CN114869850A - 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 preparations for veterinary medicine. The modified tea oil carrier is used, and the cefquinome sulfate is coated by emulsification and electrostatic deposition, so that the Oswald ripening effect in the emulsification and subsequent storage processes is inhibited. The carrier has strong dispersibility, good oxidation resistance and good anti-settling property, and can obtain good comprehensive effect without adding additional dispersing agent, suspending agent and antioxidant. After the carrier is injected into an animal body, the drug-loaded modified tea oil carrier is firstly distributed into body fluid through diffusion of a dispersion medium, then the carrier is driven by salt solution to release cefquinome sulfate, and the cefquinome sulfate reaches an affected part along with circulation of the body fluid to obtain a corresponding treatment effect.
Description
Technical Field
The invention relates to the technical field of preparations for veterinary medicine, in particular to cefquinome sulfate injection.
Background
The cefquinome sulfate is a fourth-generation cephalosporin antibiotic special for animals, and is water-insoluble white-like to light yellow crystalline powder. Has antibacterial effect by inhibiting cell wall synthesis, and has broad-spectrum antibacterial activity. The target animal is the pig, the blood concentration reaches the peak value after the cefquinome sulfate is injected into the pig body for 0.4 hour, and the elimination half-life period is about 1.4 hours, so the cefquinome sulfate injection has the characteristics of quick metabolism and short effective concentration maintenance time.
Chinese patent CN112691108A provides a cefquinome sulfate injection and a preparation method thereof, wherein cefquinome sulfate is used as a main antibacterial and antiviral drug, and hypericin, sulbactam, trimethoprim and clavulanate potassium are used as synergists, so that the antibacterial spectrum of the whole injection can be enhanced, the drug effect can be enhanced, and the cure rate can be improved. The invention adopts low temperature and high shearing, reduces the viscosity of the injection and enhances the stability. Because the viscosity of the ethyl oleate is low, a solid dispersion phase in the oily suspension injection is easy to deposit, a large amount of suspending agent needs to be added to maintain the suspension performance of the injection, and the requirement on the storage 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 drug effect can be prolonged. Chinese patent CN103751103A discloses a long-acting cefquinome sulfate injection and a preparation method thereof, wherein cefquinome sulfate is coated by a slow-release matrix, a medicament is dispersed in insoluble ethyl cellulose and a slow-release carrier in a molecular state, the release speed is regulated by combining water-soluble hydroxypropyl cellulose, the medicament is dissolved out and needs to diffuse outwards through a net structure of the carrier into an oily medium, and then is distributed into body fluid, so that the medicament is slowly released, the action time of the medicament is prolonged, and the slow-release effect is achieved. However, with the gradual dissolution of the drug, the volume of the drug-loaded carrier particles is reduced, and the volume of the insoluble ethyl cellulose is hardly changed, so that the Ostwald ripening process is accelerated, and the small-volume drug-loaded particles can be easily adsorbed on the surface of the ethyl cellulose, thereby causing the technical problem of uneven drug release.
Disclosure of Invention
In view of the above defects of the prior art, the problem to be solved by the present invention is to provide a cefquinome sulfate injection with good control effect on porcine respiratory diseases.
The formation of a coating on the surface of the droplets of the emulsion by electrostatic deposition is a common means of preparing the carrier. The emulsified liquid drops are small, the surface energy is high, and the liquid drops are easy to deposit on large liquid drops with low surface energy, so that the Oswald curing effect is intensified. The emulsion is flocculated, so that the liquid is enlarged, and the carrier formed by electrostatic deposition has larger volume and is not easy to disperse.
In order to solve the technical problems, tea oil and cefquinome sulfate form an oil phase dispersion liquid, and a propolis extract, beta-lactoglobulin, sphingomyelin and D- (+) -melezitose hydrate are used as raw materials to prepare a water phase mixed liquid; the solid particles in the water phase mixed solution have the characteristics of thickening, gelling, surface activity and the like, and in the process of preparing the emulsion by mixing the solid particles and the emulsion, the 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 small liquid drops are prevented from being aggregated to form large liquid drops. In addition, solid particles form a compact particle layer on a droplet interface through electrostatic deposition, the droplets can be effectively prevented from coalescing, and the prepared emulsion has high stability.
