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WO2023039947A1 - 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 - Google Patents

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 Download PDF

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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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Prior art keywords
cefoperazone
sodium
pharmaceutical composition
tazobactam
renal insufficiency
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Ceased
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PCT/CN2021/121325
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English (en)
French (fr)
Inventor
孙天宇
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GUANGZHOU WELMAN NEW DRUG R&D CO Ltd
Guangzhou Xin Chuangyi Biopharmaceutical Co Ltd
Nanjing Kangfushun Pharmaceutical Co Ltd
Xiangbei Welman Pharmaceutical Co Ltd
Guangzhou Century Clinical Research Co Ltd
Original Assignee
GUANGZHOU WELMAN NEW DRUG R&D CO Ltd
Guangzhou Xin Chuangyi Biopharmaceutical Co Ltd
Nanjing Kangfushun Pharmaceutical Co Ltd
Xiangbei Welman Pharmaceutical Co Ltd
Guangzhou Century Clinical Research Co Ltd
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Application filed by GUANGZHOU WELMAN NEW DRUG R&D CO Ltd, Guangzhou Xin Chuangyi Biopharmaceutical Co Ltd, Nanjing Kangfushun Pharmaceutical Co Ltd, Xiangbei Welman Pharmaceutical Co Ltd, Guangzhou Century Clinical Research Co Ltd filed Critical GUANGZHOU WELMAN NEW DRUG R&D CO Ltd
Priority to CN202180003925.XA priority Critical patent/CN114025767A/zh
