CN108714140A - The nano injection liquid and preparation method of a kind of veterinary ceftiofur and its salt - Google Patents
The nano injection liquid and preparation method of a kind of veterinary ceftiofur and its salt Download PDFInfo
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Abstract
The present invention relates to a kind of veterinary ceftiofur nano injection liquid and preparation method thereof, belong to veterinary antibiotic formulation art.The Ceftiofur nano injection liquid of the present invention, Ceftiofur or its salt are passed through specific technique by system with suitable surfactant, lipid auxiliary material, the nano-grade medicine particle of 50-200 nanometers of grain size is made, then drug microparticles is scattered in water for injection, injection is made.The injection decentralized medium of the present invention is water for injection, and compared to lipid solvent, its viscosity is lower, it is easier to be administered, irritation smaller.The product bioavilability of the present invention is high, and adverse reaction is few, and stability is good.
Description
Technical field
The invention belongs to veterinary antibiotic formulation arts, are related to nano injection liquid and its preparation side of Ceftiofur and its salt
Method.
Background technology
Ceftiofur (Ceftiofur) is first that company of Pharmacia S.P.A. of the U.S. develops the 1980s
A third-generation cephalosporin class antibiotic dedicated for animal.1988, United States drug had approved cephalo thiophene with food control office
Furan sodium is for treating bovine respiratory bacteriosis, and hereafter FDA has approved ceftiofur sodium successively again and Ceftiofur Hydrochloride is used
In 1 age in days chicken, turkey, pig, goat and sheep etc..Ceftiofur mainly acts on transpeptidase and blocks the conjunction of bacteria cell wall
At presentation fungicidal effectiveness all has super broad spectrum high-effect antibacterial action, especially to pig to gram-positive bacteria and Gram-negative bacteria
The common clinical livestock and poultry such as lung epidemic disease, actinobacillus suis pleuropneumonia, Streptococcus suis, piglet yellow-white has good control
Therapeutic effect.
Ceftiofur facile hydrolysis, and it is temperature sensitive, stability is poor.Ceftiofur be administered orally, because raw material smell compared with
Greatly, it and easily disperses, keeps its palatability poor, influence feed intake, and because drainage rate is fast, administration number of times need to be increased, be unfavorable for reaching
Drug administration by injection is mostly used to efficient therapeutic effect, therefore at present on veterinary clinic.Ceftiofur oil suspension injection is current
The primary formulation of application, said preparation are that Ceftiofur or its salt are suspended in vegetable oil or other oil type liquids, represent drug
It is the ceftiofur crystalline suspension injection of Shuo Teng companies of U.S. production.But the grain size of such drug suspension particle is larger, one
As be 15 μm, and particle size range is wide, and granularity uniformity is poor, and the drug releasing rate of particle differs greatly, and easily causes blood medicine dense
The fluctuation of degree.In addition such preparation is using vegetable oil or other oils as decentralized medium, and formulation viscosity is big, poor biocompatibility, no
Only clinical injection is not easy, and easily causes the adverse reaction of pain and injection site.Therefore urgent need is stable, efficient, low not at present
The ceftiofur formulation of good reaction ensures its clinical efficacy and increases the compliance of animal to reach therapeutic purposes.
Invention content
To solve the above-mentioned problems, the nanometer note of a kind of veterinary ceftiofur (Ceftiofur) of present invention offer and its salt
Penetrate liquid and preparation method thereof.
The purpose of the present invention is what is be achieved through the following technical solutions：
The present invention provides the nano injection liquid of a kind of veterinary ceftiofur and its salt, containing grain size is 50- in the injection
The decentralized medium of the nanoparticle of the Ceftiofur of 200nm or its salt, the injection is water for injection.
Wherein, contained Ceftiofur and its salt are by weight percentage 1%~50%, preferably 10%~25%.
In the veterinary ceftiofur of the present invention and its nano injection liquid of salt, the Ceftiofur salt can be cephalo thiophene
Hydrochloride, phosphate, tartrate or the alkali metal salt of furan.
Wherein, the nano injection liquid of the veterinary ceftiofur and its salt is also containing weight percent 1%~30%
Surfactant, the preferably surfactant also containing weight percent 5%~20%.
Wherein, the surfactant is poloxamer, lecithin, aliphatic acid LABRAFIL M 1944CS, spans table
Any one in the activating agent of face or two kinds.
