CN102846563A - Injection composition of pemetrexed disodium and preparation method of injection composition - Google Patents
Injection composition of pemetrexed disodium and preparation method of injection composition Download PDFInfo
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- CN102846563A CN102846563A CN2012103809911A CN201210380991A CN102846563A CN 102846563 A CN102846563 A CN 102846563A CN 2012103809911 A CN2012103809911 A CN 2012103809911A CN 201210380991 A CN201210380991 A CN 201210380991A CN 102846563 A CN102846563 A CN 102846563A
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Abstract
The invention relates to an injection composition, and in particular relates to an injection composition of pemetrexed disodium and a preparation method of the injection composition. The injection composition is prepared from pemetrexed disodium, mannitol and beta-cyclodextrin. The injection composition of pemetrexed disodium is simple in preparation process and effectively reduces the preparation cost. The pemetrexed disodium freeze-dried powder prepared by the invention has the advantages of excellent dissolvability, few impurity content, low moisture content and good stability.
Description
Technical field
The present invention relates to a kind of composition for injection, specifically, relate to a kind of pemetrexed disodium composition for injection and preparation method thereof.
Background technology
Pemetrexed disodium (Pemetrexed disodium), chemical name are N-(4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrroles [2,3-d] pyrimidine-5-yl) ethyl] benzoyl)-two times of semihydrates of Pidolidone disodium salt.It is a kind of novel pyrimidine analogue, the thymidylate synthase inhibitor.It brings into play antitumor action by interference cell reproduction process Folic Acid dependency metabolic process.Studies show that: pemetrexed is by polyglutamate generation cytotoxin effect in the cell, and the polyglutamic acid salinization has suppressed several folic acid dependent enzymes and comprised thymidylate synthase, dihydrofolate reductase, glycine ribonucleotide transformylase.
Pemetrexed disodium is to nonsmall-cell lung cancer, the incidence cancer, and colon cancer, breast carcinoma have certain therapeutical effect.Pemetrexed disodium also with other cancer therapy drug couplings, particularly with Cisplatin, can obtain better effect to the treatment of mesothelioma.
A kind of pemetrexed disodium freeze-dried injection and preparation method thereof is disclosed in CN101411710A, this lyophilized injectable powder is comprised of pemetrexed disodium, mannitol and sodium sulfite, sodium sulfite is antioxidant commonly used, have stronger chemism, may produce certain impact to the effectiveness of principal agent.
Also disclose a kind of pemetrexed disodium freeze-dried injection and preparation method thereof in CN102106833, this lyophilized injectable powder contains pemetrexed disodium and the mannitol of certain content.But its preparation technology is still comparatively complicated, causes cost to improve.
Summary of the invention
The composition for injection that the purpose of this invention is to provide a kind of pemetrexed disodium, it can overcome the defective of prior art, prepares the composition for injection of pemetrexed disodium with low cost.
Pemetrexed disodium freeze-dried injection of the present invention comprises pemetrexed disodium, mannitol, beta-schardinger dextrin-.
Wherein, the ratio of mannitol and beta-schardinger dextrin-is 1:1:0.4-0.8.
The present invention also provides the preparation method such as above-mentioned pemetrexed disodium freeze-dried injection, and it comprises the steps:
(1) dosing
Under lucifuge operation, mannitol and the beta-schardinger dextrin-of above-mentioned amount placed Agitation Tank, add an amount of water for injection, stirring and dissolving adds the pemetrexed disodium of above-mentioned amount, stirring and dissolving; Regulating pH value is 7.0～8.2, and benefit adds to the full amount of water for injection, and stirs evenly; Then add active carbon, at room temperature stir filtering decarbonization, degerming;
(2) lyophilization
1) the pre-freeze phase: the solution that configures is put into freeze drying box, shelf temperature is set is-40 ℃, after shelf temperature is reduced to-40 ℃, pre-freeze 3.5 hours.
2) the distillation phase: after the pre-freeze, evacuation, it is 0 ℃ that shelf temperature is set, and when treating that shelf temperature rises to this temperature, keeps 6 hours; It is 5 ℃ that shelf temperature is set, and is incubated 4 hours.
(3) dry period: continue the heating shelf, make to be warming up to about 30 ℃, and insulation 4 hours under this temperature, vacuum changes when little, finishes whole freeze-drying process.
