Breast injectant for treating mastitis of dairy cows in lactation period and preparation method of breast injectant

Abstract

The invention relates to a breast injectant for treating mastitis in lactation period of dairy cows and a preparation method of the breast injectant. The breast injectant is prepared by combining cefquinome sulfate and oleanolic acid and adding 1-5wt% of an emulsifier, 1-5wt% of a suspending aid, 0.02-0.5 wt% of an antioxidant and an oily dispersing solvent, with the balance being the oily dispersing solvent. The preparation process is simple and suitable for large-scale production, and the prepared product is small in particle size and uniform and fine in character through the combination of high-pressure homogenization technology treatment and a high-speed dispersion shearing process; meanwhile, according to the prescription, the cefquinome sulfate is matched with the oleanolic acid which is a traditional Chinese medicine extract, so that the treatment effect of the cefquinome sulfate can be reduced and enhanced.

Description

Technical Field

[0001] The invention relates to the technical field of veterinary drugs, and in particular to a breast infusion for treating mastitis in the lactation period of dairy cows and a preparation method thereof. Background Art

[0002] Bovine mastitis is an inflammation of the breast caused by infection with pathogenic microorganisms, which can lead to a decrease in milk production and milk product quality, seriously affecting the healthy development of the dairy farming industry. It is reported that the global incidence of mastitis is generally as high as 20%-40%, and the incidence of hidden mastitis is as high as 50%. The high incidence of mastitis in dairy cows not only reduces the production capacity of dairy cows and increases breeding costs, but also leads to a significant decrease in the amount and quality of milk produced by dairy cows, and the quality of milk directly affects the total production and economic benefits of milk. In addition, mastitis may also cause other health problems in dairy cows, increase the elimination rate, further impact the stable development of the breeding industry, and pose a serious threat to the sustainability of the entire dairy industry.

[0003] At present, cefquinome sulfate is the fourth-generation cephalosporin antibiotic approved by my country for the treatment of bovine mastitis. It has a good killing effect on pathogens that cause bovine mastitis, such as Staphylococcus aureus, Escherichia coli, Streptococcus agalactiae and Streptococcus dysgalactiae. However, the injection of cefquinome sulfate causes a strong stress response in animals, and with the extensive use of antibiotics in veterinary clinics, mastitis pathogens have become resistant to most veterinary β-lactam antibiotics, including cefquinome.

[0004] Breast injection is the fastest way to treat mastitis in dairy cows, but more and more cases of failure of single antibiotics to treat mastitis are occurring. Traditional Chinese medicine has the advantages of abundant sources, low toxicity and side effects, novel structure, no adverse reactions and no drug resistance. In recent years, with the implementation of the policy of "antibiotic reduction, antibiotic restriction and antibiotic substitution", the role of traditional Chinese medicine in veterinary clinics has also received more and more attention. Existing studies have found that the active ingredients of traditional Chinese medicine can play an important role in the treatment of inflammation caused by pathogen infection as the main drug or auxiliary drug through direct antibacterial, anti-virulence factor, inhibition of drug-resistant enzymes, synergistic antibacterial effects and enhancement of body immunity.

[0005] Chinese patent document CN 117180191 A discloses a method for preparing a cefquinome sulfate breast injection for dry period of dairy cows. The injection is made of the following raw materials and auxiliary materials: 3-7% cefquinome sulfate micropowder, 3-7% plant volatile oil, 0.02-0.5% antioxidant, 1-5% suspending agent, 1-10% dispersant, 0.1-1% synergist, and the balance is solvent. The breast injection has the advantages of slow drug release, easy use, and avoidance of animal stress response caused by injection. However, the cefquinome sulfate injection has poor stability, irritation, and long-term use can still increase antibiotic resistance.

[0006] Therefore, it is of great significance to develop a cefquinome sulfate breast injection for use in dairy cows during lactation, which can reduce drug resistance by reducing the cefquinome sulfate dosage while ensuring long-lasting and effective efficacy and low cost. Summary of the invention

[0007] In order to solve the above technical problems, the present invention provides a breast injection for treating mastitis in dairy cows during lactation. The injection is compounded by traditional antibiotic quinoxime sulfate and traditional Chinese medicine extract oleanolic acid, and is configured through the interaction of other auxiliary materials.

