CN104524585A - Cefathiamidine composition - Google Patents
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Abstract
The invention discloses a cefathiamidine composition. The cefathiamidine composition comprises cefathiamidine, hydroxypropyl-beta-cyclodextrin, low molecular dextran, vitamin C and citric acid. Cefathiamidine is coated with hydroxypropyl-beta-cyclodextrin. A preparation method of the cefathiamidine composition comprises the following steps of 1, dissolving hydroxypropyl-beta-cyclodextrin by injection water to obtain a hydroxypropyl-beta-cyclodextrin solution, 2, adding cefathiamidine into the hydroxypropyl-beta-cyclodextrin solution, carrying out clathration under the condition of heating stirring, carrying out cooling to a room temperature, and carrying out filtration to obtain a filtrate, and 3, heating and dissolving low molecular dextran in injection water, cooling the solution to a room temperature, carrying out filtration, adding the filtrate into an inclusion solution of hydroxypropyl-beta-cyclodextrin and cefathiamidine, carrying out stirring dissolution, adding vitamin C into the solution, carrying out stirring dissolution, adjusting a pH value by a citric acid solution, adding injection water into the solution, carrying out degerming filtration, carrying out loading, carrying out freeze-drying and carrying out packaging to obtain the cefathiamidine composition.
Description
Technical field
The present invention relates to a kind of cefathiamidine, especially a kind of cefathiamidine compositions, belongs to medical art.
Background technology
Cefathiamidine, chemistry is by name: (6R, 7R)-3 [(acetoxyl group) methyl]-7-[α-(N, N'-diisopropylamidinateand sulfenyl)-acetylamino] 8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-formic acid betaine.Molecular formula: C
19h
28n
4o
6s
2, molecular weight: 472.59.
Cefathiamidine is white or off-white color crystalline powder; Almost odorless, have draw moist.
Cefathiamidine is first generation cephalosporin, for China initiates for clinical.Antimicrobial spectrum is similar to cefalotin, stronger to S. aureus L-forms, Streptococcus viridans, pneumococcal effect, unique antibacterial activity is had to enterococcus, be mainly used in respiratory tract infection caused by S. aureus L-forms, streptococcus pneumoniae and streptococcus, the infection such as biliary tract infection, urinary tract infection, gynecological infection, septicemia, pneumonia, meningitis.
Because cefathiamidine has the unique molecular structure of amphion inner salt, heat, chance light, chance moist lability, easily decompose variable color.
Existing cefathiamidine preparation existence and stability is poor, easily oxidation deterioration, can not preserve for a long time, the shortcoming such as antibacterial time is short.
Summary of the invention
Advantages such as the object of the present invention is to provide a kind of cefathiamidine compositions, make cefathiamidine compositions have good stability, not easily oxidation deterioration, can preserve for a long time, antibacterial time is long.
For solving the problems of the technologies described above, cefathiamidine compositions of the present invention comprises cefathiamidine, HP-β-CD, low molecular dextran, vitamin C and citric acid, cefathiamidine is by enclose in HP-β-CD, and cefathiamidine compositions is standby in order to below legal system:
Step 1, dissolves HP-β-CD water for injection and obtains HP-β-CD solution;
Step 2, adds cefathiamidine in HP-β-CD solution, under heated and stirred, carries out enclose, then cool to room temperature, obtains filtrate after filtration;
Step 3, uses water for injection heating for dissolving, cool to room temperature by low molecular dextran, filter, join in HP-β-CD and cefathiamidine enclose solution, stirring and dissolving, add vitamin C again, stirring and dissolving, uses citric acid solution adjusted to ph, injects with water, aseptic filtration, fill, lyophilizing, obtains cefathiamidine compositions after encapsulation.
As preferably, the weight ratio of cefathiamidine and HP-β-CD is 1:3 ~ 5.
As preferably, the consumption of low molecular dextran is 10 ~ 30% of cefathiamidine, and ascorbic consumption is 2 ~ 10% of cefathiamidine.
As preferably, in step 1, the weight ratio of HP-β-CD and water for injection is 1:5 ~ 6.
As preferably, in step 2, enclose temperature is 40 ~ 60 DEG C, and the enclose time is 2 ~ 4 hours.
As preferably, in step 3, the weight ratio of low molecular dextran and water for injection is 1:3 ~ 5.
As preferably, in step 3, the concentration of citric acid solution is 5 ~ 10%, and pH value is adjusted to 4.5 ~ 5.0.
