CN109432101A - Cefoperazone sodium and tazobactam sodium medicament composition and preparation method thereof - Google Patents
Cefoperazone sodium and tazobactam sodium medicament composition and preparation method thereof Download PDFInfo
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- CN109432101A CN109432101A CN201811461672.7A CN201811461672A CN109432101A CN 109432101 A CN109432101 A CN 109432101A CN 201811461672 A CN201811461672 A CN 201811461672A CN 109432101 A CN109432101 A CN 109432101A
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- Prior art keywords
- sodium
- cefoperazone
- tazobactam
- cyclodextrin
- hydroxypropyl
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- NDIURPSCHWTXDC-UHFFFAOYSA-N 2-(4,5-dimethoxy-2-nitrophenyl)acetohydrazide Chemical compound COC1=CC(CC(=O)NN)=C([N+]([O-])=O)C=C1OC NDIURPSCHWTXDC-UHFFFAOYSA-N 0.000 title claims abstract description 85
- 229960000373 tazobactam sodium Drugs 0.000 title claims abstract description 85
- NCFTXMQPRQZFMZ-WERGMSTESA-M Cefoperazone sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C([O-])=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 NCFTXMQPRQZFMZ-WERGMSTESA-M 0.000 title claims abstract description 68
- 229960002417 cefoperazone sodium Drugs 0.000 title claims abstract description 68
- 239000000203 mixture Substances 0.000 title claims description 37
- 239000003814 drug Substances 0.000 title claims description 31
- 238000002360 preparation method Methods 0.000 title abstract description 15
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 23
- 229960003865 tazobactam Drugs 0.000 claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 12
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 claims description 47
- 229960004682 cefoperazone Drugs 0.000 claims description 46
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 21
- 239000012467 final product Substances 0.000 claims description 13
- 238000004108 freeze drying Methods 0.000 claims description 12
- 238000011049 filling Methods 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000008236 heating water Substances 0.000 claims description 6
- -1 hydroxypropyl Chemical group 0.000 claims description 5
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 239000002504 physiological saline solution Substances 0.000 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 claims 3
- 239000001116 FEMA 4028 Substances 0.000 claims 3
- 229960004853 betadex Drugs 0.000 claims 3
- 239000002253 acid Substances 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 7
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 abstract description 4
- 229940090044 injection Drugs 0.000 description 13
- 239000007924 injection Substances 0.000 description 13
- 238000002347 injection Methods 0.000 description 13
- 230000033228 biological regulation Effects 0.000 description 11
- 241000894006 Bacteria Species 0.000 description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 229930186147 Cephalosporin Natural products 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229940124587 cephalosporin Drugs 0.000 description 3
- 150000001780 cephalosporins Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 2
- 206010024971 Lower respiratory tract infections Diseases 0.000 description 2
- 201000009906 Meningitis Diseases 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 206010062255 Soft tissue infection Diseases 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 2
- 102000006635 beta-lactamase Human genes 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 229960001484 edetic acid Drugs 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 206010034674 peritonitis Diseases 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 208000013223 septicemia Diseases 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000019206 urinary tract infection Diseases 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 239000002132 β-lactam antibiotic Substances 0.000 description 2
- 229940124586 β-lactam antibiotics Drugs 0.000 description 2
- 241000589291 Acinetobacter Species 0.000 description 1
- 241000588624 Acinetobacter calcoaceticus Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000606124 Bacteroides fragilis Species 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- 241000588923 Citrobacter Species 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 208000004145 Endometritis Diseases 0.000 description 1
- 241000588697 Enterobacter cloacae Species 0.000 description 1
- 241000588921 Enterobacteriaceae Species 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- 241000588656 Neisseriaceae Species 0.000 description 1
- 206010058674 Pelvic Infection Diseases 0.000 description 1
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 208000007313 Reproductive Tract Infections Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 208000037386 Typhoid Diseases 0.000 description 1
- 206010046306 Upper respiratory tract infection Diseases 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 239000003781 beta lactamase inhibitor Substances 0.000 description 1
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 201000001352 cholecystitis Diseases 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 150000003388 sodium compounds Chemical class 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 201000008297 typhoid fever Diseases 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a kind of Cefoperazone Sodium and Tazobactam pharmaceutical compositions and preparation method thereof.The present invention joined hydroxypropyl-β-cyclodextrin in cefoperazone sodium and tazobactam sodium, improve stability of the cefoperazone sodium and tazobactam sodium in preparation, storage and use process, and impurity content is few, purity is high ensure that the efficacy and saferry of cefoperazone sodium and tazobactam sodium clinical use.