[0008] Therefore, the first aspect of the present invention provides a compound quinoxime sulfate and oleanolic acid breast injection, which contains 0.5-2g of quinoxime sulfate, 1-5g of oleanolic acid, 1-5g of suspending agent, 0.02-0.5g of antioxidant, 1-5g of emulsifier and oily dispersing solvent per 100mL; the oily dispersing solvent is the balance.

[0009] In a preferred embodiment of the present invention, in the compound oleanolic acid breast injection, the mass ratio of cefquinome sulfate to oleanolic acid is 1:4-1:1.

[0010] In a preferred embodiment of the present invention, the emulsifier in the compound oleanolic acid breast injection is glyceryl monostearate.

[0011] In a preferred embodiment of the present invention, the compound oleanolic acid breast injection, wherein the suspending agent is selected from one or more combinations of hydrogenated castor oil, aluminum stearate, and sodium alginate, wherein hydrogenated castor oil is further preferred.

[0012] In a preferred embodiment of the present invention, the compound oleanolic acid breast injection, wherein the dispersant is one or a combination of vitamin E and agar, among which vitamin E is further preferred.

[0013] In a preferred embodiment of the present invention, the compound oleanolic acid breast injection, wherein the non-aqueous solvent is any one of injectable soybean oil, liquid paraffin, and medium-chain oil 840, and it is further preferably injectable soybean oil.

[0014] In a preferred embodiment of the present invention, the method of preparing the compound oleanolic acid breast injection comprises:

[0015] Step 1: Heat 80% of the prescribed amount of the non-aqueous solvent and maintain it at 85° C. for later use;

[0016] Step 2: Add the wetting agent and the suspending agent to the non-aqueous solvent in order until they are completely dissolved. When the mixed solution is cooled to 30-50° C., add the antioxidant during rapid stirring until the antioxidant is evenly mixed and ready for use.

[0017] Step 3: After the non-aqueous solvent is cooled to 25°C to 30°C, oleanolic acid is added to the above solution, and the mixture is stirred slowly in one direction, and the prescribed amount of cefquinome sulfate is added, and the volume is fixed with the remaining prescribed amount of soybean oil for later use;

[0018] Step 4: The mixture obtained in the previous step is passed through a colloid mill to reach a fully dispersed uniform state, and then processed through a high-pressure homogenizer, filled, and sterilized to obtain the product.

[0019] Another aspect of the present invention provides the use of the compound cefquinome sulfate and oleanolic acid breast injection in a drug for treating mastitis in the lactation period of dairy cows.

[0020] The technical solution of the present invention has the following advantages:

[0021] (1) Considering the advantage of China as a country with rich traditional Chinese medicine resources, this study combined the traditional Chinese medicine extract oleanolic acid with the traditional antibiotic cefquinome sulfate, which not only reduced the dosage of antibiotics and reduced the hazards such as antibiotic residues and drug resistance, but also achieved antibacterial spectrum complementarity, better inhibited important mastitis pathogens such as Staphylococcus aureus, Escherichia coli and Streptococcus, and achieved better therapeutic effects.

[0022] (2) The product prepared by the present invention adopts the synergistic effect of high-speed shear technology and non-aqueous formulation, so that the obtained product has good stability. At the same time, the obtained product adopts the breast injection administration method, so that the drug can be locally and precisely penetrated into the breast lesion site, which significantly improves the utilization of the drug and comprehensively enhances the clinical treatment effect of bovine mastitis.

[0023] (3) The preparation method of this product is simple and suitable for industrial production. DETAILED DESCRIPTION

[0024] The present invention is further described below in conjunction with the embodiments and test examples, but is not limited thereto. All raw materials and equipment in the embodiments are commercially available products.

[0025] Example 1.

