CN101401795A - Imatinib mesylate orally disintegrating tablets and preparation method thereof - Google Patents
Imatinib mesylate orally disintegrating tablets and preparation method thereof Download PDFInfo
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- CN101401795A CN101401795A CNA2008102265919A CN200810226591A CN101401795A CN 101401795 A CN101401795 A CN 101401795A CN A2008102265919 A CNA2008102265919 A CN A2008102265919A CN 200810226591 A CN200810226591 A CN 200810226591A CN 101401795 A CN101401795 A CN 101401795A
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- imatinib mesylate
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- orally disintegrating
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- disintegrating tablets
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Abstract
The invention relates to the technical field of pharmaceutical preparation, in particular to an orally disintegrating tablet containing imatinib mesylate and a method for preparing the same, wherein the orally disintegrating tablet comprises effective amount of the imatinib mesylate and a pharmaceutic adjuvant which is acceptable in pharmacy and can rapidly collapse and release drugs in an oral cavity. The orally disintegrating tablet containing the imatinib mesylate has the advantages of faster action speed compared with the prior tablets and capsulated drugs, has convenient use and good taste in taking, and is more suitable for children, the elderly, and patients who can not swallow solid medicines.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that contains imatinib mesylate, more particularly, the present invention relates to a kind of imatinib mesylate orally disintegrating tablets.The invention still further relates to the preparation method of described imatinib mesylate orally disintegrating tablets.
Background technology
Imatinib mesylate (Imatinib Mesylate) is the derivant of aniline pyrimidine, be Switzerland Novartis Co.,Ltd research and development a specific tyrosine kinase inhibitor (tyrosine kinases inhibitors, TKI).May 10 calendar year 2001, the imatinib oral capsule preparation enters the U.S. FDA express train and examines passage to have breakthrough antitumor mechanism, is used for alpha-interferon administration failure blastocyte crisis stadium, chronic stadium, quickens the granulocyte leukemia medicine for treatment of stadium.
After clinical verification widely, imatinib has obtained the high evaluation of global medical circle, on February 1st, 2002, FDA ratified its 2nd suitable disease again---be used for the treatment of the treatment of gastrointestinal tract Leydig's cell tumor, at present as the first-line treatment medication of chronic myelocytic leukemia, be described as in recent years the oral cancer therapy drug of " important breakthrough is arranged " by medical circle, become another " unexpected rival " of galloping on world's medical market.
Imatinib also is first medicine according to tumor cell activity principle design, thus make many patients firm the confidence of the beat cancer serious illness.After states such as the U.S., European Union and Japan obtained the status of rare medicine, more than 80 country checked and approved and is used for chronic myelocytic leukemia in the whole world now, and also checks and approves the treatment that is used for the gastrointestinal tract Leydig's cell tumor in many developed countries and developing country.
The mechanism of action of imatinib is the binding site of competitive inhibition adenosine triphosphate (ATP) and thymidine kinase (TK) receptor such as KIT, retardance TK phosphorylation, thereby suppress the signal conduction, and can suppress that the KIT relevant with kinase activity suddenlys change (causing the KIT receptor activation) and the KIT of wild type.Its target site mainly contains 3 kinds: Abelson (ABL) albumen, KIT albumen and platelet derived growth factor (PDGF) receptor.Imatinib can cause that the activation that does not rely on stem cell factor reduces the tyrosine phosphorylation of the cell line (GIST882) from GIST, when concentration reaches 1umol/L, can suppress tyrosine phosphorylation fully by the acquired KIT sudden change of function.
After imatinib is taken, well absorbed in 2-4 hour, average bioavailability reaches 98%.According to healthy volunteer's clinical setting statistics, about 18 hours of half-life of imatinib and its major metabolite and the half-life of N-demethyl (demethylation nitrogen) is 40 hours.The average A UC value of imatinib will increase along with the growth (25mg-1000mg) of drug dose.After multiple use, the character aspect pharmacokinetics does not have significant change.Under medicine kept taking every day once situation, the effect of medicine can be stabilized between the 75%-85%.
Imatinib is after China is through more than a year clinical trial and examination, and in the production certification of acquisition on April 17th, 2002 SFDA of State Food and Drug Administration, enter hospital terminal with trade name " imatinib mesylate " third season in the same year first.The present clinical practice dosage form of imatinib mainly contains tablet and capsule, needs patient's water to swallow, and has certain inconvenience for the patient of child, old people and the solid chemicals of can not swallowing.