Wherein, the nano injection liquid of the veterinary ceftiofur and its salt also contains weight percent 20%~90%
Lipid carriers, preferred Lipid carriers also containing weight percent 50%~70%.
Wherein, the Lipid carriers are appointing in palmitic acid, stearic acid, glycerin monostearate, Compritol 888 ATO
Meaning is one or more of.
The present invention also provides the preparation methods of the veterinary ceftiofur and its nano injection liquid of salt, it is characterised in that step
It is rapid as follows：
1. Ceftiofur or Ceftiofur salt are dissolved in dimethylformamide：N-butanol (2:1) it in mixed solution, is added
Surfactant and Lipid carriers, 60 DEG C~80 DEG C heating for dissolving；
2. step 1) acquired solution is slowly added under the conditions of high-speed stirred in water, with high-shearing dispersion emulsifying machine, with
The rotating speed of 15000r/min~20000r/min persistently stirs 10-30 minutes；
3. by step, 2. acquired solution solution is rapidly cooled to 10 DEG C hereinafter, centrifugation, discards liquid, gained powder is dried
Afterwards, by required dosage be scattered in water for injection to get.
The Ceftiofur of the present invention and its nano injection liquid of salt are by Ceftiofur or its salt and suitable surface-active
Agent and lipid auxiliary material are made the drug microparticles of grain size 50-200nm, are further scattered in water for injection by special process
Nanometer suspension injection obtained.Drug is wrapped in Lipid carriers, is avoided the contact with oxygen and water, is improved drug and exist
Stability in preparation, and have the effect of delaying drug release.The present invention is using water for injection as decentralized medium, because of water for injection
Viscosity, irritation be below the lipids solvent such as vegetable oil, in addition suspended particles granularity of the invention is nanoscale, therefore this hair
Bright commercial product of comparing has the characteristics that viscosity is low, irritation is small.
Description of the drawings
Fig. 1 show the vitro release curve of Ceftiofur nano injection liquid prepared by embodiment 1-5.
Specific implementation mode
By the following example by the more specific description present invention, it should be understood that the embodiment is merely to illustrate this
Invention, rather than limit the scope of the invention in any way.
The preparation of 1 Ceftiofur nano injection liquid of embodiment
Prescription：
Preparation process：
1. Ceftiofur is dissolved in dimethylformamide：N-butanol (2:1) in mixed solution, poloxamer, ovum is added
Phosphatide, Compritol 888 ATO, 60 DEG C of heating for dissolving；
2. by step, 1. acquired solution is slowly added under the conditions of high-speed stirred in water, with high-shearing dispersion emulsifying machine, with
The rotating speed of 15000r/min~20000r/min persistently stirs 20 minutes；
3. by step 2. acquired solution be rapidly cooled to 10 DEG C hereinafter, centrifugation, discard liquid, by gained powder dry after,
Be scattered in 10L waters for injection to get.
The preparation of 2 Ceftiofur nano injection liquid of embodiment
Prescription：
Preparation process：
1. Ceftiofur Hydrochloride is dissolved in dimethylformamide：N-butanol (2:1) in mixed solution, addition lecithin,
Gelucire 44/14, Arlacel-80, glycerin monostearate, 60 DEG C of heating for dissolving；
2. by step, 1. acquired solution is slowly added under the conditions of high-speed stirred in water, with high-shearing dispersion emulsifying machine, with
The rotating speed of 15000r/min~20000r/min persistently stirs 20 minutes；
3. by step 2. acquired solution be rapidly cooled to 10 DEG C hereinafter, centrifugation, discard liquid, by gained powder dry after,
Be scattered in 10L waters for injection to get.
The preparation of 3 Ceftiofur nano injection liquid of embodiment
Prescription：
Preparation process：
1. ceftiofur sodium is dissolved in dimethylformamide：N-butanol (2:1) in mixed solution, addition poloxamer,
Lecithin, Arlacel-80, stearic acid, glycerin monostearate, 60 DEG C of heating for dissolving；
2. by step, 1. acquired solution is slowly added under the conditions of high-speed stirred in water, with high-shearing dispersion emulsifying machine, with
The rotating speed of 15000r/min~20000r/min persistently stirs 20 minutes；
3. by step 2. acquired solution be rapidly cooled to 10 DEG C hereinafter, centrifugation, discard liquid, by gained powder dry after,
Be scattered in 10L waters for injection to get.
