CN117547536A - Pharmaceutical composition, preparation method and application thereof - Google Patents
Pharmaceutical composition, preparation method and application thereof Download PDFInfo
- Publication number
- CN117547536A CN117547536A CN202311520705.1A CN202311520705A CN117547536A CN 117547536 A CN117547536 A CN 117547536A CN 202311520705 A CN202311520705 A CN 202311520705A CN 117547536 A CN117547536 A CN 117547536A
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- CN
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- Prior art keywords
- mixing
- sieving
- pharmaceutical composition
- finishing
- adhesive
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 42
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 41
- 239000000463 material Substances 0.000 claims abstract description 51
- 239000004480 active ingredient Substances 0.000 claims abstract description 30
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 18
- -1 1-methyl-1H-indol-3-yl Chemical group 0.000 claims abstract description 9
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims abstract description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims description 123
- 238000007873 sieving Methods 0.000 claims description 105
- 239000000853 adhesive Substances 0.000 claims description 78
- 230000001070 adhesive effect Effects 0.000 claims description 75
- 238000003756 stirring Methods 0.000 claims description 75
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 64
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 64
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 52
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 51
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 39
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- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 29
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 16
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 16
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- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 8
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 8
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 7
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 claims description 6
- 239000012752 auxiliary agent Substances 0.000 claims description 6
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- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 claims description 6
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- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 5
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 4
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 3
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- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
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Abstract
The invention discloses a pharmaceutical composition, a preparation method and application thereof, and provides a pharmaceutical composition containing an active ingredient N- {2- { [2- (dimethylamino) ethyl ] (methyl) amino } -6- (2, 2-trifluoro ethoxy) -5- { [4- (1-methyl-1H-indol-3-yl) pyrimidine-2-yl ] amino } pyridin-3-yl } acrylamide or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable auxiliary material.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition, a preparation method and application thereof.
Background
Lung cancer is one of the most common malignant tumors worldwide with the highest mortality, with 70-80% of cases being non-small cell lung cancer. Because of the disease characteristics of lung cancer, a plurality of lung cancer patients have metastasis during disease diagnosis, the opportunity of radical surgery is lost, and the survival rate is reduced. In recent years, with development of molecular diagnosis technology and development of targeted drugs, the mode of treatment of lung cancer has not been limited to conventional chemotherapy. Wherein, EGFR-TKI treatment has remarkable curative effect in lung cancer people with EGFR gene activation mutation.
Current EGFR-TKIs treatment is the first line standard treatment for lung adenocarcinoma patients with EGFR mutations, including the first generation EGFR-TKIs such as gefitinib, erlotinib, icotinib, and the second generation EGFR-TKIs such as afatinib, dacatinib. But all patients are still inevitably resistant to drug.
The third generation EGFR-TKIs are EGFR (EGFR) kinase inhibitors, and have irreversible inhibition effect on EGFR drug resistance or activation mutation (T790M, L858R and Del 19), and the IC50 is about 1 nM. The IC50 of the Fumetinib for inhibiting the mutant EGFR is lower than that of the wild EGFR, and the inhibition effect on tumor cells carrying the related mutation is stronger than that of the wild tumor cells.
In Chinese patent (application No. CN 201810626680.6), a crystal form and a salt form of a pyridinylaminopyrimidine derivative are disclosed, wherein N- {2- { [2- (dimethylamino) ethyl ] (methyl) amino } -6- (2, 2-trifluoro-ethoxy) -5- { [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino } pyridin-3-yl } acrylamide (a compound of formula I) serving as an Epidermal Growth Factor Receptor (EGFR) kinase inhibitor has good stability, and pharmaceutical preparation research and development is carried out on the pyridinylaminopyrimidine derivative, so that the N- {2- { [2- (dimethylamino) ethyl ] (methyl) amino } -6- (2, 2-trifluoro-ethoxy) -5- { [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino } pyridin-3-yl } acrylamide (a compound of formula I) has high stability and bioavailability, and has important clinical significance and application prospect.
Disclosure of Invention
In order to solve the problems, the invention provides a pharmaceutical composition containing an active ingredient N- {2- { [2- (dimethylamino) ethyl ] (methyl) amino } -6- (2, 2-trifluoroethoxy) -5- { [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino } pyridin-3-yl } acrylamide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable auxiliary material, and the pharmaceutical composition has good stability, drug dissolution, better pharmacodynamics and pharmacokinetics advantages, simple preparation process and suitability for industrial production.
The technical scheme provided by the invention is as follows:
in one aspect, a pharmaceutical composition comprises as active ingredient the mesylate salt of N- {2- { [2- (dimethylamino) ethyl ] (methyl) amino } -6- (2, 2-trifluoroethoxy) -5- { [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino } pyridin-3-yl } acrylamide, as well as fillers, disintegrants, binders, anti-adh-iers, disintegration aids and lubricants;
the medicine composition comprises 10-50% of active ingredient, 30-70% of filling agent, 5-10% of disintegrating agent, 1-10% of anti-adhesive, 7-8.5% of adhesive, 1-10% of disintegrating auxiliary agent and 1-5% of lubricant.
In some embodiments, the filler is microcrystalline cellulose and lactose at a mass ratio (mg: mg) of 21.0:32.0, 18.0:35.0, 15.0:38.0, 12.0:41.0, 26.0:27.0, 31.0:22.0, 36.0:17.0, 41.0:12.0.
in some embodiments, the disintegrant is one or more of sodium starch glycolate, sodium carboxymethyl starch, corn starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, croscarmellose, methylcellulose, pregelatinized starch, sodium alginate.
In some embodiments, the binder is polyethylene glycol 4000 and the disintegration aid is sodium chloride.
In some embodiments, the anti-adherent is one or more of powdered cellulose, magnesium trisilicate, colloidal silica, talc.
In some embodiments, the lubricant is one or more of stearic acid, magnesium stearate, sodium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, myristic acid, palmitic acid, sodium stearyl fumarate, talc, hydrogenated vegetable oil, mineral oil.
In some embodiments, the pharmaceutical composition is composed of the following components in weight percent: 22.0% of methanesulfonate of the compound of the formula (I) as an active ingredient, 21.0% of microcrystalline cellulose as an additive and 32.0% of lactose as an additive, 3.05% of sodium carboxymethyl cellulose as a disintegrant, 40008.4% of polyethylene glycol as an adhesive, 3.05% of colloidal silica as an anti-adhesive, 4.1% of sodium chloride as a disintegrant, 3.05% of sodium carboxymethyl cellulose as a disintegrant, 2.05% of colloidal silica as an anti-adhesive and 1.3% of sodium stearyl fumarate as a lubricant.
In another aspect, a method for preparing a pharmaceutical composition for preparing the pharmaceutical composition comprises the steps of:
s1, preparing raw material auxiliary materials and sieving: weighing materials according to the formula of the pharmaceutical composition, and sieving for standby;
s2, preparing an adhesive solution: adding purified water and an adhesive into a liquid preparation barrel, and mixing for later use;
s3, granulating: the active ingredients, the disintegrating agent, the filler, the anti-adhesion agent and the disintegrating auxiliary agent which are treated in the step S1 are sent into a granulator for dry mixing treatment; then adding the adhesive solution prepared in the step S2, and granulating;
s4, drying: the materials in the step S3 are sent into a fluidized bed for drying treatment;
s5, finishing: finishing the dry material particles obtained in the step S4;
s6, mixing: on the basis of S5, adding an anti-adhesive agent, mixing and sieving, and adding a disintegrating agent, mixing and sieving;
s7, lubrication: on the basis of S6, adding a lubricant, mixing and sieving to finish lubrication;
s8, tabletting: and (3) carrying out tabletting treatment on the lubricated material on the basis of S7 to obtain the pharmaceutical composition.