As preferably, in step 3, filtration sterilization adopts 0.22 μm of microporous filter membrane.
As preferably, in step 3, step of freeze drying is lowered the temperature from room temperature by the goods after fill, carries out low temperature pre-freeze, then carries out evacuation, then heats up and carries out vacuum and low temperature sublimation drying, then heats up and carry out vacuum drying.
As preferably, in step 3, the goods after fill were cooled to-45 ~-40 DEG C from room temperature in 1 hour, low temperature pre-freeze is carried out 3 ~ 4 hours at-45 ~-40 DEG C, then evacuation is carried out, then heat up,-20 ~-15 DEG C are warming up to from-45 ~-40 DEG C in 1 hour, a vacuum sublimation drying 10 ~ 12 hours is carried out at-20 ~-15 DEG C, then in 1 hour ,-5 ~ 0 DEG C is warming up to from-20 ~-15 DEG C, secondary vacuum sublimation drying is carried out 6 ~ 8 hours at-5 ~ 0 DEG C, 25 ~ 30 DEG C are warming up to from-5 ~ 0 DEG C again in 1 hour, finally at 25 ~ 30 DEG C, carry out vacuum drying 4 ~ 6 hours.
Cefathiamidine adopts HP-β-CD enclose, because HP-β-CD is ion-type highly-water-soluble cyclodextrin derivative, non-covalent complex can be formed well with drug molecule enclose, thus improve the stability of medicine, water solublity, safety, reduce nephrotoxicity, relax medicine hemolytic, Drug controlled release speed, prevents oxidation deterioration.HP-β-CD can delay the degraded of cefathiamidine molecule well, improves the effectiveness of medicine better.Take low molecular dextran as excipient, greatly can reduce the generation of related substance relative to mannitol.Vitamin C is a kind of safe antioxidant, can prevent the oxidation deterioration of cefathiamidine.The advantages such as the cefathiamidine compositions adopting method of the present invention to prepare has good stability, not easily oxidation deterioration, can preserve for a long time, antibacterial time is long.
The weight ratio adopting cefathiamidine and HP-β-CD is 1:3 ~ 5, can make cefathiamidine and the effective enclose of HP-β-CD, avoids waste, reduces costs.The consumption of low molecular dextran is 10 ~ 30% of cefathiamidine, can make cefathiamidine compositions in freeze-drying process, have good product design, not produce and subside.Ascorbic consumption is 2 ~ 10% of cefathiamidine, can effectively prevent cefathiamidine oxidation deterioration.HP-β-CD and cefathiamidine enclose at 40 ~ 60 DEG C of temperature, can shorten the enclose time, strengthens enclose effect.The pH value of cefathiamidine compositions is adjusted to 4.5 ~ 5.0, cefathiamidine can be made to have larger stability, prevent oxidation Decomposition.By the citric acid solution adjust ph that concentration is 5 ~ 10%, adjustment can be made more convenient.Pre-freezing temperature is-45 ~-40 DEG C, and the pre-freeze time is 3 ~ 4 hours, and what cefathiamidine goods can be made to freeze is solid, can not subside or fragmentation when drying.One time vacuum sublimation baking temperature is-20 ~-15 DEG C, and the time is 10 ~ 12 hours, can prevent cefathiamidine goods from subsiding or fragmentation, also can shorten the vacuum drying time, reduce energy consumption.Secondary vacuum sublimation drying temperature is-5 ~ 0 DEG C, and the time is 6 ~ 8 hours, can accelerate sublimation drying speed, shortens the vacuum drying time, reduces energy consumption.Vacuum drying temperature is 25 ~ 30 DEG C, and the time is 4 ~ 6 hours, effectively can remove moisture, prevents cefathiamidine oxidation deterioration simultaneously.
Detailed description of the invention
Below in conjunction with specific embodiment, embodiment of the present invention are described in detail.Should be appreciated that enforcement of the present invention is not limited to the following examples, any pro forma accommodation make the present invention and/or change all will fall into protection scope of the present invention.
Embodiment 1
First the 1500 grams of dissolvings of 250 grams of HP-β-CD waters for injection are obtained HP-β-CD solution.Again 50 grams of cefathiamidines are added in HP-β-CD solution, be heated to 40 DEG C, and heated and stirred carries out enclose in 4 hours at 40 DEG C, by mixed liquor cool to room temperature after enclose terminates, obtains filtrate after filtration.
