CN105640935A - Eribulin mesylate pharmaceutical composition for injection - Google Patents
Eribulin mesylate pharmaceutical composition for injection Download PDFInfo
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- CN105640935A CN105640935A CN201410633576.1A CN201410633576A CN105640935A CN 105640935 A CN105640935 A CN 105640935A CN 201410633576 A CN201410633576 A CN 201410633576A CN 105640935 A CN105640935 A CN 105640935A
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- injection
- methanesulfonic acid
- acid eribulin
- eribulin
- citrate buffer
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Abstract
The present invention relates to a stable eribulin mesylate pharmaceutical composition, wherein the injection specifically comprises eribulin mesylate or a pharmaceutically acceptable salt thereof, and additional agents for injection, the additional agents at least comprise a citrate buffer liquid (pH=6.2), and other additional agents are selected from sodium chloride. The eribulin mesylate injection of the present invention has characteristics of good light resistance, stable pH value, low skin irritation, and easy industrialization achieving.
Description
Technical field
The present invention relates to the medicine in field of medicaments, methanesulfonic acid eribulin pharmaceutical composition especially relating to a kind of stable injection and preparation method thereof.
Background technology
Cancer is the term for describing wide variety of various disease, and these diseases are each grown to feature with the uncontrolled of specific cell type. It starts from the tissue containing such cell, and if diagnosis time cancer be not yet diffused into any other tissue, it is possible to by such as operation, radiate or other kinds of local treatment treat. But, when evidence suggests that cancer shifts from its tissue of origin, it is common to use diverse ways is treated. It is true that owing to not can determine that transfer scope, systematic treating method is therefore usually taken when any diffusion evidence being detected. These methods include the chemotherapeutics using the growth of interference quick somatoblast such as cancerous cell. Eribulin mesylate (a kind of halichondrin b analogs) is as cancer therapy drug. Recently, eribulin mesylate accepted at least two for treating the patient suffering from metastatic breast cancer of the chemotherapeutic regimen of metastatic disease before being approved for treatment, and wherein previous therapy potentially includes anthracycline antibiotics and/or the taxane of auxiliary or transfer setting. Whether prediction cancer patient is likely to anticancer agent is had reactive ability before the treatment, it is possible to instruct the treatment selecting to be suitable for, and to benefits subjects. Therefore, for can be used for assessing in the patient suffering from cancer, particularly breast carcinoma or predict that the compositions to eribulin also exists demand.
Present invention employs with aqueous solution of citric acid (pH=6.2), and make the pH stability of medicine be improved, shelf stable for periods can reach 36 months, in the present broader pH value range of the favorite outgoing of development process (pH5.5-7.0), with external commercially available methanesulfonic acid eribulin injection, there is more excellent stability with the methanesulfonic acid eribulin injection that aqueous solution of citric acid and sodium chloride are adjuvant, and prove that the injection obtained by this formula is without hemolytic by pharmacological evaluation, blood vessel irritation and anaphylaxis, the methanesulfonic acid eribulin injection that prior art produces is to storage, the requirement of lucifuge has very strict requirement, through sunlight pH change substantially, all there is inconvenience in process of production.
The present inventor is through studying for a long period of time, have been surprisingly found that, apply special buffer system, methanesulfonic acid eribulin pharmaceutical composition prepared by special process, light resistance is good, good stability, the problem not only successfully solving the poor stability of methanesulfonic acid eribulin, easy to implement, it may be achieved industrialization, remarkable in economical benefits.
Summary of the invention
The present invention provides the stable injection of a kind of methanesulfonic acid eribulin or officinal salt, and in this injection, the concentration of methanesulfonic acid eribulin is 0.1mg/ml ~ 1mg/ml, it will be preferred that 0.5mg/ml.
The pharmaceutic adjuvant (injection additives) that the methanesulfonic acid eribulin injection of the present invention adopts includes sodium chloride and citrate buffer (pH=6.2), sodium chloride described here is as isoosmotic adjusting agent and stabilizer, wherein the concentration range of sodium chloride is 1mg/ml ~ 20g/ml, preferably 4 ~ 8mg/ml, more preferably 6mg/ml.