In some embodiments, the specific steps of the above method are:
s1, preparing raw material auxiliary materials and sieving: microcrystalline cellulose, lactose and croscarmellose sodium are respectively sieved by a high-energy sieving machine through a 30-mesh sieve, sodium chloride is crushed by a high-speed crusher and then manually sieved by a 60-mesh sieve, active compounds and colloidal silicon dioxide are combined in a medicinal low-density polyethylene bag and manually turned and primarily mixed, and then the mixture is sieved by the high-energy sieving machine through the 60-mesh sieve for 2 times;
S2, preparing an adhesive solution: adding normal-temperature purified water into a liquid preparation barrel, starting stirring, slowly adding polyethylene glycol 4000, continuing stirring for 1-2 hours after the addition, and stopping stirring when no obvious insoluble substances are visually detected;
s3, granulating: stirring paddle rotation speed is 75rpm-120rpm, cutter rotation speed is 1450rpm-1550rpm, adhesive solution is uniformly added, adhesive adding time is controlled to be 120-180 seconds, stirring and cutting granulation are continued for 180 seconds after adhesive adding, aperture of wet granule finishing screen is 10mm x 10mm, and finishing rotation speed is 250rpm-350rpm, and discharging is carried out while finishing granules;
s4, drying: and drying the prepared tablet particles by a fluidized bed, and discharging after the moisture is less than or equal to 3.0 percent.
S5, finishing: the pore diameter of the granule finishing screen is 0.6mm, and the granule finishing rotating speed is 300-400rpm;
s6, mixing: adding crosslinked sodium carboxymethyl cellulose after finishing, manually sieving with a 30-mesh sieve, adding colloidal silica into the obtained dry particles, mixing, sieving with a 30-mesh sieve for 10-15min, and mixing at 10-20 rpm;
s7, lubrication: adding sodium stearyl fumarate into the mixed materials, mixing, sieving with 60 meshes, mixing for 3-5min at 10-20rpm, and lubricating and mixing;
s8, tabletting: by usingThe round punching, the tabletting speed is 30-60 kilosheets/hour, the rotating speed of a blanking device is 20-40rpm, the average value of main pressure is 3.8-4.2KN, the thickness of the main pressing edge of a tablet is 2.0-3.0mm, the thickness of the pre-pressing edge is 2.5-3.5mm, the filling depth is 6.0-8.0mm, the average value of hardness is controlled to be 40-75N, and the single value is controlled to be 30-100N.
In some embodiments, the air inlet temperature of the fluidized bed in the step S4 is 50-80 ℃, and the air inlet quantity is 700-900m 3 /h。
The invention also provides application of the pharmaceutical composition prepared according to the pharmaceutical composition or the preparation method in preparing medicines for treating lung cancer.
In summary, the beneficial effects of the invention are as follows:
(1) The invention simplifies prescription components, reduces production cost, has better physical properties, and the appearance of the prepared tablet meets the quality requirement by a simple process, has more stable physical properties and relatively less impurity content in the composition when stored.
(2) The pharmaceutical composition has the advantages of good stability, good drug dissolution, better pharmacodynamics and pharmacokinetics, simple preparation process and suitability for industrial production.
Detailed Description
The present invention will be further described in detail with reference to the following examples, which are only for the purpose of illustrating the invention and are not to be construed as limiting the scope of the invention.
Definition: unless otherwise indicated, all weight percentages in the present invention are weight percentages of the total dosage (excluding the weight of purified water in the formulated binder solution).
The disclosure of all ranges in this disclosure should be considered to be a disclosure of all subranges and all point values within the range. For example: the disclosure of 10% -50% active ingredient should be considered as also disclosing ranges of 10% -20%, 20% -30%, 30% -40%, 40% -50% etc. as well as 15%, 20%, 28%, 36%, 45% etc. values.
In the present invention, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art. Also, the relative terms and laboratory procedures used herein are terms and conventional procedures that are widely used in the corresponding arts. Meanwhile, in order to better understand the present invention, definitions and explanations of related terms are provided below.
As used herein, the term "add-in" refers to materials added during wet granulation.
As used herein, the term "add-on" refers to adding material to the mixed and lubricated granules prior to tableting.
The drug carrier and the auxiliary materials can be better matched with active ingredients (for example, the compound shown in the formula I), and the prepared drug preparation has the dissolution rate, storage stability, impurity content and the like which meet the standards.
The invention aims to provide a pharmaceutical composition containing an active ingredient N- {2- { [2- (dimethylamino) ethyl ] (methyl) amino } -6- (2, 2-trifluoro ethoxy) -5- { [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino } pyridin-3-yl } acrylamide or a pharmaceutically acceptable salt thereof, and a filler, a disintegrating agent, an adhesive, an anti-adhesive, a disintegrating aid and a lubricant, wherein the pharmaceutical composition has good stability, drug dissolution, better pharmacodynamics and pharmacokinetics advantages, simple preparation process and suitability for industrial production.
The pharmaceutical compositions described herein are prepared for the active ingredient N- {2- { [2- (dimethylamino) ethyl ] (methyl) amino } -6- (2, 2-trifluoroethoxy) -5- { [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino } pyridin-3-yl } acrylamide or a pharmaceutically acceptable salt thereof, and the compatibility of excipients with the active ingredient is studied to examine the changes in disintegration time, dissolution rate or tablet hardness etc. of different pharmaceutical compositions and their effects on product properties (e.g., formulation appearance, bioavailability etc.).
The medicine composition comprises 10-50% of active ingredient, 30-70% of filling agent, 5-10% of disintegrating agent, 1-10% of anti-adhesive, 7-8.5% of adhesive, 1-10% of disintegrating auxiliary agent and 1-5% of lubricant.
In some embodiments, the pharmaceutically acceptable salt of (N- {2- { [2- (dimethylamino) ethyl ] (methyl) amino } -6- (2, 2-trifluoroethoxy) -5- { [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino } pyridin-3-yl } acrylamide as an active ingredient is selected from the group consisting of methanesulfonates.
Of course, the pharmaceutically acceptable salt thereof may also be a benzenesulfonate, p-toluenesulfonate, ethanesulfonate, hydrochloride or sulfate salt.
In some embodiments, the filler is selected from one or more of cellulose, microcrystalline cellulose, starch, dibasic calcium phosphate, sucrose, lactose, mannitol, xylitol, lactitol, maltodextrin.
The disintegrating agent is one or more of sodium starch glycolate, sodium carboxymethyl starch, corn starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, croscarmellose, methylcellulose, pregelatinized starch and sodium alginate.
The binder is polyethylene glycol 4000.
The anti-adhesive is one or more of powdered cellulose, magnesium trisilicate, colloidal silicon dioxide, silicon dioxide and talcum powder.
The anti-adhesive is colloidal silica.
The disintegration aid is sodium chloride.
The lubricant is one or more of stearic acid, magnesium stearate, sodium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, myristic acid, palmitic acid, sodium stearyl fumarate, pulvis Talci, hydrogenated vegetable oil, and mineral oil.
The invention optimizes the use of auxiliary materials of the composition, so that the pharmaceutical composition has good stability, drug dissolution, better pharmacodynamics and pharmacokinetics advantages, simple preparation process and suitability for industrial production.
In another aspect of the present invention, a method for preparing a pharmaceutical composition for preparing the pharmaceutical composition comprises the steps of:
s1, preparing raw material auxiliary materials and sieving: weighing materials according to the formula of the pharmaceutical composition, and sieving for standby;
s2, preparing an adhesive solution: adding purified water and an adhesive into a liquid preparation barrel, and mixing for later use;
s3, granulating: the active ingredients, the disintegrating agent, the filler, the anti-adhesion agent and the disintegrating auxiliary agent which are treated in the step S1 are sent into a granulator for dry mixing treatment; then adding the adhesive solution prepared in the step S2, and granulating;
s4, drying: the materials in the step S3 are sent into a fluidized bed for drying treatment;
s5, finishing: finishing the dry material particles obtained in the step S4;
s6, mixing: on the basis of S5, adding an anti-adhesive agent, mixing and sieving, and adding a disintegrating agent, mixing and sieving;
s7, lubrication: on the basis of S6, adding a lubricant, mixing and sieving to finish lubrication;
s8, tabletting: and (3) carrying out tabletting treatment on the lubricated material on the basis of S7 to obtain the pharmaceutical composition.
