the DSC chart of the sample of Example 19. From the figure, it can be seen that the peak of lenvatinib at 234°C disappeared, suggesting the formation of a molecular-level composition
  • Figure 15 shows the DSC chart of the sample of Example 22. From the figure, it can be seen that the peak of lenvatinib at 234°C disappeared, suggesting the formation of a molecular-level composition
  • Figure 16 shows the DSC chart of the physical mixture of lenvatinib, copovidone VA64 and SDS;
  • Figure 17 shows the DSC chart of the sample of Example 29. It can be seen from the figure that the peak of lenvatinib at 234°C disappeared, suggesting the formation of a molecular-level composition
  • Figure 18 shows the DSC chart of the sample of Example 30. From the figure, it can be seen that the peak of lenvatinib at 234°C disappeared, suggesting the formation of a molecular-level composition;
  • Figure 20 shows the DSC chart of the sample of Example 35. It can be seen from the figure that the peak of lenvatinib at 234°C disappeared, suggesting the formation of a molecular-level composition
  • Figure 21 shows the DSC chart of the sample of Example 38. From the figure, it can be seen that the peak of lenvatinib at 234°C disappeared, suggesting the formation of a molecular-level composition
  • Figure 22 shows the DSC chart of the physical mixture of lenvatinib, povidone and SDS
  • Figure 23 shows the DSC chart of the sample of Example 43. From the figure, it can be seen that the peak of lenvatinib at 234°C disappeared, suggesting the formation of a molecular-level composition
  • Figure 24 shows the DSC chart of the sample of Example 49. It can be seen from the figure that the peak of lenvatinib at 234°C disappeared, suggesting the formation of a molecular-level composition
  • Figure 25 shows the DSC chart of the sample of Example 50. It can be seen from the figure that the peak of lenvatinib at 234°C disappeared, suggesting the formation of a molecular-level composition
  • Figure 26 shows the DSC chart of the sample of Example 51. It can be seen from the figure that the peak of lenvatinib at 234°C disappeared, suggesting the formation of a molecular-level composition
  • Figure 27 shows the DSC chart of the sample of Example 52. It can be seen from the figure that the peak of lenvatinib at 234°C disappeared, suggesting the formation of a molecular-level composition
  • Figure 28 shows the original formulation Example and comparative example simulated gastric juice+simulated intestinal juice dissolution curve diagram, it can be seen from the diagram that there is no significant difference in the dissolution of the molecular-level composition preparation and the original preparation agent;
  • Figure 29 shows the original formulation Comparative example 28-32 0.1M HCl+pH 6.8 phosphate buffer dissolution curve chart, it can be seen from the figure that there is no significant difference in the dissolution of the molecular-level composition preparation and the original formulation;
  • Figure 30 shows the original research agent Example 58-63 0.1M HCl+pH 6.8 phosphate buffer dissolution curve chart, it can be seen from the figure that there is no significant difference in the dissolution of the molecular-level composition preparation and the original formulation;
  • Figure 31 shows the original research agent Comparative Example 33, Examples 64-66 0.1M HCl+pH6.8 phosphate buffer dissolution curve diagram, it can be seen from the figure that there is no significant difference in the dissolution of the molecular-level composition preparation and the original formulation;
  • Figure 32 shows the original research agent Comparative Example 34, Example 67-69 0.1M HCl+pH6.8 phosphate buffer dissolution curve diagram, it can be seen from the figure that there is no significant difference in the dissolution of the molecular-level composition preparation and the original formulation;
  • Figure 33 shows the original formulation Example 70-74 0.1M HCl+pH 6.8 phosphate buffer dissolution curve chart, it can be seen from the figure that there is no significant difference in the dissolution of the molecular-level composition preparation and the original formulation;
  • Figure 34 shows the original formulation Example 75-80 0.1M HCl+pH 6.8 phosphate buffer dissolution curve chart, it can be seen from the figure that there is no significant difference in the dissolution of the molecular-level composition preparation and the original formulation.
  • the invention discloses a pharmaceutical composition containing lenvatinib and a preparation method and application thereof.
  • Those skilled in the art can learn from the content of this article and appropriately improve the process parameters.
  • all similar substitutions and modifications are obvious to those skilled in the art, and they are all deemed to be included in the present invention.
  • the method and application of the present invention have been described through the preferred embodiments. It is obvious that relevant persons can make changes or appropriate changes and combinations to the methods and applications described herein without departing from the content, spirit and scope of the present invention to achieve and Apply the technology of the present invention.
  • a pharmaceutical composition at the molecular level of tinib is to provide a lower dose composition that can take 40%-50% of the original marketed product LENVIMA to achieve the same efficacy as the original marketed product LENVIMA, which is significant The side effects related to the administered dose are reduced; another object of the present invention is to provide a pharmaceutical composition at the molecular level of lenvatinib, which has lower intra- and inter-individual variability in the organism, and reduces the drug in plasma
  • the nephrotoxicity and neurotoxicity caused by a sudden increase in internal exposure or the ineffectiveness caused by a sudden decrease in plasma exposure have improved the safety of medication for patients.
  • the first aspect of the present invention provides a pharmaceutical composition comprising a molecular level composition of lenvatinib, the molecular level composition of lenvatinib containing:
  • Active ingredient lenvatinib or a pharmaceutically acceptable salt or solvate thereof
  • the stabilizer is selected from at least one of tromethamine, meglumine, and sodium lauryl sulfate.
  • the present invention also provides a low-dose lenvatinib composition, which includes the above-mentioned molecular-level composition, and its dosage form can be capsules, tablets, granules, suspensions, preferably capsules, tablets, and more Preferably it is a tablet.
  • low dose refers to a therapeutically effective dose of lenvatinib (or a pharmaceutically acceptable salt or solvate thereof) that is less than the conventional or conventional required to produce equal or higher therapeutic effects dose.
  • Lenvatinib (or a pharmaceutically acceptable salt or solvate thereof) can be administered at least once a day in a dosage range of about 1 mg to about 30 mg.
  • lenvatinib (or a pharmaceutically acceptable salt or solvate thereof) can be administered at least once a day in a dosage range of about 1 mg to about 20 mg.
  • lenvatinib (or a pharmaceutically acceptable salt or solvate thereof) can be administered at least once a day in a dosage range of about 1 mg to about 15 mg.
  • the polymer carrier is selected from hypromellose, hypromellose, copovidone, hypromellose phthalate, povidone, hydroxypropyl acetate At least one of methyl cellulose succinate, hydroxyethyl cellulose, and acrylic resin.
  • the polymer carrier is selected from hypromellose (HPMC), copovidone (VA64), hypromellose phthalate (HPMCP), acetic acid Hypromellose succinate (HPMCAS), ethyl acrylate-methyl methacrylate and chlorinated trimethylaminoethyl methacrylate copolymer At least one of povidone.
  • HPMC hypromellose
  • VA64 copovidone
  • HPMCP hypromellose phthalate
  • HPMCAS acetic acid Hypromellose succinate
  • ethyl acrylate-methyl methacrylate ethyl acrylate-methyl methacrylate
  • chlorinated trimethylaminoethyl methacrylate copolymer At least one of povidone.
  • the pharmaceutically acceptable salt of lenvatinib is selected from hydrochloride, hydrobromide, p-toluenesulfonate, methanesulfonate, sulfuric acid of lenvatinib At least one of salt or ethanesulfonate.
  • the pharmaceutically acceptable salt of lenvatinib is lenvatinib mesylate.
  • the solvate of lenvatinib or a pharmaceutically acceptable salt thereof is hydrate, dimethyl sulfoxide or acetate.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.05-0.75:0.5-10.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.05-0.6:1-5.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.1-0.6:1-3.
  • the active ingredient is lenvatinib and/or lenvatinib mesylate, preferably lenvatinib
  • the stabilizer is tromethamine
  • the polymer carrier It is hypromellose acetate succinate, and the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.05-0.75:0.5-10.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.05-0.4:1-5.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.075-0.3:1-2.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.1-0.3:1-2.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.15:1.
  • the active ingredient is lenvatinib and/or lenvatinib mesylate, preferably lenvatinib
  • the stabilizer is meglumine
  • the polymer carrier is For hypromellose acetate succinate, the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.05-0.75:0.5-10.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.05-0.4:1-5.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.075-0.3:1-2.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.1-0.3:1-2.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.15:1.
  • the active ingredient is lenvatinib and/or lenvatinib mesylate, preferably lenvatinib
  • the stabilizer is sodium lauryl sulfate
  • the high The molecular carrier is hypromellose, and the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.075-0.5:1-5.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.15-0.5:1-3.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.15-0.25:1-2.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.2:1.
  • the active ingredient is lenvatinib and/or lenvatinib mesylate, preferably lenvatinib
  • the stabilizer is sodium lauryl sulfate
  • the high The molecular carrier is copovidone, and the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.1-0.75:1-5.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.4-0.75:2-3.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.4-0.6:2-3.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.6:2.
  • the active ingredient is lenvatinib and/or lenvatinib mesylate, preferably lenvatinib
  • the stabilizer is sodium lauryl sulfate
  • the molecular carrier is a copolymer of ethyl acrylate-methyl methacrylate and trimethylaminoethyl methacrylate chloride, and the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.1-0.5:1-5 .
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.2-0.5:2-3.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.2-0.3:3.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.2:3.
  • the active ingredient is lenvatinib and/or lenvatinib mesylate, preferably lenvatinib
  • the stabilizer is sodium lauryl sulfate
  • the high The molecular carrier is povidone, and the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.05-0.75:1-10.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.2-0.75:2-5.
  • the weight ratio of the active ingredient, stabilizer, and high molecular weight carrier is 1:0.4-0.6:2-4.
  • the weight ratio of the active ingredient, stabilizer, and polymer carrier is 1:0.6:3.
  • the dosage form of the pharmaceutical composition is a capsule, a tablet, a granule, a suspension, preferably a capsule, a tablet, and more preferably a tablet.
  • the composition may also contain suitable excipients, such as fillers, disintegrants, binders, lubricants, glidants, etc. These excipients can be based on the needs of the dosage form. Add one or more of them.
  • suitable excipients include starch, microcrystalline cellulose, pregelatinized starch, maltitol, sorbitol, trehalose, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, lactose, and the like.
  • disintegrants examples include dry starch, pregelatinized starch, croscarmellose sodium, carboxymethyl cellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and cross-linked polyvinyl cellulose. Ketones and so on.
  • binder examples include hydroxypropyl cellulose, hypromellose, povidone, sodium carboxymethyl cellulose, starch slurry, gum arabic, and the like.
  • lubricant magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, stearic acid, polyethylene glycol, glyceryl behenate and the like can be cited.
  • the glidant examples include silica, talc, glyceryl behenate, and the like.
