CN105878731A - Pharmaceutical composition capable of improving safety of compound rhizoma polygonati injection - Google Patents
Pharmaceutical composition capable of improving safety of compound rhizoma polygonati injection Download PDFInfo
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- A61K36/88—Liliopsida (monocotyledons)
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Abstract
The invention discloses a pharmaceutical composition capable of improving the safety of a compound rhizoma polygonati injection. The pharmaceutical composition is characterized in that the pharmaceutical composition is an injection pharmaceutical composition prepared from a rhizoma polygonati extract, a bighead atractylodes rhizome extract, a platycodon root extract and glycerin polyoxyethylene ether hydroxystearate, wherein each 100ml solution contains 15 to 45g of rhizoma polygonati extract prepared from rhizoma polygonati, 10 to 10g of bighead atractylodes rhizome extract prepared from bighead atractylodes rhizome and 5 to 15g of platycodon root extract prepared from platycodon root, and the dosage ratio of the rhizoma polygonati to the bighead atractylodes rhizome to the platycodon root is 3 to 2 to 1. According to the pharmaceutical composition disclosed by the invention, a cosolvent which has better safety and more obvious solubilization effect is adopted to substitute a cosolvent polysorbate 80, which has potential safety hazards and affects the product quality, in the compound rhizoma polygonati injection, and the glycerin polyoxyethylene ether hydroxystearate has higher safety and lower dosage than those of the polysorbate 80, such that the probability and risk of adverse reactions of the pharmaceutical composition are reduced, and the safety of the clinical medication is improved.
Description
Technical field
The invention belongs to pharmaceutical technology field, improve compound Polygonatum injection in particular it relates to a kind of
The pharmaceutical composition of liquid safety.
Background technology
Compound Polygonatum injection standard is recorded in health drug standard promulgated by the ministries or commissions of the Central Government (Traditional Chinese medicine historical preparation),
Crude drug is Rhizoma Polygonati, the Rhizoma Atractylodis Macrocephalae, Radix Platycodonis, belongs to Chinese medicine injection.There is promoting blood circulation to restore menstrual flow, blood stasis dispelling
Effect of pain relieving.It is clinically used for treating dysmenorrhea, amenorrhea, injury from falling down, rheumatic arthralgia etc..
In China in wide clinical application for many years, clinical efficacy obtains compound Polygonatum injection
The favorable comment of doctor and patient.But in recent years, the Reporting of harms day of Chinese medicine injection clinical practice
Become serious, have impact on the development of the Chinese medicine injection with Chinese Medicine characteristic.Domestic expert learns
Person has carried out numerous studies to the untoward reaction of Chinese medicine injection, and its untoward reaction reported by document
Occur and the cosolvent polyoxyethylene sorbitan monoleate (tween of the existence potential safety hazard of addition in Chinese medicine injection
80) there is the biggest relation.Due to Chinese medicine injection complicated component, in storage and high temperature sterilize mistake
Journey easily occurs solute separate out and affect clarity, the problem such as solution ph is decreased obviously, because of
This adds polyoxyethylene sorbitan monoleate (Tween 80) in such injection and makees cosolvent, adds other
The solubilization-aid effect of cosolvent is the most inconspicuous.But polyoxyethylene sorbitan monoleate (Tween 80) is due to process for refining
Immature, easily become sour in storage and autoclaving process, cause impurity content high, it is difficult to
Reach injection standard, polyoxyethylene sorbitan monoleate (Tween 80) inherently have stronger hemolytic and
Anaphylaxis, applies and adds probability and the risk that untoward reaction occurs in injection.It addition,
Chinese medicine injection is asking that sterilizing and storage process itself there is also that solution ph is decreased obviously
Topic, and polyoxyethylene sorbitan monoleate (Tween 80) easily becomes sour, and more accelerates under the pH value of medicinal liquid
Fall.The compound Polygonatum injection of domestic production at present also adds polyoxyethylene sorbitan monoleate (Tween 80)
Make cosolvent, be faced with same problem.
