CN1110169A - Red sage root injection - Google Patents
Red sage root injection Download PDFInfo
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- CN1110169A CN1110169A CN 94114040 CN94114040A CN1110169A CN 1110169 A CN1110169 A CN 1110169A CN 94114040 CN94114040 CN 94114040 CN 94114040 A CN94114040 A CN 94114040A CN 1110169 A CN1110169 A CN 1110169A
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- radix salviae
- salviae miltiorrhizae
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Abstract
The present invention relates to a red sage root injection (Danshen Dashuye) and its preparation method. The invented red sage root injection is made up by using red sage root refined extract and medicinal carrier, and can be directly used for clinical venoclysis, and can prevent cross infection and raise the clinical application level and safety of red sage root, and is easy to use for patient.
Description
The present invention relates to the Radix Salviae Miltiorrhizae Injection technical field.
Radix Salviae Miltiorrhizae has now become the medicine of an important therapy of combining Chinese and Western medicine cardiovascular disease.Be used for clinical have liquid drugs injection, oral liquid, tablets and other formulations at present.
Chinese Pharmacopoeia version in 1977 is pointed out the function that it has blood circulation promoting and blood stasis dispelling, freeing vessels and nourishing heart for the 115th page in " Radix Salviae Miltiorrhizae Injection ", can be used for coronary heart disease, anginal treatment.So far, dilute in the glucose injection of Radix Salviae Miltiorrhizae Injection adding 100-500ml, use through intravenous drip again, because the liquid of getting before instiling mixes, brought some shortcomings, not only formality is loaded down with trivial details, and is subjected to the pollution of environment, apparatus easily, user produce infusion reaction as have a fever, feel sick, feel cold, tachycardia or slow excessively etc., can jeopardize patient's life in the time of seriously.
The objective of the invention is to overcome above-mentioned shortcoming, the joint product of development Radix Salviae Miltiorrhizae and infusion solutions.
The invention provides a kind of Radix Salviae Miltiorrhizae Injection (being the Radix Salviae Miltiorrhizae infusion solutions), a kind of Radix Salviae Miltiorrhizae Injection that is directly used in venoclysis.
Radix Salviae Miltiorrhizae Injection of the present invention is made up of Radix Salviae Miltiorrhizae refined liquid and pharmaceutical carrier as active component, and wherein Radix Salviae Miltiorrhizae refined liquid and pharmaceutical carrier are formed with the arbitrary proportion that contains 99.9～0.1% pharmaceutical carriers (weight ratio) to contain 0.1～99.9% Radix Salviae Miltiorrhizae refined liquid.
Pharmaceutical carrier in the Radix Salviae Miltiorrhizae Injection of the present invention has isotonic agent such as sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium lactate, glucose, xylitol, sorbitol or dextran (dextran that comprises big or middle or small-molecular weight) etc.; Buffer agent example hydrochloric acid, acetic acid, lactic acid or sodium hydroxide etc. also have water for injection.
Can not contain or contain simultaneously one or more isotonic agents in the Radix Salviae Miltiorrhizae Injection of the present invention.