Description
Technical field
The invention belongs to field of medicinal chemistry, in particular to cefoperazone sodium and tazobactam sodium medicament composition and
Preparation method.
Background technique
Cefoperazone is third generation cephalosporin, to escherichia coli, Klebsiella, Proteus, typhoid fever sramana
The enterobacteriaceae lactobacteriaceaes such as bacterium, Shigella, citrobacter category and pseudomonas aeruginosa have good antibacterial action；To production gas intestines bar
The effect of bacterium, enterobacter cloacae, bacillus typhi murium and acinetobacter etc. is poor.Bacillus influenzae, NEISSERIA GONORRHOEAE and meningitis
Neisseria is highly sensitive to cefoperazone.Cefoperazone also has good action to each group of streptococcus, pneumococcus, to staphylococcus
(methicillin-sensitivity strain) only have moderate effect, enterococcus spp is to cefoperazone drug resistance.Cefoperazone detests most Grain-positives
Oxygen bacterium and certain Grain-negative anaerobic bacterias have good action, and bacteroides fragilis is to cefoperazone drug resistance.Cefoperazone mainly inhibits
The synthesis of bacteria cell wall, suitable for various infection such as pneumonia caused by sensitive bacteria and other lower respiratory tract infection, urinary tract infections,
The treatment of infection of biliary tract, skin soft-tissue infection, septicemia, peritonitis, pelvic infection etc..
Tazobactam Sodium is beta-lactamase inhibitor, in addition to Neisseriaceae and acinetobacter calcoaceticus, to other bacteriums without antibacterial
Activity.But Tazobactam Sodium has not the most important beta-lactamases generated by beta-lactam antibiotic antibody-resistant bacterium
Reversible inhibiting effect can prevent destruction of the related drug-fast bacteria to penicillins and cephalosporins, to overcome
Clinical resistance caused by beta-lactamase bacterium is generated to infect.Therefore the compound of cephalosporin analog antibiotic and Tazobactam Sodium is developed
Preparation has important clinical meaning.
The cefoperazone sodium and tazobactam sodium compound preparation listed at present, for treating the production sensitive to cefoperazone
It does not produce in caused by the pathogen of lactamase, severe infection: the upper respiratory tract and lower respiratory tract infection；Upper urinary tract is secreted under
Urinary tract infection；Peritonitis, cholecystitis, cholangitis and other intraperitoneal infections；Septicemia；Meningitis；Skin and soft tissue infection；
Pelvic inflammatory disease, endometritis, stranguria syndrome and other reproductive tract infection.
Since cefoperazone sodium has hygroscopicity, mobility declines after deliquescing, and may occur to turn brilliant or polymerization,
Leading to the content of cefoperazone sodium reduces, and impurity content increases.During clinical use, the cefoperazone sodium of existing listing he
Zababatin sodium compound is used usually as injection, must be dissolved in diluent, cefoperazone sodium may be precipitated and muddiness occurs at this time
Phenomenon, and the content decline of cefoperazone sodium, seriously affect clinical use.Therefore, can cefoperazone sodium and tazobactam sodium pacify
It is effectively applied to the problem of clinic is at necessary concern entirely.
CN101129381 discloses a kind of antibiotic compound, by least one beta-lactam antibiotic and at least one
Ion chelating agent or at least one ion chelating agent and buffer components form.It is unfavorable largely to be caused using pH adjusting agent in the compound
It is lyophilized in cefoperazone sodium and is easier to degrade, and increase side effect.
CN104650115 discloses a kind of cefoperazone sodium and tazobactam sodium compound special type superfine powder preparation, using more
Grade crushes, and wherein the particle diameter of superfine powder is 0.5-3 μm.But it is increased after ultra micro dusting since specific surface area increases
The possibility of cefoperazone sodium polymerization, to increase impurity content, leading to clinical application, there may be risks.
