WO2023039947A1 - Composition pharmaceutique contenant de la céfopérazone sodique et du tazobactam sodique et son application - Google Patents

Composition pharmaceutique contenant de la céfopérazone sodique et du tazobactam sodique et son application Download PDF

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Publication number
WO2023039947A1
WO2023039947A1 PCT/CN2021/121325 CN2021121325W WO2023039947A1 WO 2023039947 A1 WO2023039947 A1 WO 2023039947A1 CN 2021121325 W CN2021121325 W CN 2021121325W WO 2023039947 A1 WO2023039947 A1 WO 2023039947A1
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WIPO (PCT)
Prior art keywords
cefoperazone
sodium
pharmaceutical composition
tazobactam
renal insufficiency
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PCT/CN2021/121325
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English (en)
Chinese (zh)
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孙天宇
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湘北威尔曼制药股份有限公司
广州新创忆药物临床研究有限公司
广州新创意生物医药有限公司
广州威尔曼新药研发有限公司
南京康福顺药业有限公司
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Priority to CN202180003925.XA priority Critical patent/CN114025767A/zh
Publication of WO2023039947A1 publication Critical patent/WO2023039947A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the invention relates to the field of medicine, in particular to a pharmaceutical composition containing cefoperazone sodium and tazobactam sodium and an application thereof.
  • 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, ⁇ -lactam antibiotics, and quinolone antibiotics, Select drug-specific treatment according to the drug sensitivity test.
  • 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.
  • Zhang Shengyu et al., 2014; Huang Jinping, 2017 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.
  • One of the objects of the present invention is to provide a pharmaceutical composition.
  • 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.
  • 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.
  • the weight of cefoperazone sodium (calculated as cefoperazone) in the described pharmaceutical composition is 1g ⁇ 3g
  • the weight of described tazobactam sodium (calculated as tazobactam) is 0.17 g ⁇ 0.5g.
  • the weight of cefoperazone sodium (calculated as cefoperazone) in the described pharmaceutical composition is 1g ⁇ 1.5g
  • the weight of described tazobactam sodium (calculated as tazobactam) is 0.17g ⁇ 0.25g.
  • 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.
  • the renal insufficiency is severe renal insufficiency.
  • the severe renal insufficiency refers to creatinine clearance ⁇ 30mL/min.
  • the patient with renal insufficiency is a patient with severe renal insufficiency.
  • the creatinine clearance rate of the patient with severe renal insufficiency is ⁇ 30mL/min.
  • the infection is a respiratory infection.
  • the respiratory system infection includes upper respiratory tract infection and lower respiratory tract infection.
  • upper respiratory tract infection and lower respiratory tract infection.
  • bronchial infection Such as bronchial infection, tonsillitis, pneumonia and so on.
  • the infection is a urinary system infection.
  • the urinary system infection includes upper urinary tract infection and lower urinary tract infection.
  • the bacteria are cefoperazone-resistant bacteria.
  • 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.
  • the pharmaceutical composition does not produce adverse reactions in the central nervous system in the treatment of renal insufficiency complicated with bacterial infection.
  • the central nervous system adverse reactions include convulsions, epilepsy and/or convulsions.
  • the pharmaceutical compositions also contain (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H-1 , 2,3-triazol-1-yl) butanoic acid.
  • 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.
  • the technical scheme that the present invention takes is:
  • cefoperazone sodium calculated as cefoperazone
  • sodium tazobactam calculated as tazobactam
  • cefoperazone sodium calculated as cefoperazone
  • tazobactam sodium calculated as tazobactam meter
  • the weight of cefoperazone sodium (calculated as cefoperazone) is 1 g to 3 g
  • the weight of tazobactam sodium (calculated as tazobactam) is 0.17 g to 0.5 g. g.
  • the renal insufficiency is severe renal insufficiency.
  • the severe renal insufficiency refers to creatinine clearance ⁇ 30mL/min.
  • the patient with renal insufficiency is a patient with severe renal insufficiency.
  • the creatinine clearance rate of the patient with severe renal insufficiency is ⁇ 30mL/min.
  • the infection is a respiratory infection.
  • the respiratory system infection includes upper respiratory tract infection and lower respiratory tract infection.
  • upper respiratory tract infection and lower respiratory tract infection.
  • bronchial infection such as bronchial infection, tonsillitis, pneumonia and so on.
  • the infection is a urinary system infection.
