A pharmaceutical composition containing cefoperazone sodium and tazobactam sodium for use in renal insufficiency complicated by bacterial infection.

Abstract

This invention discloses a pharmaceutical composition containing cefoperazone sodium and tazobactam sodium for the treatment of renal insufficiency complicated with bacterial infection. The weight ratio of cefoperazone sodium to tazobactam sodium is 6:1. In the treatment of renal insufficiency complicated with bacterial infection, this composition effectively improves clinical efficacy while significantly reducing the incidence of adverse reactions, achieving a good balance between efficacy and safety. This invention also provides a pharmaceutical composition that effectively reduces the production of related substances, significantly improving the product quality of the 6:1 cefoperazone sodium and tazobactam sodium mixture, and further ensuring the stability of the drug during use, storage, and transportation.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and more specifically to a pharmaceutical composition containing cefoperazone sodium and tazobactam sodium for the treatment of renal insufficiency complicated with bacterial infection. Background Technology

[0002] Renal insufficiency is a persistent decline in kidney function caused by various factors, also known as chronic kidney disease (CKD). The prevalence of renal insufficiency in adults is reported to be approximately 14.8%. Currently, there is no effective treatment for renal insufficiency in clinical practice, and the condition is rarely reversed. Treatment generally involves nutritional support, prevention of metabolic disorders, and management of related diseases such as hypertension, hyperlipidemia, diabetes, and anemia to slow the progression of renal insufficiency and prevent further deterioration.

[0003] Bacterial infections are common clinical conditions. Respiratory bacterial infections can cause inflammation of the upper or lower respiratory tract, such as bronchitis and pneumonia. Urinary tract bacterial infections, also known as urinary tract infections, include cystitis, pyelonephritis, complicated urinary tract infections, and recurrent urinary tract infections. Urinary tract infections are generally treated with sulfonamide antibiotics, β-lactam antibiotics, or quinolone antibiotics, with targeted treatment selected based on drug sensitivity testing.

[0004] In clinical practice, antibiotics are generally used to treat the infection in patients with renal insufficiency complicated by bacterial infection, with close monitoring of their renal function. However, the nephrotoxicity of these drugs is an important consideration. Cefoperazone / tazobactam is a marketed combination antibiotic used clinically to treat lower respiratory tract infections, urinary tract infections, abdominal infections, bloodstream infections, bacterial meningitis, and skin and soft tissue infections caused by susceptible bacteria. However, recent reports (e.g., Zhang Shengyu et al., 2014; Huang Jinping et al., 2017) indicate that severe adverse reactions such as seizures often occur when cefoperazone / tazobactam is used to treat patients with renal insufficiency complicated by bacterial infection, leading to discontinuation of the drug.

[0005] Therefore, a safe and effective drug needs to be developed for patients with renal insufficiency complicated by bacterial infection. Summary of the Invention

[0006] One objective of this invention is to provide a pharmaceutical composition. To achieve this objective, the technical solution adopted by this invention is as follows:

[0007] A pharmaceutical composition for treating renal insufficiency complicated with bacterial infection, the pharmaceutical composition comprising cefoperazone sodium and tazobactam sodium, wherein the weight ratio of cefoperazone sodium (calculated as cefoperazone) to tazobactam sodium (calculated as tazobactam) is 6:1.

[0008] Or:

[0009] A pharmaceutical composition for treating bacterial infections in patients with renal insufficiency, the pharmaceutical composition comprising cefoperazone sodium and tazobactam sodium, wherein the weight ratio of cefoperazone sodium (calculated as cefoperazone) to tazobactam sodium (calculated as tazobactam) is 6:1.

[0010] In some examples of pharmaceutical compositions, the weight of cefoperazone sodium (calculated as cefoperazone) in the pharmaceutical composition is 1 g to 3 g, and the weight of tazobactam sodium (calculated as tazobactam) is 0.17 g to 0.5 g.

[0011] In some examples of pharmaceutical compositions, the weight of cefoperazone sodium (calculated as cefoperazone) in the pharmaceutical composition is 1 g to 1.5 g, and the weight of tazobactam sodium (calculated as tazobactam) is 0.17 g to 0.25 g. For example, the pharmaceutical composition contains 1 g of cefoperazone sodium and 0.17 g of tazobactam sodium, or 1.5 g of cefoperazone sodium and 0.25 g of tazobactam sodium, etc.

