CN102872021A - Medicinal composition containing ceftezole sodium compound and preparation method for medicinal composition - Google Patents
Medicinal composition containing ceftezole sodium compound and preparation method for medicinal composition Download PDFInfo
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- CN102872021A CN102872021A CN201210357896XA CN201210357896A CN102872021A CN 102872021 A CN102872021 A CN 102872021A CN 201210357896X A CN201210357896X A CN 201210357896XA CN 201210357896 A CN201210357896 A CN 201210357896A CN 102872021 A CN102872021 A CN 102872021A
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Abstract
The invention provides a medicinal composition containing a ceftezole sodium compound and a preparation method for the medicinal composition. The medicinal composition contains ceftezole sodium and sodium carbonate cosolvent, and the weight ratio of the ceftezole sodium to the sodium carbonate is (5-10): 1. By reasonably proportioning the components of the medicinal composition, storage stability is realized by using a small quantity of accessories, and medication safety is ensured. Ceftezole sodium freeze-dried powder injection prepared by a secondary freeze-drying method is good in formation and re-dissolution property and high in stability and safety.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of Cefobutazine sodium compound pharmaceutical composition and preparation method thereof that contains.
Background technology
Cefobutazine sodium, have another name called ceftezole sodium, English name, ceftezole sodium, chemical name is: (6R, 7R)-3-[(1,3,4-thiadiazoles-2-yl) sulphomethyl]-8-oxo-7-[2-(1H-TETRAZOLE-1-yl) acetylamino]-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2 sodium formate, molecular formula: C
13H
11N
8NaO
4S
3, molecular weight: 462.45.
Cefobutazine sodium is first generation injection cephalosporins, be semisynthetic cephalosporins derivatives, its mechanism of action is the synthetic antibacterial activity of bringing into play by the anti-bacteria cell wall, to gram positive bacteria, especially coccus, as produce penicillinase and do not produce staphylococcus aureus, micrococcus scarlatinae, streptococcus pneumoniae, B group Hemolytic streptococcus, Streptococcus viridans, the staphylococcus epidermidis of penicillinase, and diphtheria corynebacterium, anthrax bacillus are all relatively more responsive; To some gram negative bacteria, be medium sensitivity such as escherichia coli, Klebsiella, Salmonella, Shigella and proteus mirabilis etc., this medicine can be used to secondary infection, pulmonary abscess, peritonitis, pyelonephritis, the cystitis of septicemia, pneumonia, bronchitis, bronchiectasis, chronic respiratory system diseases, the treatment of urethritis.
The sterile powder injection of existing cefobutazine sodium does not contain adjuvant, direct packaging ceftezole sodium crystal and get final product.Disclose a kind of Ceftezole sodium powder injection agent such as CN200910015121, it is that lid is rolled in tamponade, gets the Ceftezole sodium used for injection injectable powder at 100 grades of aseptic subpackaged ceftezole sodium crystals of cleaning condition in sterilizing room.But such injectable powder existence and stability is poor, and the shortcomings such as unstability of temperature and light are become turbid such as the Yin Wendu reason, can heat to make the rear use of its clarification.And, owing to be not vacuum state, easily oxidized.And rear pH value stored for a long time has larger change, therefore has certain potential safety hazard.
Summary of the invention
The object of the invention is to provides a kind of stability better ceftezole sodium pharmaceutical composition for cefobutazine sodium sterile powder injection less stable in the prior art.
For achieving the above object, the present invention adopts following technical scheme:
A kind of Cefobutazine sodium compound pharmaceutical composition that contains, this pharmaceutical composition contains cefobutazine sodium and cosolvent sodium carbonate, and the weight ratio of described cefobutazine sodium and sodium carbonate is 5-10: 1.
Preferably, the weight ratio of described cefobutazine sodium and sodium carbonate is 8: 1.
Pharmaceutical composition of the present invention, it is preferably lyophilized injectable powder.
The present invention also provides a kind of method for preparing aforementioned pharmaceutical compositions, and it comprises the steps:
1) preparation medicinal liquid: take by weighing cefobutazine sodium and the sodium carbonate of recipe quantity, dissolve with water for injection; Add 0.1% active carbon, mixing; 30min is left standstill in jolting, first coarse filtration, the microporous filter membrane fine straining of rear usefulness 0.45 μ m～0.22 μ m;
2) lyophilization:
After cooling to-45～-60 ℃ with 30～60min from room temperature, keep 120～180min;
With 60～90min, temperature is raised to-5 ℃ after, kept 180～240 minutes, vacuum degree control is at 10～14Pa;
With 120～180min, temperature is adjusted to-5 ℃～10 ℃, keep 120～180min; Then, with 30～60 minutes, temperature is adjusted to 10 ℃～30 ℃, 120～180min, vacuum degree control is less than 20Pa;
3) encapsulation.