The concentration range of above-mentioned described citrate buffer (pH=6.2) is 30% ~ 70%, preferred 50%(volume ratio), citrate buffer can pass through citric acid and sodium hydroxide reaction prepares, compound method is for taking 2.1% aqueous solution of citric acid, regulate to pH=6.2 with 50% sodium hydroxide solution, to obtain final product.
Citrate buffer of the present invention can as pH adjusting agent, it is possible to as stabilizer.
The pH scope of methanesulfonic acid eribulin injection pharmaceutical composition of the present invention is 5.5 ~ 7.0.
The invention reside in the methanesulfonic acid eribulin pharmaceutical composition providing a kind of injection, this methanesulfonic acid eribulin injection to light stably well, to improving product yield, reduces cost, it is achieved industrialization, is better applied to clinic, has more obvious advantage.
The preparation method that the invention reside in the methanesulfonic acid eribulin pharmaceutical composition providing injection of the present invention, the method is simple, prepared methanesulfonic acid eribulin pharmaceutical composition, and light is stable, good stability.
For realizing the first object of the present invention, the present invention adopts the following technical scheme that
A kind of methanesulfonic acid eribulin pharmaceutical composition of injection, every 1000 described methanesulfonic acid eribulin pharmaceutical compositions, its formula consists of:
Methanesulfonic acid eribulin 2.5g
Citrate buffer (pH=6.2) 2.5L
Sodium chloride 30g
Water for injection adds to 5L.
Methanesulfonic acid eribulin pharmaceutical composition of the present invention is adopted and is prepared with the following method:
1) weigh sodium chloride, add citrate buffer, add appropriate water for injection and be dissolved to completely;
2) add 0.1% medicinal charcoal of water for injection volume, heat 5 minutes depyrogenations, filtering decarbonization, obtain filtrate;
3) it is cooled to 40-50 DEG C, adds methanesulfonic acid eribulin, dissolve, add to the full amount of water for injection, regulate pH scope 5.5-7.0 with citric acid soln or sodium hydroxide solution if desired;
4) gained solution mixed cellulose ester microporous membrane fine straining, obtains filtrate, embedding in ampoule bottle, 121 DEG C of pressure sterilizings 15 minutes, obtain methanesulfonic acid eribulin injection finished product.
Below to the more detailed elaboration of the present invention:
One aspect of the present invention provides the methanesulfonic acid eribulin pharmaceutical composition of a kind of injection, every 1000 described methanesulfonic acid eribulin pharmaceutical compositions, and its formula consists of:
Methanesulfonic acid eribulin 2.5g
Citrate buffer (pH=6.2) 2.5L
Sodium chloride 30g
Water for injection adds to 5L.
Traditional methanesulfonic acid eribulin injection, photostability is poor, and quality cannot ensure.
In the present invention, in the stability study process to methanesulfonic acid eribulin injection light, it has been found that select citrate buffer system, re-dissolved methanesulfonic acid eribulin, it is possible to be effectively improved the said preparation stability to light, have related substance unchanged.Through the summary of the screening of tens of time test recipes and test data, optimize its recipe quantity, the problem not only solving photostability difference, and constant product quality.
The present inventor finds through substantial amounts of experimental study, and when methanesulfonic acid eribulin pharmaceutical composition is above-mentioned formula, the quality of described injection is best, and stability is best.
The preparation method that another aspect of the present invention provides methanesulfonic acid eribulin injection of the present invention, the method is simple, and prepared methanesulfonic acid eribulin injection is stable to light, good stability.
Preparation method provided by the present invention includes:
1) weigh sodium chloride, add citrate buffer, add appropriate water for injection and be dissolved to completely;
2) add 0.1% medicinal charcoal of water for injection volume, heat 5 minutes depyrogenations, filtering decarbonization, obtain filtrate;
3) it is cooled to 40-50 DEG C, adds methanesulfonic acid eribulin, dissolve, add to the full amount of water for injection, regulate pH scope 5.5-7.0 with citric acid soln or sodium hydroxide solution if desired;
4) gained solution mixed cellulose ester microporous membrane fine straining, obtains filtrate, embedding in ampoule bottle, 121 DEG C of pressure sterilizings 15 minutes, obtain methanesulfonic acid eribulin injection finished product.