[0012] In some examples of pharmaceutical compositions, the renal insufficiency is severe renal insufficiency.

[0013] In some examples of pharmaceutical compositions, severe renal insufficiency is defined as a creatinine clearance rate of <30 mL / min.

[0014] In some examples of pharmaceutical compositions, the patient with renal insufficiency is a patient with severe renal insufficiency.

[0015] In some examples of pharmaceutical compositions, the patient with severe renal insufficiency has a creatinine clearance rate of <30 mL / min.

[0016] In some examples of pharmaceutical compositions, the infection is a respiratory infection.

[0017] In some examples of pharmaceutical compositions, the respiratory infection includes both upper and lower respiratory tract infections. Examples include bronchitis, tonsillitis, pneumonia, etc.

[0018] In some examples of pharmaceutical compositions, the infection is a urinary tract infection.

[0019] In some examples of pharmaceutical compositions, the urinary tract infection includes both upper and lower urinary tract infections. Examples include cystitis, pyelonephritis, complicated urinary tract infections, recurrent urinary tract infections, and so on.

[0020] In some examples of pharmaceutical compositions, the bacteria are cefoperazone-resistant bacteria.

[0021] In some instances of pharmaceutical compositions, the pharmaceutical compositions do not produce adverse effects of decreased renal function or further reduce the patient's renal function when treating renal insufficiency complicated by bacterial infection.

[0022] In some examples of pharmaceutical compositions, the pharmaceutical composition does not produce adverse central nervous system reactions in the treatment of renal insufficiency complicated by bacterial infection.

[0023] In some examples of pharmaceutical compositions, the central nervous system adverse reactions include convulsions, seizures, and / or seizures.

[0024] In some examples of pharmaceutical compositions, the pharmaceutical composition further contains (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H-1,2,3-triazol-1-yl)butyric acid.

[0025] In some examples of pharmaceutical compositions, the weight ratio of cefoperazone sodium (calculated as cefoperazone) to (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H-1,2,3-triazol-1-yl)butyric acid in the pharmaceutical composition is 600:0.02-0.5.

[0026] A second objective of this invention is to provide an application. To achieve this objective, the technical solution adopted by this invention is as follows:

[0027] The use of a pharmaceutical composition containing cefoperazone sodium and tazobactam sodium in the preparation of a medicament for treating renal insufficiency complicated with bacterial infection, wherein the weight ratio of cefoperazone sodium (calculated as cefoperazone) to tazobactam sodium (calculated as tazobactam) is 6:1.

[0028] Or:

[0029] The use of a pharmaceutical composition containing cefoperazone sodium and tazobactam sodium in the preparation of a medicament for treating bacterial infections in patients with renal insufficiency, wherein the weight ratio of cefoperazone sodium (calculated as cefoperazone) to tazobactam sodium (calculated as tazobactam) is 6:1.

[0030] In some application examples, the pharmaceutical composition contains 1 g to 3 g of cefoperazone sodium (calculated as cefoperazone) and 0.17 g to 0.5 g of tazobactam sodium (calculated as tazobactam).

[0031] In some application instances, the renal insufficiency described is severe renal insufficiency.

[0032] In some application instances, severe renal insufficiency is defined as a creatinine clearance rate of <30 mL / min.

[0033] In some application instances, the patients with renal insufficiency are those with severe renal insufficiency.

[0034] In some application instances, the patients with severe renal insufficiency had a creatinine clearance rate of <30 mL / min.

[0035] In some applications, the infection is described as a respiratory infection.

[0036] In some applications, the respiratory infections mentioned include both upper and lower respiratory tract infections. Examples include bronchitis, tonsillitis, and pneumonia.

[0037] In some applications, the infection is described as a urinary tract infection.

[0038] In some applications, the urinary tract infection includes both upper and lower urinary tract infections. Examples include cystitis, pyelonephritis, complicated urinary tract infections, recurrent urinary tract infections, and so on.

[0039] In some applications, the bacteria described are cefoperazone-resistant.

[0040] In some application instances, the drugs described for treating renal insufficiency complicated by bacterial infection do not produce adverse effects that lead to a decline in renal function, or do not further reduce the patient's renal function.

