CN102349874B - Imatinib mesylate composition and preparation method thereof - Google Patents
Imatinib mesylate composition and preparation method thereof Download PDFInfo
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- CN102349874B CN102349874B CN 201110246860 CN201110246860A CN102349874B CN 102349874 B CN102349874 B CN 102349874B CN 201110246860 CN201110246860 CN 201110246860 CN 201110246860 A CN201110246860 A CN 201110246860A CN 102349874 B CN102349874 B CN 102349874B
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Abstract
The invention provides an imatinib mesylate composition and a preparation method thereof. The imatinib mesylate composition is prepared from imatinib mesylate used as an active ingredient through a dry granulation process, and the dissolution rate of imatinib mesylate is effectively improved.
Description
Technical field
The present invention relates to a kind of compositions of imatinib mesylate, particularly relate to a kind of methylsulfonic acid imatinib tablet agent that can rapid delivery of pharmaceuticals and preparation method thereof.
Background technology
Imatinib mesylate is a kind of selectivity tyrosine kinase inhibitor of Switzerland Novartis Co.,Ltd exploitation, belongs to the aniline quinazoline compounds.Approval is used for the treatment of chronic lymphocytic leukemia to FDA May calendar year 2001, and in February, 2002, FDA further ratified the treatment that imatinib mesylate is used for gastrointestinal stromal tumors.
Imatinib mesylate all can suppress the Bcr-Abl tyrosine kinase at cellular level in vivo and in vitro, can selectivity suppress the chronic myelocytic leukemia of Bcr-Abl positive cell line cell, Ph chromatin-positive and acute lymphoblastic leukemia patient new fresh cell propagation and induce its apoptosis.In addition, imatinib mesylate also can suppress platelet derived growth factor (PDGF) receptor, stem cell factor (SCF), the tyrosine kinase of c-Kit receptor, thus inhibition is by the cell behavior of PDGF and SCF mediation.
Imatinib mesylate is first appropriate design exploitation after the cause of disease of clear and definite cancer, and obtained the anti-tumor medicine of remarkable effect, the developing milestone of tyrosine kinase inhibitor is not only in succeeding in developing of it, more can be described as a milestone for the treatment of of cancer.
The chemical structural formula of imatinib mesylate is as follows:
Chemical name: 4-[(4-methyl isophthalic acid-piperazine) methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl]-the Benzoylamide mesylate, molecular formula is C
29H
31N
7OCH
4SO
3, molecular weight is 589.71.
The imatinib mesylate oral absorption is good, and the average absolute bioavailability is 98%, and the coefficient of variation fluctuation of oral rear blood plasma imatinib AUC is between 40～60%.
The imatinib mesylate chemical compound is open by Xi Ba-Geiz stock Corp (present Novartis) the earliest, and China Patent No. is CN93103566.X.Novartis Co.,Ltd successively discloses α, β, F, G, H, I, δ, ε and the armorphous form (CN98807303.X, CN200680044007.7, CN200880018651.6, CN201010586080.5) of this chemical compound, and having set forth beta crystal is that stability is best in each crystal formation, the most processed form, other crystal formations are especially having water, alcohol, are easily changing beta crystal when ketone exists at normal temperatures.
It is reported that imatinib mesylate is white or off-white color, light brown or light yellow crystalline powder, dissolubility is fine in the water, and is solvable in the buffer of pH≤5.5, increases with pH, and dissolubility reduces until insoluble.The methylsulfonic acid imatinib tablet trade name of drugs approved by FDA listing
Specification is 100mg and 400mg.Adjuvant is microcrystalline Cellulose, hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, magnesium stearate, micropowder silica gel, adopts wet granulation, then tabletting.Novartis is at the patent application CN03808869.X of China, and " high drug load tablet " also discloses the technique of wet granulation.
Reach according to clinical
The result of study of itself shows, the reference inlet port target level of product quality adopts the oar method, and 0.1M HCL is dissolution medium, and rotating speed is that 1000ml/50rpm measures, and imatinib mesylate 10min dissolution can surpass 90%.And according to
The prepared tablet stripping of disclosed method not exclusively or slowly, under 0.1M HCL 1000ml/50rpm (oar method) leaching condition, 10min dissolution less than 60%.If when research worker of the present invention is also found to adopt wet granulation technology according to described in the patent CN03808869.X, do not use hydroxypropyl methylcellulose, and only use microcrystalline Cellulose to be binding agent, then can't granulation, and this patent application does not have to disclose the stripping experimental result of this tablet yet.
