CN106361826A - Preparation method of pharmaceutical composition for improving safety of compound radix codonopsis injection solution - Google Patents
Preparation method of pharmaceutical composition for improving safety of compound radix codonopsis injection solution Download PDFInfo
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Abstract
The invention discloses a preparation method of a pharmaceutical composition for improving the safety of a compound radix codonopsis injection solution. The pharmaceutical composition is a pharmaceutical composition for injection, which is mainly prepared from radix codonopsis extract, rhizoma corydalis decumbentis extract, scandent schefflera root extract and tert-butyl peroxyacetate. According to the preparation method provided by the invention, a co-solvent, which has better safety and more obvious auxiliary dissolving effect, is used for replacing a co-solvent polysorbate 80 which has potential safety hazards on the compound radix codonopsis injection solution and influences product quality, the safety of the tert-butyl peroxyacetate is higher than that of the polysorbate 80 and the use amount of the tert-butyl peroxyacetate is lower; the probability and risks of untoward effects caused by medicines are reduced and the safety of clinical medication is improved.
Description
Technical field
The invention belongs to pharmaceutical technology field, in particular it relates to a kind of improve compound Codonopsis pilosula injection safety medicine group
The preparation method of compound.
Background technology
Compound Codonopsis pilosula injection standard is recorded and is issued drug standard (Traditional Chinese medicine historical preparation) in Ministry of Public Health, crude drug be Radix Codonopsis,
Rhizoma Corydalis Decumbentiss, Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae), belong to Chinese medicine injection.There is promoting blood circulation to restore menstrual flow, effect of stasis-dispelling and pain-killing.It is clinically used for treating dysmenorrhea, warp
Close, injury from falling down, rheumatic arthralgia etc..
In China in wide clinical application for many years, clinical efficacy has obtained the good of doctor and patient to compound Codonopsis pilosula injection
Comment.But in recent years, the Reporting of harms of Chinese medicine injection clinical practice is on the rise, have impact on and there is Chinese Medicine characteristic
The development of Chinese medicine injection.Domestic experts and scholars have carried out numerous studies to the untoward reaction of Chinese medicine injection, document report its
The generation of untoward reaction is had very with the cosolvent polyoxyethylene sorbitan monoleate (Tween 80) of the presence potential safety hazard of addition in Chinese medicine injection
Big relation.Due to Chinese medicine injection complicated component, solute easily occurs in storage and autoclaving process and separates out and affect clear
The problems such as lightness, solution ph are decreased obviously, therefore adds polyoxyethylene sorbitan monoleate (Tween 80) in such injection and makees hydrotropy
Agent, adds the solubilization-aid effect of other cosolvents then inconspicuous.But polyoxyethylene sorbitan monoleate (Tween 80) is immature due to process for refining,
Easily become sour in storage and autoclaving process, lead to impurity content high it is difficult to reach injection standard, polyoxyethylene sorbitan monoleate (is told
Temperature 80) inherently there are stronger hemolytic and anaphylaxis, apply increased in injection occur untoward reaction probability and
Risk.In addition, in sterilizing and storage process itself, Chinese medicine injection also has that solution ph is decreased obviously, and poly- Pyrusussuriensiss
Ester 80 (Tween 80) and easily becoming sour, more accelerates the decline of the ph value of medicinal liquid.The compound Codonopsis pilosula injection of domestic production at present
In also add polyoxyethylene sorbitan monoleate (Tween 80) and make cosolvent, be faced with same problem.
In view of the foregoing, find the poly- mountain that safety is more preferable, poor stability replaced by the more obvious cosolvent of solubilization-aid effect
Pear ester 80 (Tween 80) is this injection urgent problem.
Content of the invention
The technical problem to be solved is to provide that a kind of safety is more preferable, solubilization-aid effect more obviously improves compound recipe
The preparation method of Radix Codonopsis injection safety pharmaceutical composition.
The present invention solves above-mentioned technical problem and be the technical scheme is that a kind of raising compound Codonopsis pilosula injection safety
Pharmaceutical composition, be mainly made up of Radix Codonopsis extract, Rhizoma Corydalis Decumbentis extract, Radix Schefflerae Arboricolae extract and peroxide acetic acid butyl ester
Injection pharmaceutical composition.
Specifically, the consumption of peroxide acetic acid butyl ester is 0.005g～5.0g/100ml；Peroxide acetic acid butyl ester
Consumption is preferably 0.05g～1.0g/100ml.
