CN104524585B - Cefathiamidine composition - Google Patents
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- CN104524585B CN104524585B CN201410741207.4A CN201410741207A CN104524585B CN 104524585 B CN104524585 B CN 104524585B CN 201410741207 A CN201410741207 A CN 201410741207A CN 104524585 B CN104524585 B CN 104524585B
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Abstract
The invention discloses a kind of cefathiamidine compositions, it includes cefathiamidine, hydroxypropyl-β-cyclodextrin, D-40, vitamin C and citric acid, cefathiamidine is included in hydroxypropyl-β-cyclodextrin, and cefathiamidine composition is prepared using the following method：Step 1, hydroxypropyl-β-cyclodextrin is dissolved to obtain hydroxypropyl-β-cyclodextrin solution with water for injection；Step 2, cefathiamidine is added in hydroxypropyl-β-cyclodextrin solution, is included under heating stirring, is cooled back to room temperature, filtrate is obtained after filtering；Step 3, D-40 is dissolved by heating with water for injection, is cooled to room temperature, filtering is added to hydroxypropyl-β-cyclodextrin and is included in solution with cefathiamidine, stirring and dissolving, add vitamin C, stirring and dissolving adjusts pH value with citric acid solution, adds water for injection, aseptic filtration, filling, freeze-drying obtains cefathiamidine composition after encapsulation.
Description
Technical field
The present invention relates to a kind of cefathiamidine, especially a kind of cefathiamidine composition belongs to pharmaceutical technology field.
Background technology
Cefathiamidine, chemistry are entitled：(6R, 7R) -3 [(acetoxyl group) methyl] -7- [α-(N, N'- diisopropylamidinateand sulphur
Base)-acetylamino] 8- oxos -5- thia -1- azabicyclos [4,2,0] oct-2-ene -2- formic acid betaines.Molecular formula：
C19H28N4O6S2, molecular weight：472.59.
Cefathiamidine is white or off-white color crystalline powder；It is almost odorless, have draw it is moist.
Cefathiamidine is first generation cephalosporin, is initiated for clinic for China.Antimicrobial spectrum is similar to cefoxitin, to gold
Portugal bacterium, Streptococcus viridans, the effect of pneumococcus are stronger, have unique antibacterial activity to enterococcus, be mainly used for S. aureus L-forms,
Respiratory tract infection caused by pneumococcus and streptococcus, infection of biliary tract, urinary tract infections, gynecological infection, septicemia, pneumonia, meningitis
Deng infection.
Since there is cefathiamidine the unique molecular structure of amphoteric ion inner salt, heat to meet light, meet moist lability, easily divide
Solution discoloration.
That there are stability is poor for existing cefathiamidine preparation, be easy oxidation deterioration, to be unable to long-term preservation, antibacterial time short etc.
Disadvantage.
Invention content
The purpose of the present invention is to provide a kind of cefathiamidine composition, make cefathiamidine composition have stability it is good,
Be not easy oxidation deterioration, can with long-term preservation, antibacterial time is long the advantages that.
In order to solve the above technical problems, the cefathiamidine composition of the present invention includes cefathiamidine, hydroxy propyl-Beta-ring paste
Essence, D-40, vitamin C and citric acid, cefathiamidine are included in hydroxypropyl-β-cyclodextrin, cefathiamidine
Composition is prepared using the following method：
Step 1, hydroxypropyl-β-cyclodextrin is dissolved to obtain hydroxypropyl-β-cyclodextrin solution with water for injection；
Step 2, cefathiamidine is added in hydroxypropyl-β-cyclodextrin solution, is included under heating stirring, then cool down
To room temperature, filtrate is obtained after filtering；
Step 3, D-40 is dissolved by heating with water for injection, is cooled to room temperature, filtered, be added to hydroxypropyl
Group-beta-cyclodextrin is with cefathiamidine inclusion solution, and stirring and dissolving adds vitamin C, and stirring and dissolving uses citric acid solution
PH value is adjusted, water for injection is added, aseptic filtration is filling, and freeze-drying obtains cefathiamidine composition after encapsulation.