Certainly; existing many unit applications Orally administered composition or the preparation patent of imatinib mesylate, comprise the solid solution for the protection of astable crystal formation (CN200780032344.9) and the solid dispersion (CN200880007989.1) of the application of Novartis and Reddys Lab Ltd..A kind of imatinib mesylate chewable tablet of Beijing Chengchuang Kangyun Medicine Technology Co., Ltd.'s application and preparation method thereof (CN200810226590.4), a kind of imatinib mesylate orally disintegrating tablets and preparation method thereof (CN200810226591.9) and a kind of effervescent tablet that contains imatinib mesylate and preparation method thereof (CN200810226592.3).The clathrate of a kind of alpha crystal imatinib of Shenzhen Haiwang Pharmaceutical Co., Ltd's application and preparation method thereof (CN201010570254.9).The imatinib mesylate polymorph of Nanjing Cavan Dixu Biologicgal Enginnering Technology Co., Ltd's application and the Pharmaceutical composition (CN201110032923.1) of corresponding crystal formation.
Oral drugs absorb with dissolved state after entering in the body, and imatinib mesylate itself is easily molten, the crystal formation of imatinib mesylate is stable beta crystal among the present invention, there is no need to adopt complicated process means to make solid solution, solid dispersion or clathrate; Imatinib mesylate has bitterness, and digestive tract is had stimulation, there is no need also to be not suitable for making chewable tablet or oral cavity disintegration tablet, stimulates distance because these two kinds of preparations will prolong; The environmental requirement that the need of production of effervescent tablet is special, and take effervescent tablet and also can prolong the stimulation distance.
Imatinib mesylate wishes after taking and can reach rapidly blood drug level and onset, yet prior art is failed to provide a kind of and formed and preparation technology is simple, can realize the imatinib mesylate pharmaceutical composition that medicine discharges fast.
Summary of the invention
The invention provides and a kind ofly form her horse of the methanesulfonic acid simple, that stripping is rapid, dissolution is high for solid composite and preparation method thereof.Can reach when characteristics of the present invention are prepared tablet 10min fully and discharge.Adopt dry granulation, avoided the use of granulation solvent, shortened simultaneously the granulation time; Especially can avoid the use of the organic solvents such as ethanol, greatly improve the safety of producing.
The invention provides a kind of methylsulfonic acid imatinib tablet agent that can discharge rapidly medicine, contain imatinib mesylate and pharmaceutical excipient, it is characterized in that the weight of contained imatinib mesylate accounts for 45%～60% of tablet total weight amount.
Wherein, described drug excipient comprises: based on the disintegrating agent of tablet total weight amount meter 10%～25%, based on the filler of tablet total weight amount meter 20%～40%, based on the lubricant of tablet total weight amount meter 1%～5%.
Wherein, described imatinib mesylate is beta crystal.
Wherein, disintegrating agent is polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose or carboxymethyl starch sodium or its combination in any.Filler is microcrystalline Cellulose.Lubricant is silicon dioxide, magnesium stearate, Pulvis Talci or Polyethylene Glycol or its combination in any.
The present invention also provides a kind of method for preparing described methylsulfonic acid imatinib tablet agent, comprises the steps:
1. with imatinib mesylate and adjuvant mix homogeneously, wherein adjuvant comprise filler, in add the lubricant of part and the disintegrating agent of Nei Jia part;
2. dry granulation;
3. adding adds adjuvant, mix homogeneously, and wherein adding adjuvant is the lubricant of Extra Section and the disintegrating agent of Extra Section;
4. tabletting.
Wherein, the disintegrating agent ratio that adds part and Extra Section in is 1: 3～3: 1.In add part and the lubricant ratio of Extra Section is 1: 2～2: 1.
Wherein, step 2. in tabletting pressure be 3～10MPa.
