WO2023039947A1 - Pharmaceutical composition containing cefoperazone sodium and tazobactam sodium and application thereof - Google Patents

Abstract

Disclosed are a pharmaceutical composition containing cefoperazone sodium and tazobactam sodium, and an application thereof. In the pharmaceutical composition, the weight ratio of cefoperazone sodium to tazobactam sodium is 6:1. In the treatment of renal insufficiency combined with bacterial infection, the pharmaceutical composition can effectively increase clinical efficacy and also significantly reduce the incidence of adverse reactions, thereby excellently ensuring efficacy and safety. Also provided is a pharmaceutical composition that effectively reduces the production of related substances, significantly increasing the quality of the product containing cefoperazone sodium and tazobactam sodium in a ratio of 6:1, and can further ensure stability of the drug in use as well as during storage and transportation.

Description

A kind of pharmaceutical composition containing cefoperazone sodium and tazobactam sodium and application thereof technical field

The invention relates to the field of medicine, in particular to a pharmaceutical composition containing cefoperazone sodium and tazobactam sodium and an application thereof.

Background technique

Renal insufficiency is the persistent decline in renal function caused by various reasons, and it is also called chronic kidney disease (chronic kidney diseases, CKD). The reported prevalence of renal insufficiency in adults is about 14.8%. At present, there is no good clinical treatment for renal insufficiency, and the condition of renal insufficiency can rarely be reversed. Generally, nutritional support is used to prevent metabolic disorders and treat related diseases such as hypertension, hyperlipidemia, diabetes, anemia, etc. Treatment to slow the progression of renal insufficiency and prevent further deterioration.

Bacterial infection is a common clinical disease. Bacterial infections of the respiratory system can cause inflammation of the upper or lower airways, such as bronchitis, pneumonia, etc. Bacterial infections of the urinary system or urinary tract infections, including cystitis, pyelonephritis, complicated urinary tract infections, recurrent urinary tract infections, etc. Urinary system infections are generally treated with sulfonamide antibiotics, β-lactam antibiotics, and quinolone antibiotics, Select drug-specific treatment according to the drug sensitivity test.

Clinically, for patients with renal insufficiency and bacterial infection, antibiotics are generally used to treat the infection, and their renal function is closely monitored. However, drug nephrotoxicity is an important issue to consider. Cefoperazone/tazobactam is a marketed compound antibiotic, clinically used to treat lower respiratory tract infection, urinary system infection, abdominal infection, blood infection, bacterial meningitis, skin and soft tissue infection caused by sensitive bacteria wait. However, it has been reported in recent years (for example: Zhang Shengyu et al., 2014; Huang Jinping, 2017) that when the cefoperazone/tazobactam compound preparation is used to treat patients with renal insufficiency and bacterial infection, severe adverse reactions such as convulsions often occur, resulting in Withdrawal.

Therefore, for patients with renal insufficiency and bacterial infection, it is necessary to develop a safe and effective drug.

Contents of the invention

One of the objects of the present invention is to provide a pharmaceutical composition. In order to realize this object, the technical scheme that the present invention takes is:

A pharmaceutical composition for treating renal insufficiency combined with bacterial infection, containing cefoperazone sodium and tazobactam sodium in the pharmaceutical composition, wherein, cefoperazone sodium (calculated as cefoperazone) and tazobactam sodium (calculated as tazobactam) Zobactam) in a weight ratio of 6:1.

or it could be:

A pharmaceutical composition for treating bacterial infection in patients with renal insufficiency, containing cefoperazone sodium and tazobactam sodium in the pharmaceutical composition, wherein, cefoperazone sodium (calculated as cefoperazone) and tazobactam sodium (calculated as tazobactam) Zobactam) in a weight ratio of 6:1.

In the example of some pharmaceutical compositions, the weight of cefoperazone sodium (calculated as cefoperazone) in the described pharmaceutical composition is 1g～3g, and the weight of described tazobactam sodium (calculated as tazobactam) is 0.17 g ~ 0.5g.

