CN103006664B - One has the inhibiting pharmaceutical composition of tyrosine protein kinase - Google Patents
One has the inhibiting pharmaceutical composition of tyrosine protein kinase Download PDFInfo
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- CN103006664B CN103006664B CN201110283447.0A CN201110283447A CN103006664B CN 103006664 B CN103006664 B CN 103006664B CN 201110283447 A CN201110283447 A CN 201110283447A CN 103006664 B CN103006664 B CN 103006664B
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Abstract
The invention belongs to medical art, the invention discloses a kind of containing active component (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2, the pharmaceutical composition of 3-dihydroindene-5 amide sesquisulfates, this pharmaceutical composition be with dissolution etc. for research index, determined by the test of science.
Description
Technical field
The invention belongs to medical art, be specifically related to one and there is the inhibiting pharmaceutical composition of tyrosine protein kinase.
Background technology
Tyrosine kinase the phosphate of adenosine triphosphate is transferred to the enzyme on protein on specific tyrosine residue.Protein is once after being phosphorylated, and it is with regard to activation signal pathway, plays crucial effect, comprise Growth of Cells, metabolism, differentiation and death to various bioprocess.Normal tyrosine kinase activity in vivo controls by tight, that is it when when this phosphorylating protein should not carry out by phosphorylating protein rhythmically, result is that the growth of cell is strictly controlled.But the tyrosine kinase activity in vivo of abnormal or too much expression just loses control, it can phosphorylating protein continuously, and result is activation signal pathway continuously, the growth of cell is unrestrictedly carried out, causes the generation of tumor.
The new drug developed based on this mechanism gone on the market has imatinib (imatinib), commodity are called imatinib mesylate (gleevec), nilotinib (nilotinib), and commodity are called Ta Xina (Tasigna), Dasatinib (dasatinib), commodity are called Sprycel.These three medicines are all Bcr-Abl tyros kinase inhibitor, verified clinically, and they can treat chronic myelocytic leukemia and acute lymphoblastic leukemia effectively.
Patent WO2010072166 discloses the tyrosine protein kinase inhibitor of all new generation: dihydroindene amides compound, description embodiment 16 discloses (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, embodiment D discloses the inhibitory action of this compound to K562, KU812, MEG-01, Kasumi-1 and Sup-B15 cell strain; But this patent is not studied this compound formulation technology.
Summary of the invention
For these reasons, the applicant has determined containing active component (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2, the pharmaceutical composition that 3-dihydroindene-5 amide sesquisulfates are new, this pharmaceutical composition take dissolution as index, is determined by the experimental study of science.
The present invention is achieved through the following technical solutions.
One has the inhibiting pharmaceutical composition of tyrosine protein kinase, and pharmaceutical composition contains type I compound:
（Ⅰ）。
This compound chinesization formal name used at school: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates.
This compound English language Chemical name:
1(S)-1-(4-Methylpiperazin-1-yl)-N-{4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl}indane-5-carboxamidesesquisulfate。
Also containing filler and disintegrating agent in aforementioned pharmaceutical compositions.Aforementioned pharmaceutical compositions can also contain filler and disintegrating agent, adds or does not add lubricant.
Aforementioned pharmaceutical compositions is preferably: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 1-10 weight portions, filler 5-65 weight portion, disintegrating agent 0.3-3.5 weight portion, lubricant 0.05-1 weight portion.
Aforementioned pharmaceutical compositions is preferably: (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 1-10 weight portions, filler 5-65 weight portion, disintegrating agent 0.3-3.5 weight portion.
Filler described above includes but not limited to following: one or more in lactose, microcrystalline Cellulose, corn starch, pregelatinized Starch, mannitol, sorbitol, calcium hydrogen phosphate, calcium sulfate.
Disintegrating agent described above includes but not limited to following: one or more in low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, carboxymethylcellulose calcium.
Lubricant described above includes but not limited to following: one or more in magnesium stearate, Pulvis Talci, micropowder silica gel, Macrogol 4000, polyethylene glycol 6000.
