WO2023078265A1 - 一种固体分散体、其制备方法及包含其的固体制剂 - Google Patents

一种固体分散体、其制备方法及包含其的固体制剂 Download PDF

Info

Publication number
WO2023078265A1
WO2023078265A1 PCT/CN2022/129074 CN2022129074W WO2023078265A1 WO 2023078265 A1 WO2023078265 A1 WO 2023078265A1 CN 2022129074 W CN2022129074 W CN 2022129074W WO 2023078265 A1 WO2023078265 A1 WO 2023078265A1
Authority
WO
WIPO (PCT)
Prior art keywords
solid dispersion
compound
cancer
solid
preparation
Prior art date
Application number
PCT/CN2022/129074
Other languages
English (en)
French (fr)
Inventor
甘勇
朱淼
马元辉
刘磊
郭仕艳
沈竞康
耿美玉
高丽
熊兵
Original Assignee
上海海和药物研究开发股份有限公司
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 上海海和药物研究开发股份有限公司 filed Critical 上海海和药物研究开发股份有限公司
Priority to CA3236956A priority Critical patent/CA3236956A1/en
Publication of WO2023078265A1 publication Critical patent/WO2023078265A1/zh

Links

Images

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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • 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 in particular relates to a solid dispersion, a preparation method thereof, and a solid pharmaceutical preparation containing the same, and the preparation of the solid dispersion for preventing and/or treating diseases and tumors related to protein tyrosine kinase disorders use of the drug.
  • Patent CN104230922A discloses compound A (1- ⁇ (6-[(1-methyl)-4-pyrazolyl]-imidazo[1,2-a]pyridine)-3-sulfonyl ⁇ -6-[( 1-methyl)-4-pyrazolyl]-1-hydrogen-pyrazolo[4,3-b]pyridine), compound A and its pharmaceutically acceptable salts are listed in the preparation for prevention or treatment with In vivo protein tyrosine kinase disorder-related cell abnormal proliferation, morphological changes, and hyperkinesia-related diseases, as well as the use of medicines for diseases related to angiogenesis or cancer metastasis, especially in the preparation of C-Met inhibitors use in medicines.
  • C-Met can be found in human liver cancer, cholangiocarcinoma, pancreatic cancer, lung cancer, thyroid cancer, pleural stromal tumor, etc., especially in metastatic tumors. Its role may include affecting the adhesion between tumor cells, promoting the degradation of extracellular matrix, inducing angiogenesis and promoting cell proliferation. All these indicate that C-Met is an important target for the treatment of tumors.
  • Compound A is a highly selective C-Met inhibitor. Its inhibitory effect on C-Met and anti-tumor effect in vitro and in vivo are superior to that of the similar drug INCB28060 (CAS No.: 1029712-80-8 ). Compound A has strong activity, less toxic and side effects, and has good prospects.
  • the technical problem to be solved by the present invention is to provide a solid dispersion, a preparation method thereof and a solid preparation containing the compound A in order to overcome the defects of poor solubility in water and low bioavailability in vivo in the prior art.
  • Compound A in the solid dispersion of the present invention has a high solubility in simulated intestinal fluid. Further, the solid dispersion of the present invention can significantly improve the solubility and dissolution stability of Compound A, prevent drug precipitation, and prolong the supersaturation maintenance of the drug. time to increase the bioavailability of the drug.
  • the solid preparation of the present invention has high bioavailability.
  • the invention effectively controls the decomposition of the components in the dispersion, especially the degradation of the matrix polymer material by improving the preparation process for preparing the solid dispersion, thereby reducing the impurity content of the dispersion.
  • the present invention also greatly improves the compressibility of the tablet made from the solid dispersion by optimizing the pulverization process of the solid dispersion and the mixing process of the solid dispersion powder, avoiding low tablet hardness, poor friability, and serious powder removal during transportation and so on.
  • the present invention provides a solid dispersion comprising compound A and a pharmaceutically acceptable matrix polymer, wherein the pharmaceutically acceptable matrix polymer includes an enteric polymer and a non-enteric polymer , the compound A is 1- ⁇ (6-[(1-methyl)-4-pyrazolyl]-imidazo[1,2-a]pyridine)-3-sulfonyl ⁇ -6-[(1 -methyl)-4-pyrazolyl]-1-hydrogen-pyrazolo[4,3-b]pyridine, the weight ratio of the compound A to the pharmaceutically acceptable matrix polymer is 1:3-1 :35.
  • the solid dispersion also optionally includes one, two or three of glidants, plasticizers and surfactants.
  • the enteric polymer is selected from the group consisting of hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinic acid
  • HPMCP hydroxypropylmethylcellulose phthalate
  • hydroxypropylmethylcellulose acetate succinic acid hydroxypropylmethylcellulose phthalate and/or hydroxypropylmethylcellulose acetate succinate.
  • the non-enteric polymer is selected from polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), copovidone (i.e.
  • N-vinylpyrrolidone/vinyl acetate copolymer PVP/VA
  • povidone ie polyvinylpyrrolidone, PVP
  • polyvinyl alcohol 2-hydroxy- ⁇ -cyclodextrin
  • HPBCD 2-hydroxy- ⁇ -cyclodextrin
  • HPMC hypromellose One or more of cellulose
  • HPMC hydroxypropyl cellulose
  • HPC hydroxypropyl cellulose
  • the pharmaceutically acceptable matrix polymer comprises any combination of the following: hydroxypropylmethylcellulose phthalate and povidone, hydroxypropylmethylcellulose ortho Phthalates and Copovidone, Hydroxypropyl Methyl Cellulose Acetate Succinate and Povidone, Hydroxypropyl Methyl Cellulose Phthalate and Hypromellose, Hydroxypropyl Methyl Cellulose Acetate Methylcellulose succinate and polyvinyl alcohol, hydroxypropylmethylcellulose acetate succinate and copovidone, hydroxypropylmethylcellulose phthalate and polyvinyl alcohol, phthalic acid Cellulose acetate and povidone or cellulose acetate succinate and copovidone.
  • the weight ratio of the enteric high molecular polymer to the non-enteric high molecular polymer can be 2:1-10:1, preferably 2:1-6:1 ; for example 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1 or 6:1.
  • the weight ratio of the compound A to the pharmaceutically acceptable matrix polymer can be 1:4-1:25, preferably 1:5-1:15; for example 1:4 , 1:5, 1:5.5, 1:6, 1:7.5, 1:8, 1:9, 1:10, 1:12, 1:15, or 1:21.
  • the weight ratio of Compound A to the pharmaceutically acceptable matrix polymer is 1:4-1:25, the solubility of the prepared solid dispersion can be improved, and the in vivo exposure of Compound A can be significantly improved. .
  • the weight ratio of the compound A to the enteric polymer can be 1:2-1:15, more preferably 1:3-1:10; for example 1:3 , 1:4, 1:4.5, 1:5, 1:6, 1:8 or 1:10.
  • the weight ratio of the compound A to the non-enteric polymer can be 2:1-1:10, preferably 2:1-1:5, more preferably 1 :1-1:5, or 1:2-1:5; such as 2:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:5, 1:8 or 1 :10.
  • the glidant can be a conventional glidant in the art, preferably, the glidant is selected from colloidal silicon dioxide, animal fat, vegetable fat and wax One or more, such as colloidal silicon dioxide.
  • the amount of the glidant can be selected according to the conventional amount of the glidant in this field, preferably, the weight ratio of the glidant to the compound A is 1:1-1:100, preferably 1:4 -1:50; for example 1:6, 1:10, 1:15, 1:20, 1:30, 1:50, 1:80 or 1:100.
  • the presence of a plasticizer can improve the processability of the solid dispersion
  • the plasticizer can be a conventional plasticizer in the art, preferably, the plasticizer Acetyl tributyl citrate, acetyl triethyl citrate, benzyl benzoate, chlorobutanol, dextrin, dibutyl phthalate, diethyl phthalate, phthalic acid Dimethyl ester, glycerin, glyceryl monostearate, polyoxyl 40 stearate, mannitol, mineral oil, lanolin alcohol, palmitic acid, macrogol, macrogol monostearate, One or more of polyvinyl acetate phthalate, propylene glycol, 2-pyrrolidone, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine and triethyl citrate; more
  • the plasticizer is a plasticizer with a
  • the amount of the plasticizer can be selected according to the conventional amount of the plasticizer in this field, preferably, the weight ratio of the plasticizer to the compound A is 1:1-1:20, preferably 1:1 -1:5; for example 1:1.5, 1:2, 1:2.5, 1:5, 1:10, 1:15 or 1:20.
  • the surfactant may further enhance the therapeutic potential of the solid dispersion of the invention.
  • the surfactant can be a conventional surfactant in the art, preferably, the surfactant is selected from one or more of anionic surfactants, cationic surfactants and nonionic surfactants kind.
  • the anionic surfactant is preferably sodium lauryl sulfate (sodium lauryl sulfate) and/or sodium docusate.
  • the cationic surfactant is preferably one or more of cetrimethylene bromide, benzethonium chloride, cetylpyridinium chloride and lauric acid.
  • the nonionic surfactant is preferably polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester (such as Tween 80, 60, 40 and 20), polyoxyethylene castor oil derivative (such as hydrogenated One or more of castor oil polyoxyl ester 40 (Cremophor RH40), polyoxyethylene stearate and polyoxyethylene polyoxypropylene ether block copolymer (such as poloxamer). More preferably, the surfactant is sodium lauryl sulfate, sodium docusate, lauric acid, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative One or more of , poloxamer and polyoxyethylene stearate. Optimally, the surfactant is sodium lauryl sulfate and/or polyoxyethylene stearate.
  • the amount of the surfactant can be selected according to the conventional amount of the surfactant in the art, preferably, the weight ratio of the surfactant to the compound A is 1:1-1:10, preferably 1:1 -1:5, such as 1:2.5, 1:3, 1:4, 1:5, 1:8 or 1:10.
  • the solid dispersion comprises Compound A, a pharmaceutically acceptable matrix polymer, a glidant and a plasticizer, wherein the pharmaceutically acceptable matrix polymer includes an enteric polymer and non-enteric polymers.
  • the solid dispersion is composed of Compound A, a pharmaceutically acceptable matrix polymer, a glidant and a plasticizer, wherein the pharmaceutically acceptable matrix polymer includes an enteric polymer substances and non-enteric polymers.
  • the solid dispersion comprises Compound A, a pharmaceutically acceptable matrix polymer, a glidant, a plasticizer and a surfactant, wherein the pharmaceutically acceptable matrix polymer includes an enteric Polymers and non-enteric polymers.
  • the solid dispersion is composed of Compound A, a pharmaceutically acceptable matrix polymer, a glidant, a plasticizer and a surfactant, wherein the pharmaceutically acceptable matrix polymer comprises intestinal Soluble polymers and non-enteric polymers.
  • the pharmaceutically acceptable matrix polymer comprises an enteric high molecular polymer and a non-enteric high molecular polymer
  • the solubility of the solid dispersion can be improved, but also the processability of the solid dispersion can be improved. sex.
  • the inventors have also unexpectedly found that the solid dispersion of the present invention can form stable mixed micelles with an average particle size of 100-200 nm in simulated intestinal fluid, and then significantly improve the solubility of the drug through the principle of micellar solubilization, while further avoiding the Drug precipitation prolongs the supersaturation maintenance time of the drug and improves the bioavailability of the drug.
  • the solid dispersion of the invention overcomes the shortcoming that common solid dispersion medicines are easy to precipitate.
  • the present invention also provides a kind of preparation method of solid dispersion as described above, it comprises the following steps:
  • Each component of the solid dispersion is uniformly mixed to obtain a uniform dispersion by melting or dissolving;
  • the solidification may be a solvent volatilization method or a melt extrusion method, etc., preferably a melt extrusion method.
  • the melt extrusion method produces a uniform dispersion by applying heat and/or mechanical stress
  • the melt extrusion method is a drug such as Compound A, a pharmaceutically acceptable matrix polymer and Plasticizers and other auxiliary materials are mixed and extruded in a molten state to form a solid dispersion.
  • This method can disperse the drug (such as crystalline drug) in the carrier material (pharmaceutically acceptable matrix polymer) in an amorphous or molecular state after heating and melting, and finally improve the solubility, dissolution rate and oral bioavailability of poorly soluble drugs.
  • melt refers to a liquid state or a rubber-like state, in which one component may be evenly embedded in other components.
  • one component melts and the other dissolves in the melt to form a melt.
  • Melt formation generally involves the softening point of the pharmaceutical matrix polymer, and the preparation of the melt can occur by a variety of methods. Mixing of the components can be performed before, during or after formation of the melt. For example, the mixing of the components is carried out first, followed by heating or mixing and heating at the same time.
  • the active substance in the melt should be evenly dispersed, and the melt should be in the form of paste or viscous.
  • the working temperature in the present invention will be determined by the type of extruder or the type of extruder configuration used.
  • Part of the energy required for melting, mixing and dissolving of the components in the extruder can be provided by heating elements.
  • the friction and shear of the material in the extruder can also provide a large amount of energy to the mixture, helping to form a homogeneous melt of the components.
  • Extrusion can be achieved using the forming module of the extruder, and the extrudate can be cut into pieces before or after curing.
  • the extrusion temperature of the melt extrusion method is 70-250°C, preferably 80-230°C, most preferably 120-210°C.
  • the generation and extrusion of the melt can be carried out in conventional devices; preferably extruders and kneaders.
  • the extruder can be a rod-type extruder, including a single-screw extruder, a twin-screw extruder or other multi-screw extruders, preferably a twin-screw extruder, which can run forward or backward, and optionally Equipped with kneading disc.
  • the melt extrusion method comprises:
  • the sleeve temperature of the melt extrusion equipment is 150-220°C, preferably 150-200°C, 150-180°C, 180-200°C, more preferably 160-180°C.
  • the temperature is 150-200°C, the increase of impurities caused by the increase of temperature and the decrease of screw speed (increase of residence time) can be avoided.
  • the screw extrusion speed of the melt extrusion equipment is 50-300 rpm; preferably 50-240 rpm, 50-180 rpm, 100-210 rpm or 180-240 rpm.
  • the feeding speed is 10-100 rpm, preferably 50-100 rpm or 50-70 rpm.
  • the pharmaceutically acceptable matrix polymer comprises enteric polymer hydroxypropylmethylcellulose phthalate or polyvinyl alcohol acetate phthalate
  • the control of extrusion barrel temperature, screw speed and feed rate avoids the increase of impurity phthalic acid content.
  • the content of phthalic acid in the solid dispersion does not exceed 6wt% (based on the total components of the solid dispersion); more preferably, the content of phthalic acid does not exceed 4.8wt%.
  • the solvent evaporation method includes the following steps:
  • the solvent can be a conventional solvent in the art, preferably, the solvent is selected from one or more of ketone solvents, halogenated alkanes solvents, alcohol solvents and water.
  • the ketone solvent is preferably acetone.
  • the alcoholic solvent is preferably isopropanol, methanol and/or ethanol.
  • the halogenated alkane solvent is preferably a chlorinated alkane, more preferably dichloromethane or trichloromethane.
  • Described solvent is selected from acetone, acetone/methylene chloride, methanol/methylene chloride, acetone/water, acetone/methanol, acetone/ethanol, methylene chloride/ethanol or ethanol/water etc., wherein, "/" represents both mixed solvents.
  • the method for removing the solvent in step (2b) can be a conventional method for removing the solvent in the art, preferably rotary evaporation, vacuum drying under reduced pressure, spray drying, freeze-drying and thin-film evaporation; to achieve solvent removal; other techniques such as solvent-controlled precipitation, pH-controlled precipitation, and cryogenic co-milling can also be used.
  • the present invention also provides a solid preparation, which comprises the aforementioned solid dispersion and pharmaceutically acceptable additives.
  • the pharmaceutically acceptable additives can be conventional pharmaceutical additives in the art, preferably, the pharmaceutically acceptable additives include glidants, binders, disintegrants, fillers, colorants, pH One or more of regulators, surfactants, lubricants, stabilizers (such as antioxidants, light stabilizers, free radical scavengers, stabilizers against microbial attack, etc.) and the like.
  • the specific selection range and dosage of the additives are conventional choices in the art.
  • the binder can be a conventional binder in the art, preferably, the binder is selected from copovidone, povidone, methyl cellulose, ethyl cellulose and hydroxy One or more of propyl cellulose.
  • the coloring agent can be a conventional coloring agent in the art, and the amount of the coloring agent can be a conventional amount in the art.
  • the disintegrant promotes rapid disintegration of the solid preparation in the stomach and keeps released particles separated from each other.
  • the disintegrant includes a cross-linked polymer, such as cross-linked sodium carboxymethylcellulose and/or cross-linked polyvinylpyrrolidone (ie cross-linked polyvidone PVPP).
  • the filler is selected from one or more of lactose, sucrose, mannitol, calcium hydrogen phosphate, microcrystalline cellulose, starch and isomaltose.
  • the binder is selected from one or more of povidone, copovidone, methylcellulose, ethylcellulose, and hydroxypropylcellulose.
  • povidone and copovidone which are pharmaceutically acceptable matrix polymers, can also function as adhesives.
  • the lubricant is selected from one of polyethylene glycol (for example, a molecular weight of 1000-6000), magnesium stearate, calcium stearate and sodium stearyl fumarate, etc. or more.