Publication of WO2023039947A1 publication Critical patent/WO2023039947A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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.

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Abstract

公开了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。在所述的药物组合物中，头孢哌酮钠和他唑巴坦钠的重量比为6：1；所述药物组合物在肾功能不全合并细菌感染的治疗中能够在有效提高临床疗效的同时显著降低不良反应发生率，良好地兼顾有效性和安全性。还提供了有效降低有关物质产生的药物组合物，显著提高了头孢哌酮钠和他唑巴坦钠6：1的产品质量，能进一步确保药品使用及储存运输中的稳定性。

Description

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 技术领域
本发明涉及医药领域，具体涉及一种含头孢哌酮钠和他唑巴坦钠的药物组合物及其应用。
背景技术
肾功能不全是由各种原因造成的肾功能持续性减退，也有称其为慢性肾脏病(chronic kidney diseases,CKD)。据报道，成人肾功能不全的患病率约14.8％。目前临床上对于肾功能不全没有很好的治疗方法，肾功能不全的病情很少可以得到逆转，一般是采用营养支持、防止代谢紊乱、对相关疾病如高血压、高脂血、糖尿病、贫血等进行治疗，延缓肾功能不全的进展，防止进一步恶化。
细菌感染是临床常见疾病。呼吸系统细菌感染可引起上呼吸道或下呼吸道炎症，例如支气管炎、肺炎等。泌尿系统细菌感染或称尿路感染，包括膀胱炎、肾盂肾炎、复杂性尿路感染、复发性尿路感染等，泌尿系统感染一般使用磺胺类抗生素、β-内酰胺类抗生素、喹诺酮类抗生素，根据药敏试验情况选择药物针对性治疗。
临床上对于肾功能不全合并细菌感染的患者，一般采用抗生素以治疗感染，并密切监测其肾功能。但是，药物的肾毒性是需要考虑的一个重要问题。头孢哌酮/他唑巴坦是一种已上市的复方抗生素，在临床上用于治疗敏感菌引起的下呼吸道感染、泌尿系统感染、腹腔感染、血液感染、细菌性脑膜炎、皮肤和软组织感染等。但是近年来有报道(例如：张圣雨等,2014；黄金平等,2017)，头孢哌酮/他唑巴坦复方制剂用于治疗肾功能不全合并细菌感染患者时，常常出现抽搐等严重不良反应，导致停药。
因此对于肾功能不全合并细菌感染患者，需要开发出一种安全有效的药物。
发明内容
本发明的目的之一是提供一种药物组合物。为了实现该目的，本发明采取的技术方案是：
一种用于治疗肾功能不全合并细菌感染的药物组合物，所述药物组合物中含有头孢哌酮钠和他唑巴坦钠，其中，头孢哌酮钠(以头孢哌酮计)和他唑巴坦钠(以他唑巴坦计)的重量比为6：1。
或者是：
一种用于治疗肾功能不全患者细菌感染的药物组合物，所述药物组合物中含有头孢哌酮钠和他唑巴坦钠，其中，头孢哌酮钠(以头孢哌酮计)和他唑巴坦钠(以他唑巴坦计)的重 量比为6：1。
在一些药物组合物的实例中，所述的药物组合物中头孢哌酮钠(以头孢哌酮计)的重量为1g～3g，所述他唑巴坦钠(以他唑巴坦计)的重量为0.17g～0.5g。
在一些药物组合物的实例中，所述的药物组合物中头孢哌酮钠(以头孢哌酮计)的重量为1g～1.5g，所述他唑巴坦钠(以他唑巴坦计)的重量为0.17g～0.25g。例如所述药物组合物中头孢哌酮钠为1g，他唑巴坦钠为0.17g，或者，所述药物组合物中头孢哌酮钠为1.5g，他唑巴坦钠为0.25g，等等。
