CN105147687A - Pharmaceutical dasatinib composition capsules for treating leukemia - Google Patents
Pharmaceutical dasatinib composition capsules for treating leukemia Download PDFInfo
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- CN105147687A CN105147687A CN201510622620.3A CN201510622620A CN105147687A CN 105147687 A CN105147687 A CN 105147687A CN 201510622620 A CN201510622620 A CN 201510622620A CN 105147687 A CN105147687 A CN 105147687A
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Abstract
The invention relates to pharmaceutical dasatinib composition capsules for treating leukemia and belongs to the technical field of medicines. The pharmaceutical dasatinib composition capsules are prepared from dasatinib, tartaric acid, microcrystalline cellulose, meglumine, hydroxypropyl methylcellulose, purified water and talcum powder. The dasatinib is a novel crystal-form compound and is different from calcium folinate disclosed in the prior art, as shown in Figure 1 of an X-ray powder diffraction diagram obtained through Cu-KAlpha ray measurement. A test shows that the novel crystal-form compound is good in water solubility, low in moisture and impurity content and good in stability and does not easily absorb moisture, convenience is brought to preparation of preparations, the capsules prepared by using the dasatinib, namely the novel crystal-form compound, are high in dissolution rate, good in stability and low in moisture and impurity content compared with the prior art, and the safety of clinic application is improved.
Description
Technical field
The invention belongs to medical art, relate to one and treat leukemic medicine Dasatinib composition capsule.
Background technology
Dasatinib, trade name SPRYCELTM, be a kind of oral tyrosine kinase inhibitor researched and developed by BMS company, for Adult chronic's myelogenous leukemia (CML), also can be used for the diseases such as the acute lymphoblastic leukemia for the treatment of Philadelphia Chromosome Positive.Its chemical name is N-(the chloro-6-aminomethyl phenyl of 2-)-2-[[6-[4-(2-ethoxy)-1-piperazinyl]-2-methyl-4-pyrimidine radicals] is amino]-5-thiazole carboxamides.
Because Dasatinib can have multiple different crystalline state, these different crystalline state are known as polymorphism, and the stability of compound can change along with the polymorphous change of often kind of polymorphism.So for same Dasatinib compound, its different crystal form, polymorph are all different in stability, physical property, dissolubility and preparation method.
For the polymorphic of medicine, different polymorphics can have different chemistry and physical characteristic, comprises fusing point, chemical stability, apparent solubility, rate of dissolution, optics and engineering properties, vapour pressure and density.These character directly can affect process or the production of crude drug and preparation, and can affect the stability of preparation, dissolubility and bioavailability.Therefore, the polymorphic of medicine has great importance for the quality of pharmaceutical preparation, safety and effectiveness.
Because Dasatinib is poorly soluble, so its preparation bioavailability is lower, the absorption rate of medicine depends on dissolution rate again.In view of the pharmacy value of Dasatinib, although various crystal formation has been reported, but still in the urgent need to a kind of high specific surface area, the Dasatinib compound crystal being easy to suitability for industrialized production of stable in properties.Because obtain purity excellent, have and determine crystal form very much and the fabulous compound of repeatability is important, in preparation, consequently present the valuable characteristic of tool, and enough stable to make it can long-time storage and not to the particular/special requirement of temperature, light, humidity or oxygen level.
The present inventor starts with from the research of Dasatinib solid chemical material existence, a kind of Dasatinib crystalline compounds has been prepared through a large amount of tests, find through overtesting, this compound crystal good water solubility, not easily moisture absorption, moisture and the low and good stability of impurity content, preparation for preparation brings conveniently, the capsule prepared of this Dasatinib crystal compound comparatively prior art to compare dissolution high, good stability, moisture and impurity content low, improve the safety of clinical practice.
Summary of the invention
Goal of the invention of the present invention is to provide one to treat leukemic medicine Dasatinib composition capsule.
In order to complete object of the present invention, the technical scheme of employing is:
The present invention relates to one and treat leukemic medicine Dasatinib composition capsule, described composition capsule is made up of Dasatinib, tartaric acid, microcrystalline Cellulose, meglumine, hypromellose, purified water, Pulvis Talci; Described Dasatinib is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
First optimal technical scheme of the present invention is: with parts by weight, and described composition capsule is made up of the Dasatinib of 2 weight portions, the tartaric acid of 10-12 weight portion, the microcrystalline Cellulose of 4-6 weight portion, the meglumine of 1.0-1.4 weight portion, the hypromellose of 4-6 weight portion, the purified water of 4-5 weight portion, the Pulvis Talci of 0.4-0.6 weight portion.
