CN101401787A

CN101401787A - Ceftiofur long-acting injection and preparation method thereof

Info

Publication number: CN101401787A
Application number: CNA200810226889XA
Authority: CN
Inventors: 肖希龙; 汤树生; 肖俊
Original assignee: Individual
Current assignee: BEIJING ZHONGNONGDA ANIMAL HEALTH-CARE PRODUCT TECHNOLOGY RESEARCH INSTITUTE
Priority date: 2008-11-19
Filing date: 2008-11-19
Publication date: 2009-04-08
Anticipated expiration: 2028-11-19
Also published as: CN101401787B

Abstract

The invention discloses a ceftiofur long-acting injection and a method for preparing the same. The ceftiofur long-acting injection is a suspension injection containing ceftiofur hydrochloride, and the main compositions of the solvent system of the drug are vegetable oil for injection and grease. The preparation process of the ceftiofur long-acting injection has simple operation, and the prepared suspension injection meets the requirements and has obvious long-acting effect after intramuscular injection, so that the therapeutic effect of the drug is improved and the disadvantages that a respiratory disease has a long course and needs multiple administrations in treatment are overcome, and the waste of human resources in a farm caused by frequent administrations and the animal stress reaction caused by multiple administrations are reduced, thus the ceftiofur long-acting injection is a novel veterinary drug preparation with long-acting effect on respiratory diseases of livestock and poultry, and has very high popularization and application value.

Description

A kind of ceftiofur long-acting injection and preparation method thereof

Technical field

The invention belongs to the animal drug field, what be specifically related to is a kind of improvement preparation and preparation method thereof of cephalo-type antibiotics-ceftiofur of veterinary's special use.

Background technology

(Ceftiofur is the third generation cephalo-type antibiotics of veterinary's special use CEF) to ceftiofur, is the cephalosporins of first animal specific.The has a broad antifungal spectrum of ceftiofur, antibacterial activity is strong, and gram positive bacteria, gram negative bacteria and some anaerobe are all had extremely strong antibacterial activity; And have stable beta-lactam nucleus, good killing effect is also arranged, be difficult for producing Resistant strain and cross resistance, be mainly used in the responsive microbial various infection of multiple animal clinically for the various antibacterials that can produce beta-lactamase.Therefore, application ceftiofur treatment livestock and poultry is significant.

Along with the raising of various countries' animal husbandry intensification, scale, mechanization degree, clinical application has also become a comparatively cumbersome job gradually, and especially some courses of disease are than long disease, and more clinical treatment has brought inconvenience.Therefore, the development durative action preparation has become the urgent needs of clinical treatment work.In recent years, the incidence rate of respiratory tract disease is unprecedented soaring, and medium-and-large-sized scale animal farm is faced with the puzzlement of serious respiratory tract disease.The characteristics of livestock and birds respiratory disease are that sickness rate height, the course of disease are long, the healing difficulty is big at present, the existing conventional medicine generally needed to cure in successive administration 5-7 days, and cure rate is often not high, the disease that causes respiratory tract disease to become having a strong impact on the livestock and poultry cultivation economic benefit at present and hinder the key factor of animal husbandry development.

Therefore, if can develop and a kind of livestock and birds respiratory disease is had the novel veterinary drug preparation of long-acting, not only can reduce the medication number of times, reduce the drawback of frequent drug administration, improve the compliance of animal, save the man power and material, and can also the long period keep excellent curative.

Research to the prolonged drug effect, 03146062.X provided a solution, form by the cephalosporin sodium salt or the potassium salt of good water solubility and cephalosporin free acid or esters cephalosporin with slightly water-soluble of slow releasing function, thereby adjust the slow release of realizing a certain component release time of medicine by the different solubility of different pharmaceutical component with quick-acting effects.But because the deficiency of preparation technology aspect, the 03146062.X scheme still exists drug treating time short (3 days), poor stability and clinical manipulation inconvenience shortcomings such as (the prepared injection of example can not be used for intramuscular injection).Therefore, improve, prepare safer and more effective and make things convenient for the long-acting ceftiofur injection of administration, the treatment of current very popular livestock and birds respiratory disease is had more practical significance by preparation process.

Summary of the invention

The purpose of this invention is to provide a kind of preparation method of ceftiofur long-acting injection and a kind of safe and efficient and medication ceftiofur long-acting injection easily.

For achieving the above object, the present invention takes following design:

A kind of preparation method of ceftiofur long-acting injection, make gel macromolecular compound dicyandiamide solution by injection grease and suspending agent impalpable powder, the aseptic micropowder that will contain Ceftiofur Hydrochloride again adds, and lasting stirring obtains ceftiofur long-acting suspension injection preparation.

Specifically may further comprise the steps:

1) Ceftiofur Hydrochloride aseptic powder and antioxidant are obtained aseptic micropowder of Ceftiofur Hydrochloride and the aseptic micropowder of antioxidant through micronizing respectively;

2) preparation suspending agent impalpable powder;

3) with behind the injection grease high temperature sterilize, place under the room temperature standby;

4) in step 3) gained sterilization injection grease, add step 2) gained suspending agent impalpable powder, heating is also stirred, and makes transparent gel macromolecular compound dicyandiamide solution, places under the room temperature standby then in sterilizing room;

5) the gel macromolecular compound dicyandiamide solution that step 4) is obtained is poured the sterilizing room colloid mill into, add the aseptic micropowder of Ceftiofur Hydrochloride, the aseptic micropowder of antioxidant and local analgesic that step 1) obtains while stirring, (time is 60-120 minute to treat it fully to mix back continuation stirring, be preferably 90 minutes), obtain the ceftiofur long-acting suspension injection.

In the above preparation method, described aseptic grain size of micropowder is less than 25 microns; Described suspending agent impalpable powder is crossed the above medicine sieve of 120 orders.

Wherein: described injection grease is a kind of in a kind of and/or glyceryl monostearate, diacetine, glyceryl triacetate in injection soybean oil, Oleum Gossypii semen, the Oleum Ricini, preferred injection soybean oil or glyceryl triacetate or both mixture; Injection grease high temperature sterilize temperature is 150-160 ℃, and the time is 2-3 hour.

Wherein: gel macromolecular compound dicyandiamide solution accounts for 60～90% of preparation cumulative volume, and aseptic micropowder accounts for 10～40% of preparation cumulative volume.

