WO2021114020A1 - 含炔基化合物的药物组合物、其制备方法及应用 - Google Patents

含炔基化合物的药物组合物、其制备方法及应用 Download PDF

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Publication number
WO2021114020A1
WO2021114020A1 PCT/CN2019/124024 CN2019124024W WO2021114020A1 WO 2021114020 A1 WO2021114020 A1 WO 2021114020A1 CN 2019124024 W CN2019124024 W CN 2019124024W WO 2021114020 A1 WO2021114020 A1 WO 2021114020A1
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Prior art keywords
parts
substituted
tablet
methyl
pharmaceutical composition
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PCT/CN2019/124024
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English (en)
French (fr)
Inventor
林艳琼
温剑峰
徐峰
黄家安
李世雄
贺小玲
梁师赫
Original Assignee
苏州亚盛药业有限公司
亚盛医药集团有限公司
广州顺健生物医药科技有限公司
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Application filed by 苏州亚盛药业有限公司, 亚盛医药集团有限公司, 广州顺健生物医药科技有限公司 filed Critical 苏州亚盛药业有限公司
Priority to PCT/CN2019/124024 priority Critical patent/WO2021114020A1/zh
Priority to AU2019449883A priority patent/AU2019449883A1/en
Priority to EP19934380.7A priority patent/EP3861990A4/en
Priority to US17/259,719 priority patent/US12097195B2/en
Publication of WO2021114020A1 publication Critical patent/WO2021114020A1/zh

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/496Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4866Organic macromolecular compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia

Definitions

  • the invention relates to the field of pharmaceutical preparations, in particular to a pharmaceutical composition containing an alkynyl compound, its preparation method and application.
  • the alkynyl-containing compound of the present invention was first included in CN101885722A, and its structure is 3-((1H-pyrazole[3,4-b]pyridine-5-substituted)ethynyl)-4-methyl-N-(4 -((4-Methylpiperazine-1-substituted)methyl)-3-(trifluoromethyl)phenyl)benzamide.
  • the compound is a new type of oral biologically effective Bcr-Abl inhibitor, which can effectively treat tumors and blood system diseases, especially for chronic leukemia K562 and acute leukemia MOLT with very good inhibition rate.
  • the alkynyl-containing compound can effectively target broad-spectrum drug mutants including T3151.
  • As a Bcr-Abl inhibitor it is a very effective drug candidate and can effectively overcome the resistance of imatinib, thus causing numerous pharmaceutical companies. Wide attention.
  • the prior art has not reported that the pharmaceutical composition containing alkynyl compounds, especially a pharmaceutical composition containing alkynyl compounds with good stability and high dissolution rate, can be used for patients to take.
  • the alkynyl-containing compound has good clinical prospects, there is an urgent need to develop a composition of the alkynyl-containing compound with good dissolution and stability, which greatly facilitates the clinical use of the alkynyl-containing compound and benefits the vast majority patient.
  • the present invention provides a pharmaceutical composition containing an alkynyl compound, a preparation method and application thereof.
  • the pharmaceutical composition can effectively improve the bioavailability of the alkynyl compound, has good dissolution and stability, and improves medication safety.
  • the alkynyl-containing compound may be in the form of a free base, or a pharmaceutically acceptable salt form thereof.
  • the present invention provides a pharmaceutical composition, which comprises a pharmaceutical active ingredient and pharmaceutically usable auxiliary materials;
  • the pharmaceutical active ingredient is 3-((1H-pyrazole[3,4-b]pyridine-5-substituted) Ethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-substituted)methyl)-3-(trifluoromethyl)phenyl)benzamide, or its pharmaceutically Acceptable salts;
  • the pharmaceutically usable excipients include diluents and lubricants.
  • the amount of the active pharmaceutical ingredient is preferably 0.5-15 parts, more preferably 1-14.5 parts (for example, 1.4 parts, 1.4 parts, 3 parts, 3.3 parts, 13 parts, 13.3 parts, 14 parts or 14.3 parts).
  • the diluent can be a conventional diluent in the field, preferably including but not limited to: dibasic calcium phosphate, kaolin, dextrin, lactose, sucrose, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate One or more of, sorbitol, starch, starch derivatives, erythritol, xylitol and fructose, more preferably one or more of dextrin, lactose, microcrystalline cellulose and starch, more preferably One or more of dextrin, lactose and microcrystalline cellulose, more preferably microcrystalline cellulose (for example, microcrystalline cellulose PH102).
  • the starch derivatives may be conventional starch derivatives in the art, and preferably include one or more of corn starch, potato starch, compressible starch, modified starch and pregelatinized starch.
  • the amount of the diluent can be a conventional amount in the field, and in parts by weight, the amount of the diluent is preferably 10-98 parts, more preferably 20-98 parts, and further preferably 59-98 parts. Parts, more preferably 80-98 parts (for example, 84 parts, 84.2 parts, 85.7 parts, 86 parts, 95.7 parts, 96 parts, 96.7 parts or 97 parts).
  • the lubricant can be a conventional lubricant in the field, preferably including but not limited to: magnesium stearate, stearic acid, calcium stearate, zinc stearate, liquid paraffin, polyethylene glycol One or more of, silica, colloidal silica, micronized silica gel, talcum powder, starch and hydrogenated vegetable oil, more preferably magnesium stearate, stearic acid, calcium stearate, micronized silica gel and talc One or more of magnesium stearate, stearic acid, calcium stearate and micronized silica gel are more preferred, and magnesium stearate is more preferred.
  • magnesium stearate is more preferred.
  • the amount of the lubricant can be a conventional amount in the field.
  • the amount of the lubricant is preferably 0.1-5 parts by weight, and more preferably 0.5-3 parts (for example, 0.5 parts or 1 part). Copies).
  • the pharmaceutically usable adjuvant may also include a disintegrant, and the disintegrant may be a conventional disintegrant in the art, preferably including but not limited to: low-substituted hydroxypropyl cellulose, One or more of dipovidone, croscarmellose sodium, sodium starch glycolate and croscarmellose sodium, more preferably low-substituted hydroxypropyl cellulose, crospovidone, One or more of croscarmellose sodium, more preferably croscarmellose sodium.
  • the amount of the disintegrant can be a conventional amount in the art.
  • the amount of the disintegrant is preferably 0.5-20 parts by weight, more preferably 0.5-10 parts, more preferably 0.5 parts by weight. -3 parts (for example 1 part).
  • the pharmaceutically usable excipients may also include adhesives.
  • the adhesives may be conventional adhesives in the art, preferably including but not limited to: hydroxypropyl cellulose, hydroxypropyl One or more of methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, acacia, alginic acid, sodium alginate and gelatin, preferably hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone And one or more of polyvinyl alcohol, more preferably hydroxypropyl cellulose and/or polyvinylpyrrolidone.
  • the amount of the adhesive can be a conventional amount in the art.
  • the adhesive is preferably 0.1-5 parts, more preferably 0.5-3 parts.
  • the pharmaceutically usable adjuvant may also include a wetting agent, and the wetting agent may be a conventional wetting agent in the art, preferably including but not limited to: polysorbates, polyoxyethylene fats One or more of alcohol ethers, polyoxyethylene castor oil, phospholipids, sulfates and poloxamers, more preferably sodium lauryl sulfate.
  • a wetting agent preferably including but not limited to: polysorbates, polyoxyethylene fats One or more of alcohol ethers, polyoxyethylene castor oil, phospholipids, sulfates and poloxamers, more preferably sodium lauryl sulfate.
  • the amount of the wetting agent can be a conventional amount in the art, and in parts by weight, the amount of the wetting agent is preferably 0-10 parts, but not 0 parts, more preferably 0.1- 1 serving.
  • the pharmaceutically usable excipients may also include food additives.
  • the food additives can be conventional food additives in the field, preferably including but not limited to: preservatives, antioxidants, coloring agents, bleaching agents, sour agents, coagulants, bulking agents, thickeners, defoamers, One or more of sweeteners, colorants, emulsifiers, quality improvers, anticaking agents, flavor enhancers, enzyme preparations, coating agents, foaming agents, preservatives, flavors and nutritional fortifiers, more preferably Colorant.
  • the preservative can be a conventional preservative in the field.
  • the antioxidant can be a conventional antioxidant in the field.
  • the coloring agent can be a conventional coloring agent in the art.
  • the bleaching agent can be a conventional bleaching agent in the field.
  • the sour agent can be a conventional sour agent in the art.
  • the coagulant can be a conventional coagulant in the field.
  • the coagulant can be a conventional coagulant in the field.
  • the bulking agent can be a conventional bulking agent in the art.
  • the thickener can be a conventional thickener in the field.
  • the defoamer can be a conventional defoamer in the field.