In view of the foregoing, find that safety is more preferable, the more obvious cosolvent of solubilization-aid effect is replaced
The polyoxyethylene sorbitan monoleate (Tween 80) of poor stability is this injection urgent problem.
Summary of the invention
The technical problem to be solved be to provide a kind of safety more preferably, solubilization-aid effect more
Significantly improve the pharmaceutical composition of compound Polygonatum injection safety.
The present invention solves above-mentioned technical problem and be the technical scheme is that a kind of raising compound recipe is yellow
The pharmaceutical composition of essence injection safety, mainly by Rhizoma Polygonati extract, Rhizoma Atractylodis Macrocephalae extract, Fructus Citri tangerinae
The injection drug regimen that stalk extract and glycerin polyoxyethylene ether hydroxy stearic acid ester are made
Thing, every 100ml solution contains the Rhizoma Polygonati extract of 15-45g Rhizoma Polygonati medical material, 10-30g Rhizoma Atractylodis Macrocephalae medicine
The Rhizoma Atractylodis Macrocephalae extract of material, the Radix Platycodonis extract of 5-15g Radix Platycodonis medical material, Rhizoma Polygonati, the Rhizoma Atractylodis Macrocephalae, Radix Platycodonis
The usage ratio of medical material is 3:2:1.
For the present invention is better achieved, further, described glycerin polyoxyethylene ether hydroxy stearate
The consumption of acid esters is 0.005g～5.0g/100ml.
For the present invention is better achieved, further, described glycerin polyoxyethylene ether hydroxy stearate
The consumption of acid esters is 0.05g～1.0g/100ml.
For the present invention is better achieved, further, described pharmaceutical composition also includes poly-mountain
Pear ester 80, glycerin polyoxyethylene ether hydroxy stearic acid ester and polyoxyethylene sorbitan monoleate press different proportion connection
The amount ratio of cooperation cosolvent, glycerin polyoxyethylene ether hydroxy stearic acid ester and polyoxyethylene sorbitan monoleate
Example is 0.005g～5.0g/100ml:0.001g～2.0g/100ml.
For the present invention is better achieved, further, described medicine composition dosage form be injection,
Powder pin or lyophilizing.
The preparation method of the pharmaceutical composition of above-mentioned raising compound Polygonatum injection safety, including
Following step: (1) compound Polygonatum injection raw medicinal material Rhizoma Polygonati 100g, Rhizoma Atractylodis Macrocephalae 100g, Fructus Citri tangerinae
Stalk 100g, cosolvent 2.0g；Described cosolvent is by glycerin polyoxyethylene ether hydroxy stearic acid ester
Forming with polyoxyethylene sorbitan monoleate, wherein the content of glycerin polyoxyethylene ether hydroxy stearic acid ester is
0.005g～2.0g, surplus is polyoxyethylene sorbitan monoleate；(2) Rhizoma Polygonati, Rhizoma Atractylodis Macrocephalae boiling secondary,
Each 2 hours, collecting decoction, filter, filtrate reduced in volume to relative density is 1.27～1.30
(80 DEG C), let cool, and add ethanol and make containing amount of alcohol to be 65%, stand overnight, and filter, filtrate
Decompression recycling ethanol to be concentrated into relative density be 1.30 (80 DEG C), adds 3 times amount water, fully
Stirring, cold preservation 48 hours, filter, filtrate reduced in volume to relative density is about 1.15 (80 DEG C),
Medicinal liquid is standby；Radix Platycodonis boiling secondary, each 1 hour, collecting decoction, filter, filtrate
Being concentrated into relative density is 1.25～1.30 (80 DEG C), lets cool, and adds ethanol and makes and containing amount of alcohol is
65%, stand overnight, filter, filtrate reduced in volume to relative density is 1.20 (80 DEG C),
Adding ethanol and make containing amount of alcohol to be 70%, stand overnight, filter, filtrate is concentrated into relative density
It is 1.30 (80 DEG C), adds 3 times amount water, be sufficiently stirred for that cold preservation 48 hours filters, filtrate
Being concentrated into relative density is 1.15 (80 DEG C), merges with above-mentioned medicinal liquid, adds 2 times amount water, fill
Dividing stirring, cold preservation 24 hours, filter, filtrate adds cosolvent and water for injection is configured to
1000ml solution.Stir evenly.(3) by 20% sodium hydroxide solution regulation solution ph extremely
6.5-8.5.(4) above-mentioned solution is filtered through microporous filter membrane.(5) fill, sterilizing, to obtain final product.