在一些药物组合物的实例中，所述的肾功能不全为严重肾功能不全。
在一些药物组合物的实例中，所述的严重肾功能不全是指肌酐清除率<30mL/min。
在一些药物组合物的实例中，所述的肾功能不全患者为严重肾功能不全患者。
在一些药物组合物的实例中，所述的严重肾功能不全患者，其肌酐清除率<30mL/min。
在一些药物组合物的实例中，所述的感染为呼吸系统感染。
在一些药物组合物的实例中，所述的呼吸系统感染包括上呼吸道感染和下呼吸道感染。例如支气管感染、扁桃体炎、肺炎等等。
在一些药物组合物的实例中，所述的感染为泌尿系统感染。
在一些药物组合物的实例中，所述的泌尿系统感染包括上尿路感染和下尿路感染。例如膀胱炎、肾盂肾炎、复杂性尿路感染、复发性尿路感染等等。
在一些药物组合物的实例中，所述的细菌是对头孢哌酮耐药的细菌。
在一些药物组合物的实例中，所述的药物组合物治疗肾功能不全合并细菌感染不产生肾功能下降的不良反应，或者不会进一步降低患者肾功能。
在一些药物组合物的实例中，所述的药物组合物治疗肾功能不全合并细菌感染不产生中枢神经系统不良反应。
在一些药物组合物的实例中，所述的中枢神经系统不良反应包括抽搐、癫痫和/或惊厥。
在一些药物组合物的实例中，所述的药物组合物中还含有(2S,3S)-2-(羧基乙烯基)氨基-3-甲基-3-亚磺酰基-4-(1H-1,2,3-三唑-1-基)丁酸。
在一些药物组合物的实例中，所述的药物组合物中头孢哌酮钠(以头孢哌酮计)与(2S,3S)-2-(羧基乙烯基)氨基-3-甲基-3-亚磺酰基-4-(1H-1,2,3-三唑-1-基)丁酸的重量比为600：0.02-0.5。
本发明的目的之二是提供一种应用。为了实现该目的，本发明所采取的技术方案是：
含有头孢哌酮钠和他唑巴坦钠的药物组合物在制备治疗肾功能不全合并细菌感染的药物 中的应用，其中，头孢哌酮钠(以头孢哌酮计)和他唑巴坦钠(以他唑巴坦计)的重量比为6：1。
或者是：
含有头孢哌酮钠和他唑巴坦钠的药物组合物在制备治疗肾功能不全患者的细菌感染的药物中的应用，其中，头孢哌酮钠(以头孢哌酮计)和他唑巴坦钠(以他唑巴坦计)的重量比为6：1。
在一些应用的实例中，所述的药物组合物中，头孢哌酮钠(以头孢哌酮计)的重量为1g～3g，他唑巴坦钠(以他唑巴坦计)的重量为0.17g～0.5g。
在一些应用的实例中，所述的肾功能不全为严重肾功能不全。
在一些应用的实例中，所述的严重肾功能不全是指肌酐清除率<30mL/min。
在一些应用的实例中，所述的肾功能不全患者为严重肾功能不全患者。
在一些应用的实例中，所述的严重肾功能不全患者，其肌酐清除率<30mL/min。
在一些应用的实例中，所述的感染为呼吸系统感染。
在一些应用的实例中，所述的呼吸系统感染包括上呼吸道感染和下呼吸道感染。例如支气管感染、扁桃体炎、肺炎等等。
在一些应用的实例中，所述的感染为泌尿系统感染。
在一些应用的实例中，所述的泌尿系统感染包括上尿路感染和下尿路感染。例如膀胱炎、肾盂肾炎、复杂性尿路感染、复发性尿路感染等等。
在一些应用的实例中，所述的细菌是对头孢哌酮耐药的细菌。
在一些应用的实例中，所述的治疗肾功能不全合并细菌感染的药物不产生肾功能下降的不良反应，或者不会进一步降低患者肾功能。
在一些应用的实例中，所述的治疗肾功能不全合并细菌感染的药物不产生中枢神经系统不良反应。
在一些应用的实例中，所述的中枢神经系统不良反应包括抽搐、癫痫和/或惊厥。
在一些应用的实例中，所述的药物组合物中还含有(2S,3S)-2-(羧基乙烯基)氨基-3-甲基-3-亚磺酰基-4-(1H-1,2,3-三唑-1-基)丁酸。
在一些应用的实例中，所述的药物组合物中头孢哌酮钠(以头孢哌酮计)与(2S,3S)-2-(羧基乙烯基)氨基-3-甲基-3-亚磺酰基-4-(1H-1,2,3-三唑-1-基)丁酸的重量比为600：0.02-0.5。