  • the sweetener can be a conventional sweetener in the art.
  • the emulsifier can be a conventional emulsifier in the field.
  • the quality improver can be a conventional quality improver in the field.
  • the anti-caking agent can be a conventional anti-caking agent in the art.
  • the flavor enhancer can be a conventional flavor enhancer in the art.
  • the enzyme preparation can be a conventional enzyme preparation in the field.
  • the coating agent can be a conventional coating agent in the field.
  • the blowing agent can be a conventional blowing agent in the field.
  • the antistaling agent can be a conventional antistaling agent in the field.
  • the perfume can be a conventional perfume in the field.
  • the nutrient fortifier can be a conventional nutrient fortifier in the field.
  • the coloring agent can be a conventional coloring agent in the field, preferably amaranth, carmine, crimson red (cherry red), new red, allure red, lemon yellow, sunset yellow, brilliant blue, indigo and their respective aluminum colors
  • a conventional coloring agent in the field preferably amaranth, carmine, crimson red (cherry red), new red, allure red, lemon yellow, sunset yellow, brilliant blue, indigo and their respective aluminum colors
  • One or more of the lakes more preferably lemon yellow aluminum lake.
  • the amount of the food additive can be a conventional amount in the field, and is not particularly limited in the present invention. It can be adjusted arbitrarily according to the requirements of the prescription process. In parts by weight, the amount of the food additive is preferably 0-1 part, and Not 0 copies.
  • the salt in the "pharmaceutically acceptable salt” may be in the form of a conventional salt in the art, preferably including but not limited to: wherein the inorganic acid salt includes hydrochloride, sulfate, phosphate, and nitric acid.
  • organic acid salts include trifluoromethanesulfonate, p-toluenesulfonate, 1-naphthalenesulfonate, trifluoroacetate, malate, Fumarate, benzoate, salicylate, phenylacetate, acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate , Butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cypionate, bisgluconate, lauryl sulfate, isethionate, fumarate, glucose Enanthate, glycerophosphate, hemisulfate, heptanoate, caproate, 2-hydroxyethane sulfonate, itaconic acid, lactate, maleate, mandelate, methanesulfonic acid Salt, 2-n
  • the pharmaceutical composition includes the following components, and the components can be any of the following schemes, and the amount involved is calculated in parts by weight:
  • the active pharmaceutical ingredients, diluents, disintegrants, lubricants and food additives are the same as those described above.
  • the pharmaceutical composition may be in the form of a solid preparation, preferably a tablet, dispersion, granule or capsule, more preferably a tablet or capsule.
  • the pharmaceutical composition when the pharmaceutical composition is in the form of a tablet, the pharmaceutical composition includes the following components, and each component can be any of the following schemes, involving the amount of In parts by weight:
  • Active pharmaceutical ingredients Active pharmaceutical ingredients, diluents, disintegrants and lubricants;
  • the active pharmaceutical ingredients, diluents, disintegrants, lubricants and food additives are the same as those described above.
  • the tablet when the pharmaceutical composition is in the form of a tablet, the tablet may include a tablet core.
  • the tablet core includes the pharmaceutical composition, and the pharmaceutical composition is the same as described above.
  • the tablets can be uncoated or by known coating techniques to mask the undesirable taste of the drug or prolong the disintegration and absorption in the gastrointestinal tract, and provide longer-term drug efficacy.
  • the coating is carried out under the condition of adding a coating medium and a film-forming agent (they are generally collectively referred to as coating materials) conventional in the art, and the coating material is preferably hydroxypropyl cellulose, hydroxypropyl cellulose, and hydroxypropyl cellulose.
  • the coating is preferably a film coating (for example, a gastric-soluble film coating or an enteric-soluble film coating) or a sugar coating, more preferably a film coating, and even more preferably a gastric-soluble film coating.
  • the coating preferably accounts for 2-5% by weight of the tablet core, more preferably 2.5-4%, further preferably 2.5-3.5%.
  • the specifications of the tablet may be conventional specifications in the art, and the tablet is calculated as the active ingredient of the drug.
  • the specifications are preferably 1mg/tablet-100mg/tablet, more preferably 1mg/tablet, 2mg/tablet, 5mg/tablet, 10mg/tablet, 20mg/tablet, 30mg/tablet, 40mg/tablet, 50mg/tablet or 60mg/tablet, further Preferably, 1 mg/tablet, 10 mg/tablet, 20 mg/tablet, 30 mg/tablet or 40 mg/tablet.
  • the pharmaceutical composition when the pharmaceutical composition is in the form of a capsule, the pharmaceutical composition includes the following components, and each component can be any of the following schemes:
  • the active pharmaceutical ingredients, diluents and lubricants are the same as those mentioned above.
  • the specifications of the capsule may be conventional specifications in the art, for example: 1 mg/capsule, 10 mg/capsule, 20 mg/capsule , 30mg/grain, 40mg/grain, preferably 10mg/grain, 20mg/grain.
  • the present invention provides a method for preparing the above-mentioned pharmaceutical composition, which comprises the following steps: mixing the components.
  • the present invention provides a method for preparing the above-mentioned pharmaceutical composition.
  • the above-mentioned pharmaceutical composition is in the form of a tablet
  • the above-mentioned preparation method can be Method 1 or Method 2.
  • the first method includes the following steps:
  • A1 Screen the active ingredients and pharmaceutically usable excipients separately;
  • A2 Screen the active ingredients of the drug and part of the diluent to obtain a mixture
  • step A3 Add the remaining diluent to the mixture of step A2 in stages, and sieve to obtain the mixture;
  • step A4 Granulate the mixture of step A3 to obtain granules
  • step A5 Screen the particles and lubricant of step A4 and granulate
  • A6 Press tablet, pack, and that's it
  • the second method includes the following steps:
  • B1 Screen the active ingredients of the drug, diluent and disintegrant, and screen the internal and external lubricants;
  • premix 2 Mix the active ingredients of the drug and the diluent to obtain premix 1, sieve the premix 1, then add the disintegrant and the remaining diluent to the sieve to rinse the machine and mix with the sieved premix Mixture 1 and sieve the mixture twice to obtain premix 2;
  • premix 2 Mix premix 2 with the internal lubricant to obtain premix 3;
  • Premix 3 is granulated to obtain granules, and the granules are mixed with an external lubricant to obtain Premix 4;
  • step A1 the active pharmaceutical ingredient is sieved preferably through a 200 mesh sieve.
  • Said pharmaceutically usable excipients are preferably sieved through 40-100 mesh sieve.
  • the sieving is preferably a 40-mesh sieve.
  • the number of times of the sieving is preferably 5-15 times (for example, 10 times).
  • step A2 it is preferable to add food additives and/or disintegrants and sieving together.
  • the sieving is preferably a 40-mesh sieve.
  • the number of times of the sieving is preferably 5-15 times (for example, 10 times).
  • the granulation is preferably dry granulation.
  • the sieving is preferably a 24-mesh sieve.
  • the number of times of the sieving is preferably 5-15 times (for example, 10 times).
  • the granulation is preferably dry granulation.
  • step A5 it is preferable to add a disintegrant and sieving together.
  • the tablet in step A6, is preferably punched with a ⁇ 5.0mm shallow concave.
  • the said compressed tablet preferably has a hardness of 30-70N.
  • the active pharmaceutical ingredient is preferably pulverized by equipment such as a ball mill or a fine powder crusher, and more preferably a fine pulverizer.
  • step B1 the active pharmaceutical ingredient, diluent and disintegrant are sieved, preferably through a 20-mesh sieve.
  • step B1 the internally added and externally added lubricants are preferably sieved through a 60-mesh sieve.
  • step B2 when the active pharmaceutical ingredient and the diluent are mixed, the diluent is preferably twice the amount of the active pharmaceutical ingredient.
  • step B2 the active pharmaceutical ingredient and the diluent are mixed, and the mixing is preferably carried out in a barrel mixer.
  • the sieving is preferably Comil sieving.
  • step B3 in the mixing of the premix 2 and the internal lubricant, the mixing is preferably carried out in a mixing tank.
  • step B4 in the granulation of the premix 3, the granulation is preferably carried out in a roller press granulator.
  • the granulation is preferably dry granulation.
  • step B4 in the mixing of the particles with the external lubricant, the mixing is preferably carried out in a barrel mixer.
  • step B4 after the mixing is completed, sampling is performed to detect mixing uniformity, LOD, particle size distribution, and the like.
  • the present invention provides a method for preparing the above-mentioned pharmaceutical composition.
  • the preparation method includes the following steps:
  • step C3 Add the remaining diluent to the mixture of step C2 in stages, and sieve to obtain the mixture;
  • C5 Fill the mixture of C4 into the capsule, pack it, and that's it.