Preferably, the weight ratio of cefathiamidine and hydroxypropyl-β-cyclodextrin is 1：3~5.
Preferably, the dosage of D-40 is the 10~30% of cefathiamidine, ascorbic dosage is cephalo
The 2~10% of sulphur amidine.
Preferably, hydroxypropyl-β-cyclodextrin and the weight ratio of water for injection are 1 in step 1：5~6.
Preferably, it is 40~60 DEG C to include temperature in step 2, the inclusion time is 2~4 hours.
Preferably, the weight ratio of D-40 and water for injection is 1 in step 3：3~5.
Preferably, in step 3 citric acid solution a concentration of 5~10%, pH value is adjusted to 4.5~5.0.
Preferably, filtration sterilization uses 0.22 μm of miillpore filter in step 3.
Preferably, in step 3 step of freeze drying be will be filling after product cool down from room temperature, carry out low temperature pre-freeze,
Then it is vacuumized, then heating carries out vacuum and low temperature lyophilization, then heats up and be dried in vacuo.
Preferably, the product after will be filling in step 3 is cooled to -45~-40 DEG C in 1 hour from room temperature, -45
~-40 DEG C carry out low temperature pre-freeze 3~4 hours, are then vacuumized, are then heated up, from -45~-40 DEG C in 1 hour
- 20~-15 DEG C are warming up to, a vacuum sublimation is carried out at -20~-15 DEG C and is dried 10~12 hours, then in 1 hour
It is warming up to -5~0 DEG C from -20~-15 DEG C, secondary vacuum lyophilization 6~8 hours is carried out at -5~0 DEG C, then in 1 hour
25~30 DEG C are warming up to from -5~0 DEG C, vacuum drying 4~6 hours is finally carried out at 25~30 DEG C.
Cefathiamidine is included using hydroxypropyl-β-cyclodextrin, is since hydroxypropyl-β-cyclodextrin is ionic highly-water-soluble
Cyclodextrine derivatives can include to form non-covalent complex with drug molecule well, to improve the stability, water-soluble of drug
Property, safety, reduce renal toxicity, mitigate drug hemolytic, Drug controlled release rate prevents oxidation deterioration.Hydroxy propyl-Beta-ring
Dextrin can delay the degradation of cefathiamidine molecule well, preferably improve the validity of drug.It is with D-40
Excipient can substantially reduce the generation in relation to substance relative to mannitol.Vitamin C is a kind of safe antioxidant, can
To prevent the oxidation deterioration of cefathiamidine.Cefathiamidine composition prepared by method using the present invention has stability good, no
It is oxidizable it is rotten, can with long-term preservation, antibacterial time is long the advantages that.
Use the weight ratio of cefathiamidine and hydroxypropyl-β-cyclodextrin for 1：3~5, cefathiamidine and hydroxypropyl-can be made
Beta-cyclodextrin effectively includes, and avoids wasting, reduces cost.The dosage of D-40 be cefathiamidine 10~
30%, it can make cefathiamidine composition that there is good product design in freeze-drying process, not generate and collapse.It is ascorbic
Dosage is the 2~10% of cefathiamidine, can effectively prevent cefathiamidine oxidation deterioration.Hydroxypropyl-β-cyclodextrin and cephalo
Sulphur amidine includes at a temperature of 40~60 DEG C, can shorten the inclusion time, enhancing inclusion effect.The pH value tune of cefathiamidine composition
It is whole to 4.5~5.0, can make cefathiamidine that there is the stability of bigger, prevent oxygenolysis.With a concentration of 5~10% lemon
Lemon acid solution adjusts pH value, and adjusting can be made more convenient.Pre-freezing temperature is -45~-40 DEG C, and the pre-freeze time is 3~4 hours, can
So that cefathiamidine product jelly is solid, it will not collapse or be crushed when dry.Vacuum sublimation drying temperature is -20~-
15 DEG C, the time is 10~12 hours, can prevent cefathiamidine product from collapsing or being crushed, when can also shorten vacuum drying
Between, reduce energy consumption.Secondary vacuum lyophilization temperature is -5~0 DEG C, and the time is 6~8 hours, can accelerate lyophilization speed
Degree shortens vacuum drying time, reduces energy consumption.Vacuum drying temperature is 25~30 DEG C, and the time is 4~6 hours, can effectively be taken off
Moisture removal, while preventing cefathiamidine oxidation deterioration.