[0041] In some application examples, the drugs described for treating renal insufficiency complicated by bacterial infection do not produce adverse central nervous system reactions.

[0042] In some application examples, the aforementioned adverse central nervous system reactions include convulsions, epilepsy, and / or seizures.

[0043] In some application examples, the pharmaceutical composition further contains (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H-1,2,3-triazol-1-yl)butyric acid.

[0044] In some application examples, the weight ratio of cefoperazone sodium (calculated as cefoperazone) to (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H-1,2,3-triazol-1-yl)butyric acid in the pharmaceutical composition is 600:0.02-0.5.

[0045] A third objective of this invention is to provide a treatment method. To achieve this objective, the technical solution adopted by this invention is as follows:

[0046] A method for treating renal insufficiency complicated with bacterial infection includes administering a pharmaceutical composition to a patient in need, said pharmaceutical composition comprising cefoperazone sodium (calculated as cefoperazone) and tazobactam sodium (calculated as tazobactam) in a weight ratio of 6:1.

[0047] Or,

[0048] A method for treating bacterial infection in a patient with renal insufficiency includes administering a pharmaceutical composition to the patient in need, said pharmaceutical composition comprising cefoperazone sodium (calculated as cefoperazone) and tazobactam sodium (calculated as tazobactam) in a weight ratio of 6:1.

[0049] In some instances of the method, the renal insufficiency is severe renal insufficiency.

[0050] In some instances of the method, severe renal insufficiency is defined as a creatinine clearance rate of <30 mL / min.

[0051] In some instances of the method, the patient with renal insufficiency is a patient with severe renal insufficiency.

[0052] In some instances of the method, the patients with severe renal insufficiency had a creatinine clearance rate of <30 mL / min.

[0053] In some instances of this method, the infection is a respiratory infection.

[0054] In some instances of this method, the respiratory infection includes both upper and lower respiratory tract infections. Examples include bronchitis, tonsillitis, pneumonia, and so on.

[0055] In some instances of this method, the infection is a urinary tract infection.

[0056] In some instances of this method, the urinary tract infection includes both upper and lower urinary tract infections. Examples include cystitis, pyelonephritis, complicated urinary tract infections, recurrent urinary tract infections, and so on.

[0057] In some instances of the method, the bacteria are cefoperazone-resistant bacteria.

[0058] In some instances, the method does not produce the adverse effect of decreased renal function.

[0059] In some instances, the method does not produce adverse central nervous system reactions.

[0060] In some instances of the method, the aforementioned adverse central nervous system reactions include convulsions, seizures, and / or seizures.

[0061] In some examples of the methods, the daily dose of cefoperazone sodium (calculated as cefoperazone) is 1 g to 6 g, and the daily dose of tazobactam sodium (calculated as tazobactam) is 0.17 g to 1 g.

[0062] In some examples of the methods, the daily dose of cefoperazone sodium (calculated as cefoperazone) is 6g, and the daily dose of tazobactam sodium (calculated as tazobactam) is 1g.

[0063] In some examples of the methods, the pharmaceutical composition is used once every 8 hours or once every 12 hours.

[0064] In some examples of the method, the pharmaceutical composition further contains (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H-1,2,3-triazol-1-yl)butyric acid.

[0065] In some examples of the method, the weight ratio of cefoperazone sodium (calculated as cefoperazone) to (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H-1,2,3-triazol-1-yl)butyric acid in the pharmaceutical composition is 600:0.02-0.5.

[0066] The beneficial effects of this invention are:

[0067] Cefoperazone / tazobactam is a commonly used combination drug for the clinical treatment of urinary tract infections. However, for patients with renal insufficiency, excessively high drug concentrations can easily lead to adverse drug reactions, and antibiotic combination drugs often complicate the situation further. The cefoperazone / tazobactam 6:1 drug composition of this invention achieves a good balance between efficacy and safety in the treatment of patients with renal insufficiency complicated by bacterial infection. It not only demonstrates superior clinical efficacy compared to existing products but also shows a significant advantage in reducing the incidence of adverse reactions.

[0068] Furthermore, the cefoperazone / tazobactam 6:1 pharmaceutical composition of the present invention is more convenient for clinical application, reducing the frequency of administration and improving patient compliance while ensuring efficacy. For the treatment of moderate to severe infections, especially in patients with renal insufficiency, the pharmaceutical composition of the present invention allows for flexible increases in the dosage of the antibacterial active ingredient, ensuring the enzyme inhibitor continues to exert its inhibitory effect without increasing the burden on the kidneys.