  • the second aspect of the present invention provides a latent solvent for dissolving lenvatinib or a pharmaceutically acceptable salt or a solvate thereof, the latent solvent comprising halogenated methane and alcohols, the halogenated methane and alcohols
  • the ratio is 10:2-10:10, preferably 10:2-10:5, more preferably 10:3-10:5, the alcohol is preferably methanol and/or ethanol, and the halogenated methane is preferably Dichloromethane and/or chloroform.
  • the latent solvent comprises dichloromethane and methanol, and the ratio of the two is 10:2-10:10, preferably 10:3-10:5.
  • the latent solvent comprises dichloromethane and ethanol, and the ratio of the two is 10:3-10:10, preferably 10:4-10:5.
  • the third aspect of the present invention provides a method for preparing a molecular-level composition of lenvatinib, which comprises dissolving the active ingredient, stabilizer and polymer carrier described in the first aspect in an organic solvent, spray drying, and obtaining a solid dispersant, wherein, the organic solvent is the latent solvent described in the second aspect.
  • 0-100% of the stabilizer is first dissolved in the mixed solvent, and then the carrier and the active ingredient and the remaining stabilizer are added to dissolve, and spray-dried to obtain a molecular-level composition. More preferably, 0-50% of the stabilizer is first dissolved in the mixed solvent, and then the carrier is added to dissolve, and then the active ingredient and the remaining stabilizer are added to dissolve, and spray-dried to obtain a molecular-level composition. If necessary, the residual solvent can be further removed by drying under reduced pressure.
  • the lenvatinib molecular level composition is mixed with fillers, disintegrants, binders, etc., granulated, granulated, blended, compressed or filled into capsules. It is also possible to mix the lenvatinib molecular level composition with fillers, disintegrants, binders, etc., and directly compress or encapsulate them.
  • the fourth aspect of the present invention provides the application of a molecular-level composition of lenvatinib in the preparation of drugs for the treatment or prevention of cancer/tumor, wherein the cancer/tumor is thyroid cancer, renal cell carcinoma, liver cancer, gastric cancer, or lung cancer, But it is not limited to the above types.
  • Figures 3-7 respectively show the DSC of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide (lenvatinib) (Differential Scanning Calorimetry), TGA (Thermogravimetric Analysis), XRPD (X-Ray Powder Diffraction) and IR (Infrared Spectroscopy) results.
  • N-methylpyrrolidone, dimethyl sulfoxide, and N,N-dimethylformamide have high solubility, but these three solvents have high boiling points and are not suitable for use as solvents for spray drying. .
  • solubility of lenvatinib is very low when dichloromethane, methanol, and ethanol are used alone.
  • the solubility of the mixed solvent of dichloromethane and methanol is greater when the ratio of the two is in the range of 10:2-10:10, and the solubility is the largest when the ratio is in the range of 10:3-10:5.
  • the solubility of the mixed solvent of dichloromethane and anhydrous ethanol is greater when the ratio of the two is in the range of 10:3-10:10, and the solubility is the largest when the ratio is in the range of 10:4-10:5.
  • Comparison 1 2 3 4 5 API 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 VA64 10.0 / / / / HPMCP(HP55) / 3.0 / / / HPMC(K100LV) / / 4.0 / / HPMCAS(HG) / / / 2.0 / EUDRAGIT / / / / 6.0
  • Comparative Example 1 was prepared according to Example 5 of Patent CN109044977A, and Comparative Example 2 was prepared according to Example 146 of Patent WO2013105895A1, by replacing Nilotinib with Lenvatinib.
  • Preparation method Dissolve the API with a mixed solvent of dichloromethane and methanol (3:1), then add a polymer carrier to dissolve, and use Yamato spray drying unit for spray drying.
  • the inlet temperature is 100°C
  • the liquid inlet speed is 5, and the air volume is 7
  • the atomization pressure is 0.1MPa
  • the sprayed dry powder is collected. Dry the spray-dried powder under reduced pressure at 40°C for 24h, and the moisture content is less than 2%.
  • Genotoxic impurity B (ZZ-B) was detected by UPLC method, and total impurities were detected by HPLC method.
  • Preparation method Add API to dichloromethane methanol mixed solvent (3:1) to dissolve, then add stabilizer to dissolve, then add polymer carrier to dissolve, use Yamato spray drying unit for spray drying, inlet temperature 100°C, The liquid velocity is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and the resulting sprayed powder is collected. The spray-dried powder was dried under reduced pressure at 40°C for 4h. Put a small amount of dried and sprayed powder into a vial, crimp and seal it, and put it in a 60°C condition for 10 days. Genotoxic impurity B was detected by UPLC method, and total impurities were detected by HPLC method.
  • Example 3-14 Molecular level composition with HPMCAS as carrier, screening of optimal dosage of tromethamine and meglumine
  • Preparation method Add API to dichloromethane methanol mixed solvent (3:1) to dissolve, then add stabilizer to dissolve, then add polymer carrier to dissolve, use Yamato spray drying unit for spray drying, inlet temperature 100°C, The liquid velocity is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and the resulting sprayed powder is collected. The spray-dried powder was dried under reduced pressure at 40°C for 4h. Put a small amount of dried and sprayed powder into a vial, crimp and seal it, and put it in a 60°C condition for 10 days. Genotoxic impurity B was detected by UPLC method, and total impurities were detected by HPLC method.
  • the addition of tromethamine (Tris) in the prescription has a certain effect on stability, and the effect is better when the dosage API:Tris is 1:0.075-0.30, and the best is when API:Tris is 1:0.10-0.20. excellent.
  • Adding meglumine (Mglm) to the prescription has a certain effect on stability, and the effect is better when the amount of API:Mglm is 1:0.075-0.40, and the best when API:Mglm is 1:0.10-0.20.
  • the stabilizer is still effective when the active ingredient is changed to methanesulfonate.
  • Example 15 Comparative Examples 13-17: Preparation and stability investigation of different prescription molecular level compositions with HPMC as a carrier
  • Preparation method Add API to dichloromethane methanol mixed solvent (3:1) to dissolve, then add stabilizer to dissolve, then add polymer carrier to dissolve, use Yamato spray drying unit for spray drying, inlet temperature 100°C, The liquid velocity is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and the resulting sprayed powder is collected. The spray-dried powder was dried under reduced pressure at 40°C for 4h. Put a small amount of dried and sprayed powder into a vial, crimp and seal it, and put it in a 60°C condition for 10 days. Genotoxic impurity B was detected by UPLC method, and total impurities were detected by HPLC method.
  • Example 16-22 Screening of optimal dosage of sodium lauryl sulfate for molecular level composition of HPMC carrier
  • Example API HPMC(K15M) Sodium dodecyl sulfate Example 16 2.0 2.0 0.10 Example 17 2.0 2.0 0.20 Example 18 2.0 2.0 0.30 Example 19 2.0 2.0 0.40 Example 20 2.0 2.0 0.60 Example 21 2.0 2.0 0.80 Example 22 2.0 2.0 1.00
  • Preparation method Add API to dichloromethane methanol mixed solvent (3:1) to dissolve, then add stabilizer to dissolve, then add polymer carrier to dissolve, use Yamato spray drying unit for spray drying, inlet temperature 100°C, The liquid velocity is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and the resulting sprayed powder is collected. The spray-dried powder was dried under reduced pressure at 40°C for 4h. Put a small amount of dried and sprayed powder into a vial, crimp and seal it, and put it in a 60°C condition for 10 days. Genotoxic impurity B was detected by UPLC method, and total impurities were detected by HPLC method.
  • Example 23 Comparative Examples 18-22: Preparation and stability investigation of different prescription molecular level compositions with VA64 as a carrier
  • Preparation method Add API to dichloromethane methanol mixed solvent (3:1) to dissolve, then add stabilizer to dissolve, then add polymer carrier to dissolve, use Yamato spray drying unit for spray drying, inlet temperature 100°C, The liquid velocity is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and the resulting sprayed powder is collected. The spray-dried powder was dried under reduced pressure at 40°C for 4h. Put a small amount of dried and sprayed powder into a vial, crimp and seal it, and put it in a 60°C condition for 10 days. Genotoxic impurity B was detected by UPLC method, and total impurities were detected by HPLC method.
  • Example 24-30 Screening of optimal dosage of sodium lauryl sulfate for molecular level composition with VA64 as carrier
  • Example API VA64 Sodium dodecyl sulfate
  • Example 24 2.0 4.0 0.20
  • Example 25 2.0 4.0 0.40
  • Example 26 2.0 4.0 0.50
  • Example 27 2.0 4.0 0.80
  • Example 28 2.0 4.0 1.00
  • Example 29 2.0 4.0 1.20
  • Example 30 2.0 4.0 1.50
  • Preparation method Add API to dichloromethane methanol mixed solvent (3:1) to dissolve, then add stabilizer to dissolve, then add polymer carrier to dissolve, use Yamato spray drying unit for spray drying, inlet temperature 100°C, The liquid velocity is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and the resulting sprayed powder is collected. The spray-dried powder was dried under reduced pressure at 40°C for 4h. Put a small amount of dried and sprayed powder into a vial, crimp and seal it, and put it in a 60°C condition for 10 days. Genotoxic impurity B was detected by UPLC method, and total impurities were detected by HPLC method.
  • the dosage of sodium dodecyl sulfate (SDS) in the prescription is better when the API:SDS is 1:0.10-0.75, and the best is when the API:SDS is 1:0.40-0.75.
  • Example/Comparative Example Comparative example 23 Comparative example 24
  • Example 31 Comparative example 25
  • Comparative example 26 API 2.0 2.0 2.0 2.0 2.0 2.0 RL100 6.0 6.0 6.0 6.0 6.0 Tromethamine 0.30 / / / / Meglumine / 0.30 / / /
  • Preparation method Add API to dichloromethane methanol mixed solvent (3:1) to dissolve, then add stabilizer to dissolve, then add polymer carrier to dissolve, use Yamato spray drying unit for spray drying, inlet temperature 100°C, The liquid velocity is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and the resulting sprayed powder is collected. The spray-dried powder was dried under reduced pressure at 40°C for 4h. Put a small amount of dried and sprayed powder into a vial, crimp and seal it, and put it in a 60°C condition for 10 days. Genotoxic impurity B was detected by UPLC method, and total impurities were detected by HPLC method.
  • Example 32-38 Screening of optimal dosage of sodium lauryl sulfate for RL100 carrier molecular level composition
  • Example 32 2.0 6.0 0.10
  • Example 33 2.0 6.0 0.20
  • Example 34 2.0 6.0 0.30
  • Example 35 2.0 6.0 0.40
  • Example 36 2.0 6.0 0.60
  • Example 37 2.0 6.0 0.80
  • Example 38 2.0 6.0 1.00
  • Preparation method Add API to dichloromethane methanol mixed solvent (3:1) to dissolve, then add stabilizer to dissolve, then add polymer carrier to dissolve, use Yamato spray drying unit for spray drying, inlet temperature 100°C, The liquid velocity is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and the resulting sprayed powder is collected. The spray-dried powder was dried under reduced pressure at 40°C for 4h. Put a small amount of dried and sprayed powder into a vial, crimp and seal it, and put it in a 60°C condition for 10 days. Genotoxic impurity B was detected by UPLC method, and total impurities were detected by HPLC method.