Second optimal technical scheme of the present invention is: with parts by weight, and described composition capsule is made up of the Dasatinib of 2 weight portions, the tartaric acid of 11 weight portions, the microcrystalline Cellulose of 5 weight portions, the meglumine of 1.2 weight portions, the hypromellose of 5 weight portions, the purified water of 4.5 weight portions, the Pulvis Talci of 0.5 weight portion.
3rd optimal technical scheme of the present invention is that the preparation method of described composition capsule comprises the following steps:
(1) supplementary material process: sieve Dasatinib 80 orders;
(2) weigh: weigh according to technology preparation;
(3) preparation of binding agent: get recipe quantity hypromellose and be dissolved in purified water, stand-by;
(4) mixing granulation: be added in wet mixing pelletizer by Dasatinib, tartaric acid, microcrystalline Cellulose, meglumine, opens stirring motor and is dry mixed 10 minutes; Add the binding agent wet mixing cutting prepared, with 18 mesh sieve soft materials;
(5) dry: the wet granular of granulation gained to be joined in fluid bed dryer, set temperature 60-65 DEG C, dry 110-130 minute, by material 18 order granulate after drying;
(6) mix: granule after granulate and Pulvis Talci are dropped into three-dimensional motion mixer, premixing speed 10 revs/min, incorporation time 25 minutes are set;
(7) capsule-filling: carry out fill according to after the theoretical loading amount scope of total mixed gained material cubage;
(8) pack.
4th optimal technical scheme of the present invention is that the preparation method of described Dasatinib crystal comprises the following steps:
Prepare the saturated alcoholic solution of Dasatinib crude product of 35 DEG C, then the isobutanol of 8 times and the mixed solvent of petroleum ether that volume is saturated volumes of aqueous ethanol is added, described isobutanol, the volume ratio of petroleum ether are 3:1, after stirring, cooling limit, limit is stirred, cooling rate is 10 DEG C/h, mixing speed is 105 revs/min, add the acetone that volume is the mixed solvent volume 2 times of isobutanol and petroleum ether simultaneously, stop after being cooled to-10 DEG C stirring, leave standstill growing the grain 3 hours, filter, after drying under reduced pressure, obtain Dasatinib crystalline compounds.
Below technical scheme of the present invention is made further explanation:
The present invention is by the precise controlling to crystallization condition, and prepared a kind of Dasatinib novel crystal forms unlike the prior art, the X-ray powder diffraction pattern of this Dasatinib crystal unlike the prior art.Simultaneously due to the ins and outs of this crystal formation, find through test, the compound water soluble of this novel crystal forms structure is good, not easily moisture absorption, moisture and the low and good stability of impurity content, the preparation for preparation brings conveniently, the capsule prepared of this Dasatinib crystal compound comparatively prior art to compare dissolution high, good stability, moisture and impurity content low, improve the safety of clinical practice.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction that the Dasatinib crystal of the embodiment of the present invention 1 preparation uses the measurement of Cu-K alpha ray to obtain.
Detailed description of the invention
Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.
embodiment 1:the preparation of Dasatinib crystal
Prepare the saturated alcoholic solution of Dasatinib crude product of 35 DEG C, then the isobutanol of 8 times and the mixed solvent of petroleum ether that volume is saturated volumes of aqueous ethanol is added, described isobutanol, the volume ratio of petroleum ether are 3:1, after stirring, cooling limit, limit is stirred, cooling rate is 10 DEG C/h, mixing speed is 105 revs/min, add the acetone that volume is the mixed solvent volume 2 times of isobutanol and petroleum ether simultaneously, stop after being cooled to-10 DEG C stirring, leave standstill growing the grain 3 hours, filter, after drying under reduced pressure, obtain Dasatinib crystalline compounds.
