CN114869850B - Cefquinome sulfate injection - Google Patents
Cefquinome sulfate injection Download PDFInfo
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Abstract
The invention discloses cefquinome sulfate injection, and belongs to the technical field of veterinary preparations. According to the invention, the modified tea oil carrier is used for coating the cefquinome sulfate by emulsification and electrostatic deposition, so that the Oswald ripening effect in the emulsification and subsequent preservation processes is inhibited. The carrier has strong dispersibility, good oxidation resistance and good anti-sedimentation performance, and can obtain good comprehensive effect without adding additional dispersing agents, suspending agents and antioxidants. After the medicine-carrying modified tea oil carrier is injected into an animal body, the medicine-carrying modified tea oil carrier is firstly distributed into body fluid through diffusion of a dispersion medium, then the carrier drives and releases cefquinome sulfate through salt dissolution, and the cefquinome sulfate can reach an affected part along with the circulation of the body fluid, so that a corresponding treatment effect can be obtained.
Description
Technical Field
The invention relates to the technical field of veterinary preparations, in particular to a cefquinome sulfate injection.
Background
Cefquinome sulfate is a fourth generation cephalosporin antibiotic special for animals and is an off-white to pale yellow crystalline powder insoluble in water. The bactericidal effect is achieved by inhibiting the synthesis of cell walls, and the bactericidal composition has broad-spectrum antibacterial activity. Pig is used as target animal, and after cefquinome sulfate is injected into pig body for 0.4 hr, blood concentration reaches peak value, and elimination half-life period is about 1.4 hr, so that it has the features of fast metabolism and short effective concentration maintaining time.
Chinese patent CN112691108A provides a cefquinome sulfate injection and a preparation method thereof, which uses cefquinome sulfate as a main bactericidal and antiviral drug, and adopts hypericin, sulbactam, trimethoprim and clavulanate potassium as synergists, so that the antibacterial spectrum of the whole injection can be enhanced, and the drug effect and cure rate can be enhanced. The invention adopts low temperature high shearing, reduces the viscosity of injection and enhances the stability. Because the viscosity of the ethyl oleate is low, the oily suspension injection is compatible and easy to deposit due to solid dispersion, and a large amount of suspending agent is required to be added to keep the suspension performance of the injection, so that the requirement on the preservation environment is high.
The cefquinome sulfate is combined with a carrier mechanism, and the release of the cefquinome sulfate is controlled through the slow release of the carrier, so that the administration times of the cefquinome sulfate can be reduced, and the time for playing the drug effect can be prolonged. Chinese patent CN103751103A discloses a long-acting cefquinome sulfate injection and a preparation method thereof, wherein the cefquinome sulfate is coated by a slow-release matrix, a medicament is dispersed in a poorly soluble ethylcellulose and a slow-release carrier in a molecular state, the release speed is regulated by combining with water-soluble hydroxypropyl cellulose, and the medicament is dissolved out and needs to be diffused outwards through a network structure of the carrier to enter an oily medium and redistributed into body fluid, so that the medicament is slowly released, the acting time of the medicament is prolonged, and the slow-release effect is achieved. However, as the drug is gradually dissolved out, the volume of the drug-carrying carrier particles is reduced, but the volume of the insoluble ethylcellulose is hardly changed, so that the progress of Ostwald ripening is aggravated, and small-volume drug-carrying particles can be more easily adsorbed on the surface of the ethylcellulose, thereby causing the technical problem of uneven drug release.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, the present invention aims to provide a cefquinome sulfate injection with good prevention and treatment effects on porcine respiratory diseases.
The formation of a coating layer on the surface of droplets of an emulsion by electrostatic deposition is a common means of preparing carriers. The emulsified droplets are smaller, have high surface energy, and are easy to deposit on large droplets with low surface energy, so that the Oswald ripening effect is enhanced. The emulsion flocculates, so that the liquid becomes large, the volume of the carrier formed by electrostatic deposition is large, and the dispersion is difficult.
In order to solve the technical problems, the invention uses tea oil and cefquinome sulfate to form oil phase dispersion liquid, and uses propolis extract, beta-lactoglobulin, sphingomyelin and D- (+) -melezitose hydrate as raw materials to prepare water phase mixed liquid; the solid particles in the aqueous phase mixed solution have the characteristics of thickening, gel, surface activity and the like, and in the process of preparing the emulsion by mixing the solid particles, a compound formed by combining the solid particles forms a net structure, the internal phase of the emulsion is uniformly distributed in the continuous phase, and the accumulation of liquid drops can be effectively prevented by adsorption at an oil-water interface, so that the aggregation of small liquid drops to form large liquid drops is prevented. In addition, solid particles form a compact particle layer at the interface of liquid drops through electrostatic deposition, so that the liquid drops can be effectively prevented from coalescing, and the prepared emulsion has higher stability.
