Cefpodoxime proxetil and clavulanate potassium compound preparation and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a cefpodoxime proxetil and clavulanate potassium compound preparation and a preparation method thereof. In the cefpodoxime proxetil and potassium clavulanate compound preparation provided by the invention, the cefpodoxime proxetil and potassium clavulanate have a synergistic effect, so that the antibacterial effect can be enhanced, the antibacterial spectrum can be expanded, and drug-resistant bacterium infection can be effectively treated; according to the cefpodoxime proxetil premix, auxiliary materials such as lactose, calcium carboxymethyl cellulose and lauryl sodium sulfate are compounded, and a preparation process of firstly mixing cefpodoxime proxetil, lactose, a cosolvent and calcium carboxymethyl cellulose to prepare the premix is adopted, so that all the components are fully mixed and play a synergistic effect, the dissolution speed and bioavailability of the medicine are improved, and the bioavailability of the medicine is improved; the uniformity of preparation components is guaranteed, the stability of the whole process is enhanced, and the method is suitable for large-scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a compound preparation of cefpodoxime proxetil and potassium clavulanate and a preparation method thereof. BACKGROUND

[0002] Cefpodoxime proxetil, as an oral third-generation cephalosporin, has unique advantages. After entering the animal body, it can be hydrolyzed into cefpodoxime by non-specific enzymes, and then exert antibacterial effect. It has a wide antibacterial spectrum and can produce a wide range of antibacterial effects on gram-positive and gram-negative bacteria, and shows stable properties to β-lactamase. At present, human cefpodoxime proxetil is clinically used for the treatment of upper respiratory tract infection, lower respiratory tract infection, urinary tract infection and suppurative otitis media caused by sensitive bacteria. The cefpodoxime proxetil tablet developed by American Zoetis Company, with the trade name of SIMPLICEF, has been applied to the treatment of skin diseases caused by bacterial infection in dogs.

[0003] Potassium clavulanate is the potassium salt of clavulanic acid. As a natural lactam antibiotic produced by bacteria, clavulanic acid has weak antibacterial effect, but has strong and broad-spectrum enzyme inhibition effect, and is rapidly absorbed orally. When it is used in combination with lactam antibiotics such as amoxicillin and ticarcillin, it can protect the combined lactam antibiotics from being inactivated by β-lactamase to varying degrees, thereby significantly improving the effect of the antibiotic on enzyme-producing drug-resistant bacteria and improving the clinical treatment effect. In addition, it also has certain antibacterial effect on Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, Clostridium, Peptococcus and Peptostreptococcus which do not produce β-lactamase.

[0004] However, at present, in the field of veterinary medicine, the use of cefpodoxime proxetil or clavulanic acid alone has certain limitations. On the one hand, with the continuous development of bacterial drug resistance, a single drug is difficult to effectively deal with complex drug-resistant bacterial infections. And with the increase of use time, its activity to some β-lactamase-producing bacteria (such as ESBLs, AmpC) (such as Escherichia coli and Klebsiella pneumoniae) decreases. On the other hand, the existing veterinary drug dosage forms and formulations need to be improved in terms of drug stability, bioavailability, etc. For example, cefpodoxime proxetil raw material has poor stability, and potassium clavulanate has extremely strong hygroscopicity and is unstable under high temperature and high humidity conditions, and is extremely easy to degrade and discolor. Therefore, the development of a veterinary compound preparation reasonably combining cefpodoxime proxetil and clavulanic acid and the optimization of its preparation method to improve the drug efficacy, stability and bioavailability become the key direction to solve the current problems in the treatment of veterinary antibiotics. SUMMARY

[0005] In view of the problems of the existing veterinary cefepime ester preparation, such as the decrease of the activity of some bacteria producing beta-lactamase and the poor stability of the drug, the application provides a cefepime ester potassium clavulanate compound preparation and a preparation method thereof.

[0006] To solve the above technical problems, the technical scheme provided by the application is:

[0007] In the first aspect, the application provides a cefepime ester potassium clavulanate compound preparation, which comprises the following components in parts by weight: 100 parts of cefepime ester, 23.8-29.8 parts of a potassium clavulanate-microcrystalline cellulose compound, 37.5-52.5 parts of lactose, 18.7-37.5 parts of carboxymethyl cellulose calcium, 3.7-7.5 parts of a cosolvent, 7.5-12.5 parts of a binder and 1.2-3.8 parts of a lubricant; wherein the cefepime ester is calculated based on cefepime.