  • step C1 the active pharmaceutical ingredient is sieved, preferably a 40-mesh sieve.
  • the sieving is preferably a 40-mesh sieve.
  • the number of times of the sieving is preferably 5-15 times (for example, 10 times).
  • the sieving is preferably a 40-mesh sieve.
  • the number of times of the sieving is preferably 5-15 times (for example, 10 times).
  • the sieving is preferably a 40-mesh sieve.
  • the number of times of the sieving is preferably 5-15 times (for example, 10 times).
  • the invention also provides an application of the above-mentioned pharmaceutical composition in the preparation of medicines.
  • the drugs are preferably drugs for preventing and/or treating tumors.
  • the tumor is preferably leukemia, gastrointestinal stromal tumor, histocytic lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, One or more of epithelial cell carcinoma, prostate cancer, and nasopharyngeal carcinoma.
  • the present invention also provides a method for preventing and/or treating tumors, which comprises administering to a patient a therapeutically effective amount of the above-mentioned pharmaceutical composition.
  • the tumor is preferably leukemia, gastrointestinal stromal tumor, histocytic lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, One or more of epithelial cell carcinoma, prostate cancer, and nasopharyngeal carcinoma.
  • the open writing "including” can be converted into a closed writing "consisting of”.
  • the present invention proposes for the first time 3-((1H-pyrazole[3,4-b]pyridine-5-substituted)ethynyl)-4-methyl-N-(4-((4-methylpiperazine-
  • the present invention conducts rigorous and scientific screening of the types of excipients and the ratio of excipients in the above-mentioned pharmaceutical composition, and effectively improves the quality standard of tablets.
  • the tablet process of the present invention is prepared by dry method, which can effectively increase the stability of the tablet.
  • the production process is simple, the use of auxiliary materials is small, the operation is simple and smooth, the reproducibility is good, the product quality is good, and the packaging and storage conditions of the preparation There are no special requirements, and it is suitable for industrial production requirements.
  • the compounds mentioned in the following examples refer to 3-((1H-pyrazole[3,4-b]pyridine-5-substituted)ethynyl)-4-methyl-N-(4- ((4-Methylpiperazine-1-substituted)methyl)-3-(trifluoromethyl)phenyl)benzamide.
  • the preparation method is:
  • Step 1 Pass the compound through a 200-mesh sieve, the lemon yellow aluminum lake through a 100-mesh sieve, microcrystalline cellulose PH102, croscarmellose sodium and magnesium stearate through a 40-mesh sieve;
  • Step 2 Pass the compound, 5/100 microcrystalline cellulose PH102, lemon yellow aluminum lake, and 1/4 croscarmellose sodium through a 40-mesh sieve, and sieve 10 times to obtain a mixture (I);
  • the third step Take about 7/100 microcrystalline cellulose PH102, add it to the mixed powder in the previous step, pass a 40-mesh sieve, and sieve 10 times to obtain the mixture (II);
  • the fourth step Take about 16/100 microcrystalline cellulose PH102, add it to the mixed powder in the previous step, pass a 40-mesh sieve, and sieve 10 times to obtain the mixture (III);
  • Step 5 Take about 30/100 microcrystalline cellulose PH102, add it to the mixed powder in the previous step, pass a 40-mesh sieve, and sieve 10 times to obtain the mixture (IV);
  • Step 6 Take about 42/100 microcrystalline cellulose PH102, add it to the mixed powder in the previous step, pass a 40-mesh sieve, and sieve 10 times to obtain the mixture (V);
  • the seventh step take the pre-mixed powder and dry granulate
  • Step 8 Take the granules from the dry granulation machine and add 3/4 of croscarmellose sodium and magnesium stearate to a 24 mesh sieve and sieving for 10 times. After the total mixing, perform the second time. Dry granulation, detection of intermediate content and uniformity;
  • the ninth step choose ⁇ 5.0mm shallow concave punch to press tablets, the hardness is 30-70N;
  • the tenth step packaging.
  • the preparation method is:
  • Step 1 Pass the compound through a 200-mesh sieve, microcrystalline cellulose PH102, croscarmellose sodium and magnesium stearate through a 40-mesh sieve;
  • Step 2 Pass the compound, 16/100 microcrystalline cellulose PH102, and 1/4 croscarmellose sodium through a 40-mesh sieve, and sieve 10 times to obtain a mixture (I);
  • the third step Take about 34/100 microcrystalline cellulose PH102, add it to the mixed powder in the previous step, pass a 40-mesh sieve, and sieve 10 times to obtain the mixture (II);
  • the fourth step Take about 50/100 microcrystalline cellulose PH102, add it to the mixed powder in the previous step, pass a 40-mesh sieve, and sieve 10 times to obtain the mixture (III);
  • the fifth step take the pre-mixed powder, dry granulation
  • Step 6 Take the granules obtained by the dry granulation machine and add 3/4 of the croscarmellose sodium and magnesium stearate to a 24 mesh sieve and sieving 10 times for total mixing. After the total mixing, proceed to the second Sub-dry granulation, detection of intermediate content and uniformity;
  • the seventh step choose ⁇ 5.0mm shallow concave punch to press tablets, the hardness is 30-70N;
  • the eighth step packaging.
  • the preparation method is:
  • Step 1 Pass the compound, microcrystalline cellulose PH102, and croscarmellose sodium through a 20-mesh sieve, and pass the internal and external magnesium stearate through a 60-mesh sieve;
  • Step 2 Mix the compound and twice the amount of microcrystalline cellulose equivalent to the compound in a barrel mixer as premix 1;
  • the third step Use Comil to sieving premix 1, add all the croscarmellose sodium and the remaining microcrystalline cellulose, use Comil to sieve to rinse the machine and mix with the sieved premix 1, again Use Comil to sieve the mixture twice to obtain Premix 2;
  • the fourth step Lubrication before rolling granulation: Add premix 2 and 50% of the prescription amount of magnesium stearate into the mixing tank for lubrication;
  • the fifth step adding the premix obtained in the previous step to the roller press granulator for granulation;
  • Step 6 Use a barrel mixer to lubricate the granules with 50% of the prescription amount of magnesium stearate, and take samples to check the mixing uniformity, LOD, and particle size distribution;
  • the seventh step tablet compression, packaging.
  • N/A means no result was detected.
  • the preparation method is:
  • the first step the compound, microcrystalline cellulose PH102 and magnesium stearate are passed through a 40-mesh sieve;
  • Step 2 Take the compound and 14/100 microcrystalline cellulose PH102 through a 40-mesh sieve, and sieve 10 times to obtain the mixture (I);
  • the third step Take about 28/100 microcrystalline cellulose PH102, add it to the mixed powder in the previous step, pass a 40-mesh sieve, and sieve 10 times to obtain the mixture (II);
  • the fourth step Take about 58/100 microcrystalline cellulose PH102, add it to the mixed powder in the previous step, pass a 40-mesh sieve, and sieve 10 times to obtain the mixture (III);
  • Step 5 Take the mixture (III) and the prescribed amount of magnesium stearate through a 40-mesh sieve, sieve 10 times to obtain the total mixed powder, and detect the intermediate content and uniformity;
  • Step 6 Take the total mixed powder, fill it into 3# gelatin hollow capsules, and control the filling amount to 150mg ⁇ 7.5%;
  • the seventh step packaging.
  • N/A means no result was detected.
  • N/A means no result was detected.
  • Example 1-6 the compound in Example 4 was pretreated with a 20-mesh sieve.
  • the mixing process adopts a hopper mixer and Comil granulating equipment. This process can be used for scale-up production, and various central control indicators (mixing uniformity, dissolution, weight/load difference, friability and disintegration time limit) are all It meets the preparation standard and is better than other examples.