CN101632677 discloses a kind of suspension powder injection of cefoperazone sodium and tazobactam sodium pharmaceutical composition, by cephalo
Piperazine ketone sodium, sodium-tazobactam, emulsifier, assistant for emulsifying agent and frozen-dried supporting agent composition, are stirred in 70-90 DEG C of heating water bath to melting
State, and tissue mincer's shear agitation is used under this condition, then through high pressure dispersing emulsification machine circulating emulsion.But such high temperature
Under high pressure, polymer and other impurities are dramatically increased, and then influence drug effect.
CN103120692 discloses a kind of preparation method of Cefoperazone Sodium and Tazobactam composition, described
The grinding particle size of cefoperazone sodium and sodium-tazobactam is 50-120 mesh.Advantage is to mix well, and guarantees the uniformity, has
Conducive to guaranteeing that divided dose is accurate, it is conducive to packing.
CN102552275 discloses a kind of cefoperazone sodium and Tazobactam Sodium composition of sodium powder ampoule agent for injection, includes head
Spore piperazine ketone sodium, sodium-tazobactam and lidocaine hydrochloride.Advantage is to can reduce cefoperazone sodium and tazobactam sodium injection
Feeling of pain in clinical injection, and do not influence drug effect.
Above-mentioned document is unresolved, and cefoperazone sodium and tazobactam sodium medicament composition stability is poor, purity is low, impurity contains
Measure high problem.
Summary of the invention
In order to solve, existing Cefoperazone Sodium and Tazobactam stability is poor, purity is low, impurity content is high
Problem, the present invention provides a kind of stable cefoperazone sodium and tazobactam sodium medicament compositions and preparation method thereof.
Cefoperazone sodium and tazobactam sodium medicament composition provided by the invention includes cefoperazone sodium, sodium-tazobactam
With hydroxypropyl-β-cyclodextrin (HP- β-CD).
According to one embodiment of present invention, each component weight is such as in cefoperazone sodium and tazobactam sodium medicament composition
Under: cefoperazone: Tazobactam Sodium: HP- β-CD is 1-10:1:0.01-100.
According to one embodiment of present invention, each component weight is such as in cefoperazone sodium and tazobactam sodium medicament composition
Under: cefoperazone: Tazobactam Sodium: HP- β-CD is 4-8:1:0.01-100.
According to one embodiment of present invention, each component weight is such as in cefoperazone sodium and tazobactam sodium medicament composition
Under: cefoperazone: Tazobactam Sodium: HP- β-CD is 4-8:1:0.1-50.
According to one embodiment of present invention, each component weight is such as in cefoperazone sodium and tazobactam sodium medicament composition
Under: cefoperazone: Tazobactam Sodium: HP- β-CD is 4-8:1:0.5-50.
According to one embodiment of present invention, each component weight is such as in cefoperazone sodium and tazobactam sodium medicament composition
Under: cefoperazone: Tazobactam Sodium: HP- β-CD is 4-8:1:10-30.
According to one embodiment of present invention, each component weight is such as in cefoperazone sodium and tazobactam sodium medicament composition
Under: cefoperazone: Tazobactam Sodium: HP- β-CD is 4:1:50.
According to one embodiment of present invention, each component weight is such as in cefoperazone sodium and tazobactam sodium medicament composition
Under: cefoperazone: Tazobactam Sodium: HP- β-CD is 8:1:30.
According to one embodiment of present invention, each component weight is such as in cefoperazone sodium and tazobactam sodium medicament composition
Under: cefoperazone: Tazobactam Sodium: HP- β-CD is 4:1:100.
According to one embodiment of present invention, each component weight is such as in cefoperazone sodium and tazobactam sodium medicament composition
Under: cefoperazone: Tazobactam Sodium: HP- β-CD is 8:1:100.
According to one embodiment of present invention, each component weight is such as in cefoperazone sodium and tazobactam sodium medicament composition
Under: cefoperazone: Tazobactam Sodium: HP- β-CD is 4:1:0.5.
According to one embodiment of present invention, each component weight is such as in cefoperazone sodium and tazobactam sodium medicament composition
Under: cefoperazone: Tazobactam Sodium: HP- β-CD is 8:1:10.