Summary of the invention
Purpose of the present invention just is a kind of stable in properties, evident in efficacy is provided, and is suitable for the imatinib mesylate orally disintegrating tablets of patient's use of child, old people and the solid chemicals of can not swallowing.
Another order of the present invention is to provide the preparation method of above-mentioned imatinib mesylate orally disintegrating tablets, and it adopts modern technology of preparing, but commercial scale, high efficiency production, and it is stable that product quality keeps.
Imatinib mesylate orally disintegrating tablets of the present invention, its contain the principal agent imatinib mesylate and can be in the oral cavity rapidly the disintegrate pharmaceutic adjuvant that discharges medicine comprise that water solublity fills out agent, disintegrating agent, lubricant and wetting agent or binding agent.
Various main materials and auxiliary materials weight shares prescription in the total amount shared ratio as follows:
Principal agent 5～50%
Water-soluble filler 10～70%
Disintegrating agent 5～50%
Lubricant 0.5～5%
Wetting agent or binding agent 1～10%
Water-soluble filler is selected from erythrose, mannitol, sorbitol, xylitol or other and helps the material of moisture penetration in the pharmaceutical preparation, or the mixture of above two or more material.
Disintegrating agent is selected from the mixture of microcrystalline Cellulose (MCC), low-substituted hydroxypropyl cellulose (L-HPC), cross-linked carboxymethyl cellulose sodium (CCNa), crosslinked polyethylene pyrrole alkane ketone (PVPP), crosslinked carboxymethylstach sodium (CCMS-Na) or above two or more material.
Can also contain gas-producing disintegrant in the above-mentioned disintegrating agent, as citric acid, tartaric acid, fumaric acid, sodium bicarbonate, sodium glycine carbonate, Glycine sodium fumarate, or the mixture of above two or more material.
Lubricant can be selected magnesium stearate, Pulvis Talci, silicon dioxide for use, or the mixture of above two or more material.
The optional water of wetting agent, ethanol, or the mixture of the two.
Binding agent can be selected starch slurry, polyvidone or various cellulose family for use, or the mixture of above two or more material.
For covering the bitterness of imatinib mesylate, can also add the correctives that accounts for prescription gross weight 2～10% in the present invention, aspartame, cyclamate, saccharin sodium, Mentholum and various fruit powder essence etc. all can satisfy the requirement that improves the imatinib mesylate orally disintegrating tablets mouthfeel.
This dosage form adopts wet granulation technology, can use conventional tablet pharmaceutical equipment production.
Concrete preparation method is as described below:
Take by weighing imatinib mesylate, water-soluble filler, correctives by 100 mesh sieves; add an amount of wetting agent or binding agent granulation behind the mix homogeneously; with all the other adjuvants and dried particles mix homogeneously, the qualified back of the inspection of semifinished product adds lubricant, and tabletting promptly behind the mixing.
The imatinib mesylate orally disintegrating tablets that the present invention makes has the following advantages:
The first, disintegrate is rapid, and is rapid-action.The present invention can be in 45 seconds in mouth disintegrate fast, make the rapid stripping of medicine, compare with imatinib mesylate conventional tablet or capsule, shortened dissolution time, accelerate its absorption, make medicine can bring into play the whole body therapeutic effect rapidly.
The second, drug absorption is abundant.The present invention before reaching gastrointestinal tract rapidly disintegrate also be dispersed into trickle granule, cause medicine to distribute in the gastrointestinal tract large tracts of land, absorption point increases, and absorbs more fully, so also helps improving bioavailability of medicament.
The 3rd, medication is convenient, good mouthfeel.The present invention needn't use water delivery service, saliva can make oral cavity disintegration tablet disintegrate or dissolving, both can resemble ordinary tablet swallows, can be placed in the water again and take after the disintegrate, also can need not to take medicine with water swallow, can take whenever and wherever possible, provide a great convenience condition, can guarantee that more medicine takes on time for the patient takes medicine.
The 4th, the present invention has refrigerant Herba Menthae and fruit aroma and does not have obvious abnormal flavour after taste masking is handled, no sand type, help improving the patient take medicine compliance.