  • the pH regulator is a conventional pH regulator in the art, preferably citric acid.
  • the solid preparation also includes a film coating, which can improve the taste and provide a refined appearance, for example, a film coating of a tablet can help swallowing comfort.
  • the film coating can be a conventional film coating in the art, and the film coating can be a moisture-proof coat.
  • the film coating typically comprises polymeric film-forming materials such as hydroxypropylmethylcellulose, hydroxypropylcellulose and acrylate or methacrylate copolymers.
  • film coatings may also contain plasticizers such as polyethylene glycol, surfactants such as Tweens, anti-tacking agents such as talc, and optionally pigments such as titanium dioxide or iron oxides. These additives may comprise from about 0 to about 20% of the total weight of the solid formulation.
  • the solid dispersion can be 60-90% of the mass of the solid preparation.
  • the pharmaceutical additive can be 15-40% of the mass of the solid preparation.
  • the present invention also provides a method for preparing the aforementioned solid preparation, which includes the following steps: mixing the aforementioned solid dispersion powder or granules with pharmaceutical additives to prepare a solid preparation.
  • the powder or granule of the solid dispersion is prepared by pulverizing, milling or grinding the solid dispersion.
  • the present invention also greatly improves the compressibility of the product solid dispersion to make solid preparation tablets by optimizing the pulverization process of the solid dispersion and the optimization of the mixing process, avoiding low hardness of the preparation tablet , poor friability, serious powder removal during transportation, etc.
  • the hot melt extrusion method when using the hot melt extrusion method to prepare a solid dispersion, when the grinding speed is 5000-5400rpm, or/and the sieve mesh number is 60-120 mesh, the prepared solid dispersion has a better particle size distribution, Thereby, the tabletability in the process of preparing the solid preparation is effectively improved.
  • the mixing time of the solid dispersion and the pharmaceutical additive is 20-40min
  • the resulting mixture has better mixing uniformity, and its compressibility is better, and the hardness of the prepared preparation tablet is about 80 -135N. Therefore, the compressibility of the tablet made from the solid dispersion can be effectively improved through the optimized control of the crushing process parameters and the mixing process, thereby improving the pharmaceutical usability of the solid preparation.
  • the solid preparation of the present invention may contain 2 mg to 1500 mg of Compound A. Patients can generally be adults or children, and can also be treated in other mammals.
  • the solid preparation provided by the present invention is a preparation suitable for transmucosal administration to patients, that is, it can be administered to the mucosa for transmembrane absorption.
  • Suitable routes of administration for this purpose include administration by inhalation, as well as oral, intranasal and rectal administration. Oral administration is particularly preferred.
  • a skilled artisan can choose tablet, capsule or other preparation forms according to the route of administration. However, other routes of administration, such as parenteral, are not excluded.
  • the solid preparation according to the present invention may be tablets, capsules, granules, powders and the like.
  • the solid preparation of the present invention has higher bioavailability.
  • the relative bioavailability of the solid preparation of Compound A is more than 1000% of that of the micronized preparation
  • the relative bioavailability of the solid formulation of Compound A is more than 600% of that of common solid dispersion formulations
  • the absolute bioavailability of the solid formulation of Compound A is greater than 40% (see Experimental Example 4).
  • the improvement of bioavailability helps to reduce the required dose of the equivalent exposure observed with conventional preparations (such as ordinary micronized preparation IR tablets), which can reduce the effective therapeutic dose of the drug, improve the efficacy of the drug, save drug costs, reduce Drug side effects.
  • the present invention also provides a use of the aforementioned solid dispersion or solid preparation in the preparation of a drug for preventing and/or treating diseases and/or tumors related to protein tyrosine kinase disorders.
  • the protein tyrosine kinase disorder-related diseases and/or tumors include, but are not limited to: solid cancers; such as lung cancer, gastric cancer, esophageal cancer, colon cancer, colorectal cancer, liver cancer, renal cell cancer, head and neck cancer, thyroid cancer, ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, oral cancer, malignant glioma, rhabdomyosarcoma, or osteosarcoma.
  • the disease and/or tumor is lung cancer, gastric cancer, liver cancer, renal cell carcinoma, ovarian cancer, breast cancer, pancreatic cancer, prostate cancer or thyroid cancer.
  • the disease and/or tumor described herein is lung cancer, especially non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • the present invention also provides a use of the aforementioned solid dispersion or solid preparation in the preparation of a C-Met inhibitor.
  • the C-Met inhibitor is used for the preparation, prevention or treatment of abnormal cell proliferation, morphological changes and hyperkinesia-related diseases, angiogenesis or cancer metastasis-related diseases related to protein tyrosine kinase disorders in vivo, such as Drugs used to treat or prevent tumor growth and metastasis.
  • the present invention also provides a method for preventing and/or treating diseases and tumors related to protein tyrosine kinase disorders, comprising administering an effective amount of the above-mentioned solid dispersion or solid preparation to an individual in need.
  • the present invention provides a kit comprising the aforementioned solid dispersion or solid preparation.
  • Treatment includes administering a combination of the present invention to an individual in need thereof to achieve, including but not limited to, alleviation, cure, alleviation of symptoms, reduction of symptoms, prolongation of survival, and progression of a disease or disorder or symptoms thereof (e.g., cancer) Delay; in the case of cancer, the treatment includes inhibiting the growth of solid tumors, reducing tumor size, preventing metastatic spread of tumors and the growth or development of micrometastases, and the like.
  • a disease or disorder or symptoms thereof e.g., cancer
  • Treatment delay means the administration of the combination to a patient in a pre-morbid stage or early stage of the cancer to be treated, a pre-form of the corresponding cancer has been diagnosed and/or in a patient diagnosed in a situation where the corresponding cancer is likely to develop .
  • prevention includes the suppression or delay of the occurrence or frequency of a disease or disorder, or symptoms thereof, such as cancer, and generally refers to the occurrence of signs or symptoms before they occur, especially in individuals at risk. previous drug administration. "Prevention” also includes preventing the occurrence or recurrence of cancer.
  • an effective amount refers to an amount (e.g., a therapeutically effective amount, especially a combined therapeutically effective amount) of the active agents of the present disclosure for (i) treating a particular disease, (ii) attenuating, ameliorating or eliminating a particular disease or (iii) preventing or delaying the onset of one or more symptoms of a particular disease described herein.
  • a therapeutically effective amount of the active agent can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., to some extent slow and preferably stop) cancer cell infiltration of surrounding organs; inhibit (i.e., to some extent slow and preferably stop) tumor metastasis; inhibit tumor growth to some extent; and/or alleviate to some extent one or more symptoms associated with cancer.
  • “Individual” or “patient” as used herein refers to both mammals and non-mammals. Mammal refers to any member of the class Mammalia, which includes, but is not limited to: humans; non-human primates, cattle, horses, sheep, pigs, rabbits, dogs, and cats, etc. "Individual” is not limited to a specific age or gender. Preferably, the individual or patient is a human.
  • “Pharmaceutically acceptable” as used herein means non-toxic, biologically tolerable and suitable for administration to an individual.
  • the “pharmaceutically acceptable salt” used in the present invention refers to the non-toxic, biologically tolerable acid addition salt or base addition salt suitable for individual administration of Compound A, including but not limited to: Compound A and Acid addition salts formed from inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, etc.; and acids formed from compound A with organic acids Addition salts such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate salts, 2-hydroxyethanesulfonates, benzoates, salicylates, stearates and alkanedicarboxylates with the formula HOOC-(CH 2 ) n -COOH (wherein n is 0-4) Salts formed from acids, etc.
  • polymer refers to a macromolecule composed of repeating structural units linked by covalent bonds.
  • the term includes linear and branched polymers, cyclic polymers such as cyclic oligosaccharides (including cyclodextrins), homopolymers and copolymers, whether of natural, synthetic or semi-synthetic origin.
  • matrix polymer refers to a material exhibiting low moisture absorption and high softening temperature, including polymers or blends of two or more polymers.
  • high softening temperature refers to a material with a glass transition temperature (Tg) or melting point (Tm) > 100°C measured by differential scanning calorimetry (DSC), where Tg is suitable for an amorphous state or form A measure of a polymer, Tm is a measure of the polymer as it pertains to the crystalline state or form.
  • surfactant refers to a pharmaceutically acceptable surfactant.
  • solid dispersion refers to a system in which a compound is dispersed in an excipient carrier.
  • Solid dispersions in this sense may include compositions in which the drug is dispersed within an excipient carrier as discrete domains of crystalline or non-crystalline drug or as separate molecules, with respect to the state of the drug in the system.
  • Solid dispersions can be relatively large solid materials, such as pellets, tablets, films, or strands, in terms of the entire drug-excipient complex; A free-flowing powder consisting of aggregates exists.
  • the definition of solid dispersion does not include physical mixtures resulting from dry or wet or dry blending operations and simple mixtures of compound crystals and other auxiliary materials.
  • AUC refers to the area under the drug-time curve, using its conventional meaning, ie, eg, the area under the plasma concentration-time curve from 0 to 24 hours. AUC has units of concentration times time. Once the test concentration-time point is determined, the AUC can be conveniently calculated, for example by a computer program or by the trapezoidal method.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the solid dispersion in the present invention can significantly improve the solubility and dissolution stability of the compound A, prolong the supersaturation maintenance time of the drug and further improve the bioavailability of the solid preparation of the compound A.
  • the solid preparation of the present invention has high bioavailability. The bioavailability is high, so that the dose required for the equivalent exposure observed in conventional preparations is small, which can reduce the effective therapeutic dose of the drug, improve the efficacy of the drug, save the cost of the drug, and reduce the toxic and side effects of the drug.
  • the invention also effectively controls the decomposition of components in the dispersion by improving the process for preparing the solid dispersion, especially the extrusion process, thereby reducing the impurity content of the dispersion.
  • the present invention also greatly improves the tabletability of the tablet made from the solid dispersion by optimizing the crushing process of the solid dispersion and the mixing process of the solid dispersion powder, avoiding low tablet hardness, poor friability, and serious powder removal during transportation, etc. Condition.
  • Fig. 1 is the particle size diagram of the solid dispersion prepared in Preparation Example 1 of the present invention after being diluted with 5% SDS-simulated intestinal fluid;
  • Fig. 6 is an investigation chart of the dissolution stability of various solid preparations prepared in Preparation Examples 5, 6, 7 and Comparative Examples 1, 3 of the present invention.
  • the sources and trade names of the reagents and equipment used are all indicated when they appear for the first time. Unless otherwise specified, the same reagents used thereafter are the same as those indicated for the first time. Conventional unmarked reagents are purchased from Sinopharm Chemical Reagent Co., Ltd. company. Among them, Compound A was self-synthesized by Shanghai Institute of Materia Medica according to the method disclosed in CN104230922A.
  • Experimental animal Beagle, male, weighing 8-10kg.
  • the source is the Experimental Animal Center of Shanghai Institute of Materia Medica.
  • the test animals were fed adaptively in the test site for 3-7 days before the test day.
  • Preparation method hydroxypropyl methylcellulose phthalate (50.0 parts by weight) (Japan Shin-Etsu Chemical Industry Co., Ltd., HP-55), copovidone (25.0 parts by weight) (PVP/VA64, BASF) , polyoxyl 40 stearate (5.0 parts by weight) (Hunan Erkang Pharmaceutical Co., Ltd., S40), sodium lauryl sulfate (4.0 parts by weight) (BASF) and compound A (10.0 parts by weight) and gum State silicon dioxide (1.0 parts by weight) (EVONIK, Aerosil) is mixed, then this powdery mixture is charged into the twin-screw extruder (screw diameter 11mm, Thermo Scientific) of extruding speed 100rpm and temperature 190 °C, the mixture passes through screw Extruded in the form of strips; the hot-melt extruded strips were crushed and passed through a 60-mesh sieve to obtain a solid dispersion 1 containing compound A.
  • the solid dispersion 1 powder was added with 5% sodium dodecyl sulfate (SDS) and pH 6.8 simulated intestinal fluid (containing 6.8 g potassium dihydrogen phosphate and 0.944 g sodium hydroxide per liter of water) and then dissolved to determine the density of the formed polymer micelles.
  • SDS sodium dodecyl sulfate
  • pH 6.8 simulated intestinal fluid containing 6.8 g potassium dihydrogen phosphate and 0.944 g sodium hydroxide per liter of water
  • Particle size Zetasizer Nano ZS laser particle size analyzer, Malvern Instrument Co., Ltd., UK
  • the average particle size of this product is 182.3nm (Fig. 1).
  • the solid dispersion 1 and compound A bulk drug powder were respectively measured in pH 6.8 simulated intestinal fluid containing different concentrations of SDS surfactants (1%, 3%, 5%) to determine the solubility of compound A (37 ° C, 100 rpm shaking 6h ), wherein the solid dispersion group was sampled at 3h and 6h, and the measurement results are shown in Table 1.
  • the test results show that the solid dispersion 1 prepared by the present invention can significantly improve the solubility of the bulk drug compound A, and the solid dispersion 1 can still maintain good solubility at 6 hours without crystallization.
  • Each liter of water contains 10g sodium lauryl sulfate, 6.8g potassium dihydrogen phosphate and 0.944g sodium hydroxide;
  • Each liter of water contains 30g sodium lauryl sulfate, 6.8g potassium dihydrogen phosphate and 0.944g sodium hydroxide;
  • the solid dispersion 1 powder was placed under accelerated conditions (40°C ⁇ 2°C, 75% ⁇ 5% RH) for 6 months and then measured for solubility (37°C, 100rpm shaking for 6h), in the above 1%, 3%, 5% SDS -The solubility in simulated intestinal fluid at pH 6.8 was 153.4 ⁇ g/mL, 449.6 ⁇ g/mL, and 875.3 ⁇ g/mL, respectively. Show that after placing 6 months under accelerated conditions, solid dispersion 1 of the present invention still has good solubilizing action to compound A.
  • Preparation method hydroxypropyl methylcellulose phthalate (55.0 parts by weight) (Japan Shin-Etsu Chemical Industry Co., Ltd., HP-50), copovidone (20.0 parts by weight) (PVP/VA64, BASF) , glyceryl monostearate (6.0 parts by weight) (Hunan Erkang Pharmaceutical Co., Ltd.), sodium lauryl sulfate (6.0 parts by weight) and compound A (15.0 parts by weight) and colloidal silicon dioxide (1.0 parts by weight) part) mixing, and then the powdery mixture is loaded into a twin-screw extruder (screw diameter 11mm) with an extrusion speed of 150rpm and a temperature of 200°C, and the mixture is extruded in strips through the screw; the hot-melt extruded strips After pulverization, pass through a 100-mesh sieve to obtain a solid dispersion 2 containing Compound A.
  • hydroxypropyl methylcellulose phthalate 55.0 parts by weight) (J
  • Solid dispersion 2 was tested for the solubility of compound A in simulated intestinal fluid at pH 6.8 containing different concentrations of SDS surfactant (1%, 3%, 5%) (shaking at 100 rpm at 37°C for 6 h). It has been determined that the solubility of solid dispersion 2 containing compound A in 1% SDS-pH 6.8 simulated intestinal fluid is 115.70 ⁇ g/mL; the solubility in the above 3% SDS-pH 6.8 simulated intestinal fluid is 424.5 ⁇ g/mL; -The solubility in simulated intestinal fluid at pH 6.8 is 723.1 ⁇ g/mL. The test results show that the solid dispersion 2 containing Compound A can significantly increase the solubility of Compound A.
  • Preparation method hydroxypropyl methylcellulose acetate succinate (50.0 parts by weight) (Shin-Etsu Chemical Industry Co., Ltd., model: HF), povidone (15.0 parts by weight) (PVP K12, BASF), twelve Alkyl sodium sulfate (4.0 parts by weight) (BASF), glyceryl monostearate (12.0 parts by weight) (Hunan Erkang Pharmaceutical Co., Ltd.) and compound A (12.0 parts by weight) and colloidal silicon dioxide (2.0 parts by weight) weight) mixed, and then the powdery mixture is loaded into a twin-screw extruder (screw diameter 11mm) with an extrusion speed of 100rpm and a temperature of 180°C, and the mixture is extruded in strips through the screw; the hot-melt extruded strips After pulverization, pass through a 90-mesh sieve to obtain a solid dispersion 3 containing compound A.