Polyoxyethylene sorbitan monoleate is also included, peroxide acetic acid butyl ester is pressed not on year-on-year basis with polyoxyethylene sorbitan monoleate in aforementioned pharmaceutical compositions
Example is combined and is made cosolvent, and peroxide acetic acid butyl ester is 0.005g～5.0g/100ml with the usage ratio of polyoxyethylene sorbitan monoleate:
0.001g～2.0g/100ml.
Described pharmaceutical composition dosage form is injection, powder pin or lyophilizing.
A kind of preparation method improving compound Codonopsis pilosula injection safety pharmaceutical composition, comprises the steps:
(1) compound Codonopsis pilosula injection raw medicinal material Radix Codonopsis 100g, Rhizoma Corydalis Decumbentiss 100g, Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) 100g, cosolvent 2.0g；
(2) Radix Codonopsis, Rhizoma Corydalis Decumbentiss add water to cook secondary, 2 hours every time, collecting decoction, plus ethanol filtering and concentrating, plus 3 times amount
Water, is sufficiently stirred for, cold preservation 48 hours, filtration, and filtrate reduced in volume to relative density is about 1.15, and medicinal liquid is standby；
(3) Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) add water to cook secondary, 1 hour every time, collecting decoction, filtration, concentrate filtrate, let cool, plus ethanol make
Containing amount of alcohol be 65%, stand overnight, filtration, filtrate reduced in volume to relative density be 1.20, plus ethanol make containing amount of alcohol be
70%, stand overnight, filtration, it is 1.30 that filtrate is concentrated into relative density, plus 3 times amount water, is sufficiently stirred for, cold preservation 48 hours, filter
Cross, it is 1.15 that filtrate is concentrated into relative density,
(4) merge with above-mentioned all medicinal liquids, plus 2 times amount water, it is sufficiently stirred for, cold preservation 24 hours, filtration, filtrate adds hydrotropy
Agent and water for injection are configured to 1000ml solution, stir evenly, and the relative density of above-mentioned each filtrate is relative density when 80 DEG C；
(5) with sodium hydroxide solution regulation solution ph to 6.5-8.5；
(6) filter, fill, sterilizing, obtain final product.
In order to the method for the present invention is better achieved, further, in described step (1), cosolvent is by peracetic acid
The tert-butyl ester is formed with polyoxyethylene sorbitan monoleate, and wherein the content of peroxide acetic acid butyl ester is 0.005g～2.0g, balance of poly- Pyrusussuriensiss
Ester 80.
In order to the method for the present invention is better achieved, further, in described step (2), plus the mistake of ethanol filtering and concentrating
Cheng Wei, first filters to get filtrate, filtrate reduced in volume to relative density be 1.27～1.30, let cool, plus ethanol make containing amount of alcohol be
65%, stand overnight, filtration, decompression filtrate recycling ethanol is simultaneously concentrated into relative density for 1.30.
In order to the method for the present invention is better achieved, further, in described step (3), filtrate is concentrated into relative density
For 1.25～1.30.
In order to the method for the present invention is better achieved, further, in described step (5), the sodium hydroxide solution of use
Mass percent be 20%.
In order to the method for the present invention is better achieved, further, in described step (6), solution uses microporous filter membrane mistake
Filter.
The present invention, by substantial amounts of experimentation, finds a kind of Polyethylene Glycol (peg) 12-hydroxy stearic acid ester
(solutol) it is the preferable substitute products of polyoxyethylene sorbitan monoleate.Polyethylene Glycol (peg) 12-hydroxy stearic acid ester
(solutol) recorded in European Pharmacopoeia (ep5.5), Deutscher Arzneibucses and British Pharmacopoeia, can be used for the increasing of ejection preparation
Solvent.The pharmacological toxicology experimental data of document report shows that its toxicity is significantly lower than polyoxyethylene sorbitan monoleate (Tween 80).In addition we
By substantial amounts of experimental studies have found that, Polyethylene Glycol (peg) 12-hydroxy stearic acid ester when reaching identical solubilization-aid effect
(solutol) amount ratio polyoxyethylene sorbitan monoleate (Tween 80) low, more improve Drug safety.
The pharmacological toxicology experimental data of document report shows Polyethylene Glycol (peg) 12-hydroxy stearic acid ester (solutol) safety higher than polyoxyethylene sorbitan monoleate (Tween 80), its toxicity (sees below significantly lower than polyoxyethylene sorbitan monoleate (Tween 80)
Table 1-3).Respectively using (0.5g/100ml) Polyethylene Glycol (peg) ten dihydroxy Hard Fat of equivalent in compound Codonopsis pilosula injection
Acid esters (solutol) and polyoxyethylene sorbitan monoleate (Tween 80), safety experiment comparative study result shows, using equivalent
(0.5g/100ml) Polyethylene Glycol (peg) 12-hydroxy stearic acid ester (solutol) group hemolytic, zest,
Anaphylaxis and the toxicity aspect such as reduce blood pressure are all substantially low than being organized using polyoxyethylene sorbitan monoleate (Tween 80), bright by the present invention
The aobvious safety decreasing probability and the risk that compound Codonopsis pilosula injection occurs untoward reaction in clinical practice, improving clinical application
Property.