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Abstract

本发明涉及一种含炔基化合物的药物组合物、其制备方法及应用。本发明公开了一种药物组合物,其包括药物活性成分和药学上可用的辅料;所述的药物活性成分为3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、或其药学上可接受的盐;所述的药学上可用的辅料包括稀释剂和润滑剂。该药物组合物可以有效改善含炔基化合物的生物利用度,具有良好的溶出度和稳定性,提高用药安全。

Description

含炔基化合物的药物组合物、其制备方法及应用 技术领域
本发明涉及药物制剂领域,具体涉及一种含炔基化合物的药物组合物、其制备方法及应用。
背景技术
本发明涉及的含炔基化合物最早收录于CN101885722A,其结构为3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺。该化合物是一种新型口服生物有效Bcr-Abl抑制剂,能有效治疗肿瘤,血液系统疾病,尤其是对慢性白血病K562、急性白血病MOLT具有非常好的抑制率。该含炔基化合物能有效针对广谱表达药物突变体包括T3151,作为Bcr-Abl抑制剂,其是非常有效的候选药物,可以有效克服伊马替尼的耐药性,因而其引起众多医药公司的广泛关注。
目前现有技术未报道该含炔基化合物的药物组合物,尤其是一种稳定性好、溶出度高的含炔基化合物的药物组合物,可用于患者服用。考虑到该含炔基化合物具有良好的临床前景,迫切需要开发一种具有良好的溶出度和稳定性的该含炔基化合物的组合物,极大方便该含炔基化合物的临床使用,造福广大患者。
发明内容
本发明提供了一种含炔基化合物的药物组合物、其制备方法及应用,该药物组合物可以有效改善含炔基化合物的生物利用度,具有良好的溶出度和稳定性,提高用药安全。该含炔基化合物可以是游离碱形式,或其药学上可接受的盐形式。
本发明提供了一种药物组合物,其包括药物活性成分和药学上可用的辅料;所述的药物活性成分为3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、或其药学上可接受的盐;所述的药学上可用的辅料包括稀释剂和润滑剂。
本发明中,按重量份数计,所述的药物活性成分的用量优选0.5-15份,更优选1-14.5份(例如1.4份、1.4份、3份、3.3份、13份、13.3份、14份或14.3份)。
本发明中,所述的稀释剂可为本领域常规的稀释剂,优选包括但不限于:磷酸氢钙、高岭土、糊精、乳糖、蔗糖、微晶纤维素、粉末化纤维素、沉降碳酸钙、山梨醇、淀粉、淀粉衍生物、赤藻糖醇、木糖醇和果糖中的一种或多种,更优选糊精、乳糖、微晶纤维素 和淀粉中的一种或多种,更优选糊精、乳糖和微晶纤维素中的一种或多种,进一步优选微晶纤维素(例如微晶纤维素PH102)。所述的淀粉衍生物可为本领域常规的淀粉衍生物,优选包括玉米淀粉、土豆淀粉、可压性淀粉、改良淀粉和预胶化淀粉中的一种或多种。
本发明中,所述的稀释剂的用量可为本领域常规的用量,按重量份数计,所述的稀释剂的用量优选10-98份,更优选20-98份,进一步优选59-98份,进一步优选80-98份(例如84份、84.2份、85.7份、86份、95.7份96份、96.7份或97份)。
本发明中,所述的润滑剂可为本领域常规的润滑剂,优选包括但不限于:硬脂酸镁、硬脂酸、硬脂酸钙、硬脂酸锌、液状石蜡、聚乙二醇、二氧化硅、胶体二氧化硅、微粉硅胶、滑石粉、淀粉和氢化植物油中的一种或几种,更优选硬脂酸镁、硬脂酸、硬脂酸钙、微粉硅胶和滑石粉中的一种或几种,更优选硬脂酸镁、硬脂酸、硬脂酸钙和微粉硅胶中的一种或几种,进一步优选硬脂酸镁。
本发明中,所述的润滑剂的用量可为本领域常规的用量,按重量份数计,所述的润滑剂的用量优选0.1-5份,更优选0.5-3份(例如0.5份或1份)。
本发明中,所述的药学上可用的辅料还可包括崩解剂,所述的崩解剂可为本领域常规的崩解剂,优选包括但不限于:低取代羟丙基纤维素、交联聚维酮、交联羧甲基淀粉钠、淀粉羟基乙酸钠和交联羧甲基纤维素钠中的一种或多种,更优选低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠中的一种或多种,更优选交联羧甲基纤维素钠。
本发明中,所述的崩解剂的用量可为本领域常规的用量,按重量份数计,所述的崩解剂的用量优选0.5-20份,更优选0.5-10份,更优选0.5-3份(例如1份)。
本发明中,所述的药学上可用的辅料还可包括粘合剂,所述的粘合剂可为本领域常规的粘合剂,优选包括但不限于:羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、聚乙烯醇、阿拉伯胶、海藻酸、海藻酸钠和明胶中的一种或多种,优选羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮和聚乙烯醇中的一种或多种,更优选羟丙基纤维素和/或聚乙烯吡咯烷酮。
本发明中,所述的粘合剂的用量可为本领域常规的用量,按重量份数计,所述的粘合剂优选0.1-5份,更优选0.5-3份。
本发明中,所述的药学上可用的辅料还可包括润湿剂,所述的润湿剂可为本领域常规的润湿剂,优选包括但不限于:聚山梨酯类、聚氧乙烯脂肪醇醚类、聚氧乙烯蓖麻油类、磷脂类、硫酸化物和泊洛沙姆中的一种或几种,更优选十二烷基硫酸钠。
本发明中,所述的润湿剂的用量可为本领域常规的用量,按重量份数计,所述的润湿剂的用量优选0-10份,但不为0份,更优选0.1-1份。
本发明中,所述的药学上可用的辅料还可包括食品添加剂。所述的食品添加剂可为本领域常规的食品添加剂,优选包括但不限于:防腐剂、抗氧化剂、发色剂、漂白剂、酸味剂、凝固剂、疏松剂、增稠剂、消泡剂、甜味剂、着色剂、乳化剂、品质改良剂、抗结剂、增味剂、酶制剂、被膜剂、发泡剂、保鲜剂、香料和营养强化剂中的一种或多种,更优选着色剂。
所述的防腐剂可为本领域常规的防腐剂。所述的抗氧化剂可为本领域常规的抗氧化剂。所述的发色剂可为本领域常规的发色剂。所述的漂白剂可为本领域常规的漂白剂。所述的酸味剂可为本领域常规的酸味剂。所述的凝固剂可为本领域常规的凝固剂。所述的凝固剂可为本领域常规的凝固剂。所述的疏松剂可为本领域常规的疏松剂。所述的增稠剂可为本领域常规的增稠剂。所述的消泡剂可为本领域常规的消泡剂。所述的甜味剂可为本领域常规的甜味剂。所述的乳化剂可为本领域常规的乳化剂。所述的品质改良剂可为本领域常规的品质改良剂。所述的抗结剂可为本领域常规的抗结剂。所述的增味剂可为本领域常规的增味剂。所述的酶制剂可为本领域常规的酶制剂。所述的被膜剂可为本领域常规的被膜剂。所述的发泡剂可为本领域常规的发泡剂。所述的保鲜剂可为本领域常规的保鲜剂。所述的香料可为本领域常规的香料。所述的营养强化剂可为本领域常规的营养强化剂。所述的着色剂可为本领域常规的着色剂,优选苋菜红、胭脂红、赤鲜红(樱桃红)、新红、诱惑红、柠檬黄、日落黄、亮蓝、靛蓝和它们各自的铝色淀中的一种或多种,更优选柠檬黄铝色淀。
所述的食品添加剂的用量可为本领域常规的用量,在本发明中不作特别限制,根据处方工艺需要任意调整,按重量份数计,所述的食品添加剂的用量优选0-1份,且不为0份。
本发明中,所述的“药学上可接受的盐”中的盐可为本领域常规的盐的形式,优选包括但不限于:其中无机酸盐包括盐酸盐、硫酸盐、磷酸盐、硝酸盐、氢溴酸盐、氢碘酸盐、硫酸氢盐;有机酸盐包括三氟甲磺酸盐、对甲苯磺酸盐、1-萘磺酸盐、三氟乙酸盐、苹果酸盐、富马酸盐、苯甲酸盐、水杨酸盐、苯乙酸盐、醋酸盐、己二酸盐、藻酸盐、抗坏血酸盐、天门冬氨酸盐、安息香酸盐、苯磺酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、肉桂酸盐、环戊丙酸盐、双葡萄糖酸盐、十二烷基硫酸盐、羟乙磺酸、延胡索酸盐、葡糖庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、2-羟基乙烷磺酸盐、衣康酸盐、乳酸盐、马来酸盐、扁桃酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、草酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯丙酸盐、苦味酸盐、三甲基乙酸盐、丙酸盐、琥珀酸盐、磺酸盐、酒石酸盐、硫氰酸盐、或甲苯磺酸。
在本发明某些优选实施方案中,所述的药物组合物包括下述各组分,所述的组分可为以下任一方案,涉及用量的按重量份数计:
或者,0.5-15份药物活性成分、10-98份稀释剂和0.1-5份润滑剂;
或者,0.5-15份药物活性成分、59-98份稀释剂和0.5-3份润滑剂;
或者,0.5-15份药物活性成分、80-98份稀释剂和0.5-3份润滑剂;
