CN115252561B - Preparation method of ceftazidime avibactam sodium for injection - Google Patents
Preparation method of ceftazidime avibactam sodium for injection Download PDFInfo
- Publication number
- CN115252561B CN115252561B CN202211018268.9A CN202211018268A CN115252561B CN 115252561 B CN115252561 B CN 115252561B CN 202211018268 A CN202211018268 A CN 202211018268A CN 115252561 B CN115252561 B CN 115252561B
- Authority
- CN
- China
- Prior art keywords
- ceftazidime
- injection
- sodium
- avibactam sodium
- avibactam
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229960000484 ceftazidime Drugs 0.000 title claims abstract description 83
- NMVPEQXCMGEDNH-TZVUEUGBSA-N ceftazidime pentahydrate Chemical compound O.O.O.O.O.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 NMVPEQXCMGEDNH-TZVUEUGBSA-N 0.000 title claims abstract description 83
- 229960001496 avibactam sodium Drugs 0.000 title claims abstract description 68
- RTCIKUMODPANKX-JBUOLDKXSA-M avibactam sodium Chemical compound [Na+].NC(=O)[C@@H]1CC[C@H]2N(OS([O-])(=O)=O)C(=O)N1C2 RTCIKUMODPANKX-JBUOLDKXSA-M 0.000 title claims abstract description 67
- 238000002347 injection Methods 0.000 title claims abstract description 52
- 239000007924 injection Substances 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000002156 mixing Methods 0.000 claims abstract description 57
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 24
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 24
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000007789 gas Substances 0.000 claims abstract description 22
- 239000001307 helium Substances 0.000 claims abstract description 12
- 229910052734 helium Inorganic materials 0.000 claims abstract description 12
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 12
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 11
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 11
- 238000004806 packaging method and process Methods 0.000 claims abstract description 11
- 229930182555 Penicillin Natural products 0.000 claims abstract description 10
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims abstract description 10
- 229940049954 penicillin Drugs 0.000 claims abstract description 10
- 238000011049 filling Methods 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims description 15
- 239000005660 Abamectin Substances 0.000 claims description 14
- 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 claims description 13
- RRZXIRBKKLTSOM-XPNPUAGNSA-N avermectin B1a Chemical compound C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 RRZXIRBKKLTSOM-XPNPUAGNSA-N 0.000 claims description 13
- 229910052708 sodium Inorganic materials 0.000 claims description 13
- 239000011734 sodium Substances 0.000 claims description 13
- 239000000463 material Substances 0.000 claims description 11
- 238000005303 weighing Methods 0.000 claims description 11
- 238000005273 aeration Methods 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 238000007689 inspection Methods 0.000 claims description 9
- 238000012360 testing method Methods 0.000 claims description 8
- 239000003814 drug Substances 0.000 abstract description 18
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000007599 discharging Methods 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 15
- 239000000047 product Substances 0.000 description 10
- 229920001971 elastomer Polymers 0.000 description 6
- 238000011835 investigation Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 108090000204 Dipeptidase 1 Proteins 0.000 description 5
- 102000006635 beta-lactamase Human genes 0.000 description 5
- 238000004140 cleaning Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 238000009455 aseptic packaging Methods 0.000 description 2
- 239000003781 beta lactamase inhibitor Substances 0.000 description 2
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 2
- JEEWDSDYUSEQML-ROMZVAKDSA-M ceftazidime sodium Chemical compound [Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C([O-])=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 JEEWDSDYUSEQML-ROMZVAKDSA-M 0.000 description 2
- 229960002940 ceftazidime sodium Drugs 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000012797 qualification Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 2
- LVFGWOQWXQLVRO-XJDKXYGGSA-N (6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino)acetyl]amino]-8-oxo-3-(pyridin-1-ium-1-ylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;[(2s,5r)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl] hydrogen sulfate Chemical compound NC(=O)[C@@H]1CC[C@H]2N(OS(O)(=O)=O)C(=O)N1C2.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)/C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 LVFGWOQWXQLVRO-XJDKXYGGSA-N 0.000 description 1
- MGWGWNFMUOTEHG-UHFFFAOYSA-N 4-(3,5-dimethylphenyl)-1,3-thiazol-2-amine Chemical compound CC1=CC(C)=CC(C=2N=C(N)SC=2)=C1 MGWGWNFMUOTEHG-UHFFFAOYSA-N 0.000 description 1
- IBSREHMXUMOFBB-JFUDTMANSA-N 5u8924t11h Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O3)C=C[C@H](C)[C@@H](C(C)C)O4)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 IBSREHMXUMOFBB-JFUDTMANSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 102000028391 RNA cap binding Human genes 0.000 description 1
- 108091000106 RNA cap binding Proteins 0.000 description 1
- 229950008167 abamectin Drugs 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229920005557 bromobutyl Polymers 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 208000027096 gram-negative bacterial infections Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- -1 polyethylene tetrafluoroethylene Polymers 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000000007 visual effect Effects 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (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)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of ceftazidime avibactam sodium for injection, which comprises the steps of firstly adding ceftazidime and anhydrous sodium carbonate into a mixer for premixing, then adding avibactam sodium into the mixer for total mixing, preparing a ceftazidime avibactam sodium product for injection with the medicine mixing uniformity of less than 3%, aseptically packaging the ceftazidime avibactam sodium product for injection into a penicillin bottle, and filling mixed gas of nitrogen, helium and carbon dioxide, thereby effectively improving the content uniformity of the ceftazidime avibactam sodium for injection. Therefore, by selecting proper raw material proportion and using specific discharging sequence and mixing parameters, the uniformity of the medicine components can be improved, and the technical problems that the medicine components are unevenly mixed and are easy to be layered or unevenly distributed, so that the uniformity of the medicine content is unqualified and the quality of medicines is influenced are solved.