  • Preparation method Add API to dichloromethane methanol mixed solvent (3:1) to dissolve, then add stabilizer to dissolve, then add polymer carrier to dissolve, use Yamato spray drying unit for spray drying, inlet temperature 100°C, The liquid velocity is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and the resulting sprayed powder is collected. The spray-dried powder was dried under reduced pressure at 40°C for 4h. Put a small amount of dried and sprayed powder into a vial, crimp and seal it, and put it in a 60°C condition for 10 days. Genotoxic impurity B was detected by UPLC method, and total impurities were detected by HPLC method.
  • Preparation method of Examples 49-51 Add the API and stabilizer to the dichloromethane methanol mixed solvent (3:1) to dissolve, then add the polymer carrier to dissolve, use Yamato spray drying unit for spray drying, the inlet temperature is 100°C , The liquid inlet speed is 5, the air volume is 7, and the atomization pressure is 0.1MPa, and the resulting sprayed powder is collected. The spray-dried powder was dried under reduced pressure at 40°C for 6h.
  • the preparation method of Examples 52-54 Add the stabilizer to the dichloromethane methanol mixed solvent (3:1) to dissolve, then add the API to dissolve, then add the polymer carrier to dissolve, use Yamato spray drying unit for spray drying, and air
  • the temperature is 100°C
  • the liquid inlet speed is 5
  • the air volume is 7,
  • the atomization pressure is 0.1MPa, and the resulting sprayed powder is collected.
  • the spray-dried powder was dried under reduced pressure at 40°C for 6h.
  • Example 55-57 Add API, stabilizer, and carrier to dichloromethane and methanol mixed solvent (3:1) to dissolve, and use Yamato spray drying unit for spray drying, air inlet temperature 100°C, liquid inlet speed 5 , The air volume is 7, the atomization pressure is 0.1MPa, and the resultant spray powder is collected. The spray-dried powder was dried under reduced pressure at 40°C for 6h.
  • a small amount of the above-prepared molecular level composition was put into a vial, crimped and sealed, and placed at 60° C. for inspection for 10 days.
  • Genotoxic impurity B was detected by UPLC method, and total impurities were detected by HPLC method.
  • Tablet preparation process Weigh each material according to the above table, pass through a 50-mesh sieve 8 times to mix, single-punch tablet machine (China National Pharmaceutical Longli DP30A), 10mm diameter shallow concave punch, and press.
  • Simulated gastric juice Nacl 10g, sodium taurocholate 0.2g, lecithin 0.075g, pepsin 0.5g, add purified water to 9.5L to dissolve, adjust the pH to 1.60 with 0.1M HCL;
  • Simulated intestinal juice 187ml of simulated gastric juice, plus 63ml of conditioning solution, to obtain simulated intestinal juice with a pH of about 6.5.
  • Paddle method 100rpm, 37°C, small cup method.
  • Sampling time points are 10, 15, and 30 minutes.
  • After 30 minutes of sampling and rehydration add 63ml of conditioning solution (37°C) to the dissolution cup to adjust to simulated intestinal juice, and continue to dissolve until 3 Hour, sampling point 35, 60, 120, 180min (Note: The above time includes simulated gastric juice time).
  • the sample is filtered with a 0.45 micron filter membrane, diluted with a 0.1M hydrochloric acid solution (to prevent the precipitation of the main drug in the detection process), and then sent to the analytical liquid phase for detection.
  • the original research agent In the simulated gastric juice, the dissolution reached 100% in 15 minutes, and there was no obvious precipitation after adjusting to the simulated intestinal juice, and the dissolution did not decrease significantly, and there was no significant decrease after 3 hours.
  • the dissolution of the prescription samples of the comparative examples and the examples is the same as the original preparation Compared with no significant difference.
  • the original research agent It still has excellent dissolution performance in as low as 187ml simulated gastric juice and 250ml simulated intestinal juice.
  • the molecular-level composition preparation does not show advantages in the two-step dissolution that simulates the physiological conditions of the human body.
  • Dissolution method 37°C, paddle method, 100rpm, small cup method.
  • the original research agent The dissolution reached 100% in 15 minutes in 0.1M hydrochloric acid solution, and there was no obvious precipitation after adjusting to pH 6.8 phosphate buffer, and the dissolution did not decrease significantly, and there was no significant decrease after 3 hours.
  • the dissolution of the prescription samples of the comparative examples and the examples is the same as the original preparation Compared with no significant difference.
  • the original research agent It still has excellent dissolution performance in as low as 187ml 0.1M hydrochloric acid solution and 250ml pH6.8 phosphate buffer.
  • the solid dispersion preparation shows no advantage in the two-step dissolution that simulates the physiological conditions of the human body. Based on this result, it is expected that the molecular-level composition preparation should not be too different from the original formulation in vivo.