Described suspending agent is selected from one or both the mixture in aluminum foil stearate, polyvinylpyrrolidone and the castor oil hydrogenated; The weight/volume percent concentration of suspending agent impalpable powder is 1-3% in the described gel macromolecular compound dicyandiamide solution, is preferably 1-2%.

Described antioxidant is selected from one or both the mixture in propyl gallate, alpha-tocopherol and the thiourea; Described local analgesia agent is selected from a kind of in benzyl alcohol, chlorobutanol, lidocaine hydrochloride and salt thereof, tetracaine and salt thereof, procaine and the salt thereof.

The ceftiofur long-acting injection for preparing in order to the top method also is a summary of the invention of the present invention, and it is a suspension injection.

The weight/volume percent concentration of Ceftiofur Hydrochloride is 5-30% in the suspension injection, is preferably 5-10%.

Comprise in the auxiliary elements such as antioxidant and local analgesic one or more in the suspension injection.Antioxidant weight/volume percent concentration in preparation is 0.01-5%, is preferably 0.5-3%; The weight/volume percent concentration of local analgesia agent in preparation is 0-3%, is preferably 0.5-1%.

Ceftiofur long-acting injection single administration of the present invention (intramuscular injection) 5mg/kg dosage can be kept effective blood drug concentration 5.5 days, clinical consumption is generally the 5-7mg/kg body weight, disposable intramuscular injection can be cured various bacterial respiratory tract diseases, and serious case can be injected once at 5-7 days again.

The syringeability of the ceftiofur suspension injection that the present invention obtains is good, diameter of aspirin particle is evenly distributed, less than 0.1% (standard is less than 10%), the granule of particle size distribution in the 7-15 mu m range accounts for more than 75% of sum to particle diameter, can satisfy the requirement of suspension injection greater than the granule number of 15 μ m.

Pharmacokinetics test result (concrete data are seen test 2) shows, pig interior medicine dynamics process shows as one compartment open model behind the intravenous injection ceftiofur standard substance, the Ceftiofur Hydrochloride suspension injection (EXCENEL that pig intramuscular injection long-acting ceftiofur hydrochloride suspension injection of the present invention and Pfizer produce ) after pharmaco-kinetic processes all show as two Room open models of absorption, with the Ceftiofur Hydrochloride suspension injection EXCENEL of Pfizer

Pharmacokinetic parameter compare, the blood peak concentration of drug value of long-acting ceftiofur hydrochloride suspension injection of the present invention is than the EXCENEL of Pfizer

Significantly descend, and eliminate the half-life and obviously prolong, meet the pharmacokinetics law of durative action preparation.Therefore, the long-acting suspension injection of Ceftiofur Hydrochloride of the present invention has tangible long-acting, being used for the treatment of the animal breath tract disease and having clear superiority, is that minimal effective concentration is calculated with 0.2 μ g/mL, and single administration 5mg/kg dosage can be kept effective blood drug concentration in 5.5 days.This injection is to utilize the method delay to discharge with delayed absorption, adopt injection Semen sojae atricolor wet goods vegetable oil or grease and additives to form gel in the preparation process, form the gel skeleton thing with gel macromolecular compound form, make the oil solution of medicine, the aseptic micropowder of fine Ceftiofur Hydrochloride is scattered in the gel macromolecular compound dicyandiamide solution, thereby delay the diffusion and the stripping of medicine, with prolong drug effective acting time (having the good slow release effect), raising is good medicines of the current respiratory tract infectious disease of treatment to the therapeutic effect of various sensitive organism associated diseases.

The suspension injection that the present invention obtains meets the requirements, after intramuscular injection, has tangible long-acting, both improved the therapeutic effect of medicine, it is long to have overcome the respiratory tract disease course of disease, treatment needs the shortcoming of multiple dosing, reduced the plant's waste of manpower resource that causes because of frequent drug administration again and the animal stress that causes because of multiple dosing (reduced the medication number of times, reduce the drawback of frequent drug administration, improve the compliance of animal, save the man power and material, and can also the long period keep excellent curative), be a kind of livestock and birds respiratory disease to be had the novel veterinary drug preparation of long-acting, have high application value.

Below in conjunction with specific embodiment the present invention is described in further details.

Description of drawings

Fig. 1 for pig injection ceftiofur after (5mg/kg) plasma drug level-time graph

The specific embodiment

Method therefor is conventional method if no special instructions among the following embodiment.

Described percent concentration is mass/volume (W/V) percent concentration or volume/volume (V/V) percent concentration if no special instructions.

Target of the present invention is to obtain a kind of ceftiofur long-acting injection.The medicinal ingredient of this injection is a Ceftiofur Hydrochloride, the dicyandiamide solution of medicine is mainly vegetable oil or grease, form gel with additives, form the gel skeleton thing with gel macromolecular compound form, the aseptic micropowder of fine Ceftiofur Hydrochloride is scattered in the gel macromolecular compound dicyandiamide solution makes suspension injection with long-acting.Wherein: gel macromolecular compound dicyandiamide solution accounts for 60～90% of preparation cumulative volume, and aseptic micropowder accounts for 10～40% of preparation cumulative volume.In preparation process:

Can add antioxidant in the medicine Ceftiofur Hydrochloride, obtain particle diameter less than 25 microns aseptic micropowder through micronizing respectively; Antioxidant is selected from one or both the mixture in propyl gallate, alpha-tocopherol and the thiourea, and antioxidant weight/volume percent concentration in preparation is 0.01-5%, is preferably 0.5-3%.

Dicyandiamide solution is made transparent gel macromolecular compound dicyandiamide solution by injection grease and suspending agent impalpable powder.What wherein the injection grease can be in a kind of and/or glyceryl monostearate in injection soybean oil, Oleum Gossypii semen, the Oleum Ricini, diacetine, the glyceryl triacetate is a kind of, preferred injection soybean oil or glyceryl triacetate or both mixture; Need high temperature sterilize before the injection grease uses, temperature is 150-160 ℃, and the time is 2-3 hour; Suspending agent is selected from one or both the mixture in aluminum foil stearate impalpable powder, polyvinylpyrrolidone and the castor oil hydrogenated; The weight/volume percent concentration of suspending agent impalpable powder is 1-3% in the dicyandiamide solution, is preferably 1-2%.

Can add the local analgesia agent in the suspension injection.The local analgesia agent is selected from a kind of in benzyl alcohol, chlorobutanol, lidocaine hydrochloride and salt thereof, tetracaine and salt thereof, procaine and the salt thereof, and the weight/volume percent concentration of local analgesia agent in preparation is 0-3%, is preferably 0.5-1%.

