Cefquinome sulfate breast injectant as well as preparation method and application thereof

Abstract

The invention provides a cefquinome sulfate breast injectant as well as a preparation method and application thereof. The cefquinome sulfate breast injectant comprises cefquinome sulfate, a composite wetting agent, a composite thickening agent and a solvent, wherein the composite wetting agent is selected from one or more of liquid paraffin, span or Tween. The particle size of the cefquinome sulfate breast injectant prepared by the method can reach below 10 microns, and the cefquinome sulfate breast injectant is relatively excellent in stability, relatively high in stability in high-temperature, illumination and freezing environments and relatively excellent in comprehensive performance.

Description

Technical Field

[0001] The present application relates to the technical field of veterinary drugs, and particularly relates to a cefquinome sulfate mammary infusion and its preparation method and application. Background Art

[0002] Clinical mastitis in dairy cows is one of the most common and harmful diseases in the dairy farming industry. It is mainly caused by inflammatory changes in the mammary glands of dairy cows due to physical, chemical, and microbiological stimuli. The main harms of clinical mastitis in dairy cows are as follows: the milk production decreases significantly. Each case of clinical mastitis in dairy cows can cause a 30 - 50% decrease in milk production. In severe cases, it can even lead to no milk production or blind nipples, and ultimately the cows have to be culled. Therefore, this disease not only causes great economic losses to the breeding industry, but also seriously endangers human health. Therefore, the prevention and treatment of clinical mastitis in dairy cows is particularly important.

[0003] Cefquinome is a β - lactam antibiotic. Cefquinome sulfate mammary infusion (lactation period) is a veterinary - specific drug used to treat mastitis in lactating dairy cows caused by sensitive bacteria such as Staphylococcus aureus, Streptococcus agalactiae, Streptococcus uberis, and Escherichia coli.

[0004] Based on the problems of unevenness, easy stratification, and poor stability of cefquinome sulfate mammary infusion in the prior art, the effect of cefquinome sulfate mammary infusion is poor during use. Therefore, it is necessary to provide a cefquinome sulfate mammary infusion and its preparation method to improve the above - mentioned problems. Summary of the Invention

[0005] The main object of the present invention is to provide a cefquinome sulfate mammary infusion and its preparation method and application to solve the problem of poor stability of cefquinome sulfate mammary infusion in the prior art.

[0006] To achieve the above object, according to one aspect of the present invention, there is provided a cefquinome sulfate mammary infusion, which includes cefquinome sulfate, a composite wetting agent, a composite thickening agent, and a solvent; wherein, the composite wetting agent is selected from one or more of liquid paraffin, Span, or Tween.

[0007] Furthermore, by weight percentage, the cefquinome sulfate mammary infusion includes: 0.8 - 3.0 wt% of cefquinome sulfate, 0.1 - 6.5 wt% of the composite wetting agent, 0.15 - 5.5 wt% of the composite thickening agent, and 80 - 95 wt% of the solvent.

[0008] Furthermore, by weight percentage, the cefquinome sulfate mammary infusion includes: 0.94 - 1.29 wt% of cefquinome sulfate, 0.1 - 5.5 wt% of a composite wetting agent, 0.15 - 4.0 wt% of a composite thickening agent, and 80 - 94 wt% of a solvent.

[0009] Furthermore, the composite thickening agent is selected from one or more of gelatin, gum arabic, triethanolamine oleate, glycerol monostearate, or tragacanth; the preferred solvent is soybean oil.

[0010] Furthermore, the cefquinome sulfate mammary infusion is a suspension, and the particle size therein is 0.1 - 10 μm.

[0011] To achieve the above object, according to one aspect of the present invention, a preparation method of the above cefquinome sulfate mammary infusion is provided. The preparation method includes: Step S1, taking cefquinome sulfate and a composite wetting agent and performing a primary soaking in a pretreated solvent to obtain a main drug soaking solution; Step S2, taking a composite thickening agent and performing a secondary soaking in a pretreated solvent to obtain a thickening agent soaking solution; Step S3, taking the main drug soaking solution and the thickening agent soaking solution and performing a dispersion treatment in a homogenizer, and then supplementing the pretreated solvent to the formulated amount to obtain the cefquinome sulfate mammary infusion.