According to one embodiment of present invention, cefoperazone sodium and tazobactam sodium medicament composition provided by the invention also wraps
Containing natrium adetate.
According to one embodiment of present invention, natrium adetate quality in cefoperazone sodium and tazobactam sodium medicament composition
Percentage is 0.01-4%.
According to one embodiment of present invention, natrium adetate quality in cefoperazone sodium and tazobactam sodium medicament composition
Percentage is 0.01-3%.
According to one embodiment of present invention, natrium adetate quality in cefoperazone sodium and tazobactam sodium medicament composition
Percentage is 0.01-2%.
According to one embodiment of present invention, natrium adetate quality in cefoperazone sodium and tazobactam sodium medicament composition
Percentage is 0.1-2%.
According to one embodiment of present invention, natrium adetate quality in cefoperazone sodium and tazobactam sodium medicament composition
Percentage is 1%.
According to one embodiment of present invention, cefoperazone sodium and tazobactam sodium medicament composition is the system of parenterai administration
Agent, preferably powder ampoule agent for injection.
According to one embodiment of present invention, cefoperazone sodium and tazobactam sodium powder-injection preparation method: HP- β-is weighed
CD injects water to the aqueous solution for the HP- β-CD for obtaining 30%-50%, appropriate cefoperazone sodium, sodium-tazobactam is added,
Using ultrasonic method, ultrasonic power 200-450W, the inclusion time is 3-10min, using normal freeze-drying after taking filtrate filling
Method is lyophilized to obtain the final product.
According to one embodiment of present invention, cefoperazone sodium and tazobactam sodium powder-injection preparation method: HP- β-is weighed
CD injects water to the aqueous solution for the HP- β-CD for obtaining 30%-50%, appropriate cefoperazone sodium, sodium-tazobactam is added,
In 50-60 DEG C of heating water bath 1-2h, it is lyophilized after taking filtrate filling using normal freeze-drying method to obtain the final product.
According to one embodiment of present invention, cefoperazone sodium and tazobactam sodium powder-injection preparation method: HP- β-is weighed
CD adds water for injection to obtain the aqueous solution of the HP- β-CD of 30%-50%, and cefoperazone sodium, sodium-tazobactam and edetic acid(EDTA) is added
Disodium takes filtrate filling using ultrasonic method after ultrasonic power 200-450W, 3-10min, is frozen using normal freeze-drying method
It does to obtain the final product.
According to one embodiment of present invention, cefoperazone sodium and tazobactam sodium powder-injection preparation method: HP- β-is weighed
CD adds water for injection to obtain the aqueous solution of the HP- β-CD of 30%-50%, and cefoperazone sodium, sodium-tazobactam and edetic acid(EDTA) is added
Disodium takes filtrate filling in 50-60 DEG C of heating water bath 1-2h, is lyophilized using normal freeze-drying method to obtain the final product.
When Cefoperazone Sodium and Tazobactam pharmaceutical composition clinical use of the present invention, first infused with sodium chloride
Liquid or appropriate sterilized water for injection (5~10mL) dissolution are penetrated, then adds 5% glucose injection or sodium chloride injection dilution again
For intravenous drip.
Cefoperazone sodium and tazobactam sodium medicament composition of the invention is unexpected with good stability, redissolves
Quality is stablized afterwards；Need not introduce organic solvent, it is easy to operate, and do not have dissolvent residual, can reduce drug to immune system,
The toxicity of liver kidney organ, improves drug safety；It is easy to store, convenient transportation and can guarantee sterile, apyrogeneity.
Specific embodiment
Raw material used in the following embodiment, reagent are commercially available.
Embodiment one
It is formulated 1: cefoperazone 0.8g, Tazobactam Sodium 0.8g, hydroxypropyl-β-cyclodextrin 8mg.
It is formulated 2: cefoperazone 0.8g, Tazobactam Sodium 0.8g, hydroxypropyl-β-cyclodextrin 80g.
It is formulated 3: cefoperazone 1g, Tazobactam Sodium 0.1g, hydroxypropyl-β-cyclodextrin 1mg.
It is formulated 4: cefoperazone 1g, Tazobactam Sodium 0.1g, hydroxypropyl-β-cyclodextrin 10g.