The present invention, by substantial amounts of experimentation, finds a kind of glycerin polyoxyethylene ether hydroxy stearate
Acid esters (Solutol) it is the preferable substitute products of polyoxyethylene sorbitan monoleate.Glycerol polyoxy second
Alkene ether hydroxy stearic acid ester (Solutol) recorded in European Pharmacopoeia (EP5.5), moral
State's pharmacopeia and British Pharmacopoeia, can be used for the solubilizing agent of ejection preparation.The pharmacological toxicology of document report
Experimental data shows that its toxicity is significantly lower than polyoxyethylene sorbitan monoleate (Tween 80).Additionally we pass through
Substantial amounts of experimental studies have found that, reach glycerin polyoxyethylene ether hydroxyl during identical solubilization-aid effect hard
Fat acid ester (Solutol) amount ratio polyoxyethylene sorbitan monoleate (Tween 80) low, more carry
High Drug safety.
The pharmacological toxicology experimental data of document report shows glycerin polyoxyethylene ether hydroxy stearic acid
Ester (Solutol) safety higher than polyoxyethylene sorbitan monoleate (Tween 80), its toxicity is bright
Aobvious less than polyoxyethylene sorbitan monoleate (Tween 80) (see table 1-3).Compound Polygonatum injection divides
Shi Yong (0.5g/100ml) glycerin polyoxyethylene ether hydroxy stearic acid ester (Solutol of equivalent) and polyoxyethylene sorbitan monoleate (Tween 80), safety experiment comparative study result shows,
Use (0.5g/100ml) glycerin polyoxyethylene ether hydroxy stearic acid ester (Solutol of equivalent) group is equal in terms of hemolytic, zest, anaphylaxis and the toxicity such as reduce blood pressure
Substantially ratio uses polyoxyethylene sorbitan monoleate (Tween 80) to organize low, considerably reduces compound recipe by the present invention
There is probability and the risk of untoward reaction in Rhizoma Polygonati injection in clinical practice, improves clinical application
Safety.
To sum up, the invention has the beneficial effects as follows: provide a kind of safety more preferably, solubilization-aid effect more
Potential safety hazard is there is and affects product quality in significantly cosolvent in replacing compound Polygonatum injection
Cosolvent polyoxyethylene sorbitan monoleate (Tween 80)；Glycerin polyoxyethylene ether hydroxy stearic acid ester
(Solutol) safety higher than polyoxyethylene sorbitan monoleate (Tween 80) and consumption is lower,
Reduce probability and the risk of medicine generation untoward reaction, improve the safety of clinical application.