或者,0.5-15份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、80-98份微晶纤维素PH102和0.5-3份硬脂酸镁;
或者,3.3份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、95.7份微晶纤维素PH102和1份硬脂酸镁;
或者,13.3份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、85.7份微晶纤维素PH102和1份硬脂酸镁;
或者,药物活性成分、稀释剂、崩解剂和润滑剂;
或者,0.5-15份药物活性成分、10-98份稀释剂、0.5-20份崩解剂和0.1-5份润滑剂;
或者,0.5-15份药物活性成分、59-98份稀释剂、0.5-10份崩解剂和0.5-3份润滑剂;
或者,0.5-15份药物活性成分、80-98份稀释剂、0.5-3份崩解剂和0.5-3份润滑剂;
或者,0.5-15份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、80-98份微晶纤维素PH102、0.5-3份交联羧甲基纤维素钠和0.5-3份硬脂酸镁;
或者,14.29份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、84.21份微晶纤维素PH102、1份交联羧甲基纤维素钠和0.5份硬脂酸镁;
或者,药物活性成分、稀释剂、崩解剂、润滑剂和食品添加剂;
或者,0.5-15份药物活性成分、10-98份稀释剂、0.5-20份崩解剂、0.1-5份润滑剂和0-1份食品添加剂;
或者,0.5-15份药物活性成分、59-98份稀释剂、0.5-10份崩解剂、0.5-3份润滑剂和0-1份食品添加剂;
或者,0.5-15份药物活性成分、80-98份稀释剂、0.5-3份崩解剂、0.5-3份润滑剂和0-1份食品添加剂;
或者,0.5-15份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、80-98份微晶纤维素PH102、0.5-3份交联羧甲基纤维素钠、0.5-3份硬脂酸镁和0-1份柠檬黄铝色淀;
或者,1.43份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、96.67份微晶纤维素PH102、1份交联羧甲基纤维素钠、0.5份硬脂酸镁和0.4份柠檬黄铝色淀;
所述的药物活性成分、稀释剂、崩解剂、润滑剂和食品添加剂同前所述。
在本发明某些优选实施方案中,所述的药物组合物可以固体制剂的形式存在,优选片剂、分散剂、颗粒剂或胶囊剂,更优选片剂或胶囊。
在本发明某些优选实施方案中,当所述的药物组合物以片剂形式存在时,所述的药物组合物包括下述各组分,各组分可为以下任一方案,涉及用量的以重量份数计:
药物活性成分、稀释剂、崩解剂和润滑剂;
或者,0.5-15份药物活性成分、10-98份稀释剂、0.5-20份崩解剂和0.1-5份润滑剂;
或者,0.5-15份药物活性成分、59-98份稀释剂、0.5-10份崩解剂和0.5-3份润滑剂;
或者,0.5-15份药物活性成分、80-98份稀释剂、0.5-3份崩解剂和0.5-3份润滑剂;
或者,0.5-15份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、80-98份微晶纤维素PH102、0.5-3份交联羧甲基纤维素钠和0.5-3份硬脂酸镁;
或者,14.29份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、84.21份微晶纤维素PH102、1份交联羧甲基纤维素钠和0.5份硬脂酸镁;
或者,药物活性成分、稀释剂、崩解剂、润滑剂和食品添加剂;
或者,0.5-15份药物活性成分、10-98份稀释剂、0.5-20份崩解剂、0.1-5份润滑剂和0-1份食品添加剂;
或者,0.5-15份药物活性成分、59-98份稀释剂、0.5-10份崩解剂、0.5-3份润滑剂和0-1份食品添加剂;
或者,0.5-15份药物活性成分、80-98份稀释剂、0.5-3份崩解剂、0.5-3份润滑剂和0-1份食品添加剂;
或者,0.5-15份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、80-98份微晶纤维素PH102、0.5-3份交联羧甲基纤维素钠、0.5-3份硬脂酸镁和0-1份柠檬黄铝色淀;
或者,1.43份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、96.67份微晶纤维素PH102、1份交联羧甲基纤维素钠、0.5份硬脂酸镁和0.4份柠檬黄铝色淀;
所述的药物活性成分、稀释剂、崩解剂、润滑剂和食品添加剂同前所述。
在本发明某些优选实施方案中,当所述的药物组合物以片剂形式存在时,所述的片剂可包括片芯。所述的片芯包括所述的药物组合物,所述的药物组合物同前所述。片剂可以通过不包衣或是通过已知的包衣技术掩盖药物的不良味道或是延长在胃肠道中崩解和吸收,且提供更长时间的药物疗效。其中,所述的包衣是在添加本领域常规的包衣介质和成膜剂(它们通常统称为包衣材料)的条件下进行的,所述的包衣材料优选羟丙基纤维素、羟丙基甲基纤维素、乙基纤维素、聚乙烯基吡咯烷酮和乙烯基吡咯烷酮-乙酸乙烯酯共聚物中的一种或多种。所述包衣优选薄膜衣(例如胃溶型薄膜衣或者肠溶型薄膜衣)或糖衣,更优选薄膜衣,进一步优选胃溶型薄膜衣。所述包衣优选占片芯重量的2-5%,更优选2.5-4%,进一步优选2.5-3.5%。
在本发明某些优选实施方案中,当所述的药物组合物以片剂形式存在时,所述的片剂的规格可为本领域常规的规格,以药物活性成分计,所述的片剂的规格优选1mg/片-100mg/片,更优选1mg/片、2mg/片、5mg/片、10mg/片、20mg/片、30mg/片、40mg/片、50mg/片或60mg/片,进一步优选1mg/片、10mg/片、20mg/片、30mg/片或40mg/片。
在本发明某些优选实施方案中,当所述的药物组合物以胶囊形式存在时,所述的药物组合物包括下述各组分,各组分可为以下任一方案:
或者,0.5-15份药物活性成分、10-98份稀释剂和0.1-5份润滑剂;
或者,0.5-15份药物活性成分、59-98份稀释剂和0.5-3份润滑剂;
或者,0.5-15份药物活性成分、80-98份稀释剂和0.5-3份润滑剂;
或者,0.5-15份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、80-98份微晶纤维素PH102和0.5-3份硬脂酸镁;
或者,3.3份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、95.7份微晶纤维素PH102和1份硬脂酸镁;
所述的药物活性成分、稀释剂和润滑剂同前所述。
在本发明某些优选实施方案中,当所述的药物组合物以胶囊形式存在时,所述的胶囊的规格可为本领域常规的规格,例如:1mg/粒、10mg/粒、20mg/粒、30mg/粒、40mg/粒,优选10mg/粒、20mg/粒。
本发明提供了一种上述药物组合物的制备方法,其包括以下步骤:将各组分进行混合,即可。
本发明提供了一种上述药物组合物的制备方法,当上述的药物组合物以片剂的形式存在时,所述的制备方法可为方法一或方法二,
所述的方法一包括以下步骤:
A1:将药物活性成分、药学上可用的辅料分别过筛;
A2:将药物活性成分和部分稀释剂过筛,得混合物;
A3:将剩余的稀释剂分次加入到步骤A2的混合物中,过筛,得混合物;
A4:将步骤A3的混合物进行制粒,得颗粒;
A5:将步骤A4的颗粒和润滑剂进行过筛,制粒;
A6:压片,包装,即可;
所述的方法二包括以下步骤:
B1:将药物活性成分、稀释剂和崩解剂过筛,内加和外加的润滑剂过筛;
B2:将药物活性成分和稀释剂进行混合,得预混物1,将预混物1过筛,再加入崩解剂和剩余的稀释剂过筛以润洗机器并与过筛后的预混物1混合,再次将混合物过筛两次,得到预混物2;
B3:将预混物2与内加润滑剂进行混合,得预混物3;
B4:将预混物3进行制粒得颗粒,将颗粒与外加润滑剂混合,得预混物4;
B5:将预混物4进行压片,包装,即可;或者,将预混物4进行制粒,压片,包装,即可。
在本发明某些优选实施方案中,步骤A1中,所述的药物活性成分过筛优选过200目筛。所述的药学上可用的辅料过筛优选过40-100目筛。
在本发明某些优选实施方案中,步骤A2中,所述的过筛优选过40目筛。所述过筛的次数优选5-15次(例如10次)。
在本发明某些优选实施方案中,步骤A2中,优选加入食品添加剂和/或崩解剂一同过筛。
在本发明某些优选实施方案中,步骤A3中,所述的过筛优选过40目筛。所述过筛的次数优选5-15次(例如10次)。
在本发明某些优选实施方案中,步骤A4中,所述的制粒优选干法制粒。