In the example of some pharmaceutical compositions, the weight of cefoperazone sodium (calculated as cefoperazone) in the described pharmaceutical composition is 1g～1.5g, and the weight of described tazobactam sodium (calculated as tazobactam) is 0.17g～0.25g. For example, 1 g of cefoperazone sodium and 0.17 g of tazobactam sodium in the pharmaceutical composition, or 1.5 g of cefoperazone sodium and 0.25 g of tazobactam sodium in the pharmaceutical composition, etc.

In some examples of the pharmaceutical composition, the renal insufficiency is severe renal insufficiency.

In some examples of pharmaceutical compositions, the severe renal insufficiency refers to creatinine clearance <30mL/min.

In some examples of the pharmaceutical composition, the patient with renal insufficiency is a patient with severe renal insufficiency.

In some examples of the pharmaceutical composition, the creatinine clearance rate of the patient with severe renal insufficiency is <30mL/min.

In some examples of the pharmaceutical composition, the infection is a respiratory infection.

In some examples of the pharmaceutical composition, the respiratory system infection includes upper respiratory tract infection and lower respiratory tract infection. Such as bronchial infection, tonsillitis, pneumonia and so on.

In some examples of the pharmaceutical composition, the infection is a urinary system infection.

In some examples of the pharmaceutical composition, the urinary system infection includes upper urinary tract infection and lower urinary tract infection. Such as cystitis, pyelonephritis, complicated urinary tract infection, recurrent urinary tract infection and so on.

In some examples of the pharmaceutical composition, the bacteria are cefoperazone-resistant bacteria.

In some examples of the pharmaceutical composition, the treatment of renal insufficiency complicated by bacterial infection by the pharmaceutical composition does not produce adverse reactions of decreased renal function, or does not further reduce the renal function of the patient.

In some examples of the pharmaceutical composition, the pharmaceutical composition does not produce adverse reactions in the central nervous system in the treatment of renal insufficiency complicated with bacterial infection.

In some examples of pharmaceutical compositions, the central nervous system adverse reactions include convulsions, epilepsy and/or convulsions.

In some examples of pharmaceutical compositions, the pharmaceutical compositions also contain (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H-1 , 2,3-triazol-1-yl) butanoic acid.

In some examples of pharmaceutical compositions, in the pharmaceutical composition, cefoperazone sodium (calculated as cefoperazone) and (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl The weight ratio of -4-(1H-1,2,3-triazol-1-yl)butanoic acid is 600:0.02-0.5.

The second object of the present invention is to provide an application. In order to realize this object, the technical scheme that the present invention takes is:

Application of a pharmaceutical composition containing cefoperazone sodium and tazobactam sodium in the preparation of a drug for the treatment of renal insufficiency combined with bacterial infection, wherein, cefoperazone sodium (calculated as cefoperazone) and sodium tazobactam (calculated as tazobactam ) in a weight ratio of 6:1.

or it could be:

Application of a pharmaceutical composition containing cefoperazone sodium and tazobactam sodium in the preparation of a drug for the treatment of bacterial infections in patients with renal insufficiency, wherein, cefoperazone sodium (calculated as cefoperazone) and tazobactam sodium (calculated as tazobactam meter) weight ratio of 6:1.

In some application examples, in the pharmaceutical composition, the weight of cefoperazone sodium (calculated as cefoperazone) is 1 g to 3 g, and the weight of tazobactam sodium (calculated as tazobactam) is 0.17 g to 0.5 g. g.

In some application examples, the renal insufficiency is severe renal insufficiency.

In some application examples, the severe renal insufficiency refers to creatinine clearance <30mL/min.

In some application examples, the patient with renal insufficiency is a patient with severe renal insufficiency.

In some application examples, the creatinine clearance rate of the patient with severe renal insufficiency is <30mL/min.

In some application examples, the infection is a respiratory infection.

In some application examples, the respiratory system infection includes upper respiratory tract infection and lower respiratory tract infection. Such as bronchial infection, tonsillitis, pneumonia and so on.

In some application examples, the infection is a urinary system infection.