[0069] To further improve the product quality of cefoperazone / tazobactam compositions, and in addressing the complex related substance control issues in cefoperazone / tazobactam combination formulations, this invention provides a novel approach to effectively enhance the stability of cefoperazone / tazobactam compositions. The applicant unexpectedly discovered that adding a certain amount of compound A to the composition significantly reduces the generation of related substances in the cefoperazone / tazobactam composition, effectively improving the stability and product quality of the composition, and further ensuring the safety of the cefoperazone / tazobactam composition, especially in the anti-infective treatment of patients with impaired renal function; this has positive implications for clinical application and drug storage and transportation. Detailed Implementation

[0070] The present invention will now be described in detail with reference to specific embodiments. It should be understood that the content of the specific embodiments section is illustrative and not restrictive, that is, it does not limit the content of the present invention in any way.

[0071] definition:

[0072] "Renal insufficiency" refers to a persistent decline in kidney function caused by various reasons. It is usually diagnosed and staged using the glomerular filtration rate (GFR). A GFR of 60-89 mL / min indicates mild renal insufficiency, 30-59 mL / min indicates moderate renal insufficiency, 15-29 mL / min indicates severe renal insufficiency, and a GFR less than 15 mL / min indicates end-stage renal disease.

[0073] "Pharmaceutical composition": In this invention, a pharmaceutical composition refers to a combination of one or more substances, wherein one or more components of the combination can exert a therapeutic effect on a disease. The pharmaceutical composition of this invention may contain a certain amount of water or impurities.

[0074] The dosages or proportions mentioned in this invention are all calculated based on the amount of free matter. For example, cefoperazone sodium is calculated as cefoperazone, and tazobactam sodium is calculated as tazobactam.

[0075] The "Cefoperazone Sodium / Tazobactam Sodium for Injection (4:1)" and "Cefoperazone Sodium / Tazobactam Sodium for Injection (8:1)" used in the embodiments of this invention are both commercially available products. The Cefoperazone Sodium / Tazobactam Sodium for Injection (6:1) is provided by Xiangbei Wellman Pharmaceutical Co., Ltd., and includes various product specifications such as 1.17g (containing 1g of cefoperazone and 0.17g of tazobactam) and 1.75g ​​(containing 1.5g of cefoperazone and 0.25g of tazobactam).

[0076] Example 1: Comparative clinical trial of cefoperazone sodium / tazobactam sodium (6:1) versus cefoperazone sodium / tazobactam sodium (4:1) in the treatment of respiratory and urinary tract infections.

[0077] The efficacy and safety of cefoperazone sodium / tazobactam sodium (6:1) and cefoperazone sodium / tazobactam sodium (4:1) were investigated in a clinical trial.

[0078] Trial design: randomized, single-blind, positive-drug controlled trial.

[0079] Control drug: Cefoperazone sodium for injection / Tazobactam sodium (4:1)

[0080] Investigational drug: Cefoperazone sodium / tazobactam sodium for injection (6:1)

[0081] Subjects: Cases diagnosed with respiratory or urinary tract infections received cefoperazone monotherapy for 3 days. After 3 days, clinically ineffective cases were screened out. Sputum or urine samples were collected, and those resistant to cefoperazone monotherapy and sensitive to both the control and investigational drugs were marked as meeting the inclusion criteria and formally enrolled. Subjects with respiratory infections were divided into a control group and an investigational drug group; subjects with urinary tract infections were also divided into a control group and an investigational drug group. Subjects in the control and investigational drug groups were similar in terms of gender, age, vital signs, height, weight, and disease severity.

[0082] Administration: The control group received cefoperazone sodium / tazobactam sodium for injection (4:1) intravenously every 8 hours, with a daily dose of 4.8 g cefoperazone sodium (calculated as cefoperazone) and 1.2 g tazobactam sodium (calculated as tazobactam). The experimental group received cefoperazone sodium / tazobactam sodium for injection (6:1) intravenously every 12 hours, with a daily dose of 6.0 g cefoperazone sodium (calculated as cefoperazone) and 1.0 g tazobactam sodium (calculated as tazobactam).