15 grams of low molecular dextran waters for injection, 45 grams of heating for dissolving are obtained low molecular dextran solution, cool to room temperature, filters.Low molecular dextran solution is joined in HP-β-CD and cefathiamidine enclose solution, stirring and dissolving, add 5 grams of vitamin Cs again, stirring and dissolving, by the citric acid solution adjusted to ph to 5.0 that concentration is 5%, finally inject water to 2000ml, stir, after using 0.22 μm of filtering with microporous membrane degerming again, fill becomes 1000 injection bottles made of glass tubes.Goods after fill were cooled to-45 DEG C from room temperature in 1 hour, low temperature pre-freeze is carried out 3 hours at-45 DEG C, then evacuation is carried out, then heat up,-20 DEG C are warming up to from-45 DEG C in 1 hour, a vacuum sublimation is carried out dry 12 hours at-20 DEG C, then in 1 hour ,-5 DEG C are warming up to from-20 DEG C, secondary vacuum sublimation drying is carried out 8 hours at-5 DEG C, 25 DEG C are warming up to from-5 DEG C again in 1 hour, finally at 25 DEG C, carry out vacuum drying 6 hours, obtain cefathiamidine compositions.After lyophilizing terminates, vacuum nitrogen tamponade.
Embodiment 2
First the 2600 grams of dissolvings of 450 grams of HP-β-CD waters for injection are obtained HP-β-CD solution.Again 100 grams of cefathiamidines are added in HP-β-CD solution, be heated to 45 DEG C, and heated and stirred carries out enclose in 3.5 hours at 45 DEG C, by mixed liquor cool to room temperature after enclose terminates, obtains filtrate after filtration.
25 grams of low molecular dextran waters for injection, 80 grams of heating for dissolving are obtained low molecular dextran solution, cool to room temperature, filters.Low molecular dextran solution is joined in HP-β-CD and cefathiamidine enclose solution, stirring and dissolving, add 8 grams of vitamin Cs again, stirring and dissolving, by the citric acid solution adjusted to ph to 4.8 that concentration is 6%, finally inject water to 3500ml, stir, after using 0.22 μm of filtering with microporous membrane degerming again, fill becomes 1000 injection bottles made of glass tubes.Goods after fill were cooled to-44 DEG C from room temperature in 1 hour, low temperature pre-freeze is carried out 3 hours at-44 DEG C, then evacuation is carried out, then heat up,-18 DEG C are warming up to from-44 DEG C in 1 hour, a vacuum sublimation is carried out dry 12 hours at-18 DEG C, then in 1 hour ,-4 DEG C are warming up to from-18 DEG C, secondary vacuum sublimation drying is carried out 8 hours at-4 DEG C, 26 DEG C are warming up to from-4 DEG C again in 1 hour, finally at 26 DEG C, carry out vacuum drying 6 hours, obtain cefathiamidine compositions.After lyophilizing terminates, vacuum nitrogen tamponade.
Embodiment 3
First the 4400 grams of dissolvings of 800 grams of HP-β-CD waters for injection are obtained HP-β-CD solution.Again 200 grams of cefathiamidines are added in HP-β-CD solution, be heated to 50 DEG C, and heated and stirred carries out enclose in 3 hours at 50 DEG C, by mixed liquor cool to room temperature after enclose terminates, obtains filtrate after filtration.
40 grams of low molecular dextran waters for injection, 160 grams of heating for dissolving are obtained low molecular dextran solution, cool to room temperature, filters.Low molecular dextran solution is joined in HP-β-CD and cefathiamidine enclose solution, stirring and dissolving, add 12 grams of vitamin Cs again, stirring and dissolving, by the citric acid solution adjusted to ph to 4.7 that concentration is 7%, finally inject water to 6000ml, stir, after using 0.22 μm of filtering with microporous membrane degerming again, fill becomes 1000 injection bottles made of glass tubes.Goods after fill were cooled to-43 DEG C from room temperature in 1 hour, low temperature pre-freeze is carried out 3.5 hours at-43 DEG C, then evacuation is carried out, then heat up,-17 DEG C are warming up to from-43 DEG C in 1 hour, a vacuum sublimation is carried out dry 11 hours at-17 DEG C, then in 1 hour ,-3 DEG C are warming up to from-17 DEG C, secondary vacuum sublimation drying is carried out 7 hours at-3 DEG C, 27 DEG C are warming up to from-3 DEG C again in 1 hour, finally at 27 DEG C, carry out vacuum drying 5 hours, obtain cefathiamidine compositions.After lyophilizing terminates, vacuum nitrogen tamponade.
