CN117547536A - A pharmaceutical composition, its preparation method and application - Google Patents

A pharmaceutical composition, its preparation method and application Download PDF

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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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mixing
pharmaceutical composition
adhesive
sodium
sieving
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李庆翔
张辉
徐晖
万亚君
沈伟
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Shanghai Allist Pharmaceuticals Inc
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Shanghai Allist Pharmaceuticals Inc
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    • 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
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    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Abstract

本发明公开了一种药物组合物、其制备方法及应用，提供了一种含活性成分N‑{2‑{[2‑(二甲胺基)乙基](甲基)胺基}‑6‑(2,2,2‑三氟乙氧基)‑5‑{[4‑(1‑甲基‑1H‑吲哚‑3‑基)嘧啶‑2‑基]胺基}吡啶‑3‑基}丙烯酰胺或其药学上可接受的盐以及至少一种药学上可接受的辅料的药物组合物，该药物组合物具有良好的稳定性、药物溶出度，以及更好的药效学和药代动力学优势，制备工艺简单，适宜工业化生产。The invention discloses a pharmaceutical composition, its preparation method and application, and provides a pharmaceutical composition containing active ingredient N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6 ‑(2,2,2‑trifluoroethoxy)‑5‑{[4‑(1‑methyl‑1H‑indol‑3‑yl)pyrimidin‑2‑yl]amino}pyridin‑3‑yl }A pharmaceutical composition of acrylamide or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The pharmaceutical composition has good stability, drug dissolution, and better pharmacodynamics and pharmacokinetics. It has kinetic advantages, simple preparation process and is suitable for industrial production.

Description

Pharmaceutical composition, preparation method and application thereof
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)