Further, S1, preparing raw material auxiliary materials and sieving: microcrystalline cellulose, lactose and croscarmellose sodium are respectively sieved by a high-energy sieving machine through a 30-mesh sieve, sodium chloride is crushed by a high-speed crusher and then manually sieved by a 60-mesh sieve, active compounds and colloidal silicon dioxide are combined in a medicinal low-density polyethylene bag and manually turned and primarily mixed, and then the mixture is sieved by the high-energy sieving machine through the 60-mesh sieve for 2 times;
S2, preparing an adhesive solution: adding normal-temperature purified water into a liquid preparation barrel, starting stirring, slowly adding polyethylene glycol 4000, continuing stirring for 1-2 hours after the addition, and stopping stirring when no obvious insoluble substances are visually detected;
s3, granulating: stirring paddle rotation speed is 75rpm-120rpm, cutter rotation speed is 1450rpm-1550rpm, adhesive solution is uniformly added, adhesive adding time is controlled to be 120-180 seconds, stirring and cutting granulation are continued for 180 seconds after adhesive adding, aperture of wet granule finishing screen is 10mm x 10mm, and finishing rotation speed is 250rpm-350rpm, and discharging is carried out while finishing granules;
s4, drying: the obtained tablet is dried by a fluidized bed, the air inlet temperature of the fluidized bed is 50-80 ℃, and the air inlet quantity is 700-900m 3 And (3) discharging after the moisture is less than or equal to 3.0%.
S5, finishing: the pore diameter of the granule finishing screen is 0.6mm, and the granule finishing rotating speed is 300-400rpm;
s6, mixing: adding crosslinked sodium carboxymethyl cellulose after finishing, manually sieving with a 30-mesh sieve, adding colloidal silica into the obtained dry particles, mixing, sieving with a 30-mesh sieve for 10-15min, and mixing at 10-20 rpm;
s7, lubrication: adding sodium stearyl fumarate into the mixed materials, mixing, sieving with 60 meshes, mixing for 3-5min at 10-20rpm, and lubricating and mixing;
S8, tabletting: by usingThe round punching, the tabletting speed is 30-60 kilosheets/hour, the rotating speed of a blanking device is 20-40rpm, the average value of main pressure is 3.8-4.2KN, the thickness of the main pressing edge of a tablet is 2.0-3.0mm, the thickness of the pre-pressing edge is 2.5-3.5mm, the filling depth is 6.0-8.0mm, the average value of hardness is controlled to be 40-75N, and the single value is controlled to be 30-100N.
The invention also provides application of the pharmaceutical composition prepared according to the pharmaceutical composition or the preparation method in preparing medicines for treating lung cancer, wherein the lung cancer is locally advanced or metastatic non-small cell lung cancer with EGFR (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutation, the disease progress occurs when or after EGFR Tyrosine Kinase Inhibitor (TKI) treatment is carried out in the past, and the detection proves that EGFR T790M mutation positive locally advanced or metastatic NSCLC adult patients are treated.
The technical scheme of the present application is further explained below through specific examples.
The feeding amount of the embodiment is from small to large according to the test sequence so as to save the test raw materials.
Example 1: tablet (batch calculation feeding 1 ten thousand tablets)
Comprises 212g of methanesulfonate (active ingredient) of the compound of formula (I), 876g of cellulose, 256g of xylitol, 107.4g of sodium starch glycolate, 107.4g of powdery cellulose, 131.7g of sodium chloride, 4000169g of polyethylene glycol, 127.7g of sodium starch glycolate, 88.2g of powdery cellulose and 44.6g of stearic acid.
The preparation process comprises the following steps:
s1, preparing raw material auxiliary materials and sieving: microcrystalline cellulose, lactose and croscarmellose sodium are respectively sieved by a high-energy sieving machine through a 30-mesh sieve, sodium chloride is crushed by a high-speed crusher and then manually sieved by a 60-mesh sieve, active compounds and colloidal silicon dioxide are combined in a medicinal low-density polyethylene bag and manually turned and primarily mixed, and then the mixture is sieved by the high-energy sieving machine through the 60-mesh sieve for 2 times;
s2, preparing an adhesive solution: adding normal-temperature purified water into a liquid preparation barrel, starting stirring, slowly adding polyethylene glycol 4000, continuing stirring for 1 hour after the addition, and stopping stirring when no obvious insoluble substances are visually detected;
s3, granulating: uniformly adding the adhesive solution at the stirring paddle rotating speed of 75rpm and the cutting knife rotating speed of 1450rpm, controlling the adhesive adding time to be 120 seconds, continuously stirring and cutting for granulating for 180 seconds after the adhesive is added, wherein the aperture of a wet granule granulating screen is 10mm x 10mm, and granulating and discharging at the granulating rotating speed of 250 rpm;
s4, drying: the obtained tablet is dried by fluidized bed, the air inlet temperature of the fluidized bed is 50 ℃, and the air inlet is carried outThe amount is 700m 3 And (3) discharging after the moisture is less than or equal to 3.0%.
S5, finishing: the pore diameter of the finishing screen is 0.6mm, and the finishing rotation speed is 300rpm;
s6, mixing: adding crosslinked sodium carboxymethyl cellulose after finishing, manually sieving with a 30-mesh sieve, adding colloidal silica into the obtained dry particles, mixing, sieving with a 30-mesh sieve, and mixing at 10min and 10 rpm;
S7, lubrication: adding sodium stearyl fumarate into the mixed materials, mixing, sieving with 60 meshes, mixing for 3min at a mixing speed of 10rpm, and carrying out lubrication mixing;
s8, tabletting: by usingThe round punching, the tabletting speed is 30-60 kilosheets/hour, the rotating speed of a blanking device is 20-40rpm, the average value of main pressure is 3.8-4.2KN, the thickness of the main pressing edge of a tablet is 2.0-3.0mm, the thickness of the pre-pressing edge is 2.5-3.5mm, the filling depth is 6.0-8.0mm, the average value of hardness is controlled to be 40-75N, and the single value is controlled to be 30-100N.
The prepared tablet has smooth surface, friability less than 1.0% and qualified inspection; the disintegration time is less than 5MIN; the dissolution rate (%) of the prepared tablet in a dissolution medium is more than 85% and meets the release requirement.
Example 2: tablet (batch calculation feeding 1 ten thousand tablets)
Comprises 1060g of methanesulfonate (active ingredient) of the compound of formula (I), 313.2g of starch, 252g of lactitol, 70g of methylcellulose and corn starch, 70g of colloidal silicon dioxide and talcum powder, 65.3g of sodium chloride, 4000151.5g of polyethylene glycol, 74.1g of methylcellulose and corn starch, 42.6g of colloidal silicon dioxide and talcum powder, 21.3g of calcium stearate and hydrogenated vegetable oil.
The preparation process comprises the following steps:
s1, preparing raw material auxiliary materials and sieving: microcrystalline cellulose, lactose and croscarmellose sodium are respectively sieved by a high-energy sieving machine through a 30-mesh sieve, sodium chloride is crushed by a high-speed crusher and then manually sieved by a 60-mesh sieve, active compounds and colloidal silicon dioxide are combined in a medicinal low-density polyethylene bag and manually turned and primarily mixed, and then the mixture is sieved by the high-energy sieving machine through the 60-mesh sieve for 2 times;
S2, preparing an adhesive solution: adding normal-temperature purified water into a liquid preparation barrel, starting stirring, slowly adding polyethylene glycol 4000, continuing stirring for 2 hours after the addition, and stopping stirring when no obvious insoluble substances are visually detected;
s3, granulating: uniformly adding the adhesive solution at the stirring paddle rotating speed of 120rpm and the cutting knife rotating speed of 1550rpm, controlling the adhesive adding time to be 180 seconds, continuously stirring and cutting for granulating for 180 seconds after the adhesive is added, wherein the aperture of a wet granule finishing screen is 10mm x 10mm, and finishing and discharging at the finishing rotating speed of 350 rpm;
s4, drying: the obtained tablet is dried by a fluidized bed, the air inlet temperature of the fluidized bed is 50-80 ℃, and the air inlet quantity is 900m 3 And (3) discharging after the moisture is less than or equal to 3.0%.