[0026] Taking the preparation of 1000 mL of breast infusion as an example, the breast infusion of this embodiment is composed of the following components:

[0027] type Components quality API Cefquinome Sulfate 7.5g Chinese herbal extracts Oleanolic acid 15g Antioxidants Vitamin E 1g Suspending Agents Hydrogenated castor oil 10g Emulsifier Glyceryl Monostearate 10g solvent Soybean Oil for Injection 1000

[0028] The following steps are used to prepare the compound cefquinome sulfate oleanolic acid breast injection for dairy cows during lactation:

[0029] Step 1: Heat 80% of the prescribed amount of the non-aqueous solvent and maintain it at 85° C. for later use;

[0030] Step 2: Add the wetting agent and the suspending agent to the non-aqueous solvent in order until they are completely dissolved. When the mixed solution is cooled to 30-50° C., add the antioxidant during rapid stirring until the antioxidant is evenly mixed and ready for use.

[0031] Step 3: After the non-aqueous solvent is cooled to 25°C to 30°C, oleanolic acid is added to the above solution, and the mixture is stirred slowly in one direction, and the prescribed amount of cefquinome sulfate is added, and the volume is fixed with the remaining prescribed amount of soybean oil for later use;

[0032] Step 4: The mixture obtained in the previous step is passed through a colloid mill to reach a fully dispersed uniform state, and then processed through a high-pressure homogenizer, filled, and sterilized to obtain the product.

[0033] Example 2

[0034]

[0035]

[0036] The preparation steps of the compound oleanolic acid breast injection for dairy cows in lactation period are the same as those in Example 1.

[0037] Example 3

[0038] type Components quality API Cefquinome Sulfate 7.5g Chinese herbal extracts Oleanolic acid 7.5g Antioxidants Vitamin E 1g Suspending Agents Hydrogenated castor oil 10g Emulsifier Glyceryl Monostearate 10g solvent Soybean Oil for Injection Fill up to 1000g

[0039] The preparation steps of the compound oleanolic acid breast injection for dairy cows in lactation period are the same as those in Example 1.

[0040] Comparative Example 1

[0041] This comparative example is substantially the same as the actual example 1, except that the mass of cefquinome sulfate is adjusted from 7.5 g to 9.375 g, and the mass of oleanolic acid is adjusted from 15 g to 0 g.

[0042] Comparative Example 2

[0043] This comparative example is basically the same as Example 1, except that the mass of the suspending agent hydrogenated castor oil is adjusted from 10 g to 0.1 g.

[0044] Comparative Example 3

[0045] This comparative example is basically the same as Example 1, except that the weight of the antioxidant vitamin E is adjusted from 1 g to 0.1 g.

[0046] Comparative Example 4

[0047] This comparative example is basically the same as Example 1, except that the mass of the emulsifier glyceryl monostearate is adjusted from 10 g to 0.1 g.

[0048] Comparative Example 5

[0049] This comparative example is basically the same as Example 1, except that: in step 4, the homogenization process using a colloid mill and a high-pressure homogenizer is replaced by ordinary mechanical stirring at a stirring rate of 1000 r / min.

[0050] The product quality of the compound oleanolic acid breast injection for lactating cows obtained in Examples 1 to 3 and Comparative Examples 1 to 5 was determined. The accelerated test was carried out under the conditions of a temperature of 40±2°C and a relative humidity of 65±5%. Product quality standard requirements: 1) Related substances: If there is a chromatographic peak in the test solution that is consistent with the main peak retention time of the 5,6,7,8-tetrahydroquinoline control solution, its peak area shall not be greater than 3 times the main peak area of ​​the control solution (3.0%), and the peak area of ​​other single impurities shall not be greater than the main peak area of ​​the control solution (1.0%), and the sum of the peak areas of all impurities shall not be greater than 4 times the main peak area of ​​the control solution (4.0%). 2) Particle size: The particles below 15μm shall not be less than 90%, the particles below 20μm shall not be less than 95%, and particles of 50μm and above shall not be detected. 3) Sedimentation volume ratio: The sedimentation volume ratio should not be less than 0.9. Content: Contains cefuroxime (C 23 H 24 N6O5S2) should be 90.0%-110.0% of the labeled amount. The quality test results are shown in Table 1.

