CN102552268A - Medicinal preparation containing crystal form a imatinib mesylate - Google Patents
Medicinal preparation containing crystal form a imatinib mesylate Download PDFInfo
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- CN102552268A CN102552268A CN2010106018759A CN201010601875A CN102552268A CN 102552268 A CN102552268 A CN 102552268A CN 2010106018759 A CN2010106018759 A CN 2010106018759A CN 201010601875 A CN201010601875 A CN 201010601875A CN 102552268 A CN102552268 A CN 102552268A
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Abstract
The invention discloses a medicinal preparation containing crystal form a imatinib mesylate. The medicinal preparation comprises crystal form a imatinib mesylate, a disintegrating agent, a diluent, a lubricating agent and a flow aid, wherein the using amount of the imatinib mesylate accounts for 50-80 percent of the total weight of the medicinal preparation; the using amount of the disintegrating agent is 15-30 percent of the total weight of a tablet; the using amount of the diluent is 0-20 percent of the total weight of the tablet; the using amount of the lubricating agent is 0.1-2 percent of the total weight of the tablet; and the using amount of the flow aid is 0.1-2 percent of the total weight of the tablet. Due to the adoption of the medicinal preparation prepared in the invention, the defects of poor flowability of a crystal form a and difficulty in preparing a solid preparation can be well overcome, the prepared medicinal preparation is dissolved quickly, and the crystal form does not change in preparing and storing processes.
Description
Technical field:
The invention belongs to technical field of medicine, relate to the pharmaceutical preparation that is used to treat the chronic myelocytic leukemia imatinib mesylate, a kind of pharmaceutical preparation that contains the alpha-crystal form imatinib mesylate of saying so more specifically.
Technical background
The present invention relates to a kind of tyrosine kinase inhibitor imatinib mesylate (Imatinib mesylate), be used to treat the chronic phase patient after chronic myelocytic leukemia (CML) CML-BC, accelerated period or alpha-interferon treatment are failed.Chemistry is by name: 4-[(4-methyl isophthalic acid-piperazinyl) methyl]-N-[4-methyl-3-[4-(3-pyridine radicals)-2-pyrimidine radicals] amino] phenyl] the Benzoylamide mesylate;
This chemical compound has following structural formula:
It is leukemic 20% that chronic myelocytic leukemia (CML) accounts for all types greatly, has or not Philadelphia chromosome (Ph) to be able to diagnosis through detection.No. 9 and No. 22 long-armed mutual exchanges of chromosome, displacement cause being normally on No. 9 chromosomes fracture zone (BCR) merging on Abelson proto-oncogene (ABL) and No. 22 chromosomes; Generate paraprotein EGFR-TK (BCR-ABL), it can cause that uncontrollable propagation of leukocyte and apoptosis reduce.
The Drug therapy of chronic myelocytic leukemia (CML) has experienced several epoch of Busulfan, hydroxyurea, interferon and tyrosine kinase inhibitor.Busulfan and hydroxyurea only can make the patient obtain hematologic response, improve life quality, do not change its natural history.Interferon can make the part patient obtain the cytogenetics alleviation, thereby prolongs survival period, but regrettably only small number of patients is benefited.Because allogene HSCT (alloHSCT) can reach the purpose of radical curing of disease, therefore, for young patient, alloHSCT is the first-selection of CML treatment.
Imatinib (Imatinib) is a kind of tyrosine kinase inhibitor, can act on the BCR-ABL EGFR-TK specifically, is used for treating CML.This medicine also has activity to other unusual EGFR-TK such as C-kit, and in the patient who suffers from gastrointestinal stromal tumor (GIST), has obtained estimating.
Random research comparison imatinib and interferon therapy are just sent out the CML international I clinical trial phase of chronic phase (IRIS research) and are confirmed; Medication 1 year, imatinib can make 96% patient obtain complete hematologic response, and 69% obtains complete cytogenetics alleviates (CCR); Wherein 53% obtain main molecules alleviation (MMR); Along with the passing of administration time, curative effect obtains ratio to be increased gradually, estimates that 5 years no PD survival rates are 93%; Compare with interferon, patient's hematology, cytogenetics and molecules remission rate are greatly improved, the survival period significant prolongation, and life quality obviously improves.