1.一种药物组合物，其特征在于，包括作为活性成分的N-{2-{[2-(二甲胺基)乙基](甲基)胺基}-6-(2,2,2-三氟乙氧基)-5-{[4-(1-甲基-1H-吲哚-3-基)嘧啶-2-基]胺基}吡啶-3-基}丙烯酰胺的甲磺酸盐，以及填充剂、崩解剂、粘合剂、抗粘合剂、崩解助剂和润滑剂；1. A pharmaceutical composition, characterized in that it includes N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2, Methanesulfonate of 2-trifluoroethoxy)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide acid salts, as well as fillers, disintegrants, binders, anti-binders, disintegration aids and lubricants; 所述药物组合物重量百分含量为10％-50％活性成分、30％-70％填充剂、5％-10％崩解剂、1％-10％抗粘合剂、7％-8.5％粘合剂、1％-10％崩解助剂、1％-5％润滑剂。The weight percentage of the pharmaceutical composition is 10%-50% active ingredient, 30%-70% filler, 5%-10% disintegrant, 1%-10% anti-adhesive, 7%-8.5% Binder, 1%-10% disintegration aid, 1%-5% lubricant. 2.根据权利要求1所述的药物组合物，其特征在于，所述填充剂为微晶纤维素和乳糖，所述微晶纤维素和乳糖的质量比(mg:mg)为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。2. The pharmaceutical composition according to claim 1, wherein the filler is microcrystalline cellulose and lactose, and the mass ratio (mg:mg) of the microcrystalline cellulose and lactose is 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.根据权利要求1所述的药物组合物，其特征在于，所述崩解剂为羟乙酸淀粉钠、羧甲基淀粉钠、玉米淀粉、低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、交联羧甲基纤维素、甲基纤维素、预胶化淀粉、海藻酸钠中的一种或多种。3. The pharmaceutical composition according to claim 1, wherein the disintegrant is sodium starch glycolate, sodium carboxymethyl starch, corn starch, low-substituted hydroxypropyl cellulose, or cross-linked povidone. , one or more of croscarmellose sodium, croscarmellose, methylcellulose, pregelatinized starch, and sodium alginate. 4.根据权利要求1所述的药物组合物，其特征在于，所述粘合剂为聚乙二醇4000，所述崩解助剂为氯化钠。4. The pharmaceutical composition according to claim 1, wherein the binder is polyethylene glycol 4000 and the disintegration aid is sodium chloride. 5.根据权利要求1所述的药物组合物，其特征在于，所述抗粘合剂为粉状纤维素、三硅酸镁、胶态二氧化硅、二氧化硅、滑石粉中的一种或多种。5. The pharmaceutical composition according to claim 1, wherein the anti-adhesive agent is one of powdered cellulose, magnesium trisilicate, colloidal silicon dioxide, silicon dioxide, and talc. or more. 6.根据权利要求1所述的药物组合物，其特征在于，所述润滑剂为硬脂酸、硬脂酸镁、硬脂酸钠、硬脂酸钙、硬脂酸锌、单硬脂酸甘油酯、二硬脂酸甘油酯、三硬脂酸甘油酯、豆蔻酸、棕榈酸、硬脂富马酸钠、滑石粉、氢化植物油、矿物油中的一种或多种。6. pharmaceutical composition according to claim 1, is characterized in that, described lubricant is stearic acid, magnesium stearate, sodium stearate, calcium stearate, zinc stearate, monostearic acid One or more of glyceryl ester, glyceryl distearate, glyceryl tristearate, myristic acid, palmitic acid, sodium stearyl fumarate, talc, hydrogenated vegetable oil, and mineral oil. 7.根据权利要求1所述的药物组合物，其特征在于，所述药物组合物由下列重量百分比的成份组成：内加活性成分式(Ⅰ)化合物甲磺酸盐22.0％，内加填充剂微晶纤维素21.0％以及乳糖32.0％，内加崩解剂交联羧甲基纤维素钠3.05％，内加粘合剂聚乙二醇40008.4％，内加抗粘合剂胶态二氧化硅3.05％，内加崩解助剂氯化钠4.1％，外加崩解剂交联羧甲基纤维素钠3.05％，外加抗粘合剂胶态二氧化硅2.05％，外加润滑剂硬脂富马酸钠1.3％。7. The pharmaceutical composition according to claim 1, characterized in that the pharmaceutical composition is composed of the following weight percentages: 22.0% of the active ingredient formula (I) compound mesylate, and a filler. Microcrystalline cellulose 21.0% and lactose 32.0%, with disintegrant croscarmellose sodium 3.05%, adhesive polyethylene glycol 40008.4%, and anti-adhesive colloidal silica 3.05%, with 4.1% disintegration aid sodium chloride, 3.05% disintegration agent croscarmellose sodium, 2.05% anti-adhesive colloidal silica, and lubricant stearyl fumar Sodium acid 1.3%. 8.一种药物组合物的制备方法，用于制备权利要求1-7任意一项所述的药物组合物，其特征在于，包括以下步骤：8. A method for preparing a pharmaceutical composition, used to prepare the pharmaceutical composition according to any one of claims 1 to 7, characterized in that it includes the following steps: S1、原料辅料备料过筛：根据药物组合物配方称取物料过筛，备用；S1. Preparation and screening of raw materials and excipients: Weigh the materials according to the pharmaceutical composition formula and screen them for later use; S2、粘合剂溶液配制：在配液桶中加入纯化水和粘合剂，混合，备用；S2. Preparation of adhesive solution: Add purified water and adhesive to the liquid preparation bucket, mix and set aside; S3、制粒：将S1中处理好的活性成分、崩解剂、填充剂、抗粘接剂、崩解助剂送入制粒机先进行干混处理；然后加入S2中制备好粘合剂溶液，进行制粒；S3. Granulation: Send the active ingredients, disintegrants, fillers, anti-adhesive agents, and disintegration aids processed in S1 into the granulator for dry mixing; then add them to S2 to prepare the adhesive. solution for granulation; S4、干燥：将S3中的物料送入流化床进行干燥处理；S4. Drying: Send the materials in S3 into the fluidized bed for drying; S5、整粒：将S4中所得干燥物料颗粒进行整粒；S5. Granulation: Segment the dry material particles obtained in S4; S6、混合：在S5的基础上，先外加抗粘接剂进行混合并过筛，后外加崩解剂进行混合并过筛；S6. Mixing: On the basis of S5, first add an anti-adhesive agent for mixing and sieving, and then add a disintegrant for mixing and sieving; S7、润滑：在S6的基础上，加入润滑剂进行混合并过筛，完成润滑；S7. Lubrication: On the basis of S6, add lubricant for mixing and screening to complete lubrication; S8、压片：在S7的基础上，将完成润滑的物料进行压片处理得到所述药物组合物。