CN102319210B - Veterinary long-acting cefquinome sulfate injection and preparation method thereof - Google Patents
Veterinary long-acting cefquinome sulfate injection and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of animal medicine, and particularly discloses veterinary long-acting cefquinome sulfate injection and a preparation method thereof. 100 mL of the injection comprises 2.5-7.5 g of cefquinome sulfate, 0.2-0.4 g of suspending agents, 0.4 g of bacteriostatic agents, 0.3 g of emulsion dispersants, and the balance of solvents. The preparation method comprises the following steps: firstly adding cefquinome sulfate into the solvent, stirring for well mixing; adding the suspending agent into the solvent with a temperature of 90-100 DEG C for dissolution; cooling the dissolved solution in the second step to room temperature, adding the suspension under stirring in the first step, uniformly stirring; adding the bacteriostatic agent and the emulsion dispersant in to the suspension in the third step, fully stirring; finally adding residual amount of the solvent, uniformly stirring, orderly adding the mixture into a high-speed shearing dispenser and a colloid mill, performing radiation sterilization to prepare the product. When the product is used in pigs by intramuscular injection, the elimination half life is long; the effective action time of the medicine in the body is prolonged; and the drug administration time is reduced.
Description
Technical field
The present invention relates to the animal drug technical field, be specifically related to a kind of Veterinary long-acting cefquinome sulfate injection and preparation method thereof.
Background technology
Cefquinome is animal specific the 4th generation cephalosporins, is a kind of antibiotic wide spectrum, efficient cephalosporins, has more widely antimicrobial spectrum and stronger bactericidal action than third generation cephalosporin.Its inherent antibacterial activity is better than first three for cephalosporin, compares four generation cephalo consumptions little (fowl per kilogram injection 3-5 milligram, 2 milligrams of domestic animal per kilograms, 1 milligram of cattle and sheep per kilogram) for cephalo with first three; The treatment antimicrobial susceptibility is strong; Plasma half-life is long, without nephrotoxicity.It has extremely strong killing action to staphylococcus aureus, streptococcus, blue pus organism, enterobacteria section (escherichia coli, Salmonella, Cray Bai Shi citric acid fungus, serratia marcesens).Remarkable to bacterial respiratory tract disease (pleuropneumonia, pneumonia) effects such as actinobacillus pleuropneumoniae, the secondary haemophilus of pig, pasteurella multocida, porcine mycoplasmal, streptococcus.Can control by diseases such as the having loose bowels of causing such as intractable escherichia coli, Salmonella, bacillus pyocyaneus and staphylococcus, diarrhoea, pericarditis perihepatitis fowl; Duck oromeningitis also there is specially good effect.
The shortcoming of existing Cefquinome sulfate medicine is that action time is short, its administrated method is injection every day once substantially, be used in conjunction 3～5 days, the manpower financial capacity's of plant who causes for the frequent drug administration by injection that reduces because of cefquinome waste, and the Animal stress reaction of as far as possible avoiding multiple dosing to cause, the scientific research personnel of field of veterinary is badly in need of developing for China's aquaculture a kind of cefquinome durative action preparation of convenient drug administration, for clinical application facilitates.
Summary of the invention
For the deficiencies in the prior art, first purpose of the present invention is to provide a kind of Veterinary long-acting cefquinome sulfate injection, realizes that the technical scheme of this purpose is as follows:
A kind of Veterinary long-acting cefquinome sulfate injection is characterized in that, this injection of every 100mL is composed as follows:
Cefquinome sulfate: 2.5-7.5g,
Suspending agent: 0.2-0.4g,
Antibacterial: 0.4g,
Emulsifying dispersant: 0.3g
Solvent: to 100mL;
Described suspending agent be castor oil hydrogenated and soybean lecithin with 2: 3-2: the mixture that 5 weight ratio forms;
Described antibacterial is chlorobutanol;
Described emulsifying dispersant is Arlacel-60;
Described solvent is injection stage solvent or double solvent, and wherein the injection stage solvent is triacetyl glycerine and/or Oleum Arachidis hypogaeae semen; Double solvent is injection stage solvent and the mixture that accounts for the Macrogol 200 (PEG200) of the 10-30% of injection cumulative volume.