Imatinib mesylate mainly contains two kinds of comparatively stable crystal formations: alpha-crystal form and beta crystal.WO99/03854, US2006/0030568 and US 6894051 disclose alpha-crystal form and beta crystal, and the α type is through the definition of X-ray diffracting spectrum, and this collection of illustrative plates is 4.9,10.5; 14.9,16.5,17.7,18.1,18.6; 19.1,21.3,21.6,22.7,23.2; 23.8 24.9,27.4,28.0 and 28.6 ± 0.2 degree, 2 θ places have the peak.The β type is through the definition of X-ray diffracting spectrum, and this collection of illustrative plates is 9.7,13.9, and 14.7,17.5,18.2,20.0,20.6,21.1,22.1,22.7,23.8,29.8 and 30.8 ± 0.2 degree, 2 θ places have the peak.
In above-mentioned two kinds of crystal formations, alpha-crystal form is metastable at ambient temperature, is acicular crystal, and is mobile very poor, and has stronger hygroscopicity, and suction back viscosity increases sharply, and can change into beta crystal under certain conditions.Alpha-crystal form imatinib mesylate in addition, its inherent physics's character also is not suitable for preparation.Because the imatinib mesylate taking dose is very big, and the principal agent proportion is very big in the pharmaceutical preparation, be difficult to use a large amount of excipient to change the attribute of pharmaceutical preparation again.
Summary of the invention
The object of the present invention is to provide a kind of pharmaceutical preparation that contains the alpha-crystal form imatinib mesylate, it is characterized in that it comprises alpha-crystal form imatinib mesylate and disintegrating agent, wherein the imatinib mesylate consumption accounts for 50%～80% of pharmaceutical preparation gross weight; The amount of disintegrating agent is the 15-30% based on the tablet total weight amount.
Pharmaceutical preparation of the present invention wherein also comprises diluent, and the amount of its diluent is the 0%-20% based on the tablet total weight amount; Wherein also comprise lubricant and fluidizer: the amount of its lubricant is the 0.1%-2% based on the tablet total weight amount; The amount of fluidizer is the 0.1%-2% based on the tablet total weight amount.
Pharmaceutical preparation of the present invention, its preferred fluidizer is: colloidal silica or colloidal silica anhydrous; Lubricant is: magnesium stearate; Diluent is: one or more in lactose, sucrose, starch, mannitol, microcrystalline Cellulose, the hydroxypropyl cellulose.Preferably: lactose, starch or microcrystalline Cellulose.
Pharmaceutical preparation of the present invention, its disintegrating agent is: one or more in PVPP, CMC-Na, L-HPC, alginic acid or the sodium alginate.Preferred disintegrating agent is: L-HPC or PVPP.
The present invention further discloses the method for preparing of improving the mobile pharmaceutical preparation of alpha-crystal form imatinib mesylate, undertaken by following step:
(1), mixes the 40-100 mesh sieve that sieves with disintegrating agent with interior with the imatinib mesylate raw material pulverizing;
(2) use binding agent system wet granular, drying;
(3) with dried granule with add disintegrating agent and mix, mixture directly is pressed into tablet or encapsulated.Wherein adopt 98% to 100% methanol, ethanol or isopropyl alcohol as binding agent.Preferred 100% methanol or 100% ethanol or 100% isopropyl alcohol of adopting is as binding agent.
Method for preparing of the present invention, wherein prepared wet granular particle diameter is controlled at 0.25mm-0.6mm.