[0012] Furthermore, the pretreated solvent includes: taking the solvent and performing a sterilization treatment by keeping it at a constant temperature of 150 - 200 °C in a sterilization tank for 0.5 - 1.0 h, and after cooling to 40 - 60 °C, obtaining the pretreated solvent; preferably, in Step S1, the amount of the pretreated solvent used is 5 - 10 times the total amount of cefquinome sulfate and the composite wetting agent; preferably, in Step S2, the amount of the pretreated solvent used is 5 - 10 times the amount of the composite thickening agent.

[0013] Furthermore, in Step S3, the dispersion treatment includes taking the main drug soaking solution and the thickening agent soaking solution and performing a dispersion treatment in a homogenizer at a pressure of 15 - 22 MPa and a temperature of 25 - 85 °C.

[0014] Furthermore, after the dispersion treatment, it is also necessary to supplement the pretreated solvent to the formulated amount, and after passing the semi-finished product inspection, then successively perform filling, packaging, sending to a third party for irradiation sterilization and passing the full inspection to obtain the cefquinome sulfate mammary infusion; preferably, the primary soaking temperature is 30 - 60 °C, and the primary soaking time is 0.5 - 2.0 h; preferably, the secondary soaking temperature is 30 - 60 °C, and the secondary soaking time is 0.5 - 2.0 h.

[0015] According to another aspect of the present invention, there is provided an application of the above-mentioned cefquinome sulfate mammary infusion in the prevention and / or treatment of mastitis in dairy cows during lactation, or a cefquinome sulfate mammary infusion obtained by the preparation method of the above-mentioned cefquinome sulfate mammary infusion.

[0016] By applying the technical solution of the present invention, the particle size of the cefquinome sulfate mammary infusion can reach below 10 μm, with excellent stability, and it has high stability under high temperature, light and freezing environments, and its comprehensive performance is excellent. Detailed implementation manners

[0017] To make the objectives, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below in conjunction with the embodiments of the present application. Obviously, the described embodiments are some, but not all, of the embodiments of the present application. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present application without creative efforts shall fall within the scope of protection of the present application.

[0018] As described in the background art part of the present invention, the cefquinome sulfate mammary infusion in the prior art is uneven, prone to layering, and has poor stability, resulting in poor effectiveness during use. The present invention provides a cefquinome sulfate mammary infusion, which includes: cefquinome sulfate, a composite wetting agent, a composite thickening agent and a solvent; wherein, the composite wetting agent is selected from one or more of liquid paraffin, span or tween.

[0019] The cefquinome sulfate mammary infusion provided by the present invention contains cefquinome sulfate. Since cefquinome is a β-lactam antibiotic, the cefquinome sulfate mammary infusion (during lactation) used is a veterinary drug for treating mastitis in dairy cows during lactation caused by sensitive bacteria. Moreover, a composite wetting agent selected from one or more of liquid paraffin, span or tween is added in the present invention to make the product better blend, avoid layering of the product, and improve the stability of the product. In addition, a composite thickening agent is added in the present invention, which can further make the product have a certain consistency, stay better in the mammary gland area of dairy cows, extend the action time, and make the prevention and / or treatment of mastitis in dairy cows during lactation more effective during application.

[0020] In a preferred embodiment, by weight percentage, the cefquinome sulfate mammary infusion includes: 0.8 - 3.0 wt% of cefquinome sulfate, 0.1 - 6.5 wt% of a composite wetting agent, 0.15 - 5.5 wt% of a composite thickening agent, and 80 - 95 wt% of a solvent, so as to further promote the synergistic effect of each component, jointly play a role to enhance the uniformity and stability of the product, and make its application effect better; more preferably, the cefquinome sulfate mammary infusion includes: 0.94 - 1.29 wt% of cefquinome sulfate, 0.1 - 5.5 wt% of a composite wetting agent, 0.15 - 4.0 wt% of a composite thickening agent, and 80 - 94 wt% of a solvent.

[0021] To further promote the product to have a suitable viscosity so that it can better stay in the dairy cow's mammary gland area during application and extend the drug action time, preferably, the composite thickening agent is selected from one or more of gelatin, gum arabic, triethanolamine oleate, glycerol monostearate, or tragacanth; preferably, the solvent is soybean oil to improve the solubility of each component in the product and make its performance better.

[0022] In a preferred embodiment, the cefquinome sulfate mammary infusion is a suspension, and the particle size therein is 0.1 - 10 μm. The obtained cefquinome sulfate mammary infusion can better exert its effect to further enhance the action time of the product and make its effect better.