The preparation of 4 Ceftiofur nano injection liquid of embodiment
Prescription：
Preparation process：
1. Ceftiofur Hydrochloride is dissolved in dimethylformamide：N-butanol (2:1) in mixed solution, it is husky that pool Lip river is added
Nurse, palmitic acid, Compritol 888 ATO, 60 DEG C of heating for dissolving；
2. by step, 1. acquired solution is slowly added under the conditions of high-speed stirred in water, with high-shearing dispersion emulsifying machine, with
The rotating speed of 15000r/min~20000r/min persistently stirs 20 minutes；
3. by step 2. acquired solution be rapidly cooled to 10 DEG C hereinafter, centrifugation, discard liquid, by gained powder dry after,
Be scattered in 10L waters for injection to get.
The preparation of 5 Ceftiofur nano injection liquid of embodiment
Prescription：
Preparation process：
1. Ceftiofur is dissolved in dimethylformamide：N-butanol (2:1) in mixed solution, the poly- second of pungent capric acid two is added
Alcohol glyceride, stearic acid, glycerin monostearate, 60 DEG C of heating for dissolving；
2. by step, 1. acquired solution is slowly added under the conditions of high-speed stirred in water, with high-shearing dispersion emulsifying machine, with
The rotating speed of 15000r/min~20000r/min persistently stirs 20 minutes；
3. by step 2. acquired solution be rapidly cooled to 10 DEG C hereinafter, centrifugation, discard liquid, by gained powder dry after,
Be scattered in 10L waters for injection to get.
The preparation of 6 Ceftiofur nano injection liquid of embodiment
Prescription：
Preparation process：
1. Ceftiofur is dissolved in dimethylformamide：N-butanol (2:1) in mixed solution, poloxamer, palm fibre is added
Palmitic acid acid, Compritol 888 ATO, 60 DEG C of heating for dissolving；
2. by step, 1. acquired solution is slowly added under the conditions of high-speed stirred in water, with high-shearing dispersion emulsifying machine, with
The rotating speed of 15000r/min~20000r/min persistently stirs 20 minutes；
3. by step 2. acquired solution be rapidly cooled to 10 DEG C hereinafter, centrifugation, discard liquid, by gained powder dry after,
Be scattered in 10L waters for injection to get.
The preparation of 7 Ceftiofur Hydrochloride nano injection liquid of embodiment
Prescription：
Preparation process：
1. Ceftiofur Hydrochloride is dissolved in dimethylformamide：N-butanol (2:1) in mixed solution, it is husky that pool Lip river is added
Nurse, Arlacel-40, Compritol 888 ATO, 60 DEG C of heating for dissolving；
2. by step, 1. acquired solution is slowly added under the conditions of high-speed stirred in water, with high-shearing dispersion emulsifying machine, with
The rotating speed of 15000r/min~20000r/min persistently stirs 20 minutes；
3. by step 2. acquired solution be rapidly cooled to 10 DEG C hereinafter, centrifugation, discard liquid, by gained powder dry after,
Be scattered in 10L waters for injection to get.
The preparation of 8 Ceftiofur Hydrochloride nano injection liquid of embodiment
Prescription：
Preparation process：
1. Ceftiofur Hydrochloride is dissolved in dimethylformamide：N-butanol (2:1) in mixed solution, it is husky that pool Lip river is added
Nurse, lecithin, stearic acid, palmitic acid, Compritol 888 ATO, 60 DEG C of heating for dissolving；
2. by step, 1. acquired solution is slowly added under the conditions of high-speed stirred in water, with high-shearing dispersion emulsifying machine, with
The rotating speed of 15000r/min~20000r/min persistently stirs 20 minutes；
3. by step 2. acquired solution be rapidly cooled to 10 DEG C hereinafter, centrifugation, discard liquid, by gained powder dry after,
Be scattered in 10L waters for injection to get.
The preparation of 9 Ceftiofur Hydrochloride nano injection liquid of embodiment
Prescription：
Preparation process：
1. Ceftiofur Hydrochloride is dissolved in dimethylformamide：N-butanol (2:1) in mixed solution, it is husky that pool Lip river is added
Nurse, palmitic acid, glycerin monostearate, 60 DEG C of heating for dissolving；
2. by step, 1. acquired solution is slowly added under the conditions of high-speed stirred in water, with high-shearing dispersion emulsifying machine, with
The rotating speed of 15000r/min~20000r/min persistently stirs 20 minutes；
3. by step 2. acquired solution be rapidly cooled to 10 DEG C hereinafter, centrifugation, discard liquid, by gained powder dry after,
Be scattered in 10L waters for injection to get.