It is more that adjuvant uses, and namely the raw material proportion is less, then is conducive to disintegrate and the stripping of tablet, on the contrary the disintegrate of tablet and stripping all can slow down, dissolution also can reduce.During forming, each prescription of the present invention also found similar phenomenon.When the imatinib mesylate proportion surpasses 60%, regulate supplementary product kind and consumption and all can not realize the target that medicine discharges fully when 10min.Certainly, immoderate increase supplementary product consumption is also improper, can bring following two shortcomings: (1) increases production cost; (2) volumes of formulation is excessive, is unfavorable for swallowing.Research worker of the present invention is found, when increasing supplementary product consumption, when making imatinib mesylate proportion less than 45%, the dissolution that dissolution during prepared tablet 10min is not significantly higher than the imatinib mesylate proportion when being 45%～60% tablet 10min, and this moment with dosage be the 400mg imatinib when making tablet the weight of tablet will surpass 1066mg, be unfavorable for swallowing.So the ratio of imatinib mesylate is decided to be 45%～60%.
Disintegrating agent can be selected from polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, and disintegrating agent accounts for 10%～25% of total amount.Research worker of the present invention is found, when the disintegrating agent ratio is less than 10%, how to be regulated the target that discharges fully when prescription all can't be realized 10min.Add in disintegrating agent is existing and add, in to add ratio be 1: 3～3: 1, the dissolution when exceeding this ratio during 10min reduces obviously.
Contained filler is microcrystalline Cellulose, and filler can account for 20%～40% of tablet gross mass.Microcrystalline Cellulose has certain advantage than other filleies on mobile and water swellability, be conducive to the disintegrate of tablet.Research worker of the present invention has also been attempted such as filleies such as starch, dextrin, and effect is all not as microcrystalline Cellulose, the target that discharges fully in the time of mostly can not realizing 10min.
The present invention with lubricator is silicon dioxide, magnesium stearate, Pulvis Talci, Polyethylene Glycol, also can mix use.Account for the 1%-5% of tablet gross mass.
Why the present invention adopts dry granulation, is because research worker of the present invention has been attempted the openly interior a lot of prescriptions of scope of wet granulation preparation, the target that discharges fully when all not having to realize 10min.And the particle diameter of finding crude drug does not have impact substantially on dissolution.
When dry granulation pressure is lower than 3MPa, can not become granule, almost be fine powder entirely.When dry granulation pressure was higher than 10MPa, dissolution descended after the compacting in flakes, and the dissolution during 10min is far below 85%.The target that discharges fully in the time of can realizing 10min when granulation pressure is 3～10MPa.Granulate again with failing the fine powder of granulating that once the result of extraction of the prepared sample of grain is the same for the result of extraction of rear prepared sample and system only.
If when research worker of the present invention is also found to adopt wet granulation technology according to not using hydroxypropyl methylcellulose only to use microcrystalline Cellulose as binding agent described in the patent CN03808869.X then can't granulation; If use hydroxypropyl methylcellulose then stripping is slack-off, the dissolution during 10min is lower than 85%.So research worker of the present invention thinks that microcrystalline Cellulose can not treat as binding agent in this kind, can only treat as filler.Compare with CN03808869.X, the present invention has avoided the use of binding agent hydroxypropyl methylcellulose, has realized that still the granule granulating is good, and stripping is effect rapidly.
The specific embodiment
Following examples are to specify of the present invention, should not be construed as limiting scope of the present invention.
Embodiment 1～3
Preparation technology:
I) it is for subsequent use that imatinib mesylate, microcrystalline Cellulose and polyvinylpolypyrrolidone are crossed 60 mesh sieves;
Ii) take by weighing imatinib mesylate, microcrystalline Cellulose and Nei Jia polyvinylpolypyrrolidone mix homogeneously partly;
Iii) add silicon dioxide and the magnesium stearate of part in taking by weighing, mix homogeneously;
Iv) dry granulating machine is granulated, pressure 5MPa;
V) add the adjuvant of Extra Section in the prescription ratio, mix homogeneously;
Vi) compacting is in blocks, hardness 6～8kg/cm
2
Embodiment 4
Prescription is with embodiment 1
Preparation technology:
I) imatinib mesylate is crossed 200 mesh sieves, and it is for subsequent use that microcrystalline Cellulose and polyvinylpolypyrrolidone are crossed 60 mesh sieves;
Ii) take by weighing imatinib mesylate, microcrystalline Cellulose and Nei Jia polyvinylpolypyrrolidone mix homogeneously partly;
Iii) add silicon dioxide and the magnesium stearate of part in taking by weighing, mix homogeneously;
Iv) dry granulating machine is granulated, pressure 5MPa;
V) add the adjuvant of Extra Section in the prescription ratio, mix homogeneously;
Vi) compacting is in blocks, hardness 6～8kg/cm
2
Embodiment 5
With embodiment 1 prepared tablet Opadry coating.