[0008] Compared with the prior art, the cefepime ester potassium clavulanate compound preparation provided by the application takes cefepime ester as the core antibacterial component and cooperates with potassium clavulanate, so that the antibacterial spectrum can be significantly expanded and the killing effect on enzyme-producing drug-resistant bacteria can be enhanced; the potassium clavulanate is added in the form of a potassium clavulanate-microcrystalline cellulose compound, so that the influence of external humidity on the potassium clavulanate can be significantly reduced, and the porous structure of the microcrystalline cellulose can form a protective wrapping for the potassium clavulanate, reduce the possible adverse interaction between the potassium clavulanate and other components, delay the degradation rate of the potassium clavulanate, and ensure that the potassium clavulanate continuously plays an enzyme inhibition role during storage and use; the lactose as a diluent can improve the flowability and compressibility of the material, provide a stable basis for the formation of the preparation, and in cooperation with the microcrystalline cellulose, the lactose can also significantly reduce the influence of external humidity and temperature on the main drug components and effectively delay the degradation of the cefepime ester and the potassium clavulanate; the disintegration performance of the carboxymethyl cellulose calcium and the swelling characteristics of the microcrystalline cellulose form a complement, so that the preparation can be quickly disintegrated in the body and the release of the cefepime ester and the potassium clavulanate can be accelerated; the cosolvent can solve the hydrophobic problem of the cefepime ester and greatly improve the dissolution rate of the drug in cooperation with the disintegration aid, so as to ensure that the effective components are quickly dispersed and absorbed in the body. The synergistic effect of the series of auxiliary materials effectively solves the deficiencies of single components in terms of flowability, disintegration, dissolution rate and stability, and significantly improves the bioavailability of the preparation.

[0009] Further, the cosolvent is sodium dodecyl sulfate.

[0010] The sodium dodecyl sulfate can significantly improve the solubility and dissolution rate of cefpodoxime proxetil in water. The effect forms a high synergistic effect with the disintegration performance of carboxymethyl cellulose calcium and the swelling characteristics of microcrystalline cellulose: after the carboxymethyl cellulose calcium promotes the rapid disintegration of the preparation, the sodium dodecyl sulfate rapidly plays a solubilizing role, so that the cefpodoxime proxetil is dispersed in the body fluid faster, and then the swelling of the microcrystalline cellulose is assisted to further accelerate the drug release, so that the problem of low bioavailability of cefpodoxime proxetil caused by hydrophobicity is solved, and it is ensured that the active ingredients can be quickly absorbed by the animal body and play a role. In addition, the sodium dodecyl sulfate has good compatibility with the excipients such as lactose and carboxymethyl cellulose calcium, and will not cause adverse interactions. The sodium dodecyl sulfate can be uniformly dispersed in the preparation, improve the wettability of the material, and make the binder more uniformly act on each component to improve the uniformity of the particles in the granulation process.

[0011] Further, the binder is hydroxypropyl cellulose.

[0012] The hydroxypropyl cellulose has good film-forming property and viscosity, and can uniformly wrap the component particles such as cefpodoxime proxetil and lactose in the granulation process, so that the material forms particles with appropriate hardness and fluidity, and the uniformity of the particles in the granulation process is improved. In addition, the hydroxypropyl cellulose has good solubility in water, and can quickly dissolve and form a hydrophilic environment with the disintegration of the preparation in the animal body, promote the dissolution and diffusion of the drug ingredients in the body fluid, effectively solve the problem of low dissolution caused by the hydrophobicity of cefpodoxime proxetil, accelerate the absorption speed of the drug in the body, and improve the bioavailability.

[0013] Further, the lubricant is magnesium stearate.

[0014] The preferred lubricant can improve the fluidity in the tablet production, and in addition, can improve the hardness and smoothness of the prepared tablets.

[0015] Further, the mass ratio of clavulanate potassium to microcrystalline cellulose in the clavulanate potassium-microcrystalline cellulose compound is 1:1.

[0016] Further, the cefpodoxime proxetil clavulanate potassium compound preparation further comprises 6.2 parts to 10 parts of coating powder.

[0017] Specifically, the coating powder is Opadry.

[0018] In a second aspect, the application also provides a preparation method of the cefpodoxime proxetil clavulanate potassium compound preparation, which comprises the following steps:

[0019] S1, according to the designed ratio, the components are weighed, the weighed cefpodoxime proxetil, lactose, cosolvent and carboxymethyl cellulose calcium are uniformly mixed to obtain a premix;

[0020] S2, dissolve the adhesive in water to obtain an adhesive solution; add the adhesive solution to the premix and perform wet granulation to obtain wet granules;

[0021] S3, the wet granules are dried, sieved and granulated, and then weighed potassium clavulanate-microcrystalline cellulose complex and lubricant are added in sequence, and tablets are compressed to obtain cefpodoxime oxime potassium clavulanate compound preparation.