The X-ray powder diffraction pattern that the Dasatinib crystal prepared uses the measurement of Cu-K alpha ray to obtain as shown in Figure 1.
embodiment 2:the preparation of Dasatinib capsule
Prescription: with parts by weight
Preparation method:
(1) supplementary material process: sieve Dasatinib 80 orders;
(2) weigh: weigh according to technology preparation;
(3) preparation of binding agent: get recipe quantity hypromellose and be dissolved in purified water, stand-by;
(4) mixing granulation: be added in wet mixing pelletizer by Dasatinib, tartaric acid, microcrystalline Cellulose, meglumine, opens stirring motor and is dry mixed 10 minutes; Add the binding agent wet mixing cutting prepared, with 18 mesh sieve soft materials;
(5) dry: the wet granular of granulation gained to be joined in fluid bed dryer, set temperature 60-65 DEG C, dry 110-130 minute, by material 18 order granulate after drying;
(6) mix: granule after granulate and Pulvis Talci are dropped into three-dimensional motion mixer, premixing speed 10 revs/min, incorporation time 25 minutes are set;
(7) capsule-filling: carry out fill according to after the theoretical loading amount scope of total mixed gained material cubage;
(8) pack.
embodiment 3:the preparation of Dasatinib capsule
Prescription: with parts by weight
Preparation method:
(1) supplementary material process: sieve Dasatinib 80 orders;
(2) weigh: weigh according to technology preparation;
(3) preparation of binding agent: get recipe quantity hypromellose and be dissolved in purified water, stand-by;
(4) mixing granulation: be added in wet mixing pelletizer by Dasatinib, tartaric acid, microcrystalline Cellulose, meglumine, opens stirring motor and is dry mixed 10 minutes; Add the binding agent wet mixing cutting prepared, with 18 mesh sieve soft materials;
(5) dry: the wet granular of granulation gained to be joined in fluid bed dryer, set temperature 60-65 DEG C, dry 110-130 minute, by material 18 order granulate after drying;
(6) mix: granule after granulate and Pulvis Talci are dropped into three-dimensional motion mixer, premixing speed 10 revs/min, incorporation time 25 minutes are set;
(7) capsule-filling: carry out fill according to after the theoretical loading amount scope of total mixed gained material cubage;
(8) pack.
embodiment 4:the preparation of Dasatinib capsule
Prescription: with parts by weight
Preparation method:
(1) supplementary material process: sieve Dasatinib 80 orders;
(2) weigh: weigh according to technology preparation;
(3) preparation of binding agent: get recipe quantity hypromellose and be dissolved in purified water, stand-by;
(4) mixing granulation: be added in wet mixing pelletizer by Dasatinib, tartaric acid, microcrystalline Cellulose, meglumine, opens stirring motor and is dry mixed 10 minutes; Add the binding agent wet mixing cutting prepared, with 18 mesh sieve soft materials;
(5) dry: the wet granular of granulation gained to be joined in fluid bed dryer, set temperature 60-65 DEG C, dry 110-130 minute, by material 18 order granulate after drying;
(6) mix: granule after granulate and Pulvis Talci are dropped into three-dimensional motion mixer, premixing speed 10 revs/min, incorporation time 25 minutes are set;
(7) capsule-filling: carry out fill according to after the theoretical loading amount scope of total mixed gained material cubage;
(8) pack.
test example 1:wettability test
This test example compares the hygroscopicity of the Dasatinib of Dasatinib compound provided by the invention and prior art.
Test method: respectively under the condition of humidity 60% and 90%, room temperature, each sample thief 1g is placed on electronic balance, and time recording weight, to detect moisture absorption degree, the results are shown in Table 1.
Table 1 sample hygroscopicity measurement result
Wherein:
Sample 1: the Dasatinib that the embodiment of the present invention 1 is obtained;
Sample 2: Dasatinib crude drug product (Lianyungang Ruizhong Pharmaceutical Co., Ltd.).
As can be seen from above-mentioned result of the test, compared with the Dasatinib of prior art, the hygroscopicity that Dasatinib tool provided by the present invention has clear improvement.
test example 2:dissolubility test
Test with reference to Chinese Pharmacopoeia, method is: it is appropriate that precision takes Dasatinib, and slowly add the water of 25 DEG C, the powerful jolting 30 seconds every 5 minutes, observes the dissolving situation in 30 minutes, the results are shown in Table 2.
Table 2 dissolubility test result
As seen from the experiment, the dissolubility of Dasatinib crystalline compounds of the present invention in water improves close to 16.9 times.
test example 3:dissolution Rate Testing
Comparative example 1: import dasatinib tablet (Shi Dasai).
