CN104473883B - A kind of acetyl danshensu freeze drying powder injection and preparation method thereof - Google Patents
A kind of acetyl danshensu freeze drying powder injection and preparation method thereof Download PDFInfo
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- CN104473883B CN104473883B CN201410685656.1A CN201410685656A CN104473883B CN 104473883 B CN104473883 B CN 104473883B CN 201410685656 A CN201410685656 A CN 201410685656A CN 104473883 B CN104473883 B CN 104473883B
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Abstract
The invention discloses a kind of acetyl danshensu freeze drying powder injection, containing acetyl danshensu, cosolvent and complexing agent, the mass ratio of acetyl danshensu, cosolvent and complexing agent is 1 ~ 30：2~40：0.01~0.1.Acetyl danshensu freeze drying powder injection of the invention makes solubility of the acetyl danshensu in water improve 10 ~ 100 times, acetyl danshensu stability is increased substantially, rehydration is rapid, simply, general solvent for injection dissolving easy to use, and can be coexisted with the long period with compatible solution, greatly reducing the curative effect reduction that brings by drug degradation and relevant material increases the security hidden trouble brought to patient medication.
Description
Technical field
The present invention relates to a kind of acetyl danshensu freeze drying powder injection that can be used to prevent and treat cardiovascular and cerebrovascular disease and its complication
And preparation method thereof, belong to pharmaceutical technology field.
Background technology
Acetyl danshensu is the derivative after three hydroxyls are acetylation in danshensu structure, and its chemical name is：R-
(+) -3- (3,4- diacetoxy phenyl) -2- acetyloxypropanoic acids, chemical structural formula is：
Molecular formula is：C15H16O8Molecular weight is：324.08.
Compared with danshensu, acetyl danshensu has to be increased fat-soluble, change absorbent properties, relative increase stability, carries
The advantages of high-drug-effect, in addition its there is the effect of substantially preventing and treating cardiovascular and cerebrovascular disease and its complication, therefore by acetyl danshensu
Develop into a kind of safely and effectively preparation extremely urgent.However, the carboxyl and ester bond in acetyl danshensu structure are in acid and alkali
Unstable under the conditions of property, using common preparation method, acetyl danshensu is largely degraded in process for preparation so that curative effect of medication
Reduce and produce the impurity for triggering toxic and side effect.Additionally, acetyl danshensu solubility in water is very low, only 2 ~ 3mg/mL, category
In " slightly soluble " of States Pharmacopoeia specifications, the water soluble preparation tool for developing acetyl danshensu acquires a certain degree of difficulty.
The content of the invention
The purpose of the present invention is directed to that acetyl danshensu solubility is small and the poor problem of stability, there is provided a kind of acetyl is red
Ginseng freezing-dried powder agent and preparation method thereof.
In order to solve the above-mentioned technical problem, present invention employs following technical scheme：
A kind of acetyl danshensu freeze drying powder injection, containing acetyl danshensu, cosolvent and complexing agent, acetyl danshensu, helps
The mass ratio of solvent and complexing agent is 1 ~ 30：2~40：0.01 ~ 0.1, described cosolvent be selected from ethanol, propane diols, PEG-400,
Glycerine, Tween 80, poloxamer, sodium acid carbonate, sodium citrate, disodium hydrogen phosphate, described complexing agent are EDTA-2Na.
The mass ratio of preferred acetyl danshensu, cosolvent and complexing agent is 5 ~ 15：5~15：0.01~0.05.
Also contain excipient in acetyl danshensu freeze drying powder injection, acetyl danshensu, cosolvent, excipient and complexing agent
Mass ratio is 1 ~ 30：2~40：1~10：0.01 ~ 0.1, described excipient be selected from mannitol, lactose, dextran, amino acid,
Sorbierite, glucose, sodium chloride, glucose, fructose, sucrose.