To sum up, the invention has the beneficial effects as follows: provide that a kind of safety is more preferable, the more obvious cosolvent of solubilization-aid effect is replaced
There is potential safety hazard and the cosolvent polyoxyethylene sorbitan monoleate (Tween 80) of impact product quality in compound Codonopsis pilosula injection；Polyethylene Glycol
(peg) 12-hydroxy stearic acid ester (solutol) safety is higher than polyoxyethylene sorbitan monoleate (Tween 80) and also consumption more
Low, reduce probability and the risk that medicine occurs untoward reaction, improve the safety of clinical application.
Specific embodiment
Embodiment 1
Preparation method: Radix Codonopsis, Rhizoma Corydalis Decumbentiss add water to cook secondary, 2 hours every time, collecting decoction, filtration, filtrate reduced in volume
It is 1.27～1.30 (80 DEG C) to relative density, lets cool, plus ethanol makes containing amount of alcohol to be 65%, stands overnight, filtration, filtrate subtracts
Push back receipts ethanol and be concentrated into relative density for 1.30 (80 DEG C), plus 3 times amount water, it is sufficiently stirred for, cold preservation 48 hours, filtration, filter
Liquid is evaporated to relative density and is about 1.15 (80 DEG C), and medicinal liquid is standby；Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) add water to cook secondary, 1 hour every time, merge
Decocting liquid, filtration, it is 1.25～1.30 (80 DEG C) that filtrate is concentrated into relative density, lets cool, plus ethanol makes containing amount of alcohol to be 65%, quiet
Put overnight, filtration, filtrate reduced in volume to relative density is 1.20 (80 DEG C), plus ethanol makes containing amount of alcohol to be 70%, stands
Night, filtration, it is 1.30 (80 DEG C) that filtrate is concentrated into relative density, plus 3 times amount water, is sufficiently stirred for, cold preservation 48 hours, filtration, filter
It is 1.15 (80 DEG C) that liquid is concentrated into relative density, merges with above-mentioned medicinal liquid, plus 2 times amount water, is sufficiently stirred for, cold preservation 24 hours, filter
Cross, filtrate adds Polyethylene Glycol (peg) 12-hydroxy stearic acid ester (solutol) make cosolvent and water for injection is joined
Make 1000ml solution.Stir evenly.With 20% sodium hydroxide solution regulation solution ph to 6.5-8.5.By above-mentioned solution through micropore
Filter membrane filters.Fill, sterilizing, obtain final product.
Embodiment 2
Preparation method: Radix Codonopsis, Rhizoma Corydalis Decumbentiss add water to cook secondary, 2 hours every time, collecting decoction, filtration, filtrate reduced in volume
It is 1.27～1.30 (80 DEG C) to relative density, lets cool, plus ethanol makes containing amount of alcohol to be 65%, stands overnight, filtration, filtrate subtracts
Push back receipts ethanol and be concentrated into relative density for 1.30 (80 DEG C), plus 3 times amount water, it is sufficiently stirred for, cold preservation 48 hours, filtration, filter
Liquid is evaporated to relative density and is about 1.15 (80 DEG C), and medicinal liquid is standby；Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) add water to cook secondary, 1 hour every time, merge
Decocting liquid, filtration, it is 1.25～1.30 (80 DEG C) that filtrate is concentrated into relative density, lets cool, plus ethanol makes containing amount of alcohol to be 65%, quiet
Put overnight, filtration, filtrate reduced in volume to relative density is 1.20 (80 DEG C), plus ethanol makes containing amount of alcohol to be 70%, stands
Night, filtration, it is 1.30 (80 DEG C) that filtrate is concentrated into relative density, plus 3 times amount water, is sufficiently stirred for, cold preservation 48 hours, filtration, filter
It is 1.15 (80 DEG C) that liquid is concentrated into relative density, merges with above-mentioned medicinal liquid, plus 2 times amount water, is sufficiently stirred for, cold preservation 24 hours, filter
Cross, filtrate adds Polyethylene Glycol (peg) 12-hydroxy stearic acid ester (solutol) make cosolvent and note with tween 80
Penetrate and be configured to 1000ml solution with water.Stir evenly.With 20% sodium hydroxide solution regulation solution ph to 6.5-8.5.Will be above-mentioned molten
Liquid filters through microporous filter membrane.Fill, sterilizing, obtain final product.