The pharmaceutical preparation that there is the inhibiting pharmaceutical composition of tyrosine protein kinase and prepare described above.
Pharmaceutical preparation described above includes but not limited to tablet or capsule.
During tablet described above 30 minutes, dissolution is more than or equal to 80% and is less than or equal to 100%.
Tablet described above 30 minutes dissolutions are more than or equal to 90% and are less than 100%.
The preparation method of tablet described above includes but not limited to following:
Get (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, filler, disintegrating agent mix homogeneously, with water soft material, granulate, add lubricant, mix homogeneously, tabletting, to obtain final product.
The preparation method of tablet described above includes but not limited to following:
Get (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2, the disintegrating agent mix homogeneously of 3-dihydroindene-5 amide sesquisulfates, filler, 80%-90% weight, with water soft material, granulate, add residue disintegrating agent and lubricant, mix homogeneously, tabletting, to obtain final product.
One, preparation prescription research
In pharmaceutical composition of the present invention, active component is novel compounds, does not have preparation prescription bibliographic reference, and applicant is that index carries out preliminary study with dissolution.
(1) preliminary experiment
Prescription 1(is according to 100 tablet recipe amounts): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 1g, filler lactose 4g, disintegrating agent carboxymethyl base Starch Sodium 1g, binding agent 3%HPMC aqueous solution 0.7ml, magnesium stearate lubricant 0.3g.
Prescription 2(is according to 100 tablet recipe amounts): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 1g, filler lactose 4g, disintegrating agent carboxymethyl base Starch Sodium 1g, binding agent 5%HPMC aqueous solution 0.5ml, magnesium stearate lubricant 0.3g.
Prescription 3(is according to 100 tablet recipe amounts): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 1g, filler lactose 4g, disintegrating agent carboxymethyl base Starch Sodium 1g, binding agent 5% PVP K30 aqueous solution 0.8ml, magnesium stearate lubricant 0.3g.
Test method:
Prepared by preparation: get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates are mixed homogeneously with lactose, carboxymethyl starch sodium, binding agent soft material, granulate, add lubricant, tabletting.
Dissolution determination method: according to dissolution method (Chinese Pharmacopoeia 2010 editions annex XC second methods), 1000ml water is dissolution medium, rotating speed is 75rpm, operate in accordance with the law, after 30min or 45min, get solution with 0.45 μm of filtering with microporous membrane, precision measures in subsequent filtrate 2.5ml to 10ml measuring bottle, and distilled water is settled to scale, shaking up, is need testing solution.Another precision takes (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate reference substances are about 10mg, accurately weighed, put in 100ml measuring bottle, add water and make dissolving, add water to scale, shake up, precision measures in 5ml to 50ml measuring bottle, is settled to scale with water, is reference substance solution.According to UV-VIS spectrophotometry, measure the trap of need testing solution and reference substance solution in 257nm place, external standard method calculates the stripping quantity of every sheet.
Result of the test: in table 1.
Table 1 trial test result
Result of the test: above-mentioned result of the test shows, when the HPMC aqueous solution using 3% and 5% and 5% PVP K30 aqueous solution are granulated as binding agent, all have sticky sieve phenomenon, when prescription 2 is granulated, sticky sieve is more serious, causes pelletization difficulty.And the dissolution of prescription tablet is all defective.In process of the test, find that active component itself is met glassware for drinking water and had certain viscosity in addition, therefore, considering not add binding agent in follow-up test, is directly wetting agent soft material with water.
(2) preparation prescription test
1, prescribed study 1
Prescription 1(is according to 100 tablet recipe amounts): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 1g, filler pregelatinized Starch 4g, disintegrating agent low-substituted hydroxypropyl cellulose 1g, lubricant Pulvis Talci 0.03g.
Prescription 2(is according to 100 tablet recipe amounts): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 1g, filler pregelatinized Starch 5g, disintegrating agent low-substituted hydroxypropyl cellulose 0.3g, lubricant indurated talc powder 0.06g.
Prescription 3(is according to 100 tablet recipe amounts): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 4g, filler pregelatinized Starch 24.5g, disintegrating agent low-substituted hydroxypropyl cellulose 1.35g, lubricant indurated talc powder 0.3g.