[0083] Treatment duration: The treatment period is 7-14 days, determined by clinical researchers based on the type and severity of the disease.

[0084] Trial Results: Using the clinical cure rate (determined by clinical investigators according to relevant disease treatment guidelines) as an efficacy indicator, the FAS subject set (full analysis set) was analyzed, and the results are shown in Tables 1 and 2. The analysis revealed that, numerically, the overall efficacy of the investigational drug, as well as its efficacy against respiratory and urinary tract infections, was superior to the control drug. Using the incidence of adverse reactions as a safety indicator, the analysis of the SS subject set (safety dataset) showed that the safety profile of the investigational drug was essentially comparable to that of the control drug.

[0085] Table 1 Comparison of clinical cure rates after drug treatment in the two groups

[0086] Group Overall cure rate Among them, the cure rate of respiratory infections Among them, the cure rate of urinary tract infections Experimental drug group (6:1) 90.70% 87.65% 92.73% Control drug group (4:1) 85.19% 78.85% 90.74%

[0087] Table 2 Comparison of adverse reaction rates between the two groups after drug treatment

[0088] Group Overall adverse reaction rate Experimental drug group (6:1) 13.47% Control group (4:1) 13.04%

[0089] Example 2: Comparative clinical trial of cefoperazone sodium / tazobactam sodium (6:1) with cefoperazone sodium / tazobactam sodium (4:1) and cefoperazone sodium / tazobactam sodium (8:1) for the treatment of respiratory and urinary tract infections.

[0090] The efficacy and safety of cefoperazone sodium / tazobactam sodium (6:1), cefoperazone sodium / tazobactam sodium (4:1), and cefoperazone sodium / tazobactam sodium (8:1) were investigated in another clinical trial.

[0091] Trial design: randomized, single-blind, positive-drug controlled trial.

[0092] Control drugs: Cefoperazone sodium / tazobactam sodium for injection (4:1), Cefoperazone sodium / tazobactam sodium for injection (8:1)

[0093] Investigational drug: Cefoperazone sodium / tazobactam sodium for injection (6:1)

[0094] Subjects: Cases diagnosed with respiratory or urinary tract infections received cefoperazone monotherapy for 3 days. After 3 days, clinically ineffective cases were screened out. Sputum or urine samples were collected, and those resistant to cefoperazone monotherapy and sensitive to both the control and investigational drugs were marked as meeting the inclusion criteria and formally enrolled. Subjects with respiratory infections were divided into Control Group 1, Control Group 2, and the investigational drug group; subjects with urinary tract infections were divided into Control Group 1, Control Group 2, and the investigational drug group. Subjects in each group were similar in gender, age, vital signs, height, weight, and disease severity.

[0095] Administration: For subjects with respiratory or urinary tract infections, the control group received cefoperazone sodium / tazobactam sodium for injection (4:1) administered intravenously every 12 hours, with a total daily dose of 6.0 g cefoperazone and 1.5 g tazobactam. The second control group received cefoperazone sodium / tazobactam sodium for injection (8:1) administered intravenously every 12 hours, with a total daily dose of 6.0 g cefoperazone and 0.75 g tazobactam. The investigational drug group received cefoperazone sodium / tazobactam sodium for injection (6:1) administered intravenously every 12 hours, with a total daily dose of 6.0 g cefoperazone and 1.0 g tazobactam.

[0096] Treatment duration: The treatment period is 7-14 days, determined by clinical researchers based on the type and severity of the disease.

[0097] Trial Results: Using the clinical cure rate (determined by clinical researchers according to relevant disease treatment guidelines) as the efficacy indicator, the FAS subject set (full analysis set) was analyzed, and the results are shown in Tables 3 and 4. The analysis revealed that, numerically, the overall efficacy and efficacy against respiratory infections in the experimental group were superior to those in control group 1 and control group 2, while the efficacy against urinary tract infections was the same as that in control group 1 and control group 2. Using the adverse reaction rate as the safety indicator, the SS subject set (safety dataset) was analyzed, and the safety of the experimental group was similar to that of control group 2, and slightly superior to that of control group 1.