Wherein,
Regulate pH value with hydrochloric acid solution or sodium hydroxide solution; The consumption of active carbon is 0.1-0.3% (g/ml); With titanium filter stick filtering decarbonization, with double-deck 0.15 μ m microporous filter membrane fine straining degerming; PH value is 7.0～8.2.
Beta-schardinger dextrin-is excipient commonly used in the reagent combination, and it can help to improve stability etc.But not yet use it in the prior art in the preparation of pemetrexed disodium injection.
The inventor is in R﹠D process, if find in pemetrexed disodium injection prescription, to adopt the beta-schardinger dextrin-of special ratios, in the preparation of lyophilized injectable powder, in cryodesiccated process, need not to adopt any specific step, can prepare all good pemetrexed disodium freeze-dried injections of properties.
Beneficial effect of the present invention:
According to technical scheme of the present invention, its preparation technology is simple, and manufacturing cost is effectively reduced.And the solubility of the pemetrexed disodium freeze-dried injection of preparation of the present invention is good, and impurity content is few, and moisture is low, good stability.Because each process procedure in the preparation is all comparatively simple, control is convenient, and human cost reduces, and percent defective reduces, so economic benefit obviously improves.
The specific embodiment
The present invention is further illustrated below in conjunction with embodiment.
At first technical recipe is screened.
Weight fraction another name according to table 1 is got raw material.
Table 1
| Pemetrexed disodium | Mannitol | Beta-schardinger dextrin- | Water | |
| Embodiment 1 | 500g | 500g | 50g | 10000ml |
| Embodiment 2 | 500g | 500g | 100g | 10000ml |
| Embodiment 3 | 500g | 500g | 200g | 10000ml |
| Embodiment 4 | 500g | 500g | 300g | 10000ml |
| Embodiment 5 | 500g | 500g | 400g | 10000ml |
1, dissolubility test
Raw material according to amount described in the table 1 is dissolved in it respectively in the water for injection, jolting, dissolving.Placed 12 hours under 4 ℃ of conditions of low temperature, sample is separated out without crystal, meets the dissolving requirement again.
2, freeze-dried test
Prescription to embodiment 1-5 carries out freeze-dried test, investigates molding and the redissolution situation of dried frozen aquatic products.Following technique is adopted in lyophilizing:
The pre-freeze phase: medicine is put into freeze drying box, start freeze dryer, shelf temperature is set is-40 ℃, after shelf temperature is reduced to-40 ℃, pre-freeze 3.5 hours; The distillation phase: after the pre-freeze, evacuation, it is 0 ℃ that shelf temperature is set, and when treating that shelf temperature rises to this temperature, keeps 6 hours; It is 5 ℃ that shelf temperature is set, and is incubated 4 hours; Dry period: continue heated barrier, make to be warming up to about 30 ℃, and insulation 4 hours under this temperature, vacuum changes when little, finishes whole freeze-drying process.
Whole result is shown in the table 2.
Table 2 lyophilizing result
3, the pH scope determines
By the prescription according to embodiment 3, obtain solution, recording pH value is 7.75, for investigating the stability of solution in this pH scope, transfer pH to be respectively 6.53,7.03,7.55,8.00,8.45 with 0.1mol/l hydrochloric acid solution or 0.1mol/l sodium hydroxide solution, the room temperature lucifuge was placed 8 hours, result such as table 3.
Table 3 study on the stability result
This product is o'clock more stable in pH value 6.5～8.5 as can be known by above result of the test, so tentatively determine this product pH scope 6.5～8.5, qualified for guaranteeing finished product, the control pH value is between 7.0～8.2 during preparating liquid.
4, the screening of medicinal charcoal consumption
Medicinal charcoal is used for pigment, impurity and the pyrogen etc. of absorption supplementary material in injection powder pin, in order to purity and the yield rate that improves product.Adopt the prescription of embodiment 3, select the medicinal charcoal concentration of 0,0.05%, 0.1%, 0.2% (g/ml) to carry out adsorption test, take clarity, pyrogen, pH value and the drug content of solution as investigating index, the consumption of screening medicinal charcoal, result such as table 4:
Table 4 charcoal absorption result
By above test as can be known, clarity was against regulation when consumption was 0.05%, and the medicinal charcoal consumption can adsorb principal agent when too much, so select 0.1% charcoal as the charcoal absorption consumption of this product.