[0023] On the other hand, the present invention provides a preparation method of a cefquinome sulfate mammary infusion, and the preparation method includes: Step S1, taking cefquinome sulfate and a composite wetting agent and performing a primary soaking in a pretreated solvent to obtain a main drug soaking solution; Step S2, taking a composite thickening agent and performing a secondary soaking in a pretreated solvent to obtain a thickening agent soaking solution; Step S3, taking the main drug soaking solution and the thickening agent soaking solution, performing a dispersion treatment in a homogenizer, and supplementing the pretreated solvent to the preparation amount to obtain the cefquinome sulfate mammary infusion.

[0024] Those skilled in the art first place cefquinome sulfate and a composite wetting agent in a pretreated solvent for a primary soaking treatment to obtain a main drug soaking solution, and then place a composite thickening agent in a pretreated solvent for a secondary soaking to obtain a thickening agent soaking solution; finally, place the main drug soaking solution and the thickening agent soaking solution in a homogenizer for a dispersion treatment and then supplement the pretreated solvent to the preparation amount to obtain the cefquinome sulfate mammary infusion. The cefquinome sulfate mammary infusion prepared by this method has better stability and better effect in subsequent application. Moreover, this preparation method is simple, easy to operate, suitable for large-scale production, and has broad industrial application prospects.

[0025] In a preferred embodiment, the pretreated solvent includes: taking the solvent in a sterilization tank at 150-200°C and keeping it at a constant temperature for 0.5-1.0 h for sterilization treatment. After cooling to 40-60°C, the pretreated solvent is obtained to complete the sterilization treatment of the solvent, improve the cleanliness of the solvent, and avoid affecting the product performance.

[0026] To further improve the stability of the cefquinome sulfate immersion solution and the thickener immersion solution and make the solute fully dissolve in the solvent, preferably in step S1, the amount of the pretreated solvent is 5-10 times the total amount of cefquinome sulfate and the compound wetting agent; further preferably in step S2, the amount of the pretreated solvent is 5-10 times the amount of the compound thickener.

[0027] To further promote the uniform mixing of the cefquinome sulfate immersion solution and the thickener immersion solution, preferably in step S3, the dispersion treatment includes taking the cefquinome sulfate immersion solution and the thickener immersion solution in a homogenizer and performing dispersion treatment at a pressure of 15-22 MPa and a temperature of 25-85°C.

[0028] In a preferred embodiment, after the dispersion treatment, the pretreated solvent needs to be replenished to the preparation amount. After passing the semi-finished product inspection, filling, packaging, irradiation sterilization by a third party, and passing the full inspection are carried out in sequence to obtain the cefquinome sulfate intramammary infusion; to further improve the uniformity and stability of the cefquinome sulfate immersion solution and the thickener immersion solution, preferably the primary immersion temperature is 30-60°C and the primary immersion time is 0.5-2.0 h; the secondary immersion temperature is 30-60°C and the secondary immersion time is 0.5-2.0 h.

[0029] Another aspect of the present invention also provides an application of the above-mentioned cefquinome sulfate intramammary infusion or the cefquinome sulfate intramammary infusion obtained by the preparation method of the above-mentioned cefquinome sulfate intramammary infusion in the drugs for preventing and / or treating mastitis during the lactation period of dairy cows.

[0030] The following further describes the present application in detail with specific examples, and these examples should not be construed as limiting the scope claimed by the present application.

[0031] Example 1

[0032] Take the solvent soybean oil (for injection) in the sterilization tank, sterilize it at 160°C for 30 minutes, and let it cool naturally to 40°C for standby to obtain the pretreated solvent. Take 100 g of cefquinome sulfate, compound wetting agents Tween 80 and Tween 20, 200 g and 200 g respectively, and soak them in the pretreated solvent once. The soaking temperature is 40°C and the soaking time is 1 h to obtain the main drug soaking solution. The amount of the pretreated solvent accounts for 6 times the total amount of cefquinome sulfate and the compound wetting agents; take 10 g of the compound thickening agent gum arabic and soak it in the pretreated solvent for the second time. The soaking temperature is 40°C and the soaking time is 2 h to obtain the thickening agent soaking solution; take the main drug soaking solution and the thickening agent soaking solution and perform dispersion treatment in a homogenizer (manufacturer: Sumitomo Group's Isehi Co., Ltd., model HV-0A1-1.5S), and then add the pretreated solvent to make up to the preparation amount of 10 kg. Among them, the pressure of the dispersion treatment is 20 MPa and the temperature is 37°C. After passing the semi-finished product inspection, it is filled, packaged, sent to a third party for irradiation sterilization, and then released for sale after passing the full inspection, and finally cefquinome sulfate mammary infusion is obtained.