Detailed description of the invention
Embodiment 1
Preparation method: Rhizoma Polygonati, Rhizoma Atractylodis Macrocephalae boiling secondary, each 2 hours, collecting decoction,
Filtering, filtrate reduced in volume to relative density is 1.27～1.30 (80 DEG C), lets cool, adds second
It is 65% that alcohol makes containing amount of alcohol, stands overnight, and filters, and decompression filtrate recycling ethanol also concentrates
It is 1.30 (80 DEG C) to relative density, adds 3 times amount water, be sufficiently stirred for, cold preservation 48 hours,
Filtering, filtrate reduced in volume to relative density is about 1.15 (80 DEG C), and medicinal liquid is standby；Radix Platycodonis
Boiling secondary, each 1 hour, collecting decoction, filter, filtrate is concentrated into relative density
It is 1.25～1.30 (80 DEG C), lets cool, add ethanol and make containing amount of alcohol to be 65%, stand overnight,
Filtering, filtrate reduced in volume to relative density is 1.20 (80 DEG C), adds ethanol and makes containing amount of alcohol
Being 70%, stand overnight, filtering, it is 1.30 (80 DEG C) that filtrate is concentrated into relative density, adds
3 times amount water, are sufficiently stirred for, cold preservation 48 hours, filter, and filtrate is concentrated into relative density and is
1.15 (80 DEG C), merge with above-mentioned medicinal liquid, add 2 times amount water, are sufficiently stirred for, and cold preservation 24 is little
Time, filtering, filtrate adds glycerin polyoxyethylene ether hydroxy stearic acid ester (Solutol)
Make cosolvent and water for injection is configured to 1000ml solution.Stir evenly.Molten with 20% sodium hydroxide
Liquid regulation solution ph is to 6.5-8.5.Above-mentioned solution is filtered through microporous filter membrane.Fill, goes out
Bacterium, to obtain final product.
Embodiment 2
Preparation method: Rhizoma Polygonati, Rhizoma Atractylodis Macrocephalae boiling secondary, each 2 hours, collecting decoction,
Filtering, filtrate reduced in volume to relative density is 1.27～1.30 (80 DEG C), lets cool, adds second
It is 65% that alcohol makes containing amount of alcohol, stands overnight, and filters, and decompression filtrate recycling ethanol also concentrates
It is 1.30 (80 DEG C) to relative density, adds 3 times amount water, be sufficiently stirred for, cold preservation 48 hours,
Filtering, filtrate reduced in volume to relative density is about 1.15 (80 DEG C), and medicinal liquid is standby；Radix Platycodonis
Boiling secondary, each 1 hour, collecting decoction, filter, filtrate is concentrated into relative density
It is 1.25～1.30 (80 DEG C), lets cool, add ethanol and make containing amount of alcohol to be 65%, stand overnight,
Filtering, filtrate reduced in volume to relative density is 1.20 (80 DEG C), adds ethanol and makes containing amount of alcohol
Being 70%, stand overnight, filtering, it is 1.30 (80 DEG C) that filtrate is concentrated into relative density, adds
3 times amount water, are sufficiently stirred for, cold preservation 48 hours, filter, and filtrate is concentrated into relative density and is
1.15 (80 DEG C), merge with above-mentioned medicinal liquid, add 2 times amount water, are sufficiently stirred for, and cold preservation 24 is little
Time, filtering, filtrate adds glycerin polyoxyethylene ether hydroxy stearic acid ester (Solutol)
Make cosolvent with tween 80 and water for injection is configured to 1000ml solution.Stir evenly.With 20%
Sodium hydroxide solution regulation solution ph is to 6.5-8.5.Above-mentioned solution is filtered through microporous filter membrane.
Fill, sterilizing, to obtain final product.
Embodiment 3
Preparation method: Rhizoma Polygonati, Rhizoma Atractylodis Macrocephalae boiling secondary, each 2 hours, collecting decoction,
Filtering, filtrate reduced in volume to relative density is 1.27～1.30 (80 DEG C), lets cool, adds second
It is 65% that alcohol makes containing amount of alcohol, stands overnight, and filters, and decompression filtrate recycling ethanol also concentrates
It is 1.30 (80 DEG C) to relative density, adds 3 times amount water, be sufficiently stirred for, cold preservation 48 hours,
Filtering, filtrate reduced in volume to relative density is about 1.15 (80 DEG C), and medicinal liquid is standby；Radix Platycodonis
Boiling secondary, each 1 hour, collecting decoction, filter, filtrate is concentrated into relative density
It is 1.25～1.30 (80 DEG C), lets cool, add ethanol and make containing amount of alcohol to be 65%, stand overnight,
Filtering, filtrate reduced in volume to relative density is 1.20 (80 DEG C), adds ethanol and makes containing amount of alcohol
Being 70%, stand overnight, filtering, it is 1.30 (80 DEG C) that filtrate is concentrated into relative density, adds
3 times amount water, are sufficiently stirred for, cold preservation 48 hours, filter, and filtrate is concentrated into relative density and is
1.15 (80 DEG C), merge with above-mentioned medicinal liquid, add 2 times amount water, are sufficiently stirred for, and cold preservation 24 is little
Time, filtering, filtrate adds glycerin polyoxyethylene ether hydroxy stearic acid ester (Solutol)
Make cosolvent and water for injection is configured to solution.Stir evenly.With 20% sodium hydroxide solution regulation
Solution ph is to 6.5-8.5.Above-mentioned solution is filtered through microporous filter membrane.It is distributed into 1000,
Lyophilization, to obtain final product.
