CN102988306B - Medicinal composition containing sodium ozagrel compound - Google Patents
Medicinal composition containing sodium ozagrel compound Download PDFInfo
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- CN102988306B CN102988306B CN201210303755.XA CN201210303755A CN102988306B CN 102988306 B CN102988306 B CN 102988306B CN 201210303755 A CN201210303755 A CN 201210303755A CN 102988306 B CN102988306 B CN 102988306B
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- ozagrel
- sodium ozagrel
- sodium
- mannitol
- trisodium citrate
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Abstract
The invention relates to a medicinal composition containing sodium ozagrel, and the medicinal composition is a freeze-dried injection. Each 1,000 injections are prepared from the following components: 20g of sodium ozagrel, 100 to 200g of mannitol, 1 to 3g of ethylene diamine tetraacetic acid (EDTA) calcium, 1 to 2g of glucose, and 2,000ml of buffer solution of disodium hydrogen citrate and trisodium citrate at a mole ratio of 1: 4, wherein the pH value of the injection is 7.0.
Description
Technical field
The present invention relates to freeze-dried powder of a kind of sodium ozagrel and preparation method thereof, belong to field of medicaments.
Background technology
Ozagrel, English name: Ozagrel, chemical structural formula is as follows:
Ozagrel is thromboxane synthetase inhibitor, can suppress TXA2 and generate, thereby have antiplatelet accumulation and blood vessel dilating effect.Zoopery performance, intravenously administrable can reduce blood plasma TXB2 level, and Keto-PGF12/TXB2 ratio declines, and platelet aggregation due to different derivants is all had to inhibitory action, and the cerebral infarction that Midbrain In The Rat tremulous pulse is caused is plugged with preventive effect.
After sodium ozagrel intravenous drip, blood drug level-time graph meets two compartment model, and t1/2 β is 1.22 ± 0.44h, and Vd is 2.32 ± 0.62L/kg, and AUC is 0.47 ± 0.08 μ ghr/ml.Cl is 3.25 ± 0.82L/h/kg, and experimenter's half-life is the longest is 1.93h, and blood drug level can measure 3h after drug withdrawal, drug withdrawal 24h almost all medicines through urine, excrete.
The Ozagrel sodium injection having gone on the market is the lyophilization injectable powder of sodium ozagrel, soluble in water because of sodium ozagrel, in its formula, generally only use mannitol as filler, but find in practice, the problem that has color jaundice after existing medicament long storage time, needs low temperature storage.Some product dissolution velocity in clinical use procedure is undesirable, causes and uses inconvenience, the invention provides a kind of new prescription and preparation method, and medicament long storage time also can not be turned to be yellow, and makes dissolution velocity improve simultaneously.
Summary of the invention
The invention provides a kind of pharmaceutical composition that contains ozagrel sodium compound, is the injection freeze-dried powder take sodium ozagrel as active component, and every 1000 injections are made by the component of following proportioning:
Sodium ozagrel 20g;
Mannitol 100-200g;
EDTA calcium 1-3g;
Glucose 1-2g,
Mol ratio is DisodiumHydrogen Citrate and the trisodium citrate buffer 2000ml of 1:4;
PH is 7.0;
Its preparation method is as follows:
First join DisodiumHydrogen Citrate and trisodium citrate buffer 2000ml, then get the sodium ozagrel of above-mentioned amount, mannitol, EDTA calcium, glucose adding citric acid buffer dissolves, the filter membrane of via hole diameter molecular cut off 20000 filters, after clarity is qualified, and fill, half tamponade, inlet lyophilization, packing, obtains.
Wherein, the compound method of DisodiumHydrogen Citrate and trisodium citrate buffer is as follows: take DisodiumHydrogen Citrate 26g, trisodium citrate 120g is dissolved in the buffer solution that obtains pH value 7.0 in 2000ml water for injection.
Compositions of the present invention, every 1000 injections of most preferred formula, by the component of following proportioning, made:
Sodium ozagrel 20g;
Mannitol 150g;
EDTA calcium 2g;
Glucose 1.5g,
Mol ratio is DisodiumHydrogen Citrate and the trisodium citrate buffer 2000ml of 1:4,
PH is 7.0;
The present invention has used DisodiumHydrogen Citrate and trisodium citrate buffer to make the solution pH value obtaining of the present invention remain on 6.9-7.1, and fluctuation range is minimum, guarantees its stability.
Adopt High-dose Mannitol that powder dissolution speed after lyophilizing is accelerated, use EDTA calcium and glucose to guarantee that it places in use the long period and also can not change, guarantee its stability.
Compositions of the present invention, its formula obtains through screening, and wherein most preferred formula composition, referring to embodiment 1.Screening process is as follows:
Table 1: the formula screening experiment take dissolution time as index
Experimental technique:
The more than medicine of formula, wiring solution-forming, packing capacity into is 5ml ampulla, with the method for embodiment 1, is prepared into lyophilized formulations, carries out dissolution experiment again.