[0033] Cefquinome sulfate mammary infusion, comprising: 1 wt% of cefquinome sulfate, 4 wt% of compound wetting agents, 1 wt% of compound thickening agent and 94 wt% of solvent, wherein the particle size is 1 - 10 μm.

[0034] Comparative Example 1

[0035] The difference from Example 1 is only that: there is no step S3, that is, there is no step of performing dispersion treatment in a homogenizer.

[0036] Performance test:

[0037] 1) Sedimentation ratio

[0038] Use a graduated cylinder with a stopper to take 50 mL of the test sample, tightly stopper it, shake it vigorously for 1 minute, record the initial height H0 of the suspension, let it stand for 3 hours, and record the final height H of the suspension. Calculation formula: sedimentation volume ratio = H / H0.

[0039] 2) Stability

[0040] Perform tests under high temperature or light. If it can be maintained for 12 months, the stability is relatively good; if it can be maintained for 18 months under freezing conditions, the stability is relatively good; if it is stored in a sealed state in a cool and dark place and can be maintained for 36 months, the stability is relatively good.

[0041] Take the products prepared in the above examples and comparative examples for performance testing, and the test results are as follows.

[0042] Table 1: Particle size results of the products of Example 1 and Comparative Example 1.

[0043] Table 2: Sedimentation ratio results of the products of Example 1 and Comparative Example 1.

[0044] Table 3: Results of the destructive experiment of the product of Example 1.

[0045] Table 4: Results of the long-term stability experiment of the product of Example 1.

[0046] Table 1

[0047]

[0048] Note: The particle size requirements of "Cefquinome Sulfate Mammary Infusion (Lactating Period)" in the first part of the Chinese Veterinary Pharmacopoeia 2020 edition are as follows: the particles with a size of less than 15 μm shall not be less than 90%, the particles with a size of less than 20 μm shall not be less than 95%, and the particles with a size of 50 μm or more shall not be detected.

[0049] Table 2

[0050]

[0051] Note: The Chinese Veterinary Pharmacopoeia requires that the sedimentation volume ratio should not be less than 0.9.

[0052] Table 3

[0053]

[0054] Note: If the product color is light yellow, the stability is better; if the product color is yellow, the stability is worse.

[0055] Table 4

[0056]

[0057] Note: If the product color is light yellow, the stability is better.

[0058] From the above description, it can be seen that the above embodiments of the present invention achieve the following technical effects:

[0059] The cefquinome sulfate mammary infusion prepared by the present invention can reach a particle size of less than 10 μm, has excellent stability, is not prone to layering, and has high stability under environments such as high temperature, light, and freezing, and has excellent comprehensive performance.

[0060] While this specification contains many specific implementation details, these should not be construed as limiting the scope of any invention or the scope of what is claimed, but rather as mainly describing the features of specific embodiments of a particular invention. Certain features that are described in multiple embodiments in this specification may also be implemented in combination in a single embodiment. On the other hand, the various features described in a single embodiment may also be implemented separately in multiple embodiments or in any suitable sub-combination. Additionally, although features may operate in certain combinations as described above and even be claimed as such initially, one or more features from the claimed combination may in some cases be removed from that combination, and the claimed combination may be directed to a sub-combination or a variation of a sub-combination.

[0061] Similarly, while operations are depicted in a particular order, this should not be construed as requiring that those operations be performed in the particular order shown or sequentially, or that all of the illustrated operations be performed, to achieve the desired result. In some cases, multitasking and parallel processing may be advantageous. Additionally, the separation of various system modules and components in the above embodiments should not be construed as requiring such separation in all embodiments, and it should be understood that the described program components and systems can generally be integrated together in a single software product or packaged into multiple software products.

[0062] Thus, specific embodiments of the subject matter have been described. Other embodiments are within the scope of the appended claims. In some cases, the acts recited in the claims may be performed in a different order and still achieve the desired result. Additionally, the depicted processes are not necessarily in the particular order or sequential order shown to achieve the desired result. In some implementations, multitasking and parallel processing may be advantageous.

[0063] It should be noted that, in this context, relational terms such as "first" and "second" are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the term "comprising", "including" or any other variation thereof is intended to cover non-exclusive inclusion, such that a process, method, article or device comprising a series of elements includes not only those elements but also other elements not expressly listed, or elements that are inherent to such process, method, article or device. Without further limitation, an element defined by the statement "comprising a..." does not exclude the presence of additional identical elements in the process, method, article or device comprising the element.

