CN102133181B - Flucloxacilin sodium liposome injection - Google Patents
Flucloxacilin sodium liposome injection Download PDFInfo
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- CN102133181B CN102133181B CN2011100661956A CN201110066195A CN102133181B CN 102133181 B CN102133181 B CN 102133181B CN 2011100661956 A CN2011100661956 A CN 2011100661956A CN 201110066195 A CN201110066195 A CN 201110066195A CN 102133181 B CN102133181 B CN 102133181B
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Abstract
The invention discloses a flucloxacilin sodium liposome injection. The flucloxacilin sodium liposome injection is mainly prepared from flucloxacilin sodium, polysorbate 80, gylcocholic acid sodium salt, gelatin, glycerol and sodium chloride; the defect of instability of the flucloxacilin preparation is overcome; and the liposome injection is prepared by protecting flucloxacilin sodium package by using liposome and then performing spray drying and aseptic subpackage, so that the stability of the flucloxacilin sodium is greatly increased, the preparation process is simple, yield is high, and solubility is high. The product quality of the preparation is improved and the toxic and side effects are reduced.
Description
Technical field
The present invention relates to a kind of novel injection of flucloxacillin sodium, be specifically related to a kind of flucloxacillin sodium lipid microsphere injection, belong to field of medicine preparations.
Background technology
Flucloxacillin sodium, chemistry is by name: (2S, 5R; 6R)-and 6-[[3-(2-chloro-6-fluorophenyl)-5-methyl isophthalic acid, 2-oxazole-4-formyl] amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-formic acid sodium salt; Belong to the 4th Dai isoxazole penicillin; Be characterized in being difficult for being destroyed, the drug resistance staphylococcus aureus that produces penicillinase is had bactericidal action, be mainly used in the penicillin resistant staphy lococcus infection by penicillinase.Be used to treat the severe infections of penicillin resistant staphylococcus aureus clinically, and the urethritis, prostatitis, gonorrhea, endocarditis, the gram positive bacteria that cause after respiratory tract infection (like acute pharyngitis, suppurative tonsillitis), treatment flu secondary bacterial infection, acute and chronic tracheitis, bronchitis, pneumonia, pulmonary abscess, empyema, osteomyelitis, suppurative arthritis, acute and chronic otitis media, the secondary sinusitis of nose, periodontitis, furuncle, carbuncle, erysipelas, cellulitis, tetanus, paronychia, wound surface and wound infection, burn infection, the urethral catheterization are the septicemia that causes of staphylococcus aureus etc. especially.
The loaded British Pharmacopoeia of flucloxacillin sodium version in 2000, the preparation that goes on the market at present has injection and oral formulations, and domestic production producer is less, exists purity difference to cause the unsettled defective of quality, the prescription that can not satisfy the prescriptive period mostly.
Prior art adopted liposomal encapsulated technology to the compositions of flucloxacillin sodium and Amoxicillin Sodium; But defective also is obviously; For example the envelop rate of liposome is lower, and percolation ratio is higher, and the targeting positioning release medicine of liposome is just outstanding to the effect of concrete position.
The inventor unexpectedly finds through long-term conscientious research, uses the lipoid microsphere technology and processes injection through the spray drying packing, can solve flucloxacillin sodium quality problem of unstable, obtains better clinical result of use, has accomplished the present invention thus.
Summary of the invention
The object of the invention is exactly in order to overcome the unsettled defective of flucloxacillin preparation of sodium; Adopt lipoid microsphere that the flucloxacillin sodium parcel is protected earlier; Through spray drying and the aseptic subpackaged lipid microsphere injection of processing, increased the stability of flucloxacillin sodium greatly again, preparation technology is simple; Yield is high, redissolves good.
The technical scheme that the present invention solves:
A kind of flucloxacillin sodium lipid microsphere injection is mainly processed by flucloxacillin sodium, polyoxyethylene sorbitan monoleate, NaGC, gelatin, glycerol and sodium chloride, and each composition weight umber is:
As the present invention's one preferred embodiment, each composition weight umber of flucloxacillin sodium lipid microsphere injection is:
In the above-mentioned described component, wherein polyoxyethylene sorbitan monoleate and NaGC have greatly improved the dissolubility of flucloxacillin sodium as emulsifying agent, and it is good that it is redissolved, clarification; Gelatin is the carrier as lipoid microsphere, is the substrate that forms lipoid microsphere; Glycerol has increased the formation and the stability of lipoid microsphere as co-emulsifier; Sodium chloride plays certain dilution and skeleton function as diluent, makes the lipoid microsphere outward appearance rounding of formation, redissolves faster.