[0051] Table 1 Product quality test results of breast infusions of Examples 1 to 3 and Comparative Examples 1 to 5.

[0052] Examples Content (Cefquinome) granularity Related substances Sedimentation volume ratio in conclusion Example 1 99.8％ Comply with regulations Comply with regulations Comply with regulations Comply with regulations Example 2 98.5％ Comply with regulations Comply with regulations Comply with regulations Comply with regulations Example 3 98.7％ Comply with regulations Comply with regulations Comply with regulations Comply with regulations Comparative Example 1 98.9％ Comply with regulations Comply with regulations Comply with regulations Comply with regulations Comparative Example 2 78.5％ Not in compliance with regulations Not in compliance with regulations Not in compliance with regulations Not in compliance with regulations Comparative Example 3 80.5％ Not in compliance with regulations Not in compliance with regulations Not in compliance with regulations Not in compliance with regulations Comparative Example 4 83.4％ Not in compliance with regulations Not in compliance with regulations Not in compliance with regulations Not in compliance with regulations Comparative Example 5 87.5％ Not in compliance with regulations Not in compliance with regulations Not in compliance with regulations Not in compliance with regulations

[0053] As can be seen from Table 1, the breast injections obtained in Examples 1 to 4 fully meet the requirements, and the present invention improves the chemical stability, redispersibility, etc. of the cefquinome sulfate breast injection.

[0054] Application example: 80 cows with mastitis of uniform age and weight were selected from a dairy farm and randomly divided into 4 groups, 20 in each group. One injection was given into the milk duct, one injection was given into each infected milk chamber, once every 12 hours, for 3 times in a row. The clinical symptoms of the cows before and after treatment, the detection of pathogens in milk samples, etc., were evaluated. The elimination of pathogens and the alleviation or elimination of clinical symptoms were used to determine the treatment was effective.

[0055] Table 2 Statistical results of the prevalence of mastitis in dairy cows during lactation

[0056] Group Cow (head) Number of cavities with mastitis Effectiveness (calculated by breast chamber) Example 1 20 28 89.28％ Example 2 20 22 90.91％ Example 3 20 26 76.92％ Comparative Example 1 20 27 88.89％

[0057] As can be seen from Table 2, the compound oleanolic acid breast injection composed of cefquinome sulfate, oleanolic acid, antioxidant, suspending agent, emulsifier and solvent of the present invention has obvious therapeutic effect on mastitis of lactating dairy cows, wherein oleanolic acid has a dosage-reducing and synergistic effect on cefquinome sulfate, and the ratio thereof is 1:4-1:1.

[0058] The embodiments described above are only preferred embodiments of the present invention and are only used to explain the present invention, not to limit the scope of implementation of the present invention. For those skilled in the art, other implementation methods can certainly be easily made by replacement or modification based on the technical contents disclosed in this specification. Therefore, all changes and improvements made on the principles of the present invention should be included in the scope of the patent application of the present invention.

Claims

1. A breast infusion for treating mastitis in dairy cows during lactation, characterized in that: Each 100 ml of the breast injection contains 0.5-2 g of cefquinome sulfate micropowder, 1-5 g of oleanolic acid, 1-5 g of a suspending agent, 0.02-0.5 g of an antioxidant, 1-5 g of an emulsifier and an oily dispersing solvent; the oily dispersing solvent is the balance.

2. The breast infusion for treating mastitis in the lactation period of dairy cows according to claim 1, characterized in that: The mass ratio of the cefquinome sulfate to oleanolic acid is 1:4-1:

1.

3. The compound oleanolic acid breast injection according to any one of claims 1-2, wherein the emulsifier is glyceryl monostearate.

4. The compound oleanolic acid breast injection according to any one of claims 1-2, characterized in that: The suspending agent is selected from one of hydrogenated castor oil, aluminum stearate and sodium alginate.

5. The compound oleanolic acid breast injection according to any one of claims 1-2, wherein the dispersant is one of vitamin E and agar.

6. The compound oleanolic acid breast injection according to any one of claims 1-2, wherein the non-aqueous solvent is soybean oil for injection.

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