本发明的目的之三是提供一种治疗方法。为了实现该目的，本发明所采取的技术方案是：
一种治疗肾功能不全合并细菌感染的方法，包括向所需要的患者给予药物组合物，所述 的药物组合物中含有重量比为6：1的头孢哌酮钠(以头孢哌酮计)和他唑巴坦钠(以他唑巴坦计)。
或者是，
一种治疗肾功能不全患者细菌感染的方法，包括向所需要的患者给予药物组合物，所述的药物组合物中含有重量比为6：1的头孢哌酮钠(以头孢哌酮计)和他唑巴坦钠(以他唑巴坦计)。
在一些方法的实例中，所述的肾功能不全为严重肾功能不全。
在一些方法的实例中，所述的严重肾功能不全是指肌酐清除率<30mL/min。
在一些方法的实例中，所述的肾功能不全患者为严重肾功能不全患者。
在一些方法的实例中，所述的严重肾功能不全患者，其肌酐清除率<30mL/min。
在一些方法的实例中，所述的感染为呼吸系统感染。
在一些方法的实例中，所述的呼吸系统感染包括上呼吸道感染和下呼吸道感染。例如支气管感染、扁桃体炎、肺炎等等。
在一些方法的实例中，所述的感染为泌尿系统感染。
在一些方法的实例中，所述的泌尿系统感染包括上尿路感染和下尿路感染。例如膀胱炎、肾盂肾炎、复杂性尿路感染、复发性尿路感染等等。
在一些方法的实例中，所述的细菌是对头孢哌酮耐药的细菌。
在一些方法的实例中，所述的方法不产生肾功能下降的不良反应。
在一些方法的实例中，所述的方法不产生中枢神经系统不良反应。
在一些方法的实例中，所述的中枢神经系统不良反应包括抽搐、癫痫和/或惊厥。
在一些方法的实例中，所述头孢哌酮钠(以头孢哌酮计)的每日用量为1g～6g，所述他唑巴坦钠(以他唑巴坦计)的每日用量为0.17g～1g。
在一些方法的实例中，所述头孢哌酮钠(以头孢哌酮计)的每日用量为6g，所述他唑巴坦钠(以他唑巴坦计)的每日用量为1g。
在一些方法的实例中，所述药物组合物的使用频率为每8小时一次或每12小时一次。
在一些方法的实例中，所述的药物组合物中还含有(2S,3S)-2-(羧基乙烯基)氨基-3-甲基-3-亚磺酰基-4-(1H-1,2,3-三唑-1-基)丁酸。
在一些方法的实例中，所述的药物组合物中头孢哌酮钠(以头孢哌酮计)与(2S,3S)-2-(羧基乙烯基)氨基-3-甲基-3-亚磺酰基-4-(1H-1,2,3-三唑-1-基)丁酸的重量比为600：0.02-0.5。
本发明的有益效果是：
头孢哌酮/他唑巴坦是临床上治疗泌尿系统感染的常用复方制剂，但对于肾功能不全的患者而言，过高的药物浓度暴露更容易引起药物不良反应，抗生素复方制剂常常使情况更为复杂。本发明的头孢哌酮/他唑巴坦6：1药物组合物在肾功能不全合并细菌感染患者的治疗中实现了有效性和安全性的良好兼顾，不仅临床疗效优于现有品种，而且在不良反应发生率的降低上显示出明显优势。
此外，本发明的头孢哌酮/他唑巴坦6：1药物组合物在临床应用中更为方便，在保证疗效的前提下，可减少给药次数，改善病人依从性。对于中、重度感染的治疗，尤其是肾功能不全的患者，本发明的药物组合物可以灵活地加大抗菌活性成分的剂量，并且保证酶抑制剂持续发挥抑制酶活性，但不会加重肾脏负担。
为进一步提高头孢哌酮/他唑巴坦组合物的产品质量，在头孢哌酮/他唑巴坦复方制剂复杂的有关物质控制方面，本发明还提供了有效提高头孢哌酮/他唑巴坦组合物稳定性的新思路。申请人意外地发现在组合物中加入一定量的化合物A后，能够明显降低头孢哌酮/他唑巴坦组合物中有关物质的产生，有效提高组合物的稳定性与产品质量，进一步确保头孢哌酮/他唑巴坦组合物的安全性，尤其是在肾功能受损的患者的抗感染治疗；在临床应用和药品储存运输等方面都具有积极意义。
具体实施方式