[0064] The above description is only a specific implementation manner of the present application, enabling those skilled in the art to understand or implement the present application. Various modifications to these embodiments will be obvious to those skilled in the art, and the general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present application. Therefore, the present application will not be limited to these embodiments shown herein, but rather will be accorded the widest scope consistent with the principles and novel features claimed herein.

Claims

1. A cefquinome sulfate intramammary infusion, characterized in that, The cefquinome sulfate mammary infusion includes: cefquinome sulfate, a compound wetting agent, a compound thickening agent and a solvent; wherein, the compound wetting agent is selected from one or more of liquid paraffin, span or tween.

2. The cefquinome sulfate mammary infusion according to claim 1, wherein By weight percentage, the cefquinome sulfate mammary infusion includes: 0.8 - 3.0 wt% of the cefquinome sulfate, 0.1 - 6.5 wt% of the compound wetting agent, 0.15 - 5.5 wt% of the compound thickening agent and 80 - 95 wt% of the solvent.

3. The cefquinome sulfate mammary infusion according to claim 1 or 2, characterized in that, By weight percentage, the cefquinome sulfate mammary infusion includes: 0.94 - 1.29 wt% of the cefquinome sulfate, 0.1 - 5.5 wt% of the compound wetting agent, 0.15 - 4.0 wt% of the compound thickening agent and 80 - 94 wt% of the solvent.

4. The cefquinome sulfate mammary infusion according to any one of claims 1 to 3, characterized in that, The compound thickening agent is selected from one or more of gelatin, gum arabic, triethanolamine oleate, glycerol monostearate or tragacanth. Preferably, the solvent is soybean oil.

5. The cefquinome sulfate mammary infusion according to any one of claims 1 to 4, characterized in that, The cefquinome sulfate mammary infusion is a suspension, and the particle size therein is 0.1 - 10 μm.

6. A preparation method of cefquinome sulfate mammary infusion agent according to any one of claims 1 to 5, characterized in that, The preparation method includes: Step S1, taking cefquinome sulfate and a compound wetting agent and soaking them once in the pretreated solvent to obtain a main drug soaking solution. Step S2, taking a compound thickening agent and soaking it twice in the pretreated solvent to obtain a thickening agent soaking solution. Step S3, taking the main drug soaking solution and the thickening agent soaking solution and performing dispersion treatment in a homogenizer, and then supplementing the pretreated solvent to the formulated amount to obtain the cefquinome sulfate mammary infusion.

7. The preparation method of cefquinome sulfate mammary infusion according to claim 6, characterized in that, The pretreated solvent includes: taking the solvent and performing sterilization treatment at a constant temperature of 150 - 200 °C in a sterilization tank for 0.5 - 1.0 h, and after cooling to 40 - 60 °C, obtaining the pretreated solvent. Preferably, in step S1, the amount of the pretreated solvent is 5 - 10 times the total amount of the cefquinome sulfate and the compound wetting agent. Preferably, in step S2, the amount of the pretreated solvent is 5 - 10 times the amount of the compound thickening agent.

8. The preparation method of cefquinome sulfate mammary infusion according to claim 6 or 7, characterized in that, In step S3, the dispersion treatment includes: taking the main drug soaking solution and the thickening agent soaking solution in a homogenizer and performing the dispersion treatment at a pressure of 15 - 22 MPa and a temperature of 25 - 85 °C.

9. The preparation method of cefquinome sulfate mammary infusion according to any one of claims 6 to 8, characterized in that, After the dispersion treatment, it is also necessary to supplement the pretreated solvent to the formulated amount, and after passing the semi-finished product inspection, then perform filling, packaging, sending to a third party for irradiation sterilization and passing the full inspection to obtain the cefquinome sulfate mammary infusion. Preferably, the temperature of the first soaking is 30 - 60 °C, and the time of the first soaking is 0.5 - 2.0 h. Preferably, the temperature of the second soaking is 30 - 60 °C, and the time of the second soaking is 0.5 - 2.0 h.

10. Use of cefquinome sulfate mammary infusion agent according to any one of claims 1 to 5, or cefquinome sulfate mammary infusion agent obtained by the preparation method of cefquinome sulfate mammary infusion agent according to any one of claims 6 to 9, in the medicament for preventing and / or treating mastitis during lactation of dairy cows.

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