For lyophilized powder, add adjuvant in order to realize its better dissolubility and stability, be necessary.The present invention has done more experiment in this regard, and by continuous screening cosolvent, the unexpected discovery in the ceftezole sodium pharmaceutical composition, added after an amount of sodium carbonate, not only do not exist and adds the safety issue that adjuvant brings, and increased its stability.The present invention is by the standby ceftezole sodium freeze-dried powder injection of secondary freeze drying legal system, is shaped, solubility is good, good stability, safe.
The specific embodiment
Following examples are used for further specifying the present invention, but should not be construed as limitation of the present invention.Under the prerequisite that does not deviate from the present invention's spirit and essence, modification or replacement to the present invention does all belong to category of the present invention.
Embodiment 1
Prescription: pharmaceutical composition of the present invention comprises the composition of following ratio: cefobutazine sodium 20mg, sodium carbonate 2mg.
Preparation method:
1) preparation medicinal liquid: take by weighing cefobutazine sodium and the sodium carbonate of recipe quantity, dissolve with water for injection; Add 0.1% active carbon, mixing; 30min is left standstill in jolting, first coarse filtration, the filter membrane fine straining of rear usefulness 0.22 μ m;
2) lyophilization:
After cooling to-60 ℃ with 60min from room temperature, keep 120min;
Use 60min, temperature is risen to-10 ℃ after, kept 240 minutes, vacuum degree control is at 14Pa;
Use 120min, temperature is risen to 10 ℃, keep 180min; Then, with 60 minutes, temperature is risen to 30 ℃, keep 120min, vacuum degree control is at 15Pa;
3) encapsulation.
Embodiment 2
Prescription: pharmaceutical composition of the present invention comprises the composition of following ratio: cefobutazine sodium 24mg, sodium carbonate 3mg.
Preparation method:
1) preparation medicinal liquid: take by weighing cefobutazine sodium and the sodium carbonate of recipe quantity, dissolve with water for injection; Add 0.1% active carbon, mixing; 30min is left standstill in jolting, first coarse filtration, the filter membrane fine straining of rear usefulness 0.22 μ m;
2) lyophilization:
After cooling to-45 ℃ with 30min from room temperature, keep 180min;
Use 90min, temperature is risen to-10 ℃ after, kept 240 minutes, vacuum degree control is at 14Pa;
Use 180min, temperature is risen to 10 ℃, keep 180min; Then, with 30 minutes, temperature is risen to 20 ℃, keep 180min, vacuum degree control is at 15Pa;
3) encapsulation.
Embodiment 3
Prescription: pharmaceutical composition of the present invention comprises the composition of following ratio: cefobutazine sodium 20mg, sodium carbonate 4mg.
1) preparation medicinal liquid: take by weighing cefobutazine sodium and the sodium carbonate of recipe quantity, dissolve with water for injection; Add 0.1% active carbon, mixing; 30min is left standstill in jolting, first coarse filtration, the filter membrane fine straining of rear usefulness 0.22 μ m;
2) lyophilization:
After cooling to-45 ℃ with 50min from room temperature, keep 120min;
Use 60min, temperature is risen to-10 ℃ after, kept 180 minutes, vacuum degree control is at 10Pa;
Use 180min, temperature is risen to 10 ℃, keep 180min; Then, with 60 minutes, temperature is risen to 30 ℃, keep 120min, vacuum degree control is at 15Pa;
3) encapsulation.
Embodiment 4
Prescription: pharmaceutical composition of the present invention comprises the composition of following ratio: cefobutazine sodium 21mg, sodium carbonate 3mg.
Preparation method:
1) preparation medicinal liquid: take by weighing cefobutazine sodium and the sodium carbonate of recipe quantity, dissolve with water for injection; Add 0.1% active carbon, mixing; 30min is left standstill in jolting, first coarse filtration, the filter membrane fine straining of rear usefulness 0.22 μ m;
2) lyophilization:
After cooling to-60 ℃ with 60min from room temperature, keep 120～180min;
Use 90min, temperature is risen to-10 ℃ after, kept 240 minutes, vacuum degree control is at 12Pa;
Use 120min, temperature is risen to 10 ℃, keep 120min; Then, with 60 minutes, temperature is risen to 20 ℃, keep 180min, vacuum degree control is at 15Pa;
3) encapsulation.