Embodiment 6
Preparation technology:
I) it is for subsequent use that imatinib mesylate, microcrystalline Cellulose and polyvinylpolypyrrolidone are crossed 60 mesh sieves;
Ii) take by weighing imatinib mesylate, microcrystalline Cellulose and Nei Jia polyvinylpolypyrrolidone mix homogeneously partly;
Iii) add silicon dioxide and the magnesium stearate of part in taking by weighing, mix homogeneously;
Iv) dry granulating machine is granulated, pressure 5MPa;
V) add the adjuvant of Extra Section in the prescription ratio, mix homogeneously;
Vi) compacting is in blocks, hardness 6～8kg/cm
2
Embodiment 7
Prescription is with embodiment 6
Preparation technology:
I) it is for subsequent use that imatinib mesylate, microcrystalline Cellulose and polyvinylpolypyrrolidone are crossed 60 mesh sieves;
Ii) take by weighing imatinib mesylate, microcrystalline Cellulose and Nei Jia polyvinylpolypyrrolidone mix homogeneously partly;
Iii) add silicon dioxide and the magnesium stearate of part in taking by weighing, mix homogeneously;
Iv) dry granulating machine is granulated, pressure 7MPa;
V) add the adjuvant of Extra Section in the prescription ratio, mix homogeneously;
Vi) compacting is in blocks, hardness 8～10kg/cm
2
Comparative Examples 1～2 prepares the imatinib tablet according to the disclosed wet granulation technology of CN03808869.X, granulates with alcoholic solution
Preparation technology:
I) it is for subsequent use that imatinib mesylate is crossed 60 mesh sieves;
Ii) take by weighing the particulate component mix homogeneously;
Iii) gently grind one side on one side and drip 95% ethanol soft material processed;
Iv) crossing 30 mesh sieves granulates;
V) drying;
Vi) 30 mesh sieve granulate;
Vii) add material, mix homogeneously in the adding of prescription ratio;
Viii) compacting is in blocks, hardness 6～9kg/cm
2
Comparative Examples 3 prepares the imatinib tablet according to the disclosed wet granulation technology of CN03808869.X, granulates with binding agent hydroxypropyl methylcellulose solution
Preparation technology:
I) it is for subsequent use that imatinib mesylate is crossed 60 mesh sieves, the aqueous solution (granulation solution) of the water-soluble formation 2.5% of hydroxypropyl methylcellulose;
Ii) take by weighing particulate component, place mortar gently to grind mix homogeneously;
Iii) gently grind one side on one side and drip granulation solution soft material processed;
Iv) crossing 30 mesh sieves granulates;
V) vacuum drying;
Vi) 30 mesh sieve granulate;
Vii) add material, mix homogeneously in the adding of prescription ratio;
Viii) compacting is in blocks, hardness 6～8kg/cm
2
According to Chinese Pharmacopoeia version appendix in 2010 XC dissolution determination the second method (oar method) 50rpm, take 1000ml0.1M HCL as dissolution medium, 37 ℃, get a mensuration dissolution at 10min, 15min and 30min.The result of embodiment and Comparative Examples is as follows:
Can be seen by above-mentioned dissolution determination result, the methylsulfonic acid imatinib tablet agent (embodiment 1-7) of technical solution of the present invention preparation, when 10min, realized the release near 90%, and according to the methylsulfonic acid imatinib tablet agent (Comparative Examples 1-3) of the disclosed wet granulation of prior art preparation, dissolution when 10min can not be realized the quick release of medicine far below 90%.