S5, finishing: the pore diameter of the finishing screen is 0.6mm, and the finishing rotation speed is 400rpm;
s6, mixing: adding crosslinked sodium carboxymethyl cellulose after finishing, manually sieving with a 30-mesh sieve, adding colloidal silica into the obtained dry particles, mixing, sieving with a 30-mesh sieve for 15min, and mixing at 20 rpm;
s7, lubrication: adding sodium stearyl fumarate into the mixed materials, mixing, sieving with 60 meshes, mixing for 5min and mixing at 20rpm, and carrying out lubrication mixing;
s8, tabletting: by usingThe round punching, the tabletting speed is 30-60 kilosheets/hour, the rotating speed of a blanking device is 20-40rpm, the average value of main pressure is 3.8-4.2KN, the thickness of the main pressing edge of a tablet is 2.0-3.0mm, the thickness of the pre-pressing edge is 2.5-3.5mm, the filling depth is 6.0-8.0mm, the average value of hardness is controlled to be 40-75N, and the single value is controlled to be 30-100N.
The prepared tablet has smooth surface, friability less than 1.0% and qualified inspection; the disintegration time is less than 5min; the dissolution rate (%) of the prepared tablet in a dissolution medium for 30min is more than 85%, so that the release requirement is met.
Example 3: tablet (batch calculation feeding 1 ten thousand tablets)
Comprises 318g of methanesulfonate (active ingredient) of the compound of formula (I), 451.7g of microcrystalline cellulose, 785g of lactose, 80g of crosslinked povidone, 80g of silicon dioxide, 86g of sodium chloride, 4000.3 g of polyethylene glycol, 65g of crosslinked povidone, 44g of silicon dioxide and 28g of glyceryl monostearate.
The preparation process comprises the following steps:
s1, preparing raw material auxiliary materials and sieving: microcrystalline cellulose, lactose and croscarmellose sodium are respectively sieved by a high-energy sieving machine through a 30-mesh sieve, sodium chloride is crushed by a high-speed crusher and then manually sieved by a 60-mesh sieve, active compounds and colloidal silicon dioxide are combined in a medicinal low-density polyethylene bag and manually turned and primarily mixed, and then the mixture is sieved by the high-energy sieving machine through the 60-mesh sieve for 2 times;
s2, preparing an adhesive solution: adding normal-temperature purified water into a liquid preparation barrel, starting stirring, slowly adding polyethylene glycol 4000, continuing stirring for 1.5 hours after the addition, and stopping stirring when no obvious insoluble substances are visually detected;
S3, granulating: uniformly adding the adhesive solution at the stirring paddle rotating speed of 100rpm and the cutting knife rotating speed of 1500rpm, controlling the adhesive adding time at 140 seconds, continuously stirring and cutting for granulating for 180 seconds after the adhesive is added, wherein the aperture of a wet granule granulating screen is 10mm x 10mm, and granulating and discharging at the granulating rotating speed of 300 rpm;
s4, drying: the obtained tablet is dried by a fluidized bed, the air inlet temperature of the fluidized bed is 65 ℃, and the air inlet quantity is 800m 3 And (3) discharging after the moisture is less than or equal to 3.0%.
S5, finishing: the pore diameter of the finishing screen is 0.6mm, and the finishing rotation speed is 350rpm;
s6, mixing: adding crosslinked sodium carboxymethyl cellulose after finishing, manually sieving with a 30-mesh sieve, adding colloidal silica into the obtained dry particles, mixing, sieving with a 30-mesh sieve, and mixing at a mixing speed of 15rpm for 12 min;
s7, lubrication: adding sodium stearyl fumarate into the mixed materials, mixing, sieving with 60 meshes, mixing for 4min and mixing at 15rpm, and carrying out lubrication mixing;
s8, tabletting: by usingThe round punching, the tabletting speed is 30-60 kilosheets/hour, the rotating speed of a blanking device is 20-40rpm, the average value of main pressure is 3.8-4.2KN, the thickness of the main pressing edge of a tablet is 2.0-3.0mm, the thickness of the pre-pressing edge is 2.5-3.5mm, the filling depth is 6.0-8.0mm, the average value of hardness is controlled to be 40-75N, and the single value is controlled to be 30-100N.
The prepared tablet has smooth surface, friability less than 1.0% and qualified inspection; the disintegration time is less than 5min; the dissolution rate (%) of the prepared tablet in a dissolution medium for 30min is more than 85%, so that the release requirement is met.
Example 5: tablet (batch calculation feeding 1 ten thousand tablets)
Comprises 402.8g of methanesulfonate (active ingredient) of the compound of formula (I), 363.2g of microcrystalline cellulose, 782g of lactose, 83g of croscarmellose sodium, 83g of colloidal silicon dioxide, 86g of sodium chloride, 4000183g of polyethylene glycol, 65g of croscarmellose sodium, 44g of colloidal silicon dioxide and 28g of sodium stearyl fumarate.
The preparation process comprises the following steps:
s1, preparing raw material auxiliary materials and sieving: microcrystalline cellulose, lactose and croscarmellose sodium are respectively sieved by a high-energy sieving machine through a 30-mesh sieve, sodium chloride is crushed by a high-speed crusher and then manually sieved by a 60-mesh sieve, active compounds and colloidal silicon dioxide are combined in a medicinal low-density polyethylene bag and manually turned and primarily mixed, and then the mixture is sieved by the high-energy sieving machine through the 60-mesh sieve for 2 times;
s2, preparing an adhesive solution: adding normal-temperature purified water into a liquid preparation barrel, starting stirring, slowly adding polyethylene glycol 4000, continuing stirring for 2 hours after the addition, and stopping stirring when no obvious insoluble substances are visually detected;
S3, granulating: uniformly adding the adhesive solution at the stirring paddle rotating speed of 120rpm and the cutting knife rotating speed of 1550rpm, controlling the adhesive adding time to be 180 seconds, continuously stirring and cutting for granulating for 180 seconds after the adhesive is added, wherein the aperture of a wet granule finishing screen is 10mm x 10mm, and finishing and discharging at the finishing rotating speed of 350 rpm;
s4, drying: the obtained tablet is dried by a fluidized bed, the air inlet temperature of the fluidized bed is 50-80 ℃, and the air inlet quantity is 900m 3 And (3) discharging after the moisture is less than or equal to 3.0%.
S5, finishing: the pore diameter of the finishing screen is 0.6mm, and the finishing rotation speed is 400rpm;
s6, mixing: adding crosslinked sodium carboxymethyl cellulose after finishing, manually sieving with a 30-mesh sieve, adding colloidal silica into the obtained dry particles, mixing, sieving with a 30-mesh sieve for 15min, and mixing at 20 rpm;
s7, lubrication: adding sodium stearyl fumarate into the mixed materials, mixing, sieving with 60 meshes, mixing for 5min and mixing at 20rpm, and carrying out lubrication mixing;
s8, tabletting: by usingThe round punching, the tabletting speed is 30-60 kilosheets/hour, the rotating speed of a blanking device is 20-40rpm, the average value of main pressure is 3.8-4.2KN, the thickness of the main pressing edge of a tablet is 2.0-3.0mm, the thickness of the pre-pressing edge is 2.5-3.5mm, the filling depth is 6.0-8.0mm, the average value of hardness is controlled to be 40-75N, and the single value is controlled to be 30-100N.
The prepared tablet has smooth surface, friability less than 1.0% and qualified inspection; the disintegration time is less than 5min; the dissolution rate (%) of the prepared tablet in a dissolution medium for 30min is more than 85%, so that the release requirement is met.
Example 6: tablet (batch calculation feeding 1 ten thousand tablets)
Comprises 530g of methanesulfonate (active ingredient) of the compound of the formula (I), 253.6g of microcrystalline cellulose, 768.4g of lactose, 81g of croscarmellose sodium, 81g of colloidal silicon dioxide, 86g of sodium chloride, 4000 183g of polyethylene glycol, 65g of croscarmellose sodium, 44g of colloidal silicon dioxide and 28g of sodium stearyl fumarate.