Prepared by preparation: get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates are mixed homogeneously with pregelatinized Starch, low-substituted hydroxypropyl cellulose, add water appropriate granulation, add lubricant, tabletting.
Dissolution determination method: identical with preliminary experiment dissolution.
Result of the test: in table 2.
Table 2 prescribed study 1 result
Conclusion (of pressure testing): above-mentioned test shows, the preparation prescription dissolution not adding binding agent improves, but prescription 1 dissolution is still undesirable, and after prescription 2 and prescription 3 adjust the consumption of adjuvant, dissolution meets the requirements; Above-mentioned prescription is moderate in formulation process medium viscosity, not sticky sieve phenomenon; But prescription 2 and prescription 3 dissolution are not very good, and applicant on this basis, continues preparation prescription optimization.
2, prescribed study 2
Preparation prescription 1(is according to 100 tablet recipe amounts): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 8g, filler lactose 24.5g, microcrystalline Cellulose 37g, disintegrating agent low-substituted hydroxypropyl cellulose 3.2g, lubricant Macrogol 4000 0.85g.
Preparation prescription 2(is according to 100 tablet recipe amounts): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 8g, filler lactose 24.5g, microcrystalline Cellulose 37g, disintegrating agent cross-linking sodium carboxymethyl cellulose 3.3g, lubricant Pulvis Talci 0.9g.
Preparation prescription 3(is according to 100 tablet recipe amounts): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 8g, filler lactose 24.5g, microcrystalline Cellulose 37g, disintegrating agent polyvinylpolypyrrolidone 3.0g, lubricant Pulvis Talci 0.9g.
Prepared by preparation: get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates are mixed homogeneously with filler, disintegrating agent, add water appropriate granulation, add lubricant, tabletting.
Dissolution determination method: identical with preliminary experiment dissolution.
Result of the test: in table 3.
Table 3 prescribed study 2 result
Conclusion (of pressure testing): above-mentioned test shows, after using composite filler, the dissolution of preparation reaches requirement in 30 minutes, 45 minutes, but dissolution is not very good, and on this basis, applicant continues to optimize preparation prescription on this basis.
3, prescribed study 3
Preparation prescription 1(is according to 100 tablet recipe amounts): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 1g, filler lactose 1.7g, microcrystalline Cellulose 4g, pregelatinized Starch 0.38g, disintegrating agent carboxymethyl base Starch Sodium 0.34g, magnesium stearate lubricant 0.08g.
Preparation prescription 2(is according to 100 tablet recipe amounts): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 1g, filler lactose 1.7g, microcrystalline Cellulose 4g, mannitol 0.40g, disintegrating agent low-substituted hydroxypropyl cellulose 0.35g, magnesium stearate lubricant 0.08g.
Preparation prescription 3(is according to 100 tablet recipe amounts): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 1g, filler lactose 1.7g, microcrystalline Cellulose 4g, mannitol 0.40g, disintegrating agent low-substituted hydroxypropyl cellulose 0.25g, polyvinylpolypyrrolidone 0.30g, magnesium stearate lubricant 0.08g.
Prepared by preparation: get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates are mixed homogeneously with filler, disintegrating agent, add water appropriate granulation, add lubricant, tabletting.
Dissolution determination method: identical with preliminary experiment dissolution.
Result of the test: in table 4.
Table 4 prescribed study 3 result
Conclusion (of pressure testing): above-mentioned test shows, dissolution reached more than 90% at 30 minutes, and in order to obtain better dissolution, applicant wishes, by adjustment formulation preparation method, to reach better dissolution.
4, formulation preparation method test
Preparation prescription (according to 100 tablet recipe amounts): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 1g, filler lactose 1.7g, microcrystalline Cellulose 4.00g, pregelatinized Starch 0.34g, disintegrating agent carboxymethyl base Starch Sodium 0.34g, magnesium stearate lubricant 0.08g.
Preparation method 1: get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, filler, 0.33g disintegrating agent mix homogeneously, with water soft material, granulate, add residue 0.01g disintegrating agent, add lubricant, mix homogeneously, tabletting, to obtain final product.