The inventor makes granule after raw material and partial supplementary material are mixed, and improves its flowability.Find in the test that because imatinib mesylate has stronger hygroscopicity, use aqueous binding agent system soft material, the imatinib mesylate of alpha-crystal form absorbs water rapidly, it is big that viscosity becomes rapidly, can't further make granule.The alcohol system soft material more than 98% is used in pleasantly surprised discovery in further experiment, for example ethanol or isopropyl alcohol, and the soft material that makes can be made granule smoothly, and after drying, granule has good hardness, flowability and compressibility.And the crystal formation inspection finds that the raw material behind the system granule does not change brilliant.
The pharmaceutical preparation that the more concrete following mode of employing of the present invention prepares the alpha-crystal form imatinib mesylate:
(1) mix and to sieve, use pulverizer, for example mechanical pulverizatio machine, jet mill, grinding flour mill are pulverized imatinib mesylate, and sieve after interior disintegrating agent that adds and the mixing diluents.
(2) system granule, the alcohol of adding more than 98% is 98% ethanol for example, dehydrated alcohol, isopropyl alcohols etc. make mixture in the high speed shear mixer, carry out moistening/kneading, with waving granule mechanism granule.
(3) drying is used drying equipment, and for example fluid bed dryer, blowing-type baking oven are with wet grain drying.
(4) with dried granule and pharmaceutical excipient one or more disintegrating agents for example, a kind of lubricant, a kind of fluidizer for example mixes in Multidimensionblender.
(5) suppress the mixture tabletting that preferably uses rotary tablet machine to obtain through conventional tablet machine.
In the above-mentioned pre-treatment step (1), sieve after the mixing, the sieve number of selecting for use of sieving is 40 order to 100 orders, preferred 80 mesh sieves; The solarization mesh number that waves the granulation machine use in the step (2) is that 30 orders are to 50 orders; The dry temperature that adopts is 40 ℃ to 100 ℃ in the step (3), is preferably 60 ℃.
Be selected from PVPP with disintegrating agent in the above-mentioned steps (1), CMC-Na, L-HPC, microcrystalline Cellulose, alginic acid or sodium alginate a kind of.The preferred use: L-HPC or PVPP.
Add disintegrating agent in the above-mentioned steps (4) and be selected from PVPP, CMC-Na, L-HPC, microcrystalline Cellulose, alginic acid, sodium alginate a kind of, the preferred use: L-HPC or PVPP.Can according to circumstances add suitable lubricant and fluidizer.Lubricant is selected from, a kind of in magnesium stearate, aluminium stearate or the calcium stearate, preferred magnesium stearate; Fluidizer is selected from, colloidal silica or colloidal silica anhydrous.
In the above-mentioned steps (1), can according to circumstances add one or more suitable dilution agent, lactose for example, sucrose, starch, mannitol, microcrystalline Cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone.Preferred microcrystalline Cellulose, lactose or the starch of using.
In the above-mentioned steps (5), can be as required, hybrid particles is encapsulated, process capsule.Also can be as required with the tablet coating of processing.
According to the present invention, the amount of disintegrating agent can be for based on 15 to 30% of tablet total weight amount; The amount of lubricant can be for based on 0.1 to 2% of tablet total weight amount, and preferred 0.1% to 1%; The amount of fluidizer can be for based on 0.1 to 2% of tablet total weight amount, and preferred 0.1% to 1%.
The present invention judges particulate flowability through measuring the particulate angle of repose and the degree of compression.
Be meant the free inclined-plane and the formed maximum angular of horizontal plane of powder body accumulation horizon angle of repose.Angle of repose is more little, and frictional force is more little, and flowability is good more, it is generally acknowledged good fluidity when θ≤30 are spent, and can satisfy the need for liquidity in the production process when θ≤40 are spent.The degree of compression, the flowability of powder body can be estimated vibration charging during the expression vibrational flow, vibrosieve, vibration is filled and vibrational flow, and the degree of compression can use formula (1) to represent.When the degree of compression less than 20% the time, material better mobile, greater than 40% o'clock, material just was difficult to flow out automatically from container.
