Ceftiofur hydrochloride injection and preparation method thereof

Abstract

The invention relates to a ceftiofur hydrochloride injection and a preparation method thereof, and relates to the technical field of pharmaceutical preparations, the preparation method of the ceftiofur hydrochloride injection comprises the following steps: heating and stirring a solvent and pharmaceutic adjuvants, and then cooling to obtain a mixture; and adding ceftiofur hydrochloride into the mixture, and then carrying out alternate circulation treatment by adopting ultrasonic waves and microwaves to obtain the ceftiofur hydrochloride injection, the pharmaceutic adjuvants comprise span-80, propylene glycol, lecithin and trehalose. According to the ceftiofur hydrochloride injection and the preparation method thereof, trehalose is introduced into pharmaceutic adjuvants, and an ultrasonic-microwave combined treatment technology is matched, so that the in-vitro slow release effect and the product stability of the ceftiofur hydrochloride injection are remarkably improved, and the defects in the prior art are overcome.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a ceftiofur hydrochloride injection and a preparation method thereof. Background Art

[0002] In the field of medicine, ceftiofur hydrochloride is a broad-spectrum antibiotic that is widely used to treat infectious diseases in animals due to its strong bactericidal activity against a variety of Gram-positive and Gram-negative bacteria, especially in veterinary clinics. However, traditional ceftiofur hydrochloride injection has some obvious technical defects in the preparation and use process, which limits the effect and scope of its clinical application.

[0003] On the one hand, the traditional injection preparation process often fails to ensure the stable release of drugs in the body, resulting in the rapid clearance of drugs by the body after injection, and the inability to maintain long-term blood drug concentrations, thus affecting the therapeutic effect. In addition, drugs are also susceptible to environmental factors such as temperature and light during storage and transportation, leading to drug degradation or inactivation, further reducing the stability and reliability of the product.

[0004] On the other hand, the traditional injection excipients are relatively limited and often fail to meet the drug's requirements for stability, permeability, sustained release, etc. Especially for protein drugs like ceftiofur hydrochloride, an excipient system that can protect drug activity and improve bioavailability is needed.

[0005] In view of this, there is an urgent need to provide a long-acting and stable ceftiofur hydrochloride injection to meet the needs of clinical medication. Summary of the invention

[0006] In order to solve the above problems, the present invention provides a ceftiofur hydrochloride injection and a preparation method thereof.

[0007] In a first aspect, the present invention provides a method for preparing ceftiofur hydrochloride injection, the method for preparing ceftiofur hydrochloride injection comprising the following steps: The solvent and the pharmaceutical excipients are heated and stirred, and then cooled to obtain a mixture; adding ceftiofur hydrochloride to the mixture, and then performing alternating cycle treatment with ultrasound and microwave to obtain the ceftiofur hydrochloride injection; The pharmaceutical excipients include Span-80, propylene glycol, lecithin and trehalose.

[0008] Furthermore, the ultrasonic working condition parameters include: ultrasonic power is 1000~1200W, and the time of each ultrasonic treatment is 1~3 minutes.

[0009] Furthermore, the microwave working condition parameters include: microwave power is 260-410W, and each microwave time is 3-7 minutes.

[0010] Furthermore, the power of the ultrasound is 1100W, and the power of the microwave is 355W.

[0011] Furthermore, the number of cycles of the alternating cycle treatment is 3 to 6 times.

[0012] Furthermore, the pharmaceutical excipients are composed of Span-80, propylene glycol, lecithin and trehalose in a weight ratio of (1~2):(1~2):(0.5~1):(0.5~1).

[0013] Furthermore, the weight ratio of the solvent, the pharmaceutical excipient and the ceftiofur hydrochloride is (84-88):(2-5):(10-11).

[0014] Furthermore, the weight ratio of the solvent, the pharmaceutical excipient and the ceftiofur hydrochloride is 86:3.5:10.5; and the solvent includes soybean oil for injection.

[0015] Furthermore, the working condition parameters of the heating and stirring include: temperature of 110-130° C., time of 45-60 minutes, and stirring speed of 200-300 rpm.

[0016] In a second aspect, the present invention provides a ceftiofur hydrochloride injection, wherein the ceftiofur hydrochloride injection is prepared by the preparation method of the ceftiofur hydrochloride injection described in any one of the first aspects.