In some application examples, the urinary system infection includes upper urinary tract infection and lower urinary tract infection. Such as cystitis, pyelonephritis, complicated urinary tract infection, recurrent urinary tract infection and so on.

In some application examples, the bacteria are cefoperazone-resistant bacteria.

In some application examples, the drug for treating renal insufficiency complicated with bacterial infection does not produce adverse reactions of decreased renal function, or does not further reduce the patient's renal function.

In some application examples, the drug for treating renal insufficiency complicated with bacterial infection does not produce adverse reactions in the central nervous system.

In some application examples, the central nervous system adverse reactions include convulsions, epilepsy and/or convulsions.

In some application examples, the pharmaceutical composition also contains (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H-1,2 ,3-triazol-1-yl)butanoic acid.

In some application examples, in the pharmaceutical composition, cefoperazone sodium (calculated as cefoperazone) and (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4 The weight ratio of -(1H-1,2,3-triazol-1-yl)butanoic acid is 600:0.02-0.5.

The third object of the present invention is to provide a treatment method. In order to realize this object, the technical scheme that the present invention takes is:

A method for treating renal insufficiency combined with bacterial infection, comprising administering a pharmaceutical composition to a patient in need, the pharmaceutical composition containing cefoperazone sodium (calculated as cefoperazone) and tazoba in a weight ratio of 6:1 Tan sodium (calculated as tazobactam).

or it could be,

A method for treating bacterial infection in patients with renal insufficiency, comprising administering a pharmaceutical composition to the patient in need, the pharmaceutical composition containing cefoperazone sodium (calculated as cefoperazone) and tazoba in a weight ratio of 6:1 Tan sodium (calculated as tazobactam).

In some method instances, the renal insufficiency is severe renal insufficiency.

In some method examples, the severe renal insufficiency refers to creatinine clearance <30 mL/min.

In some method examples, the patient with renal insufficiency is a patient with severe renal insufficiency.

In some method examples, the creatinine clearance rate of the patient with severe renal insufficiency is <30 mL/min.

In some instances of the methods, the infection is a respiratory infection.

In some method examples, the respiratory infection includes upper respiratory tract infection and lower respiratory tract infection. Such as bronchial infection, tonsillitis, pneumonia and so on.

In some instances of the methods, the infection is a urinary tract infection.

In some examples of the method, the urinary tract infection includes upper urinary tract infection and lower urinary tract infection. Such as cystitis, pyelonephritis, complicated urinary tract infection, recurrent urinary tract infection and so on.

In some examples of the methods, the bacteria are cefoperazone-resistant bacteria.

In some method instances, the method does not produce adverse effects of decreased renal function.

In some method instances, the method does not produce central nervous system adverse effects.

In some examples of the method, the central nervous system adverse reaction includes convulsions, seizures and/or convulsions.

In some method examples, the daily dosage of the cefoperazone sodium (calculated as cefoperazone) is 1g-6g, and the daily dosage of the described tazobactam sodium (calculated as tazobactam) is 0.17g-1g .

In some method examples, the daily dosage of the cefoperazone sodium (calculated as cefoperazone) is 6 g, and the daily dosage of the tazobactam sodium (calculated as tazobactam) is 1 g.

In examples of some methods, the pharmaceutical composition is administered every 8 hours or every 12 hours.

In some method examples, the pharmaceutical composition further contains (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H-1,2 ,3-triazol-1-yl)butanoic acid.

In some method examples, in the pharmaceutical composition, cefoperazone sodium (calculated as cefoperazone) and (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4 The weight ratio of -(1H-1,2,3-triazol-1-yl)butanoic acid is 600:0.02-0.5.

The beneficial effects of the present invention are:

Cefoperazone/tazobactam is a commonly used compound preparation for the clinical treatment of urinary system infections, but for patients with renal insufficiency, excessive drug concentration exposure is more likely to cause adverse drug reactions, and antibiotic compound preparations often make the situation worse for complex. The cefoperazone/tazobactam 6:1 pharmaceutical composition of the present invention achieves a good balance of effectiveness and safety in the treatment of patients with renal insufficiency and bacterial infection, not only the clinical curative effect is better than the existing varieties, but also in It shows obvious advantages in reducing the incidence of adverse reactions.

