CN105640936A - Eribulin mesylate pharmaceutical composition and preparation method - Google Patents
Eribulin mesylate pharmaceutical composition and preparation method Download PDFInfo
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- CN105640936A CN105640936A CN201410633693.8A CN201410633693A CN105640936A CN 105640936 A CN105640936 A CN 105640936A CN 201410633693 A CN201410633693 A CN 201410633693A CN 105640936 A CN105640936 A CN 105640936A
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- methanesulfonic acid
- pharmaceutical composition
- acid eribulin
- microcrystalline cellulose
- pregelatinized starch
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Abstract
The present invention discloses an eribulin mesylate pharmaceutical composition, which contains eribulin mesylate, a disintegrating agent, microcrystalline cellulose and pre-gelatinized starch, and is characterized in that a weight ratio of the microcrystalline cellulose to the pre-gelatinized starch is 1-1.5. According to the present invention, the eribulin mesylate pharmaceutical composition has good stability, provides significant advantages for product yield improving, cost removing, industrialization achieving and good clinical application, and further has advantages of effective dissolution improving and significant bioavailability improving.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to methanesulfonic acid eribulin pharmaceutical composition and preparation method thereof.
Background technology
On November 15th, 2010, FDA (Food and Drug Adminstration) (FDA) announces, Halaven (methanesulfonic acid eribulin) has got permission the metastatic breast cancer patient for treating the late chemotherapy Regimen Chemotherapy before once accepting at least 2 kinds.
Halaven is a kind of a kind of synthesising preparation having chemotherapeutic activity compound extracted from the soft sponge of black (Halichondriaokadai). This injection drug is a kind of microtubule inhibitors, can anticancer growth. Before accepting Halaven treatment, patient should first accept the treatment early stage of the chemotherapy regimen based on anthracycline and based on taxane in the past or advanced breast cancer.
Its structural formula is:
The present inventor is through the research to prior art, have been surprisingly found that, apply special adjuvant, methanesulfonic acid eribulin pharmaceutical composition prepared by special process, reliable in quality, dissolution rate is fast, not only successfully solve the problem that methanesulfonic acid eribulin is unstable, and be prone to industrialization, reduce production cost, easy to implement, remarkable in economical benefits.
Summary of the invention
The first object of the present invention is in that to provide a kind of methanesulfonic acid eribulin pharmaceutical composition, and this methanesulfonic acid eribulin pharmaceutical composition is to good stability, to improving product yield, reduce cost, realize industrialization, be better applied to clinic, there is more obvious advantage.
The second object of the present invention is in that the preparation method providing methanesulfonic acid eribulin pharmaceutical composition of the present invention, and the method is simple, and prepared methanesulfonic acid eribulin pharmaceutical composition, steady quality is reliable.
For realizing the first object of the present invention, present inventors have surprisingly found that the pharmaceutical composition of a kind of methanesulfonic acid eribulin, said composition contains methanesulfonic acid eribulin, disintegrating agent, microcrystalline Cellulose and pregelatinized Starch, it is characterised in that the weight ratio of microcrystalline Cellulose and pregelatinized Starch is 1-1.5.
Specifically, the present invention containing the pharmaceutical composition of methanesulfonic acid eribulin, component and percentage by weight that it contains be:
Methanesulfonic acid eribulin 10-15%
Disintegrating agent 4-6%
Microcrystalline Cellulose 30-45%
Pregelatinized Starch 30-37.5%
Wherein, described disintegrating agent is selected from polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose or one or more in CCMS-Na. Preferred disintegrating agent is selected from polyvinylpolypyrrolidone.
Microcrystalline Cellulose and pregelatinized Starch are the filleies of the present invention, can contain appropriate lubricant as required, for instance can contain one or both the mixture in appropriate micropowder silica gel or magnesium stearate.
The preparation method of the pharmaceutical composition more than containing methanesulfonic acid eribulin is: the adjuvant taking methanesulfonic acid eribulin and formula ratio is pulverized, and sieves for subsequent use;Methanesulfonic acid eribulin is mixed homogeneously with adjuvant mixture; Measure mixture content of dispersion, calculate tablet weight, tabletting, coating and get final product.