Among the present invention, gel macromolecular compound dicyandiamide solution, the aseptic micropowder of Ceftiofur Hydrochloride, the aseptic micropowder of antioxidant and local analgesic also need fully to mix just in colloid mill to obtain the ceftiofur long-acting suspension injection.

Below will the present invention will be described in detail by specific embodiment, agents useful for same and apparatus are all commercial in the test, optical microscope is used in the diameter of aspirin particle morphologic observation, the microscope micrometer is used in particle diameter and measure of spread, the medicament contg of injection adopts high performance liquid chromatography-uv detection method, to be good linear relevant with chromatographic peak area in 5-100 μ g/mL scope for medicament contg, and its linear equation is: Y=179.74X-3331.7, R=0.9999.

The preparation of embodiment 1, ceftiofur long-acting injection

Prepare ceftiofur long-acting injection with method of the present invention, concrete grammar may further comprise the steps:

1) gets Ceftiofur Hydrochloride aseptic powder, antioxidant (alpha-tocopherol), obtain particle diameter less than the aseptic micropowder of 25 microns Ceftiofur Hydrochloride, the aseptic micropowder of alpha-tocopherol with super micron mill through micronizing between the sterile working;

2) get suspending agent (aluminium stearate), cross 120 order medicines sieve, obtain the aluminium stearate impalpable powder;

3) with the injection soybean oil behind 150-160 degree centigrade of following high temperature sterilize 2 hours (2-3 hour all can), place under the room temperature standby;

4) adding step 2 in the injection soybean oil 900mL of step 3)) the aluminium stearate impalpable powder 10g that obtains through sterilizing, 300-500 degree centigrade of heating and stirring down, make transparent gel macromolecular compound dicyandiamide solution, in sterilizing room, place under the room temperature standby then;

5) the gel macromolecular compound dicyandiamide solution that step 4) is obtained is poured the sterilizing room colloid mill into, add the aseptic micropowder 50g of Ceftiofur Hydrochloride (having amounted to into pure medicine), the aseptic micropowder 30g of alpha-tocopherol and local analgesic-benzyl alcohol 5-10g that step 1) obtains while stirring, treat that it fully mixes the back and continue to stir 90 minutes (60-120 minute all can), after packing, filling conventional treatment such as nitrogen, sealing, promptly get this routine ceftiofur long-acting suspension injection again.

With reference to " People's Republic of China's veterinary drug allusion quotation suspension injection standard ", appearance character to this long-acting ceftiofur suspension injection, particle size, the settling volume ratio, again dispersibility, projects such as consistence test detect, appearance character as a result, again distributed test, every index such as consistence test all meets the requirements, settling volume than (standard is more than 90%, promptly requires 1 hour settling volume less than 10%) near 100%, the even particle size distribution of preparation, mean diameter is 8.63 μ m, less than 0.1% (standard is 10%), the granule of particle size distribution in the 7-15 mu m range accounts for more than 75% of sum to particle diameter greater than the granule number of 15 μ m, and medicament contg is 98.6% of a dosage.

The preparation of embodiment 2, ceftiofur long-acting injection

4) adding step 2 in the injection soybean oil 900mL of step 3)) the aluminium stearate impalpable powder 15g that obtains through sterilizing, 300-500 degree centigrade of heating and stirring down, make transparent gel macromolecular compound dicyandiamide solution, in sterilizing room, place under the room temperature standby then;

5) the gel macromolecular compound dicyandiamide solution that step 4) is obtained is poured the sterilizing room colloid mill into, add the aseptic micropowder 50g of Ceftiofur Hydrochloride (having amounted to into pure medicine), the aseptic micropowder 30g of alpha-tocopherol and local analgesic-chlorobutanol 5-10g that step 1) obtains while stirring, treat that it fully mixes the back and continue to stir 90 minutes (60-120 minute all can), after packing, filling conventional treatment such as nitrogen, sealing, promptly get standard compliant ceftiofur long-acting suspension injection again.

Appearance character to this long-acting ceftiofur suspension injection, particle size, the settling volume ratio, again distributed test, projects such as consistence test detect, appearance character as a result, again distributed test, every index such as consistence test all meets the requirements, and settling volume compares near 100%, the even particle size distribution of preparation, mean diameter is 8.47 μ m, less than 0.1%, the granule of particle size distribution in the 7-15 mu m range accounts for more than 75% of sum to particle diameter greater than the granule number of 15 μ m, and medicament contg is 99.3% of a dosage.

The preparation of embodiment 3, ceftiofur long-acting injection

2) get suspending agent (polyvinylpyrrolidone), cross 120 order medicines sieve and obtain the polyvinylpyrrolidone impalpable powder;

3) with the injection glyceryl triacetate behind 150-160 degree centigrade of following high temperature sterilize 2 hours (2-3 hour all can), place under the room temperature standby;

4) adding step 2 in the injection glyceryl triacetate 900mL of step 3)) the polyvinylpyrrolidone impalpable powder 20g that obtains through sterilizing, 300-500 degree centigrade of heating and stirring down, make transparent gel macromolecular compound dicyandiamide solution, in sterilizing room, place under the room temperature standby then;

5) the gel macromolecular compound dicyandiamide solution that step 4) is obtained is poured the sterilizing room colloid mill into, add the aseptic micropowder 50g of Ceftiofur Hydrochloride (having amounted to into pure medicine), the aseptic micropowder 30g of alpha-tocopherol and local analgesic-lidocaine hydrochloride 5-10g that step 1) obtains while stirring, treat that it fully mixes the back and continue to stir 90 minutes (60-120 minute all can), after packing, filling conventional treatment such as nitrogen, sealing, promptly get standard compliant ceftiofur long-acting suspension injection again.

To the appearance character of this long-acting ceftiofur suspension injection, particle size, settling volume ratio, again distributed test, projects such as consistence test detect, as a result appearance character, the settling volume ratio, again distributed test, every index such as consistence test all meets the requirements, the even particle size distribution of preparation, mean diameter is 8.34 μ m, less than 0.1%, the granule of particle size distribution in the 7-15 mu m range accounts for more than 75% of sum to particle diameter greater than the granule number of 15 μ m, and medicament contg is 99.2% of a dosage.