The present invention also provides a kind of method for preparing of flucloxacillin sodium lipid microsphere injection, wherein adopts the spray drying method for preparation lipoid microsphere, and concrete steps are:
(1) flucloxacillin sodium, glycerol and sodium chloride are dissolved in the proper amount of water for injection, get water;
(2) polyoxyethylene sorbitan monoleate, gelatin and NaGC are dissolved in an amount of mixed solvent, get oil phase;
(3) the above-mentioned water that obtains is splashed in the oil phase under stirring condition slowly, drip off the back and stir 10-30min, be transferred to high speed homogenizer high speed then and stir 3-5 time, 5-10min at every turn obtains the white emulsion of homogeneous;
(4) with white emulsion to going in the spray dryer, the adjustment spray condition, spray drying obtains the white lipoid microsphere of shape homogeneous;
(5) the lipoid microsphere branch that obtains is filled to cillin bottle, obtains the flucloxacillin sodium lipid microsphere injection.
Above-mentioned described method for preparing; Wherein mixed solvent is selected from chloroform, dichloromethane, normal hexane, toluene, isopropyl alcohol, acetone, ethyl acetate, methyl acetate, N; Dinethylformamide, N; The mixture of two or more in the N-dimethyl acetylamide is preferably the mixed solvent of normal hexane and isopropyl alcohol, and the two volume ratio is 1: 1.
Above-mentioned described method for preparing, wherein the rate of addition of water in oil phase is 3-8ml/min.
Above-mentioned described method for preparing, wherein spray condition is: inlet temperature is 80-90 ℃, the about 50-60 of outlet temperature ℃, jet size 0.5mm-1mm, hydrojet flow velocity 2-6ml/min, compressed air stream speed 5-12L/min.
The lipoid microsphere particle diameter that above-mentioned described method for preparing makes is between 300-600nm, and medicine flucloxacillin sodium yield is 88-95%.
As another preferred embodiment of the present invention, the method for preparing of described flucloxacillin sodium lipid microsphere injection, concrete steps are:
(1) flucloxacillin sodium, glycerol and sodium chloride are dissolved in the proper amount of water for injection, get water;
(2) polyoxyethylene sorbitan monoleate, gelatin and NaGC are dissolved in an amount of mixed solvent, get oil phase;
(3) the above-mentioned water that obtains is splashed under stirring condition in the oil phase slowly, the control rate of addition is 3-8ml/min, drips off the back and stirs 10-30min; Being transferred to high speed homogenizer high speed then stirs 3-5 time; Rotating speed 12000r/min, each 5-10min obtains the white emulsion of homogeneous;
(4) with white emulsion to going in the spray dryer, the adjustment spray condition: inlet temperature is 80-90 ℃, the about 50-60 of outlet temperature ℃; Jet size 0.5mm-1mm, hydrojet flow velocity 2-6ml/min, compressed air stream speed 5-12L/min; Spray drying obtains the white lipoid microsphere of shape homogeneous;
(5) the lipoid microsphere branch that obtains is filled to cillin bottle, obtains the flucloxacillin sodium lipid microsphere injection.
Another object of the present invention provides a kind of severe infections that adopts flucloxacillin sodium lipid microsphere injection of the present invention treatment penicillin resistant staphylococcus aureus, and the urethritis, prostatitis, gonorrhea, endocarditis, the gram positive bacteria that cause after respiratory tract infection (like acute pharyngitis, suppurative tonsillitis), treatment flu secondary bacterial infection, acute and chronic tracheitis, bronchitis, pneumonia, pulmonary abscess, empyema, osteomyelitis, suppurative arthritis, acute and chronic otitis media, the secondary sinusitis of nose, periodontitis, furuncle, carbuncle, erysipelas, cellulitis, tetanus, paronychia, wound surface and wound infection, burn infection, the urethral catheterization are the method for the septicemia that causes of staphylococcus aureus etc. especially.
The flucloxacillin sodium lipid microsphere injection of the present invention's preparation, than prior art, advantage shows:
(1) good stability, the main component flucloxacillin sodium is embedded in the lipoid microsphere, has improved stability of formulation greatly;
(2) the lipoid microsphere envelop rate is high, adopts the lipoid microsphere of specific components of the present invention and spray drying method for preparation, and envelop rate improves than additive method and component greatly;
(3) preparation technology is simple, and the present invention adopts general preparation production equipment commonly used, no special operational, and cost is low;
(4) redissolve well;
(5) the present invention has improved the product quality of preparation, has reduced toxic and side effects.