  • the urinary system infection includes upper urinary tract infection and lower urinary tract infection.
  • upper urinary tract infection and lower urinary tract infection.
  • cystitis pyelonephritis
  • complicated urinary tract infection recurrent urinary tract infection and so on.
  • the bacteria are cefoperazone-resistant bacteria.
  • 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.
  • the drug for treating renal insufficiency complicated with bacterial infection does not produce adverse reactions in the central nervous system.
  • the central nervous system adverse reactions include convulsions, epilepsy and/or convulsions.
  • the pharmaceutical composition also contains (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H-1,2 ,3-triazol-1-yl)butanoic acid.
  • 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.
  • 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).
  • 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).
  • the renal insufficiency is severe renal insufficiency.
  • the severe renal insufficiency refers to creatinine clearance ⁇ 30 mL/min.
  • the patient with renal insufficiency is a patient with severe renal insufficiency.
  • the creatinine clearance rate of the patient with severe renal insufficiency is ⁇ 30 mL/min.
  • the infection is a respiratory infection.
  • the respiratory infection includes upper respiratory tract infection and lower respiratory tract infection.
  • upper respiratory tract infection and lower respiratory tract infection.
  • bronchial infection such as bronchial infection, tonsillitis, pneumonia and so on.
  • the infection is a urinary tract infection.
  • the urinary tract infection includes upper urinary tract infection and lower urinary tract infection.
  • the bacteria are cefoperazone-resistant bacteria.
  • the method does not produce adverse effects of decreased renal function.
  • the method does not produce central nervous system adverse effects.
  • the central nervous system adverse reaction includes convulsions, seizures and/or convulsions.
  • 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 .
  • 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.
  • the pharmaceutical composition is administered every 8 hours or every 12 hours.
  • the pharmaceutical composition further contains (2S,3S)-2-(carboxyvinyl)amino-3-methyl-3-sulfinyl-4-(1H-1,2 ,3-triazol-1-yl)butanoic acid.
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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.
  • 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.
  • GFR glomerular filtration rate
  • 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.
  • cefoperazone sodium is calculated as cefoperazone
  • tazobactam sodium is calculated as tazobactam.
  • 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
  • cefoperazone sodium/tazobactam sodium (6:1) and cefoperazone sodium/tazobactam sodium (4:1) were studied in a clinical 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.
  • 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.
  • 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
  • cefoperazone sodium/tazobactam sodium (6:1), cefoperazone sodium/tazobactam sodium (4:1), and cefoperazone sodium/tazobactam sodium (8:1) were studied. Effectiveness and safety.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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%)
  • tazobactam sodium is a commercially available refined product (total impurity content is less than 0.2%) .
  • Test method Place each sample under the condition of temperature 25 ⁇ 2°C 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.
  • 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.
  • 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.

Abstract

L'invention concerne une composition pharmaceutique contenant de la céfopérazone sodique et du tazobactam sodique, et une application de celle-ci. Dans la composition pharmaceutique, le rapport pondéral de céfopérazone sodique au tazobactam sodique est de 6:1. Dans le traitement de l'insuffisance rénale combinée à une infection bactérienne, la composition pharmaceutique peut efficacement augmenter l'efficacité clinique et réduire également de manière significative l'incidence de réactions indésirables, ce qui permet d'assurer une efficacité et une sûreté excellentes. L'invention concerne également une composition pharmaceutique qui réduit efficacement la production de substances apparentées, l'augmentation significative de la qualité du produit contenant de la céfopérazone sodique et du tazobactam sodique dans un rapport de 6:1, et peut en outre assurer la stabilité du médicament lors de l'utilisation ainsi que pendant le stockage et le transport.
PCT/CN2021/121325 2021-09-18 2021-09-28 Composition pharmaceutique contenant de la céfopérazone sodique et du tazobactam sodique et son application WO2023039947A1 (fr)

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CN202180003925.XA CN114025767A (zh) 2021-09-18 2021-09-28 一种含有头孢哌酮钠和他唑巴坦钠的药物组合物及其应用

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