  • a twin-screw extruder screw diameter 11mm
  • the solid dispersion 3 was tested for the solubility of compound A in 5% SDS-pH 6.8 simulated intestinal fluid (37°C, 100rpm shaking for 6h), and the solid dispersion 3 containing compound A was measured in 5% SDS-pH 6.8 simulated intestinal fluid The solubility is 815.5 ⁇ g/mL.
  • the test results show that the solid dispersion 3 of Compound A can significantly improve the solubility of Compound A and is stable.
  • hydroxypropyl methylcellulose phthalate (60.0 parts by weight) (model: HP-50), hypromellose (15.0 parts by weight) (HPMC HME 15LV, DuPont, USA), Sodium lauryl sulfate (2.0 parts by weight), polyoxyl 40 stearate (8.0 parts by weight), colloidal silicon dioxide (2.0 parts by weight) and compound A (8.0 parts by weight) were dissolved in acetone/dichloro Methane (volume ratio 2:1) in a mixed solvent, then evaporate the solvent to dryness at 30°C with a rotary evaporator, dry the resulting substance in a vacuum oven at 40°C for more than 12 hours to evaporate the residual organic solvent, and grind the obtained solid substance After treatment, pass through a 60-mesh sieve to obtain a solid dispersion 4 containing Compound A.
  • Solid dispersion 4 was tested for the solubility of compound A in 5% SDS-pH 6.8 simulated intestinal fluid (37°C, 100rpm shaking for 3h and 6h).
  • the solubility in intestinal juice at 3h and 6h was 765.5 and 715.6 ⁇ g/mL respectively.
  • the test results show that the solid dispersion 4 containing compound A can significantly improve the solubility of compound A and has a longer supersaturation maintenance time, which is beneficial to drug absorption.
  • the resulting solid dispersion 1 (95.0 parts by weight) prepared in Example 1, and copovidone (17.4 parts by weight) (PVP/VA64, BASF), crospovidone (3.6 parts by weight) (American International Special Products Co., Ltd. ) and sodium stearyl fumarate (1.0 parts by weight) (Germany JRS Group Pharmaceutical Excipients Company) were mixed uniformly, and were compressed into 585.0 mg tablets using a single-punch tablet press. Then the tablet is placed in the coating pan, and the tablet is film-coated with a film-coating aqueous dispersion (Opadry, Shanghai Colorcon Coating Technology Co., Ltd.) at a temperature of 60° C. to obtain a solid preparation containing Compound A. 1.
  • the solid preparation is a tablet.
  • the resulting solid dispersion 2 (103.0 parts by weight) prepared in Example 2, and microcrystalline cellulose (13.2 parts by weight) (Taiwan Mingtai Chemical Co., Ltd.), pregelatinized starch (8.0 parts by weight) (Shanghai Kale Kang Coating Technology Co., Ltd.), low-substituted hydroxypropyl cellulose (4.8 parts by weight) (Japan Shin-Etsu Chemical Industry Co., Ltd.) and magnesium stearate (1.0 parts by weight) (Anhui Shanhe Pharmaceutical Co., Ltd.) are mixed evenly, A filling type capsule filling machine was used to fill capsules with 0# capsules at 260 mg/capsule to obtain a solid preparation 2 containing compound A, which was a capsule.
  • the resulting solid dispersion 3 (95.0 parts by weight) prepared in Example 3 was mixed with lactose (12.0 parts by weight) (manufactured by DFE Pharma in the Netherlands), croscarmellose sodium (4.0 parts by weight) and fumarate stearyl Sodium bicarbonate (1.0 parts by weight) was mixed homogeneously, and was compressed into 467mg tablets by a single-punch tablet machine. Then the tablet is placed in the coating pan, and the tablet is film-coated with a film-coating aqueous dispersion (Opadry, Shanghai Colorcon Coating Technology Co., Ltd.) at a temperature of 60° C. to obtain a solid preparation containing Compound A. 3.
  • the solid preparation is a tablet.
  • Preparation method hydroxypropyl methylcellulose phthalate (45.0 parts by weight) (Shin-Etsu Chemical Industry Co., Ltd.), copovidone (10.0 parts by weight) (PVP/VA64, BASF), stearic acid Polyoxyl 40 ester (5.0 parts by weight) (Croda Singapore Pte Ltd) was pretreated with compound A (10.0 parts by weight) and colloidal silica (0.5 parts by weight) (JRS) and mixed uniformly to obtain a powder mixture.
  • hydroxypropyl methylcellulose phthalate 45.0 parts by weight) (Shin-Etsu Chemical Industry Co., Ltd.), copovidone (10.0 parts by weight) (PVP/VA64, BASF), stearic acid Polyoxyl 40 ester (5.0 parts by weight) (Croda Singapore Pte Ltd) was pretreated with compound A (10.0 parts by weight) and colloidal silica (0.5 parts by weight) (JRS) and mixed uniformly to obtain a powder mixture.
  • JRS colloidal silica
  • the powdery mixture is then loaded into a twin-screw extruder (18 mm in screw diameter, LEISTRITZ) at an extrusion speed of 100-240 rpm and a temperature of 160-200° C., with a feed rate of 50-70 rpm, and the mixture is extruded in strips through the screw;
  • the extrudate was extruded and cooled by a rapid cold pressing roller; the hot-melt extruded strip was added to a hammer mill for pulverization to obtain a solid dispersion 5 containing compound A.
  • the pulverization process of the solid dispersion is also studied, and it is found that when the pulverization speed is 5000-5400rpm, or/and the number of sieves after pulverization is 60-120 mesh, the solid dispersion obtained has Better particle size distribution (such as D90 ⁇ 200 ⁇ m), thus effectively improving the tabletability during the preparation of solid preparations.
  • Solid dispersion 5 (75.0 parts by weight) prepared by embodiment 8 was mixed with copovidone (16.0 parts by weight) (PVP/VA64, BASF), crospovidone (20.5 parts by weight, ASHLAND), citric acid ( 2.0 parts, Merck) in the mixing tank, mixing speed 10rpm, mixing time 20-40min; then add sodium lauryl sulfate (3.0 parts, BASF) and sodium stearyl fumarate (0.6 parts by weight, JRS) for lubrication Mixing, the mixing speed is 10rpm, and the mixing time is 3-10min, to obtain a uniformly mixed total mixed powder.
  • the tablet was compressed into 600mg tablets using a Feite tablet press to prepare the corresponding preparation 4.
  • Preparation method hydroxypropyl methylcellulose phthalate (35.0 parts by weight) (HP-55, Japan Shin-Etsu Chemical Industry Co., Ltd.), copovidone (5.0 parts by weight) (PVP/VA64, BASF) 1.
  • Polyoxyl 40 stearate 5.0 parts by weight
  • compound A 10.0 parts by weight
  • colloidal silicon dioxide 0.5 parts by weight, EVONIK
  • Preparation method 1 Dissolve the powder mixture in a mixed solvent of dichloromethane/methanol (volume ratio 10:1). After dissolving, evaporate the solvent to dryness at 40°C with a rotary evaporator, and then transfer the sample to a vacuum Drying oven (40°C, vacuum 0.9 bar) overnight (more than 12h) to remove the residual organic solvent, the resulting dried product was ground and pulverized and passed through an 80-mesh sieve for later use to obtain solid dispersion 6 powder containing compound A.
  • Preparation method 2 Put the powdery mixture into a twin-screw extruder with a screw speed of 120rpm and a temperature of 175°C, and the mixture is extruded in strips through the screws; after the hot-melt extruded strips are crushed Through an 80 mesh sieve, the solid dispersion 7 powder containing Compound A was obtained.
  • the solid dispersions prepared by the two processes were investigated by the dissolution behavior of the dispersion powder and X-ray diffraction, and it was found that there was no significant difference in the solubility of the two, and the solubility of the drug was the same.
  • Solid dispersion 6 (55.5 parts by weight), solid dispersion 7 (55.5 parts by weight) were respectively mixed with copovidone (18.5.0 parts by weight) (PVP/VA64, BASF), crospovidone (20.5 parts by weight, ASHLAND), citric acid (2.0 parts, Merck) in the mixing tank, mixing speed 15rpm, mixing time 20min, add sodium lauryl sulfate (3.0 parts, BASF) and sodium stearyl fumarate (0.5 parts, JRS ) lubrication, the mixing speed is 15rpm, and the mixing time is 5min to obtain a uniformly mixed total mixed powder. Tablets were compressed into 500 mg tablets using a tablet machine, and then solid preparations T1 and T2 containing Compound A were obtained respectively.
  • the concentration of Compound A in the sample was determined by LC-MS/MS, and the pharmacokinetic parameters of Compound A after administration to Beagle dogs were calculated using WinNonLin (version 8.3, Pharsight) according to the non-compartmental model.
  • Relative bioavailability F (AUC of solid preparation T1)/(AUC of solid preparation T2) ⁇ 100%, F value is the average value of relative bioavailability of a single animal.
  • hydroxypropyl methylcellulose phthalate (58.0 parts by weight) (Shin-Etsu Chemical Industry Co., Ltd.), polyvinyl alcohol (15.0 parts by weight) (Merck), polyoxyl stearate 40 Esters (10.0 parts by weight) (Nanjing Weier Chemical Co., Ltd.) are mixed with compound A (12.0 parts by weight) and colloidal silicon dioxide (2.0 parts by weight), and then the powdery mixture is loaded into extrusion speed 200rpm and temperature 200 °C twin-screw extruder (screw diameter 16mm), the mixture was extruded in strips through the screw; the hot-melt extruded strips were crushed and passed through a 60-mesh sieve to obtain a solid dispersion 8 containing compound A.
  • the solid dispersion 8 was tested for the solubility of compound A in 5% SDS-pH 6.8 simulated intestinal fluid (37°C, 100rpm shaking for 6h), and the solid dispersion 8 containing compound A was measured in 5% SDS-pH 6.8 simulated intestinal fluid The solubility at 6h is 657.8 ⁇ g/mL. The test results show that compound A-containing solid dispersion 8 can significantly increase the solubility of compound A.
  • Compound A was micronized with an airflow mill (MC JETMILL-50, JETPHARMA SOLUTIONS SA company) to an average particle size of about 20 ⁇ m (12.5 parts by weight), and hydroxypropyl methylcellulose phthalate (57.7 parts by weight), polyoxyl 40 stearate (4.7 parts by weight), sodium lauryl sulfate (2.3 parts by weight), colloidal silicon dioxide (0.9 parts by weight), copovidone (17.3 parts by weight) ( PVP/VA64, BASF), crospovidone (3.6 parts by weight) and sodium stearyl fumarate (1.0 parts by weight) were mixed uniformly, and were compressed into 400.0 mg micronized IR tablets by a single punch tablet machine.
  • MC JETMILL-50 JETPHARMA SOLUTIONS SA company
  • the tablet is placed in the coating pan, and the tablet is film-coated with a film-coating aqueous dispersion (Opadry, Shanghai Colorcon Coating Technology Co., Ltd.) at a temperature of 60° C. to obtain a conventional solid containing compound A.
  • a film-coating aqueous dispersion Opadry, Shanghai Colorcon Coating Technology Co., Ltd.
  • the solid preparation is a common micronized preparation.
  • Copovidone (75.0 parts by weight) (PVP VA64, BASF), polyoxyl 40 stearate (5.0 parts by weight) (Hunan Erkang Pharmaceutical Co., Ltd., S40), sodium lauryl sulfate (4.0 parts by weight) (BASF) was mixed with compound A (10.0 parts by weight) and colloidal silicon dioxide (1.0 parts by weight) (EVONIK, Aerosil), and then the powdery mixture was charged into the extrusion speed 100rpm and temperature 170°C A twin-screw extruder (screw diameter 11mm, Thermo Scientific), the mixture is extruded in strips through the screw; the hot-melt extruded strips are crushed and then passed through a 60-mesh sieve to obtain a solid dispersion containing compound A 10.
  • Solid Dispersion 10 (95.0 parts by weight) was mixed with copovidone (17.4 parts by weight) (PVP VA64, BASF), crospovidone (3.6 parts by weight) (American International Specialty Company) and stearyl fumaric acid Sodium (1.0 parts by weight) (Germany JRS Group Pharmaceutical Excipients Company) was mixed evenly, and was compressed into a tablet of 585.0 mg by a single-punch tablet machine. Then the tablets were placed in the coating pan, and the tablets were film-coated with an aqueous film coating dispersion (Opadry, Shanghai Colorcon Coating Technology Co., Ltd.) at 60°C to obtain a common solid dispersion containing compound A.
  • Body preparation III the solid preparation is a solid preparation prepared without enteric polymer solid dispersion.
  • Preparation method hydroxypropyl methylcellulose phthalate (40.0 parts by weight) (model: HP-50), polyoxyl 40 stearate (5.0 parts by weight) (Hunan Erkang Pharmaceutical Co., Ltd. company, S40), sodium lauryl sulfate (4.0 parts by weight) (BASF) mixed with compound A (10.0 parts by weight) and colloidal silicon dioxide (1.0 parts by weight), and then the powdery mixture was loaded into the extrusion A twin-screw extruder with a rotational speed of 150 rpm and a temperature of 180° C. (screw diameter of 11 mm), the mixture was extruded in strips through the screws; a solid dispersion 11 containing compound A was obtained.
  • the solid dispersion 11 was tested for the solubility of compound A in pH 6.8 simulated intestinal fluid containing SDS surfactant (1%) (37°C, shaking at 100rpm for 3h, 6h). It was determined that the solubility of the solid dispersion 6 containing compound A in 1% SDS-pH 6.8 simulated intestinal fluid was 53.7 ⁇ g/mL for 3 hours, and 43.3 ⁇ g/mL for 6 hours; the test results showed that the solid dispersion 6 containing compound A Although the solubility of compound A can be slightly improved, the solubility decreases as time goes on, indicating that drug precipitation occurs, and the stability of the supersaturated state is poor, which is not conducive to drug absorption.
  • Solid dispersion 11 (300.0 wt.), was mixed with lactose (100.0 wt.), croscarmellose sodium (20.00 wt.) and sodium stearyl fumarate (2.00 wt. Tablet machine compressed into 422mg tablets to obtain solid dispersion formulation IV containing Compound A.
  • hydroxypropyl methylcellulose phthalate (80.0 parts by weight) (model: HP-50), copovidone (50.0 parts by weight) (PVP VA64, BASF), lauryl sulfate Sodium (1.0 parts by weight), glyceryl monostearate (25.0 parts by weight), colloidal silicon dioxide (1.0 parts by weight) were mixed with compound A (50.0 parts by weight), and then the powdery mixture was loaded into the extrusion speed 150rpm and a twin-screw extruder (screw diameter 11mm) at a temperature of 200°C, the mixture was extruded in strips through the screw; the resulting solid matter was crushed and passed through a 60-mesh sieve to obtain a solid dispersion containing compound A 12 (this Invention of solid dispersions outside the range of parts by weight).
  • the solid dispersion 12 was tested for the solubility of compound A in pH 6.8 simulated intestinal fluid containing SDS surfactant (1%) (37°C, shaking at 100rpm for 3h, 6h). It was determined that the solubility of solid dispersion 6 containing compound A in 1% SDS-pH 6.8 simulated intestinal fluid was 31.3 ⁇ g/mL for 3 hours, and 22.4 ⁇ g/mL for 6 hours; the test results showed that the solid dispersion 12 containing compound A The effect on improving the solubility of compound A is very small, and the solubility decreases with time, indicating that drug precipitation occurs, and the stability of the supersaturated state is poor, which is not conducive to improving drug absorption.
  • Solid dispersion 12 (207.0 wt.), was mixed with lactose (50.0 wt.), croscarmellose sodium (10.00 wt.) and sodium stearyl fumarate (2.00 wt. Tablet machine compressed into 269mg tablets to obtain a solid dispersion formulation V containing Compound A.
  • the main solvents include water, pH 1.2 simulated gastric juice (2g potassium chloride and 7mL hydrochloric acid per liter of water), pH 4.5 phosphate buffer solution (12.9g per liter of water Citric acid and 0.63g disodium hydrogen phosphate), pH 6.8 simulated intestinal fluid, take about 0.1g of compound A, add 100mL of each of the above solvents, shake at 100rpm at 37°C for 24h, take the supernatant and centrifuge at 8000rpm for 15min, and then analyze it by HPLC The concentration of Compound A was determined.
  • the solubility of compound A in different media is shown in Table 5.
  • the solid preparation 1,2,3 prepared by embodiment 5,6,7 compares IR conventional preparation I (common micronization preparation, comparative example 1) and common solid dispersion preparation III (containing only non- The solid preparation prepared by enteric polymer solid dispersion, comparative example 3) can significantly improve the dissolution rate and solubility of compound A; Good solubilizing effect and good stability.
  • Example 6 and Example 7 Comparative Example 1 and Comparative Example 3
  • grind finely weigh each preparation of a single dosage unit and place it in 250mL at 37°C and 100rpm stirring speed
  • the simulated intestinal fluid of 3% SDS-pH 6.8, after 1h, 2h, 4h, 6h, 8h, take out the sample and centrifuge at 8000rpm for 15min, measure the concentration of Compound A by HPLC, and draw the time-concentration curve (see Figure 6) .
  • the solid preparations prepared by Examples 5, 6, and 7 of the present invention have good dissolution stability within 8 hours, stable supersaturated state, and are beneficial to the absorption of medicines, while IR conventional preparations (common micronized preparations, comparative examples 1 and Ordinary solid dispersion preparations (solid preparations not prepared by enteric polymer solid dispersions, the solubility of Comparative Example 3 decreased in 2h, and the drug concentration continued to decrease as time increased, indicating that drug precipitation occurred, supersaturation Poor state stability is not conducive to drug absorption.
  • the dosage of the preparations of Example 5, Example 7, Comparative Example 1, Comparative Example 3, Comparative Example 4 and Comparative Example 5 was 50 mg/piece. Food was uniformly provided before the test, and the drug was administered 30 minutes later. Water was not allowed during the whole test, and the washing period was 7 days.
  • 0.5 mL of blood was collected from the veins of the extremities; Centrifuge at 3500rpm for 10min, separate the plasma, and store it in a -70°C refrigerator until testing.
  • the concentration of compound A in the samples was determined by LC-MS.
  • the pharmacokinetic parameters of Compound A after administration to Beagle dogs were calculated using the non-compartmental model of Phoenix6.4 software (Pharsight, USA). The data summary is shown in Table 7.
  • Comparative Example 1 6.39 twenty four 225 3.3 Comparative Example 3 5.55 62 431 6.3 Comparative Example 4 5.02 106 851 12.4 Comparative Example 5 6.12 75 615 9.0 Comparative Example 2 3.63 / 1370 100