The cefquinome sulfate injection comprises the following raw materials in percentage by mass: 1.5-2.5 wt% of cefquinome sulfate, 2.5-5 wt% 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 1-1.5 parts of 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 an aqueous solution of sodium hydroxide, then cooling to normal temperature after heating treatment, adjusting the pH value of the mixture to be neutral 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 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 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 processing 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 sodium hydroxide aqueous 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 in steps M1 and M2, the specification of the filtration membrane is 80-100 μ M independently.
Preferably, the stirring speed in the step M3 is 240-480 rpm, and the processing time is 0.5-2 h.
Preferably, the homogenizing treatment in the step M3 has a speed of 12000-18000 rpm and a treatment time of 3-5 min.
The compound formed by the propolis extract, the beta-lactoglobulin, the sphingomyelin and the D- (+) -melezitose hydrate has good flexibility and certain deformability, and the compound 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 surface of the oil droplets to form a stable emulsion; the compound is dispersed in the continuous phase, and a three-dimensional network structure is formed by increasing the viscosity of liquid drops, so that the anti-settling capacity of the liquid drops is enhanced, and the flocculation and coalescence among the liquid drops are inhibited. The medicine-carrying modified tea oil carrier obtained by freeze drying has small particles, irregular surface and smooth porous microstructure. After the carrier and the dispersion medium are mixed, the influence of factors such as gravity is small, and the particles can be prevented from settling under the condition of not additionally adding a suspending agent; the carrier surface prepared by electrostatic deposition has the same charge or is neutral, the mutual attraction among particles is reduced, the fusion among emulsion droplets is further isolated by the coating of the inner oil phase by the outer layer of the carrier, so that the Oswald curing is inhibited, and a good dispersion effect can be obtained under the condition of not additionally 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 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 of the two to 11-12 by using an aqueous solution of sodium hydroxide, then cooling to normal temperature after heating treatment, adjusting the pH value of the mixture to be neutral by using hydrochloric acid, filtering to remove insoluble impurities, and freeze-drying to obtain a powdery mixture for later use;
s3, mixing cefquinome sulfate with tea oil, and performing ultrasonic treatment to obtain a cefquinome sulfate dispersion liquid; mixing the powdery mixture, sphingomyelin, D- (+) -melezitose hydrate and water to obtain water phase mixed liquid 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 drug-loaded emulsion, and freeze-drying the drug-loaded emulsion to obtain a drug-loaded modified tea oil carrier for later use;
s5, stirring and dispersing the drug-loaded modified tea oil carrier and a dispersion 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 1-1.5 parts of 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 an aqueous solution of sodium hydroxide, then cooling to normal temperature after heating treatment, adjusting the pH value of the mixture to be neutral 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 liquid; 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 drug-loaded emulsion, and freeze-drying the drug-loaded emulsion to obtain a drug-loaded modified tea oil carrier for later use;
s5, stirring and dispersing 4-7.5 parts of the drug-loaded modified tea oil carrier and 92.5-96 parts of a dispersion 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 processing time is 10-15 min.
Preferably, the concentration of the sodium hydroxide aqueous 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 filtration operation in steps S1 and S2, the sizes of the filtration membranes are respectively 80 to 100 μm independently.
Preferably, the ultrasonic treatment in the step S3 has a frequency of 28-40 kHz, a power of 550-800W and a treatment time of 15-30 min.
Preferably, the stirring speed in step S4 is 240-480 rpm, and the processing time is 0.5-2 h.
Preferably, the homogenizing rate in step S4 is 12000-18000 rpm, and the processing time is 3-5 min.
Preferably, the stirring speed in the step S5 is 4000-8000 rpm, and the processing time is 15-30 min.
A thin and sparse interfacial film is formed on the surface of the tea oil drop by a compound formed by the propolis extract, the beta-lactoglobulin, the sphingomyelin and the D- (+) -melezitose hydrate, so that oxygen is prevented from entering the tea oil to cause oxidation; the propolis extract contains polyphenol and flavonoid besides polysaccharide, which is also helpful for improving the oxidation resistance of the carrier, and can maintain the stability of the carrier without adding additional antioxidant.