Another object of the present invention has been to provide a kind of preparation method of above-mentioned Veterinary long-acting cefquinome sulfate injection, and the step of the method technical scheme is as follows:
(1) the Cefquinome sulfate crude drug is added in the solvent, magnetic agitation makes it abundant mixing;
(2) suspending agent is added in 90-100 ℃ the solvent and dissolve;
(3) add in the suspension of the step (1) that is stirring after the lysate of step (2) being cooled to room temperature, stir;
(4) add again antibacterial and emulsifying dispersant to the suspension of step (3), fully stir;
(5) solvent of adding surplus, stirring and evenly mixing 30min, crossing rotating speed is the high speed shear dispersion machine 30min of 1500r/min, then crosses colloid mill (rotating speed is 3500r/min) 4h, 60Co-gamma-ray irradiation sterilization finally by 3KGY makes milky or light brown suspension product.
Technical scheme of the present invention is: Cefquinome sulfate directly is scattered in makes the long-acting suspension formulations of a class in the solvent, process respectively rear a kind of suspension that obtains by high speed shear dispersion machine and colloid mill, can slowly discharge after the intramuscular injection, to reach the prolong drug effect of elimination half-life in vivo.Compared with prior art, advantage of the present invention and beneficial effect are:
1, adding Polyethylene Glycol among the present invention can increase the injection stage solvent to the bearing capacity of medicine, has improved the suspendible adhesion effect of medicine, has improved settling ratio and the heavy dispersibility of suspension;
2, the present invention share castor oil hydrogenated and soybean lecithin, can further improve the stability of suspending effect and preparation;
3, the present invention can be controlled at the particle diameter of cefquinome sulfate injection 5-12 μ m by high speed shear dispersion machine and milling treatment of colloid, has improved the flowability of suspension, has solved the in the past problem of a lot of suspension formulations wall built-ups;
4, the present invention has avoided finished product Cefquinome sulfate to heat sensitive problem and has added certain antibacterial and emulsifying dispersant (Arlacel-60) has further improved the stability of preparation by irradiation sterilization;
5, preparation technology of the present invention is simple to operate, has reduced as reaching the required size of suspension to the primary raw material in the preparation or adjuvant grinds or the troublesome operation such as micronizing;
6, beneficial effect mainly is: eliminate long half time behind the pig intramuscular injection said preparation, but prolong drug effective acting time in vivo reduces the medication number of times.
Description of drawings
Fig. 1 be the cefquinome sulfate injection produced of the long-acting cefquinome sulfate injection that makes of embodiment 7 and Intervet company to injection in the pig machine after the concentration-time curve of cefquinome in the blood plasma.
The specific embodiment
Below in conjunction with specific embodiment the inventive method is described in further detail.
Embodiment 1-8:
A kind of Veterinary long-acting cefquinome sulfate injection, this injection of every 100mL is composed as follows:
Wherein the weight ratio of castor oil hydrogenated and soybean lecithin was respectively 2: 3,2: 5,2: 4 in the suspending agent of embodiment 1-3,4-6,7-8.
The preparation method step of the injection of above-described embodiment 1-8 is as follows:
(1) the Cefquinome sulfate crude drug is added in injection stage solvent or the double solvent, magnetic agitation makes it abundant mixing;
(2) suspending agent is added in 90-100 ℃ the solvent and dissolve;
(3) add in the suspension of the step (1) that is stirring after the lysate of step (2) being cooled to room temperature, stir;
(4) add again antibacterial and emulsifying dispersant to the suspension of step (3), fully stir;
(5) injection stage solvent or the double solvent of adding surplus, stirring and evenly mixing 30min, crossing rotating speed is the high speed shear dispersion machine 30min of 1500r/min, then cross colloid mill (rotating speed is 3500r/min) 4h, the 60Co-gamma-ray irradiation sterilization of 3KGY makes milky or light brown suspension product.