Dissolution experiments method is as follows: sample thief is according to dissolution method (Chinese Pharmacopoeia version in 2010 two annex XC dissolution method second methods), the acetate buffer solution of 1%TritonX-100 and purified water three kinds of medium 1000ml are contained for dissolution medium respectively with pH1.0 hydrochloric acid solution, pH4.0, rotating speed is 60 turns per minute, 10ml is sampled respectively at when 10min, 15min, 20min, 30min, 45min, filter, filtrate is as need testing solution, and equivalent supplements synthermal fresh dissolution medium; Separately get Dasatinib reference substance appropriate, after adding the dissolving of a small amount of acetonitrile, add stripping medium, be mixed with the solution (in Dasatinib) containing 10 μ g in every 1ml.Get above-mentioned solution according to spectrophotography (Chinese Pharmacopoeia version in 2010 two annex IV), at 322nm wavelength, place measures absorbance respectively, calculates dissolution, in table 3.
Table 3 dissolution determination result (%)
As seen from the experiment, the dissolution of tablet of the present invention is significantly higher than imported product, and the dissolution especially in water improves greatly, and 45min dissolution is 16.1 times of imported product.
Similar test is carried out to other embodiments, has obtained the result similar to embodiment 2.
test example 4:stability test
Determination of related substances method: measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD).
Chromatographic condition and system suitability take octadecylsilane chemically bonded silica as filler; With the ammonium acetate buffer-methanol (35:65) of 50mM for mobile phase.Get reference substance solution continuous sample introduction 6 times, the relative standard deviation of peak area should be not more than 2%, and the theoretical cam curve of main peak should be not less than 3000, and the tailing factor of main peak should be not more than 2.0.
The preparation precision of reference substance solution takes 30mg Dasatinib reference substance, is placed in the volumetric flask of 200mL, adds appropriate mixed solvent, ultrasonic dissolution, be diluted to scale with mixed solvent, both.
Need testing solution prepare Example 2-embodiment 4, each 5/sheet of Shi Dasai sample, put in 500ml measuring bottle respectively, add the about 3/4 volume place of mixed solvent [hydrochloric acid solution of 0.1mol/L: acetonitrile (50:50)] to measuring bottle, ultrasonic 30 minutes, jolting 30 minutes, scale is diluted to mixed solvent, mixing, precision measures in right amount, makes every 1ml about containing the solution of 0.14mg with mixed solvent dilution, filter, get subsequent filtrate and get final product.
Algoscopy respectively precision measures need testing solution and each 10 μ l of reference substance solution, injection liquid chromatography, and record chromatogram, by external standard method with calculated by peak area, to obtain final product.Calculate by Self-control method, maximum single impurity must not more than 0.2%, and total impurities more than 0.6%, must not the results are shown in Table 4.
Table 4 Dasatinib capsule is the moisture of (40 DEG C, 75%) and related substance under acceleration environment
Embodiment 2-embodiment 4 and " Shi Dasai " place 1 month and 6 months respectively under acceleration environment, the Dasatinib capsule moisture that result of the test display embodiment 2-embodiment 4 obtains and its related substances are stablized, and the content (%) of the content (%) of moisture and maximum single impurity and total impurities is all lower than " Shi Dasai " sheet.
Claims (5)
1. treat a leukemic medicine Dasatinib composition capsule, it is characterized in that: described composition capsule is made up of Dasatinib, tartaric acid, microcrystalline Cellulose, meglumine, hypromellose, purified water, Pulvis Talci; Described Dasatinib is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
2. treatment according to claim 1 leukemic medicine Dasatinib composition capsule, it is characterized in that: with parts by weight, described composition capsule is made up of the Dasatinib of 2 weight portions, the tartaric acid of 10-12 weight portion, the microcrystalline Cellulose of 4-6 weight portion, the meglumine of 1.0-1.4 weight portion, the hypromellose of 4-6 weight portion, the purified water of 4-5 weight portion, the Pulvis Talci of 0.4-0.6 weight portion.
3. treatment according to claim 2 leukemic medicine Dasatinib composition capsule, it is characterized in that: with parts by weight, described composition capsule is made up of the Dasatinib of 2 weight portions, the tartaric acid of 11 weight portions, the microcrystalline Cellulose of 5 weight portions, the meglumine of 1.2 weight portions, the hypromellose of 5 weight portions, the purified water of 4.5 weight portions, the Pulvis Talci of 0.5 weight portion.