The preparation process comprises the following steps:
s1, preparing raw material auxiliary materials and sieving: microcrystalline cellulose, lactose and croscarmellose sodium are respectively sieved by a high-energy sieving machine through a 30-mesh sieve, sodium chloride is crushed by a high-speed crusher and then manually sieved by a 60-mesh sieve, active compounds and colloidal silicon dioxide are combined in a medicinal low-density polyethylene bag and manually turned and primarily mixed, and then the mixture is sieved by the high-energy sieving machine through the 60-mesh sieve for 2 times;
s2, preparing an adhesive solution: adding normal-temperature purified water into a liquid preparation barrel, starting stirring, slowly adding polyethylene glycol 4000, continuing stirring for 1.2 hours after the addition, and stopping stirring when no obvious insoluble substances are visually detected;
S3, granulating: uniformly adding the adhesive solution at the stirring paddle rotating speed of 90rpm and the cutting knife rotating speed of 1500rpm, controlling the adhesive adding time at 180 seconds, continuously stirring and cutting for granulating for 180 seconds after the adhesive is added, wherein the aperture of a wet granule finishing screen is 10mm x 10mm, and finishing and discharging at the finishing rotating speed of 250 rpm;
s4, drying: the obtained tablet is dried by a fluidized bed, the air inlet temperature of the fluidized bed is 50 ℃, and the air inlet quantity is 800m 3 And (3) discharging after the moisture is less than or equal to 3.0%.
S5, finishing: the pore diameter of the finishing screen is 0.6mm, and the finishing rotation speed is 300rpm;
s6, mixing: adding crosslinked sodium carboxymethyl cellulose after finishing, manually sieving with a 30-mesh sieve, adding colloidal silica into the obtained dry particles, mixing, sieving with a 30-mesh sieve, and mixing at a mixing speed of 15rpm for 13 min;
s7, lubrication: adding sodium stearyl fumarate into the mixed materials, mixing, sieving with 60 meshes, mixing for 4min and mixing at 15rpm, and carrying out lubrication mixing;
s8, tabletting: by usingThe round punching, the tabletting speed is 30-60 kilosheets/hour, the rotating speed of a blanking device is 20-40rpm, the average value of main pressure is 3.8-4.2KN, the thickness of the main pressing edge of a tablet is 2.0-3.0mm, the thickness of the pre-pressing edge is 2.5-3.5mm, the filling depth is 6.0-8.0mm, the average value of hardness is controlled to be 40-75N, and the single value is controlled to be 30-100N.
The prepared tablet has smooth surface, friability less than 1.0% and qualified inspection; the disintegration time is less than 5min; the dissolution rate (%) of the prepared tablet in a dissolution medium for 30min is more than 85%, so that the release requirement is met.
Example 7: tablet (batch calculation feeding 1 ten thousand tablets)
Comprises 470g of methanesulfonate (active ingredient) of the compound of formula (I), 362g of microcrystalline cellulose, 765g of lactose, 65g of croscarmellose sodium, 65g of colloidal silicon dioxide, 86g of sodium chloride, 4000178g of polyethylene glycol, 65g of croscarmellose sodium, 44g of colloidal silicon dioxide and 28g of sodium stearyl fumarate.
The preparation process comprises the following steps:
s1, preparing raw material auxiliary materials and sieving: microcrystalline cellulose, lactose and croscarmellose sodium are respectively sieved by a high-energy sieving machine through a 30-mesh sieve, sodium chloride is crushed by a high-speed crusher and then manually sieved by a 60-mesh sieve, active compounds and colloidal silicon dioxide are combined in a medicinal low-density polyethylene bag and manually turned and primarily mixed, and then the mixture is sieved by the high-energy sieving machine through the 60-mesh sieve for 2 times;
s2, preparing an adhesive solution: adding normal-temperature purified water into a liquid preparation barrel, starting stirring, slowly adding polyethylene glycol 4000, continuing stirring for 1 hour after the addition, and stopping stirring when no obvious insoluble substances are visually detected;
S3, granulating: uniformly adding the adhesive solution at the stirring paddle rotating speed of 75rpm and the cutting knife rotating speed of 1450rpm, controlling the adhesive adding time to be 120 seconds, continuously stirring and cutting for granulating for 180 seconds after the adhesive is added, wherein the aperture of a wet granule granulating screen is 10mm x 10mm, and granulating and discharging at the granulating rotating speed of 250 rpm;
s4, drying: the obtained tablet is dried by a fluidized bed, the air inlet temperature of the fluidized bed is 50 ℃, and the air inlet quantity is 700m 3 And (3) discharging after the moisture is less than or equal to 3.0%.
S5, finishing: the pore diameter of the finishing screen is 0.6mm, and the finishing rotation speed is 300rpm;
s6, mixing: adding crosslinked sodium carboxymethyl cellulose after finishing, manually sieving with a 30-mesh sieve, adding colloidal silica into the obtained dry particles, mixing, sieving with a 30-mesh sieve, and mixing at 10min and 10 rpm;
s7, lubrication: adding sodium stearyl fumarate into the mixed materials, mixing, sieving with 60 meshes, mixing for 3min at a mixing speed of 10rpm, and carrying out lubrication mixing;
s8, tabletting: by usingThe round punching, the tabletting speed is 30-60 kilosheets/hour, the rotating speed of a blanking device is 20-40rpm, the average value of main pressure is 3.8-4.2KN, the thickness of the main pressing edge of a tablet is 2.0-3.0mm, the thickness of the pre-pressing edge is 2.5-3.5mm, the filling depth is 6.0-8.0mm, the average value of hardness is controlled to be 40-75N, and the single value is controlled to be 30-100N.
The prepared tablet has smooth surface, friability less than 1.0% and qualified inspection; the disintegration time is less than 5MIN; the dissolution rate (%) of the prepared tablet in a dissolution medium is more than 85% and meets the release requirement.
Example 8: tablet (batch calculation feeding 1 ten thousand tablets)
Comprises 468g of mesylate (active ingredient) of the compound of formula (I), 447g of microcrystalline cellulose, 682g of lactose, 65g of croscarmellose sodium, 65g of colloidal silicon dioxide, 87g of sodium chloride, 4000178g of polyethylene glycol, 65g of croscarmellose sodium, 44g of colloidal silicon dioxide and 27g of sodium stearyl fumarate.
The preparation process comprises the following steps:
s1, preparing raw material auxiliary materials and sieving: microcrystalline cellulose, lactose and croscarmellose sodium are respectively sieved by a high-energy sieving machine through a 30-mesh sieve, sodium chloride is crushed by a high-speed crusher and then manually sieved by a 60-mesh sieve, active compounds and colloidal silicon dioxide are combined in a medicinal low-density polyethylene bag and manually turned and primarily mixed, and then the mixture is sieved by the high-energy sieving machine through the 60-mesh sieve for 2 times;
s2, preparing an adhesive solution: adding normal-temperature purified water into a liquid preparation barrel, starting stirring, slowly adding polyethylene glycol 4000, continuing stirring for 2 hours after the addition, and stopping stirring when no obvious insoluble substances are visually detected;
S3, granulating: uniformly adding the adhesive solution at the stirring paddle rotating speed of 120rpm and the cutting knife rotating speed of 1550rpm, controlling the adhesive adding time to be 180 seconds, continuously stirring and cutting for granulating for 180 seconds after the adhesive is added, wherein the aperture of a wet granule finishing screen is 10mm x 10mm, and finishing and discharging at the finishing rotating speed of 350 rpm;
s4, drying: the obtained tablet is dried by a fluidized bed, the air inlet temperature of the fluidized bed is 50-80 ℃, and the air inlet quantity is 900m 3 And (3) discharging after the moisture is less than or equal to 3.0%.
S5, finishing: the pore diameter of the finishing screen is 0.6mm, and the finishing rotation speed is 400rpm;
s6, mixing: adding crosslinked sodium carboxymethyl cellulose after finishing, manually sieving with a 30-mesh sieve, adding colloidal silica into the obtained dry particles, mixing, sieving with a 30-mesh sieve for 15min, and mixing at 20 rpm;
s7, lubrication: adding sodium stearyl fumarate into the mixed materials, mixing, sieving with 60 meshes, mixing for 5min and mixing at 20rpm, and carrying out lubrication mixing;
s8, tabletting: by usingThe round punching, the tabletting speed is 30-60 kilosheets/hour, the rotating speed of a blanking device is 20-40rpm, the average value of main pressure is 3.8-4.2KN, the thickness of the main pressing edge of a tablet is 2.0-3.0mm, the thickness of the pre-pressing edge is 2.5-3.5mm, the filling depth is 6.0-8.0mm, the average value of hardness is controlled to be 40-75N, and the single value is controlled to be 30-100N.