The mass ratio of preferred acetyl danshensu, cosolvent, excipient and complexing agent is 5 ~ 15：5~15：3~5：0.01~
0.05。
Preferred cosolvent is sodium citrate.
The preparation method of above-mentioned acetyl danshensu freeze drying powder injection, its specific preparation process is：Weigh the hydrotropy of recipe quantity
Agent, excipient and complexing agent, amount water for injection is allowed to dissolve plus 80%, adds the acetyl danshensu of recipe quantity, and stirring makes its complete
Portion is dissolved and is well mixed, and pH is adjusted to 4.0 ~ 6.0 with 0.1moL/L hydrochloric acid or 0.1moL/L sodium hydroxide solutions, is added
0.1% ~ 0.5% needle-use activated carbon, 25 DEG C ~ 50 DEG C 10 ~ 60min of stirring and adsorbing, suction filtration takes off charcoal, after intermediate passed examination, uses
Water for injection is settled to full dose.Solution is delivered in desinfection chamber after the filtering with microporous membrane of 0.22 μm of twice, filling in cillin bottle
In, freeze-drying in freeze drying box is put in every bottle of 1 ~ 5mL, partly butyl rubber bung, sabot beyond the Great Wall, and tamponade, outlet uses aluminium-plastic combined cover
Mouth is rolled, packaging after quality inspection is qualified is obtained final product.
The freeze-drying of above-mentioned acetyl danshensu freeze drying powder injection, comprises the following steps：
（1）After product puts freeze drying box, chamber door start refrigeration is closed, decline products temperature using conduction oil, when product temperature
Continue to freeze 2 ~ 4 hours at Du Da -40 DEG C；
（2）Stop conduction oil, open condenser, when condenser temperature reaches -40 DEG C ~ -50 DEG C, open vacuum system, product
Start preliminary distillation, vacuum control is controlled at -35 DEG C ~ 0 DEG C in 7 ~ 20Pa, sublimation stage products temperature；
（3）After distillation line reaches bottom, products temperature is to slowly warm up to 30 ~ 35 DEG C, is incubated 2 ~ 4 hours；
（4）Then tamponade under vacuum, then filtrated air is entered, make casing internal pressure consistent with air, last outlet.
Above-mentioned acetyl danshensu freeze drying powder injection can be used to prepare prevention or treatment cardiovascular and cerebrovascular disease and its complication medicine
Thing.
Acetyl danshensu freeze drying powder injection of the invention has following features：（1）Make dissolving of the acetyl danshensu in water
Degree improves 10 ~ 100 times；（2）Increase substantially acetyl danshensu stability；（3）Rehydration is rapid, simply, it is easy to use one
As solvent for injection dissolving（Such as G/W, physiological saline, water for injection and other known aqueous diluent）, and with match somebody with somebody
5 solution can be coexisted with the long period, and greatly reducing the curative effect reduction that brings by drug degradation and relevant material increases to trouble
The security hidden trouble that person's medication brings；（4）It is suitable to intravenous injection, the aseptic apyrogeneity of product；（5）Acetyl red sage root freezing-dried powder
Agent good appearance, dosage are accurate, loss on drying is small.
Specific embodiment
The present invention is further illustrated below by embodiment.Should correct understanding be：Embodiments of the invention are only
It is to be given for illustrating the present invention, rather than limitation of the present invention, so, to the present invention under the premise of the method for the present invention
Simple modifications belong to the claimed scope of invention.
Embodiment 1：Influence of the cosolvent to acetyl danshensu solubility
In order to improve the solubility of acetyl danshensu and ensure its stability, it is necessary to add certain cosolvent in water,
Such as in ethanol, PEG-400,1,2- propane diols, sodium acid carbonate, disodium hydrogen phosphate, sodium citrate, Tween-80, poloxamer
Plant or various.
Result shows：Selected cosolvent can increase in various degree the solubility of acetyl danshensu, and content is basic
Keep stabilization.