下面用具体实施方式对本发明进行详述。应该理解，具体实施方式部分的内容是属于阐释性的，而非限制性的，即不是对本发明内容的任何限制。
定义：
“肾功能不全”是指由各种原因造成的肾功能的持续性减退。通常可使用肾小球滤过率(glomerular filtration rate，GFR)来进行诊断和分期，GFR在60-89mL/min为轻度肾功能不全，GFR在30-59mL/min为中度肾功能不全，GFR在15-29mL/min为重度肾功能不全，GFR小于15mL/min为终末期肾病。
“药物组合物”：本发明中的药物组合物是指一种以上物质所形成的组合，该组合中的一种或多种组分可发挥治疗疾病的功效。本发明中的药物组合物中可以含有一定含量的水分或杂质。
本发明中所述的用量或者比例均是以游离物的量进行计算。例如头孢哌酮钠以头孢哌酮计算，他唑巴坦钠以他唑巴坦计算。
本发明实施例所用的“注射用头孢哌酮钠/他唑巴坦钠(4：1)”、“注射用头孢哌酮钠/他唑巴坦钠(8：1)”均为市售产品。注射用头孢哌酮钠/他唑巴坦钠(6：1)由湘北威尔曼制药股 份有限公司提供，包括1.17g(含头孢哌酮1g和他唑巴坦0.17g)、1.75g(含头孢哌酮1.5g和他唑巴坦0.25g)等多种产品规格。
实施例1：头孢哌酮钠/他唑巴坦钠(6：1)与头孢哌酮钠/他唑巴坦钠(4：1)治疗呼吸系统感染和泌尿系统感染的对比临床试验
在一项临床试验中研究了头孢哌酮钠/他唑巴坦钠(6：1)和头孢哌酮钠/他唑巴坦钠(4：1)的有效性和安全性。
试验设计：随机、单盲、阳性药对照试验。
对照药物：注射用头孢哌酮钠/他唑巴坦钠(4：1)
试验药物：注射用头孢哌酮钠/他唑巴坦钠(6：1)
受试者：诊断为呼吸系统感染或泌尿系统感染的病例，统一接受注射用头孢哌酮单药治疗3天。3天后，筛选出临床判断为无效的病例，提取痰液或尿液，经细菌培养对头孢哌酮单药耐药并且对对照药物和试验药物敏感的，标记为符合入组条件正式入组。呼吸系统感染受试者，分为对照药物组和试验药物组；泌尿系统感染受试者，分为对照药物组和试验药物组。对照药物组受试者和试验药物组受试者的性别、年龄、生命体征、身高、体重、病情程度等基本相似。
给药：对照药物组使用注射用头孢哌酮钠/他唑巴坦钠(4：1)，每8小时静脉注射给药一次，每日给药量为头孢哌酮钠(以头孢哌酮计)4.8g，他唑巴坦钠(以他唑巴坦计)1.2g。试验药物组使用注射用头孢哌酮钠/他唑巴坦钠(6：1)，每12小时静脉注射给药一次，每日给药量为头孢哌酮钠(以头孢哌酮计)6.0g，他唑巴坦钠(以他唑巴坦计)1.0g。
治疗周期：治疗期为7-14天，由临床研究者根据病种和病情程度决定。
试验结果：以临床治愈率(临床治愈由临床研究者根据相关疾病的诊疗指南判定)作为有效性指标，对FAS受试者集合(全分析集)进行分析，结果如表1和表2所示。分析发现，从数值上看，试验药物的总体有效性，以及对呼吸系统感染和泌尿系统感染的有效性均优于对照药物。以不良反应发生率作为安全性指标，对SS受试者集合(安全性数据集)进行分析发现，试验药物的安全性与对照药物基本相当。
表1 两组药物治疗后的临床治愈率比较
Figure PCTCN2021121325-appb-000001
表2 两组药物治疗后的不良反应发生率比较
组别 总体不良反应发生率
试验药物组(6：1) 13.47％
对照一组(4：1) 13.04％
实施例2：头孢哌酮钠/他唑巴坦钠(6：1)与头孢哌酮钠/他唑巴坦钠(4：1)、头孢哌酮钠/他唑巴坦钠(8：1)治疗呼吸系统感染和泌尿系统感染的对比临床试验
在另一项临床试验中研究了头孢哌酮钠/他唑巴坦钠(6：1)、头孢哌酮钠/他唑巴坦钠(4：1)、头孢哌酮钠/他唑巴坦钠(8：1)三者的有效性和安全性。
试验设计：随机、单盲、阳性药对照试验。