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (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

一种固体分散体、其制备方法及包含其的固体制剂。固体分散体包括化合物A、可药用基质聚合物，其中，可药用基质聚合物包括肠溶性高分子聚合物和非肠溶性高分子聚合物，所述化合物A为1-{(6-[(1-甲基)-4-吡唑基]-咪唑[1,2-a]并吡啶)-3-磺酰基}-6-[(1-甲基)-4-吡唑基]-1-氢-吡唑并[4,3-b]吡啶。固体分散体可显著提高化合物A的溶解度及溶解稳定性，延长药物的过饱和维持时间进而提高药物的生物利用度。利用固体分散体制备的固体制剂体内生物利用度满足化合物A口服给药的要求。

Description

一种固体分散体、其制备方法及包含其的固体制剂
本申请要求申请日为2021年11月5日的中国专利申请2021113088364的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于药物制剂领域，具体涉及一种固体分散体、其制备方法及包含其的固体药物制剂，以及所述固体分散体用于制备预防和/或治疗蛋白酪氨酸激酶紊乱相关疾病和肿瘤的药物的用途。
背景技术
专利CN104230922A公开了化合物A(1-{(6-[(1-甲基)-4-吡唑基]-咪唑[1,2-a]并吡啶)-3-磺酰基}-6-[(1-甲基)-4-吡唑基]-1-氢-吡唑并[4,3-b]吡啶)，列举了化合物A及其药学上可接受的盐在制备用于预防或治疗与生物体内的蛋白酪氨酸激酶紊乱相关的细胞异常增殖、形态变化以及运动功能亢进相关的疾病以及与血管新生或癌转移相关的疾病的药物中的用途，尤其是在制备作为C-Met抑制剂的药物中的用途。
C-Met的过表达可见于人肝癌、胆管癌、胰腺癌、肺癌、甲状腺癌、胸膜间质瘤等，尤其是在发生转移的肿瘤中。它的作用可能包括影响肿瘤细胞间的黏附、促进细胞外基质降解、诱导血管发生以及促进细胞增殖等。这些都说明C-Met是一个重要的治疗肿瘤的靶点。化合物A为高选择性C-Met抑制剂，其对C-Met的抑制作用、体外体内抗肿瘤作用强度等方面均优于现有临床应用中的同类药物INCB28060(CAS号：1029712-80-8)。化合物A活性强，毒副作用小，具有良好的前景。
对化合物A的进一步研究发现，其在pH 1.2～7.4的缓冲盐水溶液中平衡溶解度低于1.0μg/mL，为水难溶性药物。动物水平研究结果显示化合物A普通制剂直接给药后体内生物利用度低于1％，体内吸收差，无法有效发挥治疗作用，需增溶提高口服吸收后使用。
发明人尝试了目前常用的常规增溶促吸收手段，发现对化合物A均存在一定问题：(1)尝试将化合物A制成盐，但结果发现对其溶解度无显著改善；(2)尝试将化合物A制成不同的晶形，结果发现不同晶形溶解度无显著差异；(3)尝试将化合物A微粉化后增溶促吸收，结果发现生物利用度仅3.3％，不适合口服给药；(4)尝试将化合物A采用增溶剂制成增溶溶液，但是化合物A的熔点大于250℃，结晶倾向强，溶液在放置后出现析晶现象，长期稳定性差，析晶后不能再溶解，不能解决药物吸收差问题。
发明内容
本发明所要解决的技术问题是为了克服现有技术中化合物A在水中溶解性差、体内生物利用度低的缺陷，而提供一种固体分散体、其制备方法及包含其的固体制剂。
本发明的固体分散体中的化合物A在模拟肠液中溶解度较高，进一步地，本发明中的固体分散体可显著提高化合物A的溶解度及溶解稳定性，防止药物沉淀，延长药物的过饱和维持时间进而提高药物的生物利用度。本发明的固体制剂具有高的生物利用度。
本发明通过改进制备固体分散体的制备工艺，有效控制了分散体中组分的分解，尤其是控制了基质聚合物材料的降解，从而减少了分散体的杂质含量。本发明还通过优化固体分散体的粉碎工艺以及固体分散体粉末的混合工艺，大大提高了固体分散体制得片剂的可压片性，避免片剂硬度低，脆碎度差，运输脱粉严重等情况。
一方面，本发明提供了一种固体分散体，其包括化合物A、可药用基质聚合物，其中，所述可药用基质聚合物包括肠溶性高分子聚合物和非肠溶性高分子聚合物，所述化合物A为1-{(6-[(1-甲基)-4-吡唑基]-咪唑[1,2-a]并吡啶)-3-磺酰基}-6-[(1-甲基)-4-吡唑基]-1-氢-吡唑并[4,3-b]吡啶，所述化合物A与所述可药用基质聚合物的重量比为1:3-1:35。
进一步地，所述的固体分散体还任选地包含助流剂、增塑剂和表面活性剂中的一种、两种或三种。
在本发明的具体实施方案中，较佳地，所述肠溶性高分子聚合物选自羟丙基甲基纤维素邻苯二甲酸酯(HPMCP)、醋酸羟丙基甲基纤维素琥珀酸酯(HPMCAS)、聚甲基丙烯酸酯、聚乙烯醇乙酸苯二甲酸酯(PVAP)、邻苯二甲酸乙酸纤维素(乙酸纤维素肽酸酯)和琥珀酸乙酸纤维素中的一种或多种；更佳地，所述肠溶性高分子聚合物为羟丙基甲基纤维素邻苯二甲酸酯和/或醋酸羟丙基甲基纤维素琥珀酸酯。
在本发明的具体实施方案中，较佳地，所述非肠溶性高分子聚合物选自聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(Soluplus)、共聚维酮(即N-乙烯基吡咯烷酮/醋酸乙烯酯共聚物，PVP/VA)、聚维酮(即聚乙烯吡咯烷酮，PVP)、聚乙烯醇、2-羟基-β-环糊精(HPBCD)、羟丙甲纤维素(HPMC)和羟丙基纤维素(HPC)中的一种或多种；更佳地，所述非肠溶性高分子聚合物选自共聚维酮、聚乙烯醇、聚维酮和羟丙甲纤维素中的一种或多种。
在本发明的一个具体实施方案中，所述可药用基质聚合物包含如下任一组合：羟丙基甲基纤维素邻苯二甲酸酯和聚维酮、羟丙基甲基纤维素邻苯二甲酸酯和共聚维酮、醋酸羟丙基甲基纤维素琥珀酸酯和聚维酮、羟丙基甲基纤维素邻苯二甲酸酯和羟丙甲纤维 素、醋酸羟丙基甲基纤维素琥珀酸酯和聚乙烯醇、醋酸羟丙基甲基纤维素琥珀酸酯和共聚维酮、羟丙基甲基纤维素邻苯二甲酸酯和聚乙烯醇、邻苯二甲酸乙酸纤维素和聚维酮或琥珀酸乙酸纤维素和共聚维酮。
在本发明的一个具体实施方案中，所述肠溶性高分子聚合物与所述非肠溶性高分子聚合物的重量比可为2:1-10:1，优选为2:1-6:1；例如2:1、2.5:1、3:1、3.5:1、4:1、4.5:1、5:1或6:1。
在本发明的一个具体实施方案中，所述化合物A与所述可药用基质聚合物的重量比可为1:4-1:25，优选为1:5-1:15；例如1:4、1:5、1:5.5、1:6、1:7.5、1:8、1:9、1:10、1:12、1:15或1:21。通过体内pK试验可知，当化合物A与可药用基质聚合物的重量比为1:4-1:25，既可提高制得的固体分散体的溶解度，又显著提高了化合物A的体内暴露量。
在本发明的具体实施方案中，所述化合物A与所述肠溶性高分子聚合物的重量比可为1:2-1:15，更优选为1:3-1:10；例如1:3、1:4、1:4.5、1:5、1:6、1:8或1:10。
在本发明的具体实施方案中，所述化合物A与所述非肠溶性高分子聚合物的重量比可为2:1-1:10，优选为2:1-1:5，更优选为1:1-1:5、或1:2-1:5；例如2:1、1:1、1:1.5、1:2、1:2.5、1:3、1:5、1:8或1:10。
在本发明的具体实施方案中，所述助流剂可为本领域常规的助流剂，较佳地，所述助流剂选自胶态二氧化硅、动物脂肪、植物脂肪和蜡中的一种或多种，例如胶态二氧化硅。所述助流剂的用量可按本领域助流剂的常规用量选择，较佳地，所述助流剂与所述化合物A的重量比为1:1-1:100，优选为1:4-1:50；例如1:6、1:10、1:15、1:20、1:30、1:50、1:80或1:100。
在本发明的具体实施方案中，增塑剂的存在可提高所述固体分散体的可加工性，所述增塑剂可为本领域常规的增塑剂，较佳地，所述增塑剂选自柠檬酸乙酰三丁酯、柠檬酸乙酰三乙酯、苯甲酸苄酯、三氯叔丁醇、糊精、邻苯二甲酸二丁酯、邻苯二甲酸二乙酯、邻苯二甲酸二甲酯、甘油、单硬脂酸甘油酯、硬脂酸聚烃氧40酯、甘露醇、矿物油、羊毛脂醇、棕榈酸、聚乙二醇、聚乙二醇单硬脂酸酯、聚乙酸邻苯二甲酸乙烯酯、丙二醇、2-吡咯烷酮、山梨糖醇、硬脂酸、三醋精、柠檬酸三丁酯、三乙醇胺和柠檬酸三乙酯中的一种或多种；更佳地，所述增塑剂为具有低玻璃态转化温度的增塑剂，如单硬脂酸甘油酯和/或硬脂酸聚烃氧40酯。
所述增塑剂的用量可按本领域增塑剂的常规用量选择，较佳地，所述增塑剂与所述化合物A的重量比为1:1-1:20，优选为1:1-1:5；例如1:1.5、1:2、1:2.5、1:5、1:10、1:15或1:20。
在本发明的具体实施方案中，所述表面活性剂可进一步增强本发明固体分散体的治疗潜力。所述表面活性剂可为本领域常规的表面活性剂，较佳地，所述表面活性剂选自阴离子型表面活性剂、阳离子型表面活性剂和非离子型表面活性剂中的一种或多种。
所述阴离子型表面活性剂优选为十二烷基硫酸钠(月桂基硫酸钠)和/或多库酯钠。所述阳离子型表面活性剂优选为溴棕三甲铵、苄索氯铵、十六烷基氯化吡啶鎓和月桂酸中的一种或多种。所述非离子型表面活性剂优选为聚氧乙烯烷基醚、聚氧乙烯山梨糖醇酐脂肪酸酯(如吐温80、60、40和20)、聚氧乙烯蓖麻油衍生物(如氢化蓖麻油聚烃氧酯40(Cremophor RH40))、聚氧乙烯硬脂酸酯和聚氧乙烯聚氧丙烯醚嵌段共聚物(如泊洛沙姆)中的一种或多种。更佳地，所述表面活性剂为十二烷基硫酸钠、多库酯钠、月桂酸、聚氧乙烯烷基醚、聚氧乙烯山梨糖醇酐脂肪酸酯、聚氧乙烯蓖麻油衍生物、泊洛沙姆和聚氧乙烯硬脂酸酯中的一种或多种。最佳地，所述表面活性剂为十二烷基硫酸钠和/或聚氧乙烯硬脂酸酯。
所述表面活性剂的用量可按本领域表面活性剂的常规用量选择，较佳地，所述表面活性剂与所述化合物A的重量比为1:1-1:10，优选为1:1-1:5，例如1:2.5、1:3、1:4、1:5、1:8或1:10。
在本发明的具体实施方案中，所述固体分散体包含化合物A、可药用基质聚合物、助流剂和增塑剂，其中，所述可药用基质聚合物包括肠溶性高分子聚合物和非肠溶性高分子聚合物。
在本发明的具体实施方案中，所述固体分散体由化合物A、可药用基质聚合物、助流剂和增塑剂组成，其中，所述可药用基质聚合物包括肠溶性高分子聚合物和非肠溶性高分子聚合物。
在本发明的具体实施方案中，所述固体分散体包含化合物A、可药用基质聚合物、助流剂、增塑剂和表面活性剂，其中，所述可药用基质聚合物包括肠溶性高分子聚合物和非肠溶性高分子聚合物。
在本发明的具体实施方案中，所述固体分散体由化合物A、可药用基质聚合物、助流剂、增塑剂和表面活性剂组成，其中，所述可药用基质聚合物包括肠溶性高分子聚合物和非肠溶性高分子聚合物。
在本发明中，当可药用基质聚合物包含肠溶性高分子聚合物和非肠溶性高分子聚合物时，不仅可以提高所述固体分散体的溶解度，还有利于提高固体分散体的可加工性。发明人在现有技术的基础上尝试了使用常用的固体分散体技术对化合物A进行增溶促吸收，但是研究结果发现，按常规方法使用单种基质聚合物制成的化合物A的固体分散体 均存在一定问题，如单独使用常用非肠溶性基质聚合物共聚维酮制备的化合物A固体分散体，在模拟肠液中90分钟的溶出度低于90％，过饱和稳定性差，生物利用度仅6.3％(对比实施例3、实验实施例2、3、4)；单独使用肠溶性基质聚合物羟丙甲纤维素邻苯二甲酸酯制备的化合物A固体分散体，虽可略提高化合物A的溶解度，但随着时间延长，溶解度下降，表明出现药物析出现象，过饱和状态稳定性差(对比实施例4)，不利于提高药物吸收，体内研究结果显示其生物利用度仅12.4％(实验实施例4)。
本发明人还意外地发现，本发明的固体分散体可在模拟肠液中形成稳定的平均粒径100～200nm的混合型胶束，进而通过胶束増溶原理使药物溶解度显著提高，同时进一步避免药物沉淀，延长药物的过饱和维持时间，提高药物生物利用度。本发明的固体分散体克服了普通固体分散体药物容易沉淀的缺点。
另一方面，本发明还提供一种如前所述固体分散体的制备方法，其包括下述步骤：
(1)所述固体分散体的各成分通过熔融或溶解均匀混合得到均匀分散体；
(2)所述均匀分散体固化以得到固体分散体。
在本发明的具体实施方案中，所述固化可为溶剂挥发法或熔体挤出法等，优选熔体挤出法。
所述熔体挤出法(热熔挤出法)通过施加热和/或机械应力来制造均匀分散体，具体地，熔体挤出法是将药物如化合物A、可药用基质聚合物和增塑剂等辅料在熔融状态下混合、挤出形成固体分散体。该方法能将药物(如结晶药物)在加热熔融后以无定形或分子态分散在载体材料(可药用基质聚合物)中，最终提高难溶性药物的溶解度、溶出速率以及口服生物利用度。所述熔体挤出法获得的均匀分散体也称熔体，“熔体”指液体状态或似橡胶状态，其中可能一组分均匀包埋于其它组分中。一般，一种组分熔化，其它组分溶于熔化物中，形成熔体。形成熔体通常涉及药用基质聚合物的软化点，熔体的制备可通过多种方法来发生。在熔体形成之前、形成期间或形成之后可进行组分的混合。例如，首先进行组分的混合，然后加热或同时混合和加热。通常，熔体中活性物质应均匀分散，熔体呈糊状或粘稠状。通常，本发明中工作温度将由挤压机类型或所使用的挤压机的构造类型来决定。在挤压机中组分的熔化、混合和溶解所需要的部分能量可通过加热元件来提供。挤压机中材料的摩擦和剪切也可给混合物提供大量的能量，帮助组分均匀熔体的形成。挤出物可利用挤压机的成型模块实现，在固化前或固化后挤出物可切成块。所述熔体挤出法的挤压温度为70-250℃，优选80-230℃，最优选为120-210℃。