In addition, the cefoperazone/tazobactam 6:1 pharmaceutical composition of the present invention is more convenient in clinical application, can reduce the frequency of administration and improve patient compliance under the premise of ensuring the curative effect. For the treatment of moderate and severe infections, especially for patients with renal insufficiency, the pharmaceutical composition of the present invention can flexibly increase the dose of antibacterial active ingredients, and ensure that the enzyme inhibitor continues to inhibit the enzyme activity, but will not increase the burden on the kidneys .

In order to further improve the product quality of the cefoperazone/tazobactam composition, the present invention also provides an effective method for effectively improving the cefoperazone/tazobactam compound New ideas for composition stability. The applicant unexpectedly found that after adding a certain amount of compound A to the composition, the production of related substances in the cefoperazone/tazobactam composition can be significantly reduced, the stability and product quality of the composition can be effectively improved, and the cephalosporin The safety of the piperidone/tazobactam composition, especially in the anti-infection treatment of patients with impaired renal function; it has positive significance in clinical application and drug storage and transportation.

Detailed ways

The present invention will be described in detail below with specific embodiments. It should be understood that the content of the detailed description is illustrative rather than restrictive, that is, it does not limit any content of the present invention.

definition:

"Renal insufficiency" refers to the persistent decline of renal function caused by various reasons. Usually, the glomerular filtration rate (GFR) can be used for diagnosis and staging. A GFR of 60-89mL/min is mild renal insufficiency, and a GFR of 30-59mL/min is moderate renal insufficiency. A GFR of 15-29 mL/min is considered severe renal insufficiency, and a GFR of less than 15 mL/min is considered end-stage renal disease.

"Pharmaceutical composition": The pharmaceutical composition in the present invention refers to a combination of more than one substance, and one or more components in the combination can exert the effect of treating diseases. The pharmaceutical composition of the present invention may contain a certain amount of moisture or impurities.

The dosage or ratio described in the present invention is calculated based on the amount of free substances. For example, cefoperazone sodium is calculated as cefoperazone, and tazobactam sodium is calculated as tazobactam.

The "cefoperazone sodium/tazobactam sodium for injection (4:1)" and "cefoperazone sodium/tazobactam sodium for injection (8:1)" used in the examples of the present invention are all commercially available products. Cefoperazone sodium/tazobactam sodium for injection (6:1) was provided by Xiangbei Wellman Pharmaceutical Co., Ltd., including 1.17g (containing 1g of cefoperazone and 0.17g of tazobactam), 1.75g (containing 1g of cefoperazone 1.5g and tazobactam 0.25g) and other product specifications.

Example 1: Comparative clinical trial of cefoperazone sodium/tazobactam sodium (6:1) and cefoperazone sodium/tazobactam sodium (4:1) in the treatment of respiratory system infection and urinary system infection

The efficacy and safety of cefoperazone sodium/tazobactam sodium (6:1) and cefoperazone sodium/tazobactam sodium (4:1) were studied in a clinical trial.

Experimental Design: Randomized, single-blind, active drug-controlled trial.

Control drug: cefoperazone sodium/tazobactam sodium for injection (4:1)

Test drug: cefoperazone sodium/tazobactam sodium for injection (6:1)

Subjects: Cases diagnosed with respiratory system infection or urinary system infection received cefoperazone monotherapy for 3 days uniformly. Three days later, the clinically ineffective cases were screened out, sputum or urine was extracted, and those who were resistant to cefoperazone single drug and sensitive to control drugs and test drugs through bacterial culture were marked as meeting the entry conditions and formally enrolled. Subjects with respiratory system infection were divided into control drug group and test drug group; subjects with urinary system infection were divided into control drug group and test drug group. The sex, age, vital signs, height, weight, and disease severity of the subjects in the control drug group and the experimental drug group were basically similar.