对照药物：注射用头孢哌酮钠/他唑巴坦钠(4：1)、注射用头孢哌酮钠/他唑巴坦钠(8：1)
试验药物：注射用头孢哌酮钠/他唑巴坦钠(6：1)
受试者：诊断为呼吸系统感染或泌尿系统感染的病例，统一接受注射用头孢哌酮单药治疗3天。3天后，筛选出临床判断为无效的病例，提取痰液或尿液，经细菌培养对头孢哌酮单药耐药并且对对照药物和试验药物敏感的，标记为符合入组条件正式入组。呼吸系统感染受试者，分为对照一组、对照二组和试验药物组；泌尿系统感染受试者，分为对照一组、对照二组和试验组。各组受试者的性别、年龄、生命体征、身高、体重、病情程度等相似。
给药：对于呼吸系统感染受试者或泌尿系统感染受试者，对照一组使用注射用头孢哌酮钠/他唑巴坦钠(4：1)，每12小时静脉注射给药一次，每日总用量为头孢哌酮6.0g，他唑巴坦1.5g。对照二组使用注射用头孢哌酮钠/他唑巴坦钠(8：1)，每12小时静脉注射给药一次，每日总用量为头孢哌酮6.0g，他唑巴坦0.75g。试验药物组使用注射用头孢哌酮钠/他唑巴坦钠(6：1)，每12小时静脉注射给药一次，每日总用量为头孢哌酮6.0g，他唑巴坦1.0g。
治疗周期：治疗期为7-14天，由临床研究者根据病种和病情程度决定。
试验结果：以临床治愈率(临床治愈由临床研究者根据相关疾病的诊疗指南判定)作为有效性指标，对FAS受试者集合(全分析集)进行分析，结果如表3和表4所示。分析发现，从数值上看，试验组药物的总体有效性以及呼吸系统感染的有效性优于对照一组药物和对照二组药物，对泌尿系统感染的有效性与对照一组药物和对照二组相同。以不良反应发生率为安全性指标，对SS受试者集合(安全性数据集)进行分析发现，试验组药物的安全性与对照二组药物相似，略优于对照一组药物。
表3 三组药物治疗后的临床治愈率比较
组别 总体治愈率 其中，呼吸系统 其中，泌尿系统
    感染治愈率 感染治愈率
试验药物组(6：1) 95.00％ 90.00％ 100％
对照一组(4：1) 92.11％ 83.33％ 100％
对照二组(8：1) 88.89％ 76.47％ 100％
表4 三组药物治疗后的不良反应发生率比较
组别 总体不良反应发生率
试验药物组(6：1) 5.00％
对照一组(4：1) 7.50％
对照二组(8：1) 5.00％
该试验结束后，对试验过程再次进行梳理，发现意外给药了一些患有肾功能不全合并细菌感染的病例，病例肌酐清除率小于30mL/min并且存在呼吸系统或泌尿系统感染。对这些病例进行分析发现，三组药物呈现出非常显著的差异(表5和表6)。试验药物组仍然保持高治愈率并且无不良反应发生；而无论是对照一组还是对照二组，临床治愈率已经低于50％，并且不良反应发生率高于临床治愈率，不良反应类型包括但不限于头痛、头晕、痉挛、心悸、血清白细胞降低、转氨酶升高、血清肌酐升高、肾损伤、尿常规异常等，药物的收益风险比已经达到不可接受的程度。
表5 肾功能不全合并细菌感染患者三组药物治疗后的临床治愈率比较
Figure PCTCN2021121325-appb-000002
表6 肾功能不全合并细菌感染患者三组药物治疗后的不良反应发生率比较
组别 总体不良反应发生率
试验药物组(6：1) 0.00％
对照一组(4：1) 77.78％
对照二组(8：1) 62.50％
讨论：
虽然目前已有头孢哌酮/他唑巴坦制剂用于临床治疗呼吸系统或泌尿系统感染疾病，但是对于同时合并有肾功能不全的感染患者，其抗感染效果较差并且不良反应发生率高。
发明人分析认为，肾功能不全患者肾小球滤过率下降，药物排泄受阻，容易发生体内药物浓度过高和药物蓄积。头孢哌酮小部分通过尿液排泄，而他唑巴坦则大部分经过尿液排泄。高尿液排泄率虽然可以保证药物在泌尿系统的浓度，但同时也进一步增加了肾脏的负担。这些因素可能是头孢哌酮/他唑巴坦制剂在肾功能不全患者中容易导致不良反应的部分原因。另一方面，虽然肾功能不全合并细菌感染的患者体内药物浓度高，但并不意味着其可以从临床疗效方面获益。临床试验发现抗感染的效果可能反而变差。