The preparation of embodiment 4, ceftiofur long-acting injection

2) get and mix at 1: 1 by weight after suspending agent-aluminium stearate and polyvinylpyrrolidone are crossed 120 order medicines sieves, obtain the suspending agent impalpable powder;

3) with the injection Oleum Gossypii semen behind 150-160 degree centigrade of following high temperature sterilize 2 hours (2-3 hour all can), place under the room temperature standby;

4) adding step 2 in the injection Oleum Gossypii semen 900mL of step 3)) aluminium stearate and the polyvinylpyrrolidone impalpable powder 25g that obtains through sterilizing, 300-500 degree centigrade of heating and stirring down, make transparent gel macromolecular compound dicyandiamide solution, in sterilizing room, place under the room temperature standby then;

5) the gel macromolecular compound dicyandiamide solution that step 4) is obtained is poured the sterilizing room colloid mill into, add the aseptic micropowder 50g of Ceftiofur Hydrochloride (having amounted to into pure medicine), the aseptic micropowder 20g of alpha-tocopherol and local analgesic-tetracaine 5-10g that step 1) obtains while stirring, treat that it fully mixes the back and continue to stir 90 minutes (60-120 minute all can), after packing, filling conventional treatment such as nitrogen, sealing, promptly get standard compliant ceftiofur long-acting suspension injection again.

To the appearance character of this long-acting ceftiofur suspension injection, particle size, settling volume ratio, again distributed test, projects such as consistence test detect, as a result appearance character, the settling volume ratio, again distributed test, every index such as consistence test all meets the requirements, the even particle size distribution of preparation, mean diameter is 8.51 μ m, less than 0.1%, the granule of particle size distribution in the 7-15 mu m range accounts for more than 75% of sum to particle diameter greater than the granule number of 15 μ m, and medicament contg is 98.7% of a dosage.

The preparation of embodiment 5, ceftiofur long-acting injection

1) gets Ceftiofur Hydrochloride aseptic powder, antioxidant-alpha-tocopherol and thiourea (by weight mix at 1: 1), obtain particle diameter less than the aseptic micropowder of 25 microns Ceftiofur Hydrochloride, the aseptic micropowder of alpha-tocopherol with super micron mill through micronizing between the sterile working;

2) get suspending agent (castor oil hydrogenated), cross 120 order medicines sieve, obtain the castor oil hydrogenated impalpable powder;

4) adding step 2 in the injection soybean oil 900mL of step 3)) the castor oil hydrogenated impalpable powder 30g that obtains through sterilizing, 300-500 degree centigrade of heating and stirring down, make transparent gel macromolecular compound dicyandiamide solution, in sterilizing room, place under the room temperature standby then;

5) the gel macromolecular compound dicyandiamide solution that step 4) is obtained is poured the sterilizing room colloid mill into, add the aseptic micropowder 50g of Ceftiofur Hydrochloride (having amounted to into pure medicine), alpha-tocopherol and the aseptic micropowder 30g of thiourea and local analgesic-procaine 5-10g that step 1) obtains while stirring, treat that it fully mixes the back and continue to stir 90 minutes (60-120 minute all can), after packing, filling conventional treatment such as nitrogen, sealing, promptly get standard compliant ceftiofur long-acting suspension injection again.

To the appearance character of this long-acting ceftiofur suspension injection, particle size, settling volume ratio, again distributed test, projects such as consistence test detect, as a result appearance character, the settling volume ratio, again distributed test, every index such as consistence test all meets the requirements, the even particle size distribution of preparation, mean diameter is 8.23 μ m, less than 0.1%, the granule of particle size distribution in the 7-15 mu m range accounts for more than 75% of sum to particle diameter greater than the granule number of 15 μ m, and medicament contg is 98.9% of a dosage.

The preparation of embodiment 6, ceftiofur long-acting injection

1) gets Ceftiofur Hydrochloride aseptic powder, antioxidant-alpha-tocopherol and propyl gallate (by weight mix at 1: 1), obtain particle diameter less than the aseptic micropowder of 25 microns Ceftiofur Hydrochloride, alpha-tocopherol and the aseptic micropowder of propyl gallate with super micron mill through micronizing between the sterile working;

2) get suspending agent-aluminium stearate, cross 120 order medicines sieve, obtain the aluminium stearate impalpable powder;

4) adding step 2 in the injection glyceryl triacetate 900mL of step 3)) the aluminium stearate impalpable powder 15g that obtains through sterilizing, 300-500 degree centigrade of heating and stirring down, make transparent gel macromolecular compound dicyandiamide solution, in sterilizing room, place under the room temperature standby then;

5) the gel macromolecular compound dicyandiamide solution that step 4) is obtained is poured the sterilizing room colloid mill into, add the aseptic micropowder 100g of Ceftiofur Hydrochloride (having amounted to into pure medicine), alpha-tocopherol and the aseptic micropowder 30g of propyl gallate and local analgesic-benzyl alcohol 5-10g that step 1) obtains while stirring, treat that it fully mixes the back and continue to stir 90 minutes (60-120 minute all can), after packing, filling conventional treatment such as nitrogen, sealing, promptly get standard compliant ceftiofur long-acting suspension injection again.

To the appearance character of this long-acting ceftiofur suspension injection, particle size, settling volume ratio, again distributed test, projects such as consistence test detect, as a result appearance character, the settling volume ratio, again distributed test, every index such as consistence test all meets the requirements, the even particle size distribution of preparation, mean diameter is 8.41 μ m, less than 0.1%, the granule of particle size distribution in the 7-15 mu m range accounts for more than 75% of sum to particle diameter greater than the granule number of 15 μ m, and medicament contg is 99.4% of a dosage.

The preparation of embodiment 7, ceftiofur long-acting injection

1) gets Ceftiofur Hydrochloride aseptic powder, antioxidant-thiourea, obtain particle diameter less than the aseptic micropowder of 25 microns Ceftiofur Hydrochloride, the aseptic micropowder of alpha-tocopherol with super micron mill through micronizing between the sterile working;

2) get suspending agent-polyvinylpyrrolidone, cross 120 order medicines sieve, obtain the polyvinylpyrrolidone impalpable powder;

3) with the injection Oleum Ricini behind 150-160 degree centigrade of following high temperature sterilize 2 hours (2-3 hour all can), place under the room temperature standby;

4) adding step 2 in the injection Oleum Ricini 750mL of step 3)) the polyvinylpyrrolidone impalpable powder 15g that obtains through sterilizing, 300-500 degree centigrade of heating and stirring down, make transparent gel macromolecular compound dicyandiamide solution, in sterilizing room, place under the room temperature standby then;

5) the gel macromolecular compound dicyandiamide solution that step 4) is obtained is poured the sterilizing room colloid mill into, add the aseptic micropowder 200g of Ceftiofur Hydrochloride (having amounted to into pure medicine), the aseptic micropowder 30g of thiourea and local analgesic-chlorobutanol 5-10g that step 1) obtains while stirring, treat that it fully mixes the back and continue to stir 90 minutes (60-120 minute all can), after packing, filling conventional treatment such as nitrogen, sealing, promptly get standard compliant ceftiofur long-acting suspension injection again.