[0022] Compared to existing technologies, the method for preparing the cefpodoxime proxetil-clavulanate potassium compound formulation provided by this invention involves first mixing cefpodoxime proxetil, lactose, solubilizer, and calcium carboxymethyl cellulose to form a premix. Premixing allows for sufficient contact between cefpodoxime proxetil and the solubilizer, laying the foundation for improved dissolution performance. Simultaneously, the early addition of lactose provides a more favorable dissolution environment for cefpodoxime proxetil and the solubilizer during formulation disintegration, accelerating drug release.

[0023] Premixing calcium carboxymethyl cellulose allows it to be uniformly dispersed within the particles during wet granulation. Its porous structure can adsorb some cefpodoxime proxetil and solubilizers. When the formulation disintegrates, the expansion of calcium carboxymethyl cellulose promotes the rapid release of the adsorbed drug. At the same time, it works synergistically with the solubilizing effect of sodium dodecyl sulfate: sodium dodecyl sulfate reduces the surface tension of cefpodoxime proxetil, while calcium carboxymethyl cellulose increases the contact area between the drug and body fluids through disintegration. The synergistic effect of the two significantly improves the drug dissolution rate and avoids the problem of insufficient interaction with the active drug and solubilizer caused by the addition of disintegrants later.

[0024] In addition, calcium carboxymethyl cellulose has certain fluidity and adsorption properties. When combined with lactose, it can improve the mixing uniformity of components such as cefpodoxime proxetil (lactose acts as a filler to provide basic fluidity, while calcium carboxymethyl cellulose reduces the agglomeration of active pharmaceutical ingredient particles through adsorption), making the premix composition more uniform. This also creates favorable conditions for the uniform mixing of potassium clavulanate-microcrystalline cellulose and lubricant in the subsequent process, thereby improving the overall stability of the process.

[0025] Furthermore, in S2, the mass concentration of the adhesive solution is 2% to 5%.

[0026] Furthermore, in S3, the drying process employs fluidized bed drying to achieve a moisture content of ≤3%.

[0027] Furthermore, in S3, the sieving and granulation is performed through a 30-mesh sieve.

[0028] Furthermore, the tableting process also includes: coating the obtained tablets to obtain a cefpodoxime proxetil-clavulanate potassium compound preparation.

[0029] It should be noted that the present application can use any type of tablet press to directly compress the mixed material to obtain tablets, and the parameters of the specific compression process can be routinely adjusted by those skilled in the art.

[0030] It should be noted that the cefpodoxime proxetil potassium clavulanate compound preparation of the present application is a veterinary drug preparation, which can effectively cope with common drug-resistant bacterial infections of animals, meet the treatment needs of bacterial infections of various animals such as dogs, pigs, and cows, and provide efficient and convenient drug selection for livestock and pet breeding.

[0031] The cefpodoxime proxetil potassium clavulanate compound preparation provided by the present application has the synergistic effect of cefpodoxime proxetil and potassium clavulanate, which can enhance the antibacterial effect and expand the antibacterial spectrum, effectively coping with drug-resistant bacterial infections; by compounding lactose, carboxymethyl cellulose calcium, and sodium dodecyl sulfate as auxiliary materials, and by using the preparation process of first mixing cefpodoxime proxetil, lactose, a cosolvent, and carboxymethyl cellulose calcium to form a premix, the components are fully mixed and play a synergistic role, which not only improves the drug dissolution rate and bioavailability, ensures the uniformity of the preparation components, but also enhances the overall process stability, which is suitable for large-scale production. DETAILED DESCRIPTION

[0032] In order to make the purpose, technical scheme and advantages of the present application clearer, the present application will be further described in detail below with examples. It should be understood that the specific examples described herein are only used to explain the present application and not to limit the present application.

[0033] In order to better illustrate the present application, the following examples are further illustrated.

[0034] Example 1

[0035] The present embodiment provides a cefpodoxime proxetil potassium clavulanate compound preparation, the prescription amount is as follows:

[0036] Cefpodoxime proxetil (calculated as cefpodoxime) 100 parts, potassium clavulanate-microcrystalline cellulose (1:1) 23.8 parts, lactose 49.2 parts, carboxymethyl cellulose calcium 20 parts, sodium dodecyl sulfate 5.5 parts, hydroxypropyl cellulose 10 parts, magnesium stearate 2.5 parts, Opadry coating premix 8.5 parts.