Preparation method 2: get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, filler, 0.306g disintegrating agent mix homogeneously, with water soft material, granulate, add residue 0.024g disintegrating agent, add lubricant, mix homogeneously, tabletting, to obtain final product.
Preparation method 3: get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, filler, 0.289g disintegrating agent mix homogeneously, with water soft material, granulate, add residue 0.051g disintegrating agent, add lubricant, mix homogeneously, tabletting, to obtain final product.
Preparation method 4: get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, filler, 0.272g disintegrating agent mix homogeneously, with water soft material, granulate, add residue 0.068g disintegrating agent, add lubricant, mix homogeneously, tabletting, to obtain final product.
Dissolution determination method: identical with preliminary experiment dissolution.
Result of the test: in table 5.
Table 5 preparation method result of the test
Conclusion (of pressure testing): above-mentioned test shows, the dissolution that preparation method 1 obtains tablet changes not quite with test 3 dissolution results, and the Dissolution of Tablet that preparation method 2 to preparation method 4 prepares is close to 100%, therefore, applicant determines the preparation method of additional disintegrating agent, and additional disintegrating agent accounts for whole disintegrating agent weight 10%-20%, the result of extraction of tablet is best.
Two, stability study test
Test specimen: the tablet that embodiment 6 preparation method 2 obtains.
Investigation condition and sample time: illumination (4500 ± 500Lux); High temperature (60 DEG C); High humility (RH75%); High humility (RH92.5%).Sample under these conditions, nakedly to be put, in 0,5,10 day sample analysis.
(1) related substance
The fine powder getting this product is appropriate, add mobile phase dissolve and make in every 1ml about containing (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2, the solution of 3-dihydroindene-5 amide sesquisulfate 0.2mg, filter, getting subsequent filtrate is need testing solution; Precision measures test sample 1.0ml, puts in 100ml measuring bottle, is diluted to scale with mobile phase, shake up, in contrast solution.According to the chromatographic condition under assay item, and determined wavelength is adjusted to 220nm by 265nm, precision measures contrast solution 20 μ l injection liquid chromatography, regulate detection sensitivity, main constituent chromatograph peak height is made to be about 20% of full scale, precision measures need testing solution and each 20 μ l of contrast solution, respectively injection liquid chromatography, and record chromatogram is to 3 times of main constituent retention time.The peak area of single contaminant must not be greater than 0.5 times (0.5%) of contrast solution main peak area, each impurity peak area and the main peak area (1.0%) of contrast solution must not be greater than.
(2) dissolution
Get this product, according to dissolution method (Chinese Pharmacopoeia 2010 editions annex XC second methods), 1000ml water is dissolution medium, rotating speed is 75rpm, operates in accordance with the law, gets solution with 0.45 μm of filtering with microporous membrane after 30min, precision measures in subsequent filtrate 2.5ml to 10ml measuring bottle, distilled water is settled to scale, shakes up, and is need testing solution.Another precision takes (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate reference substances are about 10mg, accurately weighed, put in 100ml measuring bottle, add water and make dissolving, add water to scale, shake up, precision measures in 5ml to 50ml measuring bottle, is settled to scale with water, is reference substance solution.According to UV-VIS spectrophotometry, measure the trap of need testing solution and reference substance solution in 257nm place, external standard method calculates the stripping quantity of every sheet.
(3) assay adopts high performance liquid chromatography
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; Immobile phase: anti-phase C18 post (CAPCELLPAKC18, MG II, 5 μm, 4.6 × 150mm, Shiseido); Mobile phase: acetonitrile-water (0.5% triethylamine, phosphoric acid adjust ph to 6.5) (35:65); Other: determined wavelength is 265nm, and flow velocity is 1.0ml/min, and column temperature is 30 DEG C, and sample size is 20 μ l.(1S) separating degree at-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate peak-to-peaks and other impurities peak should meet the requirements.