Another object of the present invention provides the preparation method of above-mentioned Radix Salviae Miltiorrhizae Injection, and this method comprises the following steps:
(1) preparation Radix Salviae Miltiorrhizae refined liquid:
(1) preparation Radix Salviae Miltiorrhizae concentrated solution
Get red rooted salvia, after removing impurity, successively clean towards drip washing with ordinary water and distilled water, the water for injection that adds 10 times of amounts decocted 2 hours, filtered, and kept decocting liquid for the first time, the water for injection of 8 times of amounts of medicinal residues reuse decocted 2 hours, filter, keep decocting liquid for the second time, the water for injection that medicinal residues add 5 times of amounts again decocted 1 hour, filter, keep decocting liquid for the third time, medicinal residues add 5 times of amount waters for injection again and decocted 1 hour, filter, keep decocting liquid the 4th time, remove medicinal residues, merge decoction liquor then four times, evaporation and concentration is to containing the concentrated solution that Radix Salviae Miltiorrhizae is 2 grams per milliliters;
(2) preparation Radix Salviae Miltiorrhizae refined liquid
Above-mentioned Radix Salviae Miltiorrhizae concentrated solution is added ethanol to be placed 12-36 hour under 0 ℃ of-5 ℃ of condition for 70-80% to containing the alcohol amount, filter and remove precipitation, the filtrate distillation is concentrated into and contains the concentrated solution that Radix Salviae Miltiorrhizae is 3 grams per milliliters, adding ethanol again placed 48-72 hour under 0 ℃ of-5 ℃ of condition for 80-90% to containing the alcohol amount, filter and remove precipitation, the filtrate heating is concentrated into and contains the concentrated solution that Radix Salviae Miltiorrhizae is 5 grams per milliliters, adds active carbon, heated and boiled makes the Radix Salviae Miltiorrhizae refined liquid;
(2) preparation isotonic agent concentrated wiring liquid:
Get isotonic agent and add 3 times of amount distilled water and boiled five minutes, add activated carbon decolorizing, filter through the sand rod and make concentrated wiring liquid;
(3) preparation Radix Salviae Miltiorrhizae Injection:
The concentrated wiring liquid of getting former medicine refined liquid of above-mentioned Radix Salviae Miltiorrhizae and isotonic agent merges by the prescription proportional quantity, add 8 times of amount distilled water, heating for dissolving adds activated carbon decolorizing, the source of reducing phlegm and internal heat, filter, filtrate is regulated PH6.0-7.0 with sodium hydroxide or hydrochloric acid, adds distilled water to full dose, after surveying middle product content, behind the microporous filter membrane fine straining, fill makes Radix Salviae Miltiorrhizae Injection after routine sterilization, lamp inspection, quality inspection in infusion bottle of cleaning or transfusion bag.
Radix Salviae Miltiorrhizae Injection of the present invention is applicable to the infusion solutions of all size.
The survey report of the Radix Salviae Miltiorrhizae Injection that makes with method of the present invention is as follows:
The name of an article: Radix Salviae Miltiorrhizae Injection
Character: brown clear liquid
Differentiate: show positive reaction
PH：3.5-8.5
Glucose content is labelled amount % 90-110%
Other: meet requirement under the injection item
Sterility test: qualified
Pyrogen testing: qualified
The acute toxicity test of Radix Salviae Miltiorrhizae Injection of the present invention is reported as follows:
Sample: Radix Salviae Miltiorrhizae Injection
Preparation unit: Changzheng Pharmaceutical Factory, Shanghai
Detect unit: drug toxicology inspection center is regulated in China's fertility
One, test objective:
After observing medicine single intravenous injection mice, acute toxic reaction that is produced and the death condition in 7 days.
Two, animal:
ICR kind closed colony healthy mice, body weight 19.9 ± 0.86 grams, male and female half and half are provided by west, the joint Shanghai of China and Britain spectrum Er-Bi Kai (SIPPR/BK) laboratory animal company limited.
Three, dosage:
By " human body infusion solutions " acute toxicity testing requirement, establish three dosage groups altogether, be followed successively by 1.0ML/20g, 0.75ml/20g and 0.5ml/20g.
Four, method:
Get 30 mices, be divided into three groups at random, each 5 of every group of male and female are by various dose single tail vein injection respectively.Notice during injection that the medicinal liquid fltting speed is slow, increase fast and increase heart burden with long-pending not the making of control volume liquid.Observe mice ordinary circumstance, poisoning manifestations etc. after the administration.Whether observed continuously then 7 days, put to death animal on the 8th day, dissecting the macroscopy main organs has pathological changes.
Five, result:
Dosage number of animals survival number death toll
(ml/20 body weight) (only) (only) (only)
0.50 10 10 0
0.75 10 10 0
1.00 10 10 0
Above-mentioned each dosage treated animal is all survivals in 7 days after administration, do not see any untoward reaction.The 8th day high dose group zootomy, main organs naked eyes no abnormality seen.
Six, estimate:
The acute intravenous injection toxicity of this medicine (Radix Salviae Miltiorrhizae Injection) is minimum, meets quiet injecting requirement.