It is formulated 5: cefoperazone 0.8g, Tazobactam Sodium 0.2g, hydroxypropyl-β-cyclodextrin 0.1g.
It is formulated 6: cefoperazone 0.8g, Tazobactam Sodium 0.1g, hydroxypropyl-β-cyclodextrin 0.05g.
It is formulated 7: cefoperazone 0.8g, Tazobactam Sodium 0.2g, hydroxypropyl-β-cyclodextrin 10g.
It is formulated 8: cefoperazone 0.8g, Tazobactam Sodium 0.1g, hydroxypropyl-β-cyclodextrin 5g.
It is formulated 9: cefoperazone 0.8g, Tazobactam Sodium 0.2g, hydroxypropyl-β-cyclodextrin 6g.
It is formulated 10: cefoperazone 0.8g, Tazobactam Sodium 0.1g, hydroxypropyl-β-cyclodextrin 3g.
It is formulated 11: cefoperazone 0.8g, Tazobactam Sodium 0.2g, hydroxypropyl-β-cyclodextrin 2g.
It is formulated 12: cefoperazone 0.8g, Tazobactam Sodium 0.1g, hydroxypropyl-β-cyclodextrin 1g.
It is formulated 13: cefoperazone 0.8g, Tazobactam Sodium 0.1g, hydroxypropyl-β-cyclodextrin 1mg, natrium adetate 10mg.
It is formulated 14: cefoperazone 0.8g, Tazobactam Sodium 0.2g, hydroxypropyl-β-cyclodextrin 20g, natrium adetate 850mg.
It is formulated 15: cefoperazone 0.8g, Tazobactam Sodium 0.2g, hydroxypropyl-β-cyclodextrin 2mg, natrium adetate 1mg.
It is formulated 16: cefoperazone 0.8g, Tazobactam Sodium 0.1g, hydroxypropyl-β-cyclodextrin 10g, natrium adetate 0.33g.
It is formulated 17: cefoperazone 0.8g, Tazobactam Sodium 0.2g, hydroxypropyl-β-cyclodextrin 0.1g, natrium adetate 1.1mg.
It is formulated 18: cefoperazone 0.8g, Tazobactam Sodium 0.1g, hydroxypropyl-β-cyclodextrin 0.05g, natrium adetate 19mg.
It is formulated 19: cefoperazone 0.8g, Tazobactam Sodium 0.2g, hydroxypropyl-β-cyclodextrin 10g, natrium adetate 1.1mg.
It is formulated 20: cefoperazone 0.8g, Tazobactam Sodium 0.1g, hydroxypropyl-β-cyclodextrin 5g, natrium adetate 60mg.
It is formulated 21: cefoperazone 0.8g, Tazobactam Sodium 0.2g, hydroxypropyl-β-cyclodextrin 6g, natrium adetate 35mg.
It is formulated 22: cefoperazone 0.8g, Tazobactam Sodium 0.1g, hydroxypropyl-β-cyclodextrin 3g, natrium adetate 39mg.
It is formulated 23: cefoperazone 0.8g, Tazobactam Sodium 0.2g, hydroxypropyl-β-cyclodextrin 2g, natrium adetate 30mg.
It is formulated 24: cefoperazone 0.8g, Tazobactam Sodium 0.1g, hydroxypropyl-β-cyclodextrin 1g, natrium adetate 9.5mg.
Inclusion compound verifying: using microscopic method, observes cefoperazone sodium and tazobactam sodium combination obtained by above-mentioned each formula
Object is different from HP- β-CD shape, and mainly lattice arrangement, which changes, causes.
Embodiment two: cefoperazone sodium and tazobactam sodium powder-injection
HP- β-CD is weighed by formula 1-12, injects water to obtain the aqueous solution of 50% HP- β-CD, cephalo is added
Piperazine ketone sodium, sodium-tazobactam, using ultrasonic method, ultrasonic power 200-450W, the inclusion time is 5-10min, 0.45 μm of micropore
After membrane filtration, it is lyophilized after taking filtrate filling using normal freeze-drying method to obtain the final product.