Description
Technical Field
The application relates to the field of medicine preparation, in particular to a preparation method of ceftazidime avibactam sodium for injection.
Background
Ceftazidime is a cephalosporin antibiotic, and has the characteristics of wide antibacterial spectrum, high antibacterial activity and high stability to various beta-lactamase.
The avermectin sodium is a novel non-beta-lactamase inhibitor, the chemical structure of the avermectin sodium does not contain a beta-lactamase ring, the acylation reaction which occurs when the avermectin sodium is covalently combined with beta-lactamase is reversible, and the generated product cannot be hydrolyzed, so that the avermectin sodium has wider, stronger and longer-acting inhibition effect on the beta-lactamase.
The ceftazidime avibactam sodium for injection is a compound preparation prepared from cephalosporin (ceftazidime) and a beta-lactamase inhibitor (avibactam sodium) according to a certain proportion, the avibactam sodium can obviously improve the concentration and activity of the ceftazidime and can inactivate certain beta-lactamase which decomposes the ceftazidime, so that the antibacterial activity of the ceftazidime can be recovered or enhanced by combining the avibactam sodium with the ceftazidime, and the ceftazidime avibactam sodium for injection can be used for treating gram-negative bacterial infection, especially serious infection caused by drug-resistant bacteria.
Due to the difference of physical properties of ceftazidime, avibactam sodium and anhydrous sodium carbonate in relative molecular mass, density, hydrodynamic parameters and the like, the situation that medicine components are not uniform can still occur by fully mixing ceftazidime avibactam sodium for injection or layering, uneven distribution or unstable situation of a uniform final product in the process of subsequent transportation, storage and the like still occurs in the prior art, so that content uniformity is unqualified, and the quality of medicines is further influenced.
Disclosure of Invention
The application provides a preparation method of ceftazidime avibactam sodium for injection, which is used for solving the technical problems that the medicine components are unevenly mixed and are easy to be layered, unevenly distributed or unstable, so that the quality of the medicine is unqualified.
The technical scheme adopted by the invention is as follows:
the preparation method of ceftazidime avibactam sodium for injection comprises the following steps:
s1, weighing ceftazidime, avibactam sodium and anhydrous sodium carbonate according to a prescription amount, and marking, wherein the mass ratio of the ceftazidime, the anhydrous sodium carbonate and the avibactam sodium in the prescription amount is 75:7.5:17.5;
s2, premixing, and vacuum sucking the ceftazidime and the anhydrous sodium carbonate into a mixer to obtain an intermediate mixed material;
s3: mixing, namely vacuum sucking the avibactam sodium into the mixer, and mixing the avibactam sodium with the intermediate mixture to obtain ceftazidime avibactam sodium for injection;
s4: qualified inspection, namely inspecting ceftazidime avermectin sodium for injection obtained in the step S3;
s5: and (3) sterile packaging, namely sterile packaging the qualified ceftazidime avermectin sodium for injection in the step (S4) into a penicillin bottle, and filling mixed gas to obtain a ceftazidime avermectin sodium product for injection.
Optionally, the premixing time in step S2 is 20min.
Optionally, the total mixing time in the step S3 is 25-35 min.