The generation of above-mentioned effect be because, it is described: water-soluble fillers such as erythrose and mannitol orally-dissolvable rapidly, cool taste is sweet and tasty, to thermally-stabilised, non-hygroscopic, can increase the hardness of tablet, very little to the disintegrate influence, be the desirable filler of oral cavity disintegration tablet; Microcrystalline Cellulose plays dual parts to fill and disintegrate in this test recipe, it has spongiform porous tubular structured, during pressurized, loose structure is by disorderly and unsystematic and become linear array, plastic deformation in addition, make it meet water after, hydrone enters tablet inside, destroy the hydrogen bond between the crystallite, impel disintegration of tablet; Low-substituted hydroxypropyl cellulose (L-HPC) has good hygroscopicity, meets water-soluble expanding and microcrystalline Cellulose when being used, and can play the disintegrate effect of the best.Citric acid contacts low amounts of water with sodium bicarbonate just can produce a large amount of bubbles, has helped the disintegrate of tablet more; Mentholum has the bad flavor of smelling that local anesthetic action can masking agents because of it, and cool taste, share as correctives to reach the flavoring effect with sweeting agents such as aspartame and essence.
The specific embodiment
Imatinib mesylate orally disintegrating tablets of the present invention contains principal agent, water-soluble filler, disintegrating agent, lubricant, also contains wetting agent or binding agent, the main materials and auxiliary materials weight share prescription in the total amount shared preferred proportion as follows:
Principal agent 20～40%
Water-soluble filler 20～50%
Disintegrating agent 15～35%
Lubricant 1～2%
Wetting agent or binding agent 2～5%
Water-soluble filler is erythrose and mannitol preferably.
Disintegrating agent is microcrystalline Cellulose (MCC), low-substituted hydroxypropyl cellulose (L-HPC), citric acid and sodium bicarbonate preferably.
Correctives is aspartame, Mentholum and various fruit powder essence preferably.
Wetting agent or binding agent be the second alcohol and water preferably.
By specific embodiment given below, can further be well understood to the present invention, but they not limitation of the invention.
Embodiment 1
Imatinib mesylate 50g (by imatinib)
Mannitol 88g
Low-substituted hydroxypropyl cellulose 18g
Microcrystalline Cellulose 72g
Aspartame 3g
Magnesium stearate 3g
Water is an amount of
Concrete preparation method is as described below:
Take by weighing imatinib mesylate, mannitol, aspartame by 100 mesh sieves; adding suitable quantity of water behind the mix homogeneously granulates; take by weighing by prescription and to add adjuvant low-substituted hydroxypropyl cellulose, microcrystalline Cellulose and dried particles mix homogeneously; the qualified back of the inspection of semifinished product adds magnesium stearate; tabletting behind the mixing; make 1000, promptly.
Embodiment 2
Imatinib mesylate 50g (by imatinib)
Erythrose 125g
Low-substituted hydroxypropyl cellulose 32g
Microcrystalline Cellulose 96g
Aspartame 4g
Mentholum 1g
Magnesium stearate 4g
50% alcoholic solution is an amount of
Concrete preparation method is as described below:
Take by weighing imatinib mesylate, erythrose, aspartame, Mentholum by 100 mesh sieves; adding an amount of 50% alcoholic solution behind the mix homogeneously granulates; take by weighing by prescription and to add adjuvant low-substituted hydroxypropyl cellulose, microcrystalline Cellulose and dried particles mix homogeneously; the qualified back of the inspection of semifinished product adds magnesium stearate; tabletting behind the mixing; make 1000, promptly.
Embodiment 3
Imatinib mesylate 100g (by imatinib)
Erythrose 125g
Polyvinylpolypyrrolidone 40g
Microcrystalline Cellulose 80g
Citric acid 8g
Sodium bicarbonate 4g
Magnesium stearate 4g
50% alcoholic solution is an amount of
Concrete preparation method is as described below:
Take by weighing imatinib mesylate, erythrose by 100 mesh sieves; adding an amount of 50% alcoholic solution behind the mix homogeneously granulates; take by weighing by prescription and to add adjuvant polyvinylpolypyrrolidone, microcrystalline Cellulose, citric acid and sodium bicarbonate and dried particles mix homogeneously; the qualified back of the inspection of semifinished product adds magnesium stearate; tabletting behind the mixing; make 1000, promptly.