To the appearance character of this long-acting ceftiofur suspension injection, particle size, settling volume ratio, again distributed test, projects such as consistence test detect, as a result appearance character, the settling volume ratio, again distributed test, every index such as consistence test all meets the requirements, the even particle size distribution of preparation, mean diameter is 8.36 μ m, less than 0.1%, the granule of particle size distribution in the 7-15 mu m range accounts for more than 75% of sum to particle diameter greater than the granule number of 15 μ m, and medicament contg is 99.1% of a dosage.

The preparation of embodiment 8, ceftiofur long-acting injection

3) with the injection diacetine behind 150-160 degree centigrade of following high temperature sterilize 2 hours (2-3 hour all can), place under the room temperature standby;

4) adding step 2 in the injection diacetine 650mL of step 3)) the aluminium stearate impalpable powder 15g that obtains through sterilizing, 300-500 degree centigrade of heating and stirring down, make transparent gel macromolecular compound dicyandiamide solution, in sterilizing room, place under the room temperature standby then;

5) the gel macromolecular compound dicyandiamide solution that step 4) is obtained is poured the sterilizing room colloid mill into, add the aseptic micropowder 300g of Ceftiofur Hydrochloride (having amounted to into pure medicine), the aseptic micropowder 30g of thiourea and local analgesic-lidocaine hydrochloride 5-10g that step 1) obtains while stirring, treat that it fully mixes the back and continue to stir 90 minutes (60-120 minute all can) again after packing, filling conventional treatment such as nitrogen, sealing, promptly gets standard compliant ceftiofur long-acting suspension injection.

To the appearance character of this long-acting ceftiofur suspension injection, particle size, settling volume ratio, again distributed test, projects such as consistence test detect, as a result appearance character, the settling volume ratio, again distributed test, every index such as consistence test all meets the requirements, the even particle size distribution of preparation, mean diameter is 8.57 μ m, less than 0.1%, the granule of particle size distribution in the 7-15 mu m range accounts for more than 75% of sum to particle diameter greater than the granule number of 15 μ m, and medicament contg is 98.8% of a dosage.

The preparation of embodiment 9, ceftiofur long-acting injection

1) gets Ceftiofur Hydrochloride aseptic powder, antioxidant-propyl gallate, obtain particle diameter less than the aseptic micropowder of 25 microns Ceftiofur Hydrochloride, the aseptic micropowder of propyl gallate with super micron mill through micronizing between the sterile working;

2) get suspending agent-castor oil hydrogenated, cross 120 order medicines sieve, obtain the castor oil hydrogenated impalpable powder;

4) adding step 2 in the injection glyceryl triacetate 800mL of step 3)) the castor oil hydrogenated impalpable powder 15g that obtains through sterilizing, 300-500 degree centigrade of heating and stirring down, make transparent gel macromolecular compound dicyandiamide solution, in sterilizing room, place under the room temperature standby then;

5) the gel macromolecular compound dicyandiamide solution that step 4) is obtained is poured the sterilizing room colloid mill into, add the aseptic micropowder 100g of Ceftiofur Hydrochloride (having amounted to into pure medicine), the aseptic micropowder 30g of propyl gallate and local analgesic-tetracaine 5-10g that step 1) obtains while stirring, treat that it fully mixes the back and continue to stir 90 minutes (60-120 minute all can), after packing, filling conventional treatment such as nitrogen, sealing, promptly get standard compliant ceftiofur long-acting suspension injection again.

To the appearance character of this long-acting ceftiofur suspension injection, particle size, settling volume ratio, again distributed test, projects such as consistence test detect, as a result appearance character, the settling volume ratio, again distributed test, every index such as consistence test all meets the requirements, the even particle size distribution of preparation, mean diameter is 8.49 μ m, less than 0.1%, the granule of particle size distribution in the 7-15 mu m range accounts for more than 75% of sum to particle diameter greater than the granule number of 15 μ m, and medicament contg is 99.2% of a dosage.

The preparation of embodiment 10, ceftiofur long-acting injection

3) with injection soybean oil and glyceryl triacetate (mixing at 1: 1) behind 150-160 degree centigrade of following high temperature sterilize 2 hours (2-3 hour all can), place under the room temperature standby;

4) in the injection soybean oil of sterilization and glyceryl triacetate 750mL, add step 2 to step 3)) the castor oil hydrogenated impalpable powder 15g that obtains, 300-500 degree centigrade of heating and stirring down, make transparent gel macromolecular compound dicyandiamide solution, in sterilizing room, place under the room temperature standby then;

5) the gel macromolecular compound dicyandiamide solution that step 4) is obtained is poured the sterilizing room colloid mill into, add the aseptic micropowder 100g of Ceftiofur Hydrochloride (having amounted to into pure medicine), the aseptic micropowder 30g of propyl gallate and local analgesic-procaine 5-10g that step 1) obtains while stirring, treat that it fully mixes the back and continue to stir 90 minutes (60-120 minute all can), after packing, filling conventional treatment such as nitrogen, sealing, promptly get standard compliant ceftiofur long-acting suspension injection again.

To the appearance character of this long-acting ceftiofur suspension injection, particle size, settling volume ratio, again distributed test, projects such as consistence test detect, as a result appearance character, the settling volume ratio, again distributed test, every index such as consistence test all meets the requirements, the even particle size distribution of preparation, mean diameter is 8.25 μ m, less than 0.1%, the granule of particle size distribution in the 7-15 mu m range accounts for more than 75% of sum to particle diameter greater than the granule number of 15 μ m, and medicament contg is 98.7% of a dosage.