[0017] The above technical solution provided by the present invention has at least the following advantages compared with the prior art: The present invention provides a method for preparing ceftiofur hydrochloride injection. The present invention introduces trehalose into pharmaceutical excipients and uses ultrasound-microwave combined treatment technology to significantly improve the in vitro sustained release effect and product stability of ceftiofur hydrochloride injection, thus making up for the shortcomings of the prior art. Specifically: 1. Selection and function of pharmaceutical excipients Siban-80: As a non-ionic surfactant, Siban-80 mainly plays a solubilizing and stabilizing role in the preparation, which helps to evenly disperse ceftiofur hydrochloride in the solvent and improve the solubility and stability of the drug.

[0018] Propylene glycol: As a solvent and humectant, propylene glycol can enhance the permeability of drugs and promote the passage of drugs through biological membranes. It also has good solvent compatibility and helps maintain the clarity and stability of the injection solution.

[0019] Lecithin: As a natural biomembrane component, lecithin has good biocompatibility and emulsification effects. It can encapsulate drugs to form microcapsules or liposome structures, thereby slowing down the release rate of drugs and improving the targeting and bioavailability of drugs.

[0020] Trehalose: It is one of the key excipients in the present invention. As a non-reducing disaccharide, trehalose has excellent ability to protect biologically active substances from environmental stress damage such as high temperature. The introduction of trehalose can effectively stabilize the structure of ceftiofur hydrochloride drugs, prevent it from denaturing or degrading during storage and use, thereby improving the stability of the product. At the same time, trehalose can also promote the glass transition of the drug, further enhancing the sustained release effect of the drug.

[0021] Therefore, the present invention forms a complex drug delivery system through the joint action of Span-80, propylene glycol, lecithin and trehalose in the injection. Lecithin and trehalose are particularly important, not only do they play their own roles, but they may also form a more stable drug encapsulation structure through interaction to delay the release of the drug.

[0022] 2. Ultrasonic-microwave combined processing technology Ultrasonic treatment: Ultrasonic waves can promote the movement and collision of molecules in the solution through cavitation, mechanical and thermal effects, which helps to evenly disperse and suspend the drug. At the same time, it promotes the interaction between excipients such as lecithin and trehalose and the drug to form a more stable drug carrier system.

[0023] Microwave treatment: Microwaves use electromagnetic fields to cause polar molecules in the solution to rotate rapidly and generate heat. This internal heating method can heat the entire solution system more evenly, promote the interaction between the components, especially accelerate the protective effect of trehalose on the drug and the solidification of the microstructure formed by lecithin, thereby improving the stability and sustained-release performance of the injection.

[0024] Therefore, the present invention not only promotes the uniform mixing and interaction of the components through the alternating cycle treatment of ultrasound and microwaves, but also strengthens the protective mechanism of trehalose on the drug and the sustained-release structure formed by lecithin through physical effects, thereby achieving a comprehensive improvement in the performance of the injection.

[0025] In summary, the present invention effectively improves the in vitro sustained release effect and product stability of ceftiofur hydrochloride injection by rationally selecting a combination of pharmaceutical excipients (especially the introduction of trehalose) and combining ultrasound-microwave combined treatment technology, thus making up for the shortcomings of the prior art. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be clearly and completely described in combination with the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0027] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0028] In a first aspect, the present invention provides a method for preparing ceftiofur hydrochloride injection, the method for preparing ceftiofur hydrochloride injection comprising the following steps: The solvent and the pharmaceutical excipients are heated and stirred, and then cooled to obtain a mixture; adding ceftiofur hydrochloride to the mixture, and then performing alternating cycle treatment with ultrasound and microwave to obtain the ceftiofur hydrochloride injection; The pharmaceutical excipients include Span-80, propylene glycol, lecithin and trehalose.

[0029] The invention provides a method for preparing ceftiofur hydrochloride injection. The invention introduces trehalose into pharmaceutical excipients and cooperates with ultrasound-microwave combined treatment technology to significantly improve the in vitro sustained release effect and product stability of ceftiofur hydrochloride injection, thereby making up for the shortcomings of the prior art.

[0030] In some specific embodiments, the ultrasonic working condition parameters include: ultrasonic power is 1000-1200W, and the duration of each ultrasonic treatment is 1-3 minutes.

[0031] In some specific embodiments, the microwave working condition parameters include: microwave power is 260-410W, and each microwave time is 3-7 minutes.

[0032] In some specific embodiments, the power of the ultrasound is 1100W, and the power of the microwave is 355W.

[0033] In some specific embodiments, the alternating cycle treatment is performed for 3 to 6 cycles.

[0034] In some specific embodiments, the pharmaceutical excipient is composed of Span-80, propylene glycol, lecithin and trehalose in a weight ratio of (1~2):(1~2):(0.5~1):(0.5~1).