所述熔体挤出法中，所述熔体的产生、挤出可在常规装置中进行；优选为挤压机和捏合机。所述挤压机可为杆式挤压机，包括单螺杆挤压机、双螺杆挤压机或其它多螺杆 挤压机，优选双螺杆挤压机，其可以顺转或逆转，并任意地装有捏合盘。
在本发明的一个优选实施方案中，所述熔体挤出法包括：
(1a)将所述固体分散体的各成分混合均匀得粉末状混合物；
(2a)将所述粉末状混合物装入热熔挤出机加料器中，挤出，粉碎，过筛处理得到含有化合物A的固体分散体。
所述熔体挤出法中，熔体挤出设备的套筒温度为150-220℃，优选为150-200℃、150-180℃、180-200℃，更优选为160-180℃。当温度为150-200℃时，可避免由于温度升高和螺杆转速降低(滞留时间升高)从而引起的杂质增加。
所述熔体挤出法中，熔体挤出设备的螺杆挤出转速为50-300rpm；优选为50-240rpm、50-180rpm、100-210rpm或180-240rpm。
所述熔体挤出法中，喂料速度为10-100rpm，优选为50-100rpm或50-70rpm。
所述熔体挤出法中，如当可药用基质聚合物包含肠溶性高分子聚合物羟丙基甲基纤维素邻苯二甲酸酯或聚乙烯醇乙酸苯二甲酸酯时，通过对挤出套筒温度、螺杆转速和喂料速度的控制可避免杂质邻苯二甲酸含量的增加。
优选地，固体分散体中邻苯二甲酸含量不超过6wt％(以固体分散体总组份计)；更优选地，邻苯二甲酸含量不超过4.8wt％。
在另一些优选实施方式中，所述溶剂挥发法包括如下步骤：
(1b)将所述固体分散体的各成分溶解于溶剂中，得到均匀分散体；
(2b)除去所述均匀分散体中的溶剂以得到所述固体分散体。
所述步骤(1b)中，所述溶剂可为本领域常规溶剂，优选地，所述溶剂选自酮类溶剂、卤代烷烃类溶剂、醇类溶剂和水中的一种或多种。所述酮类溶剂优选为丙酮。所述醇类溶剂优选为异丙醇、甲醇和/或乙醇。所述卤代烷烃类溶剂优选为氯代烷烃，更优选为二氯甲烷或三氯甲烷。所述溶剂选自丙酮、丙酮/二氯甲烷、甲醇/二氯甲烷、丙酮/水、丙酮/甲醇、丙酮/乙醇、二氯甲烷/乙醇或乙醇/水等，其中，“/”表示二者的混合溶剂。
步骤(2b)中除去溶剂的方法可为本领域常规的去除溶剂的方法，较佳地为旋转蒸发、真空减压干燥、喷雾干燥、冻干和薄膜蒸发；或者，可以通过低温冰冻接着冻干来实现除去溶剂；也可以使用其它技术，如溶剂控制的沉淀、pH控制的沉淀和低温共研磨等。
另一方面，本发明还提供一种固体制剂，其包括如前所述固体分散体和可药用添加剂。
所述固体制剂中，所述可药用添加剂可为本领域常规药用添加剂，较佳地，所述药用添加剂包括助流剂、粘合剂、崩解剂、填充剂、着色剂、pH调节剂、表面活性剂、润 滑剂、稳定剂(例如抗氧剂、光稳定剂、自由基清除剂、对抗微生物攻击的稳定剂等)等中的一种或多种。所述添加剂的具体选择范围和用量为本领域常规选择。
所述固体制剂中，所述粘合剂可为本领域常规粘合剂，较佳地，所述粘合剂选自共聚维酮、聚维酮、甲基纤维素、乙基纤维素和羟丙基纤维素中的一种或多种。
所述固体制剂中，所述着色剂可为本领域常规着色剂，所述着色剂的用量可为本领域常规用量。
所述固体制剂中，所述崩解剂促进固体制剂在胃中快速崩解，并保持释放出的颗粒彼此分隔。较佳地，所述崩解剂包括交联聚合物，例如交联羧甲基纤维素钠和/或交联聚乙烯吡咯烷酮(即交联聚维酮PVPP)。
所述固体制剂中，较佳地，所述填充剂选自乳糖、蔗糖、甘露醇、磷酸氢钙、微晶纤维素、淀粉和异麦芽糖中的一种或多种。
所述固体制剂中，较佳地，所述粘合剂选自聚维酮、共聚维酮、甲基纤维素、乙基纤维素和羟丙基纤维素等中的一种或多种。其中，作为可药用基质聚合物的聚维酮、共聚维酮也可以起到粘合剂的作用。
所述固体制剂中，较佳地，所述润滑剂选自聚乙二醇(例如分子量为1000-6000)、硬脂酸镁、硬脂酸钙和硬脂富马酸钠等中的一种或多种。
所述固体制剂中，较佳地，所述pH调节剂为本领域常规的pH调节剂，优选为枸橼酸。
所述固体制剂还包括膜包衣，膜包衣可改善味道和提供精致的外观，例如片剂的膜包衣可助于可吞咽的舒适性。所述膜包衣可为本领域常规膜包衣，所述膜包衣可以为防潮衣。所述膜包衣通常包含聚合成膜材料，例如羟丙甲基纤维素、羟丙基纤维素和丙烯酸酯或甲基丙烯酸酯共聚物。除聚合成膜材料外，膜包衣还可包含增塑剂如聚乙二醇，表面活性剂例如吐温类，抗粘剂如滑石粉，以及任选地颜料例如二氧化钛或铁氧化物。这些添加剂可占固体制剂总重量大约0到大约20％。
在本发明的具体实施方案中，较佳地，所述固体分散体可为所述固体制剂质量的60-90％。
在本发明的具体实施方案中，较佳地，所述药用添加剂可为所述固体制剂质量的15-40％。
另一方面，本发明还提供了一种前述固体制剂的制备方法，其包括如下步骤：将前述的固体分散体的粉末或颗粒与药用添加剂混合制成固体制剂。
较佳地，所述固体分散体的粉末或颗粒为所述固体分散体通过粉碎、碾磨或研磨制 备得到。
在制备固体制剂的过程中，本发明还通过对固体分散体粉碎工艺的优化，以及混合工艺的优化，大大提高了产品固体分散体制得固体制剂片剂的可压性，避免制剂片剂硬度低，脆碎度差，运输脱粉严重等情况。例如，使用热熔挤出法制备固体分散体时，当粉碎转速为5000-5400rpm，或/和过筛目数为60-120目时，制得的固体分散体有较好的粒径分布，从而有效地提高了制备固体制剂过程中的可压片性。制备固体制剂时，当固体分散体与药用添加剂的混合时间为20-40min，所得混合物有较好的混合均匀性，且其可压性较好，制得的制剂片剂的硬度约为80-135N。因此可以通过粉碎工艺参数和混合工艺优化控制，有效地提高固体分散体制得片剂的可压性，从而提高固体制剂的可药用性。
本发明的固体制剂可包含2mg至1500mg化合物A。患者一般可为成年人或儿童，也可为其它哺乳动物的治疗。
本发明提供的固体制剂是适合经粘膜给药于患者的制剂，即可给药于粘膜以透膜吸收。为此，合适的给药途径包括通过吸入给药，以及口服、鼻内和直肠给药。特别优选口服给药。技术人员可根据给药途径选择片剂、胶囊剂或其它制剂形式。但是，不排除其它给药途径，例如肠道外。例如，根据本发明的固体制剂可以为片剂、胶囊剂、颗粒剂、散剂等。
本发明的固体制剂与其它方式获得的固体制剂相比具有更高的生物利用度，在本发明的一个具体实施方案中，化合物A的固体制剂的相对生物利用度是微粉化制剂的1000％以上，化合物A的固体制剂的相对生物利用度是普通固体分散体制剂的600％以上，化合物A的固体制剂的绝对生物利用度大于40％(参见实验实施例4)。生物利用度的提高有助于降低使用常规制剂(如普通微粉化制剂IR片剂)观察到的相当暴露量的所需的剂量，可降低药物有效治疗剂量、提高药物疗效，节约药物成本、减少药物的毒副作用。
另一方面，本发明还提供了一种如前所述固体分散体或固体制剂在制备预防和/或治疗蛋白酪氨酸激酶紊乱相关疾病和/或肿瘤的药物中的用途。
在本发明的优选实施方案中，所述蛋白酪氨酸激酶紊乱相关疾病和/或肿瘤包括但不限于：实体癌；例如肺癌、胃癌、食管癌、结肠癌、结直肠癌、肝癌、肾细胞癌、头颈癌、甲状腺癌、卵巢癌、乳腺癌、胰腺癌、前列腺癌、口腔癌、恶性胶质癌、横纹肌肉癌或骨肉癌。
较佳地，所述的疾病和/或肿瘤为肺癌、胃癌、肝癌、肾细胞癌、卵巢癌、乳腺癌、胰腺癌、前列腺癌或甲状腺癌。
更佳地，本文所述的疾病和/或肿瘤为肺癌，尤其为非小细胞肺癌(NSCLC)。
另一方面，本发明还提供了一种如前所述固体分散体或固体制剂在制备C-Met抑制 剂中的用途。
所述C-Met抑制剂为用于制备预防或治疗与生物体内的蛋白酪氨酸激酶紊乱相关的细胞异常增殖、形态变化以及运动功能亢进相关的疾病、血管新生或癌转移相关的疾病，例如用于治疗或预防肿瘤生长与转移的药物。
另一方面，本发明还提供一种预防和/或治疗蛋白酪氨酸激酶紊乱相关疾病和肿瘤的方法，包括向有需要的个体施用有效量的如前所述固体分散体或固体制剂。
另一方面，本发明提了供一种包含如前所述固体分散体或固体制剂的套装药盒。
本文所用的“治疗”包括向有需要的个体施用本发明的组合，以达到疾病或病症或其症状(例如癌症)的包括但不限于减轻、治愈、缓解症状、减少症状、存活期延长以及进展延迟；就癌症而言，所述治疗包括抑制实体瘤的生长、使肿瘤体积减小、预防肿瘤的转移性蔓延和微小转移的生长或发展等。“进展延迟”指将所述组合施用于处于待治疗癌症病前阶段或早期的患者，对应癌症的预形式已被诊断出和/或在被诊断出处于对应癌症可能会发展的情况的患者中。
本文所用的“预防”包括对疾病或病症或其症状(例如癌症)的发生或发生频率的抑制或推迟，其通常是指在病征或症状发生前，特别是在具有风险个体的病征或症状发生前的药物施用。“预防”还包括防止癌症发生或复发。
本文所用的“有效量”是指本公开的活性剂用于以下的量(例如治疗有效量，尤其是联合治疗有效量)：(i)治疗特定疾病，(ii)减弱、改善或消除特定疾病的一种或多种症状，或(iii)预防或延迟本文所述的特定疾病的一种或多种症状的发作。就癌症而言，活性剂的治疗有效量可以减少癌细胞数；减小肿瘤大小；抑制(即，在一定程度上减缓和优选地停止)癌细胞浸润周围器官；抑制(即，在一定程度上减缓和优选地停止)肿瘤转移；在一定程度上抑制肿瘤生长；和/或在一定程度上缓解癌症相关的一种或多种症状。
本文所用的“个体”或“患者”指哺乳动物和非哺乳动物。哺乳动物指哺乳类的任何成员，其包括但不限于：人；非人灵长类动物，牛、马、羊、猪、兔、狗和猫等。“个体”并不限定特定的年龄或性别。优选地，个体或患者是人。
本发明所用的“药学上可接受的”指无毒的、生物学上可耐受的、适合给个体施用的。
本发明所用的“药学上可接受的盐”指化合物A的无毒的、生物学上可耐受的适合给个体施用的酸加成盐或碱加成盐，包括但不限于：化合物A与无机酸形成的酸加成盐，例如盐酸盐、氢溴酸盐、碳酸盐、碳酸氢盐、磷酸盐、硫酸盐、亚硫酸盐、硝酸盐等；以及化合物A与有机酸形成的酸加成盐，例如甲酸盐、乙酸盐、苹果酸盐、马来酸盐、富 马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、2-羟基乙磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐和与式HOOC-(CH 2) n-COOH(其中n是0-4)的链烷二羧酸形成的盐等。“药学上可接受的盐”也包括与药学上可接受的阳离子如钠、钾、钙、铝、锂和铵形成的碱加成盐。
本文所用的“聚合物”是指由通过共价键连接的重复结构单元构成的大分子。该术语包括线型和支化聚合物、环状聚合物，如环寡糖(包括环糊精)、均聚物和共聚物，无论是天然、合成还是半合成来源的。
本文所用的“基质聚合物”是指表现出低吸湿性和高软化温度的材料，包括聚合物或两种或更多聚合物的共混物。
本文所用的“高软化温度”是指材料通过差式扫描量热法(DSC)测得玻璃态转化温度(Tg)或熔点(Tm)>100℃，其中，Tg是适合非晶状态或形式的聚合物的量度，Tm是适合结晶状态或形式的聚合物的量度。
本文所用的“表面活性剂”是指可药用的表面活性剂。
本文所用的“固体分散体”是指将化合物分散在赋形剂载体中的体系。就该体系中的药物状态而言，固体分散体在这种意义上可包括其中药物以结晶或非结晶药物的离散域或以独立分子分散在赋形剂载体内的组合物。就整个药物-赋形剂复合物而言，固体分散体可以是相对较大的固体物质，如丸粒、片剂、薄膜或条束；或它们可作为由微米级或纳米级初级粒子或其聚集体构成的自由流动粉末存在。本发明中，固体分散体的定义不包括来自干混或湿混或干掺合操作的物理混合物以及化合物晶体与其它辅料的简单混合物。
本文所用术语“AUC”是指药时曲线下面积，使用其常规含义，即，如从0至24小时的血浆浓度-时间曲线下的面积。AUC具有浓度乘以时间的单位。一旦确定了试验浓度-时间点，即可方便的计算AUC，例如通过计算机程序或通过梯形法计算。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
本发明中的固体分散体可显著提高化合物A的溶解度及溶解稳定性，延长药物的过饱和维持时间进而提高化合物A的固体制剂的生物利用度。本发明的固体制剂具有高的生物利用度。生物利用度高，使得常规制剂观察到的相当暴露量的所需的剂量少，可降低药物有效治疗剂量、提高药物疗效，节约药物成本、减少药物的毒副作用。
本发明还通过改进制备固体分散体的工艺，尤其是挤出工艺，有效地控制了分散体中组分的分解，从而减少了分散体的杂质含量。本发明还通过优化固体分散体粉碎工艺和固体分散体粉末的混合工艺，大大提高了固体分散体制得片剂的可压片性，避免片剂硬度低，脆碎度差，运输脱粉严重等情况。
附图说明
图1是本发明制备实施例1制备的固体分散体经5％SDS-模拟肠液稀释后的粒径图；
图2是本发明制备实施例5、6、7和对比实施例1、3制备的各种固体制剂的体外溶出对比图(n＝6)；
图3是本发明制备实施例5制备的固体制剂加速条件放置6月后的体外溶出与0月体外溶出对比图(n＝6)；
图4是本发明制备实施例6制备的固体制剂加速条件放置6月后的体外溶出与0月体外溶出对比图(n＝6)；
图5是本发明制备实施例7制备的固体制剂加速条件放置6月后的体外溶出与0月体外溶出对比图(n＝6)；
图6是本发明制备实施例5、6、7和对比实施例1、3制备的各种固体制剂的溶解稳定性考察图。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