When the cefquinome sulfate injection is injected into an animal body, the drug-loaded modified tea oil carrier is firstly distributed into body fluid through diffusion of a dispersion medium; the polysaccharide and the protein on the surface of the carrier have rich hydrophilic sites and good binding capacity with body fluid. The biological body fluid contains a small amount of neutral salt, the neutral salt enhances the charge on the surface of beta-lactoglobulin molecules in the carrier, so that the action with water molecules is enhanced, the solubility of the beta-lactoglobulin is increased and the beta-lactoglobulin is slowly dissolved in the body fluid, the carrier is driven to release cefquinome sulfate, and the cefquinome sulfate reaches an affected part along with the circulation of the body fluid to obtain a corresponding treatment effect.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The introduction and the function of part of raw materials in the formula of the invention are as follows:
cefquinome sulfate: the fourth generation cephalosporin products, besides the characteristics of the third generation cephalosporin, can also rapidly penetrate the outer membrane of gram-negative bacteria, are stable to the beta-lactamase I around cytoplasm, have low affinity, have high affinity with Penicillin Binding Protein (PBP), and have intrinsic antibacterial activity several times stronger than that of 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 modified tea oil carrier is used for coating the cefquinome sulfate, the carrier has strong dispersibility and good anti-settling property, and a good dispersing effect can be obtained without adding additional dispersing agents and suspending agents.
Compared with the prior art, the thin and sparse interfacial film is formed on the surface of the tea oil drop by using the compound formed by the propolis extract, the beta-lactoglobulin, the sphingomyelin and the D- (+) -melezitose hydrate, so that oxygen is prevented from entering the tea oil to initiate oxidation. The propolis extract contains polyphenol and flavonoid besides polysaccharide, which is also 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 polysaccharide and the protein on the surface of the carrier have rich hydrophilic sites and good binding capacity with body fluid. After the cefquinome sulfate enters the body fluid circulation, the salt in the body fluid enhances the charge on the surface of the beta-lactoglobulin molecules, so that the action with 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 the cefquinome sulfate.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Some raw material parameters in the comparative examples and examples of the invention are as follows:
the propolis in pharmacopoeia is black and blocky, has the purity of more than or equal to 95 percent and is provided by bee professional cooperative of licking and keeping bees in Change city;
beta-lactoglobulin, the content is more than or equal to 98 percent, the cargo number: XAQN-443, available from Seikono Biotechnology Ltd;
sphingomyelin, purity not less than 98%, CAS number: 85187-10-6, available from Guangdong Wengjiang chemical reagents, Inc.;
d- (+) -melezitose hydrate, CAS No.: 597-12-6, provided by Hubei Yunw science and technology Co., Ltd;
cp2020 pharmacopeia tea oil for injection, provided by Xian Tianzheng pharmaceutic adjuvant Co.
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 pH of the mixture to 12 with sodium hydroxide aqueous solution, heating, cooling to room temperature, adjusting pH of the mixture to neutral with hydrochloric acid, filtering to remove insoluble impurities, and freeze drying to obtain powder;
s2, mixing 250g of cefquinome sulfate with 300g of tea oil, and performing ultrasonic treatment to obtain cefquinome sulfate dispersion liquid; mixing 100g of the powdery treatment substance, 25g of sphingomyelin, 75g D- (+) -melezitose hydrate and 500g of water to obtain water phase mixed liquid 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 drug-loaded emulsion, and freeze-drying the drug-loaded emulsion to obtain a drug-loaded modified tea oil carrier for later use;
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 heat treatment in step S1 was 75 ℃ and the treatment time was 30 min.
In step S1, the concentration of the sodium hydroxide aqueous solution is 1mol/L, and the concentration of hydrochloric acid is 1 mol/L.
In the filtration operation described in step S1, the filter size was 80 μm.
The ultrasonic treatment in step S2 has a frequency of 40kHz, a power of 550W, and a treatment time of 15 min.
The stirring operation in step S3 was carried out at a rate of 480rpm for a treatment time of 0.5 h.
The rate of the homogenization treatment in step S4 was 12000rpm, and the treatment time was 5 min.
The stirring operation in step S4 was carried out at a rate of 4000rpm for a treatment time of 30 min.
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 cefquinome sulfate dispersion liquid; mixing 100g of the propolis extract, 25g of sphingomyelin, 75g D- (+) -melezitose hydrate and 500g of water to obtain water phase mixed liquid 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 drug-loaded emulsion, and freeze-drying the drug-loaded emulsion to obtain a drug-loaded modified tea oil carrier for later use;
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 in the centrifugation in step S1 was 8000rpm, and the treatment time was 15 min.
In the filtration operation described in step S1, the filter size was 80 μm.
The ultrasonic treatment in step S2 has a frequency of 40kHz, a power of 550W, and a treatment time of 15 min.
The stirring operation in step S3 was performed at a rate of 480rpm for a treatment time of 0.5 h.
The rate of the homogenization treatment in step S3 was 12000rpm, and the treatment time was 5 min.