Embodiment three: cefoperazone sodium and tazobactam sodium powder-injection
HP- β-CD is weighed by formula 13-24, injects water to obtain the aqueous solution of 30% HP- β-CD, cephalo is added
Piperazine ketone sodium, sodium-tazobactam, natrium adetate take filter after 50-70 DEG C of heating water bath 1-2h, 0.45 μm of filtering with microporous membrane
It is lyophilized after liquid is filling using normal freeze-drying method to obtain the final product.
Reference examples 1: being formulated 395 proportions by CN101129381, take cefoperazone sodium 0.5g, sodium-tazobactam 0.1g,
EDTA1mg, sodium citrate 10mg, citric acid 20mg disclose preparation method by this application and are lyophilized to obtain the final product.
Reference examples 2: cefoperazone sodium 1g, sodium-tazobactam 0.25g are uniformly mixed, and routinely freeze-drying method is lyophilized
To obtain the final product.
Reference examples 3: the proportion announced by CN101036656 claim 5 takes cefoperazone sodium 0.4g (with cefoperazone
Acid meter), sodium-tazobactam 0.1g, sodium bicarbonate 0.4g, routinely freeze-drying method is lyophilized to obtain the final product.
Example IV: stability of the cefoperazone sodium and tazobactam sodium composition in physiological saline
Take his azoles of formula 1,4,7,10,11,13,14,19 and reference examples 1, reference examples 2,3 gained cefoperazone sodium of reference examples
Batan composition of sodium is appropriate, with the normal saline dilution of 10 times of volumes, dilution is placed in 4 DEG C of preservations, observation injection in 48h
The clarity of liquid and whether there is or not drug be precipitated etc. variation.It the results are shown in Table 1.
Table 1
| Formula | Clarity | Whether there is or not drug precipitations |
| 1 | Meet regulation | Nothing |
| 4 | Meet regulation | Nothing |
| 7 | Meet regulation | Nothing |
| 10 | Meet regulation | Nothing |
| 11 | Meet regulation | Nothing |
| 13 | Meet regulation | Nothing |
| 14 | Meet regulation | Nothing |
| 19 | Meet regulation | Nothing |
| Reference examples 1 | It is against regulation | Have |
| Reference examples 2 | It is against regulation | Have |
| Reference examples 3 | It is against regulation | Have |
As it can be seen that the cefoperazone sodium and tazobactam sodium medicament composition that the present invention obtains is with good stability, it is suitable for
Clinical use.
Embodiment five: influence factor test
Hot test: the composition that formula 1,7,13,19 and reference examples 1, reference examples 2, reference examples 3 obtain is laid in training
It supports in ware, is placed 10 days at 40 ± 2 DEG C or 60 ± 2 DEG C, respectively at the 5th day and the 10th day sampling analysis.It the results are shown in Table 2.
High humidity test: the composition that formula 1,7,13,19 and reference examples 1, reference examples 2, reference examples 3 obtain is laid in training
It supports in ware, is placed 10 days under the conditions of 25 ± 2 DEG C, relative humidity 90 ± 5%, respectively at the 5th day and the 10th day sampling analysis.Knot
Fruit is shown in Table 2.
Strong illumination test: the composition that formula 1,7,13,19 and reference examples 1, reference examples 2, reference examples 3 are obtained tiles
It in culture dish, is placed 10 days under 4500lx ± 500lx strong illumination, respectively at the 5th day and the 10th day sampling analysis.As a result
It is shown in Table 2.
Table 2
*: expression appearance is buff powder；*: expression appearance is yellow powder；* *: expression appearance is brown powder
End；* * *: indicate that appearance is agglomeration.
+: indicate related substance (%) < 0.5%；: indicate related substance (%) > 0.5%.
As it can be seen that resulting composition of the present invention is with good stability and impurity content is few, it is suitble to clinical use.
Claims (10)
1. a kind of cefoperazone sodium and tazobactam sodium medicament composition, including hydroxypropyl-β-cyclodextrin.
2. pharmaceutical composition according to claim 1, wherein each component weight ratio is as follows: cefoperazone: Tazobactam Sodium: hydroxypropyl
Group-beta-cyclodextrin is 1-10:1:0.01-100.