Comparative Examples 1
According to the disclosed prescription of patent documentation CN200910015121 embodiment and manner of formulation preparation, be summarized as follows:
100g cefobutazine sodium crude product is dissolved in 1000ml water, adds the 2mol/L hydrochloric acid solution, regulating pH value is 3.0, stirs and separates out insoluble matter; Filter out this insoluble matter, obtain solid after the purified water washing, then add 1000ml ethanol in the gained solid and make its dissolving, through the D101 absorption with macroporous adsorbent resin, with 500ml chloroform eluting purification, collect eluent; The pH value of regulating this eluent with 10% sodium hydroxide solution is 8.0, separates out solid, uses the 300ml washing with alcohol behind the centrifugal 30min, 30 ℃ of vacuum dryings 10 hours, get cefobutazine sodium highly finished product 95.5g, yield is 95.5%, and adopting HPLC to measure purity is 99.5%.Cefobutazine sodium crystal 5 0g crosses 60 mesh sieves and pulverizes, and 100 grades of conditions are aseptic subpackaged in sterilizing room, and lid is rolled in tamponade, gets Ceftezole sodium used for injection powder pin, and every bottle contains cefobutazine sodium in ceftezole 0.25g.
Experimental example 1: safety
The lyophilized injectable powder of embodiment 1-4 preparation and the sterile powder injection of Comparative Examples 1 preparation are carried out the safety testing investigation, and test method and result are as follows:
One, vascular stimulation test
Get body weight and be 36 of the healthy rabbits of 2.0-2.5kg, be divided at random blank group, experiment 1-5 group, 6 every group, adopt rabbit ear edge vein slowly to inject, injection volume is 10ml/kg.Wherein the blank group adopts sodium chloride injection, and experiment 1-4 group adopts respectively the ceftezole sodium freeze-dried powder injection of embodiment 1-4 preparation, tests 5 groups of Ceftezole sodium powder injection agent of adopting respectively Comparative Examples 1 preparation.Both all are dissolved in water for injection rear injection.
Once a day, successive administration 7 days, cut short the rabbit ear in last administration after 24 hours, place 10% formalin fixed preparation, then send pathology to carry out histological examination (5 places at the different parts of rabbit ear edge vein draw materials, and namely begin centripetal end and do a section every 1cm from injecting initial position).
Through rabbit ear edge vein pathological examination, the auricular vein tube wall of blank group and test 1-5 group is complete, and the endotheliocyte structure is clear, and without obvious pathological changes, the slight dilatation and congestion of blood vessel is without cell infiltration.
Two, hemolytic experiment
Laboratory observation sodium chloride blank group, the experiment 1-5 group external haemolysis to family's Sanguis Leporis seu oryctolagi, wherein the blank group adopts sodium chloride injection, experiment 1-4 group adopts respectively the ceftezole sodium freeze-dried powder injection of embodiment 1-4 preparation, tests 5 groups of Ceftezole sodium powder injection agent of adopting respectively Comparative Examples 1 preparation.Both all are dissolved in water for injection rear injection.
The result shows 37 ℃, 3 hours, and blank group and test 1-5 group have no the erythrocyte aggregation phenomenon and occur all without haemolysis.
Three, allergic experiment
Observe the anaphylaxis of Cavia porcellus intravenous injection sodium chloride blank group, experiment 1-5 group, wherein the blank group adopts sodium chloride injection, experiment 1-4 group adopts respectively the ceftezole sodium freeze-dried powder injection of embodiment 1-4 preparation, tests 5 groups of Ceftezole sodium powder injection agent of adopting respectively Comparative Examples 1 preparation.Both all are dissolved in water for injection rear injection.
Concrete grammar is: laboratory animal every other day gives the Ceftezole sodium powder injection agent sensitization of lumbar injection Comparative Examples 1 preparation, continuous three times, then laboratory animal is divided into blank group, experiment 1-5 group, totally 6 groups, and the 14th day and 21 days of beginning in sensitization attack respectively administration, observed immediately 1 hour.
The result shows, tests 1～5 group and perpendicular hair, dyspnea, sneeze, retch, cough or rale, tic, collapse, dead anaphylaxis all do not occur.
The experiment brief summary: although the ceftezole sodium freeze-dried powder injection of preparation of the present invention has added the cosolvent sodium carbonate, compare with the injectable powder that does not add sodium carbonate, safety is without any impact.