Formula (1): (ρ
f-tap density, ρ
o-bulk density)
Raw material with in add the granule that adjuvant mixes back granulation gained, angle of repose, compression ratio showed to have good flowability all less than 20% all less than 35 °.
The dissolution test of tablet, with reference to 2010 editions appendix XC second methods of Chinese Pharmacopoeia (oar method), adopting rotating speed is 50 commentaries on classics, and temperature is 37 degrees centigrade, and dissolution medium is 900ml, the hydrochloric acid of 0.1M.Measure according to the method described above, tablet of the present invention all reached full stripping in 30 minutes.
Through x-ray powder diffraction, investigate in the preparation process and in the storage process stable crystal form property of alpha-crystal form imatinib mesylate.Before measuring raw material pulverizing respectively, after the pulverizing, behind the preparation, influence factor's illumination 10 days, high humidity (relative humidity 92%) 10 days, the X light powder diffraction of the sample of high temperature (60 ℃) after 10 days.The result shows, does not occur the characteristic peak of β type in each diffracting spectrum, explain in the preparation process and under influence factor's experiment condition, taking place changes crystalline substance, sees Fig. 2.
Description of drawings:
Fig. 1 is the stripping curve of preparation among the embodiment 1～9;
Fig. 2-a, Fig. 2-b are the X-ray powder diffraction pattern of preparation among the embodiment 1.
The specific embodiment
The present invention sets forth through following preparation and experiment in more detail, but should not be construed as the qualification to it.Imatinib mesylate wherein is with reference to CN93103566.X; The preparation of WO2004108699 method; Alpha-crystal form prepares with reference to the US6894051 method.
Embodiment 1:
The imatinib mesylate sheet of 100mg specification
Prescription:
The imatinib mesylate of * in the table: 119.5mg is counted 100mg with imatinib.1 represents the Nei Jia adjuvant in the table, and 2 representatives add adjuvant.
Preparation technology:
The alpha-crystal form imatinib mesylate is pulverized, mixed the back with the interior adjuvant that adds and cross 60 mesh sieves; Add dehydrated alcohol, mix in the high speed shear mixer, make granule with 40 mesh sieves (0.425mm), with baking oven with wet grain drying.With dried granule with add adjuvant and fully mix.With mixture direct compression (see figure 2).
Embodiment 2:
Present embodiment uses the binding agent isopropyl alcohol, and purpose is to compare with embodiment 1.
Prescription: with embodiment 1
Technology: the alpha-crystal form imatinib mesylate is pulverized, mixed the back with the interior PVPP that adds and cross 60 mesh sieves; Add isopropyl alcohol, mix in the high speed shear mixer, with 40 mesh sieve system granules, with baking oven with wet grain drying.
Embodiment 3:
Present embodiment uses binding agent 98% ethanol, and purpose is to compare with embodiment 1.
Prescription: with embodiment 1
Technology: the alpha-crystal form imatinib mesylate is pulverized, mixed the back with the interior PVPP that adds and cross 60 mesh sieves; Add 98% ethanol, mix in the high speed shear mixer, with 40 mesh sieve system granules, with baking oven with wet grain drying.
Embodiment 4:
Present embodiment uses 50 mesh sieves (0.3mm) system granule, and purpose is to compare with embodiment 1.
Prescription: with embodiment 1
Technology: the alpha-crystal form imatinib mesylate is pulverized, mixed the back with the interior PVPP that adds and cross 60 mesh sieves; Add 98% ethanol, mix in the high speed shear mixer, with 50 mesh sieve system granules, with baking oven with wet grain drying.
Embodiment 5:
Present embodiment uses 60 mesh sieves (0.25mm) system granule, and purpose is to compare with embodiment 1.
Prescription: with embodiment 1
Technology: the alpha-crystal form imatinib mesylate is pulverized, mixed the back with the interior PVPP that adds and cross 60 mesh sieves; Add 98% methanol, mix in the high speed shear mixer, with 60 mesh sieve system granules, with baking oven with wet grain drying.