The cefquinome sulfate injection comprises the following raw materials in percentage by mass: 1.5 to 2.5 weight percent of cefquinome sulfate, 2.5 to 5 weight percent of modified tea oil carrier and the balance of dispersion medium.
Preferably, the dispersion medium is any one of ethyl oleate, soybean oil for injection and tea oil for injection.
Preferably, the preparation method of the modified tea oil carrier comprises the following steps of:
m1, mixing 2-4 parts of propolis with 8-16 parts of absolute ethyl alcohol at normal temperature to obtain an ethanol solution of the propolis; centrifuging the ethanol solution of propolis to obtain supernatant, filtering the supernatant to remove insoluble impurities, concentrating, and freeze drying to obtain propolis extract;
m2, mixing 1 to 1.5 parts of the propolis extract and 0.6 to 1.2 parts of beta-lactoglobulin with 500 to 1000 parts of water at normal temperature; adjusting the pH value of the mixture to 11-12 by using sodium hydroxide aqueous solution, then cooling to normal temperature after heating treatment, adjusting the pH value of the mixture to neutrality by using hydrochloric acid, filtering to remove insoluble impurities, and freeze-drying to obtain a powdery mixture for later use;
m3, mixing 0.5-1 part of the powdery mixture, 0.125-0.25 part of sphingomyelin, 0.375-0.75 part of D- (+) -melezitose hydrate with 5-10 parts of water to obtain a water phase mixed solution; and (3) stirring and mixing 1.5-3 parts of tea oil and the water phase mixed solution at normal temperature, homogenizing to obtain tea oil emulsion, and freeze-drying the tea oil emulsion to obtain the modified tea oil carrier.
Preferably, the centrifugation speed of the centrifugation operation in the step M1 is 8000-10000 rpm, and the treatment time is 10-15 min.
Preferably, the temperature of the heating treatment in the step M2 is 70-80 ℃ and the treatment time is 15-30 min.
Preferably, the concentration of the aqueous sodium hydroxide solution in the step M2 is 1-1.5 mol/L, and the concentration of the hydrochloric acid is 1-1.5 mol/L.
Preferably, in the filtration operation described in steps M1 and M2, the filter membranes are each independently 80 to 100. Mu.m.
Preferably, the stirring operation in step M3 is carried out at a speed of 240 to 480rpm and for a treatment time of 0.5 to 2 hours.
Preferably, the rate of the homogenization treatment in the step M3 is 12000-18000 rpm, and the treatment time is 3-5 min.
The complex formed by the propolis extract, the beta-lactoglobulin, the sphingomyelin and the D- (+) -melezitose hydrate has good flexibility and certain deformability, and the complex is wrapped on the surface of the oil phase liquid drop to ensure that the liquid drop has good ductility. When the emulsion is mechanically homogenized, the complex is absorbed onto the oil droplet surface, forming a stable emulsion; the compound is dispersed in the continuous phase, and by increasing the viscosity of the liquid drops, a three-dimensional network structure is formed, the anti-sedimentation capability of the liquid drops is enhanced, and flocculation and coalescence among the liquid drops are inhibited. The medicine-carrying modified tea oil carrier obtained through freeze drying has small particles and irregular surfaces and has a smoother porous microstructure. After the carrier and the dispersion medium are mixed, the influence of factors such as gravity is small, and the sedimentation of particles can be prevented under the condition that a suspending agent is not additionally added; the surface of the carrier prepared by electrostatic deposition has the same charge or is electrically neutral, the mutual attraction between particles is reduced, and the coating of the outer layer of the carrier on the inner oil phase further isolates the fusion between emulsion droplets, so that the Oswald ripening is inhibited, and a good dispersing effect can be obtained without adding a dispersing agent.
A preparation method of cefquinome sulfate injection comprises the following steps:
s1, mixing propolis with absolute ethyl alcohol at normal temperature to obtain an ethanol solution of the propolis; centrifuging the ethanol solution of propolis to obtain supernatant, filtering the supernatant to remove insoluble impurities, concentrating, and freeze drying to obtain propolis extract;
s2, mixing the propolis extract and beta-lactoglobulin with water at normal temperature; adjusting the pH value of the mixture to 11-12 by using sodium hydroxide aqueous solution, then cooling to normal temperature after heating treatment, adjusting the pH value of the mixture to neutrality by using hydrochloric acid, filtering to remove insoluble impurities, and freeze-drying to obtain a powdery mixture for later use;
s3, mixing the cefquinome sulfate with tea oil, and performing ultrasonic treatment to obtain a cefquinome sulfate dispersion; mixing the powder mixture, sphingomyelin, D- (+) -melezitose hydrate and water to obtain water phase mixed solution for standby;
s4, stirring and mixing the cefquinome sulfate dispersion liquid and the water phase mixed liquid at normal temperature, homogenizing to obtain a medicine-carrying emulsion, and freeze-drying the medicine-carrying emulsion to obtain a medicine-carrying modified tea oil carrier for later use;
and S5, stirring and dispersing the medicine-carrying modified tea oil carrier and a dispersing medium to obtain the cefquinome sulfate injection.