The prepared tablet has smooth surface, friability less than 1.0% and qualified inspection; the disintegration time is less than 5min; the dissolution rate (%) of the prepared tablet in a dissolution medium for 30min is more than 85%, so that the release requirement is met.
Example 9: tablet (batch calculation feeding 1 ten thousand tablets)
Comprises 469g of methanesulfonate (active ingredient) of the compound of the formula (I), 489g of microcrystalline cellulose, 638g of lactose, 65g of croscarmellose sodium, 65g of colloidal silicon dioxide, 87g of sodium chloride, 4000 178g of polyethylene glycol, 65g of croscarmellose sodium, 45g of colloidal silicon dioxide and 27g of sodium stearyl fumarate.
The preparation process comprises the following steps:
s1, preparing raw material auxiliary materials and sieving: microcrystalline cellulose, lactose and croscarmellose sodium are respectively sieved by a high-energy sieving machine through a 30-mesh sieve, sodium chloride is crushed by a high-speed crusher and then manually sieved by a 60-mesh sieve, active compounds and colloidal silicon dioxide are combined in a medicinal low-density polyethylene bag and manually turned and primarily mixed, and then the mixture is sieved by the high-energy sieving machine through the 60-mesh sieve for 2 times;
s2, preparing an adhesive solution: adding normal-temperature purified water into a liquid preparation barrel, starting stirring, slowly adding polyethylene glycol 4000, continuing stirring for 1.5 hours after the addition, and stopping stirring when no obvious insoluble substances are visually detected;
S3, granulating: uniformly adding the adhesive solution at the stirring paddle rotating speed of 100rpm and the cutting knife rotating speed of 1500rpm, controlling the adhesive adding time at 140 seconds, continuously stirring and cutting for granulating for 180 seconds after the adhesive is added, wherein the aperture of a wet granule granulating screen is 10mm x 10mm, and granulating and discharging at the granulating rotating speed of 300 rpm;
s4, drying: the obtained tablet is dried by a fluidized bed, the air inlet temperature of the fluidized bed is 65 ℃, and the air inlet quantity is 800m 3 And (3) discharging after the moisture is less than or equal to 3.0%.
S5, finishing: the pore diameter of the finishing screen is 0.6mm, and the finishing rotation speed is 350rpm;
s6, mixing: adding crosslinked sodium carboxymethyl cellulose after finishing, manually sieving with a 30-mesh sieve, adding colloidal silica into the obtained dry particles, mixing, sieving with a 30-mesh sieve, and mixing at a mixing speed of 15rpm for 12 min;
s7, lubrication: adding sodium stearyl fumarate into the mixed materials, mixing, sieving with 60 meshes, mixing for 4min and mixing at 15rpm, and carrying out lubrication mixing;
s8, tabletting: by usingThe round punching, the tabletting speed is 30-60 kilosheets/hour, the rotating speed of a blanking device is 20-40rpm, the average value of main pressure is 3.8-4.2KN, the thickness of the main pressing edge of a tablet is 2.0-3.0mm, the thickness of the pre-pressing edge is 2.5-3.5mm, the filling depth is 6.0-8.0mm, the average value of hardness is controlled to be 40-75N, and the single value is controlled to be 30-100N.
The prepared tablet has smooth surface, friability less than 1.0% and qualified inspection; the disintegration time is less than 5min; the dissolution rate (%) of the prepared tablet in a dissolution medium for 30min is more than 85%, so that the release requirement is met.
Example 10: tablet (batch calculation of 10 ten thousand tablets)
Comprises 4.68kg of methanesulfonate (active ingredient) of the compound of formula (I), 4.47kg of microcrystalline cellulose, 6.82kg of lactose, 0.65kg of croscarmellose sodium, 0.65kg of colloidal silicon dioxide, 0.87kg of sodium chloride, 4000.78 kg of polyethylene glycol, 0.65kg of croscarmellose sodium, 0.44kg of colloidal silicon dioxide and 0.27kg of sodium stearyl fumarate.
The preparation process comprises the following steps:
s1, preparing raw material auxiliary materials and sieving: microcrystalline cellulose, lactose and croscarmellose sodium are respectively sieved by a high-energy sieving machine through a 30-mesh sieve, sodium chloride is crushed by a high-speed crusher and then manually sieved by a 60-mesh sieve, active compounds and colloidal silicon dioxide are combined in a medicinal low-density polyethylene bag and manually turned and primarily mixed, and then the mixture is sieved by the high-energy sieving machine through the 60-mesh sieve for 2 times;
s2, preparing an adhesive solution: adding normal-temperature purified water into a liquid preparation barrel, starting stirring, slowly adding polyethylene glycol 4000, continuing stirring for 1-2 hours after the addition, and stopping stirring when no obvious insoluble substances are visually detected;
S3, granulating: uniformly adding the adhesive solution at the stirring paddle rotating speed of 80rpm and the cutting knife rotating speed of 1530rpm, controlling the adhesive adding time to be 120-180 seconds, continuously stirring and cutting for granulating for 180 seconds after the adhesive is added, wherein the aperture of a wet granule granulating screen is 10mm x 10mm, and discharging while the granulating rotating speed is 280 rpm;
s4, drying: the obtained tablet is dried by a fluidized bed, the air inlet temperature of the fluidized bed is 70 ℃, and the air inlet quantity is 850m 3 And (3) discharging after the moisture is less than or equal to 3.0%.
S5, finishing: the pore diameter of the finishing screen is 0.6mm, and the finishing rotation speed is 380rpm;
s6, mixing: adding crosslinked sodium carboxymethyl cellulose after finishing, manually sieving with a 30-mesh sieve, adding colloidal silica into the obtained dry particles, mixing, sieving with a 30-mesh sieve, and mixing at a mixing speed of 12rpm for 14 min;
s7, lubrication: adding sodium stearyl fumarate into the mixed materials, mixing, sieving with 60 meshes, mixing for 4min at a mixing speed of 12rpm, and carrying out lubrication mixing;
s8, tabletting: by usingCircular punching, tabletting speed of 30-60 kilo-tablet/hour and blanking deviceThe rotating speed is 20-40rpm, the average value of main pressure is 3.8-4.2KN, the thickness of the main pressure edge of the tablet is 2.0-3.0mm, the thickness of the pre-pressing edge is 2.5-3.5mm, the filling depth is 6.0-8.0mm, the average value of hardness is controlled at 40-75N, and the single value is controlled at 30-100N.
The prepared tablet has smooth surface, friability less than 1.0% and qualified inspection; the disintegration time is less than 5min; the dissolution rate (%) of the prepared tablet in a dissolution medium for 30min is more than 85%, so that the release requirement is met.
The 10 ten thousand pieces of the product prepared above were sampled for stability testing, see example 14 for details.
Example 11: tablet (batch calculation of 10 ten thousand tablets)
Comprises 4.67kg of methanesulfonate (active ingredient) of the compound of formula (I), 4.48kg of microcrystalline cellulose, 6.81kg of lactose, 0.65kg of croscarmellose sodium, 0.65kg of colloidal silicon dioxide, 0.88kg of sodium chloride, 4000.78 kg of polyethylene glycol, 0.65kg of croscarmellose sodium, 0.44kg of colloidal silicon dioxide and 0.27kg of sodium stearyl fumarate.