  • Administration route and frequency single oral gavage, the animals are fasted for 10-14 hours before the administration, and feed is given 4 hours after the end of the administration. The animals eat freely during the rest of the experiment.
  • Dosage 4 mg (based on lenvatinib).
  • Groups and animals in each group a total of 10 beagle dogs, one in each group, cross-dosing for 10 cycles, the washout period at the end of each cycle is 3 days, and then the next cycle of dosing.
  • Blood collection before administration (0h), 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h and 24h after administration. Blood was collected by jugular vein puncture at 1 mL/time point, heparin sodium was anticoagulated, and placed on ice after collection.
  • Centrifugation conditions 2200g/min, 10 minutes, 2-8°C; store in -80°C refrigerator before analysis.
  • Bioanalysis and detection LC-MS/MS analysis of prototype drugs.
  • the dosage can be greatly reduced, and low-dose prescription administration can be achieved, while also reducing side effects; on the other hand, due to lower in vivo variability, adverse reactions can also be reduced .

Abstract

一种包含仑伐替尼的药物组合物及其制备方法和应用，特别涉及一种仑伐替尼分子水平的组合物，提供一种新的稳定性较好的仑伐替尼分子水平组合物。一个目的是提供一种可以服用相当于原研上市产品LENVIMA40％～50％的较低剂量组合物就可达到与原研上市产品LENVIMA相同的药效，显著降低了与给药剂量相关的副作用；另一个目的是提供仑伐替尼分子水平的药物组合物，其在生物体内具有较低的个体内及个体间变异性，降低了药物在血浆内暴露量突然升高造成的肾毒性和神经毒性或血浆暴露量突然降低造成的无效，提高了患者用药安全性。

Description

包含仑伐替尼的分子水平的药物组合物及其制备方法和应用 技术领域
本发明属于药物制剂领域，具体涉及包含仑伐替尼的药物组合物及其制备方法和应用，特别涉及一种仑伐替尼分子水平的组合物和低剂量仑伐替尼组合物。
背景技术
专利WO 2002032872、WO 2004080462公开了一种喹啉衍生物4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺(仑伐替尼)，具有很强的血管新生抑制作用和c-Kit激酶抑制作用，临床上可用于甲状腺癌、肺癌、黑色素瘤、胰腺癌、肾癌、肝癌等多种肿瘤的治疗。2015年卫材公司在美国上市了甲磺酸仑伐替尼胶囊，用于DTC(分化型甲状腺癌)的治疗，后又批准了RCC(肾细胞癌)、HCC(肝细胞癌)的治疗，商品名
Figure PCTCN2020089324-appb-000001
剂型为胶囊剂，规格为4mg、10mg，其临床上最大日剂量为24mg。
仑伐替尼结构如式I所示：
Figure PCTCN2020089324-appb-000002
有文献报道，仑伐替尼或其盐稳定性较差，如专利CN101001629报道，当将其制成药物组合物时，在加湿、加热保存条件下发生分解，分解机理如图1所示。
专利CN110404079A还报道了如下降解途径：4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺及其盐在强酸、强碱、水解及氧化条件下，特别是在碱性+湿热条件下还会大量生成4-(4-氨基-3-氯苯氧 基)-7-甲氧基喹啉-6-羧酸酰胺(如图2所示)。
根据原研卫材公司的
Figure PCTCN2020089324-appb-000003
FDA审评报告，4-(4-氨基-3-氯苯氧基)-7-甲氧基喹啉-6-羧酸酰胺为基因毒性杂质，因此其质控限度很低，
Figure PCTCN2020089324-appb-000004
原料中基因毒性杂质B控制限度为60ppm，在制剂中的控制限度为400ppm，远低于一般杂质的质控限度。
为了解决该产品稳定性问题，已经提出了几种解决方案：
CN101001629采用含有(i)其5％(W/W)水溶液或悬浊液的pH值在8以上的化合物、及/或(ii)硅酸或其盐或它们的溶剂合物。CN102470133采用碳酸镁或碳酸钙为稳定剂和溶出促进剂。专利CN106177965含有(A)选自碳酸钾、碳酸氢钾中的至少一种化合物，和(B)选自磷酸氢钙、磷酸钙或硫酸钙中的至少一种化合物。专利CN106075456、CN106551935采用磷酸氢钙来解决稳定性和溶出问题。以上稳定性解决方案，均针对普通制剂，也均未报道对基因毒性杂质B的稳定性效果。另外，以上方案中对杂质的检测均采用普通HPLC法，如上所述，因基因毒性杂质B质控限度为ppm级，普通HPLC法无法对其进行准确定量，因此，以上方案对基因毒性杂质B的稳定性效果未知。
相比普通制剂，在仑伐替尼固体分散体制剂中，仑伐替尼会很快的降解，且报道的常用稳定剂对其降解无明显效果，基因毒性杂质B在60℃放置10天就会大幅增加，超过制剂的质控限度(400ppm)。
因此，提供一种稳定的仑伐替尼制剂且该制剂具有较好的溶出特性是一种挑战。
另一方面，甲磺酸仑伐替尼和仑伐替尼还存在溶解度低的问题。为了提高溶解度，文献已经报道了几种方案：CN109044977A提供了一种仑伐替尼固体分散体，包括仑伐替尼和水溶性载体材料；所述仑伐替尼和所述水溶性载体材料的质量比为10∶1-1∶10。WO2013105895A1提供了一种包含至少一种蛋白激酶抑制剂和至少一种聚合物稳定与基质形成组分的稳定的、无定形杂化纳米颗粒的药物组合物；其中该组合物任选地进一步包含至少一种药学上可接受的增溶剂。
仑伐替尼原研公司(卫材)发表的文献(Int J Clin Pharmacol Ther.2015  Feb；53(2):190-8.)报道，其制备了不同晶型含量的甲磺酸乐伐替尼胶囊，经人体PK试验证实制剂中甲磺酸仑伐替尼C晶型含量小于4％(其余为无定形)与C晶型含量15％(其余为无定形)的制剂生物等效。据此可知，原研制剂
Figure PCTCN2020089324-appb-000005
中甲磺酸仑伐替尼也主要以无定形存在。
按专利CN109044977A、WO2013105895A1典型实施例制备的仑伐替尼固体分散体采用模拟人体生理条件的两步溶出法进行溶出试验，同
Figure PCTCN2020089324-appb-000006
相比溶出无改善，专利中也未报道仑伐替尼固体分散体同
Figure PCTCN2020089324-appb-000007
相比的体内药代动力学情况。
由此可知，单纯通过固体分散体技术并不能获得比原研制剂LENVIMA通过湿法制粒将溶解性差的甲磺酸盐C晶型转变为无定形后更优异的体外溶出效果，且在模拟人体生理条件的两步溶出介质中的溶出行为一致或无明显的改善，以上固体分散体解决方案无法获得预期生物体内的效果。
根据美国LENVIMA FDA Clinical Pharmacology and Biopharmaceutical Review,病人每天一次口服LENVIMA 24mg，68％的病人因为副作用无法耐受而不得不调整服用剂量，15％的病人因副作用而不得不终止服药；而最常见的副作用是高血压、尿蛋白、恶心、呕吐、腹泻；每天服用24mg和每天服14mg相比副作用发生的概率显著增高。
因此，如何用较少的药物服用剂量达到与原研高剂量组相同的治疗效果，且降低与剂量相关的副作用，提高病人耐受性，同时克服原研现有工艺造成的批间体外溶出差异及体内高变异，开发一种质量稳定、安全、有效、耐受性更好，具有显著临床优势的药物组合物存在极大挑战。
发明内容
有鉴于此，本发明为解决现有上市产品制剂中，仑伐替尼不稳定易降解、批间重现性差、体内高变异等问题，提供一种新的稳定性较好的仑伐替尼分子水平的药物组合物；本发明的一个目的是提供一种可以服用相当于原研上市产品LENVIMA40％～50％的较低剂量组合物就可达到与原研上市产品LENVIMA相同的药效，显著降低了与给药剂量相关的副作用； 本发明的另一个目的是提供仑伐替尼分子水平的药物组合物，其在生物体内具有较低的个体内及个体间变异性，降低了药物在血浆内暴露量突然升高造成的肾毒性和神经毒性或血浆暴露量突然降低造成的无效，提高了患者用药安全性。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了一种药物组合物，其包括仑伐替尼的分子水平组合物，所述仑伐替尼的分子水平组合物含有：
1)活性成分：仑伐替尼或其药学上可接受的盐或其溶剂合物；
2)稳定剂；
3)高分子载体；
所述药物组合物在60℃放置10天，基因毒性杂质B小于400ppm。
在本发明的一些具体实施方案中，所述药物组合物的药代动力学AUC 0-t相较原研制剂
Figure PCTCN2020089324-appb-000008
提高了至少40％。相应的，与现有上市药物
Figure PCTCN2020089324-appb-000009
比剂量或规格可以降低40％以上。
在本发明的一些具体实施方案中，所述药物组合物的药代动力学AUC 0-t相较原研制剂
Figure PCTCN2020089324-appb-000010
降低了变异性，优选CV≤30％。
在本发明的一些具体实施方案中，所述稳定剂选自氨丁三醇、葡甲胺或十二烷基硫酸钠中至少一种。
在本发明的一些具体实施方案中，所述高分子载体选自羟丙甲纤维素、羟丙纤维素、共聚维酮、羟丙甲纤维素邻苯二甲酸酯、聚维酮、醋酸羟丙甲纤维素琥珀酸酯、羟乙基纤维素、丙烯酸树脂中至少一种。
在本发明的一些具体实施方案中，所述高分子载体选自羟丙甲纤维素、共聚维酮、羟丙甲纤维素邻苯二甲酸酯、醋酸羟丙甲纤维素琥珀酸酯、丙烯酸树脂、聚维酮中的至少一种。
在本发明的一些具体实施方案中，所述其药学上可接受的盐选自仑伐替尼的盐酸盐、氢溴酸盐、对甲苯磺酸盐、甲磺酸盐、硫酸盐或乙磺酸盐中的至少一种，优选甲磺酸仑伐替尼。
在本发明的一些具体实施方案中，所述仑伐替尼或其药学上可接受的盐的溶剂合物为水合物、二甲基亚砜合物或乙酸合物。
在本发明的一些具体实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:(0.05～0.75):(0.5～10)，优选1:(0.05～0.6):(1～5)，进一步优选1:(0.1～0.6):(1～3)。
在本发明的一些具体实施方案中，所述药物组合物包括如下方案：
(1)所述稳定剂为氨丁三醇，所述高分子载体为醋酸羟丙甲纤维素琥珀酸酯；
所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼；
所述活性成分、稳定剂、高分子载体的重量比为1:(0.05～0.75):(0.5～10)，优选为1:(0.05～0.4):(1～5)，更优选为1:(0.075～0.3):(1～2)，进一步优选为1:(0.1～0.3):(1～2)；
或(2)所述稳定剂为葡甲胺，所述高分子载体为醋酸羟丙甲纤维素琥珀酸酯；
所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼；
所述活性成分、稳定剂、高分子载体的重量比为1:(0.05～0.75):(0.5～10)，优选为1:(0.05～0.4):(1～5)，更优选为1:(0.075～0.3):(1～2)，进一步优选为1:(0.1～0.3):(1～2)；
或(3)所述稳定剂为十二烷基硫酸钠，所述高分子载体为羟丙甲纤维素；