Embodiment 1
Under the lucifuge operation, in Agitation Tank, add mannitol and the beta-schardinger dextrin-of the described amount of table 1, add about 80% water for injection, stirring and dissolving, the pemetrexed disodium 500g of the described amount of adding table 1, stirring and dissolving.Hydrochloric acid solution or sodium hydroxide solution adjusting pH value with 0.1mol/L are 7.0～8.2, and benefit adds to the full amount of water for injection, and stirs evenly.Then the active carbon that adds 0.1% (g/ml), stirring at room 30 minutes is with titanium filter stick filtering decarbonization, with double-deck 0.15 μ m microporous filter membrane fine straining degerming.
Then carry out lyophilization.
(1) the pre-freeze phase: put into freeze drying box, shelf temperature is set is-40 ℃, after shelf temperature is reduced to-40 ℃, pre-freeze 3.5 hours.
(2) the distillation phase: after the pre-freeze, evacuation, it is 0 ℃ that shelf temperature is set, and when treating that shelf temperature rises to this temperature, keeps 6 hours; It is 5 ℃ that shelf temperature is set, and is incubated 4 hours.
(3) dry period: continue the heating shelf, make to be warming up to about 30 ℃, and insulation 4 hours under this temperature, vacuum changes when little, finishes whole freeze-drying process.
Embodiment 2-5
Except the amount of each raw material took by weighing according to table 1, all the other steps are identical with embodiment 1 respectively.Make respectively the lyophilized injectable powder of embodiment 2-5.
Embodiment 6
The pemetrexed disodium freeze-dried injection stability study
Test sample: the pemetrexed disodium freeze-dried injection that adopts embodiment 2～4 to prepare
1) hot test
Sample was placed 10 days under 60 ℃ of conditions, sampling in the 5th and the 10th day, the performance of sample is investigated respectively.Investigate the result shown in the table 5.
Table 5 hot test result
2) high wet test
Sample 25 ℃ of temperature, was placed 10 days under the condition of relative humidity 92.5%, sampling in the 5th and the 10th day, the performance of sample is investigated respectively.Investigate the result shown in the table 5.
Table 6 high humidity result of the test
3) accelerated test
To according to the pemetrexed disodium freeze-dried injection of embodiment 3 methods preparations 40 ℃ of temperature, place 6 months under the condition of relative humidity 75%.At duration of test, sampling was investigated respectively in the 1st, 2,3,6 month.The result is shown in the table 7.
Table 7 accelerated test result
4) long term test
To according to the pemetrexed disodium freeze-dried injection of embodiment 3 methods preparations 25 ℃ of temperature, place 18 months under the condition of relative humidity 60%.At duration of test, sampling was investigated respectively in the 0th, 3,6,9,12,18 month.The result is shown in the table 8.
Table 8 long-term test results
Can be found out that by above data pemetrexed disodium freeze-dried injection preparation method of the present invention is respectively at six months every quality index changing values corresponding with 0 day of accelerated test (40 ℃ of high temperature, relative humidity 75% ± 5%): maximum single impurity 0.004%, total impurities 0.03%, D-content of isomer 0.009%, sign content 0.1%.
Be respectively at 18 months corresponding every quality index changing values with 0 day of long term test (25 ℃ of temperature, relative humidity 60% ± 10%): maximum single assorted 0.002%, total impurities 0.05%, D-content of isomer 0.003%, indicate content 0.2%.
Claims (4)
1. pemetrexed disodium freeze-dried injection, it comprises pemetrexed disodium, mannitol, beta-schardinger dextrin-.
2. pemetrexed disodium freeze-dried injection as claimed in claim 1, wherein, the ratio of pemetrexed disodium, mannitol and beta-schardinger dextrin-is 1:1:0.4-0.8 in weight ratio.
3. the preparation method of pemetrexed disodium freeze-dried injection as claimed in claim 1, it comprises the steps:
(1) dosing
Under the lucifuge operation, mannitol and beta-schardinger dextrin-are placed Agitation Tank, add an amount of water for injection, stirring and dissolving adds pemetrexed disodium, stirring and dissolving; Regulating pH value is 7.0～8.2, and benefit adds to the full amount of water for injection, and stirs evenly; Then add active carbon, at room temperature stir filtering decarbonization, degerming;
(2) lyophilization
1) the pre-freeze phase: the solution that configures is put into freeze drying box, shelf temperature is set is-40 ℃, after shelf temperature is reduced to-40 ℃, pre-freeze 3.5 hours.