在本发明某些优选实施方案中,步骤A5中,所述的过筛优选过24目筛。所述过筛的次数优选5-15次(例如10次)。所述的制粒优选干法制粒。
在本发明某些优选实施方案中,步骤A5中,优选加入崩解剂一同过筛。
在本发明某些优选实施方案中,步骤A6中,所述的压片优选用Ф5.0mm浅凹冲。所述的压片优选硬度为30-70N。
在本发明某些优选实施方案中,步骤B1中,所述的药物活性成分优选球磨机或微粉 碎机等设备进行粉碎,更优选微粉碎机。
在本发明某些优选实施方案中,步骤B1中,所述的药物活性成分、稀释剂和崩解剂过筛优选过20目筛。
在本发明某些优选实施方案中,步骤B1中,所述的内加和外加的润滑剂过筛优选过60目筛。
在本发明某些优选实施方案中,步骤B2中,所述的药物活性成分和稀释剂进行混合中,所述的稀释剂优选为所述的药物活性成分的2倍量。
在本发明某些优选实施方案中,步骤B2中,所述的药物活性成分和稀释剂进行混合中,所述的混合优选在桶式混合机中进行。
在本发明某些优选实施方案中,步骤B2中,所述的过筛优选使用Comil过筛。
在本发明某些优选实施方案中,步骤B3中,所述的将预混物2与内加润滑剂进行混合中,所述的混合优选在混合桶中进行。
在本发明某些优选实施方案中,步骤B4中,所述的将预混物3进行制粒中,所述的制粒优选在辊压制粒机中进行。所述的制粒优选干法制粒。
在本发明某些优选实施方案中,步骤B4中,所述的将颗粒与外加润滑剂混合中,所述的混合优选在桶式混合机中进行。
在本发明某些优选实施方案中,步骤B4中,所述的混合结束后,进行取样检测混合均匀度、LOD、粒度分布等。
本发明提供了一种上述药物组合物的制备方法,当上述的药物组合物以胶囊的形式存在时,所述的制备方法包括以下步骤:
C1:将药物活性成分、药学上可用的辅料分别过筛;
C2:将药物活性成分和部分稀释剂过筛,得混合物;
C3:将剩余的稀释剂分次加入到步骤C2的混合物中,过筛,得混合物;
C4:将C3的混合物与润滑剂进行过筛,得混合物;
C5:将C4的混合物填充至胶囊中,包装,即可。
在本发明某些优选实施方案中,步骤C1中,所述的药物活性成分过筛优选过40目筛。
在本发明某些优选实施方案中,步骤C2中,所述的过筛优选过40目筛。所述过筛的次数优选5-15次(例如10次)。
在本发明某些优选实施方案中,步骤C3中,所述的过筛优选过40目筛。所述过筛的次数优选5-15次(例如10次)。
在本发明某些优选实施方案中,步骤C4中,所述的过筛优选过40目筛。所述过筛的次数优选5-15次(例如10次)。
本发明还提供了一种上述的药物组合物在制备药物中的应用。所述的药物优选预防和/或治疗肿瘤的药物。所述的肿瘤优选白血病、胃肠间质瘤子、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌,上皮细胞癌、前列腺癌和鼻咽癌中的一种或多种。
本发明还提供了一种预防和/或治疗肿瘤的方法,其包括向患者施用治疗有效量的上述的药物组合物。所述的肿瘤优选白血病、胃肠间质瘤子、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌,上皮细胞癌、前列腺癌和鼻咽癌中的一种或多种。
本发明中,所述的开放式写法“包括”可以转换成封闭式写法“由……组成”。
本发明取得有益效果:
1、本发明首次提出3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺的药物组合物,尤其是可用于临床用药的处方制剂,该制剂在产品稳定性、流动性、生物利用度上具有显著的技术优势。
2、本发明对上述药物组合物中的辅料种类,辅料之间的配比进行了严谨科学的筛选,有效提高片剂的质量标准。
3、在处方工艺筛选时,当片剂规格较小时,各组分的松密度和流动性不尽相同,采用粉末直压会影响片剂的含量均匀度。采用原辅料等量递加的方式和干法制粒工艺,实现了片剂较好的含量均匀度。
4、本发明片剂工艺采用干法制备,可有效增加片剂的稳定性,生产工艺简单,辅料种类使用少,操作简便流畅,重现性好,产品质量良好,对制剂的包装与贮藏条件也无特殊要求,适合工业化生产要求。
具体实施方式
为了简化表述,下述实施例中提及的化合物是指3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺。
实施例1:化合物片剂
处方组成:
Figure PCTCN2019124024-appb-000001
Figure PCTCN2019124024-appb-000002
制备方法为:
第一步:将化合物过200目筛、柠檬黄铝色淀过100目筛、微晶纤维素PH102、交联羧甲基纤维素钠和硬脂酸镁过40目筛;
第二步:将化合物、5/100的微晶纤维素PH102、柠檬黄铝色淀、1/4交联羧甲基纤维素钠过40目筛,过筛10次得混合物(Ⅰ);
第三步:取约7/100微晶纤维素PH102,加入上一步混合粉中,过40目筛,过筛10次得混合物(Ⅱ);
第四步:取约16/100微晶纤维素PH102,加入上一步混合粉中,过40目筛,过筛10次得混合物(Ⅲ);
第五步:取约30/100微晶纤维素PH102,加入上一步混合粉中,过40目筛,过筛10次得混合物(Ⅳ);
第六步:取约42/100微晶纤维素PH102,加入上一步混合粉中,过40目筛,过筛10次得混合物(Ⅴ);
第七步:取预混合粉末,干法制粒;
第八步:取干法制粒机制得的颗粒加入3/4的交联羧甲基纤维素钠及硬脂酸镁用24目筛过筛10次的方式总混,总混后进行第二次干法制粒,检测中间体含量及均匀度;
第九步:选用Ф5.0mm浅凹冲进行压片,硬度为30-70N;
第十步:包装。
实施例2:化合物片剂
处方组成:
Figure PCTCN2019124024-appb-000003
Figure PCTCN2019124024-appb-000004
其制备方法参见实施例1。
实施例3:化合物片剂
处方组成:
Figure PCTCN2019124024-appb-000005
制备方法为:
第一步:将化合物过200目筛、微晶纤维素PH102、交联羧甲基纤维素钠和硬脂酸镁过40目筛;
第二步:将化合物、16/100的微晶纤维素PH102、1/4交联羧甲基纤维素钠过40目筛,过筛10次得混合物(Ⅰ);
第三步:取约34/100微晶纤维素PH102,加入上一步混合粉中,过40目筛,过筛10次得混合物(Ⅱ);
第四步:取约50/100微晶纤维素PH102,加入上一步混合粉中,过40目筛,过筛10次得混合物(Ⅲ);
第五步:取预混合粉末,干法制粒;
第六步:取干法制粒机制得的颗粒加入3/4的交联羧甲基纤维素钠及的硬脂酸镁用24目筛过筛10次的方式总混,总混后进行第二次干法制粒,检测中间体含量及均匀度;
第七步:选用Ф5.0mm浅凹冲进行压片,硬度为30-70N;
第八步:包装。
实施例4:化合物片剂
处方组成:
Figure PCTCN2019124024-appb-000006
制备方法为:
第一步:将化合物、微晶纤维素PH102,交联羧甲基纤维素钠过20目筛,将内加及外加硬脂酸镁过60目筛;
第二步:将化合物和相当于化合物两倍量的微晶纤维素在桶式混合机中进行混合,作为预混物1;
第三步:使用Comil过筛预混物1,加入全部交联羧甲基纤维素钠和剩余微晶纤维素使用Comil过筛以润洗机器并与过筛后的预混物1混合,再次使用Comil将混合物过筛两次,得到预混物2;
第四步:辊压制粒前润滑:将预混物2与50%处方量的硬脂酸镁加入混合桶中润滑;
第五步:将前步得到的预混物加入辊压制粒机进行制粒;
第六步:使用桶式混合机将颗粒与50%处方量的硬脂酸镁进行润滑,并取样检测混合均匀度、LOD、粒度分布;
第七步:压片,包装。
实施例5:化合物胶囊
处方组成:
Figure PCTCN2019124024-appb-000007
Figure PCTCN2019124024-appb-000008
N/A指未检测到结果。
制备方法为:
第一步:化合物、微晶纤维素PH102和硬脂酸镁过40目筛;
第二步:取化合物、14/100的微晶纤维素PH102过40目筛,过筛10次得混合物(Ⅰ);
第三步:取约28/100微晶纤维素PH102,加入上一步混合粉中,过40目筛,过筛10次得混合物(Ⅱ);
第四步:取约58/100微晶纤维素PH102,加入上一步混合粉中,过40目筛,过筛10次得混合物(Ⅲ);
第五步:取混合物(Ⅲ)与处方量的硬脂酸镁过40目筛,过筛10次得总混粉末,检测中间体含量及均匀度;
第六步:取总混粉末,充填至3#明胶空心胶囊中,控制装量150mg±7.5%;
第七步:包装。
实施例6:化合物胶囊
处方组成:
Figure PCTCN2019124024-appb-000009
N/A指未检测到结果。
其制备方法参见实施例5。
实施例7:
分别测定以上实施例中混合粉的粉体学、混合均匀度、片重差异、脆碎度、崩解时限以及片剂的溶出度等项目,结果如下:
Figure PCTCN2019124024-appb-000010