Optionally, the mixer is a three-dimensional motion mixer, and the mixing rotating speed of the mixer is 30-40 Hz.
Optionally, mixing uniformity inspection is carried out on ceftazidime avibactam sodium for injection obtained in the step S3.
Alternatively, the RSD obtained from the blend uniformity test is <3%.
Optionally, in step S5, the mixed gas is nitrogen, helium, and carbon dioxide.
Optionally, the volume ratio of nitrogen, helium to carbon dioxide is 6:1:3.
optionally, the aeration flow rate of the mixed gas is 50-60L/min, and the aeration time is 3-5s.
Alternatively, the mixed gas filling amount is controlled to + -5%.
From the above technical solutions, the embodiments of the present application have the following advantages:
in the invention, the ceftazidime is an acidic substance, has certain hydrophobicity and is difficult to dissolve in the acidic substance, the solubility is high under the condition of near neutral pH, and the anhydrous sodium carbonate is added as a cosolvent, is alkaline, and can be adjusted to be neutral to increase the solubility of the ceftazidime.
According to the invention, the ceftazidime and the anhydrous sodium carbonate are mixed according to a specific raw material adding sequence, specific mixing time and mixing rotating speed, namely, firstly, the ceftazidime and the anhydrous sodium carbonate are added for premixing, the mixing rotating speed is set to be 35Hz, the mixing time is set to be 20min, the anhydrous sodium carbonate can be effectively and uniformly distributed in the ceftazidime, and the ceftazidime is favorably dissolved, so that the ceftazidime and the anhydrous sodium carbonate are uniformly mixed, and then the avibactam sodium is added for total mixing, the mixing rotating speed is set to be 35Hz, and the mixing time is set to be 25-35 min, so that the mixing uniformity and content uniformity of the three are further improved.
According to the invention, by controlling the inflation flow rate and the inflation time, the mixed gas of nitrogen, helium and carbon dioxide is filled, so that the residual oxygen in the penicillin bottle can be removed, oxidation of ceftazidime avibactam sodium for injection in the penicillin bottle is avoided, the chemical stability of the product is improved, and layering or uneven distribution of the product in the subsequent transportation, storage and other processes is avoided.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings that are needed in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments described in the present application, and other drawings may be obtained according to these drawings for a person having ordinary skill in the art.
Fig. 1 is a schematic flow chart of a preparation method of ceftazidime avibactam sodium for injection provided in an embodiment of the application.
Fig. 2 is a schematic flow chart of the actual production process for preparing ceftazidime avibactam sodium for injection provided in the embodiment of the application.
Detailed Description
In order to make the present application solution better understood by those skilled in the art, the following description will clearly and completely describe the technical solution in the embodiments of the present application with reference to the accompanying drawings in the embodiments of the present application, and it is apparent that the described embodiments are only some embodiments of the present application, not all embodiments. All other embodiments, which can be made by one of ordinary skill in the art without undue burden from the present disclosure, are within the scope of the present disclosure.
Example 1
The preparation method of ceftazidime avibactam sodium for injection comprises the following steps:
s1: weighing, namely weighing 2.36 parts by weight of ceftazidime, 0.55 parts by weight of avibactam sodium and 0.24 parts by weight of anhydrous sodium carbonate according to the mass ratio of 75:7.5:17.5 of ceftazidime, anhydrous sodium carbonate to avibactam sodium, and marking; the weighing step is performed in a class A laminar flow zone;
s2: premixing, namely sucking ceftazidime and anhydrous sodium carbonate into a mixer in vacuum to obtain an intermediate mixed material, setting the premixing time to be 20min, and setting the mixing rotating speed to be 35Hz;
s3: total mixing, namely sucking the avibactam sodium into the mixer in vacuum, mixing the avibactam sodium with the intermediate mixture to obtain ceftazidime avibactam sodium for injection, setting the total mixing time to be 30min, and setting the mixing rotating speed to be 35Hz;
s4: performing qualification test, namely performing mixing uniformity test on ceftazidime avibactam sodium for injection obtained in the step S3, transferring the materials into a sterilized and dried aluminum barrel after the inspection is qualified, temporarily storing the materials in a class A area, and ensuring that the stacking height of the materials is not more than 280mm;
s5: sterile packaging, namely aseptically packaging the qualified ceftazidime avibactam sodium for injection in the step S4 into a penicillin bottle, and filling nitrogen, helium and carbon dioxide in a volume ratio of 6:1:3, removing the gas in the bottle, covering the rubber plug, wherein the charging flow rate of the gas mixture is 55L/min, the charging time is 4s, and the charging amount of the gas mixture is controlled to +/-5 percent, so as to obtain the ceftazidime avibactam sodium product for injection.