Specific implementation mode
Embodiment of the present invention is described in detail with reference to specific embodiment.It should be appreciated that the reality of the present invention
It applies and is not limited to the following examples, the accommodation in any form and/or change made to the present invention fall within this hair
Bright protection domain.
Embodiment 1
250 grams of hydroxypropyl-β-cyclodextrin water for injection, 1500 grams of dissolvings are first obtained into hydroxypropyl-β-cyclodextrin solution.
50 grams of cefathiamidines are added in hydroxypropyl-β-cyclodextrin solution again, are heated to 40 DEG C, and heating stirring 4 hours at 40 DEG C
It is included, mixed liquor is cooled to room temperature after inclusion, filtrate is obtained after filtering.
15 grams of D-40 water for injection, 45 grams of heating for dissolving are obtained into D-40 solution, it is cooling
To room temperature, filtering.D-40 solution is added to hydroxypropyl-β-cyclodextrin with cefathiamidine inclusion solution, is stirred
Dissolving is mixed, 5 grams of vitamin Cs are added, stirring and dissolving adjusts pH value to 5.0 with a concentration of 5% citric acid solution, finally adds
Water for injection is stirred evenly to 2000ml, then with after 0.22 μm of filtering with microporous membrane degerming, filling to be noted at 1000 glass control
Penetrate agent bottle.Product after will be filling is cooled to -45 DEG C in 1 hour from room temperature, low temperature pre-freeze is carried out at -45 DEG C 3 hours, then
It is vacuumized, is then heated up, -20 DEG C are warming up to from -45 DEG C in 1 hour, a vacuum sublimation is carried out at -20 DEG C
It is 12 hours dry, -5 DEG C then are warming up to from -20 DEG C in 1 hour, secondary vacuum lyophilization 8 hours is carried out at -5 DEG C,
It is warming up to 25 DEG C from -5 DEG C in 1 hour again, vacuum drying 6 hours is finally carried out at 25 DEG C, obtains cefathiamidine composition.
After freeze-drying, vacuum nitrogen tamponade.
Embodiment 2
450 grams of hydroxypropyl-β-cyclodextrin water for injection, 2600 grams of dissolvings are first obtained into hydroxypropyl-β-cyclodextrin solution.
100 grams of cefathiamidines are added in hydroxypropyl-β-cyclodextrin solution again, are heated to 45 DEG C, and heating stirring 3.5 is small at 45 DEG C
Shi Jinhang is included, and mixed liquor is cooled to room temperature after inclusion, filtrate is obtained after filtering.
25 grams of D-40 water for injection, 80 grams of heating for dissolving are obtained into D-40 solution, it is cooling
To room temperature, filtering.D-40 solution is added to hydroxypropyl-β-cyclodextrin with cefathiamidine inclusion solution, is stirred
Dissolving is mixed, 8 grams of vitamin Cs are added, stirring and dissolving adjusts pH value to 4.8 with a concentration of 6% citric acid solution, finally adds
Water for injection is stirred evenly to 3500ml, then with after 0.22 μm of filtering with microporous membrane degerming, filling to be noted at 1000 glass control
Penetrate agent bottle.Product after will be filling is cooled to -44 DEG C in 1 hour from room temperature, low temperature pre-freeze is carried out at -44 DEG C 3 hours, then
It is vacuumized, is then heated up, -18 DEG C are warming up to from -44 DEG C in 1 hour, a vacuum sublimation is carried out at -18 DEG C
It is 12 hours dry, -4 DEG C then are warming up to from -18 DEG C in 1 hour, secondary vacuum lyophilization 8 hours is carried out at -4 DEG C,
It is warming up to 26 DEG C from -4 DEG C in 1 hour again, vacuum drying 6 hours is finally carried out at 26 DEG C, obtains cefathiamidine composition.