本发明中，所用试剂、设备的来源和商品名，均在首次出现时标明，其后所用相同试剂如无特殊说明，均与首次标明的内容相同，常规未标注试剂购自国药集团化学试剂有限公司。其中，化合物A由上海药物研究所按照CN104230922A中公开的方法自行合成。
实验动物：比格犬，雄性，体重8-10kg。来源为上海药物研究所实验动物中心。受试动物在试验日前3-7天均在试验场所进行适应性饲养。
实施例1
Figure PCTCN2022129074-appb-000001
Figure PCTCN2022129074-appb-000002
制备方法：将羟丙基甲基纤维素邻苯二甲酸酯(50.0份重量)(日本信越化学工业株式会社，HP-55)、共聚维酮(25.0份重量)(PVP/VA64，BASF)、硬脂酸聚烃氧40酯(5.0份重量)(湖南尔康制药股份有限公司，S40)、十二烷基硫酸钠(4.0份重量)(BASF)与化合物A(10.0份重量)和胶态二氧化硅(1.0份重量)(EVONIK，Aerosil)混合，然后将该粉末状混合物装入挤出转速100rpm和温度190℃的双螺杆挤出机(螺杆直径11mm，Thermo Scientific)，混合物经螺杆呈条状挤出；将热熔挤出的条状物经粉碎处理后过60目筛，得到含有化合物A的固体分散体1。
将固体分散体1粉末加5％十二烷基硫酸钠(SDS)和pH 6.8模拟肠液(每升水含6.8g磷酸二氢钾和0.944g氢氧化钠)溶解后测定所形成聚合物胶束的粒径(Zetasizer Nano ZS激光粒度仪，英国马尔文仪器有限公司)，测得本品的平均粒径为182.3nm(图1)。
将固体分散体1和化合物A原料药粉末分别于含不同浓度的SDS表面活性剂(1％、3％、5％)的pH 6.8模拟肠液中测定化合物A的溶解度(37℃、100rpm振摇6h)，其中，固体分散体组于3h、6h取样，测定结果见表1。该测试结果显示本发明制备的固体分散体1可显著提高原料药化合物A的溶解度，并且固体分散体1在6h时仍可保持良好的溶解度，无析晶。
表1 化合物A的原料药及固体分散体1的溶解度
Figure PCTCN2022129074-appb-000003
注： 1每升水含10g十二烷基硫酸钠、6.8g磷酸二氢钾和0.944g氢氧化钠；
2每升水含30g十二烷基硫酸钠、6.8g磷酸二氢钾和0.944g氢氧化钠；
3每升水含50g十二烷基硫酸钠、6.8g磷酸二氢钾和0.944g氢氧化钠。
将固体分散体1粉末于加速条件(40℃±2℃、75％±5％RH)放置6月后测定溶解度(37℃、100rpm振摇6h)，在上述1％、3％、5％SDS-pH 6.8模拟肠液中溶解度分别为153.4μg/mL、449.6μg/mL、875.3μg/mL。表明加速条件下放置6月后，本发明的固体分散体 1对化合物A仍有良好的増溶作用。
上述溶解度测定结果表明，本实施例制备的固体分散体1药物未析晶，可有效防止药物沉淀；且过饱和稳定性及长期放置稳定性良好，能延长药物的过饱和维持时间，确保药物在体内有效吸收。
实施例2
Figure PCTCN2022129074-appb-000004
制备方法：将羟丙基甲基纤维素邻苯二甲酸酯(55.0份重量)(日本信越化学工业株式会社，HP-50)、共聚维酮(20.0份重量)(PVP/VA64，BASF)、单硬脂酸甘油酯(6.0份重量)(湖南尔康制药股份有限公司)、十二烷基硫酸钠(6.0份重量)与化合物A(15.0重量份)和胶态二氧化硅(1.0重量份)混合，然后将该粉末状混合物装入挤出转速150rpm和温度200℃的双螺杆挤出机(螺杆直径11mm)，混合物经螺杆呈条状挤出；将热熔挤出的条状物经粉碎处理后过100目筛，得到含有化合物A的固体分散体2。
将固体分散体2于含不同浓度的SDS表面活性剂(1％、3％、5％)的pH 6.8模拟肠液中测定化合物A的溶解度(37℃、100rpm振摇6h)。经测定含化合物A的固体分散体2在1％SDS-pH 6.8模拟肠液中溶解度为115.70μg/mL；在上述3％SDS-pH 6.8模拟肠液中溶解度为424.5μg/mL；在上述5％SDS-pH 6.8模拟肠液中溶解度为723.1μg/mL。该测试结果显示含化合物A的固体分散体2可显著提高化合物A的溶解度。
实施例3
Figure PCTCN2022129074-appb-000005
制备方法：将醋酸羟丙基甲基纤维素琥珀酸酯(50.0份重量)(日本信越化学工业株式会社，型号：HF)、聚维酮(15.0份重量)(PVP K12，BASF)、十二烷基硫酸钠(4.0份重量)(BASF)、单硬脂酸甘油酯(12.0份重量)(湖南尔康制药股份有限公司)与化合物A(12.0份重量)和胶态二氧化硅(2.0份重量)混合，然后将该粉末状混合物装入挤出转速100rpm和温度180℃的双螺杆挤出机(螺杆直径11mm)，混合物经螺杆呈条状挤出；将热熔挤出的条状物经粉碎处理后过90目筛，得到含化合物A的固体分散体3。
将固体分散体3于5％SDS-pH 6.8模拟肠液中测定化合物A的溶解度(37℃、100rpm振摇6h)，经测定含化合物A的固体分散体3在5％SDS-pH 6.8模拟肠液中的溶解度为815.5μg/mL。该测试结果显示化合物A的固体分散体3可显著提高化合物A的溶解度，且稳定。
实施例4
Figure PCTCN2022129074-appb-000006
制备方法：将羟丙基甲基纤维素邻苯二甲酸酯(60.0份重量)(型号：HP-50)、羟丙甲纤维素(15.0份重量)(HPMC HME 15LV，美国杜邦公司)、十二烷基硫酸钠(2.0重量份)、硬脂酸聚烃氧40酯(8.0重量份)、胶态二氧化硅(2.0份重量)与化合物A(8.0份重量)溶解于丙酮/二氯甲烷(体积比2:1)混合溶剂中，然后将该溶剂用旋转蒸发仪于30℃挥干，将所得物质于40℃真空干燥箱干燥12h以上挥去残留有机溶剂，将所得固体物质经粉碎处理后过60目筛，得到含有化合物A的固体分散体4。
将固体分散体4于5％SDS-pH 6.8模拟肠液中测定化合物A的溶解度(37℃、100rpm振摇3h和6h)，经测定含化合物A的固体分散体4在5％SDS-pH 6.8模拟肠液中3h、6h的溶解度分别为765.5和715.6μg/mL。该测试结果显示含化合物A的固体分散体4可显著提高化合物A的溶解度且具有较长的过饱和维持时间，利于药物吸收。
实施例5
将实施例1制备所得的固体分散体1(95.0份重量)，与共聚维酮(17.4份重量)(PVP/VA64，BASF)、交联聚维酮(3.6份重量)(美国国际特品公司)和硬脂富马酸钠(1.0份 重量)(德国JRS集团药用辅料公司)混合均匀，采用单冲压片机压制成585.0mg的片剂。然后将药片置于包衣锅中，于60℃温度下用薄膜包衣用水性分散液(Opadry，上海卡乐康包衣技术有限公司)对药片进行薄膜包衣，得到含有化合物A的固体制剂1，该固体制剂为片剂。
实施例6
将实施例2制备所得的固体分散体2(103.0份重量)，与微晶纤维素(13.2份重量)(台湾名台化工股份有限公司)、预胶化淀粉(8.0份重量)(上海卡乐康包衣技术有限公司)、低取代羟丙基纤维素(4.8份重量)(日本信越化学工业株式会社)和硬脂酸镁(1.0份重量)(安徽山河药用股份有限公司)混合均匀，采用填充式胶囊灌装机以0#胶囊按260mg/粒灌装胶囊，得到含有化合物A的固体制剂2，该固体制剂为胶囊剂。
实施例7
将实施例3制备所得的固体分散体3(95.0份重量)，与乳糖(12.0份重量)(荷兰DFE Pharma公司制造)、交联羧甲基纤维素钠(4.0份重量)和硬脂富马酸钠(1.0份重量)混合均匀，采用单冲压片机压制成467mg的片剂。然后将药片置于包衣锅中，于60℃温度下用薄膜包衣用水性分散液(Opadry，上海卡乐康包衣技术有限公司)对药片进行薄膜包衣，得到含有化合物A的固体制剂3，该固体制剂为片剂。
实施例8
Figure PCTCN2022129074-appb-000007
制备方法：将羟丙基甲基纤维素邻苯二甲酸酯(45.0份重量)(日本信越化学工业株式会社)、共聚维酮(10.0份重量)(PVP/VA64，BASF)、硬脂酸聚烃氧40酯(5.0份重量)(Croda Singapore Pte Ltd)与化合物A(10.0重量份)和胶态二氧化硅(0.5份重量)(JRS)预处理后混合均匀，得到粉末状混合物。然后将该粉末状混合物装入挤出转速100-240rpm和温度160-200℃的双螺杆挤出机(螺杆直径18mm，LEISTRITZ)，喂料速度50-70rpm，混合物经螺杆呈条状挤出；挤出物在快速冷压辊轮挤压冷却；将热熔挤出的条状物加入锤式粉碎机中粉碎处理，得到含有化合物A的固体分散体5。
在此实施例中，对于获得的粉末状混合物，分别经由不同工艺参数的熔体挤出设备 得到不同的含有化合物A的固体分散体；经DSC和XRPD测试，这些分散体均为无定型。此外，还对制备过程中的固体分散体的降解产物邻苯二甲酸分别进行了检测，结果见下表2。
表2 热熔挤出不同工艺参数研究结果
工艺参数 参数1 参数2 参数3 参数4 参数5 参数6 参数7
套筒温度(℃) 150 160 160 170 180 180 180
螺杆速度(rpm) 210 210 240 210 210 180 50
喂料速度(rpm) 60 60 70 60 60 50 25
邻苯二甲酸(wt％) 1 2.8 3.0 3.0 3.5 4.5 4.7 4.8
注： 1邻苯二甲酸含量以固体分散体总组份计。
结果表明：随着热熔挤出温度升高，邻苯二甲酸降解水平升高，随着螺杆转速和加料速度降低，邻苯二甲酸降解水平升高。通过工艺参数优化，可有效避免温度升高和滞留时间升高从而引起的杂质邻苯二甲酸增长。
在此实施例中还对固体分散体的粉碎工艺进行了研究，研究发现，当粉碎转速5000-5400rpm，或/和粉碎后过筛目数为60-120目时，制得的固体分散体有较好的粒径分布(如D90<200μm)，从而有效地提高了制备固体制剂过程中的可压片性。
实施例9
将实施例8制备得到的固体分散体5(75.0份重量)与共聚维酮(16.0份重量)(PVP/VA64，BASF)、交联聚维酮(20.5份重量，ASHLAND)、枸橼酸(2.0份，Merck)于混合桶内，混合转速10rpm，混合时间20-40min；再加入十二烷基硫酸钠(3.0份，BASF)和硬脂富马酸钠(0.6份重量，JRS)进行润滑混合，混合转速10rpm，混合时间3-10min，得到混合均匀的总混粉。采用菲特压片机压片压制成600mg的片剂，制得相应的制剂4。
在此实施例中，对固体分散体5进行混合压片时，对不同混合工艺进行了研究，以考察在制备片剂时片剂的可压性。结果表明，当固体分散体与药用添加剂的混合时间为20-40min时，所得总混粉有较好的混合均匀性，且总混粉末的可压性较好，片剂硬度约为80-135N。另外，在加入药用添加剂进行混合时，尤其是加入表面活性剂和润滑剂(如有)时，控制润滑混合时间在10min内时所得总混粉的可压性较好。当润滑混合时间过长时，存在影响粉末可压性的问题；所得片剂硬度为50-70N，进而影响脆碎度。
实施例10
Figure PCTCN2022129074-appb-000008
Figure PCTCN2022129074-appb-000009
制备方法：将羟丙基甲基纤维素邻苯二甲酸酯(35.0份重量)(HP-55，日本信越化学工业株式会社)、共聚维酮(5.0份重量)(PVP/VA64，BASF)、硬脂酸聚烃氧40酯(5.0份重量)(Croda Singapore Pte Ltd)与化合物A(10.0重量份)和胶态二氧化硅(0.5份重量，EVONIK)混合，得到粉末状混合物。再将该混合物用不同的制备方法得到相应固体制剂。
制备方法1)：将粉末状混合物溶解于二氯甲烷/甲醇(体积比10：1)混合溶剂中，待溶解后，将该溶剂用旋转蒸发仪于40℃挥干后，将样品转移至真空干燥烘箱(40℃，真空度0.9bar)过夜(12h以上)除去残留的有机溶剂，将所得干燥物研磨粉碎后过80目筛备用，得到含有化合物A的固体分散体6粉末。
制备方法2)：将粉末状混合物装入挤出机螺杆转速120rpm和温度175℃的双螺杆挤出机，混合物经螺杆呈条状挤出；将热熔挤出的条状物经粉碎处理后过80目筛，得到含化合物A的固体分散体7粉末。
以分散体粉末的溶解行为和X-射线衍射考察两种工艺制备的固体分散体，发现两者的溶解度无显著性差异，对药物的増溶能力相同。
将固体分散体6(55.5份重量)、固体分散体7(55.5份重量)分别与共聚维酮(18.5.0份重量)(PVP/VA64，BASF)、交联聚维酮(20.5份重量，ASHLAND)、枸橼酸(2.0份，Merck)于混合桶内，混合转速15rpm，混合时间20min，加入十二烷基硫酸钠(3.0份，BASF)和硬脂富马酸钠(0.5份，JRS)润滑，混合转速15rpm，混合时间5min，得到混合均匀的总混粉。采用压片机压片压制成500mg的片剂，随后分别得到含有化合物A的固体制剂T1、T2。
表3 不同方法制得的固体制剂的溶出速率
Figure PCTCN2022129074-appb-000010
注： 1溶出条件：pH 6.8的磷酸盐缓冲液+1％SDS，75rpm，桨法。
由表3可知，通过溶剂挥发法制备得到的固体制剂T1的溶出速率相对于热熔挤出法制备得到的固体制剂T2的溶出速率更快，但30min后两者均释放完全，两者溶出行为基本一致，无显著性差异，表明溶剂挥发法、热熔挤出法这两种工艺制得的制剂两者质量 基本一致，从而推测固体分散体6、7的溶解度无显著性差异。