所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼；
所述活性成分、稳定剂、高分子载体的重量比为1:(0.075～0.5):(1～5)，优选为1:(0.15～0.5):(1～3)，更优选为1:(0.15～0.25):(1～2)；
或(4)所述稳定剂为十二烷基硫酸钠，所述高分子载体为共聚维酮；
所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼；
所述活性成分、稳定剂、高分子载体的重量比为1:(0.1～0.75):(1～5)，优选为1:(0.4～0.75):(2～3)，更优选为1:(0.4～0.6):(2～3)；
或(5)所述稳定剂为十二烷基硫酸钠，所述高分子载体为丙烯酸乙酯-甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯共聚物；
所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼；
所述活性成分、稳定剂、高分子载体的重量比为1:(0.1～0.5):(1～5)， 优选为1:(0.2～0.5):(2～3)，更优选为1:(0.2～0.3):3。
或(6)所述稳定剂为十二烷基硫酸钠，所述高分子载体为聚维酮；
所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼；
所述活性成分、稳定剂、高分子载体的重量比为1:(0.05～0.75):(1～10)，优选为1:(0.2～0.5):(2～3)，更优选为1:(0.2～0.3):3。
在本发明的一些具体实施方案中，所述药物组合物还含有药学上可接受的赋形剂，所述赋形剂选自填充剂、崩解剂、粘合剂、润滑剂、矫味剂、助悬剂中的至少一种。
在本发明的一些具体实施方案中，所述药物组合物的剂型为胶囊剂、片剂、颗粒剂、混悬剂，优选为胶囊剂、片剂，更优选为片剂。
在上述研究的基础上，本发明还提供了一种溶解仑伐替尼或其药学上可接受的盐或其溶剂合物的潜溶剂，所述潜溶剂包含卤代甲烷和醇类。
在本发明的一些具体实施方案中，所述醇类优选甲醇和/或乙醇。
在本发明的一些具体实施方案中，所述卤代甲烷优选为二氯甲烷。
在本发明的一些具体实施方案中，所述卤代甲烷与醇类的比例为10:2～10:10，优选为10:2～10:5，更优选为10:3～10:5。
在本发明的一些具体实施方案中，所述潜溶剂包括如下方案：
(1)所述潜溶剂包含二氯甲烷和甲醇；
二氯甲烷和甲醇的比例为10:2～10:10，优选为10:3～10:5；
或(2)所述潜溶剂包含二氯甲烷和乙醇；
二氯甲烷和乙醇的比例为10:3～10:10，优选为10:4～10:5。
此外，本发明还提供了一种提高仑伐替尼或其药学上可接受的盐或其溶剂合物的溶解度的方法，使用所述的潜溶剂。
在上述研究的基础上，本发明还提供了仑伐替尼的分子水平组合物的制备方法，包括将所述的活性成分、稳定剂及高分子载体溶解在有机溶剂中，喷雾干燥，获得固体分散剂。
在本发明的一些具体实施方案中，所述有机溶剂为所述的潜溶剂。
本发明还提供了所述的药物组合物或如所述制备方法制备的仑伐替尼的分子水平组合物在制备治疗或预防癌症/肿瘤的药物中的应用。在本 发明的一些具体实施方案中，所述癌症/肿瘤为甲状腺癌、肾细胞癌、肝癌、胃癌或肺癌。
本发明还提供了一种治疗或预防癌症/肿瘤的方法，使用了所述的药物组合物或述的制备方法制备的仑伐替尼的分子水平组合物。在本发明的一些具体实施方案中，所述癌症/肿瘤为甲状腺癌、肾细胞癌、肝癌、胃癌或肺癌。
本发明提供了一种新的稳定性较好的仑伐替尼分子水平组合物，能够明显提高体内的生物利用度。本发明还提供了一种治疗或预防癌症/肿瘤的方法，使用了所述的药物组合物或述的制备方法制备的仑伐替尼的分子水平组合物。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1示当将仑伐替尼或其盐制成药物组合物时，在加湿、加热保存条件下发生分解的分解机理；
图2示仑伐替尼的降解途径；
图3示式(I)化合物：4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺的DSC；
图4示式(I)化合物：4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺的TGA；
图5示式(I)化合物：4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺的XRPD；
图6示式(I)化合物：4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺的IR；
图7示对比例1样品DSC图，由图可知仑伐替尼在234℃的峰消失，提示形成分子水平组合物；
图8示对比例3样品DSC图，由图可知仑伐替尼在234℃的峰消失，提示形成分子水平组合物；
图9示对比例4样品DSC图，由图可知仑伐替尼在234℃的峰消失，提示形成分子水平组合物；
图10示仑伐替尼、HPMCAS、氨丁三醇物理混合物DSC图；
图11示实施例8样品DSC图，由图可知仑伐替尼在234℃的峰消失，提示形成分子水平组合物；
图12示实施例14样品DSC图，由图可知仑伐替尼在234℃的峰消失，提示形成分子水平组合物；
图13示仑伐替尼、HPMC K15M、SDS物理混合物DSC图；
图14示实施例19样品DSC图，由图可知仑伐替尼在234℃的峰消失，提示形成分子水平组合物；
图15示实施例22样品DSC图，由图可知仑伐替尼在234℃的峰消失，提示形成分子水平组合物；
图16示仑伐替尼、共聚维酮VA64、SDS物理混合物DSC图；
图17示实施例29样品DSC图，由图可知仑伐替尼在234℃的峰消失，提示形成分子水平组合物；
图18示实施例30样品DSC图，由图可知仑伐替尼在234℃的峰消失，提示形成分子水平组合物；
图19示仑伐替尼、
Figure PCTCN2020089324-appb-000011
SDS物理混合物DSC图；
图20示实施例35样品DSC图，由图可知仑伐替尼在234℃的峰消失，提示形成分子水平组合物；
图21示实施例38样品DSC图，由图可知仑伐替尼在234℃的峰消失，提示形成分子水平组合物；
图22示仑伐替尼、聚维酮、SDS物理混合物DSC图；
图23示实施例43样品DSC图，由图可知仑伐替尼在234℃的峰消失，提示形成分子水平组合物；
图24示实施例49样品DSC图，由图可知仑伐替尼在234℃的峰消失，提示形成分子水平组合物；
图25示实施例50样品DSC图，由图可知仑伐替尼在234℃的峰消失，提示形成分子水平组合物；
图26示实施例51样品DSC图，由图可知仑伐替尼在234℃的峰消失，提示形成分子水平组合物；
图27示实施例52样品DSC图，由图可知仑伐替尼在234℃的峰消失，提示形成分子水平组合物；
图28示原研制剂
Figure PCTCN2020089324-appb-000012
实施例、对比例模拟胃液+模拟肠液溶出曲线图，由图可知分子水平组合物制剂同原研制剂比溶出无明显差异；
图29示原研制剂
Figure PCTCN2020089324-appb-000013
对比例28-32 0.1M HCl+pH 6.8磷酸盐缓冲液溶出曲线图，由图可知分子水平组合物制剂同原研制剂比溶出无明显差异；
图30示原研制剂
Figure PCTCN2020089324-appb-000014
实施例58-63 0.1M HCl+pH 6.8磷酸盐缓冲液溶出曲线图，由图可知分子水平组合物制剂同原研制剂比溶出无明显差异；
图31示原研制剂
Figure PCTCN2020089324-appb-000015
对比例33、实施例64-66 0.1M HCl+pH6.8磷酸盐缓冲液溶出曲线图，由图可知分子水平组合物制剂同原研制剂比溶出无明显差异；
图32示原研制剂
Figure PCTCN2020089324-appb-000016
对比例34、实施例67-69 0.1M HCl+pH6.8磷酸盐缓冲液溶出曲线图，由图可知分子水平组合物制剂同原研制剂比溶出无明显差异；
图33示原研制剂
Figure PCTCN2020089324-appb-000017
实施例70-74 0.1M HCl+pH 6.8磷酸盐缓冲液溶出曲线图，由图可知分子水平组合物制剂同原研制剂比溶出无明显差异；
图34示原研制剂
Figure PCTCN2020089324-appb-000018
实施例75-80 0.1M HCl+pH 6.8磷酸盐缓冲液溶出曲线图，由图可知分子水平组合物制剂同原研制剂比溶出无明显差异。
具体实施方式
本发明公开了包含仑伐替尼的药物组合物及其制备方法和应用，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的 是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
本发明为解决现有仑伐替尼分子水平组合物制剂中，仑伐替尼不稳定易降解、批间重现性差、体内高变异等问题，提供一种新的稳定性较好的仑伐替尼分子水平的药物组合物；本发明的一个目的是提供一种可以服用相当于原研上市产品LENVIMA40％～50％的较低剂量组合物就可达到与原研上市产品LENVIMA相同的药效，显著降低了与给药剂量相关的副作用；本发明的另一个目的是提供仑伐替尼分子水平的药物组合物，其在生物体内具有较低的个体内及个体间变异性，降低了药物在血浆内暴露量突然升高造成的肾毒性和神经毒性或血浆暴露量突然降低造成的无效，提高了患者用药安全性。
为此，本发明第一方面提供一种药物组合物，其包括仑伐替尼的分子水平组合物，所述仑伐替尼的分子水平组合物含有：
1)活性成分：仑伐替尼或其药学上可接受的盐或其溶剂合物；
2)稳定剂；
3)高分子载体，
其中，所述稳定剂选自氨丁三醇、葡甲胺、十二烷基硫酸钠中至少一种。
在本发明还提供一种低剂量仑伐替尼组合物，其包括上述分子水平组合物，其剂型可以为胶囊剂、片剂、颗粒剂、混悬剂，优选为胶囊剂、片剂，更优选为片剂。
通过制备具有低剂量的分子水平组合物以使其在生物体内表现出与原研LENVIMA制剂或其仿制品比相似或增加的AUC；以低于通常或常规剂量的剂量给药也可以减少副作用。
如本文所用，术语“低剂量”是指仑伐替尼(或其药学上可接受的盐或溶剂合物)的治疗有效剂量，该剂量小于产生相等或更高治疗效果所需的常规或常规剂量。
仑伐替尼(或其药学上可接受的盐或溶剂合物)可以每天至少一次施用，剂量范围为约1mg至约30mg。优选地，仑伐替尼(或其药学上可接受的盐或溶剂合物)可以每天至少一次施用，剂量范围为约1mg至约20mg。优选地，仑伐替尼(或其药学上可接受的盐或溶剂合物)可以每天至少一次施用，剂量范围为约1mg至约15mg。
在本发明的一些实施方案中，所述高分子载体选自羟丙甲纤维素、羟丙纤维素、共聚维酮、羟丙甲纤维素邻苯二甲酸酯、聚维酮、醋酸羟丙甲纤维素琥珀酸酯、羟乙基纤维素、丙烯酸树脂中至少一种。
在本发明的一些优选的实施方案中，所述高分子载体选自羟丙甲纤维素(HPMC)、共聚维酮(VA64)、羟丙甲纤维素邻苯二甲酸酯(HPMCP)、醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)、丙烯酸乙酯-甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯共聚物
Figure PCTCN2020089324-appb-000019
聚维酮中的至少一种。
在本发明的另一些实施方案中，所述仑伐替尼药学上可接受的盐选自仑伐替尼的盐酸盐、氢溴酸盐、对甲苯磺酸盐、甲磺酸盐、硫酸盐或乙磺酸盐中的至少一种。
在本发明的另一些优选的实施方案中，所述仑伐替尼药学上可接受的盐为甲磺酸仑伐替尼。
在本发明的一些实施方案中，所述仑伐替尼或其药学上可接受的盐的溶剂合物为水合物、二甲基亚砜合物或乙酸合物。
在本发明的另一些实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.05-0.75:0.5-10。
在本发明的另一些优选的实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.05-0.6:1-5。
在本发明的另一些更为优选的实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.1-0.6:1-3。
在本发明的一些实施方案中，所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼，所述稳定剂为氨丁三醇，所述高分子载体为醋酸羟丙甲纤维素琥珀酸酯，所述活性成分、稳定剂、高分子载体的重量比 为1:0.05-0.75:0.5-10。