According to the inventive method prepare methanesulfonic acid eribulin injection through industrial amplification production machine study on the stability, it was demonstrated that product is stable, and through pharmacology, toxicological test, solution is non-stimulated to blood vessel, without anaphylaxis, also without haemolysis, to human body fanout free region.
In preparation method of the present invention, the consumption of described medicinal charcoal is 0.1%.
Add appropriate medicinal charcoal and can improve the clarity of solution, thermal source, pigment can be adsorbed again, methanesulfonic acid eribulin be there is no absorption by medicinal charcoal, the present inventor adopts UV-VIS spectrophotometry to measure the content of methanesulfonic acid eribulin, has investigated medicinal charcoal, temperature, adsorption time to the impact of methanesulfonic acid eribulin content in injection. It is shown that medicinal charcoal consumption is 0.1%, adsorption time at 30 minutes, adsorption temp at 40-50 DEG C, best results.
In preparation method of the present invention, described sterilizing is 121 DEG C of pressure sterilizings 15-20 minute, it is preferred to 121 DEG C of pressure sterilizings 15 minutes.
Product of the present invention is the sterile water solution of methanesulfonic acid eribulin, and sterilising conditions is very crucial, should reach sterilization effect, can not destroy again solution, and sterilising conditions has been investigated by the present inventor, refers to test example. It is shown that 121 DEG C of pressure sterilizings 15-20 minute, wherein 121 DEG C of pressure sterilizings 15 minutes, best results.
Compared with prior art, present invention have the advantage that
1) new methanesulfonic acid eribulin injection provided by the present invention thoroughly solves the chance light pH value instability problem of methanesulfonic acid eribulin.
2) methanesulfonic acid eribulin injection provided by the present invention is for improving the yield of this product, reducing the market risk of product, and being better applied to clinical treatment has very big help.
3) 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, through pharmacology, toxicological test, solution is non-stimulated to blood vessel, without anaphylaxis, also without haemolysis, to human body fanout free region.
4) preparation method of new methanesulfonic acid eribulin compositions provided by the present invention, the method is simple, and prepared methanesulfonic acid eribulin injection is stable to light, good stability.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in further detail
Embodiment 1
Every 1000 described methanesulfonic acid eribulin pharmaceutical compositions, its formula consists of:
Methanesulfonic acid eribulin 2.5g
Citrate buffer (pH=6.2) 2.5L
Sodium chloride 30g
Water for injection adds to 5L.
Preparation technology:
1) weigh sodium chloride, add citrate buffer, add appropriate water for injection and be dissolved to completely;
2) add 0.1% medicinal charcoal of water for injection volume, heat 5 minutes depyrogenations, filtering decarbonization, obtain filtrate;
3) it is cooled to 40-50 DEG C, adds methanesulfonic acid eribulin, dissolve, add to the full amount of water for injection, regulate pH scope 5.5-7.0 with citric acid soln or sodium hydroxide solution if desired;
4) gained solution mixed cellulose ester microporous membrane fine straining, obtains filtrate, embedding in ampoule bottle, 121 DEG C of pressure sterilizings 15 minutes, obtain methanesulfonic acid eribulin injection finished product.
Embodiment 2
Every 1000 described methanesulfonic acid eribulin pharmaceutical compositions, its formula consists of:
Methanesulfonic acid eribulin 2.5g
Citrate buffer (pH=6.2) 3L
Sodium chloride 30g
Water for injection adds to 5L.
Preparation technology: with embodiment 1.
Test example 1
Commercially available product light stability research
Place 10 when illumination 4500lx �� 500lx, sunlight, sampled in 0,5 days, 10 days, be measured, investigate solution character and have related substance and pH value.
Above result of the test shows: commercially available product is placed 10 days when illumination 4500lx �� 500lx, sunlight, and pH changes greatly, and impurity A substantially increases, and illustrates that said preparation is to photo-labile.