The preparation of embodiment 11, ceftiofur long-acting injection

3) with the injection glyceryl monostearate behind 150-160 degree centigrade of following high temperature sterilize 2 hours (2-3 hour all can), place under the room temperature standby;

4) adding step 2 in the injection glyceryl monostearate 850mL of step 3)) the polyvinylpyrrolidone impalpable powder 15g that obtains through sterilizing, 300-600 degree centigrade of heating and stirring down, make transparent gel macromolecular compound dicyandiamide solution, in sterilizing room, place under the room temperature standby then;

5) the gel macromolecular compound dicyandiamide solution that step 4) is obtained is poured the sterilizing room colloid mill into, add the aseptic micropowder 100g of Ceftiofur Hydrochloride (having amounted to into pure medicine), the aseptic micropowder 50g of propyl gallate and local analgesic-benzyl alcohol 5-10g that step 1) obtains while stirring, treat that it fully mixes the back and continue to stir 90 minutes (60-120 minute all can), after packing, filling conventional treatment such as nitrogen, sealing, promptly get standard compliant ceftiofur long-acting suspension injection again.

To the appearance character of this long-acting ceftiofur suspension injection, particle size, settling volume ratio, again distributed test, projects such as consistence test detect, as a result appearance character, the settling volume ratio, again distributed test, every index such as consistence test all meets the requirements, the even particle size distribution of preparation, mean diameter is 8.38 μ m, less than 0.1%, the granule of particle size distribution in the 7-15 mu m range accounts for more than 75% of sum to particle diameter greater than the granule number of 15 μ m, and medicament contg is 99.1% of a dosage.

Experiment 1: ceftiofur long-acting injection local excitation test

For guaranteeing the safety of ceftiofur long-acting suspension injection, with the long-acting suspension injection of embodiment 2 gained Ceftiofur Hydrochlorides is sample, regulation according to " local excitation test requirement specification ", carried out the local excitation test of intramuscular injection and two kinds of route of administration of subcutaneous injection, after understanding injection gained ceftiofur long-acting suspension injection of the present invention, whether produce the local irritation reaction, determine suitable clinical safe administration approach.Concrete test method comprises as follows:

One, test material

1, is subjected to the reagent product: 5% long-acting ceftiofur hydrochloride suspension injection (embodiment 2 systems).

2, experimental animal: 36 of random choose healthy adult new zealand white rabbits, body weight 2.06 ± 0.13kg, male and female half and half.

3, feedstuff: rabbit standard granule feedstuff, free choice feeding.Fed before the administration for 1 week, conform.

Two, test method

1, EXPERIMENTAL DESIGN: 36 healthy adult new zealand white rabbits are divided into 6 processed group at random, 6 every group, male and female half and half.With the White Rabbit of 3 processed group wherein long-acting ceftiofur hydrochloride suspension injection of intramuscular injection recommended dose 1 multiple dose (5mg/kg), 2 multiple doses (10mg/kg) and 5 multiple doses (25mg/kg) respectively, the White Rabbit of other 3 processed group is the long-acting ceftiofur hydrochloride suspension injection of subcutaneous injection recommended dose 1 multiple dose, 2 multiple doses and 5 multiple doses respectively, and whether injection post-evaluation White Rabbit injection site produces the local irritation reaction.

2, administration: test the preceding healthy adult new zealand white rabbit that was used for intramuscular injection in 24 hours in the rabbit hair that cuts off quadriceps femoris position, both sides with Shearing shears, be used for hypodermic white rabbit and cut off both sides, the back rabbit hair, the reuse knife blade scrapes off undercoat.With iodine tincture and ethanol disinfection, the intramuscular injection irritant test injects medicine at the right lateral thigh musculus quadriceps to healthy rabbit earlier during test, injects isopyknic sterile saline at the left side quadriceps femoris simultaneously and compares; Subcutaneous irritant test is subcutaneous injection medicine at the back, right side, and back, the left side isopyknic sterile saline of subcutaneous injection compares.

3, sampling: reaction and situation of change that the every interval 6h in injection back observes a skin surface.White Rabbit injects air execution by ear vein behind the 48h, cuts skin of back and quadriceps femoris open, observes the response situation of injection site, determines the order of reaction by the standards of grading of table 1; And the medicinal liquid absorbing state of observing the injection site, check whether injection site produces irritative responses such as hyperemia, edema, scleroma, degeneration or necrosis, gets injection site tissue in case of necessity and does pathological section, and observation there is NIP.

Table 1 irritant reaction standards of grading

Three, result of the test

All be in a good state of health in the 48h behind high, medium and low three groups of new zealand white rabbit subcutaneous injections and the intramuscular injection gained ceftiofur long-acting of the present invention suspension injection, movable normal, also no abnormality seen reaction of skin surface, irritant reaction sum of series matched group equally is 0 grade, and the medicinal liquid of its injection site absorbs good, and injection site does not also have irritative response phenomenons such as hyperemia, edema, scleroma, degeneration or necrosis.Result of the test shows that the gained ceftiofur long-acting suspension injection of the present invention of intramuscular injection and the high, medium and low dosage of subcutaneous injection all has no stimulation to new zealand white rabbit.

By this description of test, ceftiofur long-acting suspension injection of the present invention intramuscular injection and subcutaneous injection under recommended dose all have safety preferably, also make things convenient for administration.And similar suspension injection (for example 03146062.X introduce) can only subcutaneous injection and can not intramuscular injection, and safety is relatively poor, and route of administration is restricted.

Experiment 2: ceftiofur long-acting injection is at the intravital pharmacokinetics test of pig

Long-acting for checking ceftiofur long-acting suspension injection of the present invention, with the long-acting suspension injection sample of embodiment 2 gained Ceftiofur Hydrochlorides is that example is carried out intramuscular injection, carried out the intravital pharmacokinetic study of pig, and the Ceftiofur Hydrochloride suspension injection (EXCENEL that produces with Pfizer

) compare research, carried out the intravenous pharmacokinetic study of Ceftiofur Hydrochloride standard substance simultaneously, long-acting, the bioavailability of ceftiofur long-acting suspension injection of the present invention are carried out overall merit, concrete test method comprises as follows:

One, test material

1, main agents and medicine

The former powder of Ceftiofur Hydrochloride (the grand for a long time Fine Chemical Co., Ltd in Shandong); Ceftiofur standard substance (China Veterinery Drug Inspection Office); Remove furanylcarbonyl ceftiofur (DFC) standard substance (Sigma company); Dithioerythritol (Sigma company); Highly effective liquid phase chromatographic system (day island proper Tianjin); 5% long-acting ceftiofur hydrochloride suspension injection (embodiment 2 systems); Ceftiofur Hydrochloride suspension injection (the EXCENEL of 5% Pfizer Inc.

) buy by market.