Specifically, the preparation method of the cefquinome sulfate injection comprises the following steps of:
s1, mixing 2-4 parts of propolis with 8-16 parts of absolute ethyl alcohol at normal temperature to obtain an ethanol solution of the propolis; centrifuging the ethanol solution of propolis to obtain supernatant, filtering the supernatant to remove insoluble impurities, concentrating, and freeze drying to obtain propolis extract;
s2, mixing 1 to 1.5 parts of the propolis extract and 0.6 to 1.2 parts of beta-lactoglobulin with 500 to 1000 parts of water at normal temperature; adjusting the pH value of the mixture to 11-12 by using sodium hydroxide aqueous solution, then cooling to normal temperature after heating treatment, adjusting the pH value of the mixture to neutrality by using hydrochloric acid, filtering to remove insoluble impurities, and freeze-drying to obtain a powdery mixture for later use;
s3, mixing 1.5-2.5 parts of cefquinome sulfate with 1.5-3 parts of tea oil, and performing ultrasonic treatment to obtain a cefquinome sulfate dispersion; mixing 0.5-1 part of the powdery mixture, 0.125-0.25 part of sphingomyelin, 0.375-0.75 part of D- (+) -melezitose hydrate with 5-10 parts of water to obtain a water phase mixed solution for standby;
s4, stirring and mixing the cefquinome sulfate dispersion liquid and the water phase mixed liquid at normal temperature, homogenizing to obtain a medicine-carrying emulsion, and freeze-drying the medicine-carrying emulsion to obtain a medicine-carrying modified tea oil carrier for later use;
s5, stirring and dispersing 4-7.5 parts of the medicine-carrying modified tea oil carrier and 92.5-96 parts of dispersing medium to obtain the cefquinome sulfate injection.
Preferably, the centrifugation speed of the centrifugation operation in the step S1 is 8000-10000 rpm, and the treatment time is 10-15 min.
Preferably, the concentration of the aqueous sodium hydroxide solution in the step S2 is 1-1.5 mol/L, and the concentration of the hydrochloric acid is 1-1.5 mol/L.
Preferably, the temperature of the heating treatment in the step S2 is 70-80 ℃ and the treatment time is 15-30 min.
Preferably, in the filtering operation in the steps S1 and S2, the specification of the filter membrane is 80-100 μm independently.
Preferably, the frequency of the ultrasonic treatment in the step S3 is 28-40 kHz, the power is 550-800W, and the treatment time is 15-30 min.
Preferably, the stirring operation in step S4 is performed at a speed of 240 to 480rpm and for a treatment time of 0.5 to 2 hours.
Preferably, the rate of the homogenization treatment in step S4 is 12000-18000 rpm, and the treatment time is 3-5 min.
Preferably, the stirring operation in step S5 is performed at a speed of 4000 to 8000rpm and for a treatment time of 15 to 30 minutes.
The compound formed by propolis extract, beta-lactoglobulin, sphingomyelin and D- (+) -melezitose hydrate forms a thin and sparse interface film on the surface of tea oil drops, so that oxygen is prevented from entering the tea oil to cause oxidization; the propolis extract contains polyphenol and flavonoid besides polysaccharide, which is helpful for improving the oxidation resistance of the carrier, and can maintain the stability of the carrier without adding additional antioxidant.
After cefquinome sulfate injection is injected into an animal body, the medicine-carrying modified tea oil carrier is firstly distributed into body fluid through diffusion of a dispersion medium; the polysaccharide and protein on the surface of the carrier have rich hydrophilic sites and good binding capacity with body fluid. The biological fluid contains a small amount of neutral salt, the neutral salt enhances the electric charge on the surface of the beta-lactoglobulin molecules in the carrier, so that the effect of the beta-lactoglobulin molecules on water molecules is enhanced, the solubility of the beta-lactoglobulin is increased and the beta-lactoglobulin molecules are slowly dissolved in the biological fluid, the carrier is driven to release cefquinome sulfate, and the cefquinome sulfate can achieve a corresponding treatment effect along with the circulation of the biological fluid to an affected part.
On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the invention.
The invention has the following description and functions of partial raw materials in the formula:
cefquinome sulfate: the fourth generation cephalosporin products, besides the characteristics of the third generation cephalosporin, can rapidly penetrate through the outer membrane of gram negative bacteria, are stable to type I beta-lactamase around cytoplasm and have low affinity, have high affinity with Penicillin Binding Protein (PBP), and have several times stronger inherent antibacterial activity than the third generation cephalosporin.