The preparation of 10 Ceftiofur nano injection liquid of embodiment
Prescription：
Preparation process：
1. Ceftiofur is dissolved in dimethylformamide：N-butanol (2:1) in mixed solution, Arlacel-20, palm is added
Acid, 60 DEG C of heating for dissolving；
2. by step, 1. acquired solution is slowly added under the conditions of high-speed stirred in water, with high-shearing dispersion emulsifying machine, with
The rotating speed of 15000r/min~20000r/min persistently stirs 20 minutes；
3. by step 2. acquired solution be rapidly cooled to 10 DEG C hereinafter, centrifugation, discard liquid, by gained powder dry after,
Be scattered in 10L waters for injection to get.
The preparation of 11 Ceftiofur nano injection liquid of embodiment
Prescription：
| Formulation ingredients | 1000g nanoparticle dosages (g) | Weight percent (%) |
| Ceftiofur sodium | 180 | 18 |
| Lecithin | 100 | 10 |
| Stearic acid | 200 | 20 |
| Compritol 888 ATO | 520 | 52 |
Preparation process：
1. ceftiofur sodium is dissolved in dimethylformamide：N-butanol (2:1) in mixed solution, lecithin, hard is added
Resin acid, Compritol 888 ATO, 60 DEG C of heating for dissolving；
2. by step, 1. acquired solution is slowly added under the conditions of high-speed stirred in water, with high-shearing dispersion emulsifying machine, with
The rotating speed of 15000r/min~20000r/min persistently stirs 20 minutes；
3. by step 2. acquired solution be rapidly cooled to 10 DEG C hereinafter, centrifugation, discard liquid, by gained powder dry after,
Be scattered in 10L waters for injection to get.
The preparation of 12 Ceftiofur nano injection liquid of embodiment
Prescription：
Preparation process：
1. Ceftiofur is dissolved in dimethylformamide：N-butanol (2:1) in mixed solution, poloxamer, oil is added
Acid polyethylene glycol glyceride, Arlacel-60, Compritol 888 ATO, palmitic acid, stearic acid, glycerin monostearate, 60 DEG C of heating are molten
Solution；
2. by step, 1. acquired solution is slowly added under the conditions of high-speed stirred in water, with high-shearing dispersion emulsifying machine, with
The rotating speed of the r/min of 15000r/min~20000 persistently stirs 20 minutes；
3. by step 2. acquired solution be rapidly cooled to 10 DEG C hereinafter, centrifugation, discard liquid, by gained powder dry after,
Be scattered in 10L waters for injection to get.
Test example 1 according to the embodiment 1-5 Ceftiofur nano injection liquid prepared study on the stability
Experimental method：Ceftiofur nano injection liquid is prepared respectively according to the method for embodiment 1-5, in 40 ± 2 DEG C of temperature,
It is placed 6 months under conditions of relative humidity 75 ± 5%.It was sampled at the 0th, 1,2,3,62 month once, presses stability emphasis respectively
Investigation project is detected.
Experimental result：1 is the results are shown in Table according to the Acceleration study of the embodiment 1-5 Ceftiofur nano injection liquid prepared.
Table 1 according to the embodiment 1-5 Ceftiofur nano injection liquid prepared accelerated test result
Experiment conclusion：According to the embodiment 1-5 Ceftiofur nano injection liquid prepared 6 are placed under the conditions of accelerated test
A month, content and appearance had good stability without significant changes.
The outer dissolution test experimental method of Ceftiofur nano injection liquid that test example 2 is prepared according to embodiment 1-5：According to
The method of embodiment 1-5 prepares Ceftiofur nano injection liquid respectively, and using PBS buffer solution as dissolution medium, with slurry processes, rotating speed is
50 turns per minute, the rate of release of sample is investigated, draws release curve, and carry out with commercially available Ceftiofur Hydrochloride injecta
Compare, test result is shown in Fig. 1.
Experiment conclusion：Rate of release of the Ceftiofur nano injection liquid prepared according to embodiment 1-5 in PBS buffer solution
It is substantially reduced, shows there is preferable slow release effect.