Administration: The control drug group used cefoperazone sodium/tazobactam sodium for injection (4:1), administered intravenously once every 8 hours, and the daily dosage was 4.8 g of cefoperazone sodium (calculated as cefoperazone), and tazobactam Bactam sodium (calculated as tazobactam) 1.2g. The test drug group used cefoperazone sodium/tazobactam sodium for injection (6:1), administered intravenously once every 12 hours, and the daily dosage was cefoperazone sodium (calculated as cefoperazone) 6.0g, tazobactam sodium (calculated as tazobactam) 1.0g.

Treatment cycle: The treatment period is 7-14 days, which is determined by the clinical researcher according to the type and severity of the disease.

Test results: Taking the clinical cure rate (clinical cure is judged by clinical researchers according to the diagnosis and treatment guidelines of related diseases) as the effectiveness index, the FAS subject set (full analysis set) was analyzed, and the results are shown in Table 1 and Table 2 . The analysis found that, from a numerical point of view, the overall effectiveness of the test drug, as well as the effectiveness of the respiratory system infection and urinary system infection are better than the control drug. Taking the incidence of adverse reactions as the safety index, the analysis of the SS subject set (safety data set) found that the safety of the experimental drug was basically equivalent to that of the control drug.

Table 1 Comparison of clinical cure rates between the two groups after drug treatment

Table 2 Comparison of the incidence of adverse reactions between the two groups after drug treatment

group	Overall incidence of adverse reactions
Test drug group (6:1)	13.47%
Control group (4:1)	13.04%

Example 2: Cefoperazone Sodium/Tazobactam Sodium (6:1) and Cefoperazone Sodium/Tazobactam Sodium (4:1), Cefoperazone Sodium/Tazobactam Sodium (8:1) Treat Respiratory System Infection and Urinary System Infection Comparative clinical trials of

In another clinical trial, the effects of cefoperazone sodium/tazobactam sodium (6:1), cefoperazone sodium/tazobactam sodium (4:1), and cefoperazone sodium/tazobactam sodium (8:1) were studied. Effectiveness and safety.

Experimental Design: Randomized, single-blind, active drug-controlled trial.

Control drugs: cefoperazone sodium/tazobactam sodium for injection (4:1), cefoperazone sodium/tazobactam sodium for injection (8:1)

Test drug: cefoperazone sodium/tazobactam sodium for injection (6:1)

Subjects: Cases diagnosed with respiratory system infection or urinary system infection received cefoperazone monotherapy for 3 days uniformly. Three days later, the clinically ineffective cases were screened out, sputum or urine was extracted, and those who were resistant to cefoperazone single drug and sensitive to control drugs and test drugs through bacterial culture were marked as meeting the entry conditions and formally enrolled. Subjects with respiratory system infection were divided into control group 1, control group 2 and test drug group; subjects with urinary system infection were divided into control group 1, control group 2 and test group. The gender, age, vital signs, height, weight, and disease severity of the subjects in each group were similar.

Administration: For subjects with respiratory system infection or urinary system infection, the control group was given cefoperazone sodium/tazobactam sodium for injection (4:1), administered intravenously once every 12 hours, the total daily dosage Cefoperazone 6.0g, tazobactam 1.5g. The control group used cefoperazone sodium/tazobactam sodium for injection (8:1), intravenously administered once every 12 hours, and the total daily dosage was 6.0 g of cefoperazone and 0.75 g of tazobactam. The experimental drug group used cefoperazone sodium/tazobactam sodium for injection (6:1), intravenously administered once every 12 hours, and the total daily dosage was 6.0 g of cefoperazone and 1.0 g of tazobactam.

Treatment cycle: The treatment period is 7-14 days, which is determined by the clinical researcher according to the type and severity of the disease.

Test results: Taking the clinical cure rate (clinical cure is judged by clinical researchers according to the diagnosis and treatment guidelines of related diseases) as the effectiveness index, the FAS subject set (full analysis set) was analyzed, and the results are shown in Table 3 and Table 4 . The analysis found that, from a numerical point of view, the overall effectiveness of the drugs in the test group and the effectiveness of the respiratory system infection were better than those of the control group and the control group two, and the effectiveness of the urinary system infection was comparable to that of the control group and the control group two. same. Taking the incidence rate of adverse reactions as a safety indicator, an analysis of the SS subject set (safety data set) found that the safety of the drug in the test group was similar to that of the drugs in the control group, and slightly better than that in the control group.