After freeze-drying, vacuum nitrogen tamponade.
Embodiment 3
800 grams of hydroxypropyl-β-cyclodextrin water for injection, 4400 grams of dissolvings are first obtained into hydroxypropyl-β-cyclodextrin solution.
200 grams of cefathiamidines are added in hydroxypropyl-β-cyclodextrin solution again, are heated to 50 DEG C, and heating stirring 3 hours at 50 DEG C
It is included, mixed liquor is cooled to room temperature after inclusion, filtrate is obtained after filtering.
40 grams of D-40 water for injection, 160 grams of heating for dissolving are obtained into D-40 solution, it is cold
But room temperature is arrived, is filtered.D-40 solution is added to hydroxypropyl-β-cyclodextrin to include in solution with cefathiamidine,
Stirring and dissolving, adds 12 grams of vitamin Cs, and stirring and dissolving adjusts pH value to 4.7, finally with a concentration of 7% citric acid solution
6000ml is injected water to, is stirred evenly, then with after 0.22 μm of filtering with microporous membrane degerming, it is filling at 1000 glass control
Injection bottle.Product after will be filling is cooled to -43 DEG C in 1 hour from room temperature, low temperature pre-freeze is carried out at -43 DEG C 3.5 hours,
Then it is vacuumized, is then heated up, -17 DEG C are warming up to from -43 DEG C in 1 hour, a vacuum is carried out at -17 DEG C
Lyophilization 11 hours, is then warming up to -3 DEG C in 1 hour from -17 DEG C, and it is small that secondary vacuum lyophilization 7 is carried out at -3 DEG C
When, then 27 DEG C are warming up to from -3 DEG C in 1 hour, vacuum drying 5 hours is finally carried out at 27 DEG C, obtains cefathiamidine combination
Object.After freeze-drying, vacuum nitrogen tamponade.
Embodiment 4
1050 grams of hydroxypropyl-β-cyclodextrin water for injection, 5460 grams of dissolvings are first obtained into hydroxypropyl-β-cyclodextrin solution.
300 grams of cefathiamidines are added in hydroxypropyl-β-cyclodextrin solution again, are heated to 55 DEG C, and heating stirring 3 hours at 55 DEG C
It is included, mixed liquor is cooled to room temperature after inclusion, filtrate is obtained after filtering.
45 grams of D-40 water for injection, 160 grams of heating for dissolving are obtained into D-40 solution, it is cold
But room temperature is arrived, is filtered.D-40 solution is added to hydroxypropyl-β-cyclodextrin to include in solution with cefathiamidine,
Stirring and dissolving, adds 12 grams of vitamin Cs, and stirring and dissolving adjusts pH value to 4.6, finally with a concentration of 8% citric acid solution
7500ml is injected water to, is stirred evenly, then with after 0.22 μm of filtering with microporous membrane degerming, it is filling at 1000 glass control
Injection bottle.Product after will be filling is cooled to -45 DEG C in 1 hour from room temperature, low temperature pre-freeze is carried out at -45 DEG C 3 hours, connects
It and is vacuumized, then heated up, -16 DEG C are warming up to from -42 DEG C in 1 hour, a vacuum liter is carried out at -16 DEG C
China is 10 hours dry, is then warming up to -2 DEG C from -16 DEG C in 1 hour, and it is small that secondary vacuum lyophilization 6 is carried out at -2 DEG C
When, then 28 DEG C are warming up to from -2 DEG C in 1 hour, vacuum drying 4 hours is finally carried out at 28 DEG C, obtains cefathiamidine combination
Object.After freeze-drying, vacuum nitrogen tamponade.
