CN105055327A - Dasatinib composite granules capable of treating leukaemia - Google Patents
Dasatinib composite granules capable of treating leukaemia Download PDFInfo
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- CN105055327A CN105055327A CN201510454597.1A CN201510454597A CN105055327A CN 105055327 A CN105055327 A CN 105055327A CN 201510454597 A CN201510454597 A CN 201510454597A CN 105055327 A CN105055327 A CN 105055327A
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Abstract
The invention relates to dasatinib composite granules capable of treating leukaemia, belonging to the technical field of medicines. The dasatinib composite is prepared from dasatinib, sorbitol, mannitol, sodium sulfite, apple flavour, povidone K30, lauryl sodium sulfate and purified water, wherein dasatinib is a novel crystal form compound, and is different from dasatinib reported in the prior art; an X-ray powder diffraction diagram obtained by adopting Cu-K alpha rays is shown in the figure I; the test shows that the novel crystal form compound is good in water solubility, has small possibility of absorbing moisture, low in content of water and impurities, and good in stability, therefore, convenience is brought to the forming of the preparation; the granules prepared by the dasatinib novel crystal form compound are good in stability, low in contents of water and impurities, and high in bioavailability, and the safety in clinical application is improved.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine Dasatinib composition granule for the treatment of leukemia.
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, surprisingly 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, granule good stability prepared by this Dasatinib crystal compound, moisture and impurity content low, bioavailability is high, improves the safety of clinical practice.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of medicine Dasatinib composition granule for the treatment of leukemia.
In order to complete object of the present invention, the technical scheme of employing is:
The present invention relates to a kind of medicine Dasatinib composition granule for the treatment of leukemia, described compositions is made up of Dasatinib, sorbitol, mannitol, sodium sulfite, apple spice, PVP K30, sodium lauryl sulphate, purified water; 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.
As preferably, with parts by weight, described compositions is made up of the Dasatinib of 1-3 weight portion, the sorbitol of 17-19 weight portion, the mannitol of 16-17.2 weight portion, the sodium sulfite of 1.5-2.5 weight portion, the apple spice of 0.2-0.4 weight portion, the PVP K30 of 0.3-0.5 weight portion, the sodium lauryl sulphate of 0.08-0.12 weight portion, the purified water of 4-6 weight portion.
As preferably, with parts by weight, described compositions is made up of the Dasatinib of 2 weight portions, the sorbitol of 18 weight portions, the mannitol of 16.6 weight portions, the sodium sulfite of 2 weight portions, the apple spice of 0.3 weight portion, the PVP K30 of 0.4 weight portion, the sodium lauryl sulphate of 0.1 weight portion, the purified water of 5 weight portions.
As preferably, the preparation method of described compositions comprises the following steps:
1) supplementary material process: raw material Dasatinib is crossed 80 mesh sieves with oscillating sieving machine;
2) weigh: weigh according to technology preparation amount;
3) binding agent preparation: the PVP K30 of recipe quantity and sodium lauryl sulphate are joined in the purified water of recipe quantity, is stirred to and is uniformly dissolved;
4) mixing granulation: the Dasatinib of recipe quantity, sorbitol, mannitol, sodium sulfite, apple spice are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add the binding agent prepared, wet mixing cutting 140-180 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
5) drying and screening: regulate boiling drier inlet temperature 55-65 DEG C, wet granular is placed in boiling drier and carries out drying, be dried to moisture lower than 3.0%, granule shaking screen after drying is sieved the granule got between 16 order-30 orders;
6) always mix: the dry granule after granulate is joined in mixer, mixing velocity 12r/min, open mixer and mix 5 minutes;
7) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
The preparation method of the Dasatinib crystal in the present composition comprises the following steps:
(1) be dissolved in by Dasatinib in the mixed solvent of acetone, dimethyl sulfoxide and water, the solvent load that needs of every gram of Dasatinib is 80ml, and the volume ratio of acetone, dimethyl sulfoxide and water is 0.5:4:1;
(2), after being heated to 35 DEG C of dissolvings, after cool to room temperature, crystal seed is added;
(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-15 DEG C, filters, dry, collects crystal and namely obtains Dasatinib crystal.
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, granule good stability prepared by this Dasatinib crystal compound, moisture and impurity content low, bioavailability is high, improves 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
(1) be dissolved in by Dasatinib in the mixed solvent of acetone, dimethyl sulfoxide and water, the solvent load that needs of every gram of Dasatinib is 80ml, and the volume ratio of acetone, dimethyl sulfoxide and water is 0.5:4:1;
(2), after being heated to 35 DEG C of dissolvings, after cool to room temperature, crystal seed is added;
(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-15 DEG C, filters, dry, collects crystal and namely obtains Dasatinib crystal.