Embodiment 6:
Compare with embodiment 1, present embodiment uses different disintegrating agents to carry out preparation.
The preparation of 100mg tablet
Prescription
1 represents the Nei Jia adjuvant in the table, and 2 representatives add adjuvant.
Preparation technology:
The alpha-crystal form imatinib mesylate is pulverized, mixed the back with the interior adjuvant that adds and cross 80 mesh sieves; Add dehydrated alcohol, mix in the high speed shear mixer, make granule with 30 mesh sieves (0.6mm), with baking oven with wet grain drying.With dried granule with add adjuvant and fully mix.With the mixture direct compression.
Embodiment 7:
Compare with embodiment 1, present embodiment uses different diluent to carry out preparation.
The preparation of 100mg tablet
Prescription
1 represents the Nei Jia adjuvant in the table, and 2 representatives add adjuvant.
Technology is with embodiment 1
Embodiment 8:
Present embodiment does not contain diluent, and contains more a high proportion of principal agent.
The preparation of 100mg tablet
Prescription
1 represents the Nei Jia adjuvant in the table, and 2 representatives add adjuvant.
Technology is with embodiment 1.
Embodiment 9:
The imatinib mesylate sheet of 300mg specification.
Prescription:
1 represents the Nei Jia adjuvant in the table, and 2 representatives add adjuvant.
Technology is with embodiment 1.
Embodiment 10:
The capsule of 100mg specification
Prescription:
1 represents the Nei Jia adjuvant in the table, and 2 representatives add adjuvant.
Technology: the alpha-crystal form imatinib mesylate is pulverized, mixed the back with the interior adjuvant that adds and cross 60 mesh sieves; Add dehydrated alcohol, mix in the high speed shear mixer, with 40 mesh sieve system granules, with baking oven with wet grain drying.After adding adds adjuvant, encapsulated.
Test case 1:
Can find out that from table 1 untreated alpha-crystal form imatinib mesylate reaches 46.2 ° angle of repose greater than 40 °, shows mobile very poor; Its degree of compression reaches 40%, and powder body is difficult to flow out automatically from container.And treated raw material, angle of repose, compression ratio showed to have good flowability all less than 20% all less than 35 °.
The micromeritis parameter of dried granule and raw material among table 1 embodiment
| Angle of repose (°) | Bulk density (g/ml) | Tap density (g/ml) | The degree of | |
| Embodiment | ||||
| 1 | 27.7 | 0.385 | 0.465 | 17.2 |
| Embodiment | ||||
| 2 | 29.4 | 0.373 | 0.452 | 17.5 |
| Embodiment | ||||
| 3 | 32.6 | 0.357 | 0.436 | 18.1 |
| Embodiment | ||||
| 4 | 31.8 | 0.394 | 0.483 | 18.4 |
| Embodiment | ||||
| 5 | 33.2 | 0.397 | 0.495 | 19.8％ |
| Raw material | 46.2 | 0.232 | 0.387 | 40.1％ |
Test case 2:
Under mimic gastrointestinal conditions, to embodiment 1,6, the tablet of preparation carries out the stripping test in 7,8,9,10.
Dissolving-out method [with reference to 2010 editions appendix XC second methods of Chinese Pharmacopoeia (oar method)]: dissolution medium, 0.1M hydrochloric acid solution; The dissolution medium volume, 900ml; The dissolution medium temperature, 37 ℃; Stirring paddle speed, 50r/min; Sampling time point: 5min, 10min, 15min, 20min, 30min.
The stripping assay method: ultraviolet spectrophotometry (with reference to two appendix IVA of Chinese Pharmacopoeia version in 2010), measure at the 264nm place.
Test data such as table 2, the result is as shown in Figure 1.
The result shows that embodiment 1,6, and prepared preparation in 7,8,9,10 all can reach more than 85% in stripping within the 15min.