The preparation process comprises the following steps:
s1, preparing raw material auxiliary materials and sieving: microcrystalline cellulose, lactose and croscarmellose sodium are respectively sieved by a high-energy sieving machine through a 30-mesh sieve, sodium chloride is crushed by a high-speed crusher and then manually sieved by a 60-mesh sieve, active compounds and colloidal silicon dioxide are combined in a medicinal low-density polyethylene bag and manually turned and primarily mixed, and then the mixture is sieved by the high-energy sieving machine through the 60-mesh sieve for 2 times;
s2, preparing an adhesive solution: adding normal-temperature purified water into a liquid preparation barrel, starting stirring, slowly adding polyethylene glycol 4000, continuing stirring for 2 hours after the addition, and stopping stirring when no obvious insoluble substances are visually detected;
S3, granulating: stirring paddle rotation speed 110rpm, cutting knife rotation speed 1480rpm, uniformly adding adhesive solution, controlling adhesive adding time at 160 seconds, continuously stirring and cutting for granulating for 180 seconds after adhesive adding, wherein the aperture of a wet granule granulating screen is 10mm x 10mm, and granulating and discharging at the same time of granulating rotation speed 330 rpm;
s4, drying: the obtained tablet is dried by a fluidized bed, the air inlet temperature of the fluidized bed is 60 ℃, and the air inlet quantity is 750m 3 And (3) discharging after the moisture is less than or equal to 3.0%.
S5, finishing: the pore diameter of the granule finishing screen is 0.6mm, and the granule finishing rotating speed is 320rpm;
s6, mixing: adding crosslinked sodium carboxymethyl cellulose after finishing, manually sieving with a 30-mesh sieve, adding colloidal silica into the obtained dry particles, mixing, sieving with a 30-mesh sieve for 10min, and mixing at 20rpm;
s7, lubrication: adding sodium stearyl fumarate into the mixed materials, mixing, sieving with 60 meshes, mixing for 5min and mixing at 20rpm, and carrying out lubrication mixing;
s8, tabletting: by usingThe round punching, the tabletting speed is 30-60 kilosheets/hour, the rotating speed of a blanking device is 20-40rpm, the average value of main pressure is 3.8-4.2KN, the thickness of the main pressing edge of a tablet is 2.0-3.0mm, the thickness of the pre-pressing edge is 2.5-3.5mm, the filling depth is 6.0-8.0mm, the average value of hardness is controlled to be 40-75N, and the single value is controlled to be 30-100N.
The prepared tablet has smooth surface, friability less than 1.0% and qualified inspection; the disintegration time is less than 5min; the dissolution rate (%) of the prepared tablet in a dissolution medium for 30min is more than 85%, so that the release requirement is met.
The 10 ten thousand pieces of the product prepared above were sampled for stability testing, see example 14 for details.
Example 12: tablet (batch calculation of 20 ten thousand tablets)
Comprises 9.36kg of methanesulfonate (active ingredient) of the compound of formula (I), 8.94kg of microcrystalline cellulose, 13.64kg of lactose, 1.3kg of croscarmellose sodium, 1.3kg of colloidal silicon dioxide, 1.74kg of sodium chloride, 4000.56 kg of polyethylene glycol, 1.31kg of croscarmellose sodium, 0.88kg of colloidal silicon dioxide and 0.53kg of sodium stearyl fumarate.
The preparation process comprises the following steps:
s1, preparing raw material auxiliary materials and sieving: microcrystalline cellulose, lactose and croscarmellose sodium are respectively sieved by a high-energy sieving machine through a 30-mesh sieve, sodium chloride is crushed by a high-speed crusher and then manually sieved by a 60-mesh sieve, active compounds and colloidal silicon dioxide are combined in a medicinal low-density polyethylene bag and manually turned and primarily mixed, and then the mixture is sieved by the high-energy sieving machine through the 60-mesh sieve for 2 times;
s2, preparing an adhesive solution: adding normal-temperature purified water into a liquid preparation barrel, starting stirring, slowly adding polyethylene glycol 4000, continuing stirring for 1.2 hours after the addition, and stopping stirring when no obvious insoluble substances are visually detected;
S3, granulating: uniformly adding the adhesive solution at the stirring paddle rotating speed of 90rpm and the cutting knife rotating speed of 1500rpm, controlling the adhesive adding time at 180 seconds, continuously stirring and cutting for granulating for 180 seconds after the adhesive is added, wherein the aperture of a wet granule finishing screen is 10mm x 10mm, and finishing and discharging at the finishing rotating speed of 250 rpm;
s4, drying: the obtained tablet is dried by a fluidized bed, the air inlet temperature of the fluidized bed is 50 ℃, and the air inlet quantity is 800m 3 And (3) discharging after the moisture is less than or equal to 3.0%.
S5, finishing: the pore diameter of the finishing screen is 0.6mm, and the finishing rotation speed is 300rpm;
s6, mixing: adding crosslinked sodium carboxymethyl cellulose after finishing, manually sieving with a 30-mesh sieve, adding colloidal silica into the obtained dry particles, mixing, sieving with a 30-mesh sieve, and mixing at a mixing speed of 15rpm for 13 min;
s7, lubrication: adding sodium stearyl fumarate into the mixed materials, mixing, sieving with 60 meshes, mixing for 4min and mixing at 15rpm, and carrying out lubrication mixing;
s8, tabletting: by usingRound punching, tabletting speed of 30-60 kilo tablets/hour, rotating speed of a blanking device of 20-40rpm, main pressure average value of 3.8-4.2KN and main pressure edge thickness of tablets2.0-3.0mm, 2.5-3.5mm of pre-pressed edge thickness, 6.0-8.0mm of filling depth, the average hardness is controlled at 40-75N, and the single value is controlled at 30-100N.
The prepared tablet has smooth surface, friability less than 1.0% and qualified inspection; the disintegration time is less than 5min; the dissolution rate (%) of the prepared tablet in a dissolution medium for 30min is more than 85%, so that the release requirement is met.
Samples of the 20-thousand batch product prepared above were taken for stability testing, see example 14 for details.
Example 13: tablet (batch calculation of 20 ten thousand tablets)
Comprises 9.37kg of mesylate of the compound of formula (I) (active ingredient), 8.98kg of microcrystalline cellulose, 13.61kg of lactose, 1.3kg of croscarmellose sodium, 1.3kg of colloidal silicon dioxide, 1.74kg of sodium chloride, 4000.56 kg of polyethylene glycol, 1.31kg of croscarmellose sodium, 0.88kg of colloidal silicon dioxide and 0.53kg of sodium stearyl fumarate.
The preparation process comprises the following steps:
s1, preparing raw material auxiliary materials and sieving: microcrystalline cellulose, lactose and croscarmellose sodium are respectively sieved by a high-energy sieving machine through a 30-mesh sieve, sodium chloride is crushed by a high-speed crusher and then manually sieved by a 60-mesh sieve, active compounds and colloidal silicon dioxide are combined in a medicinal low-density polyethylene bag and manually turned and primarily mixed, and then the mixture is sieved by the high-energy sieving machine through the 60-mesh sieve for 2 times;
s2, preparing an adhesive solution: adding normal-temperature purified water into a liquid preparation barrel, starting stirring, slowly adding polyethylene glycol 4000, continuing stirring for 1.5 hours after the addition, and stopping stirring when no obvious insoluble substances are visually detected;
S3, granulating: uniformly adding the adhesive solution at the stirring paddle rotating speed of 100rpm and the cutting knife rotating speed of 1500rpm, controlling the adhesive adding time at 140 seconds, continuously stirring and cutting for granulating for 180 seconds after the adhesive is added, wherein the aperture of a wet granule granulating screen is 10mm x 10mm, and granulating and discharging at the granulating rotating speed of 300 rpm;
s4, drying: the obtained tablet is dried by a fluidized bed, the air inlet temperature of the fluidized bed is 65 ℃, and the air inlet quantity is 800m 3 And (3) discharging after the moisture is less than or equal to 3.0%.
S5, finishing: the pore diameter of the finishing screen is 0.6mm, and the finishing rotation speed is 350rpm;
s6, mixing: adding crosslinked sodium carboxymethyl cellulose after finishing, manually sieving with a 30-mesh sieve, adding colloidal silica into the obtained dry particles, mixing, sieving with a 30-mesh sieve, and mixing at a mixing speed of 15rpm for 12 min;
s7, lubrication: adding sodium stearyl fumarate into the mixed materials, mixing, sieving with 60 meshes, mixing for 4min and mixing at 15rpm, and carrying out lubrication mixing;
s8, tabletting: by usingThe round punching, the tabletting speed is 30-60 kilosheets/hour, the rotating speed of a blanking device is 20-40rpm, the average value of main pressure is 3.8-4.2KN, the thickness of the main pressing edge of a tablet is 2.0-3.0mm, the thickness of the pre-pressing edge is 2.5-3.5mm, the filling depth is 6.0-8.0mm, the average value of hardness is controlled to be 40-75N, and the single value is controlled to be 30-100N.