4., according to the arbitrary described treatment leukemic medicine Dasatinib composition capsule of claim 1-3, it is characterized in that, the preparation method of described composition capsule comprises the following steps:
(1) supplementary material process: sieve Dasatinib 80 orders;
(2) weigh: weigh according to technology preparation;
(3) preparation of binding agent: get recipe quantity hypromellose and be dissolved in purified water, stand-by;
(4) mixing granulation: be added in wet mixing pelletizer by Dasatinib, tartaric acid, microcrystalline Cellulose, meglumine, opens stirring motor and is dry mixed 10 minutes; Add the binding agent wet mixing cutting prepared, with 18 mesh sieve soft materials;
(5) dry: the wet granular of granulation gained to be joined in fluid bed dryer, set temperature 60-65 DEG C, dry 110-130 minute, by material 18 order granulate after drying;
(6) mix: granule after granulate and Pulvis Talci are dropped into three-dimensional motion mixer, premixing speed 10 revs/min, incorporation time 25 minutes are set;
(7) capsule-filling: carry out fill according to after the theoretical loading amount scope of total mixed gained material cubage;
(8) pack.
5. treatment according to claim 1 leukemic medicine Dasatinib composition capsule, is characterized in that, the preparation method of described Dasatinib crystal comprises the following steps:
Prepare the saturated alcoholic solution of Dasatinib crude product of 35 DEG C, then the isobutanol of 8 times and the mixed solvent of petroleum ether that volume is saturated volumes of aqueous ethanol is added, described isobutanol, the volume ratio of petroleum ether are 3:1, after stirring, cooling limit, limit is stirred, cooling rate is 10 DEG C/h, mixing speed is 105 revs/min, add the acetone that volume is the mixed solvent volume 2 times of isobutanol and petroleum ether simultaneously, stop after being cooled to-10 DEG C stirring, leave standstill growing the grain 3 hours, filter, after drying under reduced pressure, obtain Dasatinib crystalline compounds.
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| CN201510622620.3A CN105147687A (en) | 2015-09-28 | 2015-09-28 | Pharmaceutical dasatinib composition capsules for treating leukemia |
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| CN201510622620.3A CN105147687A (en) | 2015-09-28 | 2015-09-28 | Pharmaceutical dasatinib composition capsules for treating leukemia |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106389435A (en) * | 2016-09-05 | 2017-02-15 | 深圳海王医药科技研究院有限公司 | Pharmaceutical composition containing naprotinib or salt thereof and impurity control method of pharmaceutical composition |
| CN107033137A (en) * | 2016-02-03 | 2017-08-11 | 正大天晴药业集团股份有限公司 | A kind of crystal formation of Dasatinib and preparation method thereof |
| US11684620B2 (en) | 2015-02-10 | 2023-06-27 | Astex Therapeutics Ltd | Pharmaceutical compositions comprising N-(3,5-dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine |
| US11918576B2 (en) | 2014-03-26 | 2024-03-05 | Astex Therapeutics Ltd | Combination of an FGFR inhibitor and a CMET inhibitor |
-
2015
- 2015-09-28 CN CN201510622620.3A patent/CN105147687A/en not_active Withdrawn
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11918576B2 (en) | 2014-03-26 | 2024-03-05 | Astex Therapeutics Ltd | Combination of an FGFR inhibitor and a CMET inhibitor |
| US11684620B2 (en) | 2015-02-10 | 2023-06-27 | Astex Therapeutics Ltd | Pharmaceutical compositions comprising N-(3,5-dimethoxyphenyl)-N′-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine |
| CN107033137A (en) * | 2016-02-03 | 2017-08-11 | 正大天晴药业集团股份有限公司 | A kind of crystal formation of Dasatinib and preparation method thereof |
| CN106389435A (en) * | 2016-09-05 | 2017-02-15 | 深圳海王医药科技研究院有限公司 | Pharmaceutical composition containing naprotinib or salt thereof and impurity control method of pharmaceutical composition |
| WO2018041246A1 (en) * | 2016-09-05 | 2018-03-08 | 深圳海王医药科技研究院有限公司 | Pharmaceutical composition comprising neptinib or salt thereof and method for controlling impurity thereof |
| CN106389435B (en) * | 2016-09-05 | 2019-07-05 | 深圳海王医药科技研究院有限公司 | It is a kind of to replace Buddhist nun or the pharmaceutical composition and its impurity control method of its salt containing Nabumetone |
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