S8. Tablet compression: On the basis of S7, the lubricated material is compressed to obtain the pharmaceutical composition. 9.根据权利要求8所述的药物组合物的制备方法，其特征在于，具体步骤为：9. The preparation method of pharmaceutical composition according to claim 8, characterized in that, the specific steps are: S1、原料辅料备料过筛：微晶纤维素、乳糖、交联羧甲基纤维素钠分别用高能筛分机过30目筛，氯化钠用高速粉碎机粉碎后手工过60目筛，活性化合物与胶态二氧化硅合并于药用低密度聚乙烯袋中手工翻动初混，再用高能筛分机过60目筛2遍；S1. Preparation and sieving of raw materials and auxiliary materials: microcrystalline cellulose, lactose, and croscarmellose sodium were passed through a 30-mesh sieve with a high-energy sieving machine. Sodium chloride was crushed with a high-speed pulverizer and passed through a 60-mesh sieve manually. The active compound Combine it with colloidal silica in a medicinal low-density polyethylene bag and stir it by hand for initial mixing, then pass it through a 60-mesh sieve twice with a high-energy screening machine; S2、粘合剂溶液配制：常温纯化水先加入到配液桶中，开启搅拌，再缓慢加入聚乙二醇4000，加料结束后继续搅拌时间1-2小时，且目测无明显不溶物时停止搅拌；S2. Preparation of adhesive solution: First add purified water at room temperature into the liquid preparation bucket, start stirring, then slowly add polyethylene glycol 4000, continue stirring for 1-2 hours after the addition, and stop stirring when there is no obvious insoluble matter visually. ; S3、制粒：搅拌桨转速75rpm-120rpm，切割刀转速1450rpm-1550rpm，均匀加入粘合剂溶液，粘合剂加入时间控制在120-180秒，粘合剂加入后，继续搅拌并切割制粒180秒，湿颗粒整粒筛网孔径10mm*10mm，整粒转速250rpm-350rpm边整粒边出料；S3. Granulation: The stirring paddle rotates at 75rpm-120rpm, the cutting knife rotates at 1450rpm-1550rpm, and the binder solution is evenly added. The binder addition time is controlled at 120-180 seconds. After the binder is added, continue stirring and cutting for granulation. 180 seconds, wet granule screening screen aperture 10mm*10mm, granulation speed 250rpm-350rpm while granulating and discharging; S4、干燥：制得的片粒通过流化床干燥后，流化床进风温度50-80℃，进风风量为700-900m3/h，水分≤3.0％后出料。S4. Drying: After the prepared tablets are dried through the fluidized bed, the inlet air temperature of the fluidized bed is 50-80°C, the inlet air volume is 700-900m 3 /h, and the moisture content is ≤3.0% before being discharged. S5、整粒：整粒筛网孔径为0.6mm，整粒转速300-400rpm；S5. Granulation: The aperture of the granulation screen is 0.6mm, and the granulation speed is 300-400rpm; S6、混合：在整粒后加入交联羧甲基纤维素钠手工过30目筛，得到的干颗粒再加胶态二氧化硅混合后再过30目筛，时间10-15min和混合转速10-20rpm混合；S6. Mixing: After granulation, add croscarmellose sodium and manually pass through a 30-mesh sieve. The obtained dry particles are mixed with colloidal silica and then passed through a 30-mesh sieve. The time is 10-15 minutes and the mixing speed is 10 -20rpm mixing; S7、润滑：混合后物料加硬脂富马酸钠混合后再过60目，混合时间3-5min和混合转速10-20rpm，进行润滑混合；S7. Lubrication: The mixed materials are mixed with sodium stearyl fumarate and then passed through 60 mesh. The mixing time is 3-5min and the mixing speed is 10-20rpm for lubrication and mixing; S8、压片：采用φ8.0mm圆形冲，压片速度在30-60千片/小时，下料器转速20-40rpm、主压力均值3.8-4.2KN、药片主压边缘厚度2.0-3.0mm、预压边缘厚度2.5-3.5mm、填充深度6.0-8.0mm，硬度均值控制在40-75N，单值控制在30-100N。S8. Tablet pressing: using φ8.0mm circular punch, the tableting speed is 30-60 thousand tablets/hour, the feeder speed is 20-40rpm, the average main pressure is 3.8-4.2KN, and the tablet main pressure edge thickness is 2.0-3.0mm , The pre-pressed edge thickness is 2.5-3.5mm, the filling depth is 6.0-8.0mm, the average hardness is controlled at 40-75N, and the single value is controlled at 30-100N. 10.权利要求1-7任意一项所述的药物组合物或权利要求8-9任一项所述的方法制备得到的药物组合物在制备治疗肺癌的药物中的应用。10. Use of the pharmaceutical composition according to any one of claims 1 to 7 or the pharmaceutical composition prepared by the method according to any one of claims 8 to 9 in the preparation of drugs for the treatment of lung cancer.
CN202311520705.1A 2023-11-15 2023-11-15 A pharmaceutical composition, its preparation method and application Pending CN117547536A (en)

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CN107163026A (en) * 2016-03-07 2017-09-15 上海艾力斯医药科技有限公司 Salt of pyridine amine pyrimidine derivates and its preparation method and application
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CN107163027A (en) * 2016-03-07 2017-09-15 上海艾力斯医药科技有限公司 Crystalline form of pyridylaminopyrimidine derivative mesylate and its preparation and application
CN107163026A (en) * 2016-03-07 2017-09-15 上海艾力斯医药科技有限公司 Salt of pyridine amine pyrimidine derivates and its preparation method and application
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