Embodiment 4
Imatinib mesylate 100g (by imatinib)
Erythrose 125g
Cross-linking sodium carboxymethyl cellulose 30g
Microcrystalline Cellulose 80g
Citric acid 8g
Chocolate powder essence 10g
Sodium bicarbonate 8g
Magnesium stearate 4g
Silicon dioxide 4g
50% alcoholic solution is an amount of
Concrete preparation method is as described below:
Take by weighing imatinib mesylate, erythrose, chocolate powder essence by 100 mesh sieves; adding an amount of 50% alcoholic solution behind the mix homogeneously granulates; take by weighing by prescription and to add adjuvant cross-linked carboxymethyl cellulose, microcrystalline Cellulose, citric acid and sodium bicarbonate and dried particles mix homogeneously; the qualified back of the inspection of semifinished product adds magnesium stearate and silicon dioxide; tabletting behind the mixing; make 1000, promptly.
Embodiment 5
Imatinib mesylate 100g (by imatinib)
Mannitol 80g
Low-substituted hydroxypropyl cellulose 20g
Microcrystalline Cellulose 70g
Citric acid 3g
Aspartame 3g
Mentholum 1g
Chocolate powder essence 3g
Sodium bicarbonate 9g
Magnesium stearate 3g
Water is an amount of
Concrete preparation method is as described below:
Take by weighing imatinib mesylate, mannitol, aspartame, Mentholum, chocolate powder essence by 100 mesh sieves; adding suitable quantity of water solution behind the mix homogeneously granulates; take by weighing by prescription and to add adjuvant low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, citric acid and sodium bicarbonate and dried particles mix homogeneously; the qualified back of the inspection of semifinished product adds magnesium stearate; tabletting behind the mixing; make 1000, promptly.
Embodiment 6
Imatinib mesylate 200g (by imatinib)
Erythrose 120g
Low-substituted hydroxypropyl cellulose 30g
Microcrystalline Cellulose 100g
Citric acid 6g
Aspartame 4g
Mentholum 1g
Chocolate powder essence 8g
Sodium bicarbonate 20g
Magnesium stearate 4g
50% alcoholic solution is an amount of
Concrete preparation method is as described below:
Take by weighing imatinib mesylate, erythrose, aspartame, Mentholum, chocolate powder essence by 100 mesh sieves; adding an amount of 50% alcoholic solution behind the mix homogeneously granulates; take by weighing by prescription and to add adjuvant low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, citric acid and sodium bicarbonate and dried particles mix homogeneously; the qualified back of the inspection of semifinished product adds magnesium stearate; tabletting behind the mixing; make 1000, promptly.
Embodiment 7
Imatinib mesylate 200g (by imatinib)
Erythrose 125g
Polyvinylpolypyrrolidone 50g
Microcrystalline Cellulose 60g
Citric acid 8g
Aspartame 5g
Mentholum 2g
Chocolate powder essence 5g
Sodium bicarbonate 4g
Magnesium stearate 4g
50% alcoholic solution is an amount of
Concrete preparation method is as described below:
Take by weighing imatinib mesylate, erythrose, aspartame, Mentholum, chocolate powder essence by 100 mesh sieves; adding an amount of 50% alcoholic solution behind the mix homogeneously granulates; take by weighing by prescription and to add adjuvant polyvinylpolypyrrolidone, microcrystalline Cellulose, citric acid and sodium bicarbonate and dried particles mix homogeneously; the qualified back of the inspection of semifinished product adds magnesium stearate; tabletting behind the mixing; make 1000, promptly.
Claims (8)
1, a kind of oral cavity disintegration tablet that contains imatinib mesylate is characterized in that, it contain effective dose imatinib mesylate and pharmaceutically acceptable and can be in the oral cavity rapidly disintegrate discharge the pharmaceutic adjuvant of medicine.
2, according to the described imatinib mesylate orally disintegrating tablets of claim 1, it is characterized in that containing principal agent imatinib mesylate, water-soluble filler, disintegrating agent, lubricant, also contain wetting agent or binding agent, each main materials and auxiliary materials weight share shared ratio in the prescription total amount is:
Principal agent 5～50%
Water-soluble filler 10～70%
Disintegrating agent 10～50%
Lubricant 0.5～5%
Wetting agent or binding agent 1～10%.
3,, it is characterized in that main materials and auxiliary materials weight share shared ratio in the prescription total amount is according to the described imatinib mesylate orally disintegrating tablets of claim 2:
Principal agent 20～40%
Water-soluble filler 20～50%
Disintegrating agent 15～35%
Lubricant 1～2%
Wetting agent or binding agent 2～5%.