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 granule
Prescription: with parts by weight, Dasatinib crystal-form compound 2 parts, sorbitol 17 parts, 16 parts, mannitol, sodium sulfite 1.5 parts, apple spice 0.2 part, PVP K30 0.3 part, sodium lauryl sulphate 0.08 part, purified water 4 parts that embodiment 1 is obtained.
Preparation method:
1) supplementary material process: raw material Dasatinib is crossed 80 mesh sieves with oscillating sieving machine;
2) weigh: weigh according to technology preparation amount;
3) binding agent preparation: the PVP K30 of recipe quantity and sodium lauryl sulphate are joined in the purified water of recipe quantity, is stirred to and is uniformly dissolved;
4) mixing granulation: the Dasatinib of recipe quantity, sorbitol, mannitol, sodium sulfite, apple spice are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add the binding agent prepared, wet mixing cutting 140-180 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
5) drying and screening: regulate boiling drier inlet temperature 55-65 DEG C, wet granular is placed in boiling drier and carries out drying, be dried to moisture lower than 3.0%, granule shaking screen after drying is sieved the granule got between 16 order-30 orders;
6) always mix: the dry granule after granulate is joined in mixer, mixing velocity 12r/min, open mixer and mix 5 minutes;
7) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
embodiment 3:the preparation of Dasatinib granule
Prescription: with parts by weight, Dasatinib crystal-form compound 2 parts, sorbitol 18 parts, 16.6 parts, mannitol, sodium sulfite 2 parts, apple spice 0.3 part, PVP K30 0.4 part, sodium lauryl sulphate 0.1 part, purified water 5 parts that embodiment 1 is obtained.
Preparation method:
1) supplementary material process: raw material Dasatinib is crossed 80 mesh sieves with oscillating sieving machine;
2) weigh: weigh according to technology preparation amount;
3) binding agent preparation: the PVP K30 of recipe quantity and sodium lauryl sulphate are joined in the purified water of recipe quantity, is stirred to and is uniformly dissolved;
4) mixing granulation: the Dasatinib of recipe quantity, sorbitol, mannitol, sodium sulfite, apple spice are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add the binding agent prepared, wet mixing cutting 140-180 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
5) drying and screening: regulate boiling drier inlet temperature 55-65 DEG C, wet granular is placed in boiling drier and carries out drying, be dried to moisture lower than 3.0%, granule shaking screen after drying is sieved the granule got between 16 order-30 orders;
6) always mix: the dry granule after granulate is joined in mixer, mixing velocity 12r/min, open mixer and mix 5 minutes;
7) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
embodiment 4:the preparation of Dasatinib granule:
Prescription: with parts by weight, Dasatinib crystal-form compound 2 parts, sorbitol 19 parts, 17.2 parts, mannitol, sodium sulfite 2.5 parts, apple spice 0.4 part, PVP K30 0.5 part, sodium lauryl sulphate 0.12 part, purified water 6 parts that embodiment 1 is obtained.
Preparation method:
1) supplementary material process: raw material Dasatinib is crossed 80 mesh sieves with oscillating sieving machine;
2) weigh: weigh according to technology preparation amount;
3) binding agent preparation: the PVP K30 of recipe quantity and sodium lauryl sulphate are joined in the purified water of recipe quantity, is stirred to and is uniformly dissolved;
4) mixing granulation: the Dasatinib of recipe quantity, sorbitol, mannitol, sodium sulfite, apple spice are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add the binding agent prepared, wet mixing cutting 140-180 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
5) drying and screening: regulate boiling drier inlet temperature 55-65 DEG C, wet granular is placed in boiling drier and carries out drying, be dried to moisture lower than 3.0%, granule shaking screen after drying is sieved the granule got between 16 order-30 orders;
6) always mix: the dry granule after granulate is joined in mixer, mixing velocity 12r/min, open mixer and mix 5 minutes;
7) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
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 18.4 times than contrast medicine.
test example 3: 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.
The preparation of need testing solution: Dasatinib granule prepared by embodiment 2-embodiment 4, Shi Dasai sheet, 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 3.
Table 3 Dasatinib granule is the moisture of (40 DEG C, 75%) and related substance under acceleration environment
Dasatinib granule, the Shi Dasai sheet of embodiment 2-embodiment 4 preparation are placed 1 month and 6 months respectively under acceleration environment, the Dasatinib granule moisture that result of the test display embodiment 2-embodiment 4 obtains and its related substances are stablized, and lower than Shi Dasai sheet.