[0098] Table 3 Comparison of clinical cure rates after three groups of drug treatments

[0099] Group Overall cure rate Among them, the cure rate of respiratory infections Among them, the cure rate of urinary tract infections Experimental drug group (6:1) 95.00% 90.00% 100% Control group (4:1) 92.11% 83.33% 100% Control group 2 (8:1) 88.89% 76.47% 100%

[0100] Table 4 Comparison of the incidence of adverse reactions after three groups of drug treatments

[0101] Group Overall adverse reaction rate Experimental drug group (6:1) 5.00% Control group (4:1) 7.50% Control group 2 (8:1) 5.00%

[0102] Following the trial, a review of the process revealed that some patients with renal insufficiency and bacterial infection were unexpectedly administered the drug. These patients had a creatinine clearance rate of less than 30 mL / min and presented with respiratory or urinary tract infections. Analysis of these cases showed highly significant differences among the three drug groups (Tables 5 and 6). The experimental drug group maintained a high cure rate with no adverse reactions; however, in both control groups 1 and 2, the clinical cure rate was below 50%, and the incidence of adverse reactions was higher than the clinical cure rate. Adverse reactions included, but were not limited to, headache, dizziness, convulsions, palpitations, decreased serum leukocytes, elevated transaminases, elevated serum creatinine, kidney damage, and abnormal urinalysis results. The benefit-risk ratio of the drug had reached an unacceptable level.

[0103] Table 5. Comparison of clinical cure rates among three groups of patients with renal insufficiency complicated by bacterial infection after drug treatment.

[0104] Group Overall cure rate Among them, the cure rate of respiratory infections Among them, the cure rate of urinary tract infections Experimental drug group (6:1) 90.00% 85.71% 100.00% Control group (4:1) 33.33% 50.00% 20.00% Control group 2 (8:1) 37.50% 50.00% 25.00%

[0105] Table 6. Comparison of adverse reaction rates among the three groups of patients with renal insufficiency complicated by bacterial infection after drug treatment.

[0106] Group Overall adverse reaction rate Experimental drug group (6:1) 0.00% Control group (4:1) 77.78% Control group 2 (8:1) 62.50%

[0107] discuss:

[0108] Although cefoperazone / tazobactam preparations are currently available for the clinical treatment of respiratory or urinary tract infections, their anti-infective efficacy is poor and the incidence of adverse reactions is high in infected patients with concurrent renal insufficiency.

[0109] The inventors believe that patients with renal insufficiency have a decreased glomerular filtration rate, leading to impaired drug excretion and a higher risk of excessive drug concentrations and accumulation in the body. A small portion of cefoperazone is excreted in the urine, while the majority of tazobactam is excreted through the urine. While a high urinary excretion rate ensures sufficient drug concentration in the urinary system, it also further increases the burden on the kidneys. These factors may be partly responsible for the increased likelihood of adverse reactions in cefoperazone / tazobactam preparations in patients with renal insufficiency. Furthermore, although patients with renal insufficiency and bacterial infections may have high drug concentrations, this does not necessarily mean they will benefit from clinical efficacy. Clinical trials have shown that the anti-infective effect may actually be worse.

[0110] Unexpectedly, it was discovered that the cefoperazone / tazobactam 6:1 combination can balance efficacy and safety. The aforementioned clinical trials found that, overall, the cefoperazone / tazobactam 6:1 combination showed superior clinical efficacy compared to cefoperazone / tazobactam 4:1 and cefoperazone / tazobactam 8:1, and slightly better safety profile. In particular, for patients with renal insufficiency and bacterial infection, the cefoperazone / tazobactam 6:1 combination showed significantly better efficacy and safety than cefoperazone / tazobactam 4:1 and cefoperazone / tazobactam 8:1, with the most significant advantage in urinary tract infections.

[0111] Example 3: Stability study of cefoperazone sodium / tazobactam sodium (6:1)

[0112] Subsequent studies further investigated the stability of the cefoperazone sodium / tazobactam sodium (6:1) composition. In one study, the effect of compound A ((2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H-1,2,3-triazol-1-yl)butyric acid) (CAS No.: 120701-86-2) on the stability of the cefoperazone sodium / tazobactam sodium (6:1) composition was investigated.

[0113] The study was conducted by adding compound A to a cefoperazone sodium / tazobactam sodium (6:1) composition. Compound A was a commercially available refined product (total impurities content less than 0.2%), cefoperazone sodium was a commercially available refined product (total impurities content less than 3%), and tazobactam sodium was a commercially available refined product (total impurities content less than 0.2%).