The dissolution data of table 2 embodiment preparation
| Time (min) | 5 | 10 | 15 | 20 | 30 |
| |
36.5 | 85.7 | 96.8 | 98.3 | 99.7 |
| |
27.8 | 76.6 | 93.6 | 97.3 | 99.8 |
| |
28.4 | 78.4 | 91.6 | 94.6 | 100.2 |
| Embodiment 8 | 20.2 | 70.1 | 86.2 | 92.7 | 99.4 |
| |
22.7 | 73.8 | 91.2 | 95.7 | 100.6 |
| |
39.4 | 86.9 | 97.2 | 99.3 | 100.2 |
Claims (10)
1. pharmaceutical preparation that contains the alpha-crystal form imatinib mesylate is characterized in that it comprises alpha-crystal form imatinib mesylate and disintegrating agent, and wherein the imatinib mesylate consumption accounts for 50%～80% of pharmaceutical preparation gross weight; The amount of disintegrating agent is the 15-30% based on the tablet total weight amount.
2. the described pharmaceutical preparation of claim 1 wherein also comprises diluent, and the amount of its diluent is the 0%-20% based on the tablet total weight amount.
3. the described pharmaceutical preparation of claim 1 wherein also comprises lubricant and fluidizer; The amount of its lubricant is the 0.1%-2% based on the tablet total weight amount; The amount of fluidizer is the 0.1%-2% based on the tablet total weight amount.
4. claim 2 or 3 described pharmaceutical preparatioies, its fluidizer is colloidal silica or colloidal silica anhydrous; Lubricant is a magnesium stearate; Diluent is one or more in lactose, sucrose, starch, mannitol, microcrystalline Cellulose, the hydroxypropyl cellulose.
5. the described pharmaceutical preparation of claim 1, disintegrating agent wherein are one or more in PVPP, CMC-Na, L-HPC, alginic acid or the sodium alginate.
6. claim 2 or 5 described pharmaceutical preparatioies, disintegrating agent wherein is L-HPC or PVPP; Diluent is lactose, starch or microcrystalline Cellulose.
7. said method for preparing that contains the pharmaceutical preparation of alpha-crystal form imatinib mesylate of claim 1 is characterized in that being undertaken by following step:
(1), mixes the 40-100 mesh sieve that sieves with disintegrating agent with interior with the imatinib mesylate raw material pulverizing;
(2) use binding agent system wet granular, drying;
(3) with dried granule with add disintegrating agent and mix, mixture directly is pressed into tablet or encapsulated.
8. the described method for preparing of claim 7 wherein adopts 98% to 100% methanol, ethanol or isopropyl alcohol as binding agent.
9. the described method for preparing of claim 8 wherein adopts 100% methanol or 100% ethanol or 100% isopropyl alcohol as binding agent.
10. the described method for preparing of claim 7, wherein prepared wet granular particle diameter is controlled at 0.25mm-0.6mm.
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Cited By (5)
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| WO2013017100A1 (en) * | 2011-08-04 | 2013-02-07 | 上海创诺制药有限公司 | Imatinib mesylate tablet |
| WO2014115082A1 (en) * | 2013-01-22 | 2014-07-31 | Dr. Reddys Laboratories Limited | Pharmaceutical formulations of imatinib |
| CN104288115A (en) * | 2014-10-30 | 2015-01-21 | 江苏豪森药业股份有限公司 | Medicinal preparation containing imatinib mesylate, and preparation method thereof |
| CN107233325A (en) * | 2017-06-23 | 2017-10-10 | 南京优科生物医药研究有限公司 | A kind of composition containing Imatinib and preparation method thereof |
| US10777331B2 (en) | 2016-11-11 | 2020-09-15 | Curium Us Llc | Processes for generating germanium-68 with reduced volatiles |
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| US10777331B2 (en) | 2016-11-11 | 2020-09-15 | Curium Us Llc | Processes for generating germanium-68 with reduced volatiles |
| CN107233325A (en) * | 2017-06-23 | 2017-10-10 | 南京优科生物医药研究有限公司 | A kind of composition containing Imatinib and preparation method thereof |
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Application publication date: 20120711 |