Embodiment 4:
The Rhizoma Polygonati extract of the present invention, Rhizoma Atractylodis Macrocephalae extract, Radix Platycodonis extract and glycerin polyoxyethylene
Ether hydroxy stearic acid ester (Solutol) the injection pharmaceutical composition made can lead to
Cross what techniques below scheme realized:
(1) compound Polygonatum injection raw medicinal material Rhizoma Polygonati 100g, Rhizoma Atractylodis Macrocephalae 100g, Radix Platycodonis 100g,
Glycerin polyoxyethylene ether hydroxy stearic acid ester (Solutol)2.0g；
(2) Rhizoma Polygonati, Rhizoma Atractylodis Macrocephalae boiling secondary, each 2 hours, collecting decoction, filter,
Filtrate reduced in volume to relative density is 1.27～1.30 (80 DEG C), lets cool, and adds ethanol and makes to contain
Amount of alcohol is 65%, stands overnight, and filters, and decompression filtrate recycling ethanol is also concentrated into relatively
Density is 1.30 (80 DEG C), adds 3 times amount water, is sufficiently stirred for, cold preservation 48 hours, filters,
Filtrate reduced in volume to relative density is about 1.15 (80 DEG C), and medicinal liquid is standby；Radix Platycodonis adds decocting
Boil secondary, each 1 hour, collecting decoction, filter, filtrate be concentrated into relative density be 1.25～
1.30 (80 DEG C), let cool, and add ethanol and make containing amount of alcohol to be 65%, stand overnight, and filter,
Filtrate reduced in volume to relative density is 1.20 (80 DEG C), adds ethanol and makes containing amount of alcohol to be 70%,
Standing overnight, filter, it is 1.30 (80 DEG C) that filtrate is concentrated into relative density, adds 3 times amount water,
Being sufficiently stirred for, cold preservation 48 hours, filter, it is 1.15 (80 DEG C) that filtrate is concentrated into relative density,
Merge with above-mentioned medicinal liquid, add 2 times amount water, be sufficiently stirred for, cold preservation 24 hours, filter, filter
Liquid adds glycerin polyoxyethylene ether hydroxy stearic acid ester (Solutol) make cosolvent and
Water for injection is configured to 1000ml solution.Stir evenly.
(3) by 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, to obtain final product.
In the present invention, cosolvent can be glycerin polyoxyethylene ether hydroxy stearic acid ester, its consumption
For the arbitrary value in 0.005g～5.0g/100ml, as 0.005g/100ml, 0.01g/100ml,
0.05g/100ml, 1.0g/100ml, 5.0g/100ml etc.；Cosolvent can also be gathered by glycerol
Oxygen vinyl Ether hydroxy stearic acid ester and polyoxyethylene sorbitan monoleate form, its usage ratio be 0.005g～
5.0g/100ml:0.001g～2.0g/100ml.