[0035] In some specific embodiments, the weight ratio of the solvent, the pharmaceutical excipient and the ceftiofur hydrochloride is (84-88): (2-5): (10-11).

[0036] In some specific embodiments, the weight ratio of the solvent, the pharmaceutical excipient and the ceftiofur hydrochloride is 86:3.5:10.5; and the solvent includes soybean oil for injection.

[0037] In some specific embodiments, the working condition parameters of the heating and stirring include: temperature of 110-130° C., time of 45-60 minutes, and stirring speed of 200-300 rpm.

[0038] In a second aspect, based on the same inventive concept, the present invention provides a ceftiofur hydrochloride injection, wherein the ceftiofur hydrochloride injection is prepared by the preparation method of the ceftiofur hydrochloride injection described in any one of the first aspects.

[0039] It should be noted that, for the components and raw materials involved in the ceftiofur hydrochloride injection and the preparation method thereof provided by the present invention, unless otherwise specified or explained, each component can be directly made from commercially available products or prepared in-house according to the preparation method disclosed in the prior art; the operation steps involved, unless otherwise specified or explained, can be carried out in accordance with the operation method disclosed in the prior art or using existing equipment according to its use method.

[0040] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually measured according to national standards. If there is no corresponding national standard, then the conditions recommended by the manufacturer are followed.

[0041] Example 1 This example provides a ceftiofur hydrochloride injection, and the preparation method of the ceftiofur hydrochloride injection comprises the following steps: Step (1): heating and stirring the solvent and pharmaceutical excipients at 120° C. for 60 minutes at a stirring speed of 260 rpm, and then cooling to room temperature to obtain a mixture; Step (2): adding ceftiofur hydrochloride to the mixture obtained in step (1), and then performing alternating cycle treatment with ultrasound and microwave, wherein the number of cycles of the alternating cycle treatment is 5 times, the power of the ultrasound is 1100 W, the time of each ultrasound is 2 minutes, the power of the microwave is 355 W, and the time of each microwave is 5 minutes, to obtain the ceftiofur hydrochloride injection; The weight ratio of the solvent, the pharmaceutical excipient and the ceftiofur hydrochloride is 86:3.5:10.5; the pharmaceutical excipient is composed of Span-80, propylene glycol, lecithin and trehalose in a weight ratio of 1.5:1.8:0.7:0.8; and the solvent is soybean oil for injection.

[0042] Example 2 This example provides a ceftiofur hydrochloride injection, and the preparation method of the ceftiofur hydrochloride injection comprises the following steps: Step (1): heating and stirring the solvent and the pharmaceutical excipients at 130° C. for 45 minutes at a stirring speed of 200 rpm, and then cooling to room temperature to obtain a mixture; Step (2): adding ceftiofur hydrochloride to the mixture obtained in step (1), and then performing alternating cycle treatment with ultrasound and microwave, wherein the number of cycles of the alternating cycle treatment is 6 times, the power of the ultrasound is 1000 W, the time of each ultrasound is 1 minute, the power of the microwave is 410 W, and the time of each microwave is 3 minutes, to obtain the ceftiofur hydrochloride injection; The weight ratio of the solvent, the pharmaceutical excipient and the ceftiofur hydrochloride is 88:2:10; the pharmaceutical excipient is composed of Span-80, propylene glycol, lecithin and trehalose in a weight ratio of 1:2:0.5:1; and the solvent is soybean oil for injection.

[0043] Example 3 This example provides a ceftiofur hydrochloride injection, and the preparation method of the ceftiofur hydrochloride injection comprises the following steps: Step (1): heating and stirring the solvent and pharmaceutical excipients at 110° C. for 60 minutes at a stirring speed of 300 rpm, and then cooling to room temperature to obtain a mixture; Step (2): adding ceftiofur hydrochloride to the mixture obtained in step (1), and then performing alternating cycle treatment with ultrasound and microwave, wherein the number of cycles of the alternating cycle treatment is 3 times, the power of the ultrasound is 1200 W, the time of each ultrasound is 3 minutes, the power of the microwave is 260 W, and the time of each microwave is 7 minutes, to obtain the ceftiofur hydrochloride injection; The weight ratio of the solvent, the pharmaceutical excipient and the ceftiofur hydrochloride is 84:5:11; the pharmaceutical excipient is composed of Span-80, propylene glycol, lecithin and trehalose in a weight ratio of 2:1:1:0.5; and the solvent is soybean oil for injection.