The stirring operation in step S4 was carried out at a rate of 4000rpm for a treatment time of 30 min.
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 pH of the mixture to 12 with sodium hydroxide aqueous solution, heating, cooling to room temperature, adjusting pH of the mixture to neutral with hydrochloric acid, filtering to remove insoluble impurities, and lyophilizing to obtain powder mixture;
s3, mixing 250g of cefquinome sulfate with 300g of tea oil, and performing ultrasonic treatment to obtain cefquinome sulfate dispersion liquid; mixing 100g of the powdery mixture, 25g of sphingomyelin, 75g D- (+) -melezitose hydrate and 500g of water to obtain water-phase mixed liquor 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 drug-loaded emulsion, and freeze-drying the drug-loaded emulsion to obtain a drug-loaded modified tea oil carrier for later use;
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 in the centrifugation in step S1 was 8000rpm, and the treatment time was 15 min.
The temperature of the heat treatment in step S2 was 75 ℃ and the treatment time was 30 min.
In step S2, the concentration of the sodium hydroxide aqueous solution is 1mol/L, and the concentration of hydrochloric acid is 1 mol/L.
In the filtration operation described in steps S1 and S2, the sizes of the filtration membranes are each 80 μm independently.
The ultrasonic treatment in step S3 has a frequency of 40kHz, a power of 550W, and a treatment time of 15 min.
The stirring operation in step S4 was performed at a rate of 480rpm for a treatment time of 0.5 h.
The rate of the homogenization treatment in step S4 was 12000rpm, and the treatment time was 5 min.
The stirring operation in step S5 was carried out at a rate of 4000rpm for a treatment time of 30 min.
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 propolis extract with 90g of beta-lactoglobulin at normal temperature and 50kg of water; adjusting pH of the mixture to 12 with sodium hydroxide aqueous solution, heating, cooling to room temperature, adjusting pH of the mixture to neutral with hydrochloric acid, filtering to remove insoluble impurities, and lyophilizing to obtain powder mixture;
s3, mixing 250g of cefquinome sulfate with 300g of tea oil, and performing ultrasonic treatment to obtain cefquinome sulfate dispersion liquid; mixing 100g of the powdery mixture, 25g of sphingomyelin, 37.5g of D- (+) -melezitose hydrate and 500g of water to obtain water-phase mixed liquid 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 drug-loaded emulsion, and freeze-drying the drug-loaded emulsion to obtain a drug-loaded modified tea oil carrier for later use;
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 in the centrifugation in step S1 was 8000rpm, and the treatment time was 15 min.
The temperature of the heat treatment in step S2 was 75 ℃ and the treatment time was 30 min.
In step S2, the concentration of the sodium hydroxide aqueous solution is 1mol/L, and the concentration of hydrochloric acid is 1 mol/L.
In the filtration operation described in steps S1 and S2, the sizes of the filtration membranes are each 80 μm independently.
The ultrasonic treatment in step S3 has a frequency of 40kHz, a power of 550W, and a treatment time of 15 min.
The stirring operation in step S4 was performed at a rate of 480rpm for a treatment time of 0.5 h.
The rate of the homogenization treatment in step S4 was 12000rpm, and the treatment time was 5 min.
The stirring operation in step S5 was carried out at a rate of 4000rpm for a treatment time of 30 min.
Comparative example 1
The cefquinome sulfate injection is prepared by the following method:
stirring and dispersing 250g of cefquinome sulfate and 9.75kg of ethyl oleate to obtain the cefquinome sulfate injection.
The stirring operation was carried out at 4000rpm for a treatment time of 30 min.