在本发明的一些实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.05-0.4:1-5。
在本发明的另一些实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.075-0.3:1-2。
在本发明的另一些优选的实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.1-0.3:1-2。
在本发明的另一些更为优选的实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.15:1。
在本发明的一些实施方案中，所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼，所述稳定剂为葡甲胺，所述高分子载体为醋酸羟丙甲纤维素琥珀酸酯，所述活性成分、稳定剂、高分子载体的重量比为1:0.05-0.75:0.5-10。
在本发明的一些实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.05-0.4:1-5。
在本发明的另一些实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.075-0.3:1-2。
在本发明的另一些优选的实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.1-0.3:1-2。
在本发明的另一些更为优选的实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.15:1。
在本发明的一些实施方案中，所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼，所述稳定剂为十二烷基硫酸钠，所述高分子载体为羟丙甲纤维素，所述活性成分、稳定剂、高分子载体的重量比为1:0.075-0.5:1-5。
在本发明的另一些实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.15-0.5:1-3。
在本发明的另一些优选的实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.15-0.25:1-2。
在本发明的另一些更为优选的实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.2:1。
在本发明的一些实施方案中，所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼，所述稳定剂为十二烷基硫酸钠，所述高分子载体为共聚维酮，所述活性成分、稳定剂、高分子载体的重量比为1:0.1-0.75:1-5。
在本发明的另一些实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.4-0.75:2-3。
在本发明的另一些优选的实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.4-0.6:2-3。
在本发明的另一些更为优选的实施方案中，所述活性成分、稳定剂、高分子载体的重量比1:0.6:2。
在本发明的一些实施方案中，所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼，所述稳定剂为十二烷基硫酸钠，所述高分子载体为丙烯酸乙酯-甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯共聚物，所述活性成分、稳定剂、高分子载体的重量比为1:0.1-0.5:1-5。
在本发明的一些优选的实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.2-0.5:2-3。
在本发明的另一些优选的实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.2-0.3:3。
在本发明的另一些更为优选的实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.2:3。
在本发明的一些实施方案中，所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼，所述稳定剂为十二烷基硫酸钠，所述高分子载体为聚维酮，所述活性成分、稳定剂、高分子载体的重量比为1:0.05-0.75:1-10。
在本发明的另一些实施方案中，所述活性成分、稳定剂、高分子载体的重量比为1:0.2-0.75:2-5。
在本发明的另一些优选的实施方案中，所述活性成分、稳定剂、高分 子载体的重量比为1:0.4-0.6:2-4。
在本发明的另一些更为优选的实施方案中，所述活性成分、稳定剂、高分子载体的重量比1:0.6:3。
在本发明的一些实施方案中，所述药物组合物的剂型为胶囊剂、片剂、颗粒剂、混悬剂，优选为胶囊剂、片剂，更优选为片剂。
为了制备便于病人使用的剂型，该组合物中还可以含有适宜的赋形剂，如填充剂、崩解剂、粘合剂、润滑剂、助流剂等，这些赋形剂可以根据剂型的需要加入其中的一种或多种。作为上述填充剂，可以列举出淀粉、微晶纤维素、预胶化淀粉、麦芽糖醇、山梨醇、海藻糖、磷酸钙、磷酸氢钙、硫酸钙、乳糖等。作为上述崩解剂，可以列举出干淀粉、预胶化淀粉、交联羧甲基纤维素钠、羧甲纤维素钙、羧甲基淀粉钠、低取代羟丙基纤维素、交联聚维酮等。作为上述粘合剂，可以列举出羟丙纤维素、羟丙甲纤维素、聚维酮、羧甲基纤维素钠、淀粉浆、阿拉伯胶等。作为上述润滑剂，可以列举出硬脂酸镁、硬脂酸钙、硬脂富马酸钠、滑石粉、硬脂酸、聚乙二醇、山嵛酸甘油酯等。作为上述助流剂，可以列举出二氧化硅、滑石粉、山嵛酸甘油酯等。
本发明第二方面提供一种溶解仑伐替尼或其药学上可接受的盐或其溶剂合物的潜溶剂，所述潜溶剂包含卤代甲烷和醇类，所述卤代甲烷与醇类的比例为10:2-10:10，优选为10:2-10:5，更优选为10:3-10:5，所述醇类优选甲醇和/或乙醇，所述卤代甲烷优选为二氯甲烷和/或三氯甲烷。
在本发明的一些优选的实施方案中，所述潜溶剂包含二氯甲烷和甲醇，二者比例为10:2-10:10，优选为10:3-10:5。
在本发明的另一些优选的实施方案中，所述潜溶剂包含二氯甲烷和乙醇，二者比例为10:3-10:10，优选为10:4-10:5。
本发明第三方面提供仑伐替尼的分子水平组合物的制备方法，包括将第一方面所述的活性成分、稳定剂及高分子载体溶解在有机溶剂中，喷雾干燥，获得固体分散剂，其中，所述有机溶剂为第二方面所述的潜溶剂。
优选的，先将0-100％的稳定剂溶解在混合溶剂中，再加入载体和活性成分和剩余的稳定剂溶解，喷雾干燥，获得分子水平组合物。更优选的， 先将0-50％的稳定剂溶解在混合溶剂中，再加入载体溶解，再加入活性成分和剩余的稳定剂溶解，喷雾干燥，获得分子水平组合物。必要时可以采用减压干燥进一步去除残留溶剂。
在本发明的一些实施方案中，将仑伐替尼分子水平组合物及填充剂、崩解剂、粘合剂等混合，制粒，整粒，总混，压片或填充胶囊。也可以将仑伐替尼分子水平组合物及填充剂、崩解剂、粘合剂等混合，直接压片或装胶囊。
本发明第四方面提供仑伐替尼的分子水平组合物在制备治疗或预防癌症/肿瘤的药物中的应用，其中，所述癌症/肿瘤为甲状腺癌、肾细胞癌、肝癌、胃癌、肺癌，但不限于上述种类。
下述实施例中的实验方法，如果没有特殊说明，均为常规实验方法。实验所用到的原料药、试剂、试剂盒、实验仪器，如无特殊说明，均可市售购买得到。
附图3～7分别展示了4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺(仑伐替尼)的DSC(差示扫描量热法)、TGA(热重分析)、XRPD(X-射线粉末衍射)及IR(红外光谱分析)结果。
下面结合实施例，进一步阐述本发明：
实验例1 仑伐替尼溶解溶剂筛选
称取仑伐替尼原料药(API)，加入有机溶剂50℃水浴加热并振摇30min，使原料药溶解。
表1 单一有机溶剂筛选
Figure PCTCN2020089324-appb-000020
Figure PCTCN2020089324-appb-000021
由以上结果可知，N-甲基吡咯烷酮、二甲基亚砜、N,N-二甲基甲酰胺三种溶解溶解度较大，但这三种溶剂沸点很高，不适合喷雾干燥时作为溶剂使用。另外，二氯甲烷、甲醇、乙醇单独应用时仑伐替尼溶解度非常低。
表2 混合有机溶剂筛选(2:1)
Figure PCTCN2020089324-appb-000022
根据以上结果，我们惊喜的发现二氯甲烷和甲醇混合溶剂、二氯甲烷和无水乙醇混合溶剂对仑伐替尼溶解度大幅提高，为了探索最佳比例，对这两种混合溶剂体系进行了进一步筛选。
表3 二氯甲烷-甲醇溶剂体系
Figure PCTCN2020089324-appb-000023
Figure PCTCN2020089324-appb-000024
根据以上结果可知，二氯甲烷甲醇混合溶剂，当二者比例在10:2-10:10范围内时溶解度较大，在10:3-10:5范围时溶解度最大。
表4 二氯甲烷-乙醇溶剂体系
Figure PCTCN2020089324-appb-000025
根据以上结果可知，二氯甲烷无水乙醇混合溶剂，当二者比例在10:3-10:10范围内时溶解度较大，在10:4-10:5范围时溶解度最大。
实验例2 分子水平组合物制备及稳定性考察
表5 对比例分子水平组合物处方(g)
对比例 1 2 3 4 5
API 2.0 2.0 2.0 2.0 2.0
VA64 10.0 / / / /
HPMCP(HP55) / 3.0 / / /
HPMC(K100LV) / / 4.0 / /
HPMCAS(HG) / / / 2.0 /
EUDRAGIT / / / / 6.0
(RL100)          
注：对比例1根据专利CN109044977A实施例5制备，对比例2根据专利WO2013105895A1实施例146，将尼罗替尼换为仑伐替尼制备。
制备方法：将API加入二氯甲烷甲醇混合溶剂(3:1)溶解，再加入高分子载体溶解，采用雅马拓喷雾干燥机组进行喷雾干燥，进风温度100℃，进液速度5，风量7，雾化压力0.1MPa，收集所得喷干粉。将喷干粉40℃减压干燥24h，水分均低于2％。
将表5制备的分子水平组合物取适量与稳定剂过80目筛8遍混合，放入西林瓶，轧盖密封，放入60℃条件考察10天。基因毒性杂质B(ZZ-B)采用UPLC法检测，总杂采用HPLC法检测。
表6 不同分子水平组合物稳定剂筛选结果
Figure PCTCN2020089324-appb-000026
Figure PCTCN2020089324-appb-000027
Figure PCTCN2020089324-appb-000028
Figure PCTCN2020089324-appb-000029
Figure PCTCN2020089324-appb-000030
Figure PCTCN2020089324-appb-000031
由上表可知，专利文献中公布的常用稳定剂均对仑伐替尼分子水平组合物没有明显效果，其在60℃放置10天，基因毒性杂质B均大于400ppm。
实施例1、2，对比例6-12：HPMCAS为载体的不同处方分子水平组合物制备及稳定性考察
表7 分子水平组合物处方(g)
Figure PCTCN2020089324-appb-000032
制备方法：将API加入二氯甲烷甲醇混合溶剂(3:1)溶解，再加入 稳定剂溶解，再加入高分子载体溶解，采用雅马拓喷雾干燥机组进行喷雾干燥，进风温度100℃，进液速度5，风量7，雾化压力0.1MPa，收集所得喷干粉。将喷干粉40℃减压干燥4h。将少量干燥后喷干粉放入西林瓶，轧盖密封，放入60℃条件考察10天。基因毒性杂质B采用UPLC法检测，总杂采用HPLC法检测。
表8 HPMCAS载体处方稳定性结果
Figure PCTCN2020089324-appb-000033
根据以上结果可知，对仑伐替尼分子水平组合物，我们惊喜的发现处方内加氨丁三醇或葡甲胺对稳定性有较明显效果，60℃条件考察10天基因毒性杂质B均小于400ppm，其他稳定剂无明显效果。
实施例3-14：HPMCAS为载体的分子水平组合物，氨丁三醇和葡甲胺最佳用量筛选
表9 分子水平组合物处方(g)