After the present invention uses glycerin polyoxyethylene ether hydroxy stearic acid ester as cosolvent, its safety
Property is more preferable, solubilization-aid effect is more obviously better than polyoxyethylene sorbitan monoleate, and concrete data see following table:
Table 1 SolutolWith polyoxyethylene sorbitan monoleate (Tween 80) LD50Toxicity test data compare
Table 2 intravenous injection SolutolWith polyoxyethylene sorbitan monoleate (Tween 80) haemolysis afterwards and serum
Histamine levels compares
Table 3 intravenous injection SolutolCompare with polyoxyethylene sorbitan monoleate (Tween 80) blood pressure lowering level afterwards
It addition, the present invention is by experimental studies have found that, in compound Polygonatum injection, reach identical
Solubilization-aid effect time glycerin polyoxyethylene ether hydroxy stearic acid ester (Solutol) use
Amount is lower than polyoxyethylene sorbitan monoleate (Tween 80), more improves Drug safety.Medicine
Glycerin polyoxyethylene ether hydroxy stearic acid ester (Solutol in compositions) consumption be
0.005g-5.0g/100ml, preferable amount is 0.05g-1.0g/100ml.Pharmaceutical composition also may be used
Use glycerin polyoxyethylene ether hydroxy stearic acid ester (Solutol) and Polysorbate
80 (Tween 80s) combine by different proportion be used as cosolvent with reduce polyoxyethylene sorbitan monoleate (Tween 80)
Amount, glycerin polyoxyethylene ether hydroxy stearic acid ester (Solutol) (tell with polyoxyethylene sorbitan monoleate
Warm 80) usage ratio is 0.005g-5.0g/100ml:0.001g-2.0g/100ml.
Claims (5)
1. the pharmaceutical composition improving compound Polygonatum injection safety, it is characterized in that, the main injection pharmaceutical composition being made up of Rhizoma Polygonati extract, Rhizoma Atractylodis Macrocephalae extract, Radix Platycodonis extract and glycerin polyoxyethylene ether hydroxy stearic acid ester, every 100ml solution is containing the Rhizoma Polygonati extract of 15-45g Rhizoma Polygonati medical material, the Rhizoma Atractylodis Macrocephalae extract of 10-30g Rhizoma Atractylodis Macrocephalae, the Radix Platycodonis extract of 5-15g Radix Platycodonis medical material, and Rhizoma Polygonati, the Rhizoma Atractylodis Macrocephalae, the usage ratio of Radix Platycodonis medical material are 3:2:1.
The pharmaceutical composition of raising compound Polygonatum injection safety the most according to claim 1, it is characterised in that the consumption of described glycerin polyoxyethylene ether hydroxy stearic acid ester is 0.005g～5.0g/100ml.
The pharmaceutical composition of raising compound Polygonatum injection safety the most according to claim 1, it is characterised in that the consumption of described glycerin polyoxyethylene ether hydroxy stearic acid ester is 0.05g～1.0g/100ml.
The pharmaceutical composition of raising compound Polygonatum injection safety the most according to claim 1, it is characterized in that, described pharmaceutical composition also includes polyoxyethylene sorbitan monoleate, glycerin polyoxyethylene ether hydroxy stearic acid ester and polyoxyethylene sorbitan monoleate are combined by different proportion and are made cosolvent, and glycerin polyoxyethylene ether hydroxy stearic acid ester is 0.005g～5.0g/100ml:0.001g～2.0g/100ml with the usage ratio of polyoxyethylene sorbitan monoleate.
5. according to the pharmaceutical composition improving compound Polygonatum injection safety described in claim 1 to 5 any one, it is characterised in that described medicine composition dosage form is injection, powder pin or lyophilizing.
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| CN101518617A (en) * | 2009-04-02 | 2009-09-02 | 四川升和制药有限公司 | Pharmaceutical composition for improving safety of Shenmai injection and method for preparing same |
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| CN101518617A (en) * | 2009-04-02 | 2009-09-02 | 四川升和制药有限公司 | Pharmaceutical composition for improving safety of Shenmai injection and method for preparing same |
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Application publication date: 20160824 |