Test example 2
According to physicochemical property, available data, formulate prescribed regimen, enter following table:
Prescription 1 preparation technology:
Prepare: configure 10% sodium hydroxide solution and 10% hydrochloric acid solution is appropriate, standby. Carry out raw material pure calculating actual inventory according to recipe quantity;
In preparing container, add the water for injection of recipe quantity 80%, adding after methanesulfonic acid eribulin dissolves, regulate medicinal liquid pH6.0-6.2, water for injection is to full dose, add 0.15% medicinal charcoal decolouring, filter to clear and bright, with sintered glass filter and membrane filter, and embedding under stream of nitrogen gas, last in 121 DEG C of hot pressing sterilizing in 15 minutes, to obtain final product.
Prescription 2 preparation technology:
Prepare: configure 10% sodium hydroxide solution and 10% hydrochloric acid solution is appropriate, standby. Carry out raw material pure calculating actual inventory according to recipe quantity;
In preparing container, add the water for injection of recipe quantity 80%, adding after methanesulfonic acid eribulin dissolves, regulate medicinal liquid pH6.0-6.2, water for injection is to full dose, add 0.15% medicinal charcoal decolouring, filter to clear and bright, with sintered glass filter and membrane filter, and embedding under stream of nitrogen gas, last in 121 DEG C of hot pressing sterilizing in 15 minutes, to obtain final product.
Prescription 3 preparation technology:
Prepare: configure 10% sodium hydroxide solution and 10% hydrochloric acid solution is appropriate, standby. Carry out raw material pure calculating actual inventory according to recipe quantity;
Prepared by citrate buffer: take 2.1% aqueous solution of citric acid, regulates to pH=6.2 with 50% sodium hydroxide solution, and 3L is standby in preparation;
1, weigh sodium chloride and citrate buffer, add appropriate water for injection and be dissolved to completely;
2, add 0.1% medicinal charcoal of water for injection volume, heat 5 minutes depyrogenations, filtering decarbonization, obtain filtrate;
3, it is cooled to 40-50 DEG C, adds methanesulfonic acid eribulin, dissolve, add to the full amount of water for injection, regulate pH scope 5.5-7.0 with citric acid soln or sodium hydroxide solution if desired;
4, gained solution mixed cellulose ester microporous membrane fine straining, obtains filtrate, embedding in ampoule bottle, 121 DEG C of pressure sterilizings 15 minutes, obtain methanesulfonic acid eribulin injection finished product.
Prescription 1 to prescription 3 is carried out the mensuration of index of correlation, investigates result as follows:
Above result of the test shows, all less after the maximum single impurity level of prescription 3 and total impurities amount sterilizing, is better than prescription 1 and prescription 2.
Test example 3
This test example is in that to investigate the temperature impact on methanesulfonic acid eribulin injection content under sterilising conditions:
This product is the sterile water solution of methanesulfonic acid eribulin, sterilising conditions is very crucial, sterilization effect should be reached, solution can not be destroyed again, sterilising conditions has been investigated by the present inventor, by prescription prepare certain volume methanesulfonic acid eribulin solution after, be packaged in ampoule bottle respectively at 115 DEG C 30 minutes, 121 DEG C 20 minutes, 121 DEG C 15 minutes,121 DEG C of sterilizings in 20 minutes, drug content result following table in solution after observation sterilizing:
The sterilising conditions impact on methanesulfonic acid eribulin injection content
As can be seen from the above tests: sterilising temp condition is little on this product impact, selects 121 DEG C 15 minutes, F0 > 12 reaches sterilization effect, on solution content almost without impact.
Test example 4
The accelerated test of methanesulfonic acid eribulin injection
Three batches of methanesulfonic acids eribulin injection (lot number is HK1006011, HK1006012, HK1006013 respectively) are prepared according to commercially available back according to the method for the embodiment of the present invention 1, 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, pH value, visible foreign matters, osmotic pressure molar density, have related substance and content.
2, following table is shown in by test data
Accelerated test result
Above conclusion (of pressure testing) it can be seen that this product long term test with accelerated test when place 6 months every Testing index and compare no significant difference, good stability in 0 month.
