CN106389317A - Preparation method of pharmaceutical composition for improving safety of compound puerarin injection - Google Patents
Preparation method of pharmaceutical composition for improving safety of compound puerarin injection Download PDFInfo
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Abstract
The invention discloses a preparation method of a pharmaceutical composition for improving safety of compound puerarin injection; the pharmaceutical composition is a pharmaceutical composition for injection made mainly from puerarin extract, Bupleurum sinensis extract, hairy antler extract and dibutyl fumarate; a cosolvent with better safety and more significant solubilizing effect is used to replace the cosolvent polysorbate 80, which has potential safety hazards and may affect product quality, in compound saffron injection, the safety of dibutyl fumarate is better than that of polysorbate 80 while usage is less, the chance and risk for adverse reactions of drugs are decreased, and clinical medication safety is improved.
Description
Technical field
The invention belongs to pharmaceutical technology field, in particular it relates to a kind of improve compound puerarin injection safety medicine
The preparation method of compositionss.
Background technology
Compound puerarin injection standard is recorded and is issued drug standard (Traditional Chinese medicine historical preparation) in Ministry of Public Health, and crude drug is Radix Puerariae
Element, Radix Bupleuri, Cornu Cervi Pantotrichum, 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 puerarin 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 puerarin injection of domestic production at present
Also add polyoxyethylene sorbitan monoleate (Tween 80) in liquid 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 pharmaceutical composition preparation method of puerarin injection safety.
The present invention solves above-mentioned technical problem and be employed technical scheme comprise that：A kind of raising compound puerarin injection safety
The pharmaceutical composition of property, the confession being mainly made up of puerarin extract, Radix Bupleuri extract, Cornu Cervi Pantotrichum extract and dibutyl fumarate
Medicinal composition for injections.
Specifically, the consumption of dibutyl fumarate is 0.005g～5.0g/100ml；The consumption of dibutyl fumarate is preferred
For 0.05g～1.0g/100ml.
Polyoxyethylene sorbitan monoleate is also included, dibutyl fumarate and polyoxyethylene sorbitan monoleate press different proportion connection in aforementioned pharmaceutical compositions
Cooperation cosolvent, dibutyl fumarate 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 puerarin injection safety pharmaceutical composition, comprises the steps：
(1) compound puerarin injection raw medicinal material puerarin 100g, Radix Bupleuri 100g, Cornu Cervi Pantotrichum 100g, cosolvent 2.0g；
(2) puerarin, Radix Bupleuri 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) Cornu Cervi Pantotrichum add water to cook secondary, 1 hour every time, collecting decoction, filtration, concentrate filtrate, let cool, plus ethanol make to contain
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 fumaric acid two fourth
Ester is formed with polyoxyethylene sorbitan monoleate, and wherein the content of dibutyl fumarate is 0.005g～2.0g, balance of polyoxyethylene sorbitan monoleate.
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).In compound puerarin injection, (0.5g/100ml) Polyethylene Glycol (PEG) ten dihydroxy using equivalent are hard respectively
Fat acid ester (Solutol) and polyoxyethylene sorbitan monoleate (Tween 80), safety experiment comparative study result shows, using etc.
(0.5g/100ml) Polyethylene Glycol (PEG) 12-hydroxy stearic acid ester (Solutol of amount) group is in hemolytic, stimulation
Property, anaphylaxis and the toxicity aspect such as reduce blood pressure are all substantially low than being organized using polyoxyethylene sorbitan monoleate (Tween 80), by this
Bright considerably reduce probability and the risk that compound puerarin injection occurs untoward reaction in clinical practice, improve clinical application
Safety.
To sum up, the invention has the beneficial effects as follows：There is provided 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 puerarin injection；Poly- second two
Alcohol (PEG) 12-hydroxy stearic acid ester (Solutol) safety is higher than polyoxyethylene sorbitan monoleate (Tween 80) and also consumption
Lower, reduce probability and the risk that medicine occurs untoward reaction, improve the safety of clinical application.
Specific embodiment
Embodiment 1
Preparation method：Puerarin, Radix Bupleuri 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；Cornu Cervi Pantotrichum add water to cook secondary, 1 hour every time, merge decoct
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%, standing
Overnight, filter, filtrate reduced in volume to relative density is 1.20 (80 DEG C), plus ethanol make containing amount of alcohol to be 70%, stands overnight,
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, and filtrate is dense
Being reduced to relative density is 1.15 (80 DEG C), merges with above-mentioned medicinal liquid, plus 2 times amount water, is sufficiently stirred for, cold preservation 24 hours, filtration, filter
Liquid adds Polyethylene Glycol (PEG) 12-hydroxy stearic acid ester (Solutol) make cosolvent and water for injection is configured to
1000ml solution.Stir evenly.With 20% sodium hydroxide solution regulation solution ph to 6.5-8.5.By above-mentioned solution through microporous filter membrane
Filtration.Fill, sterilizing, obtain final product.
Embodiment 2
Preparation method：Puerarin, Radix Bupleuri 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；Cornu Cervi Pantotrichum add water to cook secondary, 1 hour every time, merge decoct
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%, standing
Overnight, filter, filtrate reduced in volume to relative density is 1.20 (80 DEG C), plus ethanol make containing amount of alcohol to be 70%, stands overnight,
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, and filtrate is dense
Being reduced to relative density is 1.15 (80 DEG C), merges with above-mentioned medicinal liquid, plus 2 times amount water, is sufficiently stirred for, cold preservation 24 hours, filtration, filter
Liquid adds Polyethylene Glycol (PEG) 12-hydroxy stearic acid ester (Solutol) make cosolvent and injection with tween 80
Water is configured to 1000ml solution.Stir evenly.With 20% sodium hydroxide solution regulation solution ph to 6.5-8.5.By above-mentioned solution warp
Microporous filter membrane filters.Fill, sterilizing, obtain final product.