而意外地发现，头孢哌酮/他唑巴坦6：1的组合物可以兼顾有效性和安全性。上述临床试验发现，总体而言，头孢哌酮/他唑巴坦6：1的组合物的临床疗效优于头孢哌酮/他唑巴坦4：1和头孢哌酮/他唑巴坦8：1，安全性方面略优于头孢哌酮/他唑巴坦4：1和头孢哌酮/他唑巴坦8：1。特别地，对于肾功能不全合并细菌感染的患者，头孢哌酮和他唑巴坦6：1的组合物的有效性和安全性均显著优于头孢哌酮/他唑巴坦4：1和头孢哌酮/他唑巴坦8：1，而在泌尿系统感染方面的优势最为突出。
实施例3：头孢哌酮钠/他唑巴坦钠(6：1)的稳定性研究
后续试验进一步对头孢哌酮钠/他唑巴坦钠(6：1)组合物的稳定性进行了研究。在一项试验中研究了化合物A((2S,3S)-2-(羧基乙烯基)氨基-3-甲基-3-亚磺酰基-4-(1H-1,2,3-三唑-1-基)丁酸)(CAS号：120701-86-2)对头孢哌酮钠/他唑巴坦钠(6：1)组合物稳定性的影响。
通过在头孢哌酮钠/他唑巴坦钠(6：1)组合物中加入化合物A来进行研究。化合物A为市售品精制品(总杂质含量小于0.2％)，头孢哌酮钠为市售精制品(总杂质含量小于3％)，他唑巴坦钠为市售精制品(总杂质含量小于0.2％)。
取同一批次的化合物A、头孢哌酮钠、他唑巴坦钠。分别将不同重量(0.02g、0.1g、0.5g、1.5g)的化合物A，分别添加到含头孢哌酮钠(以头孢哌酮计)600g和他唑巴坦钠100g(以他唑巴坦计)的四个组合物中，依次得到四组含化合物A的组合物：化合物A组合物一组、化合物A组合物二组、化合物A组合物三组、化合物A组合物四组，分别充分混合均匀后，分别取样用于稳定性试验。同时另取头孢哌酮钠600g和他唑巴坦钠100g，充分混合均匀后，取样用于稳定性试验。
试验方法：将各样品于温度25±2℃、相对湿度60±10％的条件下放置24个月，分别于0月、3月、6月、12月、24月时取样，用HPLC法测定样品中有关物质(杂质)含量。HPLC色谱条件为：色谱柱：zorbax SB C18；流动相：乙腈：磷酸二氢钾溶液(0.03mol/L)：10％四丁基氢氧化铵溶液(190：795：15)，并用磷酸调pH值至4.0；检测波长：230nm。有关物质含量按照HPLC图谱中其他峰(除头孢哌酮、他唑巴坦和化合物A三者峰之外的所有峰)的面 积之和占头孢哌酮、他唑巴坦和化合物A三者峰面积之和的百分比来计算。试验结果见表7。
表7 稳定性试验中各组样品中有关物质含量(％)
Figure PCTCN2021121325-appb-000003
在稳定性试验中可以看出，不含化合物A的头孢哌酮钠/他唑巴坦钠(6：1)组合物，其杂质含量增加非常明显，24月时有关物质含量接近4％。含化合物A的头孢哌酮钠/他唑巴坦钠(6：1)组合物能够有效降低有关物质的产生，尤其是化合物A组合物一组、二组、三组，其杂质含量增加不明显，24月时有关物质含量仍然在2％以下，组合物的稳定性得到了显著的提高。化合物A组合物四组的稳定性也得到了提高，其24月时有关物质含量控制在3％以下，但效果不如组合物一组、二组、三组。因此，化合物A似乎可以对头孢哌酮钠/他唑巴坦钠(6：1)组合物起到稳定作用，但其用量最好控制在一定范围之内。
参考文献：
[1]张圣雨等.慢性肾功能不全患者使用头孢哌酮钠/他唑巴坦钠致抽搐6例报道[J].安徽医药,2014,18(11)：2193-2195.
[2]黄金平等.头孢哌酮舒巴坦/他唑巴坦致肾衰竭病人抽搐12例临床分析[J].安徽医药,2017,21(06)：1154-1156.