Table 3 Comparison of clinical cure rates after three groups of drug treatment

group

overall cure rate

Among them, the respiratory system

Among them, the urinary system

the	the	infection cure rate	infection cure rate
Test drug group (6:1)	95.00%	90.00%	100%
Control group (4:1)	92.11%	83.33%	100%
Control group two (8:1)	88.89%	76.47%	100%

Table 4 Comparison of the incidence of adverse reactions after drug treatment in the three groups

group	Overall incidence of adverse reactions
Test drug group (6:1)	5.00%
Control group (4:1)	7.50%
Control group two (8:1)	5.00%

After the trial ended, the trial process was sorted out again, and it was found that some cases with renal insufficiency and bacterial infection were accidentally administered, and the creatinine clearance rate of the cases was less than 30mL/min and there were respiratory or urinary system infections. Analysis of these cases found that the three groups of drugs showed very significant differences (Table 5 and Table 6). The experimental drug group still maintains a high cure rate and no adverse reactions; however, whether it is the control group or the second control group, the clinical cure rate has been lower than 50%, and the incidence of adverse reactions is higher than the clinical cure rate. The types of adverse reactions include but Not limited to headache, dizziness, convulsions, palpitations, decreased serum leukocytes, elevated transaminases, elevated serum creatinine, kidney damage, abnormal urine routine, etc., the benefit-risk ratio of the drug has reached an unacceptable level.

Table 5 Comparison of the clinical cure rates of three groups of patients with renal insufficiency and bacterial infection after drug treatment

Table 6 Comparison of the incidence of adverse reactions after drug treatment in three groups of patients with renal insufficiency and bacterial infection

group	Overall incidence of adverse reactions
Test drug group (6:1)	0.00%
Control group (4:1)	77.78%
Control group two (8:1)	62.50%

discuss:

Although cefoperazone/tazobactam preparations have been used in the clinical treatment of respiratory or urinary system infections, their anti-infection effects are poor and the incidence of adverse reactions is high for infected patients with renal insufficiency.

According to the analysis of the inventors, patients with renal insufficiency have decreased glomerular filtration rate, blocked drug excretion, and prone to excessive drug concentration and drug accumulation in the body. A small portion of cefoperazone is excreted in urine, whereas tazobactam is mostly excreted in urine. Although the high urinary excretion rate can ensure the concentration of drugs in the urinary system, it also further increases the burden on the kidneys. These factors may be part of the reason why cefoperazone/tazobactam formulations are prone to adverse reactions in patients with renal insufficiency. On the other hand, although patients with renal insufficiency and bacterial infection have high drug concentrations in their bodies, it does not mean that they can benefit from clinical efficacy. Clinical trials have found that the effect of anti-infection may be worse.

It was unexpectedly found that the composition of cefoperazone/tazobactam 6:1 can take into account both effectiveness and safety. The above clinical trials found that, overall, the clinical efficacy of the combination of cefoperazone/tazobactam 6:1 was superior to that of cefoperazone/tazobactam 4:1 and cefoperazone/tazobactam 8: 1. In terms of safety, it is slightly better than cefoperazone/tazobactam 4:1 and cefoperazone/tazobactam 8:1. In particular, for patients with renal insufficiency and bacterial infection, the efficacy and safety of the combination of cefoperazone and tazobactam 6:1 were significantly better than that of cefoperazone/tazobactam 4:1 and cefoperazone Piperidone/tazobactam 8:1, and the advantage in urinary system infection is the most prominent.

Example 3: Stability study of cefoperazone sodium/tazobactam sodium (6:1)

Follow-up experiments further studied the stability of the cefoperazone sodium/tazobactam sodium (6:1) composition. Compound A ((2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H-1,2,3-triazole- 1-yl)butyric acid) (CAS No.: 120701-86-2) on the stability of cefoperazone sodium/tazobactam sodium (6:1) composition.