Beta-lactoglobulin: one of the proteins in the fresh milk accounts for about 7-12% of the protein in the fresh milk.
The invention has the beneficial effects that:
compared with the prior art, the cefquinome sulfate is coated by using the modified tea oil carrier, the carrier has strong dispersibility and good anti-sedimentation performance, and a good dispersing effect can be obtained without adding additional dispersing agents and suspending agents.
Compared with the prior art, the compound formed by the propolis extract, the beta-lactoglobulin, the sphingomyelin and the D- (+) -melezitose hydrate forms a thin and sparse interface film on the surface of the tea oil drop, and prevents oxygen from entering the tea oil to cause oxidization. The propolis extract contains polyphenol and flavonoid besides polysaccharide, which is helpful for improving the oxidation resistance of the carrier, and can maintain the stability of the carrier without adding additional antioxidant.
Compared with the prior art, the carrier surface polysaccharide and protein have rich hydrophilic sites and good binding capacity with body fluid. After the salt in the body fluid enters the body fluid circulation, the electric charge on the surface of the beta-lactoglobulin molecules is enhanced, so that the effect of the beta-lactoglobulin molecules on water molecules is enhanced, the solubility of the beta-lactoglobulin is increased and the beta-lactoglobulin is slowly dissolved in the body fluid, and the carrier is driven to release cefquinome sulfate.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
The comparative example and the examples of the present invention have the following parameters of part of raw materials:
the purity of the pharmacopoeia propolis and black blocks is more than or equal to 95 percent, and the propolis is provided by the specialty Cooperation of bees in Daku city;
beta-lactoglobulin, the content is more than or equal to 98 percent, and the product number is: XAQN-443, available from SiAnqian Biotechnology Co., ltd;
sphingomyelin with purity not less than 98%, CAS number: 85187-10-6, available from Guangdong Weng Jiang chemical company, inc.;
d- (+) -melezitose hydrate, CAS no: 597-12-6, provided by Hubei cloud magnesium technologies Co., ltd;
the cp2020 edition pharmacopoeia tea oil for injection is provided by the company Limited for pharmaceutical excipients in the western Antian.
Example 1
The cefquinome sulfate injection is prepared by the following method:
s1, mixing 90g of beta-lactoglobulin with 50kg of water at normal temperature; adjusting the pH of the mixture to 12 by using sodium hydroxide aqueous solution, then cooling to normal temperature after heating treatment, adjusting the pH of the mixture to neutrality by using hydrochloric acid, filtering to remove insoluble impurities, and freeze-drying to obtain powdery treatment substance for later use;
s2, mixing 250g of cefquinome sulfate with 300g of tea oil, and performing ultrasonic treatment to obtain a cefquinome sulfate dispersion; mixing 100g of the powdery treatment substance, 25g of sphingomyelin, 75g D- (+) -melezitose hydrate and 500g of water to obtain an aqueous phase mixed solution for later use;
s3, stirring and mixing the cefquinome sulfate dispersion liquid and the water phase mixed liquid at normal temperature, homogenizing to obtain a medicine carrying emulsion, and freeze-drying the medicine carrying emulsion to obtain a medicine carrying modified tea oil carrier for later use;
and S4, stirring and dispersing 750g of the drug-loaded modified tea oil carrier and 9.25kg of ethyl oleate to obtain the cefquinome sulfate injection.
The temperature of the heating treatment in the step S1 is 75 ℃, and the treatment time is 30min.
The concentration of the sodium hydroxide aqueous solution in the step S1 is 1mol/L, and the concentration of the hydrochloric acid is 1mol/L.
In the filtration operation described in step S1, the size of the filter membrane was 80. Mu.m.
The ultrasonic treatment in the step S2 has the frequency of 40kHz, the power of 550W and the treatment time of 15min.
The stirring operation in step S3 was performed at a speed of 480rpm for a treatment time of 0.5h.
The rate of the homogenization treatment in step S4 was 12000rpm, and the treatment time was 5min.
The stirring operation in step S4 was performed at a rate of 4000rpm for a treatment time of 30 minutes.
Example 2
The cefquinome sulfate injection is prepared by the following method:
s1, mixing 200g of propolis with 800g of absolute ethyl alcohol at normal temperature to obtain an ethanol solution of the propolis; centrifuging the ethanol solution of propolis to obtain supernatant, filtering the supernatant to remove insoluble impurities, concentrating, and freeze drying to obtain propolis extract;
s2, mixing 250g of cefquinome sulfate with 300g of tea oil, and performing ultrasonic treatment to obtain a cefquinome sulfate dispersion; mixing 100g of propolis extract, 25g of sphingomyelin, 75g D- (+) -melezitose hydrate and 500g of water to obtain water phase mixed solution for later use;
s3, stirring and mixing the cefquinome sulfate dispersion liquid and the water phase mixed liquid at normal temperature, homogenizing to obtain a medicine carrying emulsion, and freeze-drying the medicine carrying emulsion to obtain a medicine carrying modified tea oil carrier for later use;
and S4, stirring and dispersing 750g of the drug-loaded modified tea oil carrier and 9.25kg of ethyl oleate to obtain the cefquinome sulfate injection.