Embodiment 2：Influences of the pH to acetyl danshensu stability
Weigh acetyl danshensu appropriate, add 20% ethanol and 15%PEG-400 hydrotropies, 50mg/ is configured to water for injection
The acetyl danshensu solution of mL, respectively with 0.1moL/L hydrochloric acid or 0.1moL/L sodium hydroxide solutions adjust pH to 3.5,4.5,
5.0th, 5.5,6.0,6.5,7.5,8.5, the change of the acetyl content of Danshensu after different condition places different time is investigated, determine
The results are shown in Table 2.
Result shows：As the increase of pH value of solution, the degraded of acetyl danshensu are more and more faster, solution colour is more and more deeper.
With reference to the pH scopes that intravenous injection is required（4.0-9.0）, the pH scopes for selecting acetyl danshensu solution are 4.0 ~ 6.0, preferably
4.5~5.5。
Embodiment 3：Influence of the excipient to formed product
The sodium citrate of selection 10% prepares 15% acetyl danshensu solution as cosolvent.Selection mannitol and dextrorotation
Sugared acid anhydride is excipient, designs following prescription and freezes, and the results are shown in Table 3.
From prescription screening result of the test, when in prescription containing 10% sodium citrate, it is prepared into by being not added with excipient
Skeleton is complete, the fine and smooth loose block-type freeze-dried product of the white of good moldability, and homogeneous, and solubility is good, is stood after the shaking that adds water
Dissolve（In 10 seconds）.Cost consideration is freezed from saving, when containing sodium citrate in prescription, it may not be necessary to use excipient.
Embodiment 4：The screening of activated carbon
Clarity, depyrogenation that activated carbon is usually used in adsorbing contaminant, decolouring in injection technique, improves liquid.Activity
The consumption of charcoal, temperature in use and mixing time directly determine the adsorbed degree of main ingredient, therefore are the emphasis of experiment.From not
With the activated carbon of consumption, respectively in different temperatures stirring and adsorbing different time, content, the inspection of main ingredient and impurity before and after absorption are determined
Solution colour and clarity are surveyed, and it is whether qualified using the pyrogen of the prepared lyophilized formulations of Rabbit viscera detection.
Note：1. solution colour inspection：Tested by Chinese Pharmacopoeia two annex IX the first methods of A of version in 2010.2.
Clarity is checked：Tested by two annex IX B of Chinese Pharmacopoeia version in 2010.3. about material：Use efficient liquid phase
Chromatography（Two annex V D of Chinese Pharmacopoeia version in 2010）, detected using area normalization method.4. pyrogen：Using family
Rabbit method, is detected by two annex XI D of Chinese Pharmacopoeia version in 2010, and three rabbit body temperatures raise summation and must not exceed 1.3
℃。
Result shows：Activated carbon does not cause very big absorption to acetyl danshensu, little on medicament contg influence, but
It is that can well remove pyrogen removal.
Embodiment 6：
Prescription
The sodium citrate and EDTA-2Na of recipe quantity are weighed, plus 80mL waters for injection are allowed to dissolve, and then add 16g second
Acyl danshensu, stirring makes its whole dissolve and be well mixed, and is adjusted with 0.1moL/L hydrochloric acid or 0.1moL/L sodium hydroxide solutions
PH to 4.5, adds 0.3% needle-use activated carbon, and 30 DEG C of stirring and adsorbing 25min, suction filtration takes off charcoal, after intermediate passed examination, uses
Water for injection is settled to full dose.Solution is delivered in desinfection chamber after the filtering with microporous membrane of 0.22 μm of twice, is sub-packed in 10mL west
In woods bottle, every bottle of filling 2mL, partly butyl rubber bung, sabot beyond the Great Wall in putting freeze drying box, closes chamber door, start refrigeration, using leading
Deep fat declines products temperature, continues to freeze 4 hours when products temperature reaches -40 DEG C；Stop conduction oil, condenser is opened, when cold
When condenser temperature reaches -40 DEG C, open vacuum system, product starts preliminary distillation, vacuum control in 10Pa, products temperature rises to -
At 35 DEG C be incubated 24h, -20 DEG C when insulation 4h, 0 DEG C when be incubated 4h；After distillation line reaches bottom, products temperature is to slowly warm up to
30 DEG C, it is incubated 2h；Then tamponade under vacuum, then filtrated air is entered, make casing internal pressure consistent with air, last outlet uses aluminium
Modeling combination cover rolls mouth, packaging after quality inspection is qualified, obtains final product acetyl danshensu freeze drying powder injection.