Embodiment 3
Preparation method: Radix Codonopsis, Rhizoma Corydalis Decumbentiss add water to cook secondary, 2 hours every time, collecting decoction, filtration, filtrate reduced in volume
It is 1.27～1.30 (80 DEG C) to relative density, lets cool, plus ethanol makes containing amount of alcohol to be 65%, stands overnight, filtration, filtrate subtracts
Push back receipts ethanol and be concentrated into relative density for 1.30 (80 DEG C), plus 3 times amount water, it is sufficiently stirred for, cold preservation 48 hours, filtration, filter
Liquid is evaporated to relative density and is about 1.15 (80 DEG C), and medicinal liquid is standby；Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) add water to cook secondary, 1 hour every time, merge
Decocting liquid, filtration, it is 1.25～1.30 (80 DEG C) that filtrate is concentrated into relative density, lets cool, plus ethanol makes containing amount of alcohol to be 65%, quiet
Put overnight, filtration, filtrate reduced in volume to relative density is 1.20 (80 DEG C), plus ethanol makes containing amount of alcohol to be 70%, stands
Night, filtration, it is 1.30 (80 DEG C) that filtrate is concentrated into relative density, plus 3 times amount water, is sufficiently stirred for, cold preservation 48 hours, filtration, filter
It is 1.15 (80 DEG C) that liquid is concentrated into relative density, merges with above-mentioned medicinal liquid, plus 2 times amount water, is sufficiently stirred for, cold preservation 24 hours, filter
Cross, filtrate adds Polyethylene Glycol (peg) 12-hydroxy stearic acid ester (solutol) make cosolvent and water for injection is joined
Make solution.Stir evenly.With 20% sodium hydroxide solution regulation solution ph to 6.5-8.5.Above-mentioned solution is filtered through microporous filter membrane
Cross.It is distributed into 1000, lyophilization, obtain final product.
Embodiment 4:
The Radix Codonopsis extract of the present invention, Rhizoma Corydalis Decumbentis extract, Radix Schefflerae Arboricolae extract and Polyethylene Glycol (peg) ten dihydroxy are hard
Fat acid ester (solutol) the injection pharmaceutical composition made can be achieved through the following technical solutions:
(1) compound Codonopsis pilosula injection raw medicinal material Radix Codonopsis 100g, Rhizoma Corydalis Decumbentiss 100g, Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) 100g, Polyethylene Glycol (peg)
12-hydroxy stearic acid ester (solutol)2.0g；
(2) Radix Codonopsis, Rhizoma Corydalis Decumbentiss add water to cook secondary, 2 hours every time, collecting decoction, filtration, filtrate reduced in volume is to relatively
Density is 1.27～1.30 (80 DEG C), lets cool, plus ethanol makes containing amount of alcohol to be 65%, stands overnight, filtration, filtrate decompression reclaims
Ethanol is simultaneously concentrated into relative density for 1.30 (80 DEG C), plus 3 times amount water, is sufficiently stirred for, cold preservation 48 hours, filtration, filtrate decompression
It is concentrated into relative density and is about 1.15 (80 DEG C), medicinal liquid is standby；Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) add water to cook secondary, 1 hour every time, collecting decoction,
Filtration, it is 1.25～1.30 (80 DEG C) that filtrate is concentrated into relative density, lets cool, plus ethanol makes containing amount of alcohol to be 65%, stands
Night, filtration, filtrate reduced in volume to relative density is 1.20 (80 DEG C), plus ethanol makes containing amount of alcohol to be 70%, stands overnight, filter
Cross, it is 1.30 (80 DEG C) that filtrate is concentrated into relative density, plus 3 times amount water, is sufficiently stirred for, cold preservation 48 hours, filtration, and filtrate concentrates
It is 1.15 (80 DEG C) to relative density, merge with above-mentioned medicinal liquid, plus 2 times amount water, it is sufficiently stirred for, cold preservation 24 hours, filtration, filtrate
Add Polyethylene Glycol (peg) 12-hydroxy stearic acid ester (solutol) make cosolvent and water for injection is configured to
1000ml solution.Stir evenly.
(3) with 20% sodium hydroxide solution regulation solution ph to 6.5-8.5.
(4) above-mentioned solution is filtered through microporous filter membrane.
(5) fill, sterilizing, obtain final product.