The study was performed by adding compound A to the cefoperazone sodium/tazobactam sodium (6:1) composition. Compound A is a commercially available refined product (total impurity content is less than 0.2%), cefoperazone sodium is a commercially available refined product (total impurity content is less than 3%), and tazobactam sodium is a commercially available refined product (total impurity content is less than 0.2%) .

Get the same batch of compound A, cefoperazone sodium, and tazobactam sodium. Compound A with different weights (0.02g, 0.1g, 0.5g, 1.5g) was added to the mixture containing cefoperazone sodium (calculated as cefoperazone) 600g and sodium tazobactam 100g (calculated as tazobactam) respectively. Among the four compositions, four groups of compositions containing Compound A were sequentially obtained: one group of Compound A compositions, two groups of Compound A compositions, three groups of Compound A compositions, and four groups of Compound A compositions. , samples were taken for the stability test. At the same time, another 600 g of cefoperazone sodium and 100 g of tazobactam sodium were taken, and after mixing well, samples were taken for the stability test.

Test method: Place each sample under the condition of temperature 25±2℃ and relative humidity 60±10% for 24 months, take samples at 0 month, March, June, December and 24 months respectively, and measure by HPLC method The content of related substances (impurities) in the sample. HPLC chromatographic conditions are: chromatographic column: zorbax SB C18; Mobile phase: acetonitrile: potassium dihydrogen phosphate solution (0.03mol/L): 10% tetrabutylammonium hydroxide solution (190:795:15), and adjust the pH value to 4.0; detection wavelength: 230nm. The content of related substances is based on the sum of the areas of other peaks in the HPLC chromatogram (all peaks except cefoperazone, tazobactam and compound A) to account for the peak areas of cefoperazone, tazobactam and compound A Calculated as a percentage of the sum. The test results are shown in Table 7.

Table 7 Contents of related substances in each group of samples in the stability test (%)

It can be seen from the stability test that the impurity content of the cefoperazone sodium/tazobactam sodium (6:1) composition without compound A increases significantly, and the content of related substances is close to 4% at 24 months. The cefoperazone sodium/tazobactam sodium (6:1) composition containing compound A can effectively reduce the production of related substances, especially the compound A composition group 1, group 2, and group 3, whose impurity content does not increase significantly. When the content of related substances is still below 2%, the stability of the composition is significantly improved. The stability of the compound A composition four groups has also been improved, and its content of related substances was controlled below 3% in 24 months, but the effect was not as good as that of the composition one, two and three groups. Therefore, compound A seems to be able to stabilize the composition of cefoperazone sodium/tazobactam sodium (6:1), but its dosage should be controlled within a certain range.

references:

[1] Zhang Shengyu et al. Report of 6 cases of convulsions induced by cefoperazone sodium/tazobactam sodium in patients with chronic renal insufficiency [J]. Anhui Medicine, 2014, 18(11): 2193-2195.

[2] Huang Jinping. Clinical analysis of 12 cases of convulsions in patients with renal failure induced by cefoperazone sulbactam/tazobactam [J]. Anhui Medicine, 2017, 21(06): 1154-1156.

The present invention has been described in detail with general description and specific implementation above. On this basis, those skilled in the art can make some changes or improvements to it, and these changes or improvements all belong to the claimed content of the present invention.

Claims (28)