[0037] The preparation method of the above-mentioned cefpodoxime proxetil potassium clavulanate compound preparation is as follows:

[0038] S1, weigh the prescription amount of cefpodoxime proxetil, lactose, sodium dodecyl sulfate, and carboxymethyl cellulose calcium, mix uniformly, and add into a wet granulator;

[0039] S2, weigh the prescription amount of hydroxypropyl cellulose, add purified water to prepare a 4% hydroxypropyl cellulose solution;

[0040] S3, the hydroxypropyl cellulose solution is added into the wet granulator by peristaltic pump, and shearing stirring is performed during the addition to obtain wet granules;

[0041] S4, the wet granules are dried in a fluidized bed at 70°C, the moisture content is controlled to be less than or equal to 3%, the dried granules are collected, sieved through a 30-mesh sieve to granulate, and fine powder and agglomerates are removed, potassium clavulanate-microcrystalline cellulose (1:1) is added, mixed uniformly, magnesium stearate is added, mixed uniformly, tableted, and coated to obtain the cefpodoxime proxetil-potassium clavulanate compound preparation.

[0042] Example 2

[0043] The present embodiment provides a cefpodoxime proxetil-potassium clavulanate compound preparation, the prescription amount is shown as follows:

[0044] Cefpodoxime proxetil (calculated as cefpodoxime) 100 parts, potassium clavulanate-microcrystalline cellulose (1:1) 25.75 parts, lactose 52.5 parts, carboxymethyl cellulose calcium 18.75 parts, sodium dodecyl sulfate 7.5 parts, hydroxypropyl cellulose 7.5 parts, magnesium stearate 1.25 parts, Opadry coating premix 6.25 parts.

[0045] The preparation method of the above cefpodoxime proxetil-potassium clavulanate compound preparation is as follows:

[0046] S1, the prescription amount of cefpodoxime proxetil, lactose, sodium dodecyl sulfate and carboxymethyl cellulose calcium is weighed and mixed uniformly, and then added into a wet granulator;

[0047] S2, the prescription amount of hydroxypropyl cellulose is weighed and added into purified water to prepare a hydroxypropyl cellulose solution with a mass concentration of 3%;

[0048] S3, the hydroxypropyl cellulose solution is added into the wet granulator by peristaltic pump, and shearing stirring is performed during the addition to obtain wet granules;

[0049] S4, the wet granules are dried in a fluidized bed at 70°C, the moisture content is controlled to be less than or equal to 3%, the dried granules are collected, sieved through a 30-mesh sieve to granulate, and fine powder and agglomerates are removed, potassium clavulanate-microcrystalline cellulose (1:1) is added, mixed uniformly, magnesium stearate is added, mixed uniformly, tableted, and coated to obtain the cefpodoxime proxetil-potassium clavulanate compound preparation.

[0050] Example 3

[0051] The present embodiment provides a cefpodoxime proxetil-potassium clavulanate compound preparation, the prescription amount is shown as follows:

[0052] Cefpodoxime proxetil (as cefpodoxime) 100 parts, Potassium clavulanate-microcrystalline cellulose (1:1) 29.8 parts, lactose 37.5 parts, carboxymethyl cellulose calcium 20.45 parts, sodium lauryl sulfate 5.5 parts, hydroxypropyl cellulose 12.5 parts, magnesium stearate 3.75 parts, Opadry coating premix 10 parts.

[0053] The preparation method of the above-mentioned cefpodoxime proxetil potassium clavulanate compound preparation is as follows:

[0054] S1, the prescription amount of cefpodoxime proxetil, lactose, sodium lauryl sulfate and carboxymethyl cellulose calcium is weighed, mixed uniformly, and added into a wet granulator;

[0055] S2, the prescription amount of hydroxypropyl cellulose is weighed, and purified water is added to prepare a hydroxypropyl cellulose solution with a mass concentration of 2%;

[0056] S3, the hydroxypropyl cellulose solution is added into the wet granulator through a peristaltic pump, and shearing stirring is performed during the addition to granulate, to obtain wet granules;

[0057] S4, the above-mentioned wet granules are dried in a fluidized bed at 70°C, the water content is controlled to be ≤3%, the dried granules are collected, sieved through a 30-mesh sieve to granulate, and fine powder and agglomerates are removed, potassium clavulanate-microcrystalline cellulose (1:1) is added, mixed uniformly, magnesium stearate is added, mixed uniformly, tableted, coated, to obtain the cefpodoxime proxetil potassium clavulanate compound preparation.