The external hemolytic test of Radix Salviae Miltiorrhizae Injection of the present invention is reported as follows:
Sample: Radix Salviae Miltiorrhizae Injection
Preparation unit: Changzheng Pharmaceutical Factory, Shanghai
Detect unit: drug toxicology inspection center is regulated in China's fertility
One, test objective:
Directly contact with blood by Radix Salviae Miltiorrhizae Injection, measure erythrocyte and discharge hemoglobin content, whether acute haemolysis is arranged to detect Radix Salviae Miltiorrhizae Injection.
Two, experimental procedure:
Get Freshman blood 15ml, except that after defibrinating, use normal saline flushing 3 times, the reuse normal saline is made into 2% red blood cell suspension.During test, each adds various solution by table 1 order after adding 2% red blood cell suspension 2.5ml, and the vibration insulation is 60 minutes in 37 ℃ of aqueous solutions.Take out, at 4 ℃, centrifugal 15 minutes of 2500rpm measures absorbance with UV-240 type ultraviolet spectrophotometer 540nm wavelength place, Tianjin, island.
Positive control replaces Radix Salviae Miltiorrhizae Injection with distilled water; Negative control replaces Radix Salviae Miltiorrhizae Injection with 0.9% sodium chloride.
The absorption value of positive control should be 0.8 ± 0.3; The absorption value of negative control should＜0.02.
Calculate the haemolysis degree by following formula, have % to represent:
(Dt-Dnc)/(Dpt-Dnc) ×100%
* Dt=test specimen absorbance.* Dnc=negative control absorbance.
* Dpt=positive control absorbance.
The absorption value of each developmental tube and control tube is all got the meansigma methods of tee pipe.
Table 1 hemolytic test application of sample program
Pipe 2%RBC (ml) H
2O Radix Salviae Miltiorrhizae normal saline
No suspension (ml) is (ml) (ml)
1 2.5 2.5 0 0
2 2.5 0 0 2.5
3 2.5 0 0.1 2.4
4 2.5 0 0.2 2.3
5 2.5 0 0.3 2.2
6 2.5 0 0.4 2.1
7 2.5 0 0.5 2.0
Three. the result:
Negative Radix Salviae Miltiorrhizae Injection (ml) positive
Contrast 0.1 0.2 0.3 0.4 0.5 contrasts
Blood molten 0.01 0.01 0.01 0.01 0.01 0.012 0.6
Degree ± ± ± ± ± ± ±
(%) 0.003 0.002 0.001 0.002 0.001 0.001 0.4
The mean+SD of three times (pipes).
Four, estimate:
The haemolysis degree of each concentration group of Radix Salviae Miltiorrhizae Injection is all identical with negative control (normal saline) as can be known by the result, and can think: Radix Salviae Miltiorrhizae Injection does not have acute haemolysis.
The vein local excitation test of Radix Salviae Miltiorrhizae Injection of the present invention:
Sample: Radix Salviae Miltiorrhizae Injection
Preparation unit: Changzheng Pharmaceutical Factory, Shanghai
Detect unit: drug toxicology inspection center is regulated in China's fertility
One, test objective: observe the instil degree of the direct irritant reaction that produces behind the tame rabbit ear vein of Radix Salviae Miltiorrhizae Injection.
Two, laboratory animal: the big ear rabbit of adult healthy Japan, five of body weight 2.0-2.5Kg, fur gloss, no ear vein infringement is provided by China and Britain's joint SIPPR/BK laboratory animal company limited.
Three, experimental technique: experimental rabbit is placed in the experiment frame, fixing head, slowly injecting the about 40-50 of this product 15ml at left auricular vein pushes away complete second, auris dextra edge vein every rabbit, with the same manner bolus infusion normal saline 15ml, observing 24,48 and 72 hours auricular veins in injection back and surrounding tissue has and haemolysis, swelling even necrosis do not occur.
Four, criterion: by the irritant reaction standards of grading of ISD standard specifications requirement, observed injection vein and surrounding tissue had and oozing of blood, swelling, necrosis and the order of severity thereof do not occur at 24,48 and 72 hours.