The performance test of each embodiment products obtained therefrom sees Table 1.
The performance test results of each embodiment products obtained therefrom of table 1
Annotate: accelerated test is to be 2 ℃ of temperature 40 scholars in condition, and relative humidity is to carry out under 65 scholars' 5% the condition.
Can find out that by above result embodiment 7 is optimised process, through microscopic examination (10 * 40 object lens), two ends are cylinder crystal, this suspension mean diameter is 8.52 μ m, settling ratio is 1.0, accelerated test after 3 months content significant change is not arranged, stable in properties still is the milky suspension.
The pharmacokinetic study of long-acting cefquinome sulfate injection of the present invention in the pig body
1 test material
1.1 key instrument equipment
The Agilent1100 high performance liquid chromatograph, U.S. Agilent company;
JY2002 type electronic balance, Shanghai City exact science Instr Ltd.;
BP211D type analysis balance, German Sartoraus company;
KQ-100B type ultrasonic washing unit, Kunshan Ultrasonic Instruments Co., Ltd.;
1.2 main medicine and reagent
Cefquinome standard substance (98.0%), Sigma company;
Long-acting cefquinome sulfate injection (5%) m/v, content: 102.45%, Wuhan Hvsen Biotechnology Co., Ltd.
Produce, by embodiment 7 preparations.
Cefquinome sulfate injection (2.5%) m/v, Intervet Internat B. V. produces.
One perchloric acid hydrate sodium: analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group;
1.3 laboratory animal
Experimental animal: 12 of the white bi-crossbreedings of healthy DABAI * length, body weight 25 ± 2kg is purchased from Hubei Jian Feng animal husbandry company limited innovation pig farm.
Feedstuff: duration of test is raised routinely, freely drinks water and searches for food, and feedstuff is not for containing the adequate diet of antibacterials.
1.4 main solution preparation
Cefquinome standard stock solution (200 μ g/mL): accurately take by weighing the 20.4mg standard substance in the 100mL volumetric flask, with dissolve with methanol and standardize solution, save backup at-20 ℃.
Cefquinome standard operation liquid: pipette respectively an amount of standard reserving solution and make an addition in the 100mL volumetric flask, dilute standardize solution with tri-distilled water, be mixed with the standard operation liquid of 0.05,0.1,0.5,2,5,10,20 μ g/mL, 4 ℃ of preservations.
1.5 chromatograph testing conditions
Mobile phase: get a perchloric acid hydrate sodium 3.45g and be dissolved in the 1000mL water, add phosphoric acid 12mL and acetonitrile 90mL, regulate pH to 3.6 with triethylamine;
Chromatographic column: Sapphire C18 (4.6 * 250mm, 5 μ m);
Detect wavelength: 270nm; Flow velocity: 1mL/min; Column temperature: 30 ℃; Sample size: 20 μ L.
1.6 experimental animal grouping, administration and blood specimen collection
1.6.1 laboratory animal grouping and administration
Experimental animal is divided into two groups at random, 6 every group, first group of intramuscular injection 2.5% cefquinome sulfate injection administration group (Intervet company product), second group of intramuscular injection 5% long-acting cefquinome sulfate injection (embodiment 7 preparations).The administering mode of intramuscular injection is the disposable injection cefquinome sulfate injection of cervical region intramuscular.Before the administration every pig is weighed, through prerun, absorb in vivo, distribute and eliminate rule and determine the sampling time point according to medicine, with 5mg/kg body weight dosage cervical region intramuscular injection 2.5% cefquinome sulfate injection and 5% long-acting cefquinome sulfate injection.