Algoscopy: get this product, porphyrize, precision takes powder formulation and (is about equivalent to (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2 in right amount, 3-dihydroindene-5 amide sesquisulfate 10mg) to 50ml measuring bottle, add mobile phase ultrasonic dissolution and be diluted to scale, shake up, filter with 0.45 μm of microporous filter membrane, discard just filtrate, get subsequent filtrate, the accurate subsequent filtrate 2ml that draws, in 10ml measuring bottle, adds mobile phase and is settled to scale, shake up.The accurate 20 μ l that draw, in high performance liquid chromatograph, record peak area.Separately get (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate reference substances are appropriate, accurately weighed, add mobile phase dissolve and be quantitatively diluted to the solution containing 40 μ g in every 1ml, be measured in the same method, calculate, to obtain final product.
Investigate result:
This product through the influence factor such as high temperature, high humidity, exposure experiments to light test, separated in time sample analysis, analysis result and 0 day data and trace analysis.
Specific experiment the results are shown in Table 6.
Table 6 influence factor result of the test
Result shows that this product is under high temperature, high humidity and exposure experiments to light condition, and outward appearance has no change, and content has no reduction, and under each condition, content has no remarkable decline, but related substance has the trend of increase, and prompting this product should pack.
Three, embodiment is prepared
Embodiment 1
Pharmaceutical composition is (1000 preparation unit amount): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 10g, filler pregelatinized Starch 64g, disintegrating agent low-substituted hydroxypropyl cellulose 3.1g, lubricant Pulvis Talci 0.95g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, pregelatinized Starch, low-substituted hydroxypropyl cellulose mix homogeneously, with water soft material, granulate, add lubricant Pulvis Talci mix homogeneously, tabletting, to obtain final product.
Or, get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, pregelatinized Starch, 2.6g low-substituted hydroxypropyl cellulose mix homogeneously, with water soft material, granulate, add 0.5g low-substituted hydroxypropyl cellulose, add lubricant Pulvis Talci, mix homogeneously, tabletting, to obtain final product.
Embodiment 2
Pharmaceutical composition is (1000 preparation unit amount): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 40g, filler pregelatinized Starch 248g, disintegrating agent low-substituted hydroxypropyl cellulose 13.3g, lubricant indurated talc powder 3g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, pregelatinized Starch, low-substituted hydroxypropyl cellulose mix homogeneously, with water soft material, granulate, add lubricant Pulvis Talci mix homogeneously, tabletting, to obtain final product.
Or, get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, pregelatinized Starch, 11g low-substituted hydroxypropyl cellulose mix homogeneously, with water soft material, granulate, add 2.3g low-substituted hydroxypropyl cellulose, add lubricant Pulvis Talci, mix homogeneously, tabletting, to obtain final product.
Embodiment 3
Pharmaceutical composition (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 80g, filler lactose 246g, microcrystalline Cellulose 372g, disintegrating agent low-substituted hydroxypropyl cellulose 32.4g, lubricant polyethylene glycol 6000 8.7g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose mix homogeneously, with water soft material, granulate, add lubricant polyethylene glycol 6000 mix homogeneously, tabletting, to obtain final product.
Or, get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, 26g low-substituted hydroxypropyl cellulose mix homogeneously, with water soft material, granulate, add 6.4g low-substituted hydroxypropyl cellulose, add lubricant polyethylene glycol 6000, mix homogeneously, tabletting, to obtain final product.
Embodiment 4
Pharmaceutical composition (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 80g, filler lactose 241g, microcrystalline Cellulose 370g, disintegrating agent cross-linking sodium carboxymethyl cellulose 33g, lubricant Pulvis Talci 8.5g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose mix homogeneously, with water soft material, granulate, add lubricant Pulvis Talci mix homogeneously, tabletting, to obtain final product.
Or, get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, 28g cross-linking sodium carboxymethyl cellulose mix homogeneously, with water soft material, granulate, add 5g cross-linking sodium carboxymethyl cellulose, add lubricant Pulvis Talci, mix homogeneously, tabletting, to obtain final product.