Embodiment 4
First the 5460 grams of dissolvings of 1050 grams of HP-β-CD waters for injection are obtained HP-β-CD solution.Again 300 grams of cefathiamidines are added in HP-β-CD solution, be heated to 55 DEG C, and heated and stirred carries out enclose in 3 hours at 55 DEG C, by mixed liquor cool to room temperature after enclose terminates, obtains filtrate after filtration.
45 grams of low molecular dextran waters for injection, 160 grams of heating for dissolving are obtained low molecular dextran solution, cool to room temperature, filters.Low molecular dextran solution is joined in HP-β-CD and cefathiamidine enclose solution, stirring and dissolving, add 12 grams of vitamin Cs again, stirring and dissolving, by the citric acid solution adjusted to ph to 4.6 that concentration is 8%, finally inject water to 7500ml, stir, after using 0.22 μm of filtering with microporous membrane degerming again, fill becomes 1000 injection bottles made of glass tubes.Goods after fill were cooled to-45 DEG C from room temperature in 1 hour, low temperature pre-freeze is carried out 3 hours at-45 DEG C, then evacuation is carried out, then heat up,-16 DEG C are warming up to from-42 DEG C in 1 hour, a vacuum sublimation is carried out dry 10 hours at-16 DEG C, then in 1 hour ,-2 DEG C are warming up to from-16 DEG C, secondary vacuum sublimation drying is carried out 6 hours at-2 DEG C, 28 DEG C are warming up to from-2 DEG C again in 1 hour, finally at 28 DEG C, carry out vacuum drying 4 hours, obtain cefathiamidine compositions.After lyophilizing terminates, vacuum nitrogen tamponade.
Embodiment 5
First the 7500 grams of dissolvings of 1500 grams of HP-β-CD waters for injection are obtained HP-β-CD solution.Again 500 grams of cefathiamidines are added in HP-β-CD solution, be heated to 60 DEG C, and heated and stirred carries out enclose in 2 hours at 60 DEG C, by mixed liquor cool to room temperature after enclose terminates, obtains filtrate after filtration.
50 grams of low molecular dextran waters for injection, 150 grams of heating for dissolving are obtained low molecular dextran solution, cool to room temperature, filters.Low molecular dextran solution is joined in HP-β-CD and cefathiamidine enclose solution, stirring and dissolving, add 10 grams of vitamin Cs again, stirring and dissolving, by the citric acid solution adjusted to ph to 4.5 that concentration is 10%, finally inject water to 10000ml, stir, after using 0.22 μm of filtering with microporous membrane degerming again, fill becomes 1000 injection bottles made of glass tubes.Goods after fill were cooled to-40 DEG C from room temperature in 1 hour, low temperature pre-freeze is carried out 4 hours at-40 DEG C, then carry out evacuation, then heat up, in 1 hour, be warming up to-15 DEG C from-40 DEG C, a vacuum sublimation is carried out dry 10 hours at-15 DEG C, then in 1 hour, be warming up to 0 DEG C from-15 DEG C, at 0 DEG C, carry out secondary vacuum sublimation drying 6 hours, then be warming up to 30 DEG C from 0 DEG C in 1 hour, finally at 30 DEG C, carry out vacuum drying 4 hours, obtain cefathiamidine compositions.After lyophilizing terminates, vacuum nitrogen tamponade.
Hot test
Respectively each 1 batch of the sample of the cefathiamidine compositions of Example 1-5 and the commercially available cefathiamidine freeze-dried powder of reference examples, sample opening is placed in clean container, place 10 days at 60 DEG C of temperature, in the 0th day, the 5th day and sampling in the 10th day, detect by stability high spot reviews project, study on the stability the results are shown in Table 1.
Table 1
Result shows: in hot test, cefathiamidine compositions of the present invention at appearance character, clarity, related substance, content etc. without significant change, and commercially available cefathiamidine freeze-dried powder in changes such as appearance character, related substance, content obviously, therefore cefathiamidine compositions of the present invention is more stable, and its stability is much higher than commercially available cefathiamidine freeze-dried powder.YG and yellow green, yellow green, lower same.