1.6.2 blood specimen collection
Pig Baoding of lying on the back, take a blood sample from vena cava anterior, every pig gathers respectively the primary blank blood sample before the administration, respectively every pig is taken a blood sample in different time points after the administration, wherein, administration animal blood taking time point be 0.13,0.25,0.5,1,2,4,5,6,8,12,24,48,72,96,120,144,168h.Each about 5mL of blood sampling volume, gather complete after immediately immigration be added with in the centrifuge tube of anticoagulant, the centrifugal 15min separated plasma of 1500r/min places-20 ℃ of Refrigerator stores, and is to be determined.
1.7 plasma sample pre-treatment
Accurately draw plasma sample 2mL, place 15mL tool plug plastic centrifuge tube, add the extraction of 7mL dichloromethane, vortex 1min; The centrifugal 20min of 10000r/min gets supernatant and carries out the SPE purification.Bond Elut C18 solid phase extraction column is respectively with methanol 3mL, water 3mL activation, the sample upper prop, 5% methanol aqueous solution 3mL drip washing, after draining with the vacuum solid-phase extraction device, methanol 3mL eluting is collected eluent, and 35 ℃ of nitrogen dry up to 0.2mL, with 0.5mL tri-distilled water standardize solution, get 20 μ L behind the centrifugal 10min of 9000r/min and carry out the HPLC detection.
1.8 Criterion curve
Each the 20 μ L of standard operation solution that get respectively concentration and be 0.05,0.1,0.5,2,5,10,20 μ g/mL advance HPLC and analyze.Take concentration as abscissa, peak area is vertical coordinate drawing standard curve, and obtains regression equation and correlation coefficient.
1.9 methodology checking
1.9.1 sensitivity (determining of detectability and quantitative limit)
Lowest detectable limit: the sample introduction medication amount during the three times of signal to noise ratios (S/N) that can measure take instrument is as lowest detectable limit, and the concentration of corresponding medicine in biological sample is its minimal detectable concentration.
Minimum quantitative limit: the sample introduction medication amount during ten times of signal to noise ratios can measuring take instrument is as minimum quantitative limit.
1.9.2 the investigation of the response rate and the coefficient of variation
The cefquinome standard stock solution of high, medium and low three concentration is added in the blank porcine blood plasma, abundant mixing is respectively the blood plasma of 5.0,1.0 and 0.05 μ g/mL to obtain cefquinome, process by the plasma sample pre-treating method, carrying out HPLC detects, each concentration arranges 5 duplicate samples, measures 5 times in the 1d, to investigate a day within variance coefficient, connect repetition measurement in the 5d fixed 5 times, every day 1 time, investigating the in the daytime coefficient of variation, and the absolute recovery of investigation method.
1.9.3 data analysis
Use the statistics such as Excel, 3p97 pharmacokinetics software and pharmacokinetics software that test data is analyzed.
2 result of the tests
2.1 the coefficient of variation and the response rate
Add the response rate and the coefficient of variation of cefquinome in the table 2 pig blank plasma and investigate result (n=5)
2.2 blood drug level-time data in the blood plasma
After the long-acting cefquinome injection of embodiment 7 and the administration of Intervet cefquinome sulfate injection in the blood plasma concentration-time curve of cefquinome see accompanying drawing 1, the cefquinome sulfate injection of long-acting slow-release preparation of the present invention and Intervet is compared and is had the long half-life as we know from the figure, the effective blood drug concentration prolongation of holding time.
2.3 pharmacokinetic data analysis
Behind the long-acting cefquinome sulfate injection and Intervet cefquinome sulfate injection to the pig difference intramuscular injection embodiment of the invention 7, pharmacokinetic parameter sees Table 3.Through the compartment model analysis, two kinds of its blood drug level-time datas of preparation all meet one-level and absorb two compartment model.