2) the distillation phase: after the pre-freeze, evacuation, it is 0 ℃ that shelf temperature is set, and when treating that shelf temperature rises to this temperature, keeps 6 hours; It is 5 ℃ that shelf temperature is set, and is incubated 4 hours.
(3) dry period: continue the heating shelf, make to be warming up to about 30 ℃, and insulation 4 hours under this temperature, vacuum changes when little, finishes whole freeze-drying process.
4. the preparation method of pemetrexed disodium freeze-dried injection as claimed in claim 3 wherein, is regulated pH value with hydrochloric acid solution or sodium hydroxide solution; The consumption of active carbon is 0.1-0.3% (g/ml); With titanium filter stick filtering decarbonization, with double-deck 0.15 μ m microporous filter membrane fine straining degerming; PH value is 7.0～8.2.
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| CN201210380991.1A CN102846563B (en) | 2012-10-10 | 2012-10-10 | Injection composition of pemetrexed disodium and preparation method of injection composition |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103432086A (en) * | 2013-08-28 | 2013-12-11 | 南京正大天晴制药有限公司 | Pemetrexed disodium freeze-dried powder injection for injection and preparation method thereof |
| CN105726492A (en) * | 2014-12-08 | 2016-07-06 | 博瑞生物医药（苏州）股份有限公司 | Freeze-dried powder injection of pemetrexed dipotassium and preparation method thereof |
| WO2019043569A1 (en) | 2017-08-29 | 2019-03-07 | Fresenius Kabi Oncology Limited | Stable liquid compositions of pemetrexed |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1459284A (en) * | 2003-06-10 | 2003-12-03 | 肖广常 | Neohouttuynin sodium freeze-dried powder-injection, and its prepn. method |
| CN101411710A (en) * | 2008-11-25 | 2009-04-22 | 江苏奥赛康药业有限公司 | Pemetrexed disodium freeze-dried injection and preparation method thereof |
| CN102106833A (en) * | 2011-02-12 | 2011-06-29 | 海南锦瑞制药股份有限公司 | Pemetrexed disodium freeze-dried powder injection and preparation method thereof |
-
2012
- 2012-10-10 CN CN201210380991.1A patent/CN102846563B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1459284A (en) * | 2003-06-10 | 2003-12-03 | 肖广常 | Neohouttuynin sodium freeze-dried powder-injection, and its prepn. method |
| CN101411710A (en) * | 2008-11-25 | 2009-04-22 | 江苏奥赛康药业有限公司 | Pemetrexed disodium freeze-dried injection and preparation method thereof |
| CN102106833A (en) * | 2011-02-12 | 2011-06-29 | 海南锦瑞制药股份有限公司 | Pemetrexed disodium freeze-dried powder injection and preparation method thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103432086A (en) * | 2013-08-28 | 2013-12-11 | 南京正大天晴制药有限公司 | Pemetrexed disodium freeze-dried powder injection for injection and preparation method thereof |
| CN103432086B (en) * | 2013-08-28 | 2015-07-22 | 南京正大天晴制药有限公司 | Pemetrexed disodium freeze-dried powder injection for injection and preparation method thereof |
| CN105726492A (en) * | 2014-12-08 | 2016-07-06 | 博瑞生物医药（苏州）股份有限公司 | Freeze-dried powder injection of pemetrexed dipotassium and preparation method thereof |
| WO2019043569A1 (en) | 2017-08-29 | 2019-03-07 | Fresenius Kabi Oncology Limited | Stable liquid compositions of pemetrexed |
| CN111093626A (en) * | 2017-08-29 | 2020-05-01 | 费森尤斯卡比肿瘤学有限公司 | Stable liquid composition of pemetrexed |
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| CN102846563B (en) | 2014-10-08 |
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Address after: 253019 Dongfang Hongdong Road, Dezhou economic and Technological Development Zone, Shandong 6000 Patentee after: Dezhou Deyao Pharmaceutical Co., Ltd. Address before: 253015 No. 38 Middle Road, Decheng District, Dezhou, Shandong, 538 Patentee before: Dezhou Deyao Pharmaceutical Co., Ltd. |