此外，还对固体制剂T1、T2分别对比格犬(北京玛斯生物技术有限公司，n＝6)进行了生物利用度的测试，药代动力学测试方法同实验实施例4中实施例5；以LC-MS/MS测定样品中化合物A的浓度，使用WinNonLin(8.3版，Pharsight)按照非房室模型，计算比格犬给药后化合物A的药代动力学参数。
表4 含有化合物A的固体制剂的药物动力学数据
PK参数 固体制剂T1 固体制剂T2
AUC (0-t)(h*ng/mL) 1240±674 2960±1160
相对生物利用度F(％) 1 57.67±25.00 --
注： 1相对生物利用度F＝(固体制剂T1的AUC)/(固体制剂T2的AUC)×100％，F值取单只动物的相对生物利用度的平均值。
结果表明，通过溶剂挥发法(旋转蒸发)制备得到的固体制剂T1的相对生物利用度为通过熔体挤出法制备得到的固体制剂T2的相对生物利用度为57.67％。
实施例11
Figure PCTCN2022129074-appb-000011
制备方法：将羟丙基甲基纤维素邻苯二甲酸酯(58.0份重量)(日本信越化学工业株式会社)、聚乙烯醇(15.0份重量)(Merck)、硬脂酸聚烃氧40酯(10.0份重量)(南京威尔化工有限公司)与化合物A(12.0重量份)和胶态二氧化硅(2.0重量份)混合，然后将该粉末状混合物装入挤出转速200rpm和温度200℃的双螺杆挤出机(螺杆直径16mm)，混合物经螺杆呈条状挤出；将热熔挤出的条状物经粉碎处理后过60目筛，得到含有化合物A的固体分散体8。
将固体分散体8于5％SDS-pH 6.8模拟肠液中测定化合物A的溶解度(37℃、100rpm振摇6h)，经测定含化合物A的固体分散体8在5％SDS-pH 6.8模拟肠液中6h的溶解度为657.8μg/mL。该测试结果显示含化合物A的固体分散体8可显著提高化合物A的溶解度。
对比实施例
对比实施例1
将化合物A以气流粉碎机(MC JETMILL-50，JETPHARMA SOLUTIONS SA公司)进行微粉化处理至平均粒径约20μm(12.5份重量)，与羟丙基甲基纤维素邻苯二甲酸酯(57.7份重量)、硬脂酸聚烃氧40酯(4.7份重量)、十二烷基硫酸钠(2.3份重量)、胶态二氧化硅(0.9份重量)、共聚维酮(17.3份重量)(PVP/VA64，BASF)、交联聚维酮(3.6份重量)和硬脂富马酸钠(1.0份重量)混合均匀，采用单冲压片机压制成400.0mg的微粉化IR片剂。然后将药片置于包衣锅中，于60℃温度下用薄膜包衣用水性分散液(Opadry，上海卡乐康包衣技术有限公司)对药片进行薄膜包衣，得到含有化合物A的常规固体制剂I，该固体制剂为普通微粉化制剂。
对比实施例2
将化合物A(0.3份重量)，与丙二醇(40.7份重量)(美国陶氏化学公司)，聚氧乙烯蓖麻油(59.0份重量)(BASF)置适宜容器中，在70-110℃下以300rpm速度搅拌至化合物A完全溶解，即得含化合物A且浓度为3mg/mL(1wt％)的液体制剂，得到含有化合物A的液体制剂II。
对比实施例3
Figure PCTCN2022129074-appb-000012
制备方法：将共聚维酮(75.0份重量)(PVP VA64，BASF)、硬脂酸聚烃氧40酯(5.0份重量)(湖南尔康制药股份有限公司，S40)、十二烷基硫酸钠(4.0份重量)(BASF)与化合物A(10.0份重量)和胶态二氧化硅(1.0份重量)(EVONIK，Aerosil)混合，然后将该粉末状混合物装入挤出转速100rpm和温度170℃的双螺杆挤出机(螺杆直径11mm，Thermo Scientific)，混合物经螺杆呈条状挤出；将热熔挤出的条状物经粉碎处理后过60目筛，得到含有化合物A的固体分散体10。
将固体分散体10(95.0份重量)，与共聚维酮(17.4份重量)(PVP VA64，BASF)、交联聚维酮(3.6份重量)(美国国际特品公司)和硬脂富马酸钠(1.0份重量)(德国JRS集团药用辅料公司)混合均匀，采用单冲压片机压制成585.0mg的片剂。然后将药片置于包衣锅中， 于60℃下用薄膜包衣用水性分散液(Opadry，上海卡乐康包衣技术有限公司)对药片进行薄膜包衣，得到含有化合物A的普通固体分散体制剂III，该固体制剂为不含肠溶性高分子聚合物固体分散体制备的固体制剂。
对比实施例4
Figure PCTCN2022129074-appb-000013
制备方法：将羟丙基甲基纤维素邻苯二甲酸酯(40.0份重量)(型号：HP-50)、硬脂酸聚烃氧40酯(5.0份重量)(湖南尔康制药股份有限公司，S40)、十二烷基硫酸钠(4.0份重量)(BASF)与化合物A(10.0重量份)和胶态二氧化硅(1.0重量份)混合，然后将该粉末状混合物装入挤出转速150rpm和180℃的双螺杆挤出机(螺杆直径11mm)，混合物经螺杆呈条状挤出；得到含有化合物A的固体分散体11。
将固体分散体11于含SDS表面活性剂(1％)的pH 6.8模拟肠液中测定化合物A的溶解度(37℃、100rpm振摇3h、6h)。经测定含化合物A的固体分散体6在1％SDS-pH 6.8模拟肠液中3h的溶解度为53.7μg/mL，6h的溶解度为43.3μg/mL；该测试结果显示含化合物A的固体分散体6虽可略提高化合物A的溶解度，但随着时间延长，溶解度下降，表明出现药物析出现象，过饱和状态稳定性差，不利于药物吸收。
将固体分散体11(300.0份重量)，与乳糖(100.0份重量)、交联羧甲基纤维素钠(20.00份重量)和硬脂富马酸钠(2.00份重量)混合均匀，采用单冲压片机压制成422mg的片剂，得到含有化合物A的固体分散体制剂IV。
对比实施例5
Figure PCTCN2022129074-appb-000014
制备方法：将羟丙基甲基纤维素邻苯二甲酸酯(80.0份重量)(型号：HP-50)、共聚维酮(50.0份重量)(PVP VA64，BASF)、十二烷基硫酸钠(1.0重量份)、单硬脂酸甘油酯(25.0重量份)、胶态二氧化硅(1.0份重量)与化合物A(50.0份重量)混合，然后将该粉末状混合物装入挤出转速150rpm和温度200℃的双螺杆挤出机(螺杆直径11mm)，混合物经螺杆呈条状挤出；将所得固体物质经粉碎处理后过60目筛，得到含有化合物A的固体分散体12(本发明重量份范围外的固体分散体)。
将固体分散体12于含SDS表面活性剂(1％)的pH 6.8模拟肠液中测定化合物A的溶解度(37℃、100rpm振摇3h、6h)。经测定含化合物A的固体分散体6在1％SDS-pH 6.8模拟肠液中3h的溶解度为31.3μg/mL，6h的溶解度为22.4μg/mL；该测试结果显示含化合物A的固体分散体12对化合物A的溶解度提高作用极小，且随着时间延长，溶解度下降，表明出现药物析出现象，过饱和状态稳定性差，不利于提高药物吸收。
将固体分散体12(207.0份重量)，与乳糖(50.0份重量)、交联羧甲基纤维素钠(10.00份重量)和硬脂富马酸钠(2.00份重量)混合均匀，采用单冲压片机压制成269mg的片剂，得到含有化合物A的固体分散体制剂V。
实验实施例
实验实施例1
平衡溶解度及渗透率考察
平衡溶解度考察：考察化合物A原料在一系列溶剂中的溶解度，主要溶剂包括水、pH 1.2模拟胃液(每升水含2g氯化钾和7mL盐酸)、pH 4.5磷酸盐缓冲液(每升水含12.9g柠檬酸和0.63g磷酸氢二钠)、pH 6.8模拟肠液，取化合物A约0.1g，加入上述溶剂各100mL，于37℃摇床100rpm振摇24h，取上层清液以8000rpm离心15min后以HPLC测定化合物A的浓度。化合物A在不同介质中的溶解度见表5。
表5 化合物A在不同溶剂中的溶解度
溶剂 平衡溶解度(μg/mL)，24h
水 0.1
pH 1.2模拟胃液 0.5
pH 4.5磷酸盐缓冲液 0.1
pH 6.8模拟肠液 0.1
渗透率考察：采用Caco-2细胞模型评价化合物A的渗透性。采用LC/MS/MS法测定化合物A、阳性对照药阿替洛尔、普萘洛尔和地高辛的浓度，计算表观渗透系数(Papp)和表观渗透系数的比率Papp比率＝Papp (B→A)/Papp (A→B)，并据此来评判该化合物的渗透性 及其是否为P-gp的底物。结果见表6。
表6 化合物A在Caco-2细胞模型中渗透率考察结果(n＝3，±SD)
Figure PCTCN2022129074-appb-000015
注：A＝顶端，B＝基底外侧
由表6可知，上述溶解度试验结果中化合物A在不同pH值介质中溶解度均低于1μg/mL，为几乎不溶或不溶性药物；由表6中渗透率考察结果表明化合物A具有高渗透性的特征，高浓度时可能由于药物的溶解度原因渗透系数与低浓度有较大区别，在2.00和50.0μM浓度范围内在Caco-2细胞上没有明显的外排作用。
实验实施例2
体外溶出试验考察
取上述实施例5、实施例6和实施例7制得的固体制剂1、2、3，以及对比实施例1和对比实施例3制得的固体制剂I、III，根据中国药典2015年版四部通则(0931)第二法装置(桨法)进行溶出度试验。将单个剂量单位的各制剂在37℃和50rpm搅拌速度下置于1000mL 5％SDS-pH 6.8的模拟肠液中，在5、10、15、30、45、60和90min后，取出8mL样品并给予同体积的补液。将取出的样品稀释3倍后照紫外-可见分光光度法(中国药典2015年版四部通则0401)，在316nm的波长处分别测定吸光度，计算相应制剂的溶出量，并绘制溶出曲线(见图2)。
将实施例5、6、7制备的固体制剂1、2、3于40±2℃，75％±5％RH加速条件下放置6月后采用上述相同条件测定药物的溶出行为，并绘制溶出曲线(见图3、图4及图5)。
由图2-5可知，实施例5、6、7制备的固体制剂1、2、3较IR常规制剂I(普通微粉化制剂，对比实施例1)和普通固体分散体制剂III(仅含非肠溶性高分子聚合物固体分散体制备的固体制剂，对比实施例3)可显著提高化合物A的溶出速度和溶解度；且加速条件放置后本发明的固体制剂的溶出行为未发生显著改变，对药物増溶效果良好，稳定性良好。
实验实施例3
溶解稳定性考察
取上述实施例5、实施例6和实施例7、对比实施例1和对比实施例3制得的制剂，研细，称取单个剂量单位的各制剂在37℃和100rpm搅拌速度下置于250mL 3％SDS-pH 6.8的模拟肠液中，在1h、2h、4h、6h、8h后，取出样品以8000rpm离心15min后，以HPLC测定化合物A的浓度，并绘制时间-浓度曲线(见图6)。
由图6可知，本发明实施例5、6、7制备的固体制剂8h内溶解稳定性良好，过饱和状态稳定，利于药物的吸收，而IR常规制剂(普通微粉化制剂，对比实施例1和普通固体分散体制剂(不含肠溶性高分子聚合物固体分散体制备的固体制剂，对比实施例3在2h即出现溶解度降低，并随时间增加药物浓度持续降低，表明出现药物析出现象，过饱和状态稳定性差，不利于药物的吸收。
实验实施例4
犬体内生物利用度研究
取上述实施例5、实施例7、对比实施例1、对比实施例3、对比实施例4和对比实施例5制得的制剂分别口服给予饱腹比格犬(n＝3，上海药物研究所实验动物中心)。实施例5、实施例7、对比实施例1、对比实施例3、对比实施例4和对比实施例5制剂的给药量为50mg/只。试验前统一提供食物，30min后给药，整个试验过程不禁水，清洗期为7天。在给药前(0h)及给药后0.25、0.5、1.0、2.0、4.0、6.0、8.0、12、24、48和72h经四肢静脉取血0.5mL；置EDTA-K 2抗凝试管中，3500rpm离心10min，分离血浆，–70℃冰箱中冷冻保存待测。
取上述对比实施例2的液体制剂，以生理盐水稀释6倍后以1mg/kg化合物A的剂量(2mL/kg)静脉注射给予饱腹比格犬(n＝3)。试验前统一提供食物，30min后给药，整个试验过程不禁水。给药前(0h)及给药后5min、0.25、0.5、1.0、2.0、4.0、6.0、8.0、12、24、48和72h取血样0.5mL，置EDTA-K 2抗凝试管中，3500rpm离心10min，分离血浆，–70℃冰箱中冷冻保存待测。
以LC-MS测定样品中化合物A的浓度。采用Phoenix6.4软件(美国Pharsight公司)的非房室模型计算比格犬给药后化合物A的药代动力学参数，数据概要见表7。
表7 化合物A的药物动力学数据(n＝3)
制剂 T 1/2(h) C max(ng/mL) AUC (0-∞)(h*ng/mL) 绝对生物利用度(％) 1
实施例5 4.59 359 3610 52.7
实施例7 5.21 301 2880 42.0
对比实施例1 6.39 24 225 3.3
对比实施例3 5.55 62 431 6.3
对比实施例4 5.02 106 851 12.4
对比实施例5 6.12 75 615 9.0
对比实施例2 3.63 / 1370 100
注： 1绝对生物利用度以液体制剂(对比例实施例2)的生物利用为100％，测试其他实施例相对于对比例实施例2的生物利用度。
由结果可见，与对比实施例1制得的IR常规制剂(普通微粉化制剂)、对比实施例3制得的普通固体分散体制剂(仅含非肠溶性高分子聚合物固体分散体制备的固体制剂)、对比实施例4制得的固体分散体制剂(仅含肠溶性高分子聚合物固体分散体制备的固体制剂)、对比实施例5制得的固体分散体制剂(本发明重量份范围外的固体分散体制剂)相比，本发明实施例5制得的固体制剂1和实施例7制得的固体制剂3均可显著提高化合物A的生物利用度，体内吸收良好。而对比实施例1、对比实施例3、对比实施例4、对比实施例5体内吸收差。