[0058] Example 4

[0059] The present embodiment provides a cefpodoxime proxetil potassium clavulanate compound preparation, and the prescription amount is as follows:

[0060] Cefpodoxime proxetil (as cefpodoxime) 100 parts, Potassium clavulanate-microcrystalline cellulose (1:1) 23.8 parts, lactose 38 parts, carboxymethyl cellulose calcium 37.5 parts, sodium lauryl sulfate 3.75 parts, hydroxypropyl cellulose 8.45 parts, magnesium stearate 1.5 parts, Opadry coating premix 6.5 parts.

[0061] The preparation method of the above-mentioned cefpodoxime proxetil potassium clavulanate compound preparation is as follows:

[0062] S1, the prescription amount of cefpodoxime proxetil, lactose, sodium lauryl sulfate and carboxymethyl cellulose calcium is weighed, mixed uniformly, and added into a wet granulator;

[0063] S2, the prescription amount of hydroxypropyl cellulose is weighed, and purified water is added to prepare a hydroxypropyl cellulose solution with a mass concentration of 5%;

[0064] S3, the hydroxypropyl cellulose solution is added into the wet granulator through a peristaltic pump, and shearing stirring is performed during the addition to granulate, to obtain wet granules;

[0065] S4, drying the wet granules in a fluid bed at 70°C, controlling the moisture content to be ≤3%, collecting the dried granules, sizing the granules through a 30 mesh sieve, removing the fine powder and lumps, adding potassium clavulanate-microcrystalline cellulose (1:1), mixing uniformly, adding magnesium stearate, mixing uniformly, tabletting, coating, to obtain the cefpodoxime proxetil-potassium clavulanate compound preparation.

[0066] Comparative Example 1

[0067] This comparative example provides a cefpodoxime proxetil-potassium clavulanate compound preparation, which is different from Example 1 only in that the mass of potassium clavulanate-microcrystalline cellulose (1:1) is replaced by 19 parts, and the rest is exactly the same. The specific prescription amount is shown below:

[0068] Cefpodoxime proxetil (calculated as cefpodoxime) 100 parts, potassium clavulanate-microcrystalline cellulose (1:1) 19 parts, lactose 49.2 parts, carboxymethyl cellulose calcium 20 parts, sodium dodecyl sulfate 5.5 parts, hydroxypropyl cellulose 10 parts, magnesium stearate 2.5 parts, Opadry coating premix 8.5 parts.

[0069] The cefpodoxime proxetil-potassium clavulanate compound preparation is prepared by the same method as Example 1, which will not be repeated here.

[0070] Comparative Example 2

[0071] This comparative example provides a cefpodoxime proxetil-potassium clavulanate compound preparation, which is different from Example 1 only in that the mass of potassium clavulanate-microcrystalline cellulose (1:1) is replaced by 35.7 parts, and the rest is exactly the same. The specific prescription amount is shown below:

[0072] Cefpodoxime proxetil (calculated as cefpodoxime) 100 parts, potassium clavulanate-microcrystalline cellulose (1:1) 35.7 parts, lactose 49.2 parts, carboxymethyl cellulose calcium 20 parts, sodium dodecyl sulfate 5.5 parts, hydroxypropyl cellulose 10 parts, magnesium stearate 2.5 parts, Opadry coating premix 8.5 parts.

[0073] The cefpodoxime proxetil-potassium clavulanate compound preparation is prepared by the same method as Example 1, which will not be repeated here.

[0074] Comparative Example 3

[0075] This comparative example provides a cefpodoxime proxetil-potassium clavulanate compound preparation, which is different from Example 1 only in that the amount of sodium dodecyl sulfate is replaced by 3 parts. The specific prescription amount is as follows:

[0076] Cefpodoxime proxetil (as cefpodoxime) 100 parts, Potassium clavulanate-microcrystalline cellulose (1:1) 23.8 parts, lactose 49.2 parts, carboxymethyl cellulose calcium 20 parts, sodium dodecyl sulfate 3 parts, hydroxypropyl cellulose 10 parts, magnesium stearate 2.5 parts, Opadry coating premix 8.5 parts.

[0077] The cefpodoxime proxetil potassium clavulanate compound preparation is prepared by using the same method as that of Example 1, and details are not repeated here.