The prepared tablet has smooth surface, friability less than 1.0% and qualified inspection; the disintegration time is less than 5min; the dissolution rate (%) of the prepared tablet in a dissolution medium for 30min is more than 85%, so that the release requirement is met.
Samples of the 20-thousand batch product prepared above were taken for stability testing, see example 14 for details.
Example 14: stability test
Samples of the products obtained in examples 10, 11, 12 and 13 were left under accelerated conditions (40 ℃ C./75% RH) for 90 days, and were sampled and tested after 180 days, respectively, to examine the stability of the products.
TABLE 1 stability test results
The dissolution and content of the examples 10, 11, 12 and 13 are not changed significantly under the condition of 40 ℃/75% RH, the sample stability is good, and the dissolution degree meets the standard of more than 85% in 30 min.
While the foregoing description illustrates and describes the preferred embodiments of the present invention, as noted above, it is to be understood that the invention is not limited to the forms disclosed herein but is not to be construed as excluding other embodiments, and that various other combinations, modifications and environments are possible and may be made within the scope of the inventive concepts described herein, either by way of the foregoing teachings or by those of skill or knowledge of the relevant art. And that modifications and variations which do not depart from the spirit and scope of the invention are intended to be within the scope of the appended claims.
Claims (10)
1. A pharmaceutical composition comprising as active ingredient the mesylate salt of N- {2- { [2- (dimethylamino) ethyl ] (methyl) amino } -6- (2, 2-trifluoroethoxy) -5- { [4- (1-methyl-1H-indol-3-yl) pyrimidin-2-yl ] amino } pyridin-3-yl } acrylamide, as well as fillers, disintegrants, binders, anti-adh-tants, disintegration aids and lubricants;
the pharmaceutical composition comprises, by weight, 10% -50% of active ingredient, 30% -70% of filler, 5% -10% of disintegrant, 1% -10% of anti-adhesive, 7% -8.5% of adhesive, 1% -10% of disintegration auxiliary agent and 1% -5% of lubricant.
2. The pharmaceutical composition according to claim 1, wherein the filler is microcrystalline cellulose and lactose in a mass ratio (mg: mg) of 21.0:32.0, 18.0:35.0, 15.0:38.0, 12.0:41.0, 26.0:27.0, 31.0:22.0, 36.0:17.0, 41.0:12.0.
3. the pharmaceutical composition of claim 1, wherein the disintegrant is one or more of sodium starch glycolate, sodium carboxymethyl starch, corn starch, low-substituted hydroxypropyl cellulose, crospovidone, sodium croscarmellose, methylcellulose, pregelatinized starch, sodium alginate.
4. The pharmaceutical composition according to claim 1, wherein the binder is polyethylene glycol 4000 and the disintegration aid is sodium chloride.
5. The pharmaceutical composition of claim 1, wherein the anti-adherent is one or more of powdered cellulose, magnesium trisilicate, colloidal silica, talc.
6. The pharmaceutical composition of claim 1, wherein the lubricant is one or more of stearic acid, magnesium stearate, sodium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, myristic acid, palmitic acid, sodium stearyl fumarate, talc, hydrogenated vegetable oil, mineral oil.
7. The pharmaceutical composition according to claim 1, characterized in that it consists of the following components in weight percentage: 22.0% of methanesulfonate of the compound of the formula (I) as an active ingredient, 21.0% of microcrystalline cellulose as an additive and 32.0% of lactose as an additive, 3.05% of sodium carboxymethyl cellulose as a disintegrant, 40008.4% of polyethylene glycol as an adhesive, 3.05% of colloidal silica as an anti-adhesive, 4.1% of sodium chloride as a disintegrant, 3.05% of sodium carboxymethyl cellulose as a disintegrant, 2.05% of colloidal silica as an anti-adhesive and 1.3% of sodium stearyl fumarate as a lubricant.
8. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 7, comprising the steps of:
s1, preparing raw material auxiliary materials and sieving: weighing materials according to the formula of the pharmaceutical composition, and sieving for standby;
s2, preparing an adhesive solution: adding purified water and an adhesive into a liquid preparation barrel, and mixing for later use;
s3, granulating: the active ingredients, the disintegrating agent, the filler, the anti-adhesion agent and the disintegrating auxiliary agent which are treated in the step S1 are sent into a granulator for dry mixing treatment; then adding the adhesive solution prepared in the step S2, and granulating;
s4, drying: the materials in the step S3 are sent into a fluidized bed for drying treatment;
s5, finishing: finishing the dry material particles obtained in the step S4;
s6, mixing: on the basis of S5, adding an anti-adhesive agent, mixing and sieving, and adding a disintegrating agent, mixing and sieving;
s7, lubrication: on the basis of S6, adding a lubricant, mixing and sieving to finish lubrication;
s8, tabletting: and (3) carrying out tabletting treatment on the lubricated material on the basis of S7 to obtain the pharmaceutical composition.
9. The method for preparing the pharmaceutical composition according to claim 8, wherein the specific steps are as follows:
S1, preparing raw material auxiliary materials and sieving: microcrystalline cellulose, lactose and croscarmellose sodium are respectively sieved by a high-energy sieving machine through a 30-mesh sieve, sodium chloride is crushed by a high-speed crusher and then manually sieved by a 60-mesh sieve, active compounds and colloidal silicon dioxide are combined in a medicinal low-density polyethylene bag and manually turned and primarily mixed, and then the mixture is sieved by the high-energy sieving machine through the 60-mesh sieve for 2 times;
s2, preparing an adhesive solution: adding normal-temperature purified water into a liquid preparation barrel, starting stirring, slowly adding polyethylene glycol 4000, continuing stirring for 1-2 hours after the addition, and stopping stirring when no obvious insoluble substances are visually detected;
s3, granulating: stirring paddle rotation speed is 75rpm-120rpm, cutter rotation speed is 1450rpm-1550rpm, adhesive solution is uniformly added, adhesive adding time is controlled to be 120-180 seconds, stirring and cutting granulation are continued for 180 seconds after adhesive adding, aperture of wet granule finishing screen is 10mm x 10mm, and finishing rotation speed is 250rpm-350rpm, and discharging is carried out while finishing granules;
s4, drying: the obtained tablet is dried by fluidized bed, the air inlet temperature of the fluidized bed is 50-80 ℃, and the air inlet quantity is 700-900m 3 And (3) discharging after the moisture is less than or equal to 3.0%.
S5, finishing: the pore diameter of the granule finishing screen is 0.6mm, and the granule finishing rotating speed is 300-400rpm;
S6, mixing: adding crosslinked sodium carboxymethyl cellulose after finishing, manually sieving with a 30-mesh sieve, adding colloidal silica into the obtained dry particles, mixing, sieving with a 30-mesh sieve for 10-15min, and mixing at 10-20 rpm;
s7, lubrication: adding sodium stearyl fumarate into the mixed materials, mixing, sieving with 60 meshes, mixing for 3-5min at 10-20rpm, and lubricating and mixing;
s8, tabletting: the method is characterized in that phi 8.0mm circular punching is adopted, the tabletting speed is 30-60 kilo tablets/hour, the rotating speed of a blanking device is 20-40rpm, the average value of main pressure is 3.8-4.2KN, the thickness of the main pressure edge of a tablet is 2.0-3.0mm, the thickness of the pre-pressed edge is 2.5-3.5mm, the filling depth is 6.0-8.0mm, the average value of hardness is controlled to be 40-75N, and the single value is controlled to be 30-100N.
10. Use of a pharmaceutical composition according to any one of claims 1-7 or a pharmaceutical composition prepared by a method according to any one of claims 8-9 in the manufacture of a medicament for the treatment of lung cancer.
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