In the present invention, cosolvent can be peroxide acetic acid butyl ester, and its consumption is in 0.005g～5.0g/100ml
Arbitrary value, such as 0.005g/100ml, 0.01g/100ml, 0.05g/100ml, 1.0g/100ml, 5.0g/100ml etc.；Cosolvent
Can also be made up of with polyoxyethylene sorbitan monoleate peroxide acetic acid butyl ester, its usage ratio is 0.005g～5.0g/100ml:
0.001g～2.0g/100ml.
Claims (6)
1. a kind of preparation method improving compound Codonopsis pilosula injection safety pharmaceutical composition, comprises the steps:
(1) compound Codonopsis pilosula injection raw medicinal material Radix Codonopsis 100g, Rhizoma Corydalis Decumbentiss 100g, Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) 100g, cosolvent 2.0g；
(2) Radix Codonopsis, Rhizoma Corydalis Decumbentiss add water to cook secondary, 2 hours every time, collecting decoction, plus ethanol filtering and concentrating, plus 3 times amount water, fill
Divide stirring, cold preservation 48 hours, filtration, filtrate reduced in volume to relative density is about 1.15, and medicinal liquid is standby；
(3) Radix Schefflerae Arboricolae (Caulis et Folium Schefflerae Arboricolae) add water to cook secondary, 1 hour every time, collecting decoction, filtration, concentrate filtrate, let cool, plus ethanol make containing second
Alcohol amount is 65%, stands overnight, filtration, and filtrate reduced in volume to relative density is 1.20, plus ethanol makes containing amount of alcohol to be 70%,
Stand overnight, filtration, it is 1.30 that filtrate is concentrated into relative density, plus 3 times amount water, is sufficiently stirred for, cold preservation 48 hours, filtration, filter
It is 1.15 that liquid is concentrated into relative density,
(4) merge with above-mentioned all medicinal liquids, plus 2 times amount water, be sufficiently stirred for, cold preservation 24 hours, filtration, filtrate add cosolvent and
Water for injection is configured to 1000ml solution, stirs evenly, and the relative density of above-mentioned each filtrate is relative density when 80 DEG C；
(5) with sodium hydroxide solution regulation solution ph to 6.5-8.5；
(6) filter, fill, sterilizing, obtain final product.
2. a kind of preparation method improving compound Codonopsis pilosula injection safety pharmaceutical composition according to claim 1, its
It is characterised by, in described step (1), cosolvent is made up of with polyoxyethylene sorbitan monoleate peroxide acetic acid butyl ester, wherein peroxidating second
The content of tert-butyl acrylate is 0.005g～2.0g, balance of polyoxyethylene sorbitan monoleate.
3. a kind of preparation method improving compound Codonopsis pilosula injection safety pharmaceutical composition according to claim 1, its
It is characterised by, in described step (2), plus the process of ethanol filtering and concentrating is first to filter to get filtrate, filtrate reduced in volume is to relatively
Density is 1.27～1.30, lets cool, plus ethanol makes containing amount of alcohol to be 65%, stands overnight, filtration, decompression filtrate recycling ethanol is simultaneously
Being concentrated into relative density is 1.30.
4. a kind of preparation method improving compound Codonopsis pilosula injection safety pharmaceutical composition according to claim 1, its
It is characterised by, in described step (3), it is 1.25～1.30 that filtrate is concentrated into relative density.
5. a kind of preparation method improving compound Codonopsis pilosula injection safety pharmaceutical composition according to claim 1, its
It is characterised by, in described step (5), the mass percent of the sodium hydroxide solution of use is 20%.
6. a kind of preparation method improving compound Codonopsis pilosula injection safety pharmaceutical composition according to claim 1, its
It is characterised by, in described step (6), solution uses filtering with microporous membrane.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610968048.0A CN106361826A (en) | 2016-11-06 | 2016-11-06 | Preparation method of pharmaceutical composition for improving safety of compound radix codonopsis injection solution |
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| CN105079067A (en) * | 2015-09-23 | 2015-11-25 | 成都艾比科生物科技有限公司 | Pharmaceutical composition for improving safety of compound gastrodin injection |
| CN105106111A (en) * | 2015-09-23 | 2015-12-02 | 成都艾比科生物科技有限公司 | Safe medicine composition for compound gastrodin injection and preparation method of safe medicine composition |
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| CN105079067A (en) * | 2015-09-23 | 2015-11-25 | 成都艾比科生物科技有限公司 | Pharmaceutical composition for improving safety of compound gastrodin injection |
| CN105106111A (en) * | 2015-09-23 | 2015-12-02 | 成都艾比科生物科技有限公司 | Safe medicine composition for compound gastrodin injection and preparation method of safe medicine composition |
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