Embodiment 5
Pharmaceutical composition (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 80g, filler lactose 245g, microcrystalline Cellulose 376g, disintegrating agent polyvinylpolypyrrolidone 32.8g, lubricant Pulvis Talci 9g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, polyvinylpolypyrrolidone mix homogeneously, with water soft material, granulate, add lubricant Pulvis Talci mix homogeneously, tabletting, to obtain final product.
Or, get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, 27.9g polyvinylpolypyrrolidone mix homogeneously, with water soft material, granulate, add 4.9g polyvinylpolypyrrolidone, add lubricant Pulvis Talci, mix homogeneously, tabletting, to obtain final product.
Embodiment 6
Pharmaceutical composition (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 10g, filler lactose 17g, microcrystalline Cellulose 40g, pregelatinized Starch 3.8g, disintegrating agent carboxymethyl base Starch Sodium 3.4g, magnesium stearate lubricant 0.8g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, pregelatinized Starch, carboxymethyl starch sodium mix homogeneously, with water soft material, granulate, add magnesium stearate lubricant mix homogeneously, tabletting, to obtain final product.
Or, get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, pregelatinized Starch, 2.9g carboxymethyl starch sodium mix homogeneously, with water soft material, granulate, add 0.5g carboxymethyl starch sodium, add magnesium stearate lubricant, mix homogeneously, tabletting, to obtain final product.
Embodiment 7
Pharmaceutical composition (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 10g, filler lactose 17g, microcrystalline Cellulose 40g, mannitol 4g, disintegrating agent low-substituted hydroxypropyl cellulose 3.5g, magnesium stearate lubricant 0.8g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, mannitol, low-substituted hydroxypropyl cellulose mix homogeneously, with water soft material, granulate, add magnesium stearate lubricant mix homogeneously, tabletting, to obtain final product.
Or, get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, mannitol, 2.8g low-substituted hydroxypropyl cellulose mix homogeneously, with water soft material, granulate, add 0.6g low-substituted hydroxypropyl cellulose, add magnesium stearate lubricant, mix homogeneously, tabletting, to obtain final product.
Embodiment 8
Pharmaceutical composition (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 10g, filler lactose 17g, microcrystalline Cellulose 40g, mannitol 4.2g, disintegrating agent low-substituted hydroxypropyl cellulose 2.5g, polyvinylpolypyrrolidone 1g, magnesium stearate lubricant 0.8g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, mannitol, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone mix homogeneously, with water soft material, granulate, add magnesium stearate lubricant mix homogeneously, tabletting, to obtain final product.
Or, get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, mannitol, 2g low-substituted hydroxypropyl cellulose, 0.85g polyvinylpolypyrrolidone mix homogeneously, with water soft material, granulate, add 0.5g low-substituted hydroxypropyl cellulose and 0.15g polyvinylpolypyrrolidone, add magnesium stearate lubricant, mix homogeneously, tabletting, to obtain final product.
Embodiment 9
Pharmaceutical composition is (1000 preparation unit amount): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 10g, filler pregelatinized Starch 50g, disintegrating agent low-substituted hydroxypropyl cellulose 3.1g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, pregelatinized Starch, low-substituted hydroxypropyl cellulose mix homogeneously, with water soft material, granulate, incapsulate, to obtain final product.
Embodiment 10
Pharmaceutical composition is (1000 preparation unit amount): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 40g, filler pregelatinized Starch 248g, disintegrating agent low-substituted hydroxypropyl cellulose 13.3g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, pregelatinized Starch, low-substituted hydroxypropyl cellulose mix homogeneously, with water soft material, granulate, incapsulate, to obtain final product.
Embodiment 11
Pharmaceutical composition (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 80g, filler lactose 246g, microcrystalline Cellulose 372g, disintegrating agent low-substituted hydroxypropyl cellulose 32.4g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose mix homogeneously, with water soft material, granulate, incapsulate, to obtain final product.
Embodiment 12
Pharmaceutical composition (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 80g, filler lactose 241g, microcrystalline Cellulose 370g, disintegrating agent cross-linking sodium carboxymethyl cellulose 33g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose mix homogeneously, with water soft material, granulate, incapsulate, to obtain final product.