1. Application of a pharmaceutical composition containing cefoperazone sodium and tazobactam sodium in the preparation of a drug for the treatment of renal insufficiency combined with bacterial infection, in the pharmaceutical composition, cefoperazone sodium (calculated as cefoperazone) and tazobactam sodium (calculated as other Zobactam) in a weight ratio of 6:1.
2. The application according to claim 1, the weight of cefoperazone sodium (calculated as cefoperazone) in the pharmaceutical composition is 1g～3g, and the weight of the sodium tazobactam (calculated as tazobactam) is 0.17g ~0.5g.
3. According to the application according to claim 1, the renal insufficiency is severe renal insufficiency.
4. The application according to claim 3, wherein said severe renal insufficiency refers to creatinine clearance <30mL/min.
5. According to the application according to claim 1, the bacterial infection is selected from respiratory system infection and/or urinary system infection.
6. According to the application according to claim 1, the medicine for treating renal insufficiency complicated with bacterial infection does not produce adverse reactions of decreased renal function.
7. According to the application of claim 1, the medicine for treating renal insufficiency complicated with bacterial infection does not produce central nervous system adverse reactions.
8. According to the application of claim 1, the pharmaceutical composition also contains (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H-1, 2,3-triazol-1-yl) butanoic acid.
9. The application according to claim 8, in the pharmaceutical composition, cefoperazone sodium (calculated as cefoperazone) and (2S, 3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl The weight ratio of -4-(1H-1,2,3-triazol-1-yl)butanoic acid is 600:0.02-0.5.
10. A pharmaceutical composition for treating renal insufficiency combined with bacterial infection, containing cefoperazone sodium and tazobactam sodium in the pharmaceutical composition, wherein, cefoperazone sodium (calculated as cefoperazone) and tazobactam sodium (calculated as tazobactam) Zobactam) in a weight ratio of 6:1.
11. The pharmaceutical composition according to claim 10, in the pharmaceutical composition, the weight of cefoperazone sodium (in cefoperazone) is 1g～3g, and the weight of described tazobactam sodium (in tazobactam) is 0.17g～0.5g.
12. The pharmaceutical composition according to claim 10, wherein the renal insufficiency is severe renal insufficiency.
13. The pharmaceutical composition according to claim 12, wherein said severe renal insufficiency refers to creatinine clearance <30mL/min.
14. The pharmaceutical composition according to claim 10, said infection is selected from respiratory system infection and/or urinary system infection.
15. The pharmaceutical composition according to claim 10, the treatment of renal insufficiency with bacterial infection by the pharmaceutical composition does not produce adverse reactions of decreased renal function.
16. The pharmaceutical composition according to claim 10, which does not produce central nervous system adverse reactions in the treatment of renal insufficiency complicated with bacterial infection.
17. The pharmaceutical composition according to claim 10, which also contains (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H -1,2,3-triazol-1-yl) butanoic acid.
18. The pharmaceutical composition according to claim 17, in the pharmaceutical composition, cefoperazone sodium (calculated as cefoperazone) and (2S, 3S)-2-(carboxyvinyl)amino-3-methyl-3-ylidene The weight ratio of sulfonyl-4-(1H-1,2,3-triazol-1-yl)butanoic acid is 600:0.02-0.5.
19. A method for treating bacterial infection in patients with renal insufficiency, comprising administering a pharmaceutical composition to patients in need, the pharmaceutical composition containing cefoperazone sodium (calculated as cefoperazone) and tazobactam in a weight ratio of 6:1 Sodium (calculated as tazobactam).
20. The method according to claim 19, said patient with renal insufficiency is a patient with severe renal insufficiency.
21. The method according to claim 20, in the patient with severe renal insufficiency, the creatinine clearance <30mL/min.
22. The method according to claim 19, the infection is a respiratory system infection and/or a urinary system infection.
23. The method according to claim 19, which does not produce adverse reactions of decreased renal function.
24. The method according to claim 19, which does not produce central nervous system adverse reactions.
25. The method according to claim 19, the pharmaceutical composition also contains (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H-1, 2,3-triazol-1-yl) butanoic acid.
26. The method according to claim 25, in the pharmaceutical composition, cefoperazone (calculated as cefoperazone) and (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinic acid The weight ratio of acyl-4-(1H-1,2,3-triazol-1-yl)butanoic acid is 600:0.02-0.5.
27. The method according to claim 19, the daily dosage of the cefoperazone sodium (calculated as cefoperazone) is 1g～6g, and the daily dosage of the described tazobactam sodium (calculated as tazobactam) is 0.17g ~1g.
28. The method according to claim 19, the use frequency of the pharmaceutical composition is once every 8 hours or once every 12 hours.