Embodiment 5
1500 grams of hydroxypropyl-β-cyclodextrin water for injection, 7500 grams of dissolvings are first obtained into hydroxypropyl-β-cyclodextrin solution.
500 grams of cefathiamidines are added in hydroxypropyl-β-cyclodextrin solution again, are heated to 60 DEG C, and heating stirring 2 hours at 60 DEG C
It is included, mixed liquor is cooled to room temperature after inclusion, filtrate is obtained after filtering.
50 grams of D-40 water for injection, 150 grams of heating for dissolving are obtained into D-40 solution, it is cold
But room temperature is arrived, is filtered.D-40 solution is added to hydroxypropyl-β-cyclodextrin to include in solution with cefathiamidine,
Stirring and dissolving, adds 10 grams of vitamin Cs, and stirring and dissolving adjusts pH value to 4.5, most with a concentration of 10% citric acid solution
After inject water to 10000ml, stir evenly, then with after 0.22 μm of filtering with microporous membrane degerming, it is filling at 1000 glass
Tubular injection bottle.Product after will be filling is cooled to -40 DEG C in 1 hour from room temperature, and it is small that low temperature pre-freeze 4 is carried out at -40 DEG C
When, it is then vacuumized, is then heated up, -15 DEG C are warming up to from -40 DEG C in 1 hour, carried out at -15 DEG C primary
Vacuum sublimation is dried 10 hours, is then warming up to 0 DEG C from -15 DEG C in 1 hour, and secondary vacuum lyophilization 6 is carried out at 0 DEG C
Hour, then 30 DEG C are warming up to from 0 DEG C in 1 hour, vacuum drying 4 hours is finally carried out at 30 DEG C, obtains cefathiamidine group
Close object.After freeze-drying, vacuum nitrogen tamponade.
Hot test
The cefathiamidine composition of Example 1-5 and the sample of the commercially available cefathiamidine freeze-dried powder of reference examples are each respectively
1 batch, sample opening is placed in clean container, is placed 10 days at a temperature of 60 DEG C, sampled, press in the 0th day, the 5th day and the 10th day
Stability high spot reviews project is detected, and study on the stability the results are shown in Table 1.
Table 1
The result shows that：In hot test, cefathiamidine composition of the invention is in appearance character, clarity, related object
Matter, content etc. are without significant change, and commercially available cefathiamidine freeze-dried powder is bright in the variation such as appearance character, related substance, content
It is aobvious, therefore the cefathiamidine composition of the present invention is more stable, stability is much higher than commercially available cefathiamidine freeze-dried powder
Needle.YG, that is, yellow green, yellow green, similarly hereinafter.
Accelerated test
The cefathiamidine composition of Example 1-5 and the sample of the commercially available cefathiamidine freeze-dried powder of reference examples are each respectively
It 1 batch, is placed in 40 DEG C and 75% humidity light protected environment, the 1st after placement, sampling investigation in 2,3,6 months, was investigated with 0 month
Data are compared, and test result is shown in Table 2.
Table 2
The result shows that：In accelerated test, cefathiamidine composition of the invention is in appearance character, clarity, related object
Matter, content etc. are without significant change, and commercially available cefathiamidine freeze-dried powder is bright in the variation such as appearance character, related substance, content
It is aobvious, therefore the cefathiamidine composition of the present invention is more stable, stability is much higher than commercially available cefathiamidine freeze-dried powder
Needle.
Long term test
The cefathiamidine composition of Example 1-5 and the sample of the commercially available cefathiamidine freeze-dried powder of reference examples are each respectively
It 1 batch, is placed in 25 DEG C and 60% humidity light protected environment, the 3rd after placement, sampling investigation in 6,9,12 months, was investigated with 0 month
Data are compared, and test result is shown in Table 3.
Table 3
The result shows that：In long term test, cefathiamidine composition of the invention is in appearance character, clarity, related object
Matter, content etc. are without significant change, and commercially available cefathiamidine freeze-dried powder is bright in the variation such as appearance character, related substance, content
It is aobvious, therefore the cefathiamidine composition of the present invention is more stable, stability is much higher than commercially available cefathiamidine freeze-dried powder
Needle.