[0044] Comparative Example 1 This example provides a ceftiofur hydrochloride injection and a preparation method thereof, which is different from Example 1 only in that the pharmaceutical excipient is composed of Span-80, propylene glycol and lecithin in a weight ratio of 1.5:1.8:0.7 (i.e., no trehalose is added to the pharmaceutical excipient); the remaining steps and parameters are the same.

[0045] Comparative Example 2 This example provides a ceftiofur hydrochloride injection and a preparation method thereof, which is different from Example 1 only in that only ultrasonic treatment is performed in step (2); the remaining steps and parameters are the same.

[0046] The preparation method of the above-mentioned ceftiofur hydrochloride injection comprises the following steps: Step (1): heating and stirring the solvent and pharmaceutical excipients at 120° C. for 60 minutes at a stirring speed of 260 rpm, and then cooling to room temperature to obtain a mixture; Step (2): adding ceftiofur hydrochloride to the mixture obtained in step (1), and then subjecting the mixture to ultrasonic treatment, wherein the ultrasonic power is 1100 W and the ultrasonic time is 20 minutes, to obtain the ceftiofur hydrochloride injection; The weight ratio of the solvent, the pharmaceutical excipient and the ceftiofur hydrochloride is 86:3.5:10.5; the pharmaceutical excipient is composed of Span-80, propylene glycol, lecithin and trehalose in a weight ratio of 1.5:1.8:0.7:0.8; and the solvent is soybean oil for injection.

[0047] Comparative Example 3 This example provides a ceftiofur hydrochloride injection and a preparation method thereof, which is different from Example 1 only in that only microwave treatment is performed in step (2); the remaining steps and parameters are the same.

[0048] The preparation method of the above-mentioned ceftiofur hydrochloride injection comprises the following steps: Step (1): heating and stirring the solvent and pharmaceutical excipients at 120° C. for 60 minutes at a stirring speed of 260 rpm, and then cooling to room temperature to obtain a mixture; Step (2): adding ceftiofur hydrochloride to the mixture obtained in step (1), and then treating the mixture with microwaves, wherein the microwave power is 355 W and the microwave time is 20 minutes, to obtain the ceftiofur hydrochloride injection; The weight ratio of the solvent, the pharmaceutical excipient and the ceftiofur hydrochloride is 86:3.5:10.5; the pharmaceutical excipient is composed of Span-80, propylene glycol, lecithin and trehalose in a weight ratio of 1.5:1.8:0.7:0.8; and the solvent is soybean oil for injection.

[0049] Test Case In this example, the performance of the ceftiofur hydrochloride injection obtained in the above Examples 1 to 3 and Comparative Examples 1 to 3 was tested.

[0050] 1) In vitro drug release test: According to the test method reported in the prior art literature, the in vitro release characteristics of the ceftiofur hydrochloride injection provided in Examples 1 to 3 and Comparative Examples 1 to 3 were evaluated and compared.

[0051] According to the method reported in the prior art, the sample preparations of ceftiofur hydrochloride injection obtained in Examples 1 to 3 and Comparative Examples 1 to 3 were respectively measured and placed in a dialysis bag, the two ends were tied tightly, 0.05 mol / L acetamide: acetonitrile (80: 20 v / v) was used as the release medium, the mixture was stirred at a speed of 100 rpm, and dialyzed at a constant temperature of 37.5°C. 0.4 ml of the release solution was drawn at different time points, and the same amount of the release medium was supplemented at the same time. The concentration of ceftiofur in the release medium was detected by HPLC to investigate the in vitro release of the sample.

[0052] 1.1 Sample preparation: Accurately measure the ceftiofur hydrochloride injection samples prepared in Examples 1 to 3 and Comparative Examples 1 to 3 to ensure that the amount of each sample is consistent for subsequent comparative analysis.

[0053] 1.2 Dialysis device setup: Use pre-treated dialysis bags to ensure no leakage, inject the above samples into the dialysis bags respectively, and tie the two ends tightly to prevent sample leakage. Select a suitable dialysis medium, i.e., a mixture of 0.05 mol / L acetamide and acetonitrile (volume ratio of 80:20), which is designed to simulate the physiological environment and promote effective drug release.

[0054] 1.3 Release condition control: Place the dialysis bag containing the sample in a thermostatic stirrer, set the temperature to 37.5°C (simulating human body temperature), and adjust the stirring speed to 100 rpm to ensure uniform mixing of the release medium and sustained release of the drug. Draw 0.4 ml of release solution at different time points and add the same amount of release medium at the same time.