N/A指未检测到结果。
在实施例1-6中,实施例4对化合物采用20目筛预处理。混合工序采用料斗混合机及Comil整粒设备,该工艺能用于放大生产,且各项中控指标(混合均匀度、溶出度、重/装量差异、脆碎度有及崩解时限)均符合制剂标准,优于其余实施例。
虽然以上描述了本发明的具体实施方式,但是本领域的技术人员应当理解,这些仅是举例说明,在不背离本发明的原理和实质的前提下,可以对这些实施方式做出多种变更或修改。因此,本发明的保护范围由所附权利要求书限定。

Claims (20)

  1. 一种药物组合物,其包括药物活性成分和药学上可用的辅料;所述的药物活性成分为3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、或其药学上可接受的盐;所述的药学上可用的辅料包括稀释剂和润滑剂。
  2. 如权利要求1所述的药物组合物,其特征在于,按重量份数计,所述的活性成分的用量为0.5-15份,优选1-14.5份;
    和/或,所述的稀释剂为磷酸氢钙、高岭土、糊精、乳糖、蔗糖、微晶纤维素、粉末化纤维素、沉降碳酸钙、山梨醇、淀粉、淀粉衍生物、赤藻糖醇、木糖醇和果糖中的一种或多种,优选糊精、乳糖、微晶纤维素和淀粉中的一种或多种,更优选糊精、乳糖和微晶纤维素中的一种或多种,进一步优选微晶纤维素;
    和/或,按重量份数计,所述的稀释剂的用量为10-98份,优选20-98份,进一步优选59-98份,进一步优选80-98份;
    和/或,所述的润滑剂为硬脂酸镁、硬脂酸、硬脂酸钙、硬脂酸锌、液状石蜡、聚乙二醇、二氧化硅、胶体二氧化硅、微粉硅胶、滑石粉、淀粉和氢化植物油中的一种或几种,优选硬脂酸镁、硬脂酸、硬脂酸钙、微粉硅胶和滑石粉中的一种或几种,更优选硬脂酸镁、硬脂酸、硬脂酸钙和微粉硅胶中的一种或几种,进一步优选硬脂酸镁;
    和/或,按重量份数计,所述的润滑剂的用量为0.1-5份,优选0.5-3份。
  3. 如权利要求2所述的药物组合物,其特征在于,当所述的稀释剂为微晶纤维素时,所述的微晶纤维素为微晶纤维素PH102;
    和/或,当所述的稀释剂为淀粉衍生物时,所述的淀粉衍生物为玉米淀粉、土豆淀粉、可压性淀粉、改良淀粉和预胶化淀粉中的一种或多种。
  4. 如权利要求1-3中至少一项所述的药物组合物,其特征在于,所述的药学上可用的辅料还包括崩解剂,所述的崩解剂优选低取代羟丙基纤维素、交联聚维酮、交联羧甲基淀粉钠、淀粉羟基乙酸钠和交联羧甲基纤维素钠中的一种或多种,更优选低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠中的一种或多种,更优选交联羧甲基纤维素钠;按重量份数计,所述的崩解剂的用量优选0.5-20份,更优选0.5-10份,更优选0.5-3份。
  5. 如权利要求1-4中至少一项所述的药物组合物,其特征在于,所述的药学上可用的辅料还包括粘合剂,所述的粘合剂优选羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、聚乙烯醇、阿拉伯胶、海藻酸、海藻酸钠和明胶中的一种或多种,更优选羟丙基 纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮和聚乙烯醇中的一种或多种,更优选羟丙基纤维素和/或聚乙烯吡咯烷酮;按重量份数计,所述的粘合剂优选0.1-5份,更优选0.5-3份。
  6. 如权利要求1-5中至少一项所述的药物组合物,其特征在于,所述的药学上可用的辅料还包括润湿剂,所述的润湿剂优选聚山梨酯类、聚氧乙烯脂肪醇醚类、聚氧乙烯蓖麻油类、磷脂类、硫酸化物和泊洛沙姆中的一种或几种,更优选十二烷基硫酸钠;按重量份数计,所述的润湿剂的用量优选0-10份,但不为0份,更优选0.1-1份。
  7. 如权利要求1-6中至少一项所述的药物组合物,其特征在于,所述的药学上可用的辅料还包括食品添加剂,所述的食品添加剂优选防腐剂、抗氧化剂、发色剂、漂白剂、酸味剂、凝固剂、疏松剂、增稠剂、消泡剂、甜味剂、着色剂、乳化剂、品质改良剂、抗结剂、增味剂、酶制剂、被膜剂、发泡剂、保鲜剂、香料和营养强化剂中的一种或多种,更优选着色剂;所述的食品添加剂的用量优选0-1份,且不为0份;
    所述的着色剂优选苋菜红、胭脂红、赤鲜红、新红、诱惑红、柠檬黄、日落黄、亮蓝、靛蓝和它们各自的铝色淀中的一种或多种,更优选柠檬黄铝色淀。
  8. 如权利要求1-7中至少一项所述的药物组合物,其特征在于,所述的药物组合物包括下述各组分,各组分为以下任一方案,涉及用量的以重量份数计:
    0.5-15份药物活性成分、10-98份稀释剂和0.1-5份润滑剂;
    或者,0.5-15份药物活性成分、59-98份稀释剂和0.5-3份润滑剂;
    或者,0.5-15份药物活性成分、80-98份稀释剂和0.5-3份润滑剂;
    或者,0.5-15份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、80-98份微晶纤维素PH102和0.5-3份硬脂酸镁;
    或者,3.3份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、95.7份微晶纤维素PH102和1份硬脂酸镁;
    或者,13.3份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、85.7份微晶纤维素PH102和1份硬脂酸镁;
    或者,药物活性成分、稀释剂、崩解剂和润滑剂;
    或者,0.5-15份药物活性成分、10-98份稀释剂、0.5-20份崩解剂和0.1-5份润滑剂;
    或者,0.5-15份药物活性成分、59-98份稀释剂、0.5-10份崩解剂和0.5-3份润滑剂;
    或者,0.5-15份药物活性成分、80-98份稀释剂、0.5-3份崩解剂和0.5-3份润滑剂;
    或者,0.5-15份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、80-98份微晶纤维素PH102、0.5-3份交联羧甲基 纤维素钠和0.5-3份硬脂酸镁;
    或者,14.29份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、84.21份微晶纤维素PH102、1份交联羧甲基纤维素钠和0.5份硬脂酸镁;
    或者,药物活性成分、稀释剂、崩解剂、润滑剂和食品添加剂;
    或者,0.5-15份药物活性成分、10-98份稀释剂、0.5-20份崩解剂、0.1-5份润滑剂和0-1份食品添加剂;
    或者,0.5-15份药物活性成分、20-98份稀释剂、0.5-10份崩解剂、0.5-3份润滑剂和0-1份食品添加剂;
    或者,0.5-15份药物活性成分、80-98份稀释剂、0.5-3份崩解剂、0.5-3份润滑剂和0-1份食品添加剂;
    或者,0.5-15份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、80-98份微晶纤维素PH102、0.5-3份交联羧甲基纤维素钠、0.5-3份硬脂酸镁和0-1份柠檬黄铝色淀;
    或者,1.43份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、96.67份微晶纤维素PH102、1份交联羧甲基纤维素钠、0.5份硬脂酸镁和0.4份柠檬黄铝色淀;
    所述的药物活性成分、稀释剂、崩解剂、润滑剂和食品添加剂如权利要求1-4和7中的至少一项所述。
  9. 如权利要求1-8中至少一项所述的药物组合物,其特征在于,所述的药物组合物以固体制剂的形式存在,优选片剂、分散剂、颗粒剂或胶囊剂,更优选片剂或胶囊。
  10. 如权利要求1-9中至少一项所述的药物组合物,其特征在于,当所述的药物组合物以片剂形式存在时,所述的药物组合物包括下述各组分,各组分为以下任一方案,涉及用量的按重量份数计:
    药物活性成分、稀释剂、崩解剂和润滑剂;
    或者,0.5-15份药物活性成分、10-98份稀释剂、0.5-20份崩解剂和0.1-5份润滑剂;
    或者,0.5-15份药物活性成分、59-98份稀释剂、0.5-10份崩解剂和0.5-3份润滑剂;
    或者,0.5-15份药物活性成分、80-98份稀释剂、0.5-3份崩解剂和0.5-3份润滑剂;
    或者,0.5-15份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、80-98份微晶纤维素PH102、0.5-3份交联羧甲基纤维素钠和0.5-3份硬脂酸镁;
    或者,14.29份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、84.21份微晶纤维素PH102、1份交联羧甲基纤维素钠和0.5份硬脂酸镁;