The centrifugation speed of the centrifugation operation in step S1 was 8000rpm, and the treatment time was 15 minutes.
In the filtration operation described in step S1, the size of the filter membrane was 80. Mu.m.
The ultrasonic treatment in the step S2 has the frequency of 40kHz, the power of 550W and the treatment time of 15min.
The stirring operation in step S3 was performed at a speed of 480rpm for a treatment time of 0.5h.
The rate of the homogenization treatment in step S3 was 12000rpm, and the treatment time was 5min.
The stirring operation in step S4 was performed at a rate of 4000rpm for a treatment time of 30 minutes.
Example 3
The cefquinome sulfate injection is prepared by the following method:
s1, mixing 200g of propolis with 800g of absolute ethyl alcohol at normal temperature to obtain an ethanol solution of the propolis; centrifuging the ethanol solution of propolis to obtain supernatant, filtering the supernatant to remove insoluble impurities, concentrating, and freeze drying to obtain propolis extract;
s2, mixing 150g of the propolis extract and 90g of beta-lactoglobulin with 50kg of water at normal temperature; adjusting the pH of the mixture to 12 by using sodium hydroxide aqueous solution, then cooling to normal temperature after heating treatment, adjusting the pH of the mixture to neutrality by using hydrochloric acid, filtering to remove insoluble impurities, and freeze-drying to obtain a powdery mixture for later use;
s3, mixing 250g of cefquinome sulfate with 300g of tea oil, and performing ultrasonic treatment to obtain a cefquinome sulfate dispersion; mixing 100g of the powdery mixture, 25g of sphingomyelin, 75g D- (+) -melezitose hydrate and 500g of water to obtain an aqueous phase mixed solution for later use;
s4, stirring and mixing the cefquinome sulfate dispersion liquid and the water phase mixed liquid at normal temperature, homogenizing to obtain a medicine-carrying emulsion, and freeze-drying the medicine-carrying emulsion to obtain a medicine-carrying modified tea oil carrier for later use;
and S5, stirring and dispersing 750g of the drug-loaded modified tea oil carrier and 9.25kg of ethyl oleate to obtain the cefquinome sulfate injection.
The centrifugation speed of the centrifugation operation in step S1 was 8000rpm, and the treatment time was 15 minutes.
The temperature of the heating treatment in the step S2 is 75 ℃, and the treatment time is 30min.
The concentration of the sodium hydroxide aqueous solution in the step S2 is 1mol/L, and the concentration of the hydrochloric acid is 1mol/L.
In the filtration operations described in steps S1, S2, the filter membranes were each independently 80. Mu.m.
The ultrasonic treatment in the step S3 has the frequency of 40kHz, the power of 550W and the treatment time of 15min.
The stirring operation in step S4 was performed at a speed of 480rpm for a treatment time of 0.5h.
The rate of the homogenization treatment in step S4 was 12000rpm, and the treatment time was 5min.
The stirring operation in step S5 was performed at a rate of 4000rpm for a treatment time of 30 minutes.
Example 4
The cefquinome sulfate injection is prepared by the following method:
s1, mixing 200g of propolis with 800g of absolute ethyl alcohol at normal temperature to obtain an ethanol solution of the propolis; centrifuging the ethanol solution of propolis to obtain supernatant, filtering the supernatant to remove insoluble impurities, concentrating, and freeze drying to obtain propolis extract;
s2, mixing 150g of the propolis extract and 90g of beta-lactoglobulin with 50kg of water at normal temperature; adjusting the pH of the mixture to 12 by using sodium hydroxide aqueous solution, then cooling to normal temperature after heating treatment, adjusting the pH of the mixture to neutrality by using hydrochloric acid, filtering to remove insoluble impurities, and freeze-drying to obtain a powdery mixture for later use;
s3, mixing 250g of cefquinome sulfate with 300g of tea oil, and performing ultrasonic treatment to obtain a cefquinome sulfate dispersion; mixing 100g of the powdery mixture, 25g of sphingomyelin, 37.5g of D- (+) -melezitose hydrate and 500g of water to obtain a water phase mixed solution for later use;
s4, stirring and mixing the cefquinome sulfate dispersion liquid and the water phase mixed liquid at normal temperature, homogenizing to obtain a medicine-carrying emulsion, and freeze-drying the medicine-carrying emulsion to obtain a medicine-carrying modified tea oil carrier for later use;
and S5, stirring and dispersing 750g of the drug-loaded modified tea oil carrier and 9.25kg of ethyl oleate to obtain the cefquinome sulfate injection.