上文中用一般性说明及具体实施方式对本发明作了详尽的描述，在此基础上，本领域技术人员可以对之做一些变化或改进，这些变化或改进均属于本发明要求保护的内容。

Claims (28)

  1. 含有头孢哌酮钠和他唑巴坦钠的药物组合物在制备治疗肾功能不全合并细菌感染的药物中的应用，所述药物组合物中头孢哌酮钠(以头孢哌酮计)和他唑巴坦钠(以他唑巴坦计)的重量比为6：1。
  2. 根据权利要求1所述的应用，所述药物组合物中头孢哌酮钠(以头孢哌酮计)的重量为1g～3g，所述他唑巴坦钠(以他唑巴坦计)的重量为0.17g～0.5g。
  3. 根据权利要求1所述的应用，所述的肾功能不全为严重肾功能不全。
  4. 根据权利要求3所述的应用，所述的严重肾功能不全是指肌酐清除率<30mL/min。
  5. 根据权利要求1所述的应用，所述的细菌感染选自呼吸系统感染或/和泌尿系统感染。
  6. 根据权利要求1所述的应用，所述治疗肾功能不全合并细菌感染的药物不产生肾功能下降的不良反应。
  7. 根据权利要求1所述的应用，所述治疗肾功能不全合并细菌感染的药物不产生中枢神经系统不良反应。
  8. 根据权利要求1所述的应用，所述药物组合物中还含有(2S,3S)-2-(羧基乙烯基)氨基-3-甲基-3-亚磺酰基-4-(1H-1,2,3-三唑-1-基)丁酸。
  9. 根据权利要求8所述的应用，所述的药物组合物中头孢哌酮钠(以头孢哌酮计)和(2S,3S)-2-(羧基乙烯基)氨基-3-甲基-3-亚磺酰基-4-(1H-1,2,3-三唑-1-基)丁酸的重量比为600：0.02-0.5。
  10. 一种用于治疗肾功能不全合并细菌感染的药物组合物，所述药物组合物中含有头孢哌酮钠和他唑巴坦钠，其中，头孢哌酮钠(以头孢哌酮计)和他唑巴坦钠(以他唑巴坦计)的重量比为6：1。
  11. 根据权利要求10所述的药物组合物，所述药物组合物中头孢哌酮钠(以头孢哌酮计)的重量为1g～3g，所述他唑巴坦钠(以他唑巴坦计)的重量为0.17g～0.5g。
  12. 根据权利要求10所述的药物组合物，所述的肾功能不全为严重肾功能不全。
  13. 根据权利要求12所述的药物组合物，所述的严重肾功能不全是指肌酐清除率<30mL/min。
  14. 根据权利要求10所述的药物组合物，所述的感染选自呼吸系统感染或/和泌尿系统感染。
  15. 根据权利要求10所述的药物组合物，所述的药物组合物治疗肾功能不全合并细菌感染不产生肾功能下降的不良反应。
  16. 根据权利要求10所述的药物组合物，所述的药物组合物治疗肾功能不全合并细菌感染不产生中枢神经系统不良反应。
  17. 根据权利要求10所述的药物组合物，所述的药物组合物中还含有(2S,3S)-2-(羧基乙烯基)氨基-3-甲基-3-亚磺酰基-4-(1H-1,2,3-三唑-1-基)丁酸。
  18. 根据权利要求17所述的药物组合物，所述的药物组合物中头孢哌酮钠(以头孢哌酮计)与(2S,3S)-2-(羧基乙烯基)氨基-3-甲基-3-亚磺酰基-4-(1H-1,2,3-三唑-1-基)丁酸的重量比为600：0.02-0.5。
  19. 一种治疗肾功能不全患者细菌感染的方法，包括向所需要的患者给予药物组合物，所述药物组合物中含有重量比为6：1的头孢哌酮钠(以头孢哌酮计)和他唑巴坦钠(以他唑巴坦计)。
  20. 根据权利要求19所述的方法，所述的肾功能不全患者是严重肾功能不全患者。
  21. 根据权利要求20所述的方法，所述的严重肾功能不全患者，其肌酐清除率<30mL/min。
  22. 根据权利要求19所述的方法，所述感染为呼吸系统感染和/或泌尿系统感染。
  23. 根据权利要求19所述的方法，所述的方法不产生肾功能下降的不良反应。
  24. 根据权利要求19所述的方法，所述的方法不产生中枢神经系统不良反应。
  25. 根据权利要求19所述的方法，所述药物组合物中还含有(2S,3S)-2-(羧基乙烯基)氨基-3-甲基-3-亚磺酰基-4-(1H-1,2,3-三唑-1-基)丁酸。
  26. 根据权利要求25所述的方法，所述药物组合物中头孢哌酮(以头孢哌酮计)与(2S,3S)-2-(羧基乙烯基)氨基-3-甲基-3-亚磺酰基-4-(1H-1,2,3-三唑-1-基)丁酸的重量比为600：0.02-0.5。
  27. 根据权利要求19所述的方法，所述头孢哌酮钠(以头孢哌酮计)的每日用量为1g～6g，所述他唑巴坦钠(以他唑巴坦计)的每日用量为0.17g～1g。
  28. 根据权利要求19所述的方法，所述药物组合物的使用频率为每8小时一次或每12小时一次。
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