Claims (5)
1. treat a medicine Dasatinib composition granule for leukemia, it is characterized in that: described compositions is made up of Dasatinib, sorbitol, mannitol, sodium sulfite, apple spice, PVP K30, sodium lauryl sulphate, purified water; 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. the medicine Dasatinib composition granule for the treatment of leukemia according to claim 1, it is characterized in that: with parts by weight, described compositions is made up of the Dasatinib of 1-3 weight portion, the sorbitol of 17-19 weight portion, the mannitol of 16-17.2 weight portion, the sodium sulfite of 1.5-2.5 weight portion, the apple spice of 0.2-0.4 weight portion, the PVP K30 of 0.3-0.5 weight portion, the sodium lauryl sulphate of 0.08-0.12 weight portion, the purified water of 4-6 weight portion.
3. the medicine Dasatinib composition granule for the treatment of leukemia according to claim 1, it is characterized in that: with parts by weight, described compositions is made up of the Dasatinib of 2 weight portions, the sorbitol of 18 weight portions, the mannitol of 16.6 weight portions, the sodium sulfite of 2 weight portions, the apple spice of 0.3 weight portion, the PVP K30 of 0.4 weight portion, the sodium lauryl sulphate of 0.1 weight portion, the purified water of 5 weight portions.
4. prepare a method for the medicine Dasatinib composition granule of the arbitrary described treatment leukemia of claim 1-3, it is characterized in that comprising the following steps:
1) supplementary material process: raw material Dasatinib is crossed 80 mesh sieves with oscillating sieving machine;
2) weigh: weigh according to technology preparation amount;
3) binding agent preparation: the PVP K30 of recipe quantity and sodium lauryl sulphate are joined in the purified water of recipe quantity, is stirred to and is uniformly dissolved;
4) mixing granulation: the Dasatinib of recipe quantity, sorbitol, mannitol, sodium sulfite, apple spice are added in wet mixing pelletizer, open stirring motor and be dry mixed 10 minutes, add the binding agent prepared, wet mixing cutting 140-180 soft material second, selects 18 order nylon wires to be arranged in oscillating granulator and granulates;
5) drying and screening: regulate boiling drier inlet temperature 55-65 DEG C, wet granular is placed in boiling drier and carries out drying, be dried to moisture lower than 3.0%, granule shaking screen after drying is sieved the granule got between 16 order-30 orders;
6) always mix: the dry granule after granulate is joined in mixer, mixing velocity 12r/min, open mixer and mix 5 minutes;
7) pack: granule is joined particles packing machine intermediate package, control content uniformity and meet inner quality standard.
5. the medicine Dasatinib composition granule for the treatment of leukemia according to claim 1, is characterized in that: the preparation method of the crystal of described compositions comprises the following steps:
(1) be dissolved in by Dasatinib in the mixed solvent of acetone, dimethyl sulfoxide and water, the solvent load that needs of every gram of Dasatinib is 80ml, and the volume ratio of acetone, dimethyl sulfoxide and water is 0.5:4:1;
(2), after being heated to 35 DEG C of dissolvings, after cool to room temperature, crystal seed is added;
(3) be cooled to less than 0 DEG C, stirring and crystallizing, the temperature of crystallize is-15 DEG C, filters, dry, collects crystal and namely obtains Dasatinib crystal.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| JP2019116435A (en) * | 2017-12-27 | 2019-07-18 | 日本化薬株式会社 | Pharmaceutical compositions comprising dasatinib as effective ingredient |
| CN113321647A (en) * | 2018-06-15 | 2021-08-31 | 汉达癌症医药责任有限公司 | Salts of kinase inhibitors and compositions thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| JP2019116435A (en) * | 2017-12-27 | 2019-07-18 | 日本化薬株式会社 | Pharmaceutical compositions comprising dasatinib as effective ingredient |
| JP7000148B2 (en) | 2017-12-27 | 2022-01-19 | 日本化薬株式会社 | A pharmaceutical composition containing dasatinib as an active ingredient |
| CN113321647A (en) * | 2018-06-15 | 2021-08-31 | 汉达癌症医药责任有限公司 | Salts of kinase inhibitors and compositions thereof |
| CN115192540A (en) * | 2018-06-15 | 2022-10-18 | 汉达癌症医药责任有限公司 | Salts of kinase inhibitors and compositions thereof |
| TWI787523B (en) * | 2018-06-15 | 2022-12-21 | 漢達生技醫藥股份有限公司 | Crystalline of dasatinib lauryl sulfate salt |
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Inventor after: Xu Fuhou Inventor after: Fan Dongmei Inventor before: Liu Xuejian |
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Application publication date: 20151118 |