Accelerated test
Respectively each 1 batch of the sample of the cefathiamidine compositions of Example 1-5 and the commercially available cefathiamidine freeze-dried powder of reference examples, be placed in 40 DEG C and 75% humidity light protected environment, respectively at after placement the 1st, sampling in 2,3,6 months investigates, and within 0 month, investigates data and compares, result of the test is in table 2.
Table 2
Result shows: in accelerated test, cefathiamidine compositions of the present invention at appearance character, clarity, related substance, content etc. without significant change, and commercially available cefathiamidine freeze-dried powder in changes such as appearance character, related substance, content obviously, therefore cefathiamidine compositions of the present invention is more stable, and its stability is much higher than commercially available cefathiamidine freeze-dried powder.
Long term test
Respectively each 1 batch of the sample of the cefathiamidine compositions of Example 1-5 and the commercially available cefathiamidine freeze-dried powder of reference examples, be placed in 25 DEG C and 60% humidity light protected environment, respectively at after placement the 3rd, sampling in 6,9,12 months investigates, and within 0 month, investigates data and compares, result of the test is in table 3.
Table 3
Result shows: in long term test, cefathiamidine compositions of the present invention at appearance character, clarity, related substance, content etc. without significant change, and commercially available cefathiamidine freeze-dried powder in changes such as appearance character, related substance, content obviously, therefore cefathiamidine compositions of the present invention is more stable, and its stability is much higher than commercially available cefathiamidine freeze-dried powder.
In vitro Bactericidal Experiments
Adopt cefathiamidine compositions prepared by embodiment 3, application minimal inhibitory concentration (MIC) method carries out antibacterial tests, with 0.1mol/L phosphate buffer (pH=6.0) as solvent, medicine will be tested dissolve, after two-fold dilution, medicinal liquid and Muller-Hintin culture medium are mixed into a series of pastilles flat boards that concentration is 512-0.015 μ g/ml in proportion, 6-8 hour equal culture physiological saline solution to be measured is diluted to Maxwell 0.5 and manages (10
8cFU/ml) 10 times (10 is diluted to again
7cFU/ml), the bacterium liquid prepared is added the application of sample after high pressure steam sterilization and hold in plate, inoculate instrument with MIC and be seeded in the culture medium containing variable concentrations medicinal liquid respectively, each vaccination 10 is all measured in final inoculation
4cFU.Put 35 DEG C to cultivate 18 hours, by NCCLS standard judged result.From naked eyes asepsis growth test tube, get 0.1ml solution is again poured into not in pastille blood plate, cultivates 18 hours for 37 DEG C, record clump count, and the minimum liquor strength of its clump count≤5 is minimum bactericidal concentration (MBC).Result of the test is in table 4.
Table 4
Antibacterial activity in vitro test shows, cefathiamidine compositions of the present invention has antibacterial, bactericidal action preferably, and cefathiamidine compositions of the present invention has significant antibiotic and sterilizing effect to S. aureus L-forms, staphylococcus epidermidis, streptococcus pneumoniae, micrococcus scarlatinae, moraxelle catarrhalis, hemophilus influenza etc.
Antibacterial tests in body
Select NIH white mice 40, body weight 18-22 gram, male and female half and half, be divided into 4 groups, often organize 10, fasting 12 hours before test.Test the previous day, quantitative inoculated bacteria is in 2ml nutrient broth, 35 DEG C of temperature incubate 6 hours, then 0.1ml bacterium liquid transferred species is got in 10ml nutrient broth, 35 DEG C of temperature incubate 18 hours, and under 721 spectrophotometer 550 μm (S. aureus L-forms) and 680 μm of (enterococcus) wavelength, measure the light transmittance of every strain bacterium liquid, the light transmittance of bacterium liquid is often planted in fixing day-to-day test, for test original bacteria liquid, be diluted to the bacterial concentration needed for infection animal with 5% dry yeast liquid.Respectively to four groups of mice by intraperitoneal injection S. aureus L-forms, streptococcus pneumoniae, micrococcus scarlatinae, enterococcus; every Mus injection bacterium amount is 1MLD/0.5ml (MLD is minimum 100% lethal bacterium amount); after mouse infection at once and infect latter 6 hours secondary subcutaneous injections and give cefathiamidine compositions prepared by embodiment 3; observe 7 days animal survival numbers, calculate medicine to the half protective number (ED of various bacteriological infection mice
50), medicine is to the half protective number ED of various bacteriological infection mice
50, ED
5095% fiducial limit (L95) all uses Litchfield & Wilcoxon to improve Bliss program and calculates, and concrete outcome is in table 5.