The pharmacokinetic parameter of two kinds of preparations of table 3
Claims (1)
1. a Veterinary long-acting cefquinome sulfate injection is characterized in that, this injection of every 100mL is composed as follows:
Cefquinome sulfate: 5g,
Suspending agent: 0.35g,
Chlorobutanol: 0.4g,
Arlacel-60: 0.3g,
Solvent: to 100mL;
The described suspending agent mixture that to be castor oil hydrogenated and soybean lecithin form with the weight ratio of 2:4;
Described solvent is the double solvent of triacetyl glycerine and 20mL Macrogol 200;
The step of the preparation method of described Veterinary long-acting cefquinome sulfate injection is as follows:
(1) the Cefquinome sulfate crude drug is added in the double solvent, magnetic agitation makes it abundant mixing;
(2) suspending agent is added in 90-100 ℃ the solvent and dissolve;
(3) add in the suspension of the step (1) that is stirring after the lysate of step (2) being cooled to room temperature, stir;
(4) add again chlorobutanol and Arlacel-60 to the suspension of step (3), fully stir;
(5) double solvent of adding surplus, stirring and evenly mixing 30min, crossing rotating speed is the high speed shear dispersion machine 30min of 1500r/min, then crossing rotating speed is the colloid mill 4h of 3500r/min, the 60Co-gamma-ray irradiation sterilization of 3KGY makes milky or light brown suspension product.
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| CN104127382A (en) * | 2014-07-25 | 2014-11-05 | 重庆市畜牧科学院 | Emulsion cefquinome sulfate injection and preparation method thereof |
| CN104127419B (en) * | 2014-08-12 | 2016-09-28 | 中国药科大学 | A kind of stable Cefquinome sulfate oil suspension type injection |
| CN104473868A (en) * | 2014-12-01 | 2015-04-01 | 上海同仁药业有限公司 | Cefquinome sulfate suspension injection and preparation method thereof |
| CN104758245B (en) * | 2015-03-10 | 2017-07-21 | 河南牧翔动物药业有限公司 | A kind of Cefquinome sulfate oiliness suspension injection and preparation method thereof |
| CN105640881A (en) * | 2015-12-30 | 2016-06-08 | 中国药科大学 | Cefquinome sulfate muscle injection and preparation method thereof |
| CN106491532A (en) * | 2016-11-01 | 2017-03-15 | 四川美嘉龙生物科技有限公司 | A kind of cefquinome sulfate injection and preparation technology |
| CN107157927A (en) * | 2017-05-31 | 2017-09-15 | 合肥中龙神力动物药业有限公司 | Animal cefquinome sulfate injection and preparation method thereof |
| CN107334730B (en) * | 2017-06-30 | 2020-05-15 | 广东温氏大华农生物科技有限公司 | Cefquinome sulfate injection and low-temperature high-shear preparation method thereof |
| CN110559264A (en) * | 2019-09-24 | 2019-12-13 | 李会芳 | Composition for preparing cefquinome drug sensitive tablets |
| CN113209014A (en) * | 2020-01-21 | 2021-08-06 | 江西邦诚动物药业有限公司 | Long-acting cefquinome sulfate suspension injection and preparation process thereof |
| CN111714501A (en) * | 2020-07-03 | 2020-09-29 | 杭州爱力迈动物药业有限公司 | Method for improving dissolution rate of cefquinome sulfate and dissolution rate detection method thereof |
| CN112156011A (en) * | 2020-08-19 | 2021-01-01 | 四川爱邦伟业生物工程有限责任公司 | Preparation method for producing cefquinome sulfate injection by using emulsification stirring tank and colloid mill in combined manner |
| CN117982413A (en) * | 2024-04-03 | 2024-05-07 | 山东恒邦中科生物工程有限公司 | Preparation method of cefquinome sulfate injection |
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Address after: 430042 Hubei province Dongxihu District of Wuhan City Road No. 208 Zhang Patentee after: Wuhan Sheng Sheng biological Polytron Technologies Inc Address before: 430042 Hubei province Dongxihu District of Wuhan City Road No. 208 Zhang Patentee before: Wuhan Hvsen Biotechnology Co., Ltd. |