Sample:
Each 10 bottles of the sample of each formula, every bottle adds sodium chloride for injection solution 5ml, with hand moving.
Dissolve index:
Naked eyes are seen without floccule and are existed for whole dissolvings.
Table 2: the dissolution velocity table of each prescription drug (minute)
As seen from the above table, formula 4 dissolution velocities are the fastest, are applicable to application.
Table 3 is investigated embodiment 1 and the indices result of the Ozagrel Sodium for Injection sample that gone on the market
| Embodiment 1 sample | The ozagrel sodium sample having gone on the market | |
| Mouldability | Good | Generally |
| Dissolubility | Good | Generally |
| Water content | 1.32% | 1.30% |
| Condition of storage | Room temperature | 0-8℃ |
As seen from table, embodiment 1 is better than reference substance.
Ozagrel Sodium for Injection three batch samples that table 4 is investigated embodiment 1 and gone on the market, detect heavy metal and impurity content
From test data, the three batches of injection heavy metals and the impurity content of embodiment 1 are less than the medicine having gone on the market.
Another experimental group room temperature of table 5 is placed 90 days, then detects three batches of heavy metal and impurity contents, and result is as following table:
From test data, injection heavy metal and the impurity content of embodiment 1 are obviously less than the medicine having gone on the market.
Laboratory sample room temperature is placed 90 days in addition, and the fluctuation range of embodiment 1 solution pH value is 6.9-7.1, and the sodium ozagrel having gone on the market is 6.7～7.4.
Dissolution velocity test:
The lyophilized injectable powder of the present invention of preparing by the method for the embodiment of the present invention 1 and the ozagrel sodium freeze-dried powder injection having gone on the market carry out dissolution velocity test, result demonstration, and the product dissolution velocity of the embodiment of the present invention 1 is higher than matched group.
Storage-stable test
Embodiment 1 and the ozagrel sodium freeze-dried powder injection that gone on the market are at room temperature preserved 18 months, take impurity as investigating index, carry out long-time stability and investigate test.The results are shown in following table:
Different prescriptions long-time stability under 2 ~ 8 ℃ of holding conditions
| Minute | Embodiment 1 | The ozagrel sodium freeze-dried powder injection having gone on the market |
| 0 month | 0.5% | 0.6% |
| June | 1.0% | 0.9% |
| December | 1.2% | 1.3% |
| 18 months | 1.4% | 1.9% |
Drug standard requires the content of impurity should not be greater than 1.5%.From table, the sample of the more commercially available formula preparation of the present invention is more stable.
To the freeze dried injection that contains sodium ozagrel of buying on market of the present invention.Carried out the research of stability test, result shows that stability of the present invention is better than the product on market.
New Ozagrel Sodium for Injection freeze-drying medicinal composition provided by the invention, has good stability, and invariant color, does not stimulate during injection, and better tolerance is dissolved the multiple advantages such as rapid, easy to use, meets greatly patient's needs.
Specific implementation method
Embodiment 1
Sodium ozagrel 20g;
Mannitol 150g;
EDTA calcium 2g;
Glucose 1.5g,
Mol ratio is DisodiumHydrogen Citrate and the trisodium citrate buffer 2000ml of 1:4;
Preparation method
(1) by recipe quantity, take supplementary material
(2) mannitol, EDTA calcium, glucose being added to mol ratio is DisodiumHydrogen Citrate and the trisodium citrate buffer 1000ml of 1:4, stirring and dissolving.
(3) sodium ozagrel that adds recipe quantity joins in solution, is stirred to dissolve completely.Add DisodiumHydrogen Citrate that mol ratio is 1:4 and trisodium citrate buffer to full dose, stir and make mix homogeneously.
(4) surveying solution pH value is 7.0.
(5) with the microporous filter membrane fine straining of 0.2 μ m, check solution clarity.
(6) according to measurement result, with the volume of about 2ml by liquid medicine filling in the vial of XiLin.
(7) sample is put into the 18h of 35 ℃ of low-temperature vacuum dryings of 35 ℃ of pre-freeze 4h ， – of freeze dryer lyophilization ， –, 50 ℃ of intensifications dry 4h again.
(8) lyophilizing finishes, and sample is jumped a queue, gland.
Embodiment 2
Sodium ozagrel 20g;
Mannitol 100g;
EDTA calcium 1g;
Glucose 1g,
Mol ratio is DisodiumHydrogen Citrate and the trisodium citrate buffer 2000ml of 1:4;
Preparation method
(1) by recipe quantity, take supplementary material
(2) mannitol, EDTA calcium, glucose being added to mol ratio is DisodiumHydrogen Citrate and the trisodium citrate buffer 1000ml of 1:4, stirring and dissolving.