Test example 3 prepares the clinical effect experiment of Ceftiofur nano injection liquid according to embodiment 1-3
Experimental method：The growing and fattening pigs 100 that weight 30kg ± 5kg is diagnosed as asthma are chosen, are randomly divided into five groups, every group
20.1-3 groups give the Ceftiofur nano injection liquid prepared by embodiment 1-3 methods, a secondary amounts, with Ceftiofur respectively
Meter, per kilogram of body weight 5mg；4th group is given commercially available Ceftiofur Hydrochloride injecta, a secondary amounts, in terms of Ceftiofur, per kilogram
Weight 5mg；5th group is blank control group, is not administered.The feeding management all same of each group.
Curative effect judges.It cures：After medication a couple of days, appetite, breathing restore normal, cough, breathing completely disappears, 10 after drug withdrawal
Not recidivist in it, referred to as cures；It improves：Clinical symptoms are mitigated or clinical symptoms temporary extinction, but after drug withdrawal in 10 days
Recidivist again, referred to as improves.
Experimental result：It the results are shown in Table according to the clinical effect experiment of the embodiment 1-3 Ceftiofur nano injection liquid prepared
2。
Table 2 according to the embodiment 1-3 Ceftiofur nano injection liquid prepared clinical effect experiment result
Experiment conclusion：The Ceftiofur nano injection liquid energy of the present invention enough improves the clinical efficacy of Ceftiofur, especially exists
Medication anaphase effect is significantly better than commercial product, and cure rate highest rapid according to the sample curative effect of the preparation of embodiment 1, through clinic
Experiment confirms that the sample clinical effectiveness prepared according to preferred proportion is more preferable.
Test example 4 according to the embodiment 1-3 Ceftiofur nano injection liquid prepared internal pharmacokinetic trial
Test method：The healthy growing and fattening pigs 20 for choosing weight 50kg ± 5kg, are randomly divided into four groups, every group 5.1-3
Group gives the Ceftiofur nano injection liquid prepared by embodiment 1-3 methods respectively, and the 4th group is given commercially available Ceftiofur Hydrochloride
Injection.Dosage, in terms of Ceftiofur, every 1 kg body weight 5mg.After administration 5min, 30min, 1h, 2h, 4h,
8h, 12h, for 24 hours, 48h, 72h, 96h, 144h take, take the metabolin for measuring Ceftiofur in blood after plasma treatment to remove furans
The concentration of methyl Ceftiofur (DFC).
Experimental result：According to the internal pharmacokinetic trial knot of the embodiment 1-3 Ceftiofur nano injection liquid prepared
Fruit is shown in Table 3.
The internal pharmacokinetic trial result for the Ceftiofur nano injection liquid that table 3 is prepared according to embodiment 1
Experiment conclusion：The Ceftiofur nano injection liquid energy of the present invention enough extends the efficiency time of Ceftiofur, and blood medicine is dense
It spends more stable.
Test example 5 according to the embodiment 1-5 Ceftiofur nano injection liquid prepared particle size distribution
The size distribution according to the embodiment 1-5 Ceftiofur nano injection liquid prepared, examination are measured with Malvern ParticleSizer
It tests and the results are shown in Table 4.
The particle size distribution for the Ceftiofur nano injection liquid that table 4 is prepared according to embodiment 1
| Diameter nm | D(i50)nm | D(i90)nm | PdI | |
| The sample prepared according to 1 method of embodiment | 124 | 134 | 175 | 0.58 |
| The sample prepared according to 2 method of embodiment | 138 | 141 | 186 | 0.49 |
| The sample prepared according to 3 method of embodiment | 155 | 168 | 190 | 0.47 |
| The sample prepared according to 4 method of embodiment | 153 | 172 | 188 | 0.62 |
| The sample prepared according to 5 method of embodiment | 129 | 138 | 169 | 0.41 |
Conclusion (of pressure testing)：According to the embodiment 1-5 Ceftiofur nano injection liquid prepared average particle size 200nm with
Under, and even particle size distribution, according to embodiment 1 and the sample granularity smaller of the preparation of embodiment 5 and evenly, it was demonstrated that preferred method
It is better than non-optimum choosing method.
Comparative example
Prescription one：
Prescription two：
Prescription three：
Prepared by three above prescription preparation process according to the invention, particle adhesion is serious, and it is equal to be unable to get grain size
Even drug microparticles.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, without departing from the technical principles of the invention, several improvements and modifications can also be made, these improvements and modifications
Also it should be regarded as protection scope of the present invention.