The specific embodiment
The preparation of embodiment 1 flucloxacillin sodium lipid microsphere injection
Prescription: (100 bottles)
The preparation process:
(1) 50g flucloxacillin sodium, 100g glycerol and 25g sodium chloride are dissolved in the 2000ml water for injection, get water;
(2) 200g polyoxyethylene sorbitan monoleate, 150g gelatin and 25g NaGC being dissolved in the 2000ml volume ratio is in 1: 1 the mixed solvent of normal hexane and isopropyl alcohol, oil phase;
(3) the above-mentioned water that obtains is splashed under stirring condition in the oil phase slowly, the control rate of addition is 3ml/min, drips off the back and stirs 10min; Being transferred to high speed homogenizer high speed then stirs 3 times; Rotating speed 12000r/min, each 5min obtains the white emulsion of homogeneous;
(4) with white emulsion to going in the spray dryer, the adjustment spray condition: inlet temperature is 90 ℃, about 60 ℃ of outlet temperature, jet size 1mm, hydrojet flow velocity 2ml/min, compressed air stream speed 5L/min, spray drying obtains the white lipoid microsphere of shape homogeneous;
(5) the lipoid microsphere branch that obtains is filled to cillin bottle, obtains the flucloxacillin sodium lipid microsphere injection.
The preparation of embodiment 2 flucloxacillin sodium lipid microsphere injections
Prescription: (100 bottles)
The preparation process:
(1) 50g flucloxacillin sodium, 450g glycerol and 150g sodium chloride are dissolved in the 4000ml water for injection, get water;
(2) 400g polyoxyethylene sorbitan monoleate, 500g gelatin and 250g NaGC being dissolved in the 4000ml volume ratio is in 1: 1 the mixed solvent of normal hexane and isopropyl alcohol, oil phase;
(3) the above-mentioned water that obtains is splashed under stirring condition in the oil phase slowly, the control rate of addition is 8ml/min, drips off the back and stirs 30min; Being transferred to high speed homogenizer high speed then stirs 5 times; Rotating speed 12000r/min, each 10min obtains the white emulsion of homogeneous;
(4) with white emulsion to going in the spray dryer, the adjustment spray condition: inlet temperature is 80 ℃, about 50 ℃ of outlet temperature; Jet size 0.5mm, hydrojet flow velocity 6ml/min, compressed air stream speed 12L/min; Spray drying obtains the white lipoid microsphere of shape homogeneous;
(5) the lipoid microsphere branch that obtains is filled to cillin bottle, obtains the flucloxacillin sodium lipid microsphere injection.
The preparation of embodiment 3 flucloxacillin sodium lipid microsphere injections
Prescription: (100 bottles)
The preparation process:
(1) 100g flucloxacillin sodium, 200g glycerol and 50g sodium chloride are dissolved in the 3000ml water for injection, get water;
(2) 400g polyoxyethylene sorbitan monoleate, 300g gelatin and 50g NaGC being dissolved in the 3000ml volume ratio is in 1: 1 the mixed solvent of normal hexane and isopropyl alcohol, oil phase;
(3) the above-mentioned water that obtains is splashed under stirring condition in the oil phase slowly, the control rate of addition is 5ml/min, drips off the back and stirs 20min; Being transferred to high speed homogenizer high speed then stirs 4 times; Rotating speed 12000r/min, each 8min obtains the white emulsion of homogeneous;
(4) with white emulsion to going in the spray dryer, the adjustment spray condition: inlet temperature is 85 ℃, about 50 ℃ of outlet temperature; Jet size 0.8mm, hydrojet flow velocity 4ml/min, compressed air stream speed 8L/min; Spray drying obtains the white lipoid microsphere of shape homogeneous;
(5) the lipoid microsphere branch that obtains is filled to cillin bottle, obtains the flucloxacillin sodium lipid microsphere injection.