Five, result of the test:
Irritant reaction irritant reaction integration
Hours 24 48 72
Radix Salviae Miltiorrhizae Injection 000
Injection normal saline 000
Six, evaluation: Radix Salviae Miltiorrhizae Injection, injection back in the rabbit vein was observed 72 hours continuously, compare with the vein of injecting with normal saline and there is no vein and any irritant reaction of surrounding tissue.
The Radix Salviae Miltiorrhizae Injection study on the stability:
By Ministry of Public Health " new drug reviewing way " (85 years) requirement, infusion solutions quality stability is investigated because of through 40 ℃ of three months (quite room temperature is 2 years) study on the stability, and the result is as follows:
Sample number glucose content Radix Salviae Miltiorrhizae (281NM A value) solution color (410NM A value)
0 month March of March, 0 month 0 month March
A
1102.5% 101.6% >0.35 >0.35 0.30 0.30
A
2103.1% 102.8% >0.35 >0.35 0.25 0.25
A
3101.9% 100.1% >0.35 >0.35 0.35 0.36
B
297.5% 97.4% >0.35 >0.35 0.30 0.31
B
398.7% 97.9% >0.35 >0.35 0.29 0.31
(all less than standard 4
Yellow)
Above data show, steady quality in this product room temperature 2 years.
Radix Salviae Miltiorrhizae Injection of the present invention can be directly used in venoclysis, has reduced the dilution in the existing medicining condition, avoids cross infection, and improves the clinical practice level and the safety of Radix Salviae Miltiorrhizae, also is convenient to patient and uses.
Example 1: preparation Radix Salviae Miltiorrhizae refined liquid
Get Radix Salviae Miltiorrhizae 500 grams, use ordinary water, behind the distilled water flushing, respectively with 10 times, 8 times, the distilled water of 5 times and 5 times amounts, first, secondary decocted 2 hours, and the 3rd, decocted 1 hour, and merged four times the liquid of boiling medicine for four times, be concentrated into 200ml, add 80% ethanol and be 75-76%,, filter and remove post precipitation in 2 ℃ of placements 40 hours to containing the alcohol amount, filtrate concentrating removed ethanol to medicinal liquid 150ml, add 95% ethanol and be 85-86%, placed filtration 48 hours in 2 ℃ to containing the alcohol amount, remove precipitation, filtrate adds 50 gram activated carbon decolorizings, removes thermal source, filters, remove precipitation, filtrate is concentrated into 150ml, concentrates and removes ethanol, and adding distil water is to 2000ml, cold preservation 24 hours, filter, reconcentration is to 200ml, and cold preservation is stand-by.
Example 2: preparation glucose concentrated wiring liquid
Get glucose for injection 1000 grams, adding distil water boiled 5 minutes to 3000ml, added 10 gram active carbons, and it is stand-by that the sand rod filters the back.
Example 3: preparation Radix Salviae Miltiorrhizae Injection
The glucose concentrated wiring liquid that Radix Salviae Miltiorrhizae refined liquid that example 1 is made and example 2 make merges, and adding distil water adds 3 gram activated carbon decolorizings to 9000ml, remove thermal source, sand rod elimination active carbon is regulated PH6.0-6.9 with 0.1NNaOH or 0.1NHCL, adding distil water is to 1000ml, product content is qualified in the middle of surveying, through 1.0 microporous filter membrane fine straining, fill is in infusion bottle of cleaning or transfusion bag, with 121 ℃ of saturated vapors, sterilized 20 minutes, promptly get Radix Salviae Miltiorrhizae Injection after the class inspection of cooling back, the product inspection.
Example 4: preparation contains the Radix Salviae Miltiorrhizae Injection of sorbitol
Press the method for example 1-3, make as raw material with the sorbitol place of glucose.
Example 5: preparation contains the Radix Salviae Miltiorrhizae Injection of xylitol
Press the method for example 1-3, make as raw material with the xylitol place of glucose.
Example 6: preparation contains the dextran Radix Salviae Miltiorrhizae Injection of (comprising large, medium and small molecular weight dextran)
Press the method for example 1-3, make as raw material with the dextran place of glucose.
Example 7: the Radix Salviae Miltiorrhizae Injection of preparation sodium chloride-containing
Press the method for example 1-3, make as raw material with the sodium chloride place of glucose.