Table 5
Antibacterial activity in vivo test shows, cefathiamidine compositions of the present invention has antibacterial, bactericidal action preferably, and cefathiamidine compositions of the present invention has significant antibiotic and sterilizing effect to S. aureus L-forms, streptococcus pneumoniae, micrococcus scarlatinae, enterococcus etc.
Claims (10)
1. a cefathiamidine compositions, it is characterized in that: described cefathiamidine compositions comprises cefathiamidine, HP-β-CD, low molecular dextran, vitamin C and citric acid, cefathiamidine is by enclose in HP-β-CD, and cefathiamidine compositions is standby in order to below legal system:
Step 1, dissolves HP-β-CD water for injection and obtains HP-β-CD solution;
Step 2, adds cefathiamidine in HP-β-CD solution, under heated and stirred, carries out enclose, then cool to room temperature, obtains filtrate after filtration;
Step 3, uses water for injection heating for dissolving, cool to room temperature by low molecular dextran, filter, join in HP-β-CD and cefathiamidine enclose solution, stirring and dissolving, add vitamin C again, stirring and dissolving, uses citric acid solution adjusted to ph, injects with water, aseptic filtration, fill, lyophilizing, obtains cefathiamidine compositions after encapsulation.
2. cefathiamidine compositions according to claim 1, is characterized in that: the weight ratio of described cefathiamidine and HP-β-CD is 1:3 ~ 5.
3. cefathiamidine compositions according to claim 1, is characterized in that: the consumption of described low molecular dextran is 10 ~ 30% of cefathiamidine, and ascorbic consumption is 2 ~ 10% of cefathiamidine.
4. cefathiamidine compositions according to claim 1, is characterized in that: in described step 1, the weight ratio of HP-β-CD and water for injection is 1:5 ~ 6.
5. cefathiamidine compositions according to claim 1, is characterized in that: in described step 2, enclose temperature is 40 ~ 60 DEG C, and the enclose time is 2 ~ 4 hours.
6. cefathiamidine compositions according to claim 1, is characterized in that: in described step 3, the weight ratio of low molecular dextran and water for injection is 1:3 ~ 5.
7. cefathiamidine compositions according to claim 1, is characterized in that: in described step 3, the concentration of citric acid solution is 5 ~ 10%, and pH value is adjusted to 4.5 ~ 5.0.
8. cefathiamidine compositions according to claim 1, is characterized in that: in described step 3, filtration sterilization adopts 0.22 μm of microporous filter membrane.
9. cefathiamidine compositions according to claim 1, it is characterized in that: in described step 3, step of freeze drying is lowered the temperature from room temperature by the goods after fill, carries out low temperature pre-freeze, then carries out evacuation, then heat up and carry out vacuum and low temperature sublimation drying, then vacuum drying is carried out in intensification.
10. cefathiamidine compositions according to claim 9, it is characterized in that: in described step 3, the goods after fill were cooled to-45 ~-40 DEG C from room temperature in 1 hour, low temperature pre-freeze is carried out 3 ~ 4 hours at-45 ~-40 DEG C, then evacuation is carried out, then heat up,-20 ~-15 DEG C are warming up to from-45 ~-40 DEG C in 1 hour, a vacuum sublimation drying 10 ~ 12 hours is carried out at-20 ~-15 DEG C, then in 1 hour ,-5 ~ 0 DEG C is warming up to from-20 ~-15 DEG C, secondary vacuum sublimation drying is carried out 6 ~ 8 hours at-5 ~ 0 DEG C, 25 ~ 30 DEG C are warming up to from-5 ~ 0 DEG C again in 1 hour, finally at 25 ~ 30 DEG C, carry out vacuum drying 4 ~ 6 hours.
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|---|---|---|---|---|
| CN106727615A (en) * | 2016-12-17 | 2017-05-31 | 郑州郑先医药科技有限公司 | A kind of Western medicine compound for treating the infection of the upper respiratory tract |
| CN106822239A (en) * | 2016-12-17 | 2017-06-13 | 郑州郑先医药科技有限公司 | It is a kind of to treat Chinese and western medicinal composition of the infection of the upper respiratory tract and preparation method thereof |
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| CN104524585B (en) | 2018-11-09 |
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