3. pharmaceutical composition according to claim 2, wherein each component weight ratio is as follows: cefoperazone: Tazobactam Sodium: hydroxypropyl
Group-beta-cyclodextrin is 4-8:1:0.1-100；It preferably, is 4-8:1:0.5-50；It is further preferred that being 4-8:1:10-30.
4. pharmaceutical composition according to claim 3, wherein each component weight ratio is as follows: cefoperazone: Tazobactam Sodium: hydroxypropyl
Group-beta-cyclodextrin is 4:1:50,8:1:30,4:1:100,8:1:100,4:1:0.5 or 8:1:10.
5. pharmaceutical composition according to any one of claims 1-4 further includes natrium adetate.
6. pharmaceutical composition according to claim 5, wherein the mass percent of natrium adetate is 0.01-4%；Preferably,
For 0.01-3%；It is further preferred that being 0.01-2%；It still more preferably, is 0.1-2%；More preferably 1%.
7. pharmaceutical composition described in -6 any one according to claim 1, the composition can be with physiological saline or 5% Portugal
Grape sugar is applied in combination.
8. the method for preparing pharmaceutical composition described in claim 1-4 any one, weighs hydroxypropyl-β-cyclodextrin, fill
The aqueous solution for obtaining the hydroxypropyl-β-cyclodextrin of 30%-50% with water is penetrated, cefoperazone sodium, sodium-tazobactam is added, using super
Sound method is taken filtrate filling after ultrasonic power 200-450W, 3-10min, is lyophilized using normal freeze-drying method to obtain the final product.
9. the method for preparing pharmaceutical composition described in claim 1-4 any one, weighs hydroxypropyl-β-cyclodextrin, fill
The aqueous solution for obtaining the hydroxypropyl-β-cyclodextrin of 30%-50% with water is penetrated, cefoperazone sodium, sodium-tazobactam is added, in 50-
60 DEG C of heating water bath 1-2h, take filtrate filling, are lyophilized using normal freeze-drying method to obtain the final product.
10. the method for preparing pharmaceutical composition as claimed in any one of claims 5 to 6 weighs hydroxypropyl-β-cyclodextrin, filling
The aqueous solution for obtaining the hydroxypropyl-β-cyclodextrin of 30%-50% with water is penetrated, cefoperazone sodium, sodium-tazobactam is added and according to ground
Acid disodium takes filtrate filling, using normal freeze-drying method using ultrasonic method after ultrasonic power 200-450W, 3-10min
It is lyophilized to obtain the final product；Or in 50-60 DEG C of heating water bath 1-2h, take filtrate filling, it is lyophilized using normal freeze-drying method to obtain the final product.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101129381A (en) * | 2006-08-25 | 2008-02-27 | 天津和美生物技术有限公司 | Antibiotic compound containing beta-lactam antibiotic and ion chelating agent |
| CN101264088A (en) * | 2008-04-25 | 2008-09-17 | 黄芝芳 | Antibiotics composition with stable content and rapid solubility |
| WO2010061330A1 (en) * | 2008-11-26 | 2010-06-03 | Viroblock S.A. | Methods for inhibiting gram-positive bacteria using non-phospholipid lipid vesicules |
| CN103948602A (en) * | 2014-04-30 | 2014-07-30 | 成都苑东药业有限公司 | Cefoperazone sodium and tazobactam sodium medicinal composition for injection and preparation method thereof |
-
2018
- 2018-12-03 CN CN201811461672.7A patent/CN109432101A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101129381A (en) * | 2006-08-25 | 2008-02-27 | 天津和美生物技术有限公司 | Antibiotic compound containing beta-lactam antibiotic and ion chelating agent |
| CN101264088A (en) * | 2008-04-25 | 2008-09-17 | 黄芝芳 | Antibiotics composition with stable content and rapid solubility |
| WO2010061330A1 (en) * | 2008-11-26 | 2010-06-03 | Viroblock S.A. | Methods for inhibiting gram-positive bacteria using non-phospholipid lipid vesicules |
| CN103948602A (en) * | 2014-04-30 | 2014-07-30 | 成都苑东药业有限公司 | Cefoperazone sodium and tazobactam sodium medicinal composition for injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 关志宇主编: "《药物制剂辅料与包装材料》", 31 January 2017, 中国医药科技出版社 * |
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