Embodiment 3
Preparation method：Puerarin, Radix Bupleuri 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；Cornu Cervi Pantotrichum add water to cook secondary, 1 hour every time, merge decoct
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%, standing
Overnight, filter, filtrate reduced in volume to relative density is 1.20 (80 DEG C), plus ethanol make containing amount of alcohol to be 70%, stands overnight,
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, and filtrate is dense
Being reduced to relative density is 1.15 (80 DEG C), merges with above-mentioned medicinal liquid, plus 2 times amount water, is sufficiently stirred for, cold preservation 24 hours, filtration, filter
Liquid adds Polyethylene Glycol (PEG) 12-hydroxy stearic acid ester (Solutol) make cosolvent and water for injection be configured to molten
Liquid.Stir evenly.With 20% sodium hydroxide solution regulation solution ph to 6.5-8.5.Above-mentioned solution is filtered through microporous filter membrane.Subpackage
Become 1000, lyophilization, obtain final product.
Embodiment 4：
The puerarin extract of the present invention, Radix Bupleuri extract, Cornu Cervi Pantotrichum extract and Polyethylene Glycol (PEG) ten dihydroxy Hard Fat
Acid esters (Solutol) the injection pharmaceutical composition made can be achieved through the following technical solutions：
(1) compound puerarin injection raw medicinal material puerarin 100g, Radix Bupleuri 100g, Cornu Cervi Pantotrichum 100g, Polyethylene Glycol (PEG)
12-hydroxy stearic acid ester (Solutol)2.0g；
(2) puerarin, Radix Bupleuri 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；Cornu Cervi Pantotrichum add water to cook secondary, 1 hour every time, collecting decoction, filter
Cross, it is 1.25～1.30 (80 DEG C) that filtrate is concentrated into relative density, lets cool, plus ethanol make containing amount of alcohol to be 65%, stands 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 overnight, 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, and filtrate is concentrated into
Relative density is 1.15 (80 DEG C), merges with above-mentioned medicinal liquid, plus 2 times amount water, is sufficiently stirred for, cold preservation 24 hours, filtration, and filtrate adds
Enter 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 dibutyl fumarate, and its consumption is any in 0.005g～5.0g/100ml
Value, such as 0.005g/100ml, 0.01g/100ml, 0.05g/100ml, 1.0g/100ml, 5.0g/100ml etc.；Cosolvent also may be used
To be made up of with polyoxyethylene sorbitan monoleate dibutyl fumarate, its usage ratio is 0.005g～5.0g/100ml：0.001g～2.0g/
100ml.
Claims (6)
1. a kind of preparation method improving compound puerarin injection safety pharmaceutical composition, comprises the steps：
（1）Compound puerarin injection raw medicinal material puerarin 100g, Radix Bupleuri 100g, Cornu Cervi Pantotrichum 100g, cosolvent 2.0g；
（2）Puerarin, Radix Bupleuri 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）Cornu Cervi Pantotrichum add water to cook secondary, 1 hour every time, collecting decoction, filtration, concentrate filtrate, let cool, plus ethanol make containing ethanol
Measure as 65%, stand overnight, filtration, filtrate reduced in volume to relative density is 1.20, plus ethanol makes containing amount of alcohol to be 70%, quiet
Put 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, filtrate
Being concentrated into relative density is 1.15,
（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 puerarin injection safety pharmaceutical composition according to claim 1,
It is characterized in that, described step（1）In, cosolvent is made up of with polyoxyethylene sorbitan monoleate dibutyl fumarate, wherein fumaric acid two fourth
The content of ester is 0.005g～2.0g, balance of polyoxyethylene sorbitan monoleate.
3. a kind of preparation method improving compound puerarin injection safety pharmaceutical composition according to claim 1,
It is characterized in that, described step（2）In, plus the process of ethanol filtering and concentrating is first to filter to get filtrate, filtrate reduced in volume is to phase
It is 1.27～1.30 to density, lets cool, plus ethanol makes containing amount of alcohol to be 65%, stands overnight, filtration, decompression filtrate recycling ethanol
And it is concentrated into relative density for 1.30.
4. a kind of preparation method improving compound puerarin injection safety pharmaceutical composition according to claim 1,
It is characterized in that, described step（3）In, it is 1.25～1.30 that filtrate is concentrated into relative density.
5. a kind of preparation method improving compound puerarin injection safety pharmaceutical composition according to claim 1,
It is characterized in that, described step（5）In, the mass percent of the sodium hydroxide solution of use is 20%.
6. a kind of preparation method improving compound puerarin injection safety pharmaceutical composition according to claim 1,
It is characterized in that, described step（6）In, solution uses filtering with microporous membrane.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114225003A (en) * | 2022-01-25 | 2022-03-25 | 深圳前海惠馀堂健康管理咨询有限公司 | Traditional Chinese medicine composition for tonifying fire, supporting yang, warming middle-jiao and dispelling cold and preparation method and application thereof |
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| CN1408399A (en) * | 2001-09-29 | 2003-04-09 | 吉林省力源药业股份有限公司 | Medicine for curing hyperthermia and its prepn |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114225003A (en) * | 2022-01-25 | 2022-03-25 | 深圳前海惠馀堂健康管理咨询有限公司 | Traditional Chinese medicine composition for tonifying fire, supporting yang, warming middle-jiao and dispelling cold and preparation method and application thereof |
| CN114225003B (en) * | 2022-01-25 | 2024-03-01 | 深圳前海惠馀堂健康管理咨询有限公司 | Traditional Chinese medicine composition for tonifying fire and yang, warming middle-jiao and dispelling cold, and preparation method and application thereof |
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