Figure PCTCN2020089324-appb-000034
Figure PCTCN2020089324-appb-000035
制备方法：将API加入二氯甲烷甲醇混合溶剂(3:1)溶解，再加入稳定剂溶解，再加入高分子载体溶解，采用雅马拓喷雾干燥机组进行喷雾干燥，进风温度100℃，进液速度5，风量7，雾化压力0.1MPa，收集所得喷干粉。将喷干粉40℃减压干燥4h。将少量干燥后喷干粉放入西林瓶，轧盖密封，放入60℃条件考察10天。基因毒性杂质B采用UPLC法检测，总杂采用HPLC法检测。
表10 HPMCAS载体处方稳定性结果(API 2.0g+HPMCAS 2.0g)
Figure PCTCN2020089324-appb-000036
Figure PCTCN2020089324-appb-000037
根据以上结果可知，处方中加氨丁三醇(Tris)对稳定性有一定效果，且用量API:Tris为1:0.075-0.30时效果较好，在API:Tris为1:0.10-0.20时最优。处方中加葡甲胺(Mglm)对稳定性有一定效果，且用量API:Mglm为1:0.075-0.40时效果较好，在API:Mglm为1:0.10-0.20时最优。
将活性成分改为甲磺酸盐时稳定剂仍有效果。
实施例15，对比例13-17：HPMC为载体的不同处方分子水平组合物制备及稳定性考察
表11 分子水平组合物处方(g)
Figure PCTCN2020089324-appb-000038
制备方法：将API加入二氯甲烷甲醇混合溶剂(3:1)溶解，再加入稳定剂溶解，再加入高分子载体溶解，采用雅马拓喷雾干燥机组进行喷雾干燥，进风温度100℃，进液速度5，风量7，雾化压力0.1MPa，收集所得喷干粉。将喷干粉40℃减压干燥4h。将少量干燥后喷干粉放入西林瓶，轧盖密封，放入60℃条件考察10天。基因毒性杂质B采用UPLC法检测，总杂采用HPLC法检测。
表12 HPMC载体处方稳定性结果
Figure PCTCN2020089324-appb-000039
根据以上结果可知，对以HPMC为载体的仑伐替尼分子水平组合物，我们惊喜的发现处方内加十二烷基硫酸钠对稳定性有较明显效果，其他稳定剂(包括HPMCAS载体有明显效果的氨丁三醇和葡甲胺)无明显效果。
实施例16-22：HPMC载体的分子水平组合物十二烷基硫酸钠最佳用量筛选
表13 分子水平组合物处方(g)
实施例 API HPMC(K15M) 十二烷基硫酸钠
实施例16 2.0 2.0 0.10
实施例17 2.0 2.0 0.20
实施例18 2.0 2.0 0.30
实施例19 2.0 2.0 0.40
实施例20 2.0 2.0 0.60
实施例21 2.0 2.0 0.80
实施例22 2.0 2.0 1.00
制备方法：将API加入二氯甲烷甲醇混合溶剂(3:1)溶解，再加入稳定剂溶解，再加入高分子载体溶解，采用雅马拓喷雾干燥机组进行喷雾干燥，进风温度100℃，进液速度5，风量7，雾化压力0.1MPa，收集所得喷干粉。将喷干粉40℃减压干燥4h。将少量干燥后喷干粉放入西林瓶，轧盖密封，放入60℃条件考察10天。基因毒性杂质B采用UPLC法检测， 总杂采用HPLC法检测。
表14 HPMC载体处方稳定性结果(API 2.0g+HPMC 2.0g)
Figure PCTCN2020089324-appb-000040
根据以上结果可知，处方中加十二烷基硫酸钠(SDS)，用量API:SDS为1:0.075-0.50时效果较好，在API:SDS为1:0.15-0.50时最优。
实施例23，对比例18-22：VA64为载体的不同处方分子水平组合物制备和稳定性考察
表15 分子水平组合物处方(g)
Figure PCTCN2020089324-appb-000041
制备方法：将API加入二氯甲烷甲醇混合溶剂(3:1)溶解，再加入稳定剂溶解，再加入高分子载体溶解，采用雅马拓喷雾干燥机组进行喷雾干燥，进风温度100℃，进液速度5，风量7，雾化压力0.1MPa，收集所得喷干粉。将喷干粉40℃减压干燥4h。将少量干燥后喷干粉放入西林瓶，轧盖密封，放入60℃条件考察10天。基因毒性杂质B采用UPLC法检测，总杂采用HPLC法检测。
表16 VA64载体处方稳定性结果
Figure PCTCN2020089324-appb-000042
根据以上结果可知，对以VA64为载体的仑伐替尼分子水平组合物，我们惊喜的发现内加十二烷基硫酸钠对稳定性有一定效果，其他稳定剂无明显效果。
实施例24-30：VA64为载体的分子水平组合物十二烷基硫酸钠最佳用量筛选
表17 分子水平组合物处方(g)
实施例 API VA64 十二烷基硫酸钠
实施例24 2.0 4.0 0.20
实施例25 2.0 4.0 0.40
实施例26 2.0 4.0 0.50
实施例27 2.0 4.0 0.80
实施例28 2.0 4.0 1.00
实施例29 2.0 4.0 1.20
实施例30 2.0 4.0 1.50
制备方法：将API加入二氯甲烷甲醇混合溶剂(3:1)溶解，再加入稳定剂溶解，再加入高分子载体溶解，采用雅马拓喷雾干燥机组进行喷雾干燥，进风温度100℃，进液速度5，风量7，雾化压力0.1MPa，收集所得喷干粉。将喷干粉40℃减压干燥4h。将少量干燥后喷干粉放入西林瓶，轧盖密封，放入60℃条件考察10天。基因毒性杂质B采用UPLC法检测，总杂采用HPLC法检测。
表18 VA64载体处方稳定性结果(API 2.0g+VA64 4.0g)
Figure PCTCN2020089324-appb-000043
根据以上结果可知，处方中加十二烷基硫酸钠(SDS)用量API:SDS为1:0.10-0.75时效果较好，在API:SDS为1:0.40-0.75时最优。
实施例31，对比例23-26：
Figure PCTCN2020089324-appb-000044
不同处方分子水平组合物制备
表19 分子水平组合物处方(g)
实施例/对比例 对比例23 对比例24 实施例31 对比例25 对比例26
API 2.0 2.0 2.0 2.0 2.0
RL100 6.0 6.0 6.0 6.0 6.0
氨丁三醇 0.30 / / / /
葡甲胺 / 0.30 / / /
十二烷基硫酸钠 / / 0.30 / /
二乙胺 / / / 0.30 /
三乙醇胺 / / / / 0.30
制备方法：将API加入二氯甲烷甲醇混合溶剂(3:1)溶解，再加入稳定剂溶解，再加入高分子载体溶解，采用雅马拓喷雾干燥机组进行喷雾干燥，进风温度100℃，进液速度5，风量7，雾化压力0.1MPa，收集所得喷干粉。将喷干粉40℃减压干燥4h。将少量干燥后喷干粉放入西林瓶，轧盖密封，放入60℃条件考察10天。基因毒性杂质B采用UPLC法检测，总杂采用HPLC法检测。
表20 RL100载体处方稳定性结果
Figure PCTCN2020089324-appb-000045
根据以上结果可知，对以RL100为载体的仑伐替尼分子水平组合物，我们惊喜的发现内加十二烷基硫酸钠对稳定性有一定效果，其他稳定剂无明显效果。
实施例32-38：RL100载体分子水平组合物十二烷基硫酸钠最佳用量筛选
表21 分子水平组合物处方(g)
实施例 API RL100 十二烷基硫酸钠
实施例32 2.0 6.0 0.10
实施例33 2.0 6.0 0.20
实施例34 2.0 6.0 0.30
实施例35 2.0 6.0 0.40
实施例36 2.0 6.0 0.60
实施例37 2.0 6.0 0.80
实施例38 2.0 6.0 1.00
制备方法：将API加入二氯甲烷甲醇混合溶剂(3:1)溶解，再加入稳定剂溶解，再加入高分子载体溶解，采用雅马拓喷雾干燥机组进行喷雾干燥，进风温度100℃，进液速度5，风量7，雾化压力0.1MPa，收集所得喷干粉。将喷干粉40℃减压干燥4h。将少量干燥后喷干粉放入西林瓶，轧盖密封，放入60℃条件考察10天。基因毒性杂质B采用UPLC法检测，总杂采用HPLC法检测。
表22 RL100载体处方稳定性结果(API 2.0g+RL100 6.0g)
Figure PCTCN2020089324-appb-000046
根据以上结果可知，处方内加十二烷基硫酸钠(SDS)用量API:SDS为1:0.10-0.50时效果较好，在API:SDS为1:0.20-0.50时最优。
实施例39-30：聚维酮为载体的分子水平组合物制备
表23 聚维酮载体分子水平组合物处方(g)
Figure PCTCN2020089324-appb-000047
Figure PCTCN2020089324-appb-000048
制备方法：将API加入二氯甲烷甲醇混合溶剂(3:1)溶解，再加入稳定剂溶解，再加入高分子载体溶解，采用雅马拓喷雾干燥机组进行喷雾干燥，进风温度100℃，进液速度5，风量7，雾化压力0.1MPa，收集所得喷干粉。将喷干粉40℃减压干燥4h。将少量干燥后喷干粉放入西林瓶，轧盖密封，放入60℃条件考察10天。基因毒性杂质B采用UPLC法检测，总杂采用HPLC法检测。
表24 聚维酮载体处方稳定性结果
Figure PCTCN2020089324-appb-000049
Figure PCTCN2020089324-appb-000050
根据以上结果可知，在以聚维酮为载体的分子水平组合物处方中加十二烷基硫酸钠(SDS)可以改善ZZ-B杂质的产生，用量API:SDS为1:0.10-0.75时效果较好。
实施例49-57分子水平组合物的制备和稳定性考察
表25 分子水平组合物处方(g)
Figure PCTCN2020089324-appb-000051
实施例49-51制备方法：将API、稳定剂加入二氯甲烷甲醇混合溶剂(3:1)溶解，再加入高分子载体溶解，采用雅马拓喷雾干燥机组进行喷雾干燥，进风温度100℃，进液速度5，风量7，雾化压力0.1MPa，收集所得喷干粉。将喷干粉40℃减压干燥6h。
实施例52-54制备方法：将稳定剂加入二氯甲烷甲醇混合溶剂(3:1) 溶解，再加入API溶解，再加入高分子载体溶解，采用雅马拓喷雾干燥机组进行喷雾干燥，进风温度100℃，进液速度5，风量7，雾化压力0.1MPa，收集所得喷干粉。将喷干粉40℃减压干燥6h。
实施例55-57制备方法：将API、稳定剂、载体加入二氯甲烷甲醇混合溶剂(3:1)溶解，采用雅马拓喷雾干燥机组进行喷雾干燥，进风温度100℃，进液速度5，风量7，雾化压力0.1MPa，收集所得喷干粉。将喷干粉40℃减压干燥6h。
将以上制备的分子水平组合物少量放入西林瓶，轧盖密封，放入60℃条件考察10天。基因毒性杂质B采用UPLC法检测，总杂采用HPLC法检测。
表26 不同处方分子水平组合物稳定性结果
Figure PCTCN2020089324-appb-000052
根据以上结果可知，以上处方制备的分子水平组合物稳定性均较好。对比例28-34，实施例58-80：片剂制备
表27 片剂处方(250片/批)
Figure PCTCN2020089324-appb-000053
Figure PCTCN2020089324-appb-000054
Figure PCTCN2020089324-appb-000055
Figure PCTCN2020089324-appb-000056
片剂制备工艺：按上表称取各物料，过50目筛8遍混合，单冲压片机(国药龙立DP30A)，直径10mm浅凹冲，压片。
效果例1 模拟人体生理条件的两步溶出法检测
(1)模拟胃液+模拟肠液溶出检测
模拟胃液：Nacl 10g、牛胆酸钠0.2g、卵磷脂0.075g、胃蛋白酶0.5g，加纯化水至9.5L溶解，用0.1M HCL调pH至1.60；
调节液：牛胆酸钠13.44g、卵磷脂1.14g、顺丁烯二酸17.752g、NaOH 24g，加纯化水至4L溶解；
模拟肠液：模拟胃液187ml，加调节液63ml，得模拟肠液，pH约为6.5。
溶出方法及结果：
桨法，100rpm，37℃，小杯法。
溶出杯中先加入模拟胃液187ml，进行溶出检测，取样时间点10、15、30min，待30min取样补液后，向溶出杯中加入调节液(37℃)63ml，调节为模拟肠液，继续溶出直至3小时，取样点35、60、120、180min(注：以上时间包含模拟胃液中时间)。样品用孔径0.45微米滤膜滤过，加0.1M盐酸溶液稀释(以防止检测过程主药析出)后送分析液相检测。
表28 模拟胃液+模拟肠液两步溶出考察
Figure PCTCN2020089324-appb-000057
Figure PCTCN2020089324-appb-000058
根据以上结果可知，原研制剂
Figure PCTCN2020089324-appb-000059