The preparation of embodiment 4 flucloxacillin sodium lipid microsphere injections
Prescription: (100 bottles)
The preparation process:
(1) 100g flucloxacillin sodium, 900g glycerol and 300g sodium chloride are dissolved in the 5000ml water for injection, get water;
(2) 800g polyoxyethylene sorbitan monoleate, 1000g gelatin and 500g NaGC being dissolved in the 5000ml volume ratio is in 1: 1 the mixed solvent of normal hexane and isopropyl alcohol, oil phase;
(3) the above-mentioned water that obtains is splashed under stirring condition in the oil phase slowly, the control rate of addition is 8ml/min, drips off the back and stirs 10min; Being transferred to high speed homogenizer high speed then stirs 3 times; Rotating speed 12000r/min, each 8min obtains the white emulsion of homogeneous;
(4) with white emulsion to going in the spray dryer, the adjustment spray condition: inlet temperature is 80 ℃, about 50 ℃ of outlet temperature, jet size 1mm, hydrojet flow velocity 2ml/min, compressed air stream speed 5L/min, spray drying obtains the white lipoid microsphere of shape homogeneous;
(5) the lipoid microsphere branch that obtains is filled to cillin bottle, obtains the flucloxacillin sodium lipid microsphere injection.
The preparation of embodiment 5 flucloxacillin sodium lipid microsphere injections
Prescription: (100 bottles)
The preparation process makes the flucloxacillin sodium lipid microsphere injection with embodiment 1.
The preparation of embodiment 6 Comparative Examples 1-3
Adopt the excipient of the preparation lipoid microsphere disclosed in CN101716153A, CN101703481A, the CN101536979A, make Comparative Examples 1-3 of the present invention according to the preparation technology of the embodiment of the invention 1.
Form, particle diameter and the distribution thereof of Test Example 1 lipoid microsphere
The form of lipoid microsphere, particle diameter and distribution thereof are to guarantee that the medicine performance should have an important ring of effect.Adopt the light microscope determining embodiment of the invention 1-5 of corrected band eyepiece micrometer and the particle diameter of the lipoid microsphere that Comparative Examples 1-3 prepares.
The particle diameter of the product 80% of embodiment of the invention 1-5 is less than 500nm, and all between 300-600nm, form is the spherical or oval-shaped spheroid of rounding, is evenly distributed.
The particle diameter of the product 90% of Comparative Examples 1-3 is greater than 900nm, and form is irregular, and it is disorderly and unsystematic to distribute.
The entrapment efficiency determination of Test Example 2 lipoid microsphere
After lipoid microsphere separated with methods such as centrifugal or filtrations, detect the content of the interior medicine flucloxacillin sodium of lipoid microsphere with the HPLC method, through formula:
Dose in envelop rate=lipoid microsphere/(dose in the dose+medium in the lipoid microsphere) * 100%
Calculate the envelop rate of the lipoid microsphere of embodiment 1-5 and Comparative Examples 1-3 preparation.
The envelop rate of the product of embodiment of the invention 1-5 is all between 88%-95%.
The envelop rate of the product of Comparative Examples 1-3 is all less than 60%.
Test Example 3 study on the stability
With the not other accelerated test 6 months under 40 ℃ of high temperature, relative humidity 75% condition of the flucloxacillin sodium for injection of the sample of embodiment of the invention 1-5 and Comparative Examples 1-3 preparation and Shanxi Zhendongtaisheng Pharmaceutical Co., Ltd. production; Detect the variation of each item index, result such as following table:
Can find out that by above test data sample each item of embodiment of the invention preparation detects index and has no significant change; Related substance obviously increases after 6 months and the sample of listing preparation and Comparative Examples 1-3 preparation quickens; Content obviously reduces, and the back clarity of redissolving is against regulation.Explained that the present invention is increasing superior aspect the product stability.
Claims (13)
1. a flucloxacillin sodium lipid microsphere injection is characterized in that mainly being processed by flucloxacillin sodium, polyoxyethylene sorbitan monoleate, NaGC, gelatin, glycerol and sodium chloride, and each composition weight umber is:
2. flucloxacillin sodium lipid microsphere injection according to claim 1 is characterized in that each composition weight umber is:
3. a method for preparing for preparing claim 1 or 2 each said flucloxacillin sodium lipid microsphere injections is characterized in that adopting the spray drying method for preparation lipoid microsphere, comprises the steps:
(1) flucloxacillin sodium, glycerol and sodium chloride are dissolved in the proper amount of water for injection, get water;
(2) polyoxyethylene sorbitan monoleate, gelatin and NaGC are dissolved in an amount of mixed solvent, get oil phase;
(3) the above-mentioned water that obtains is splashed in the oil phase under stirring condition slowly, drip off the back and stir 10-30min, be transferred to high speed homogenizer high speed then and stir 3-5 time, 5-10min at every turn obtains the white emulsion of homogeneous;
(4) with white emulsion to going in the spray dryer, the adjustment spray condition, spray drying obtains the white lipoid microsphere of shape homogeneous;
(5) the lipoid microsphere branch that obtains is filled to cillin bottle, obtains the flucloxacillin sodium lipid microsphere injection.