Test example 1
The test of the curative effect of the cefquinome sulfate injection on the porcine bacterial respiratory disease is carried out by a specific method in a reference document (Yueyongdu, Yangyuan, Fangxiaoping. curative effect test of cefquinome sulfate on the porcine bacterial respiratory disease [ J ]. Chinese veterinary journal, 2008, 44 (7): 45-47. DOI: 10.3969/j.issn.0529-6005.2008.07.024.). Investigating the history of bacterial pneumonia in a pig farm, performing a caesarean test on dead growing pigs, taking lung disease materials to perform bacteriological separation and identification when typical pulmonary liver changes and cellulosic pleuropneumonia are found, and selecting growing pigs with disease symptoms in the pig farm as experimental animals when pasteurella multocida and/or actinobacillus pleuropneumoniae can be separated. The experimental pigs had the following symptoms: decreased appetite, coughing and mild lassitude, increased rectal temperature in pigs, etc. 120 tripartite hybridization sick pigs of 3-4 months age are selected, and the weight of the tripartite hybridization sick pigs is 30-50 kg. The infected growing pigs of the same batch with the symptoms are divided into 6 groups, 20 pigs of each group are the example 1-4, the control example 1 and the blank control group (no administration for natural infection), all the pigs are raised under the same raising condition, and the composition and the nutrition level of the daily ration are completely the same. The administration was carried out intramuscularly, once per 2.5mg per 1kg body weight, in terms of cefquinome sulfate, once a day for 3 days. And (3) continuing the experiment for 21 days, recording the death rate of each group of pigs, weighing the weight of each pig at the beginning and the end of the experiment, comparing the weight increment conditions of the live pigs of each group, and calculating the relative weight increment rate according to the average weight increment ratio of each medicine group and a blank control group. The results of the test on the curative effect of the cefquinome sulfate injection on the porcine bacterial respiratory disease are shown in table 1.
TABLE 1
As can be seen from the results in Table 1, the use of cefquinome sulfate injection can effectively prevent and treat bacterial respiratory diseases of pigs, reduce the death rate and improve the weight gain of stocked pigs. The recommended administration adopts intramuscular injection, the dose is once, 2.5mg is injected once a day by cefquinome sulfate every 1kg of body weight, and the administration is continuously carried out for 3 days, so that the good treatment effect on the porcine bacterial respiratory disease can be achieved. The reason may be that after the cefquinome sulfate injection is injected into an animal body, the drug-loaded 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 abundant hydrophilic sites and have good binding capacity with the body fluid; the biological body fluid contains a small amount of neutral salt, the neutral salt enables the charge on the surface of beta-lactoglobulin molecules in the carrier to be enhanced, the action with water molecules is enhanced, the solubility of the beta-lactoglobulin is increased and the beta-lactoglobulin is slowly dissolved in the body fluid, the carrier is driven to release cefquinome sulfate, the duration of the drug effect is prolonged, and compared with the comparative example 1, the various embodiments achieve better treatment effect.
Test example 2
In the process of preparing cefquinome sulfate injection in the embodiment 1-3, the prepared drug-loaded modified tea oil carrier is taken for oxidation resistance test. The obtained drug-loaded modified tea oil carrier is oxidized for 7 days at the temperature of 60 ℃. In the oxidation process of the tea oil loaded in the carrier, a primary oxidation product is unstable and is further oxidized to generate a secondary oxidation product; the secondary oxidation product is decomposed into a series of small molecular compounds, such as aldehyde, ketone, acid and aromatic compounds, and the content of malonaldehyde is used as an index for representing the oxidation degree. The content of malondialdehyde after accelerated oxidation for 7d is determined by a thiobarbituric acid method, and a malondialdehyde detection kit (TBA method) is provided by Shanghai Shangbao Biotech Co., Ltd. Mixing 0.1g of the carrier in the embodiment 1-3 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 taking supernatant; and (3) measuring the absorbance at 532nm by using an ultraviolet spectrophotometer to further obtain the content of the malondialdehyde. The test results of the malondialdehyde content after the accelerated oxidation of the drug-loaded modified tea oil carrier are shown in table 2.
TABLE 2
| Name (R) | Malondialdehyde content (mmol/kg) |
| Example 1 | 112.10 |
| Example 2 | 93.17 |
| Example 3 | 86.48 |
Higher malondialdehyde content indicates greater oxidation. As can be seen from the test results of table 2, example 3 has the best antioxidant property, and the propolis extract has a better effect in improving the antioxidant property, compared to examples 1 and 2. The reason for this may be that the complex formed by the propolis extract, beta-lactoglobulin, sphingomyelin and D- (+) -melezitose hydrate forms a thin and sparse interfacial film on the surface of the tea oil droplets, blocking the oxygen from entering the tea oil to initiate oxidation; the propolis extract contains polyphenol and flavonoid besides polysaccharide, and is also helpful for improving the oxidation resistance of the carrier.
Test example 3
The sedimentation performance test of the cefquinome sulfate injection is carried out according to a specific method in an appendix of Chinese pharmacopoeia (2015 edition). 50mL of cefquinome sulfate injection is placed in a test tube with a plug, shaken for 1min, and the original height H of the suspension before sedimentation is recorded 0 And when the settlement surface is observed to be not changed after standing for 24 hours, recording the height of the settlement as H, and calculating the settlement volume ratio F according to the following formula:
measuring the redispersion of the settled cefquinome sulfate injection, placing the cefquinome sulfate injection in a measuring cylinder with a plug, sealing, placing and settling for 24 hours, inverting the measuring cylinder, inverting the cylinder, uniformly shaking (counting once for each time), and taking the number of times of inversion required by the disappearance of the settled matters as an evaluation index.