Claims (9)
1. a methanesulfonic acid eribulin pharmaceutical composition for injection, containing methanesulfonic acid eribulin or its must use salt and injection additives, it is characterised in that: injection additives include (1) citrate buffer (pH=6.2) and (2) sodium chloride.
2. methanesulfonic acid eribulin injection according to claim 1, it is characterised in that the concentration range of methanesulfonic acid eribulin is 0.1mg/ml ~ 1mg/ml.
3. methanesulfonic acid eribulin injection according to claim 2, it is characterised in that the concentration range of methanesulfonic acid eribulin is 0.5mg/ml.
4. methanesulfonic acid eribulin injection according to claim 1, it is characterised in that pH scope is 5.5-7.0.
5. any one methanesulfonic acid eribulin injection according to claim 1-4, it is characterised in that: its injection additives are citrate buffer (pH=6.2) and sodium chloride.
6. methanesulfonic acid eribulin injection according to claim 1, the compound method of its described citrate buffer (pH=6.2) is take 2.1% aqueous solution of citric acid, regulates to pH=6.2 with 50% sodium hydroxide solution, to obtain final product.
7. methanesulfonic acid eribulin injection according to claim 1, the concentration range of its described citrate buffer (pH=6.2) is 30%-70%.
8. any one methanesulfonic acid eribulin injection according to claim 1-7, it is characterised in that every 1000 its formula consist of:
Methanesulfonic acid eribulin 2.5g
Citrate buffer (pH=6.2) 2.5L
Sodium chloride 30g
Water for injection adds to 5L.
9. the method preparing methanesulfonic acid eribulin injection according to claim 1, it is characterised in that the method includes procedure below:
1)Weigh sodium chloride, add citrate buffer, add appropriate water for injection and be dissolved to completely;
2)Add 0.1% medicinal charcoal of water for injection volume, heat 5 minutes depyrogenations, filtering decarbonization, obtain filtrate;
3)It is cooled to 40-50 DEG C, adds methanesulfonic acid eribulin, dissolve, add to the full amount of water for injection, regulate pH scope 5.5-7.0 with citric acid soln or sodium hydroxide solution if desired;
4)Gained solution mixed cellulose ester microporous membrane fine straining, obtains filtrate, embedding in ampoule bottle, 121 DEG C of pressure sterilizings 15 minutes, obtain methanesulfonic acid eribulin injection finished product.
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| CN201410633576.1A CN105640935A (en) | 2014-11-12 | 2014-11-12 | Eribulin mesylate pharmaceutical composition for injection |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018221487A1 (en) * | 2017-05-31 | 2018-12-06 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Injection containing eribulin and pharmaceutically acceptable salt thereof |
| US11071713B2 (en) | 2009-03-30 | 2021-07-27 | Eisai R&D Management Co., Ltd. | Liposome composition |
| US11083705B2 (en) | 2019-07-26 | 2021-08-10 | Eisai R&D Management Co., Ltd. | Pharmaceutical composition for treating tumor |
| US12029724B2 (en) | 2016-04-28 | 2024-07-09 | Eisai R&D Management Co., Ltd. | Method for inhibiting tumor growth |
-
2014
- 2014-11-12 CN CN201410633576.1A patent/CN105640935A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11071713B2 (en) | 2009-03-30 | 2021-07-27 | Eisai R&D Management Co., Ltd. | Liposome composition |
| US12029724B2 (en) | 2016-04-28 | 2024-07-09 | Eisai R&D Management Co., Ltd. | Method for inhibiting tumor growth |
| WO2018221487A1 (en) * | 2017-05-31 | 2018-12-06 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Injection containing eribulin and pharmaceutically acceptable salt thereof |
| CN110545808A (en) * | 2017-05-31 | 2019-12-06 | 卫材R&D管理有限公司 | Injection containing eribulin or pharmaceutically acceptable salt thereof |
| US11083705B2 (en) | 2019-07-26 | 2021-08-10 | Eisai R&D Management Co., Ltd. | Pharmaceutical composition for treating tumor |
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Application publication date: 20160608 |