In vitro Bactericidal Experiments
The cefathiamidine composition prepared using embodiment 3 carries out antibacterial examination using minimal inhibitory concentration (MIC) method
Test, use 0.1mol/L phosphate buffers (pH=6.0) as solvent, will test medicine dissolving, after two-fold dilution, liquid with
Muller-Hintin culture mediums were mixed into a series of drug containing tablets of a concentration of 512-0.015 μ g/ml in proportion, by 6-8 hours
Equal culture to be measured is diluted to the pipe of Maxwell 0.5 (10 with sterile saline8CFU/ml it) is diluted to 10 times (10 again7CFU/ml), will
The sample-adding that the bacterium solution for preparing is added after high pressure steam sterilization holds in plate, is seeded to respectively with MIC inoculation instrument dense containing difference
It spends on the culture medium of liquid, each vaccination 10 is measured in final inoculation4CFU.It sets 35 DEG C to cultivate 18 hours, sentence by NCCLS standards
Disconnected result.0.1ml solution is taken to be poured into not drug containing blood plate from naked eyes asepsis growth test tube again, 37 DEG C are cultivated 18 hours,
Clump count is recorded, the minimum liquor strength of clump count≤5 is minimum bactericidal concentration (MBC).Test result is shown in Table 4.
Table 4
Antibacterial activity in vitro experiments have shown that, cefathiamidine composition of the invention have preferable antibacterial, bactericidal effect, this
The cefathiamidine composition of invention to S. aureus L-forms, staphylococcus epidermis, streptococcus pneumonia, micrococcus scarlatinae, moraxelle catarrhalis,
Haemophilus influenzae etc. has significant antibiotic and sterilizing effect.
Internal antibacterial tests
NIH small white mouses 40,18-22 grams of weight, half male and half female is selected to be divided into 4 groups, every group 10, test preceding fasting
12 hours.It tests the previous day, quantitative inoculated bacteria in 2ml nutrient broths, incubate 6 hours by 35 DEG C of temperature, and 0.1ml bacterium solutions is then taken to turn
Kind is in 10ml nutrient broths, and 35 DEG C of temperature are incubated 18 hours, in 721 spectrophotometer 550 μm (S. aureus L-forms) and 680 μm (enterococcus)
Measure the light transmittance of every plant of bacterium solution under wavelength, the light transmittance of each bacterium solution of fixed day-to-day test, for experiment original bacteria liquid, with 5%
Dry ferment liquid is diluted to the bacterial concentration needed for infection animal.Respectively to four groups of mice by intraperitoneal injection S. aureus L-forms, pneumonia streptococcus
Bacterium, micrococcus scarlatinae, enterococcus, per mouse, injection bacterium amount is 1MLD/0.5ml (MLD is minimum 100% lethal bacterium amount), mouse
6 hours secondary are subcutaneously injected give cefathiamidine composition prepared by embodiment 3 at once and after infection after infection, observe 7 days and move
Object existence number, calculates half protective number (ED of the drug to various bacterium infection mouse50), drug is to various bacterium infection mouse
Half protective number ED50, ED5095% fiducial limit (L95) is counted using Litchfield&Wilcoxon improvement Bliss programs
It calculates, concrete outcome is shown in Table 5.
Table 5
Antibacterial activity in vivo experiments have shown that, cefathiamidine composition of the invention have preferable antibacterial, bactericidal effect, this
The cefathiamidine composition of invention there is significant antibacterial to kill S. aureus L-forms, streptococcus pneumonia, micrococcus scarlatinae, enterococcus etc.
Bacterium effect.