One of preferred version of the present invention is:
Methanesulfonic acid eribulin 10%
Polyvinylpolypyrrolidone 6%
Microcrystalline Cellulose 40%
Pregelatinized Starch 35%
Magnesium stearate 4.5%
Micropowder silica gel 4.5%
Another preferred scheme of the present invention is:
Methanesulfonic acid eribulin 15%
Polyvinylpolypyrrolidone 6%
Microcrystalline Cellulose 45%
Pregelatinized Starch 30%
Magnesium stearate 2%
Micropowder silica gel 2%
The concrete preparation method of above-mentioned methanesulfonic acid eribulin pharmaceutical composition comprises the steps:
1)Prepare: polyvinylpolypyrrolidone, pregelatinized Starch, microcrystalline Cellulose, magnesium stearate and micropowder silica gel are dried 4 hours under 80 DEG C of conditions, standby;
2)By the pregelatinized Starch of recipe quantity, microcrystalline Cellulose and methanesulfonic acid eribulin, put in container, after mix homogeneously, be ground to granularity at 80 �� 10um, standby;
3)By 2) item mixs homogeneously with the polyvinylpolypyrrolidone of recipe quantity, magnesium stearate and micropowder silica gel;
4)Tabletting: regulate suitable stiff and tablet weight, carry out tabletting;
5) coating: with 70% ethanol, the film coating agent of recipe quantity is configured to the solution that content is 10%, regulates coating pan rotating speed, inlet temperature, pressure, carries out coating;
6)Packaging: adopt aluminium-plastic bubble plate packing machine to pack;
7)Warehouse-in.
On the basis of existing pharmaceutical adjunct and preparation technology, the present inventor finds through substantial amounts of experimental study, filler is selected, find two kinds of necessary proportion relations of filler, when to make methanesulfonic acid eribulin pharmaceutical composition be above-mentioned formula and preparation technology, described pharmaceutical composition quality is effectively ensured.
Compared with prior art, present invention have the advantage that
1) methanesulfonic acid eribulin pharmaceutical composition provided by the present invention is for improving the yield of this product, reducing production cost, and being better applied to clinical treatment has very big help.
2) new methanesulfonic acid eribulin compositions provided by the present invention is through industrialized great production and study on the stability, it was demonstrated that constant product quality.
3) preparation method of new methanesulfonic acid eribulin compositions provided by the present invention, the method is simple, prepared methanesulfonic acid eribulin pharmaceutical composition reliable in quality.
4) new methanesulfonic acid eribulin compositions provided by the present invention, dissolution is fast, has higher bioavailability, is rapidly reached and needs concentration.
Detailed description of the invention
Following example are only used for explaining the present invention rather than the restriction present invention. Unless otherwise indicated, the experiment condition in the embodiment of the present invention is the experiment condition that this area is conventional.
Embodiment 1
Every 1000 described methanesulfonic acid eribulin pharmaceutical compositions, its formula consists of:
Methanesulfonic acid eribulin 40g
Polyvinylpolypyrrolidone 12g
Microcrystalline Cellulose 70g
Pregelatinized Starch 70g
Magnesium stearate 4g
Micropowder silica gel 4g
Preparation technology:
1)Prepare: polyvinylpolypyrrolidone, pregelatinized Starch, microcrystalline Cellulose, magnesium stearate and micropowder silica gel are dried 4 hours under 80 DEG C of conditions, standby;
2)By the pregelatinized Starch of recipe quantity, microcrystalline Cellulose and methanesulfonic acid eribulin, put in container, after mix homogeneously, be ground to granularity at 80 �� 10um, standby;
3)By 2) item mixs homogeneously with the polyvinylpolypyrrolidone of recipe quantity, magnesium stearate and micropowder silica gel;
4)Tabletting: regulate suitable stiff and tablet weight, carry out tabletting;
5) coating: with 70% ethanol, the film coating agent of recipe quantity is configured to the solution that content is 10%, regulates coating pan rotating speed, inlet temperature, pressure, carries out coating;
6)Packaging: adopt aluminium-plastic bubble plate packing machine to pack;
7)Warehouse-in.
Embodiment 2
Every 1000 described methanesulfonic acid eribulin pharmaceutical compositions, its formula consists of:
Methanesulfonic acid eribulin 80g
Polyvinylpolypyrrolidone 24g
Microcrystalline Cellulose 140g
Pregelatinized Starch 140g
Magnesium stearate 8g
Micropowder silica gel 8g
Preparation technology: with embodiment 1.
Embodiment 3
Every 1000 described methanesulfonic acid eribulin pharmaceutical compositions, its formula consists of:
Methanesulfonic acid eribulin 40g
Polyvinylpolypyrrolidone 16g
Microcrystalline Cellulose 120g
Pregelatinized Starch 80g
Magnesium stearate 5.3g
Micropowder silica gel 5.3g
Preparation technology: with embodiment 1.
Test example 1
This test example is in that to investigate the stability of methanesulfonic acid eribulin compositions provided by the present invention.
The accelerated test of methanesulfonic acid eribulin pharmaceutical composition
Methanesulfonic acid eribulin pharmaceutical composition is prepared according to the method for embodiment of the present invention 1-3, at 40 DEG C �� 2 DEG C, the condition of RH75% �� 5% is placed 6 months, period respectively at the 1st, 2,3, sampling in 6 months, survey according to stability check item visual inspection, and compare with 0 day data.