    或者,药物活性成分、稀释剂、崩解剂、润滑剂和食品添加剂;
    或者,0.5-15份药物活性成分、10-98份稀释剂、0.5-20份崩解剂、0.1-5份润滑剂和0-1份食品添加剂;
    或者,0.5-15份药物活性成分、59-98份稀释剂、0.5-10份崩解剂、0.5-3份润滑剂和0-1份食品添加剂;
    或者,0.5-15份药物活性成分、80-98份稀释剂、0.5-3份崩解剂、0.5-3份润滑剂和0-1份食品添加剂;
    或者,0.5-15份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、80-98份微晶纤维素PH102、0.5-3份交联羧甲基纤维素钠、0.5-3份硬脂酸镁和0-1份柠檬黄铝色淀;
    或者,1.43份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、96.67份微晶纤维素PH102、1份交联羧甲基纤维素钠、0.5份硬脂酸镁和0.4份柠檬黄铝色淀;
    所述的药物活性成分、稀释剂、崩解剂、润滑剂和食品添加剂如权利要求1-4和7中的至少一项所述。
  11. 如权利要求10所述的药物组合物,其特征在于,当所述的药物组合物以片剂形式存在时,所述的片剂包括片芯;所述的片芯优选包括所述的药物组合物,所述的药物组合物如权利要求1-10中至少一项所述;
    和/或,以药物活性成分计,所述的片剂的规格为1mg/片-100mg/片,优选1mg/片、2mg/片、5mg/片、10mg/片、20mg/片、30mg/片、40mg/片、50mg/片或60mg/片,进一步优选1mg/片、10mg/片、20mg/片、30mg/片或40mg/片。
  12. 如权利要求11所述的药物组合物,其特征在于,当所述的药物组合物以片剂形式存在时,所述的片剂包括包衣,所述包衣的包衣材料优选丙基纤维素、羟丙基甲基纤维素、乙基纤维素、聚乙烯基吡咯烷酮和乙烯基吡咯烷酮-乙酸乙烯酯共聚物中的一种或多种;所述包衣优选薄膜衣或糖衣,更优选薄膜衣,进一步优选胃溶型薄膜衣;所述包衣优选占片芯重量的2-5%,更优选2.5-4%,进一步优选2.5-3.5%。
  13. 如权利要求1-9中至少一项所述的药物组合物,其特征在于,当所述的药物组合物以胶囊形式存在时,所述的药物组合物包括下述各组分,各组分为以下任一方案:
    0.5-15份药物活性成分、10-98份稀释剂和0.1-5份润滑剂;
    或者,0.5-15份药物活性成分、59-98份稀释剂和0.5-3份润滑剂;
    或者,0.5-15份药物活性成分、80-98份稀释剂和0.5-3份润滑剂;
    或者,0.5-15份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、80-98份微晶纤维素PH102和0.5-3份硬脂酸镁;
    或者,3.3份3-((1H-吡唑[3,4-b]吡啶-5-取代)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-取代)甲基)-3-(三氟甲基)苯基)苯甲酰胺、95.7份微晶纤维素PH102和1份硬脂酸镁;
    所述的药物活性成分、稀释剂和润滑剂如权利要求1-3中至少一项所述。
  14. 一种如权利要求1-8中至少一项所述的药物组合物的制备方法,其包括以下步骤:将各组分进行混合,即可。
  15. 一种如权利要求1-12中至少一项所述的药物组合物的制备方法,当上述的药物组合物以片剂的形式存在时,所述的制备方法为方法一或方法二,
    所述的方法一包括以下步骤:
    A1:将药物活性成分、药学上可用的辅料分别过筛;
    A2:将药物活性成分和部分稀释剂过筛,得混合物;
    A3:将剩余的稀释剂分次加入到步骤A2的混合物中,过筛,得混合物;
    A4:将步骤A3的混合物进行制粒,得颗粒;
    A5:将步骤A4的颗粒和润滑剂进行过筛,制粒;
    A6:压片,包装,即可;
    所述的方法二包括以下步骤:
    B1:将药物活性成分、稀释剂和崩解剂过筛,内加和外加的润滑剂过筛;
    B2:将药物活性成分和稀释剂进行混合,得预混物1,将预混物1过筛,再加入崩解剂和剩余的稀释剂过筛以润洗机器并与过筛后的预混物1混合,再次将混合物过筛两次,得到预混物2;
    B3:将预混物2与内加润滑剂进行混合,得预混物3;
    B4:将预混物3进行制粒得颗粒,将颗粒与外加润滑剂混合,得预混物4;
    B5:将预混物4进行压片,包装,即可;或者,将预混物4进行制粒,压片,包装,即可。
  16. 如权利要求15所述的制备方法,其特征在于,步骤A1中,所述的药物活性成分过筛为过200目筛;
    和/或,步骤A1中,所述的药学上可用的辅料过筛为过40-100目筛;
    和/或,步骤A2中,所述的过筛为过40目筛;
    和/或,步骤A2中,所述过筛的次数为5-15次;
    和/或,步骤A2中,加入食品添加剂和/或崩解剂一同过筛;
    和/或,步骤A3中,所述的过筛为过40目筛;
    和/或,步骤A3中,所述过筛的次数为5-15次;
    和/或,步骤A4中,所述的制粒为干法制粒;
    和/或,步骤A5中,所述的过筛为过24目筛;
    和/或,步骤A5中,所述过筛的次数为5-15次;
    和/或,步骤A5中,所述的制粒为干法制粒;
    和/或,步骤A5中,加入崩解剂一同过筛;
    和/或,步骤A6中,所述的压片用Ф5.0mm浅凹冲;
    和/或,步骤A6中,所述的压片硬度为30-70N;
    和/或,步骤B1中,所述的药物活性成分通过球磨机或微粉碎机进行粉碎,优选微粉碎机;
    和/或,步骤B1中,所述的药物活性成分、稀释剂和崩解剂过筛为过20目筛;
    和/或,步骤B1中,所述的内加和外加的润滑剂过筛为过60目筛;
    和/或,步骤B2中,所述的药物活性成分和稀释剂进行混合中,所述的稀释剂为所述的药物活性成分的2倍量;
    和/或,步骤B2中,所述的药物活性成分和稀释剂进行混合中,所述的混合在桶式混合机中进行;
    和/或,步骤B2中,所述的过筛使用Comil过筛;
    和/或,步骤B3中,所述的将预混物2与内加润滑剂进行混合中,所述的混合在混合桶中进行;
    和/或,步骤B4中,所述的将预混物3进行制粒中,所述的制粒在辊压制粒机中进行;
    和/或,步骤B4中,所述的制粒为干法制粒;
    和/或,步骤B4中,所述的将颗粒与外加润滑剂混合中,所述的混合在桶式混合机中进行;
    和/或,步骤B4中,所述的混合结束后,进行取样检测混合均匀度、LOD、粒度分布。
  17. 一种如权利要求1-9和13中至少一项所述的药物组合物的制备方法,当上述的 药物组合物以胶囊的形式存在时,所述的制备方法包括以下步骤:
    C1:将药物活性成分、药学上可用的辅料分别过筛;
    C2:将药物活性成分和部分稀释剂过筛,得混合物;
    C3:将剩余的稀释剂分次加入到步骤C2的混合物中,过筛,得混合物;
    C4:将C3的混合物与润滑剂进行过筛,得混合物;
    C5:将C4的混合物填充至胶囊中,包装,即可。
  18. 如权利要求17所述的制备方法,其特征在于,步骤C1中,所述的药物活性成分过筛为过40目筛;
    和/或,步骤C2中,所述的过筛为过40目筛;
    和/或,步骤C2中,所述过筛的次数为5-15次;
    和/或,步骤C3中,所述的过筛为过40目筛;
    和/或,步骤C3中,所述过筛的次数为5-15次;
    和/或,步骤C4中,所述的过筛为过40目筛;
    和/或,步骤C4中,所述过筛的次数为5-15次。
  19. 一种如权利要求1-13中至少一项所述的药物组合物在制备药物中的应用;所述的药物优选预防和/或治疗肿瘤的药物;所述的肿瘤优选白血病、胃肠间质瘤子、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌,上皮细胞癌、前列腺癌和鼻咽癌中的一种或多种。
  20. 一种预防和/或治疗肿瘤的方法,其包括向患者施用治疗有效量的如权利要求1-13中至少一项所述的药物组合物;所述的肿瘤优选白血病、胃肠间质瘤子、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌,上皮细胞癌、前列腺癌和鼻咽癌中的一种或多种。
PCT/CN2019/124024 2019-12-09 2019-12-09 含炔基化合物的药物组合物、其制备方法及应用 WO2021114020A1 (zh)

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