Claims (11)

  1. 一种固体分散体，其特征在于，其包括化合物A、可药用基质聚合物，其中，所述可药用基质聚合物包括肠溶性高分子聚合物和非肠溶性高分子聚合物，所述化合物A为1-{(6-[(1-甲基)-4-吡唑基]-咪唑[1,2-a]并吡啶)-3-磺酰基}-6-[(1-甲基)-4-吡唑基]-1-氢-吡唑并[4,3-b]吡啶，所述化合物A与所述可药用基质聚合物的重量比为1:3-1:35。
  2. 如权利要求1所述的固体分散体，其特征在于，所述肠溶性高分子聚合物选自羟丙基甲基纤维素邻苯二甲酸酯、醋酸羟丙基甲基纤维素琥珀酸酯、聚甲基丙烯酸酯、聚乙烯醇乙酸苯二甲酸酯、邻苯二甲酸乙酸纤维素和琥珀酸乙酸纤维素中的一种或多种；
    和/或，所述非肠溶性高分子聚合物选自聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、共聚维酮、聚维酮、聚乙烯醇、2-羟基-β-环糊精、羟丙甲纤维素和羟丙基纤维素中的一种或多种；
    和/或，所述肠溶性高分子聚合物与所述非肠溶性高分子聚合物的重量比为2:1-10:1。
  3. 如权利要求1所述的固体分散体，其特征在于，所述固体分散体满足下述条件中的一种或多种：
    ①所述肠溶性高分子聚合物为羟丙基甲基纤维素邻苯二甲酸酯和/或醋酸羟丙基甲基纤维素琥珀酸酯；
    ②所述非肠溶性高分子聚合物选自共聚维酮、聚乙烯醇、聚维酮和羟丙甲纤维素中的一种或多种；
    ③所述固体分散体还任选地包含助流剂、增塑剂和表面活性剂中的一种或多种；
    ④所述肠溶性高分子聚合物与所述非肠溶性高分子聚合物的重量比为2:1-6:1；
    和⑤所述化合物A与所述可药用基质聚合物的重量比为1:4-1:25，优选为1:5-1:15。
  4. 如权利要求3所述的固体分散体，其特征在于，所述固体分散体满足下述条件中的一种或多种：
    ①所述化合物A与所述肠溶性高分子聚合物的重量比为1:2-1:15，优选为1:3-1:10；
    ②所述化合物A与所述非肠溶性高分子聚合物的重量比为2:1-1:10，优选为2:1-1:5；
    ③所述助流剂选自胶态二氧化硅、动物脂肪、植物脂肪和蜡中的一种或多种；
    ④所述助流剂与所述化合物A的重量比为1:1-1:100；
    ⑤所述增塑剂选自柠檬酸乙酰三丁酯、柠檬酸乙酰三乙酯、苯甲酸苄酯、三氯叔丁醇、糊精、邻苯二甲酸二丁酯、邻苯二甲酸二乙酯、邻苯二甲酸二甲酯、甘油、单硬脂酸甘油酯、硬脂酸聚烃氧40酯、甘露醇、矿物油、羊毛脂醇、棕榈酸、聚乙二醇、聚乙二醇单硬脂酸酯、聚乙酸邻苯二甲酸乙烯酯、丙二醇、2-吡咯烷酮、山梨糖醇、硬脂酸、三 醋精、柠檬酸三丁酯、三乙醇胺和柠檬酸三乙酯中的一种或多种；
    ⑥所述增塑剂与所述化合物的重量比为1:1-1:20；
    ⑦所述表面活性剂选自阴离子型表面活性剂、阳离子型表面活性剂和非离子型表面活性剂中的一种或多种；所述阴离子型表面活性剂优选为十二烷基硫酸钠和/或多库酯钠；所述阳离子型表面活性剂优选为溴棕三甲铵、苄索氯铵、十六烷基氯化吡啶鎓和月桂酸中的一种或多种；所述非离子型表面活性剂优选为聚氧乙烯烷基醚、聚氧乙烯山梨糖醇酐脂肪酸酯、聚氧乙烯蓖麻油衍生物、聚氧乙烯硬脂酸酯和聚氧乙烯聚氧丙烯醚嵌段共聚物中的一种或多种；
    和⑧所述表面活性剂与所述化合物A的重量比为1:1-1:10。
  5. 一种如权利要求1-4任一项所述固体分散体的制备方法，其特征在于，其包括下述步骤：
    (1)所述固体分散体的各成分通过熔融或溶解均匀混合得到均匀分散体；
    (2)所述均匀分散体固化以得到固体分散体。
  6. 如权利要求5所述固体分散体的制备方法，其特征在于，所述固化为熔体挤出法，所述固体分散体的制备方法满足下述条件中的一种或多种：
    ①所述熔体挤出法中，熔体挤出设备的套筒温度为150-220℃；
    ②所述熔体挤出法中，熔体挤出设备的螺杆挤出转速为50-300rpm；
    ③所述熔体挤出法中，喂料速度为10-100rpm；
    和④所述熔体挤出法包括：
    (1a)将所述固体分散体的各成分混合均匀得粉末状混合物；
    (2a)将所述粉末状混合物装入热熔挤出机加料器中，挤出，粉碎，过筛处理得到含有化合物A的固体分散体。
  7. 一种固体制剂，其特征在于，其包括如权利要求1-4任一项所述固体分散体和可药用添加剂；较佳地，所述可药用添加剂包括助流剂、粘合剂、崩解剂、填充剂、润滑剂、着色剂、pH调节剂、表面活性剂、润滑剂和稳定剂中的一种或多种。
  8. 如权利要求1-4任一项所述固体分散体或如权利要求7所述固体制剂，其中，以所述固体分散体总组份计，邻苯二甲酸含量≤6.0wt％，优选地，≤4.8wt％。
  9. 一种如权利要求1-4任一项所述固体分散体或如权利要求7所述固体制剂在制备预防和/或治疗蛋白酪氨酸激酶紊乱相关疾病和/或肿瘤的药物中的用途。
  10. 如权利要求9所述的用途，其中，所述疾病和/或肿瘤包括实体癌；例如肺癌、胃癌、食管癌、结肠癌、结直肠癌、肝癌、肾细胞癌、头颈癌、甲状腺癌、卵巢癌、乳腺癌、胰腺癌、前列腺癌、口腔癌、恶性胶质癌、横纹肌肉癌或骨肉癌；
    较佳地，所述疾病和/或肿瘤为肺癌、胃癌、肝癌、肾细胞癌、卵巢癌、乳腺癌、胰腺癌、前列腺癌或甲状腺癌；
    更佳地，所述疾病和/或肿瘤为肺癌，例如非小细胞肺癌。
  11. 一种预防和/或治疗蛋白酪氨酸激酶紊乱相关疾病和/或肿瘤的方法，包括向有需要的个体施用有效量的如权利要求1-4任一项所述固体分散体或如权利要求7所述固体制剂。
PCT/CN2022/129074 2021-11-05 2022-11-01 一种固体分散体、其制备方法及包含其的固体制剂 WO2023078265A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CA3236956A CA3236956A1 (en) 2021-11-05 2022-11-01 Solid dispersion, preparation method therefor, and solid formulation comprising same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111308836.4 2021-11-05
CN202111308836 2021-11-05

Publications (1)

Publication Number Publication Date
WO2023078265A1 true WO2023078265A1 (zh) 2023-05-11

Family

ID=86240675

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/129074 WO2023078265A1 (zh) 2021-11-05 2022-11-01 一种固体分散体、其制备方法及包含其的固体制剂

Country Status (2)

Country Link
CA (1) CA3236956A1 (zh)
WO (1) WO2023078265A1 (zh)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104230922A (zh) * 2013-06-19 2014-12-24 中国科学院上海药物研究所 一类五元杂环并吡啶类化合物及其制备方法和用途
CN105829310A (zh) * 2013-12-20 2016-08-03 阿斯特克斯治疗有限公司 双环杂环化合物及其治疗用途
CN112930215A (zh) * 2018-08-30 2021-06-08 阿雷生物药品公司 作为TAM和MET激酶抑制剂的吡唑并[3，4-b]吡啶化合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104230922A (zh) * 2013-06-19 2014-12-24 中国科学院上海药物研究所 一类五元杂环并吡啶类化合物及其制备方法和用途
CN105829310A (zh) * 2013-12-20 2016-08-03 阿斯特克斯治疗有限公司 双环杂环化合物及其治疗用途
CN112930215A (zh) * 2018-08-30 2021-06-08 阿雷生物药品公司 作为TAM和MET激酶抑制剂的吡唑并[3，4-b]吡啶化合物

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AI JING, CHEN YI, PENG XIA, JI YINCHUN, XI YONG, SHEN YANYAN, YANG XINYING, SU YI, SUN YIMING, GAO YINGLEI, MA YUCHI, XIONG BING, : "Preclinical Evaluation of SCC244 (Glumetinib), a Novel, Potent, and Highly Selective Inhibitor of c-Met in MET-dependent Cancer Models", MOLECULAR CANCER THERAPEUTICS, AMERICAN ASSOCIATION FOR CANCER RESEARCH, US, vol. 17, no. 4, 1 April 2018 (2018-04-01), US , pages 751 - 762, XP093064250, ISSN: 1535-7163, DOI: 10.1158/1535-7163.MCT-17-0368 *
PORTER, J. ; LUMB, S. ; FRANKLIN, R.J. ; GASCON-SIMORTE, J.M. ; CALMIANO, M. ; RICHE, K.L. ; LALLEMAND, B. ; KEYAERTS, J. ; EDWARD: "Discovery of 4-azaindoles as novel inhibitors of c-Met kinase", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 19, no. 10, 15 May 2009 (2009-05-15), Amsterdam NL , pages 2780 - 2784, XP026085966, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2009.03.110 *
TANG, XING: "Solid Dispersion", PHARMACY, 31 December 2019 (2019-12-31), XP009546210 *

Also Published As

Publication number Publication date
CA3236956A1 (en) 2023-05-11

Similar Documents

Publication Publication Date Title
CN106265580B (zh) Somcl-9112固体分散体、其制备方法及包含其的somcl-9112固体制剂
TWI702953B (zh) 包含ａｚｄ９２９１之醫藥組合物及錠劑以及其用途
AU2014221630B2 (en) Suspension for oral administration comprising amorphous tolvaptan
US20230355620A1 (en) Amorphous solid dispersions of dasatinib and uses thereof
AU2018335391A1 (en) Abiraterone-cyclic oligomer pharmaceutical formulations and methods of formation and administration thereof
KR20180102584A (ko) 페닐아미노피리미딘 유도체를 포함하는 약제학적 조성물
KR102197465B1 (ko) 디메틸푸마르산염을 함유한 장용성 정제
WO2023078265A1 (zh) 一种固体分散体、其制备方法及包含其的固体制剂
WO2022028264A1 (zh) 富马酸奥比特嗪肠溶微丸及其制备方法和用途
CN118139620A (zh) 一种固体分散体、其制备方法及包含其的固体制剂
WO2021175274A1 (zh) 奥拉帕尼溶出增强组合物
KR20170056574A (ko) 알펠리십을 포함하는 제약 조성물
US20230041852A1 (en) Pharmaceutical compositions and crushable tablets including amorphous solid dispersions of dasatinib and uses
JPWO2013062073A1 (ja) 低用量ラモセトロン含有口腔内崩壊錠
EP4135659A1 (en) Methods and compositions for treating prostate cancer
WO2022138717A1 (ja) 経口固形製剤
JP2021181483A (ja) 低１日用量で投与するためのフマル酸ジメチルを含む医薬組成物
EA040951B1 (ru) Лекарственные формы цис-4-[2-{[(3s,4r)-3-фтороксан-4-ил]амино}-8-(2,4,6-трихлоранилино)-9н-пурин-9-ил]-1-метилциклогексан-1-карбоксамида и их применение в способе лечения рака
WO2017163268A2 (en) A sustained release pharmaceutical dosage form of divalproex

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: 22889288

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 312480

Country of ref document: IL

ENP Entry into the national phase

Ref document number: 3236956

Country of ref document: CA

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112024008728

Country of ref document: BR