1, project is investigated
High spot reviews: character, have related substance and content.
2, accelerated test result
Above conclusion (of pressure testing) is it can be seen that embodiments of the invention 1-3 places 6 months every Testing index when accelerated test and compares no significant difference, good stability in 0 month, and impurity content is few, has good dissolution simultaneously.
Test example 2
Adopt 2010 editions annex XC dissolution method the second method (slurry processes) 75rpm of Chinese Pharmacopoeia. Using the Ph4.5 acetate buffer 900mL containing 0.2%SDS as dissolution medium, the stripping curve of the tablet of the detection embodiment of the present invention 1 and embodiment 3 preparation, result is as follows:
Testing result illustrates, the sample adopting the method for the present invention to prepare, and has quick dissolution rate.
Claims (7)
1. a methanesulfonic acid eribulin pharmaceutical composition, said composition contains methanesulfonic acid eribulin, disintegrating agent, microcrystalline Cellulose and pregelatinized Starch, it is characterised in that the weight ratio of microcrystalline Cellulose and pregelatinized Starch is 1-1.5.
2. methanesulfonic acid eribulin pharmaceutical composition according to claim 1, it is characterised in that the percentage by weight of described each component is:
Methanesulfonic acid eribulin 15-25%
Disintegrating agent 4-6%
Microcrystalline Cellulose 30-45%
Pregelatinized Starch 30-37.5%.
3. methanesulfonic acid eribulin pharmaceutical composition according to claim 1 and 2, it is characterised in that described disintegrating agent is selected from polyvinylpolypyrrolidone.
4. methanesulfonic acid eribulin pharmaceutical composition according to claim 3, it is characterised in that possibly together with one or both in magnesium stearate or micropowder silica gel.
5. methanesulfonic acid eribulin pharmaceutical composition according to claim 4, it is characterised in that described component and percentage by weight be:
Methanesulfonic acid eribulin 20%
Polyvinylpolypyrrolidone 6%
Microcrystalline Cellulose 35%
Pregelatinized Starch 35%
Magnesium stearate 2%
Micropowder silica gel 2%.
6. methanesulfonic acid eribulin pharmaceutical composition according to claim 4, it is characterised in that described component and percentage by weight be:
Methanesulfonic acid eribulin 15%
Polyvinylpolypyrrolidone 6%
Microcrystalline Cellulose 45%
Pregelatinized Starch 30%
Magnesium stearate 2%
Micropowder silica gel 2%.
7. a preparation method for the methanesulfonic acid eribulin pharmaceutical composition according to claim 4-6 any one, the method comprises the steps:
1)Prepare: polyvinylpolypyrrolidone, pregelatinized Starch, microcrystalline Cellulose, magnesium stearate and micropowder silica gel are dried 4 hours under 80 DEG C of conditions, standby;
2)By the pregelatinized Starch of recipe quantity, microcrystalline Cellulose and methanesulfonic acid eribulin, put in container, after mix homogeneously, be ground to granularity at 80 �� 10um, standby;
3)By 2) item mixs homogeneously with the polyvinylpolypyrrolidone of recipe quantity, magnesium stearate and micropowder silica gel;
4)Tabletting: regulate suitable stiff and tablet weight, carry out tabletting;
5) coating: with 70% ethanol, the film coating agent of recipe quantity is configured to the solution that content is 10%, regulates coating pan rotating speed, inlet temperature, pressure, carries out coating;
6)Packaging: adopt aluminium-plastic bubble plate packing machine to pack;
7)Warehouse-in.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201410633693.8A CN105640936A (en) | 2014-11-12 | 2014-11-12 | Eribulin mesylate pharmaceutical composition and preparation method |
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| CN201410633693.8A CN105640936A (en) | 2014-11-12 | 2014-11-12 | Eribulin mesylate pharmaceutical composition and preparation method |
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| CN105640936A true CN105640936A (en) | 2016-06-08 |
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| CN201410633693.8A Pending CN105640936A (en) | 2014-11-12 | 2014-11-12 | Eribulin mesylate pharmaceutical composition and preparation method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109694379A (en) * | 2017-10-24 | 2019-04-30 | 江苏恒瑞医药股份有限公司 | It is used to prepare the intermediate and preparation method thereof of eribulin |
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2014
- 2014-11-12 CN CN201410633693.8A patent/CN105640936A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109694379A (en) * | 2017-10-24 | 2019-04-30 | 江苏恒瑞医药股份有限公司 | It is used to prepare the intermediate and preparation method thereof of eribulin |
| CN109694379B (en) * | 2017-10-24 | 2020-09-11 | 江苏恒瑞医药股份有限公司 | Intermediate for preparing eribulin and preparation method thereof |
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Application publication date: 20160608 |