The centrifugation speed of the centrifugation operation in step S1 was 8000rpm, and the treatment time was 15 minutes.
The temperature of the heating treatment in the step S2 is 75 ℃, and the treatment time is 30min.
The concentration of the sodium hydroxide aqueous solution in the step S2 is 1mol/L, and the concentration of the hydrochloric acid is 1mol/L.
In the filtration operations described in steps S1, S2, the filter membranes were each independently 80. Mu.m.
The ultrasonic treatment in the step S3 has the frequency of 40kHz, the power of 550W and the treatment time of 15min.
The stirring operation in step S4 was performed at a speed of 480rpm for a treatment time of 0.5h.
The rate of the homogenization treatment in step S4 was 12000rpm, and the treatment time was 5min.
The stirring operation in step S5 was performed at a rate of 4000rpm for a treatment time of 30 minutes.
Comparative example 1
The cefquinome sulfate injection is prepared by the following method:
250g of cefquinome sulfate and 9.75kg of ethyl oleate are stirred and dispersed to obtain the cefquinome sulfate injection.
The stirring operation was carried out at a rate of 4000rpm for a treatment time of 30min.
Test example 1
The treatment of bacterial respiratory diseases by cefquinome sulfate injection is carried out by a specific method in the reference (Yue Yongdu, yang Fang, fan Xiaoping. Treatment test of bacterial respiratory diseases by cefquinome sulfate [ J ]. J.J.Chinese veterinarian journal, 2008, 44 (7): 45-47.DOI: 10.3969/j.issn.0529-6005.2008.07.024.). The bacterial pneumonia medical history of the pig farm is investigated, the dead growing pigs are subjected to section inspection, when typical pulmonary liver changes and cellulose pleuropneumonia are found, the pulmonary disease is taken for bacteriological separation identification, and when the pasteurella multocida and/or the actinobacillus pleuropneumoniae can be separated, the growing pigs with the disease symptoms of the pig farm are selected as experimental animals. Experimental pigs had the following symptoms: decreased appetite, cough and slight lassitude, elevated pig rectal temperature, etc. 120 ternary hybridization disease pigs with the age of 3-4 months are selected, and the weight of the ternary hybridization disease pigs is 30-50 kg. The same batch of infected growing pigs with the symptoms is divided into 6 groups, and 20 pigs in each group, namely examples 1-4, comparative example 1 and blank control group (natural infection is not dosed), and all pigs are fed under the same feeding condition, wherein the daily ration composition and the nutrition level are the same. The administration is intramuscular injection, and the dose is 2.5mg for every 1kg body weight, once daily for 3d, calculated by cefquinome sulfate. The experiment was continued for 21d, the mortality of each group of pigs was recorded, the weight of each pig was weighed at the beginning and end of the experiment, the weight gain of each group of surviving pigs was compared, and the relative weight gain was calculated as the ratio of the average weight gain of each drug group to the average weight gain of the blank group. The test results of the curative effect of cefquinome sulfate injection on the bacterial respiratory disease of pigs are shown in table 1.
TABLE 1
From the results in table 1, it can be seen that the cefquinome sulfate injection can effectively prevent and treat bacterial respiratory diseases of pigs, reduce mortality and increase weight gain of stock pigs. The recommended administration adopts intramuscular injection, one dose is calculated by cefquinome sulfate, 2.5mg is injected every 1kg body weight, and 3 days are used continuously, so that good treatment effect can be achieved on the bacterial respiratory diseases of pigs. The reason is probably that after cefquinome sulfate injection is injected into an animal body, the medicine-carrying modified tea oil carrier is firstly distributed into body fluid through diffusion of a dispersion medium, and polysaccharide and protein on the surface of the carrier have rich hydrophilic sites and good combination ability with the body fluid; the biological fluid contains a small amount of neutral salt, the neutral salt enhances the electric charge on the surface of the beta-lactoglobulin molecules in the carrier, so that the effect of the beta-lactoglobulin molecules is enhanced, the solubility of the beta-lactoglobulin molecules is increased and the beta-lactoglobulin molecules are slowly dissolved in the biological fluid, the carrier is driven to release cefquinome sulfate, the duration of the drug effect is prolonged, and compared with comparative example 1, better treatment effect is achieved in each embodiment.