Example 8: preparation compound NaCl Radix Salviae Miltiorrhizae Injection
Get sodium chloride for injection 85 grams, potassium chloride 3 grams, calcium chloride 3.3 gram adding 2000ml distilled water, add Radix Salviae Miltiorrhizae refined liquid 200ml then.Method by example 3 makes again.
Example 9: preparation compound sodium lactate Radix Salviae Miltiorrhizae Injection
Getting injection sodium lactate 25 grams adds in the 500ml distilled water, add the proper amount of active carbon heating, decolorization filtering is stand-by, other gets sodium chloride for injection 85 grams, potassium chloride 3 grams, calcium chloride 3.3 gram and stand-by sodium lactate solutions, add 2000ml distilled water and Radix Salviae Miltiorrhizae refined liquid 200ml then, make by example 3 methods again.
Example 10: preparation compound recipe glucose Radix Salviae Miltiorrhizae Injection
Get dextran for injection (can be arbitrarily the dextran of large, medium and small molecular weight) and add in the 2000ml distilled water, boil, activated carbon decolorizing filters stand-by; Other gets glucose for injection 500 gram and adds the 1500ml distilled water, boil activated carbon decolorizing after, merge to add with the stand-by liquid of dextran and make Radix Salviae Miltiorrhizae refined liquid 200ml, make by example 3 methods again.
Example 11: preparation contains the Radix Salviae Miltiorrhizae Injection of glucose, sodium chloride
Get glucose for injection 500 grams, sodium chloride 90 grams add in the 2000ml distilled water, behind the activated carbon decolorizing, add Radix Salviae Miltiorrhizae refined liquid 200ml, make by example 3 methods again.
Example 12: preparation Radix Salviae Miltiorrhizae Injection
Getting Radix Salviae Miltiorrhizae refined liquid 200ml adds distilled water diluting and makes by example 3 methods to 10000ml again.
Claims (5)
1, a kind of Radix Salviae Miltiorrhizae Injection is characterized in that this Radix Salviae Miltiorrhizae Injection is made up of as active component and pharmaceutical carrier the Radix Salviae Miltiorrhizae refined liquid, and it can be formed with arbitrary proportion with the pharmaceutical carrier that contains 99.9-0.1% by the Radix Salviae Miltiorrhizae refined liquid that contains 0.1～～99.9%.
2, Radix Salviae Miltiorrhizae Injection according to claim 1 is characterized in that wherein said pharmaceutical carrier has isotonic agent, buffer agent and water for injection.
3,, it is characterized in that wherein used isotonic agent can be sodium chloride, potassium chloride, magnesium chloride, calcium chloride, sodium lactate, glucose, xylitol, sorbitol or dextran (dextran that comprises big or middle or small-molecular weight) according to claim 1 and 2 described Radix Salviae Miltiorrhizae Injectiones.
4,, it is characterized in that not contain or to contain simultaneously multiple isotonic agent in this injection according to claim 1 and 2 described Radix Salviae Miltiorrhizae Injectiones.