Embodiment 7：
Prescription
Sodium citrate, EDTA-2Na and the mannitol of recipe quantity are weighed, plus 80mL waters for injection are allowed to dissolve, and then add again
Enter 10g acetyl danshensus, stirring makes its whole dissolve and be well mixed, molten with 0.1moL/L hydrochloric acid or 0.1moL/L NaOH
Liquid adjusts pH to 4.8, adds 0.4% needle-use activated carbon, 35 DEG C of stirring and adsorbing 15min, and suction filtration takes off charcoal, and intermediate inspection is closed
After lattice, full dose is settled to water for injection.Solution is delivered in desinfection chamber after the filtering with microporous membrane of 0.22 μm of twice, is sub-packed in
In 10mL cillin bottles, every bottle of filling 3mL, partly butyl rubber bung, sabot beyond the Great Wall is put in freeze drying box, closes chamber door, and start is freezed,
Decline products temperature using conduction oil, continue to freeze 3 hours when products temperature reaches -45 DEG C；Stop conduction oil, open condensation
Device, when condenser temperature reaches -40 DEG C, opens vacuum system, and product starts preliminary distillation, and vacuum control is in 7Pa, products temperature
When rising to -35 DEG C be incubated 12h, -25 DEG C when insulation 12h, 0 DEG C when be incubated 6h；After distillation line reaches bottom, products temperature is slow
34 DEG C are warming up to, 3h is incubated；Then tamponade under vacuum, then filtrated air is entered, make casing internal pressure consistent with air, finally go out
Case, mouth is rolled with aluminium-plastic combined cover, and packaging after quality inspection is qualified obtains final product acetyl danshensu freeze drying powder injection.
Embodiment 8：
Prescription
Sodium citrate, EDTA-2Na and the mannitol of recipe quantity are weighed, plus 80mL waters for injection are allowed to dissolve, and then add again
Enter 5g acetyl danshensus, stirring makes its whole dissolve and be well mixed, molten with 0.1moL/L hydrochloric acid or 0.1moL/L NaOH
Liquid adjusts pH to 5.0, adds 0.2% needle-use activated carbon, 40 DEG C of stirring and adsorbing 20min, and suction filtration takes off charcoal, and intermediate inspection is closed
After lattice, full dose is settled to water for injection.Solution is delivered in desinfection chamber after the filtering with microporous membrane of 0.22 μm of twice, is sub-packed in
In 25mL cillin bottles, every bottle of filling 5mL, partly butyl rubber bung, sabot beyond the Great Wall is put in freeze drying box, closes chamber door, and start is freezed,
Decline products temperature using conduction oil, continue to freeze 2 hours when products temperature reaches -50 DEG C；Stop conduction oil, open condensation
Device, when condenser temperature reaches -40 DEG C, opens vacuum system, and product starts preliminary distillation, and vacuum control is in 20Pa, product temperature
Degree insulation 20h when rising to -30 DEG C, -15 DEG C when insulation 20h, 0 DEG C when be incubated 4h；After distillation line reaches bottom, products temperature delays
It is slow to be warming up to 35 DEG C, it is incubated 2h；Then tamponade under vacuum, then filtrated air is entered, make casing internal pressure consistent with air, finally go out
Case, mouth is rolled with aluminium-plastic combined cover, and packaging after quality inspection is qualified obtains final product acetyl danshensu freeze drying powder injection.