Claims (7)
1. a kind of cefathiamidine composition, it is characterised in that：The cefathiamidine composition includes cefathiamidine, hydroxy propyl-Beta-
Cyclodextrin, D-40, vitamin C and citric acid, cefathiamidine are included in hydroxypropyl-β-cyclodextrin, cephalo
Sulphur amidine composition is prepared using the following method：
Step 1, hydroxypropyl-β-cyclodextrin is dissolved to obtain hydroxypropyl-β-cyclodextrin solution with water for injection；
Step 2, cefathiamidine is added in hydroxypropyl-β-cyclodextrin solution, is included under heating stirring, is cooled back to room
Temperature obtains filtrate after filtering；
Step 3, D-40 is dissolved by heating with water for injection, is cooled to room temperature, filtered, be added to hydroxy propyl-Beta-
Cyclodextrin is with cefathiamidine inclusion solution, and stirring and dissolving adds vitamin C, and stirring and dissolving adjusts pH with citric acid solution
Value, adds water for injection, and aseptic filtration is filling, and freeze-drying obtains cefathiamidine composition after encapsulation；
The weight ratio of the cefathiamidine and hydroxypropyl-β-cyclodextrin is 1：3~5；
The dosage of the D-40 be cefathiamidine 10~30%, ascorbic dosage be cefathiamidine 2~
10%；
Hydroxypropyl-β-cyclodextrin and the weight ratio of water for injection are 1 in the step 1：5~6.
2. cefathiamidine composition according to claim 1, it is characterised in that：In the step 2 include temperature be 40~
60 DEG C, the inclusion time is 2~4 hours.
3. cefathiamidine composition according to claim 1, it is characterised in that：D-40 in the step 3
Weight ratio with water for injection is 1：3~5.
4. cefathiamidine composition according to claim 1, it is characterised in that：Citric acid solution is dense in the step 3
Degree is 5~10%, and pH value is adjusted to 4.5~5.0.
5. cefathiamidine composition according to claim 1, it is characterised in that：Filtration sterilization uses in the step 3
0.22 μm of miillpore filter.
6. cefathiamidine composition according to claim 1, it is characterised in that：Step of freeze drying is that will fill in the step 3
Product after dress cools down from room temperature, carries out low temperature pre-freeze, is then vacuumized, and then heating carries out vacuum and low temperature distillation
It is dry, then heat up and be dried in vacuo.
7. cefathiamidine composition according to claim 6, it is characterised in that：Product after will be filling in the step 3
- 45~-40 DEG C are cooled to from room temperature in 1 hour, low temperature pre-freeze is carried out at -45~-40 DEG C 3~4 hours, then carries out taking out true
Then sky heats up, -20~-15 DEG C are warming up to from -45~-40 DEG C in 1 hour, is carried out at -20~-15 DEG C primary
Vacuum sublimation is dried 10~12 hours, is then warming up to -5~0 DEG C from -20~-15 DEG C in 1 hour, is carried out at -5~0 DEG C
Secondary vacuum lyophilization 6~8 hours, then 25~30 DEG C are warming up to from -5~0 DEG C in 1 hour, finally at 25~30 DEG C
Carry out vacuum drying 4~6 hours.
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| CN1493293A (en) * | 2003-07-03 | 2004-05-05 | 浙江震元制药有限公司 | Cefathiamidine freeze dried agent and its preparation method |
| CN1593422A (en) * | 2003-09-10 | 2005-03-16 | 深圳市立国药物研究有限公司 | Method for preparing freeze dried cefathiamidine |
| CN101693010A (en) * | 2009-08-18 | 2010-04-14 | 海南美大制药有限公司 | Cefathiamidine prosoma liposome preparation |
| CN102755325A (en) * | 2012-07-04 | 2012-10-31 | 深圳信立泰药业股份有限公司 | Cefoxitin sodium medicinal composition, powder injection and preparation method thereof |
| CN103142493A (en) * | 2013-03-08 | 2013-06-12 | 深圳立健药业有限公司 | Process for preparing cefuroxime axetil granule medicament composition |
| CN103751196A (en) * | 2014-01-08 | 2014-04-30 | 中国农业科学院兰州畜牧与兽药研究所 | Ceftiofur hydroxypropyl-beta-cyclodextrin inclusion compound and preparation method thereof |
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