4, according to claim 2 or 3 described imatinib mesylate orally disintegrating tablets, it is characterized in that water-soluble filler selects erythrose, mannitol, sorbitol or xylitol for use, or 1, the mixture of two or more material of 2_k.
5, according to claim 2 or 3 described imatinib mesylate orally disintegrating tablets, it is characterized in that disintegrating agent selects microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, crosslinked polyethylene pyrrole alkane ketone or crosslinked carboxymethylstach sodium for use, or the mixture of above two or more material.
6, according to claim 2 or 3 described imatinib mesylate orally disintegrating tablets, it is characterized in that lubricant selects magnesium stearate, silicon dioxide or Pulvis Talci for use, or the mixture of above two or more material.
7, according to claim 2 or 3 described imatinib mesylate orally disintegrating tablets, it is characterized in that selecting for use wetting agent, is water or ethanol and wetting agent is selected for use, or water and alcoholic acid mixture.
8, according to claim 2 or 3 described imatinib mesylate orally disintegrating tablets, it is characterized in that selecting for use binding agent, is starch slurry, polyvidone or various cellulose family and binding agent is selected for use, or the mixture of above two or more material.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008102265919A CN101401795A (en) | 2008-11-17 | 2008-11-17 | Imatinib mesylate orally disintegrating tablets and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008102265919A CN101401795A (en) | 2008-11-17 | 2008-11-17 | Imatinib mesylate orally disintegrating tablets and preparation method thereof |
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| CN101401795A true CN101401795A (en) | 2009-04-08 |
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| CNA2008102265919A Pending CN101401795A (en) | 2008-11-17 | 2008-11-17 | Imatinib mesylate orally disintegrating tablets and preparation method thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102302464A (en) * | 2011-08-04 | 2012-01-04 | 上海希迪制药有限公司 | Imatinib mesylate tablet |
| WO2013077815A1 (en) | 2011-11-24 | 2013-05-30 | Ak Farma İlaç Sanayi Ve Ticaret A.Ş. | Imatinib solid dosage forms reconstituted just before use |
| CN103222965A (en) * | 2013-01-29 | 2013-07-31 | 青岛大学 | Imatinib mesylate tablet and preparation method thereof |
| CN103405393A (en) * | 2013-08-02 | 2013-11-27 | 浙江华海药业股份有限公司 | Imatinib mesylate pill and preparation method thereof |
| CN104013589A (en) * | 2014-05-07 | 2014-09-03 | 万特制药(海南)有限公司 | Axitinib orally disintegrating tablet and preparation method thereof |
| WO2017129624A1 (en) | 2016-01-25 | 2017-08-03 | Krka, D.D., Novo Mesto | Fast dispersible pharmaceutical composition comprising tyrosine-kinase inhibitor |
-
2008
- 2008-11-17 CN CNA2008102265919A patent/CN101401795A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102302464A (en) * | 2011-08-04 | 2012-01-04 | 上海希迪制药有限公司 | Imatinib mesylate tablet |
| CN102302464B (en) * | 2011-08-04 | 2015-12-16 | 上海创诺制药有限公司 | A kind of imatinib mesylate tablet |
| WO2013077815A1 (en) | 2011-11-24 | 2013-05-30 | Ak Farma İlaç Sanayi Ve Ticaret A.Ş. | Imatinib solid dosage forms reconstituted just before use |
| CN103222965A (en) * | 2013-01-29 | 2013-07-31 | 青岛大学 | Imatinib mesylate tablet and preparation method thereof |
| CN103405393A (en) * | 2013-08-02 | 2013-11-27 | 浙江华海药业股份有限公司 | Imatinib mesylate pill and preparation method thereof |
| CN104013589A (en) * | 2014-05-07 | 2014-09-03 | 万特制药(海南)有限公司 | Axitinib orally disintegrating tablet and preparation method thereof |
| WO2017129624A1 (en) | 2016-01-25 | 2017-08-03 | Krka, D.D., Novo Mesto | Fast dispersible pharmaceutical composition comprising tyrosine-kinase inhibitor |
| EA035891B1 (en) * | 2016-01-25 | 2020-08-27 | КРКА, д.д., НОВО МЕСТО | Fast dispersible pharmaceutical composition comprising tyrosine-kinase inhibitor |
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Open date: 20090408 |