Claims (10)
1. the nano injection liquid of a kind of veterinary ceftiofur and its salt, which is characterized in that the injection contains particle size range 50-
The nanoparticle of the Ceftiofur of 200nm or its salt, and using water for injection as decentralized medium.
2. the nano injection liquid of veterinary ceftiofur according to claim 1 and its salt, which is characterized in that contained cephalo
Thiophene furan and its salt are by weight percentage 1%~50%.
3. the nano injection liquid of veterinary ceftiofur according to claim 2 and its salt, which is characterized in that contained cephalo
Thiophene furan and its salt, by weight percentage preferably 10%~25%.
4. the nano injection liquid of veterinary ceftiofur according to claim 2 or 3 and its salt, which is characterized in that described
Ceftiofur salt is hydrochloride, phosphate, tartrate or the alkali metal salt of Ceftiofur.
5. the nano injection liquid of veterinary ceftiofur according to claim 1 and its salt, which is characterized in that also contain weight
Percentage 1%~30%, preferably 5%~20% surfactant.
6. the nano injection liquid of veterinary ceftiofur according to claim 4 or 5 and its salt, which is characterized in that described
Surfactant is any one in poloxamer, lecithin, aliphatic acid LABRAFIL M 1944CS, spans surfactant
Or two kinds.
7. the nano injection liquid of veterinary ceftiofur according to claim 1 and its salt, which is characterized in that also contain weight
The Lipid carriers of percentage 20%~90%.
8. the nano injection liquid of veterinary ceftiofur according to claim 7 and its salt, which is characterized in that preferably also contain
The Lipid carriers of weight percent 50%~70%.
9. the nano injection liquid of veterinary ceftiofur according to claim 7 or 8 and its salt, which is characterized in that described
Lipid carriers are any one or a few in palmitic acid, stearic acid, glycerin monostearate, Compritol 888 ATO.
10. the preparation method of the nano injection liquid of claim 1-9 any one of them veterinary ceftiofur and its salt, feature
It is, includes the following steps：
1) Ceftiofur or Ceftiofur salt are dissolved in dimethylformamide：N-butanol (2:1) in mixed solution, surface is added
Activating agent and Lipid carriers, 60 DEG C~80 DEG C heating for dissolving；
2) it by step 1) acquired solution under the conditions of high-speed stirred, is slowly added in water, with high-shearing dispersion emulsifying machine, with
The rotating speed of 15000r/min~20000r/min persistently stirs 10-30 minutes；
3) step 2) acquired solution is rapidly cooled to 10 DEG C hereinafter, centrifugation, discards liquid, after gained powder is dried, by institute
Need dosage to be scattered in water for injection to get.
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Citations (4)
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|---|---|---|---|---|
| CN102327235A (en) * | 2011-07-14 | 2012-01-25 | 海南美大制药有限公司 | Solid cefixime lipid nanoparticle preparation |
| CN103191058A (en) * | 2012-01-05 | 2013-07-10 | 洛阳惠中兽药有限公司 | Aqueous suspension injection of cephalosporin medicines, and preparation method thereof |
| CN103705459A (en) * | 2012-09-29 | 2014-04-09 | 瑞普（天津）生物药业有限公司 | Crystallized ceftiofur free acid nano-emulsion injection and preparation method thereof |
| CN106580878A (en) * | 2015-10-19 | 2017-04-26 | 瑞普（天津）生物药业有限公司 | Ceftiofur hydrochloride lipidosome injection and preparation method thereof |
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2018
- 2018-07-11 CN CN201810594586.7A patent/CN108714140A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102327235A (en) * | 2011-07-14 | 2012-01-25 | 海南美大制药有限公司 | Solid cefixime lipid nanoparticle preparation |
| CN103191058A (en) * | 2012-01-05 | 2013-07-10 | 洛阳惠中兽药有限公司 | Aqueous suspension injection of cephalosporin medicines, and preparation method thereof |
| CN103705459A (en) * | 2012-09-29 | 2014-04-09 | 瑞普（天津）生物药业有限公司 | Crystallized ceftiofur free acid nano-emulsion injection and preparation method thereof |
| CN106580878A (en) * | 2015-10-19 | 2017-04-26 | 瑞普（天津）生物药业有限公司 | Ceftiofur hydrochloride lipidosome injection and preparation method thereof |
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