Embodiment 9：
Prescription
The sodium citrate and EDTA-2Na of recipe quantity are weighed, plus 80mL waters for injection are allowed to dissolve, and then add 20g second
Acyl danshensu, stirring makes its whole dissolve and be well mixed, and is adjusted with 0.1moL/L hydrochloric acid or 0.1moL/L sodium hydroxide solutions
PH to 5.5, adds 0.5% needle-use activated carbon, and 25 DEG C of stirring and adsorbing 10min, suction filtration takes off charcoal, after intermediate passed examination, uses
Water for injection is settled to full dose.Solution is delivered in desinfection chamber after the filtering with microporous membrane of 0.22 μm of twice, is sub-packed in 25mL west
In woods bottle, every bottle of filling 3mL, partly butyl rubber bung, sabot beyond the Great Wall in putting freeze drying box, closes chamber door, start refrigeration, using leading
Deep fat declines products temperature, continues to freeze 2.5 hours when products temperature reaches -50 DEG C；Stop conduction oil, open condenser, when
When condenser temperature reaches -40 DEG C, vacuum system is opened, product starts preliminary distillation, and vacuum control is in 15Pa, products temperature liter
6h is incubated when being incubated 6h, 0 DEG C when being incubated 10h, -15 DEG C when 24h, -25 DEG C are incubated at -35 DEG C；After distillation line reaches bottom,
Products temperature is to slowly warm up to 33 DEG C, is incubated 3h；Then tamponade under vacuum, then filtrated air is entered, make casing internal pressure and air
Unanimously, last outlet, mouth is rolled with aluminium-plastic combined cover, and packaging after quality inspection is qualified obtains final product acetyl danshensu freeze drying powder injection.
Embodiment 10：Particulate matter is determined
Acetyl danshensu freeze drying powder injection prepared by Example 6 ~ 9, is dissolved with 1 ~ 5mL waters for injection respectively, is then added to
In 100 or 250mL glucose or sodium chloride transfusion, carried out by Chinese Pharmacopoeia two annex IX the first methods of C of version in 2010 respectively
Determine, it is as a result as follows.
Embodiment 11：The stability of acetyl danshensu freeze drying powder injection
Factors influencing is carried out respectively to acetyl danshensu freeze drying powder injection prepared by embodiment 6 ~ 9.By sample in height
Temperature（60℃）, strong illumination（4500Lx）And high humidity（Relative humidity 90%）Under the conditions of place, respectively at 0,5,10 days sample, survey
Determine indices, measurement result is shown in Table 7.
Note：Visible foreign matters：It is measured by Chinese Pharmacopoeia two annex IX the first methods of H of version in 2010.
From data in table, acetyl danshensu freeze drying powder injection is in high temperature（60℃）, strong illumination（4500Lx）, high humidity
（Relative humidity 90%）Under conditions of place 10 days, the measurement result of indices compared no significant difference with 0 day, qualified
In the range of, simply there is moisture absorption phenomenon under super-humid conditions, it is contemplated that the custom requirements of freeze drying powder injection, storage of samples condition is fixed tentatively and is
Closed preservation.
Claims (5)
1. a kind of acetyl danshensu freeze drying powder injection, it is characterised in that：Powder-injection is by acetyl danshensu, sodium citrate, mannitol
With EDTA-2Na compositions, the mass ratio of acetyl danshensu, sodium citrate, mannitol and EDTA-2Na is 1 ~ 30：2~40：1~10：
0.01~0.1。
2. acetyl danshensu freeze drying powder injection according to claim 1, it is characterised in that：It is acetyl danshensu, sodium citrate, sweet
The mass ratio of dew alcohol and EDTA-2Na is 5 ~ 15：5~15：3~5：0.01~0.05.