[0055] 1.4 Drug concentration detection and statistical analysis: High performance liquid chromatography (HPLC) was used to detect the concentration of ceftiofur in the release solution collected at each time point, and the in vitro release rate of the samples was statistically analyzed to obtain the in vitro drug release concentration T 50% (In the in vitro release test, the time required for the drug to be released from the preparation to reach 50% of the total release, h) The test results are shown in Table 1.

[0056] Table 1 As shown in Table 1, compared with Comparative Examples 1 to 3, the ceftiofur hydrochloride injection provided in the embodiment of the present invention has a longer in vitro drug release concentration T 50%, the sustained-release effect is better.

[0057] 2) Product stability test: Based on the above test, the samples of ceftiofur hydrochloride injection obtained in Examples 1 to 3 were placed in a 40±2°C water bath for stability test. The test time was 6 months, and the color change of the samples of ceftiofur hydrochloride injection was observed. The test results showed that the samples of ceftiofur hydrochloride injection obtained in Examples 1 to 3 did not change in color before and after the test, and the product stability was good.

[0058] In summary, the present invention provides a ceftiofur hydrochloride injection and a preparation method thereof. The present invention significantly improves the in vitro sustained release effect and product stability of ceftiofur hydrochloride injection by introducing trehalose into pharmaceutical excipients and combining ultrasound-microwave combined treatment technology, thereby making up for the shortcomings of the prior art.

[0059] Various embodiments of the present invention may be presented in the form of a range; it should be understood that the description in the form of a range is only for convenience and brevity, and should not be understood as a rigid limitation on the scope of the present invention; therefore, the range description should be considered to have specifically disclosed all possible sub-ranges and single numerical values ​​within the range. For example, the range description from 1 to 6 should be considered to have specifically disclosed sub-ranges, such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as single numbers within the range, such as 1, 2, 3, 4, 5 and 6, which apply regardless of the range. In addition, whenever a numerical range is indicated herein, it is meant to include any cited number (fractional or integer) within the indicated range.

[0060] The foregoing is merely a specific embodiment of the present invention, which enables those skilled in the art to understand or implement the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features claimed herein.

Claims

1. A method for preparing ceftiofur hydrochloride injection, characterized in that: The preparation method of the ceftiofur hydrochloride injection comprises the following steps: The solvent and the pharmaceutical excipients are heated and stirred, and then cooled to obtain a mixture; adding ceftiofur hydrochloride to the mixture, and then performing alternating cycle treatment with ultrasound and microwave to obtain the ceftiofur hydrochloride injection; The pharmaceutical excipients include Span-80, propylene glycol, lecithin and trehalose.

2. The method for preparing ceftiofur hydrochloride injection according to claim 1, characterized in that: The ultrasonic working condition parameters include: ultrasonic power is 1000-1200W, and the time of each ultrasonic treatment is 1-3 minutes.

3. The method for preparing ceftiofur hydrochloride injection according to claim 1, characterized in that: The working condition parameters of the microwave include: microwave power of 260-410W, and each microwave time of 3-7 minutes.

4. The method for preparing ceftiofur hydrochloride injection according to claim 1, characterized in that: The power of the ultrasound is 1100W, and the power of the microwave is 355W.

5. The method for preparing ceftiofur hydrochloride injection according to claim 1, characterized in that: The number of cycles of the alternating cycle treatment is 3 to 6 times.

6. The method for preparing ceftiofur hydrochloride injection according to claim 1, characterized in that: The pharmaceutical excipients are composed of Span-80, propylene glycol, lecithin and trehalose in a weight ratio of (1-2):(1-2):(0.5-1):(0.5-1).

7. The method for preparing ceftiofur hydrochloride injection according to claim 1, characterized in that: The weight ratio of the solvent, the pharmaceutical excipient and the ceftiofur hydrochloride is (84-88): (2-5): (10-11).

8. The method for preparing ceftiofur hydrochloride injection according to claim 1, characterized in that: The weight ratio of the solvent, the pharmaceutical excipient and the ceftiofur hydrochloride is 86:3.5:10.5; the solvent includes soybean oil for injection.

9. The method for preparing ceftiofur hydrochloride injection according to claim 1, characterized in that: The working condition parameters of the heating and stirring include: temperature of 110-130° C., time of 45-60 minutes, and stirring speed of 200-300 rpm.

10. A ceftiofur hydrochloride injection, characterized in that: The ceftiofur hydrochloride injection is prepared by the preparation method according to any one of claims 1 to 9.

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