[0114] Take compound A, cefoperazone sodium, and tazobactam sodium from the same batch. Add different weights (0.02 g, 0.1 g, 0.5 g, and 1.5 g) of compound A to four compositions containing 600 g of cefoperazone sodium (calculated as cefoperazone) and 100 g of tazobactam sodium (calculated as tazobactam), respectively, to obtain four groups of compositions containing compound A: Composition 1, Composition 2, Composition 3, and Composition 4. After thorough mixing, samples were taken from each group for stability testing. Simultaneously, 600 g of cefoperazone sodium and 100 g of tazobactam sodium were separately mixed thoroughly and samples were taken for stability testing.

[0115] Experimental Method: Samples were stored at 25±2℃ and 60±10% relative humidity for 24 months. Samples were taken at 0, 3, 6, 12, and 24 months, and the content of related substances (impurities) in the samples was determined by HPLC. HPLC chromatographic conditions were as follows: column: Zorbax SB C18; mobile phase: acetonitrile: potassium dihydrogen phosphate solution (0.03 mol / L): 10% tetrabutylammonium hydroxide solution (190:795:15), with pH adjusted to 4.0 using phosphoric acid; detection wavelength: 230 nm. The content of related substances was calculated as the percentage of the sum of the areas of other peaks (excluding cefoperazone, tazobactam, and compound A) in the HPLC chromatogram relative to the sum of the peak areas of cefoperazone, tazobactam, and compound A. The experimental results are shown in Table 7.

[0116] Table 7. Content (%) of related substances in each group of samples during stability testing

[0117]

[0118] Stability tests showed that the cefoperazone sodium / tazobactam sodium (6:1) composition without compound A exhibited a significant increase in impurity content, with related substances reaching nearly 4% after 24 months. The cefoperazone sodium / tazobactam sodium (6:1) composition containing compound A effectively reduced the formation of related substances, especially in groups one, two, and three, where the increase in impurity content was not significant, and the related substance content remained below 2% after 24 months, indicating a significant improvement in composition stability. The stability of group four, containing compound A, was also improved, with the related substance content controlled below 3% after 24 months, but the effect was not as good as groups one, two, and three. Therefore, compound A appears to have a stabilizing effect on the cefoperazone sodium / tazobactam sodium (6:1) composition, but its dosage is best controlled within a certain range.

[0119] References:

[0120] [1] Zhang Shengyu et al. A report of 6 cases of convulsions caused by cefoperazone sodium / tazobactam sodium in patients with chronic renal insufficiency [J]. Anhui Medical Journal, 2014, 18(11): 2193-2195.

[0121] [2] Huang Jinping et al. Clinical analysis of 12 cases of convulsions in patients with renal failure caused by cefoperazone / sulbactam / tazobactam [J]. Anhui Medical Journal, 2017, 21(06): 1154-1156.

[0122] The present invention has been described in detail above with general descriptions and specific embodiments. Based on this, those skilled in the art can make some changes or improvements, and these changes or improvements are all within the scope of protection claimed by the present invention.

Claims

1. A pharmaceutical composition for treating renal insufficiency complicated by bacterial infection, which contains cefoperazone sodium, tazobactam sodium and (2S, 3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H-1,2,3-triazol-1-yl)butyric acid, wherein, cefoperazone sodium is in a weight ratio of 6:1 with cefoperazone and tazobactam sodium is in a weight ratio of 1:1 with tazobactam; the renal insufficiency is severe renal insufficiency, the severe renal insufficiency refers to creatinine clearance rate < 30 mL / min; the bacterial infection is selected from respiratory system infection or / and urinary system infection; the weight ratio of cefoperazone sodium to (2S, 3S)-2-(carboxyvinyl) amino-3-methyl-3-sulfinyl-4-(1H-1, 2, 3-triazole-1-yl) butyric acid in the pharmaceutical composition is 600:0.02-0.

5.

2. The pharmaceutical composition according to claim 1, the weight of cefoperazone sodium is 1 g-3 g in terms of cefoperazone, and the weight of tazobactam sodium is 0.17 g-0.5 g in terms of tazobactam.

3. Use of the pharmaceutical composition according to any one of claims 1-2 in the preparation of a medicament for treating renal insufficiency combined with bacterial infection.

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