5, a kind of preparation method of Radix Salviae Miltiorrhizae Injection as claimed in claim 1 is characterized in that this preparation method comprises the following steps:
(1) preparation Radix Salviae Miltiorrhizae refined liquid:
(1) preparation Radix Salviae Miltiorrhizae concentrated solution
Get red rooted salvia, after removing impurity, successively clean towards drip washing with ordinary water and distilled water, the water for injection that adds 10 times of amounts decocted 2 hours, filtered, and kept decocting liquid for the first time, the water for injection of 8 times of amounts of medicinal residues reuse decocted 2 hours, filter, keep decocting liquid for the second time, the water for injection that medicinal residues add 5 times of amounts again decocted 1 hour, filter, keep decocting liquid for the third time, the water for injection that medicinal residues add 5 times of amounts again decocted 1 hour, filtered, keep decocting liquid the 4th time, remove medicinal residues, merge decoction liquor then four times, evaporation and concentration is to containing the concentrated solution that Radix Salviae Miltiorrhizae is 2 grams per milliliters;
(2) preparation Radix Salviae Miltiorrhizae refined liquid
Above-mentioned Radix Salviae Miltiorrhizae concentrated solution is added ethanol to be placed 12-36 hour under 0 ℃ of-5 ℃ of condition for 70-80% to containing the alcohol amount, filter and remove precipitation, the filtrate distillation is concentrated into and contains the concentrated solution that Radix Salviae Miltiorrhizae is 3 grams per milliliters, adding ethanol again placed 48-72 hour under 0 ℃ of-5 ℃ of condition for 80-90% to containing the alcohol amount, filter and remove precipitation, the filtrate distillation is concentrated into the concentrated solution that contains Radix Salviae Miltiorrhizae 3 grams per milliliters, the water for injection that adds 4 times of amounts was placed 12-36 hour under 0 ℃ of-5 ℃ of condition, filter and remove precipitation, the filtrate heating is concentrated into and contains the concentrated solution that Radix Salviae Miltiorrhizae is 5 grams per milliliters, add 4 times of amount waters for injection again, after placing 48-72 hour under 0 ℃ of-5 ℃ of condition, filter and remove precipitation, the filtrate heating is concentrated into and contains the concentrated solution that Radix Salviae Miltiorrhizae is 5 grams per milliliters, add active carbon, heated and boiled makes the Radix Salviae Miltiorrhizae refined liquid;
(2) preparation isotonic agent concentrated wiring liquid:
Get isotonic agent and add 3 times of amount distilled water and boiled five minutes, add activated carbon decolorizing, filter through the sand rod and make concentrated wiring liquid;
(3) preparation Radix Salviae Miltiorrhizae Injection:
The concentrated wiring liquid of getting former medicine refined liquid of above-mentioned Radix Salviae Miltiorrhizae and isotonic agent merges by the prescription proportional quantity, add 8 times of amount distilled water, heating for dissolving adds activated carbon decolorizing, the source of reducing phlegm and internal heat, filter, filtrate is regulated PH6.0-7.0 with sodium hydroxide or hydrochloric acid, adds distilled water to full dose, after surveying middle product content, behind the microporous filter membrane fine straining, fill makes Radix Salviae Miltiorrhizae Injection after routine sterilization, lamp inspection, quality inspection in infusion bottle of cleaning or transfusion bag.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94114040A CN1049132C (en) | 1994-12-17 | 1994-12-17 | Red sage root injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94114040A CN1049132C (en) | 1994-12-17 | 1994-12-17 | Red sage root injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1110169A true CN1110169A (en) | 1995-10-18 |
| CN1049132C CN1049132C (en) | 2000-02-09 |
Family
ID=5036995
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94114040A Expired - Lifetime CN1049132C (en) | 1994-12-17 | 1994-12-17 | Red sage root injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1049132C (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1049836C (en) * | 1996-11-18 | 2000-03-01 | 地方国营吉林集安药厂 | Red sage root injection extracting process |
| CN101129463B (en) * | 2007-08-20 | 2011-09-14 | 正大青春宝药业有限公司 | Method of preparing red sage root injection |
| CN106821953A (en) * | 2016-12-31 | 2017-06-13 | 上海华源安徽锦辉制药有限公司 | Red sage root extracting method is used in one kind transfusion |
| CN107441163A (en) * | 2017-08-04 | 2017-12-08 | 上海华源安徽锦辉制药有限公司 | A kind of preparation method for improving red sage root dropping liquid stability |
-
1994
- 1994-12-17 CN CN94114040A patent/CN1049132C/en not_active Expired - Lifetime
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1049836C (en) * | 1996-11-18 | 2000-03-01 | 地方国营吉林集安药厂 | Red sage root injection extracting process |
| CN101129463B (en) * | 2007-08-20 | 2011-09-14 | 正大青春宝药业有限公司 | Method of preparing red sage root injection |
| CN106821953A (en) * | 2016-12-31 | 2017-06-13 | 上海华源安徽锦辉制药有限公司 | Red sage root extracting method is used in one kind transfusion |
| CN107441163A (en) * | 2017-08-04 | 2017-12-08 | 上海华源安徽锦辉制药有限公司 | A kind of preparation method for improving red sage root dropping liquid stability |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1049132C (en) | 2000-02-09 |
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