2, the preparation of solution

Standard reserving solution (500 μ g/mL): remove furanylcarbonyl ceftiofur standard substance 5mg and be dissolved in an amount of methanol, be mixed with the standard reserving solution of the 10mL of 500 μ g/mL.At-20 ℃, under the lucifuge condition, the standard stock solution can be stablized preservation 1 month.

Standard is added solution (10 μ g/mL): take out standard reserving solution (500 μ g/mL) and be back to room temperature from refrigerator, get standard reserving solution 0.2mL in volumetric flask, add the dilution of 0.1M ammonium acetate solution and be settled to 10mL.At-20 ℃, under the lucifuge condition, the standard annex solution can be stablized 1 week of preservation.

Standard operation liquid: the 10 μ g/mL that get 50,100,200,400,800,1000 μ L respectively go furanylcarbonyl ceftiofur standard stock solution in the 10mL volumetric flask; be settled to scale with the 0.1M ammonium acetate, obtain concentration successively and be 50,100,200,400,800, the standard operation liquid of 1000ng/mL.

Drug plasma extracting solution: take by weighing 19g sodium borate and 3.7g sodium chloride, add the suitable quantity of water dissolving, dilution is settled to 1000mL, be mixed with borate buffer solution (pH 9), and then take by weighing in an amount of dithioerythritol adding borate buffer solution (pH 9), being made into concentration is the drug plasma extracting solution of 0.4% (W/V).

HPLC mobile phase: take by weighing an amount of ammonium acetate dilute with water and be settled to 0.01M, be mixed with mobile phase with methanol by the mixed of 76: 24 (V/V) then, the degassing is the filtering with microporous membrane of 0.22 μ m with the aperture after handling.

3, key instrument equipment

High performance liquid chromatograph (containing LC-10AT vp pump, DGU-12A degassing equipment, SPD-M10A vp Ultraviolet Detector, Class-VP5.03 work station, Japanese Shimadzu); TDL-40B centrifuge (Anting Scientific Instrument Factory, Shanghai); GM-0.33II vacuum diaphragm pump (Tianjin rise filter element factory); WH-1 whirling motion blender (Shanghai Hu Xi analytical tool factory); CX-100 ultrasonic cleaner (Beijing armarium two factories).

4, experimental animal

Select 15 of the long Large Whites of healthy hybridization, 70 ages in days, body weight 20.2-23.6kg.Raising is freely drunk water in the clean animal room, feeds not contain the adequate diet of antibacterials, and timing every day feed once.Raised for 1 week before the administration, to conform.

Two, test method

1, administration

Experimental animal is divided into three groups at random, every group 5, the first group of disposable injection Ceftiofur Hydrochloride of auricular vein standard substance, second group of intramuscular injection salt manufacturing acid of the present invention ceftiofur long-acting suspension injection (5%), the EXCENEL of the 3rd group of intramuscular injection Pfizer Inc. (5%), the dosage of three treated animals is 5mg/kg, and wherein the administering mode of intramuscular injection is the disposable injection Cefliofur injection of back leg muscle.

2, sample collecting

0.083,0.167,0.25,0.5,0.75,1,2,3,4,8,12,24,48,72 hour vena cava anterior blood sampling 10mL after (0h) and the administration before the pig administration respectively behind the intravenous injection ceftiofur standard substance, the EXCENEL of intramuscular injection salt manufacturing acid ceftiofur long-acting suspension injection of the present invention and Pfizer Inc.

After respectively before the pig administration after (0h) and the administration 0.13,0.25,0.5,1,2,4,6,8,12,24,48,72,96,120,144,168,192,216 and 240h vena cava anterior blood sampling 10mL, institute's blood sampling after all room temperature leaves standstill 2h in the test tube that contains the anticoagulant heparin sodium 2500rpm centrifugal, get upper plasma ,-20 ℃ of preservations.

3, blood sample is handled

Draw blood plasma 0.5mL in 50mL tool plug centrifuge tube, add the 7mL extracting solution, whirling motion 1min; 50 ℃ of water-bath 15min, during water-bath every 3min whirling motion 10s.After placing room temperature extracting solution is transferred on the activatory 30mgHLB pillar, regulate flow velocity to 1 droplet/second, use 2.0mL methanol: water (5: 95) washing, use 2.0mL acetic acid: acetonitrile (5: 95) eluting, 35 ℃ of nitrogen blow to 0.2mL, be settled to 0.5mL with the 0.1M Spirit of Mindererus., advance HPLC mensuration with getting 100 μ L behind the organic membrane filtration of 0.2 μ m.

4, the drafting of standard curve

Get concentration respectively and be 50,100,200,400,800, each 100 μ l of 1000ng/mL standard operation solution advance HPLC and analyze.With concentration is abscissa, and peak area is a vertical coordinate drawing standard curve.

5, the response rate and precision test

Get the blank plasma sample respectively; add the furanylcarbonyl ceftiofur standard of going of certain volume and add solution; making sample Chinese medicine concentration is 0.1 μ g/mL, 0.5 μ g/mL, 2 μ g/mL; handling back HPLC respectively by above-mentioned sample-pretreating method measures; each concentration is got 4 parallel sample in one day; measure calculate recovery rate and day within variance coefficient respectively.

6, chromatographic condition

UV-detector; Column temperature: room temperature; Chromatographic column: Symstry

C18 (5 μ m, 4.6mm * 150mm i.d.); Detect wavelength: 266nm; Mobile phase is the 0.01mol/L liquor ammonii acetatis: methanol (76: 24); Flow velocity is 0.5mL/min; Sample size: 100 μ L.

7, date processing

The 3P97 pharmacokinetics software that blood drug level after the three treated animal administrations-time data adopts the establishment of mathematics major committee of Chinese Pharmacological Society to medicine-time data handle; To the significance of difference of the main pharmacokinetic parameter of the ceftiofur suspension injection of homemade and Pfizer, test with the T testing procedure of SPSS 12.0 statistical softwares.

Three, result of the test

1, the response rate of drug plasma detection method of content and precision

The drug plasma content assaying method is the good linear relation with peak area in drug level is 0.05-5 μ g/mL scope, its linear equation is: Y=9.8782X+519.22, R=0.999.Detectability and quantitative limit are respectively 0.05 and 0.16 μ g/mL.When medicine added level at 0.1-2 μ g/mL, average recovery rate was 75.2-89.7%, and the coefficient of variation is 4.8-6.9% (seeing table 2 for details).