3. the preparation method of acetyl danshensu freeze drying powder injection described in claim 1, it is characterised in that comprise the following steps：
（1）Sodium citrate, mannitol and the EDTA-2Na of recipe quantity are weighed, amount water for injection is allowed to dissolve plus 80%；
（2）The acetyl danshensu of recipe quantity is added, stirring makes its whole dissolve and be well mixed；
（3）PH to 4.0 ~ 6.0 is adjusted with 0.1moL/L hydrochloric acid or 0.1moL/L sodium hydroxide solutions；
（4）0.1% ~ 0.5% needle-use activated carbon, 25 DEG C ~ 50 DEG C 10 ~ 60min of stirring and adsorbing, suction filtration is added to take off charcoal, middle physical examination
Look into it is qualified after, be settled to full dose with water for injection；
（5）Solution is delivered in desinfection chamber after 0.22 μm of filtering with microporous membrane, is sub-packed in cillin bottle, every bottle of 1 ~ 5mL, and half fills in
Upper butyl rubber bung, sabot, freeze-drying.
4. preparation method according to claim 3, it is characterised in that step（5）Middle freeze-drying is comprised the following steps：
（1）After product puts freeze drying box, close chamber door start refrigeration, decline products temperature using conduction oil, when products temperature up to-
Continue to freeze 2 ~ 4 hours at 40 DEG C；
（2）Stop conduction oil, open condenser, when condenser temperature reaches -40 DEG C ~ -50 DEG C, open vacuum system, product starts
Preliminary distillation, vacuum control is controlled at -35 DEG C ~ 0 DEG C in 7 ~ 20Pa, sublimation stage products temperature；
（3）After distillation line reaches bottom, products temperature is to slowly warm up to 30 ~ 35 DEG C, is incubated 2 ~ 4 hours；
（4）Then tamponade under vacuum, then filtrated air is entered, make casing internal pressure consistent with air, last outlet.
5. the acetyl danshensu freeze drying powder injection described in claim 1 is in prevention or treatment cardiovascular and cerebrovascular diseases medicament is prepared
Using.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1939403A (en) * | 2005-09-26 | 2007-04-04 | 孙毅 | Production of compound Danshen root injection |
| CN101073566A (en) * | 2006-05-19 | 2007-11-21 | 秦长青 | Production and use for tanshinone component injection |
| CN101596182A (en) * | 2008-06-05 | 2009-12-09 | 山东靶点药物研究有限公司 | Contain pharmaceutical composition, its preparation method, the purposes of salviol acid A and contain the lyophilized injectable powder and the aqueous injection of said composition |
| CN103232350A (en) * | 2013-04-28 | 2013-08-07 | 中国人民解放军第四军医大学 | Acylated Danshensu derivative and application thereof to preventing and treating cerebrovascular and liver and kidney diseases |
| CN103919759A (en) * | 2014-04-06 | 2014-07-16 | 吴静 | Pharmaceutical composition comprising salvianic acid a sodium and salvianolic acid F and preparation of pharmaceutical composition |
-
2014
- 2014-11-26 CN CN201410685656.1A patent/CN104473883B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1939403A (en) * | 2005-09-26 | 2007-04-04 | 孙毅 | Production of compound Danshen root injection |
| CN101073566A (en) * | 2006-05-19 | 2007-11-21 | 秦长青 | Production and use for tanshinone component injection |
| CN101596182A (en) * | 2008-06-05 | 2009-12-09 | 山东靶点药物研究有限公司 | Contain pharmaceutical composition, its preparation method, the purposes of salviol acid A and contain the lyophilized injectable powder and the aqueous injection of said composition |
| CN103232350A (en) * | 2013-04-28 | 2013-08-07 | 中国人民解放军第四军医大学 | Acylated Danshensu derivative and application thereof to preventing and treating cerebrovascular and liver and kidney diseases |
| CN103919759A (en) * | 2014-04-06 | 2014-07-16 | 吴静 | Pharmaceutical composition comprising salvianic acid a sodium and salvianolic acid F and preparation of pharmaceutical composition |
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