Test example 2
In the process of preparing cefquinome sulfate injection in examples 1-3, the prepared medicine-carrying modified tea oil carrier is additionally taken for oxidation resistance test. The obtained medicine-carrying modified tea oil carrier accelerates the oxidation for 7d at 60 ℃. In the oxidation process of tea oil loaded in a carrier, primary oxidation products are unstable, and secondary oxidation products are further generated by oxidation; the secondary oxidation products decompose into a series of small molecule compounds such as aldehydes, ketones, acids and aromatics, with the level of malondialdehyde being used as an indicator of the extent of oxidation. The thiobarbituric acid method is adopted to measure the content of malondialdehyde after 7d of accelerated oxidation, and a malondialdehyde detection kit (TBA method) is provided by Shanghai Shang Bao biotechnology Co. Mixing 0.1g of the carriers of examples 1 to 3 with 1.9mL of distilled water and 4mL of thiobarbituric acid reagent in a boiling water bath for 15min, cooling to normal temperature, centrifuging at 12000rpm for 15min, and collecting supernatant; the absorbance at 532nm was measured using an ultraviolet spectrophotometer to obtain the content of malondialdehyde. The test results of malondialdehyde content after accelerated oxidation of the drug-loaded modified tea oil carrier are shown in Table 2.
TABLE 2
| Name of the name | Malondialdehyde content (mmol/kg) |
| Example 1 | 112.10 |
| Example 2 | 93.17 |
| Example 3 | 86.48 |
Higher levels of malondialdehyde represent greater degrees of oxidation. As can be seen from the test results of table 2, example 3 has the best oxidation resistance, and the propolis extract has a better effect in improving oxidation resistance compared with examples 1 and 2. The reason for this phenomenon may be that the complex formed by propolis extract, beta-lactoglobulin, sphingomyelin and D- (+) -melezitose hydrate forms a thin and sparse interfacial film on the surface of tea oil droplets, which blocks oxygen from entering the oxidation induced by tea oil; the propolis extract contains polyphenol and flavonoid besides polysaccharide, and is also helpful for improving oxidation resistance of carrier.
Test example 3
The sedimentation performance test of cefquinome sulfate injection is carried out by referring to a specific method in the annex of Chinese pharmacopoeia (2015 edition). Taking 50mL of cefquinome sulfate injection, placing the cefquinome sulfate injection in a test tube with a plug, shaking for 1min, and recording the original height H of the suspension before sedimentation 0 When the sedimentation surface is observed not to change after standing for 24 hours, recording the sediment height as H, and calculating the sedimentation volume ratio F according to the following formula:
and (3) measuring the redispersibility of the cefquinome sulfate injection after sedimentation, placing the cefquinome sulfate injection in a measuring cylinder with a plug, sealing, placing the measuring cylinder for sedimentation for 24 hours, inverting the measuring cylinder, turning over, uniformly shaking (one time for one time), and taking the turning-over times required by the disappearance of sediments as an evaluation index.
The sedimentation performance and the redispersibility test result of the cefquinome sulfate injection are shown in table 3.
TABLE 3 Table 3
| Name of the name | Sedimentation volume ratio | Redispersion of the number of turns |
| Example 3 | 0.99 | 1 |
| Example 4 | 0.95 | 2 |
| Comparative example 1 | 0.71 | 9 |
The larger the sedimentation volume ratio value is, the closer the sedimentation height is to the original height of the suspension, the more stable the suspension is, the smaller the redispersion turn-over number is, and the better the redispersibility of the suspension injection is. As can be seen from the results of table 3, example 4 shows better anti-settling and redispersion properties compared to example 3, which added a lower amount of D- (+) -melezitose hydrate, and examples 3 and 4 do not add additional suspending and dispersing agents compared to comparative example 1.
The reason for this result may be that the complex formed by propolis extract, beta-lactoglobulin, sphingomyelin and D- (+) -melezitose hydrate has good flexibility and a certain deformability, and the complex wraps the surface of the oil phase droplets to make the droplets have good ductility. When the emulsion is mechanically homogenized, the complex is absorbed onto the oil droplet surface, forming a stable emulsion; the compound is dispersed in the continuous phase, and by increasing the viscosity of the liquid drops, a three-dimensional network structure is formed, the anti-sedimentation capability of the liquid drops is enhanced, and flocculation and coalescence among the liquid drops are inhibited. The medicine-carrying modified tea oil carrier obtained through freeze drying has small particles and irregular surfaces and has a smoother porous microstructure. After the carrier and the dispersion medium are mixed, the influence of factors such as gravity is small, and the sedimentation of particles can be prevented under the condition that a suspending agent is not additionally added; the surface of the carrier prepared by electrostatic deposition has the same charge or is electrically neutral, the mutual attraction between particles is reduced, and the coating of the outer layer of the carrier on the inner oil phase further isolates the fusion between emulsion droplets, so that the Oswald ripening is inhibited, and a good dispersing effect can be obtained without adding a dispersing agent.