Embodiment 13
Pharmaceutical composition (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 80g, filler lactose 245g, microcrystalline Cellulose 376g, disintegrating agent polyvinylpolypyrrolidone 32.8g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, polyvinylpolypyrrolidone mix homogeneously, with water soft material, granulate, incapsulate, to obtain final product.
Embodiment 14
Pharmaceutical composition (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 10g, filler lactose 17g, microcrystalline Cellulose 40g, pregelatinized Starch 3.8g, disintegrating agent carboxymethyl base Starch Sodium 3.4g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, pregelatinized Starch, carboxymethyl starch sodium mix homogeneously, with water soft material, granulate, incapsulate, to obtain final product.
Embodiment 15
Pharmaceutical composition (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 10g, filler lactose 17g, microcrystalline Cellulose 40g, mannitol 4g, disintegrating agent low-substituted hydroxypropyl cellulose 3.5g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, mannitol, low-substituted hydroxypropyl cellulose mix homogeneously, with water soft material, granulate, incapsulate, to obtain final product.
Embodiment 16
Pharmaceutical composition (1000 preparation unit): (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 10g, filler lactose 17g, microcrystalline Cellulose 40g, mannitol 4.2g, disintegrating agent low-substituted hydroxypropyl cellulose 2.5g, polyvinylpolypyrrolidone 1g.
Preparation method:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, lactose, microcrystalline Cellulose, mannitol, low-substituted hydroxypropyl cellulose mix homogeneously, with water soft material, granulate, incapsulate, to obtain final product.
Described embodiment includes but not limited to above-mentioned.
Claims (1)
1. one kind has the inhibiting pharmaceutical composition of tyrosine protein kinase, it is characterized in that (1S)-1-(4-methylpiperazine-1-yl)-N-in pharmaceutical composition (4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfate 1g, filler lactose 1.7g, microcrystalline Cellulose 4.00g, pregelatinized Starch 0.34g, disintegrating agent carboxymethyl base Starch Sodium 0.34g, magnesium stearate lubricant 0.08g;
Tablet prepared by pharmaceutical composition, its preparation method is:
Get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, filler, 0.289g disintegrating agent mix homogeneously, with water soft material, granulate, add residue 0.051g disintegrating agent, add lubricant, mix homogeneously, tabletting, to obtain final product;
Or get recipe quantity (1S)-1-(4-methylpiperazine-1-yl)-N-(4-methyl-3-[(4-pyridin-3-yl pyrimidine-2-base) is amino] phenyl)-2,3-dihydroindene-5 amide sesquisulfates, filler, 0.272g disintegrating agent mix homogeneously, with water soft material, granulate, add residue 0.068g disintegrating agent, add lubricant, mix homogeneously, tabletting, to obtain final product.
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| CN201110283447.0A CN103006664B (en) | 2011-09-22 | 2011-09-22 | One has the inhibiting pharmaceutical composition of tyrosine protein kinase |
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| CN201110283447.0A CN103006664B (en) | 2011-09-22 | 2011-09-22 | One has the inhibiting pharmaceutical composition of tyrosine protein kinase |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101759683A (en) * | 2008-12-25 | 2010-06-30 | 北京美迪赛医药技术有限公司 | Preparation method of hydrindene amide compound, medical composition comprising hydrindene amide compound and application thereof as protein kinase inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101759683A (en) * | 2008-12-25 | 2010-06-30 | 北京美迪赛医药技术有限公司 | Preparation method of hydrindene amide compound, medical composition comprising hydrindene amide compound and application thereof as protein kinase inhibitor |
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Effective date of registration: 20170808 Address after: 150025, No. 29, Beijing Road, Limin economic and Technological Development Zone, Hulan District, Heilongjiang, Harbin Patentee after: Harbin Yu Heng Pharmaceutical Co., Ltd. Address before: 100016 B87, G 21, Jiuxianqiao, Beijing, Chaoyang District Co-patentee before: Harbin Gloria Pharmaceuticals Co., Ltd. Patentee before: Beijing Medconxin Pharmaceutical Technology Co., Ltd. |