Claims (8)
1. methylsulfonic acid imatinib tablet agent that can discharge rapidly medicine, contain imatinib mesylate and pharmaceutical excipient, the weight that it is characterized in that contained imatinib mesylate is based on 45% ~ 60% of tablet total weight amount meter, described drug excipient comprises: based on the disintegrating agent of tablet total weight amount meter 10% ~ 25%, filler based on tablet total weight amount meter 20% ~ 40%, based on the lubricant of tablet total weight amount meter 1% ~ 5%, the preparation method of this tablet comprises the steps:
1. with imatinib mesylate and adjuvant mix homogeneously, wherein adjuvant comprise filler, in add the lubricant of part and the disintegrating agent of Nei Jia part;
2. dry granulation;
3. adding adds adjuvant, mix homogeneously, and wherein adding adjuvant is the lubricant of Extra Section and the disintegrating agent of Extra Section;
4. tabletting.
2. methylsulfonic acid imatinib tablet agent according to claim 1 is characterized in that described imatinib mesylate is beta crystal.
3. methylsulfonic acid imatinib tablet agent according to claim 1 is characterized in that described disintegrating agent is polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose or carboxymethyl starch sodium or its combination in any.
4. methylsulfonic acid imatinib tablet agent according to claim 1 is characterized in that described filler is microcrystalline Cellulose.
5. methylsulfonic acid imatinib tablet agent according to claim 1 is characterized in that described lubricant is silicon dioxide, magnesium stearate, Pulvis Talci or Polyethylene Glycol or its combination in any.
6. methylsulfonic acid imatinib tablet agent according to claim 1, the disintegrating agent ratio that adds part and Extra Section in it is characterized in that is 1:3 ~ 3:1.
7. methylsulfonic acid imatinib tablet agent according to claim 1, the lubricant ratio that adds part and Extra Section in it is characterized in that is 1:2 ~ 2:1.
8. methylsulfonic acid imatinib tablet agent according to claim 1, it is characterized in that step 2. in tabletting pressure be 3 ~ 10MPa.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2014115082A1 (en) * | 2013-01-22 | 2014-07-31 | Dr. Reddys Laboratories Limited | Pharmaceutical formulations of imatinib |
| CN103222965A (en) * | 2013-01-29 | 2013-07-31 | 青岛大学 | Imatinib mesylate tablet and preparation method thereof |
| CN103251599A (en) * | 2013-05-11 | 2013-08-21 | 辽宁大学 | Pharmaceutical preparation for rapidly releasing citric acid benzene ring tinib and preparation method thereof |
| CN104739785A (en) * | 2013-12-25 | 2015-07-01 | 辰欣药业股份有限公司 | Imatinib mesylate tablet with high dissolution behavior and preparation method thereof |
| CN104784133A (en) * | 2014-01-19 | 2015-07-22 | 广东东阳光药业有限公司 | Zidovudine tablets and preparation method thereof |
| CN106913547B (en) * | 2015-12-28 | 2021-09-14 | 山东新时代药业有限公司 | Acixtinib tablet and preparation method thereof |
| CN107019678A (en) * | 2016-01-30 | 2017-08-08 | 江苏奥赛康药业股份有限公司 | A kind of pharmaceutical composition containing maleic acid Afatinib |
| PL3539138T3 (en) | 2016-11-11 | 2021-12-13 | Curium Us Llc | Processes for generating germanium-68 with reduced volatiles |
| CN112137979B (en) * | 2020-10-29 | 2023-08-25 | 瑞阳制药股份有限公司 | Teposinib tablet and preparation method thereof |
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| US5521184A (en) * | 1992-04-03 | 1996-05-28 | Ciba-Geigy Corporation | Pyrimidine derivatives and processes for the preparation thereof |
| CN1646103A (en) * | 2002-04-23 | 2005-07-27 | 诺瓦提斯公司 | High drug load tablet |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5521184A (en) * | 1992-04-03 | 1996-05-28 | Ciba-Geigy Corporation | Pyrimidine derivatives and processes for the preparation thereof |
| CN1646103A (en) * | 2002-04-23 | 2005-07-27 | 诺瓦提斯公司 | High drug load tablet |
Non-Patent Citations (1)
| Title |
|---|
| 林宁等.片剂.《药剂学》.湖北科学技术出版社,2008,(第1版),第145页，第147页，第148页，第163页. * |
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