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 PDFInfo
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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
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Abstract
Description
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 |
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 | -- |
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 |
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 |
Claims (11)
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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%。
- 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。
- 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。
- 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。
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