4. method according to claim 3 is characterized in that said mixed solvent is selected from the mixed solvent of normal hexane and isopropyl alcohol, and the two volume ratio is 1: 1.
5. according to claim 3 or 4 each described methods, it is characterized in that wherein the rate of addition of water in oil phase is 3-8ml/min in the step (3).
6. method according to claim 5 is characterized in that, wherein spray condition is: inlet temperature is 80-90 ℃, outlet temperature 50-60 ℃, and jet size 0.5mm-1mm, hydrojet flow velocity 2-6ml/min, compressed air stream speed 5-12L/min.
7. method according to claim 6 is characterized in that, the lipoid microsphere particle diameter that described method for preparing makes is between 300-600nm.
8. the method for preparing of the described flucloxacillin sodium lipid microsphere injection of claim 1 is characterized in that comprising the steps:
(1) flucloxacillin sodium, glycerol and sodium chloride are dissolved in the proper amount of water for injection, get water;
(2) polyoxyethylene sorbitan monoleate, gelatin and NaGC are dissolved in an amount of mixed solvent, get oil phase;
(3) the above-mentioned water that obtains is splashed under stirring condition in the oil phase slowly, the control rate of addition is 3-8ml/min, drips off the back and stirs 10-30min; Being transferred to high speed homogenizer high speed then stirs 3-5 time; Rotating speed 12000r/min, each 5-10min obtains the white emulsion of homogeneous;
(4) with white emulsion to going in the spray dryer, the adjustment spray condition: inlet temperature is 80-90 ℃, outlet temperature 50-60 ℃; Jet size 0.5mm-1mm, hydrojet flow velocity 2-6ml/min, compressed air stream speed 5-12L/min; Spray drying obtains the white lipoid microsphere of shape homogeneous;
(5) the lipoid microsphere branch that obtains is filled to cillin bottle, obtains the flucloxacillin sodium lipid microsphere injection.
9. flucloxacillin sodium lipid microsphere injection according to claim 1 is at the severe infections of preparation treatment penicillin resistant staphylococcus aureus, and the application in the urethritis that causes after treatment flu secondary bacterial infection, acute and chronic tracheitis, bronchitis, pulmonary abscess, empyema, osteomyelitis, suppurative arthritis, acute and chronic otitis media, the secondary sinusitis of nose, periodontitis, furuncle, carbuncle, erysipelas, cellulitis, tetanus, paronychia, wound surface and wound infection, burn infection, the urethral catheterization, prostatitis, gonorrhea, endocarditic medicine.
10. the application of flucloxacillin sodium lipid microsphere injection according to claim 1 in the medicine of preparation treatment acute pharyngitis, suppurative tonsillitis.
11. the application of flucloxacillin sodium lipid microsphere injection according to claim 1 in the medicine of the microbial septicemia of preparation treatment Grain-positive.
12. the application of flucloxacillin sodium lipid microsphere injection according to claim 1 in the medicine of preparation treatment respiratory tract infection.
13. the application of flucloxacillin sodium lipid microsphere injection according to claim 1 in the medicine of preparation treatment pneumonia.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100661956A CN102133181B (en) | 2011-03-18 | 2011-03-18 | Flucloxacilin sodium liposome injection |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100661956A CN102133181B (en) | 2011-03-18 | 2011-03-18 | Flucloxacilin sodium liposome injection |
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| CN102133181A CN102133181A (en) | 2011-07-27 |
| CN102133181B true CN102133181B (en) | 2012-06-27 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101536979A (en) * | 2009-04-08 | 2009-09-23 | 邓菊娟 | Edaravone lipid microsphere formulation and preparation method |
| CN101703481A (en) * | 2009-10-30 | 2010-05-12 | 王明 | Ribavirin lipid microsphere effervescent granules |
| CN101716153A (en) * | 2009-12-22 | 2010-06-02 | 海南永田药物研究院有限公司 | Ornidazole ester microsphere solid preparation |
-
2011
- 2011-03-18 CN CN2011100661956A patent/CN102133181B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101536979A (en) * | 2009-04-08 | 2009-09-23 | 邓菊娟 | Edaravone lipid microsphere formulation and preparation method |
| CN101703481A (en) * | 2009-10-30 | 2010-05-12 | 王明 | Ribavirin lipid microsphere effervescent granules |
| CN101716153A (en) * | 2009-12-22 | 2010-06-02 | 海南永田药物研究院有限公司 | Ornidazole ester microsphere solid preparation |
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