(3) sodium ozagrel that adds recipe quantity joins in solution, is stirred to dissolve completely.Add DisodiumHydrogen Citrate that mol ratio is 1:4 and trisodium citrate buffer to full dose, stir and make mix homogeneously.
(4) surveying solution pH value, is 7.0.
(5) with the microporous filter membrane fine straining of 0.2 μ m, check solution clarity.
(6) according to measurement result, with the volume of about 2ml by liquid medicine filling in the vial of XiLin.
(7) sample is put into the 18h of 35 ℃ of low-temperature vacuum dryings of 35 ℃ of pre-freeze 4h ， – of freeze dryer lyophilization ， –, 50 ℃ of intensifications dry 4h again.
(9) lyophilizing finishes, and sample is jumped a queue, gland.
Embodiment 3
Sodium ozagrel 20g;
Mannitol 200g;
EDTA calcium 3g;
Glucose 2g,
Mol ratio is DisodiumHydrogen Citrate and the trisodium citrate buffer 2000ml of 1:4;
Preparation method
(1) by recipe quantity, take supplementary material
(2) mannitol, EDTA calcium, glucose being added to mol ratio is DisodiumHydrogen Citrate and the trisodium citrate buffer 1000ml of 1:4, stirring and dissolving.
(3) sodium ozagrel that adds recipe quantity joins in solution, is stirred to dissolve completely.Add DisodiumHydrogen Citrate that mol ratio is 1:4 and trisodium citrate buffer to full dose, stir and make mix homogeneously.
(4) surveying solution pH value, is 7.0.
(5) with the microporous filter membrane fine straining of 0.2 μ m, check solution clarity.
(6) according to measurement result, with the volume of about 2ml by liquid medicine filling in the vial of XiLin.
(7) sample is put into the 18h of 35 ℃ of low-temperature vacuum dryings of 35 ℃ of pre-freeze 4h ， – of freeze dryer lyophilization ， –, 50 ℃ of intensifications dry 4h again.
(9) lyophilizing finishes, and sample is jumped a queue, gland.
Claims (1)
1. containing a pharmaceutical composition for sodium ozagrel, is freezing-dried powder injection, and every 1000 injections are made by the component of following proportioning:
Sodium ozagrel 20g;
Mannitol 150g;
EDTA calcium 2g;
Glucose 1.5g;
Mol ratio is DisodiumHydrogen Citrate and the trisodium citrate buffer 2000ml of 1:4;
PH is 7.0;
Its preparation method is as follows: first prepare DisodiumHydrogen Citrate and trisodium citrate buffer 2000ml, then get sodium ozagrel, mannitol, EDTA calcium, glucose adds mixed dissolution in DisodiumHydrogen Citrate and trisodium citrate buffer, and the filter membrane of via hole diameter molecular cut off 20000 filters, fill, half tamponade, lyophilization, obtains.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210303755.XA CN102988306B (en) | 2012-07-12 | 2012-08-22 | Medicinal composition containing sodium ozagrel compound |
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|---|---|---|---|
| CN201210240309 | 2012-07-12 | ||
| CN201210240309.9 | 2012-07-12 | ||
| CN201210303755.XA CN102988306B (en) | 2012-07-12 | 2012-08-22 | Medicinal composition containing sodium ozagrel compound |
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| CN102988306A CN102988306A (en) | 2013-03-27 |
| CN102988306B true CN102988306B (en) | 2014-04-16 |
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| CN103271881A (en) * | 2013-05-30 | 2013-09-04 | 瑞阳制药有限公司 | Small-size sodium ozagrel freeze-dried powder needle as well as preparation method and production device thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101596167A (en) * | 2008-06-03 | 2009-12-09 | 哈药集团生物工程有限公司 | A kind of preparation method of new Ozagrel sodium powder injection |
| CN101695475A (en) * | 2009-10-17 | 2010-04-21 | 海南利能康泰制药有限公司 | Ozagrel sodium injection and preparation method thereof |
| CN102276533A (en) * | 2011-09-06 | 2011-12-14 | 周晓东 | New ozagrel sodium compound and medicinal composition thereof |
| CN102429903A (en) * | 2011-11-09 | 2012-05-02 | 天津市汉康医药生物技术有限公司 | Ozagrel sodium medicinal composition for injection |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101596167A (en) * | 2008-06-03 | 2009-12-09 | 哈药集团生物工程有限公司 | A kind of preparation method of new Ozagrel sodium powder injection |
| CN101695475A (en) * | 2009-10-17 | 2010-04-21 | 海南利能康泰制药有限公司 | Ozagrel sodium injection and preparation method thereof |
| CN102276533A (en) * | 2011-09-06 | 2011-12-14 | 周晓东 | New ozagrel sodium compound and medicinal composition thereof |
| CN102429903A (en) * | 2011-11-09 | 2012-05-02 | 天津市汉康医药生物技术有限公司 | Ozagrel sodium medicinal composition for injection |
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