Claims (8)
1. The cefquinome sulfate injection is characterized by comprising the following raw materials in percentage by mass: 1.5-2.5wt% of cefquinome sulfate, 2.5-5wt% of modified tea oil carrier and the balance of dispersion medium; the dispersion medium is any one of ethyl oleate, soybean oil for injection and tea oil for injection;
the preparation method of the modified tea oil carrier comprises the following steps of:
m1, mixing 2-4 parts of propolis with 8-16 parts of absolute ethyl alcohol at normal temperature to obtain an ethanol solution of the propolis; centrifuging the ethanol solution of the propolis at a speed of 8000-10000 rpm for 10-15 min, taking supernatant, filtering the supernatant to remove insoluble impurities, concentrating, and freeze-drying to obtain propolis extract for later use;
m2, mixing 1-1.5 parts of the propolis extract and 0.6-1.2 parts of beta-lactoglobulin with 500-1000 parts of water at normal temperature; adjusting the pH value of the mixture of the two to 11-12 by using 1-1.5 mol/L sodium hydroxide aqueous solution, then heating to 70-80 ℃, treating for 15-30 min, cooling to normal temperature, adjusting the pH value of the mixture to be neutral by using 1-1.5 mol/L hydrochloric acid, filtering to remove insoluble impurities, and freeze-drying to obtain a powdery mixture for later use;
mixing 0.5-1 part of the powdery mixture, 0.125-0.25 part of sphingomyelin, 0.375-0.75 part of D- (+) -melezitose hydrate and 5-10 parts of water to obtain an aqueous phase mixed solution; stirring and mixing 1.5-3 parts of tea oil and the water phase mixed solution at the normal temperature at the speed of 240-480 rpm for 0.5-2 hours, homogenizing at the speed of 12000-18000 rpm for 3-5 minutes to obtain tea oil emulsion, and freeze-drying the tea oil emulsion to obtain the modified tea oil carrier;
in the filtering operation in the steps M1 and M2, the specification of the filter membrane is respectively and independently 80-100 μm.
2. A method for preparing the cefquinome sulfate injection as claimed in claim 1, which is characterized by comprising the following steps in parts by weight:
s1, mixing 2-4 parts of propolis with 8-16 parts of absolute ethyl alcohol at normal temperature to obtain an ethanol solution of the propolis; centrifuging the ethanol solution of propolis to obtain supernatant, filtering the supernatant to remove insoluble impurities, concentrating, and freeze drying to obtain propolis extract;
s2, mixing 1-1.5 parts of the propolis extract and 0.6-1.2 parts of beta-lactoglobulin with 500-1000 parts of water at normal temperature; adjusting the pH value of the mixture of the two to 11-12 by using a sodium hydroxide aqueous solution, then cooling to normal temperature after heating treatment, adjusting the pH value of the mixture to neutrality by using hydrochloric acid, filtering to remove insoluble impurities, and freeze-drying to obtain a powdery mixture for later use;
s3, mixing 1.5-2.5 parts of cefquinome sulfate with 1.5-3 parts of tea oil, and performing ultrasonic treatment to obtain a cefquinome sulfate dispersion; mixing 0.5-1 part of the powdery mixture, 0.125-0.25 part of sphingomyelin, 0.375-0.75 part of D- (+) -melezitose hydrate and 5-10 parts of water to obtain a water phase mixed solution for later use;
s4, stirring and mixing the cefquinome sulfate dispersion liquid and the water phase mixed liquid at normal temperature, homogenizing to obtain a medicine-carrying emulsion, and freeze-drying the medicine-carrying emulsion to obtain a medicine-carrying modified tea oil carrier for later use;
and S5, stirring and dispersing 4-7.5 parts of the medicine-carrying modified tea oil carrier and 92.5-96 parts of a dispersing medium to obtain the cefquinome sulfate injection.
3. The method according to claim 2, characterized in that: and (3) the centrifugal speed of the centrifugal operation in the step (S1) is 8000-10000 rpm, and the treatment time is 10-15 min.
4. The method according to claim 2, characterized in that: and in the step S3, the frequency of ultrasonic treatment is 28-40 kHz, the power is 550-800W, and the treatment time is 15-30 min.
5. The method according to claim 2, characterized in that: the stirring operation in the step S4 is carried out at a speed of 240-480 rpm, and the treatment time is 0.5-2 h.
6. The method according to claim 2, characterized in that: the rate of the homogenization treatment in the step S4 is 12000-18000 rpm, and the treatment time is 3-5 min.
7. The method according to claim 2, characterized in that: the stirring operation in the step S5 is carried out at a speed of 4000-8000 rpm for 15-30 min.
8. The method according to claim 2, characterized in that: in the filtering operation in the steps S1 and S2, the specification of the filter membrane is respectively and independently 80-100 μm.
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