在模拟胃液中15min溶出达100％，调整为模拟肠液后无明显析出，溶出无明显降低，且3h时也无未明显降低。各对比例和实施例处方样品溶出同原研制剂
Figure PCTCN2020089324-appb-000060
比无明显差异。
由此可知，原研制剂
Figure PCTCN2020089324-appb-000061
在低至187ml模拟胃液和250ml模拟肠液中仍具有优异的溶出性能，分子水平组合物制剂在模拟人体生理条件的两步溶出中未表现出优势。
(2)0.1M盐酸溶液+pH6.8磷酸盐缓冲液溶出检测
考虑到模拟胃液和模拟肠液中加入了软磷脂，牛胆酸钠等表面活性剂，为了进一步考察分子水平组合物制剂和原研制剂
Figure PCTCN2020089324-appb-000062
的差异，采用更为苛刻的溶出条件(不加表面活性剂)进行两步溶出考察。
溶出方法：37℃，桨法，100rpm，小杯法。
先将溶出杯中加入0.1mol盐酸溶液187ml，进行溶出检测，取样时间点10、15、30min，待30min取样补液后，向溶出杯中加入0.2M磷酸钠溶液(37℃)63ml，调节为pH6.8磷酸盐缓冲液，继续溶出直至3小时，取样点35、60、120、180min(注：以上时间包含0.1M盐酸溶液中时间)。样品用孔径0.45微米滤膜滤过，加0.1M盐酸溶液稀释(以防止检测过程主药析出)进行高效液相色谱检测。
表29 0.1M HCl+pH6.8磷酸盐缓冲液中两步溶出考察
Figure PCTCN2020089324-appb-000063
Figure PCTCN2020089324-appb-000064
根据以上结果可知，原研制剂
Figure PCTCN2020089324-appb-000065
在0.1M盐酸溶液中15min溶出达100％，调整为pH6.8磷酸盐缓冲液后无明显析出，溶出无明显降低，且3h时也无未明显降低。各对比例和实施例处方样品溶出同原研制剂
Figure PCTCN2020089324-appb-000066
比无明显差异。
由此可知，原研制剂
Figure PCTCN2020089324-appb-000067
在低至187ml 0.1M盐酸溶液和250ml pH6.8磷酸盐缓冲液中仍具有优异的溶出性能，固体分散体制剂在模拟人体生理条件的两步溶出中未表现出优势。根据该结果预计，分子水平组合物制剂制剂在生物体内同原研制剂应该也不会有太明显差异。
效果例2 比格犬药代动力学研究(单次给药)
动物：比格犬，
Figure PCTCN2020089324-appb-000068
给药途径和频度：单次灌胃口服，动物在给药前禁食10-14小时，给药结束4小时后给予饲料，其余实验期间动物自由摄食。
给药剂量：4mg(以仑伐替尼计)。
组别和每组动物：共10只比格犬，每组1只，10周期交叉给药，每周期结束洗脱期3天，再进行下一周期给药。
血液采集：给药前(0h)，给药后0.5h，1h，1.5h，2h，3h，4h，6h，8h，12h和24h。经颈静脉穿刺采血1mL/时间点，肝素钠抗凝，采集后放置冰上。
离心条件：2200g/分钟，10分钟，2-8℃；分析前存放于-80℃冰箱内。
生物分析检测：LC-MS/MS分析原型药物。
数据处理：Phoenix WinNonlin计算药代动力学参数(包括Tmax、T 1/2、Cmax、AUC 0-t)。
表30 比格犬药代动力学结果(n＝10)
Figure PCTCN2020089324-appb-000069
Figure PCTCN2020089324-appb-000070
根据以上结果，我们惊讶的发现，对比例(对比例1、对比例13分子水平组合物制剂制备的制剂)同原研制剂
Figure PCTCN2020089324-appb-000071
比生物利用度无明显提高，而实施例同原研制剂
Figure PCTCN2020089324-appb-000072
比则有不同程度提高。
同时，对比实施例和原研制剂
Figure PCTCN2020089324-appb-000073
的CV％，我们惊喜的发现，实施例具有更小的体内变异性。
一方面，因具有高的生物利用度，其给药剂量可以大幅降低，可以实现低剂量处方给药，同时还可以降低副作用；另一方面，因较低的体内变异性，也可以降低不良反应。
以上对本发明所提供的包含仑伐替尼的分子水平的药物组合物及其制备方法和应用进行了详细介绍。本文应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (27)

  1. 一种药物组合物，其特征在于，其包括仑伐替尼或其药学上可接受的盐或其溶剂合物；
    所述药物组合物的药代动力学AUC 0-t相较原研制剂
    Figure PCTCN2020089324-appb-100001
    提高了至少40％～50％。
  2. 如权利要求1所述的药物组合物，其特征在于，所述药物组合物降低了与给药剂量相关的副作用。
  3. 如权利要求1或2所述的药物组合物，其特征在于，所述药物组合物在生物体内具有较低的个体内及个体间变异性。
  4. 如权利要求3所述的药物组合物，其特征在于，所述药物组合物的药代动力学AUC 0-t相较原研制剂
    Figure PCTCN2020089324-appb-100002
    降低了变异性，优选CV≤30％。
  5. 如权利要求1至4任一项所述的药物组合物，其特征在于，降低了药物在血浆内暴露量突然升高造成的肾毒性和神经毒性或血浆暴露量突然降低造成的无效，提高了患者用药安全性。
  6. 如权利要求1至5任一项所述的药物组合物，其特征在于，其包括仑伐替尼的分子水平药物组合物，所述仑伐替尼的分子水平药物组合物含有：
    1)活性成分：仑伐替尼或其药学上可接受的盐或其溶剂合物；
    2)稳定剂；
    3)高分子载体；
    所述药物组合物在60℃放置10天，基因毒性杂质B小于400ppm。
  7. 根据权利要求1至6任一项所述的药物组合物，其特征在于，所述稳定剂选自氨丁三醇、葡甲胺或十二烷基硫酸钠中至少一种。
  8. 根据权利要求1至7中任一项所述的药物组合物，其特征在于，所述高分子载体选自羟丙甲纤维素、羟丙纤维素、共聚维酮、羟丙甲纤维素邻苯二甲酸酯、聚维酮、醋酸羟丙甲纤维素琥珀酸酯、羟乙基纤维素、丙烯酸树脂中至少一种。
  9. 根据权利要求1至8中任一项所述的药物组合物，其特征在于，所述高分子载体选自羟丙甲纤维素、共聚维酮、羟丙甲纤维素邻苯二甲酸酯、醋酸羟丙甲纤维素琥珀酸酯、丙烯酸树脂、聚维酮中的至少一种。
  10. 根据权利要求1至9中任一项所述的药物组合物，其特征在于，所述其药学上可接受的盐选自仑伐替尼的盐酸盐、氢溴酸盐、对甲苯磺酸盐、甲磺酸盐、硫酸盐或乙磺酸盐中的至少一种，优选甲磺酸仑伐替尼。
  11. 根据权利要求1至10中任一项所述的药物组合物，其特征在于，所述仑伐替尼或其药学上可接受的盐的溶剂合物为水合物、二甲基亚砜合物或乙酸合物。
  12. 根据权利要求1至11中任一项所述的药物组合物，其特征在于，所述活性成分、稳定剂、高分子载体的重量比为1∶0.05～0.75∶0.5～10，优选1∶0.05～0.6∶1～5，进一步优选1∶0.1～0.6∶1～3。
  13. 根据权利要求1至12中任一项所述的药物组合物，其特征在于，包括如下方案：
    (1)所述稳定剂为氨丁三醇，所述高分子载体为醋酸羟丙甲纤维素琥珀酸酯；
    所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼；
    所述活性成分、稳定剂、高分子载体的重量比为1∶0.05～0.75∶0.5～10，优选为1∶0.05～0.4∶1～5，更优选为1∶0.075～0.3∶1～2，进一步优选为1∶0.1～0.3∶1～2；
    或(2)所述稳定剂为葡甲胺，所述高分子载体为醋酸羟丙甲纤维素琥珀酸酯；
    所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼；
    所述活性成分、稳定剂、高分子载体的重量比为1∶0.05～0.75∶0.5～10，优选为1∶0.05～0.4∶1～5，更优选为1∶0.075～0.3∶1～2，进一步优选为1∶0.1～0.3∶1～2；
    或(3)所述稳定剂为十二烷基硫酸钠，所述高分子载体为羟丙甲纤维素；
    所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼；
    所述活性成分、稳定剂、高分子载体的重量比为1∶0.075～0.5∶1～5，优选为1∶0.15～0.5∶1～3，更优选为1∶0.15～0.25∶1～2；
    或(4)所述稳定剂为十二烷基硫酸钠，所述高分子载体为共聚维酮；
    所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼；
    所述活性成分、稳定剂、高分子载体的重量比为1∶0.1～0.75∶1～5，优选为1∶0.4～0.75∶2～3，更优选为1∶0.4～0.6∶2～3；
    或(5)所述稳定剂为十二烷基硫酸钠，所述高分子载体为丙烯酸乙酯-甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯共聚物；
    所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼；
    所述活性成分、稳定剂、高分子载体的重量比为1∶0.1～0.5∶1～5，优选为1∶0.2～0.5∶2～3，更优选为1∶0.2～0.3∶3；
    或(6)所述稳定剂为十二烷基硫酸钠，所述高分子载体为聚维酮；
    所述活性成分为仑伐替尼和/或甲磺酸仑伐替尼，优选仑伐替尼；
    所述活性成分、稳定剂、高分子载体的重量比为1∶0.05～0.75∶1～10；优选为1∶0.2～0.75∶2～5，更优选为1∶0.4～0.6∶2～4；最优选为1∶0.6∶3。
  14. 根据权利要求1至13中任一项所述的药物组合物，其特征在于，所述药物组合物还含有药学上可接受的赋形剂，所述赋形剂选自填充剂、崩解剂、粘合剂、润滑剂、矫味剂、助悬剂中的至少一种。
  15. 根据权利要求1至14中任一项所述的药物组合物，其特征在于，所述药物组合物的剂型为胶囊剂、片剂、颗粒剂、混悬剂，优选为胶囊剂、片剂，更优选为片剂。
  16. 一种溶解仑伐替尼或其药学上可接受的盐或其溶剂合物的潜溶剂，所述潜溶剂包含卤代甲烷和醇类。
  17. 根据权利要求16所述的潜溶剂，其特征在于，所述醇类优选甲醇和/或乙醇。
  18. 根据权利要求17所述的潜溶剂，其特征在于，所述卤代甲烷优选为二氯甲烷。
  19. 根据权利要求16至18任一项所述的潜溶剂，其特征在于，所述卤代甲烷与醇类的比例为10∶2～10∶10，优选为10∶2～10∶5，更优选为10∶3～10∶5。
  20. 根据权利要求16至19任一项所述的潜溶剂，其特征在于，包括如下方案：
    (1)所述潜溶剂包含二氯甲烷和甲醇；
    二氯甲烷和甲醇的比例为10∶2～10∶10，优选为10∶3～10∶5；
    或(2)所述潜溶剂包含二氯甲烷和乙醇；
    二氯甲烷和乙醇的比例为10∶3～10∶10，优选为10∶4～10∶5。
  21. 一种提高仑伐替尼或其药学上可接受的盐或其溶剂合物的溶解度的方法，其特征在于，使用如权利要求16至20任一项所述的潜溶剂。
  22. 仑伐替尼的分子水平的药物组合物的制备方法，包括将权利要求6至15中任一项所述的药物组合物中的活性成分、稳定剂及高分子载体溶解在有机溶剂中，通过喷雾干燥，获得分子水平的药物组合物。
  23. 如权利要求22所述的制备方法，其特征在于，所述有机溶剂为如权利要求16至20任一项中任一项所述的潜溶剂。
  24. 权利要求1至15中任一项所述的药物组合物或如权利要求16至20中任一项所述制备方法制备的仑伐替尼的分子水平的药物组合物在制备治疗或预防癌症/肿瘤的药物中的应用。
  25. 如权利要求24所述的应用，其特征在于，所述癌症/肿瘤为甲状腺癌、肾细胞癌、肝癌、胃癌或肺癌。
  26. 一种治疗或预防癌症/肿瘤的方法，其特征在于，使用了如权利要求1至15中任一项所述的药物组合物或如权利要求16至20中任一项所述的制备方法制备的仑伐替尼的分子水平的药物组合物。
  27. 如权利要求26所述的方法，其特征在于，所述癌症/肿瘤为甲状腺癌、肾细胞癌、肝癌、胃癌或肺癌。
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