[0078] Comparative Example 4

[0079] This comparative example provides a cefpodoxime proxetil potassium clavulanate compound preparation, which is different from Example 1 only in that the amount of carboxymethyl cellulose calcium is replaced by 15 parts, and the specific prescription amount is as follows:

[0080] Cefpodoxime proxetil (as cefpodoxime) 100 parts, Potassium clavulanate-microcrystalline cellulose (1:1) 23.8 parts, lactose 49.2 parts, carboxymethyl cellulose calcium 15 parts, sodium dodecyl sulfate 5.5 parts, hydroxypropyl cellulose 10 parts, magnesium stearate 2.5 parts, Opadry coating premix 8.5 parts.

[0081] The cefpodoxime proxetil potassium clavulanate compound preparation is prepared by using the same method as that of Example 1, and details are not repeated here.

[0082] Comparative Example 5

[0083] This comparative example provides a cefpodoxime proxetil potassium clavulanate compound preparation, which is different from Example 1 only in that the lactose is replaced by an equal amount of mannitol, and the specific prescription is as follows:

[0084] Cefpodoxime proxetil (as cefpodoxime) 100 parts, Potassium clavulanate-microcrystalline cellulose (1:1) 23.8 parts, lactose 49.2 parts, carboxymethyl cellulose calcium 15 parts, sodium dodecyl sulfate 5.5 parts, hydroxypropyl cellulose 10 parts, magnesium stearate 2.5 parts, Opadry coating premix 8.5 parts.

[0085] The cefpodoxime proxetil potassium clavulanate compound preparation is prepared by using the same method as that of Example 1, and details are not repeated here.

[0086] Comparative Example 6

[0087] This comparative example provides a cefpodoxime proxetil potassium clavulanate compound preparation, which is different from Example 1 only in that the carboxymethyl cellulose calcium is replaced by an equal amount of carboxymethyl starch sodium, and the specific prescription is as follows:

[0088] Cefpodoxime proxetil (as cefpodoxime proxetil) 100 parts, potassium clavulanate-microcrystalline cellulose (1:1) 23.8 parts, lactose 49.2 parts, sodium carboxymethyl starch 20 parts, sodium lauryl sulfate 5.5 parts, hydroxypropyl cellulose 10 parts, magnesium stearate 2.5 parts, Opadry coating premix 8.5 parts.

[0089] The cefpodoxime proxetil potassium clavulanate compound preparation is prepared by using the same method as that in Example 1, which is not described here.

[0090] Comparative Example 7

[0091] This comparative example provides a cefpodoxime proxetil potassium clavulanate compound preparation, which has the same prescription as Example 1, and the only difference is that the addition order of potassium clavulanate-microcrystalline cellulose (1:1) is changed, and the specific steps are as follows:

[0092] S1, the prescription amount of cefpodoxime proxetil, potassium clavulanate-microcrystalline cellulose (1:1), lactose, sodium lauryl sulfate and carboxymethyl cellulose calcium is weighed and mixed uniformly, and then added into a wet granulator;

[0093] S2, the prescription amount of hydroxypropyl cellulose is weighed and added into purified water to prepare a hydroxypropyl cellulose solution with a mass concentration of 5%;

[0094] S3, the hydroxypropyl cellulose solution is added into the wet granulator through a peristaltic pump, and shearing stirring is performed during the addition to granulate, and wet granules are obtained;

[0095] S4, the above wet granules are dried in a fluidized bed at 70°C, the water content is controlled to be ≤3%, the dried granules are collected, sieved through a 30-mesh sieve to granulate, and the fine powder and lumps are removed, magnesium stearate is added and mixed uniformly, and then tableting, coating are performed to obtain the cefpodoxime proxetil potassium clavulanate compound preparation.

[0096] Comparative Example 8

[0097] This comparative example provides a cefpodoxime proxetil potassium clavulanate compound preparation, which has the same prescription as Example 1, and the only difference is that the addition order of carboxymethyl cellulose calcium is changed, and the specific steps are as follows:

[0098] S1, the prescription amount of cefpodoxime proxetil, lactose, sodium lauryl sulfate is weighed and mixed uniformly, and then added into a wet granulator;

[0099] S2, the prescription amount of hydroxypropyl cellulose is weighed and added into purified water to prepare a hydroxypropyl cellulose solution with a mass concentration of 5%;

[0100] S3, the hydroxypropyl cellulose solution is added into the wet granulator through a peristaltic pump, and shearing stirring is performed during the addition to granulate, and wet granules are obtained;

[0101] S4, drying the wet granules in a fluid bed at 70°C to control the moisture content to be less than or equal to 3%, collecting the dried granules, sieving the granules through a 30 mesh sieve to remove fine powder and lumps, adding potassium clavulanate-microcrystalline cellulose (1:1), carboxymethylcellulose calcium, mixing uniformly, adding magnesium stearate, mixing uniformly, tabletting, coating, to obtain the cefpodoxime proxetil-potassium clavulanate compound preparation.