Conclusion: the ceftezole sodium freeze-drying powder of embodiments of the invention 1-4 preparation easily is shaped, solubility is good, good stability, safe.
Experimental example 2: stability test
The sample of embodiment 1～4 gained and the sample of Comparative Examples 1, under the condition of 40 ℃ ± 2 ℃ of temperature, humidity 75% ± 5%, place (0,6,12,24 months) carry out detection and the long-term stable experiment of the indexs such as outward appearance, clarity, related substance and content, the result is as follows:
Table 1 sample indices testing result
Described sample is placed indices testing result after 6 months:
Table 2 sample indices testing result (placing after 6 months)
Described sample is placed indices testing result after 12 months:
Table 3 sample indices testing result (placing after 12 months)
Described sample is placed the testing result of indices after 24 months:
Table 4 sample indices testing result (placing after 24 months)
The long-time stability experimental result sees Table 1～4, can find out: lyophilized injectable powder provided by the invention meets the regulation of every national standard, the long-time rear stability height of placing, the indices such as content, related substance, clarity change all not obvious, pH value does not change along with the prolongation of storage time yet, shows the comparable existing sterile powder injection significant prolongation of storage time.
Although above used general explanation, the specific embodiment and experiment, the present invention is described in detail, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (4)
1. one kind contains the Cefobutazine sodium compound pharmaceutical composition, it is characterized in that, this pharmaceutical composition contains cefobutazine sodium and cosolvent sodium carbonate, and the weight ratio of described cefobutazine sodium and sodium carbonate is 5-10: 1.
2. pharmaceutical composition according to claim 1 is characterized in that, the weight ratio of described cefobutazine sodium and sodium carbonate is 8: 1.
3. pharmaceutical composition according to claim 1 is characterized in that, this pharmaceutical composition is lyophilized injectable powder.
4. prepare the method for each described pharmaceutical composition of claim 1～3, it comprises the steps:
1) preparation medicinal liquid: take by weighing cefobutazine sodium and the sodium carbonate of recipe quantity, dissolve with water for injection; Add 0.1% active carbon, mixing; 30min is left standstill in jolting, first coarse filtration, the filter membrane fine straining of rear usefulness 0.45 μ m～0.22 μ m;
2) lyophilization:
After cooling to-45～-60 ℃ with 30～60min from room temperature, keep 120～180min;
With 60～90min, temperature is risen to-10 ℃ after, kept 180～240 minutes, vacuum degree control is at 10～14Pa;
With 120～180min, temperature is risen to 10 ℃, keep 120～180min; Then, with 30～60 minutes, temperature is risen to 20 ℃～30 ℃, keep 120～180min, vacuum degree control is less than 20Pa;
3) encapsulation.
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| CN201210357896XA CN102872021A (en) | 2012-09-25 | 2012-09-25 | Medicinal composition containing ceftezole sodium compound and preparation method for medicinal composition |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105055423A (en) * | 2015-09-16 | 2015-11-18 | 青岛华之草医药科技有限公司 | Medicine ceftezole sodium composition for curing infectious diseases |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1706387A (en) * | 2004-06-09 | 2005-12-14 | 北京盛世伟唐科技有限公司 | Stable cephalosporin powder injection |
| CN101229129A (en) * | 2008-01-18 | 2008-07-30 | 山东罗欣药业股份有限公司 | Ceftezole sodium powder injection and synthesizing method thereof |
| CN101780044A (en) * | 2009-01-16 | 2010-07-21 | 海南中化联合制药工业有限公司 | Ceftezole sodium powder-needle preparation for injection and preparation method thereof |
-
2012
- 2012-09-25 CN CN201210357896XA patent/CN102872021A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1706387A (en) * | 2004-06-09 | 2005-12-14 | 北京盛世伟唐科技有限公司 | Stable cephalosporin powder injection |
| CN101229129A (en) * | 2008-01-18 | 2008-07-30 | 山东罗欣药业股份有限公司 | Ceftezole sodium powder injection and synthesizing method thereof |
| CN101780044A (en) * | 2009-01-16 | 2010-07-21 | 海南中化联合制药工业有限公司 | Ceftezole sodium powder-needle preparation for injection and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105055423A (en) * | 2015-09-16 | 2015-11-18 | 青岛华之草医药科技有限公司 | Medicine ceftezole sodium composition for curing infectious diseases |
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Application publication date: 20130116 |