The furanylcarbonyl ceftiofur response rate (n=4) is gone in the interpolation of table 2 porcine blood plasma

2, medicine-time data

The drug level that the different time points blood sampling records behind the intravenous injection ceftiofur standard substance sees Table 3; The drug level that the different time points blood sampling records behind the intramuscular injection self-control long-acting ceftiofur hydrochloride suspension injection sees Table 4; The drug level that the different time points blood sampling records behind the Ceftiofur Hydrochloride suspension injection of intramuscular injection Pfizer Inc. sees Table 5.

Plasma drug level (μ g/mL) behind the table 3 intravenous injection ceftiofur standard substance

ND does not detect (not detectable)

Plasma drug level behind the table 4 intramuscular injection long-acting ceftiofur suspension injection of the present invention (μ g/mL)

ND does not detect (not detectable)

The table 5 intramuscular injection EXCENEL of Pfizer

After plasma drug level (μ g/mL)

ND does not detect (not detectable)

3. pharmacokinetic parameter

According to data in table 3, table 4 and the table 5, with the 3P97 pharmacokinetics software of mathematics major committee of Chinese Pharmacological Society establishment use one, two respectively, the three-compartment model match, through the F check, according to goodness of fit value, AIC and R ²Carrying out model judges, the result shows that the body giving drugs into nose behind the Ceftiofur Hydrochloride suspension injection of pig intramuscular injection self-control long-acting ceftiofur hydrochloride suspension injection and Pfizer all shows as two Room open models of absorption for dynamic process, pig body giving drugs into nose shows as one compartment open model for dynamic process behind the intravenous injection ceftiofur standard substance, and its main pharmacokinetic parameter sees Table 6 and table 7 respectively.

Main pharmacokinetic parameter (n=5) behind the table 6 intramuscular injection ceftiofur suspension injection

The main pharmacokinetic parameter (n=5) of table 7 intravenous injection ceftiofur standard substance

4, the long-acting of preparation detects

The development target of durative action preparation is to make medicine enter slowly absorption and release of back in the body by the reasonable preparation of suitable formulations carrier and additives and ideal preparation process, thereby blood Chinese medicine peak concentration is reduced and prolong persistent period of effective blood drug concentration, the concrete manifestation of relative medicine kinetic parameter should be that blood medicine peak time is slower, blood medicine peak value is lower, it is longer to eliminate the half-life.From table 6 and Fig. 1 as can be seen, the EXCENEL of long-acting suspension injection of Ceftiofur Hydrochloride of the present invention and Pfizer

Pharmacokinetic parameter compare, slower 1.5 times of the blood drug level peaking time of ceftiofur long-acting suspension injection of the present invention, the highest blood drug level is low 2.34 times, eliminate the half-life and prolonged 1.65 times.Therefore, the pharmacokinetic parameter of the prepared ceftiofur suspension injection of the present invention meets the pharmacokinetics law of durative action preparation, and blood drug level is higher than (T＞0.2 of holding time of 3 times of minimum inhibitory concentrations (0.06 μ g/mL), be the persistent period that blood drug level is higher than 0.2 μ g/mL) prolonged 1.55 times, show that the prepared ceftiofur suspension injection of the present invention has obvious long-acting, with the disposable intramuscular injection of 5mg/kg dosage, effective blood drug concentration can be kept 135.36 hours (about 5.5 days).This time also will be grown than 3 days the effective drug duration of long-acting suspension injection that 03146062.X introduces.

Claims

1, a kind of preparation method of ceftiofur long-acting injection, the gel macromolecular compound dicyandiamide solution of making by injection grease and suspending agent impalpable powder, the aseptic micropowder that will contain Ceftiofur Hydrochloride again adds, and lasting stirring obtains the ceftiofur long-acting suspension injection.

2, preparation method according to claim 1 is characterized in that: specifically may further comprise the steps:

2) preparation suspending agent impalpable powder;

4) adding step 2 in the sterilization injection grease of step 3) gained) the suspending agent impalpable powder of gained, heating is also stirred, and makes transparent gel macromolecular compound dicyandiamide solution, places under the room temperature standby then in sterilizing room;

5) the gel macromolecular compound dicyandiamide solution that step 4) is obtained is poured the sterilizing room colloid mill into, add the aseptic micropowder of Ceftiofur Hydrochloride, the aseptic micropowder of antioxidant and local analgesic that step 1) obtains while stirring, treat that it fully mixes the back and continues to stir, and obtains the ceftiofur long-acting suspension injection.

3, preparation method according to claim 1 and 2 is characterized in that: described aseptic grain size of micropowder is less than 25 microns; Described suspending agent impalpable powder is crossed the above medicine sieve of 120 orders.

4, preparation method according to claim 1 and 2, it is characterized in that: described injection grease is a kind of in a kind of and/or glyceryl monostearate, diacetine, glyceryl triacetate in injection soybean oil, Oleum Gossypii semen, the Oleum Ricini, preferred injection soybean oil or glyceryl triacetate or both mixture; Injection grease high temperature sterilize temperature is 150-160 ℃, and the time is 2-3 hour.

5, preparation method according to claim 1 is characterized in that: gel macromolecular compound dicyandiamide solution accounts for 60～90% of preparation cumulative volume, and aseptic micropowder accounts for 10～40% of preparation cumulative volume.

6, preparation method according to claim 1 is characterized in that: described suspending agent is selected from one or both the mixture in aluminum foil stearate, polyvinylpyrrolidone and the castor oil hydrogenated; The weight/volume percent concentration of suspending agent impalpable powder is 1-3% in the described gel macromolecular compound dicyandiamide solution.

7, preparation method according to claim 2 is characterized in that: described antioxidant is selected from one or both the mixture in propyl gallate, alpha-tocopherol and the thiourea; Described local analgesia agent is selected from a kind of in benzyl alcohol, chlorobutanol, lidocaine hydrochloride and salt thereof, tetracaine and salt thereof, procaine and the salt thereof.

8, ceftiofur long-acting injection is the suspension injection for preparing in order to the described method of last arbitrary claim.

9, ceftiofur long-acting injection according to claim 8 is characterized in that: the weight/volume percent concentration of Ceftiofur Hydrochloride described in the preparation is 5-30%.

10, ceftiofur long-acting injection according to claim 9 is characterized in that: antioxidant weight/volume percent concentration in preparation is 0.01-5%; The weight/volume percent concentration of local analgesia agent in preparation is 0-3%.