[0102] 1. Drug sensitivity test

[0103] 1.1 Sample preparation

[0104] One tablet of the cefpodoxime proxetil-potassium clavulanate compound preparation prepared in Examples 1 to 4 and Comparative Examples 1 to 2 and one tablet of commercially available cefpodoxime proxetil tablet (trade name: SIMPLICEF, batch number: 1232) were each dissolved in a 0.1% sodium bicarbonate solution to prepare a diluent containing 1 mg / mL of cefpodoxime proxetil, and the drug-containing diluent was adsorbed on No. 1 qualitative filter paper to prepare a test sample of 10 μg / paper (paper diameter: 5 mm).

[0105] 1.2 Test strains

[0106] The preservation numbers of the strains used for the test are shown in Table 1.

[0107] Table 1 Strain numbers

[0108] Bacterial strain Strain No. Escherichia coli CMCC(B)44102 Staphylococcus aureus CMCC(B)26003 Pseudomonas aeruginosa CMCC(B)10104 Klebsiella pneumoniae CMCC(B)46117 Micrococcus luteus CMCC(B)28001 Bacillus pumilus CMCC(B)63202

[0109] 1.3 Agar disk diffusion test

[0110] The test strains were inoculated on MH agar plates in an amount of 1.5 x 10 8 CFU / mL using the disk diffusion method, and the drug-containing paper prepared above was placed on the surface of the agar plates, which were then incubated in an inverted 37°C constant temperature incubator for 18 to 24 hours, and the size of the inhibition zone was measured using an automatic caliper. The test results are shown in Table 2.

[0111] Table 2 Results of drug sensitivity test

[0112]

[0113] Note: S = sensitive (MIC > 18 mm), I = intermediate (15 mm < MIC < 17 mm), and R = resistant (MIC < 14 mm).

[0114] The test results show that the cefpodoxime proxetil-potassium clavulanate compound preparation has a synergistic antibacterial effect against antibiotic-resistant bacteria, particularly Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa, compared to cefpodoxime proxetil alone. The antibacterial effect of the compound preparation of the present application on Micrococcus luteus is more superior than that of the compound preparation of the comparative examples. Example 1 also has a certain antibacterial activity against Bacillus pumilus.

[0115] 2. Dissolution profile determination

[0116] Cefpodoxime proxetil and clavulanate potassium compound preparations prepared in Examples 1 to 4, Comparative Examples 3 to 4, and Comparative Example 8 of the present application and cefpodoxime proxetil commercially available tablets (trade name: SIMPLICEF, batch number: 1232) were subjected to dissolution profile determination in 900 mL of water at 75 rpm (paddle method) at 37°C in accordance with the dissolution and release determination method of Appendix 0931 of the 2020 edition of the Chinese Pharmacopoeia, and the similarity factors were compared, and the results are shown in Table 3.

[0117] Table 3 Dissolution amount (%) at each time point

[0118]

[0119]

[0120] The test results show that the amounts of disintegrant and cosolvent have a significant effect on the dissolution profile of cefpodoxime proxetil, and the similarity factor is ≤ 50 after changing the amounts of disintegrant and cosolvent or the addition order of disintegrant, and the compound preparation is not similar to the commercially available product.

[0121] 3. Stability test

[0122] Cefpodoxime proxetil and clavulanate potassium compound preparations prepared in Examples 1 to 4, Comparative Examples 5 to 7 of the present application and cefpodoxime proxetil commercially available tablets (trade name: SIMPLICEF, batch number: 1232) were placed at a temperature of 40°C and a humidity of 75% RH for 6 months, and samples were taken at the 1st, 2nd, 3rd, and 6th months, respectively, and the contents of the samples were determined, in which the content of cefpodoxime proxetil was determined in accordance with the chromatographic conditions under cefpodoxime proxetil tablets in the 2020 edition of the Chinese Pharmacopoeia, and the content of clavulanate potassium was determined in accordance with the chromatographic conditions under clavulanate potassium in the 2020 edition of the Chinese Pharmacopoeia. The results are shown in Table 4.

[0123] Table 4 Content test results

[0124]

[0125]

[0126] The experimental results show that changing the types of diluent and disintegrant, and changing the addition timing of clavulanate potassium-microcrystalline cellulose (1:1) in the preparation process, all result in a decrease in the stability of cefpodoxime proxetil and clavulanate potassium in the compound preparation.