The results of the test on the sedimentation performance and the redispersibility of the cefquinome sulfate injection are shown in table 3.
TABLE 3
| Name (R) | Volume ratio of sedimentation | Number of turnover in weight dispersion |
| 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 less times of re-dispersion and turning are, and the better the re-dispersion of the suspension injection is. As can be seen from the results of table 3, example 4 exhibited better anti-settling and re-dispersing properties than example 3, in which a lower content of D- (+) -melezitose hydrate was added, and examples 3 and 4 did not add additional suspending and dispersing agents as compared to comparative example 1.
The reason for this may be that 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 liquid drop has good ductility due to the wrapping of the oil phase liquid drop surface. When the emulsion is homogenized mechanically, the complex is absorbed to the surface of oil droplets to form a stable emulsion; the compound is dispersed in the continuous phase, and a three-dimensional network structure is formed by increasing the viscosity of liquid drops, so that the anti-settling capacity of the liquid drops is enhanced, and the flocculation and coalescence among the liquid drops are inhibited. The medicine-carrying modified tea oil carrier obtained by freeze drying has small particles, irregular surface and smooth porous microstructure. After the carrier and the dispersion medium are mixed, the influence of factors such as gravity is small, and the particles can be prevented from settling under the condition of not additionally adding a suspending agent; the carrier surface prepared by electrostatic deposition has the same charge or is neutral, the mutual attraction among particles is reduced, the fusion among emulsion droplets is further isolated by the coating of the inner oil phase by the outer layer of the carrier, so that the Oswald curing is inhibited, and a good dispersion effect can be obtained under the condition of not additionally adding a dispersing agent.
Claims (10)
1. The cefquinome sulfate injection is characterized by comprising the following raw materials in percentage by mass: 1.5-2.5 wt% of cefquinome sulfate, 2.5-5 wt% of modified tea oil carrier and the balance of dispersion medium.
2. The cefquinome sulfate injection as claimed in claim 1, wherein: the dispersion medium is any one of ethyl oleate, soybean oil for injection and tea oil for injection.
3. The cefquinome sulfate injection as claimed in claim 1, wherein the modified tea oil carrier is prepared by the following steps:
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 propolis ethanol solution at 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 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 a mixture of the two to 11-12 by using 1-1.5 mol/L sodium hydroxide aqueous solution, 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;
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 and 5-10 parts of water to obtain a water 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 h, then homogenizing at the speed of 12000-18000 rpm for 3-5 min to obtain tea oil emulsion, and freeze-drying the tea oil emulsion to obtain the modified tea oil carrier;
in the filtration operation in the steps M1 and M2, the specifications of the filtration membranes are respectively 80-100 μ M independently.
4. A method for preparing cefquinome sulfate injection as claimed in claim 1, 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 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 an aqueous solution of sodium hydroxide, then cooling to normal temperature after heating treatment, adjusting the pH value of the mixture to be neutral 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 liquid; 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 drug-loaded emulsion, and freeze-drying the drug-loaded emulsion to obtain a drug-loaded modified tea oil carrier for later use;
s5, stirring and dispersing 4-7.5 parts of the drug-loaded modified tea oil carrier and 92.5-96 parts of a dispersion medium to obtain the cefquinome sulfate injection.
5. The method of claim 4, wherein: the centrifugation speed of the centrifugation operation in the step S1 is 8000-10000 rpm, and the processing time is 10-15 min.
6. The method of claim 4, wherein: in the step S3, the ultrasonic treatment frequency is 28-40 kHz, the power is 550-800W, and the treatment time is 15-30 min.
7. The method of claim 4, wherein: in step S4, the stirring speed is 240-480 rpm, and the processing time is 0.5-2 h.
8. The method of claim 4, wherein: in the step S4, the homogenizing speed is 12000-18000 rpm, and the processing time is 3-5 min.
9. The method of claim 4, wherein: the stirring operation in the step S5 has a speed of 4000-8000 rpm and a processing time of 15-30 min.
10. The method of claim 4, wherein: in the filtration operation in steps S1 and S2, the specifications of the filtration membranes are respectively 80 to 100 μm independently.
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