[0127] 4. Cough treatment effect in dogs

[0128] The cefpodoxime proxetil potassium clavulanate compound preparation prepared in Example 1 and the cefpodoxime proxetil commercially available tablet (trade name: SIMPLICEF, batch number: 1232) were administered to a coughing dog, one tablet each time, twice a day, and the symptoms after administration were recorded to evaluate the curative effect. No coughing symptom and good mental state were cured; the coughing symptom was alleviated, which was effective; and the coughing symptom was not alleviated, which was ineffective. The results are shown in Table 5.

[0129] Table 5 Treatment effect

[0130] Group Number of dogs Cured Effective Invalid Cure rate Total effective rate Commercial product group 10 0 2 8 0 20％ Example 1 group 15 12 3 0 80％ 100％

[0131] The test results show that the compound preparation prepared in the embodiment of the present application can make more sick dogs reach the cured state in the treatment of canine diseases, and the treatment effect is significantly better than that of the commercially available product, which can effectively solve the problem of bacterial infection of animals, provide a more reliable drug use scheme for livestock breeding and pet medical treatment, and help to improve the treatment effect and health protection level of animal diseases.

[0132] In summary, the cefpodoxime proxetil and clavulanate potassium are prepared into a compound preparation, which not only ensures the original curative effect of the single preparation, but also expands the antibacterial spectrum, is suitable for pet cat and dog cough, dyspnea, pneumonia caused by Klebsiella pneumoniae, Pasteurella multocida, etc.; and senile cat and dog urinary system infection caused by ESBLs- Escherichia coli, and has a broad application prospect.

[0133] The above only describes the preferred embodiments of the present application and should not be used to limit the present application, and any modification, equivalent replacement or improvement made within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims

1. A compound preparation of cefpodoxime proxetil and potassium clavulanate, characterized in that, The composition comprises the following components in parts by weight: cefpodoxime proxetil 100 parts, potassium clavulanate-microcrystalline cellulose complex 23.8-29.8 parts, lactose 37.5-52.5 parts, carboxymethyl cellulose calcium 18.7-37.5 parts, a cosolvent 3.7-7.5 parts, a binder 7.5-12.5 parts and a lubricant 1.2-3.8 parts; wherein the cefpodoxime proxetil is calculated as cefpodoxime.

2. The cefpodoxime proxetil-potassium clavulanate combined preparation as claimed in claim 1, wherein The cosolvent is sodium dodecyl sulfate.

3. The cefpodoxime proxetil-potassium clavulanate combined preparation as claimed in claim 1, wherein The binder is hydroxypropyl cellulose; and / or The lubricant is magnesium stearate.

4. The cefpodoxime proxetil-potassium clavulanate combined preparation as claimed in claim 1, wherein The mass ratio of potassium clavulanate to microcrystalline cellulose in the potassium clavulanate-microcrystalline cellulose complex is 1:

1.

5. The cefpodoxime proxetil-potassium clavulanate combined preparation as claimed in any one of claims 1 to 4, wherein It further comprises coating powder 6.2-10 parts.

6. The method of preparing the cefpodoxime proxetil-potassium clavulanate combined preparation according to any one of claims 1 to 5, characterized by, The method comprises the following steps: S1. According to the designed ratio, each component is weighed, and the weighed cefpodoxime proxetil, lactose, cosolvent and carboxymethyl cellulose calcium are mixed uniformly to obtain a premix; S2. The binder is dissolved in water to obtain a binder solution; the binder solution is added to the premix to perform wet granulation to obtain wet granules; S3. The wet granules are dried, sieved and granulated, the weighed potassium clavulanate-microcrystalline cellulose and lubricant are sequentially added, and the tablet is pressed to obtain cefpodoxime proxetil potassium clavulanate compound preparation.

7. The preparation method of the cefpodoxime proxetil clavulanate potassium compound preparation as described in claim 6, characterized in that, In S2, the mass concentration of the binder solution is 2%-5%.

8. The preparation method of the cefpodoxime proxetil clavulanate potassium compound preparation as described in claim 6, characterized in that, In S3, the drying is performed by using a fluidized bed dryer, and the moisture content is dried to ≤3%.

9. The preparation method of the cefpodoxime proxetil clavulanate potassium compound preparation as described in claim 6, characterized in that, In S3, the sieving and granulating is performed by passing through a 30-mesh sieve.

10. The method for preparing the cefpodoxime proxetil-clavulanate potassium compound preparation as described in claim 6, characterized in that, After tabletting, the obtained plain tablet is coated to obtain cefpodoxime proxetil potassium clavulanate compound preparation.

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