Example 2
The procedure of this example was essentially the same as in example 1, except that the total mixing time of step S3 was 25 minutes and the mixing speed was 40Hz.
Example 3
The procedure of this example was essentially the same as in example 1, except that the total mixing time of step S3 was 35min and the mixing speed was 30Hz.
Example 4
The procedure of this example was the same as that of example 1, except that the aeration flow rate of the mixed gas in step S5 was 50L/min and the aeration time was 3S.
Example 5
The procedure of this example was substantially the same as that of example 1, except that the mixing time of the total mixing of S3 was 25min, the mixing speed was 40Hz, the aeration flow rate of the mixed gas in step S5 was 60L/min, and the aeration time was 5S.
Comparative example 1
S1: weighing 2.36 parts by weight of ceftazidime, 0.55 parts by weight of avibactam sodium and 0.24 parts by weight of anhydrous sodium carbonate, and marking; the weighing step is performed in a class A laminar flow zone;
s2: mixing, namely vacuum sucking ceftazidime, anhydrous sodium carbonate and avibactam sodium into a mixer to obtain a mixed material, setting the mixing time to be 50min, and setting the mixing rotating speed to be 35Hz;
s3: qualified inspection, namely performing mixing uniformity inspection on ceftazidime avibactam sodium for injection obtained in the step S2;
s4: sterile packaging, namely aseptically packaging the qualified ceftazidime avibactam sodium for injection in the step S3 into a penicillin bottle, and filling nitrogen, helium and carbon dioxide in a volume ratio of 6:1:3, removing the gas in the bottle, covering the rubber plug, and controlling the filling quantity of the gas mixture to +/-5% to obtain the ceftazidime avermectin sodium product for injection.
Comparative example 2
The procedure of this comparative example was essentially the same as in example 1, except that the premixing time was 20min, the mixing speed was 45Hz, the total mixing time was 45min, and the mixing speed was 45Hz.
Comparative example 3
The procedure of this comparative example was essentially the same as in example 1, except that in step S5, the volume ratio of nitrogen, helium to carbon dioxide was 4:4: 2.
Comparative example 4
The procedure of this comparative example was essentially the same as in example 1, except that in step S5, nitrogen, helium and carbon dioxide were charged in a volume ratio of 3:3: 4.
Comparative example 5
The procedure of this comparative example was substantially the same as in example 1, except that the aeration flow rate of the mixed gas in step S5 was 80L/min and the aeration time was 2S.
Mixing uniformity test:
the ceftazidime avermectin sodium products for injection prepared in examples 1-3 and comparative examples 1-2 are taken and inspected with a proper amount, specifically, 10min, 20min and 30min in the total mixing process, a stainless steel sterile sampler is adopted to measure the mixing uniformity by a 10-point sampling method, and the measurement results are shown in the following table 1:
table 1 list of measurement results
| Ceftazidime | Abamectin sodium | RSD | |
| Example 1 | 658μg/mg | 162μg/mg | 1.6％ |
| Example 2 | 659μg/mg | 163μg/mg | 1.7％ |
| Example 3 | 657μg/mg | 164μg/mg | 1.5％ |
| Comparative example 1 | 652μg/mg | 168μg/mg | 3.1％ |
| Comparative example 2 | 655μg/mg | 166μg/mg | 3.6％ |
As can be seen from the table, by comparing the ceftazidime and avibactam sodium for injection prepared by the examples with the comparative examples, weighing the ceftazidime, anhydrous sodium carbonate and avibactam sodium according to the mass ratio of 75:7.5:17.5, adding the ceftazidime and the anhydrous sodium carbonate into a three-dimensional motion mixer for premixing at one time, and adding the avibactam sodium for total mixing, wherein the premixing and total mixing set a specific mixing time and a specific mixing rotating speed, and finally RSD <3% is obtained, which indicates that the obtained product has good uniformity of substances and high mixing uniformity.
Stability test:
according to the requirements of the current edition on drug stability investigation in Chinese pharmacopoeia and annex and according to the quality standard of ceftazidime avermectin for injection and the investigation items listed in the injection stability investigation project table, the samples obtained in examples 1, 4-5 and comparative examples 3-5 are respectively placed under the acceleration condition for 6 months to conduct stable line investigation and evaluate the quality change, wherein the investigation items comprise properties, ceftazidime and avermectin sodium content, total impurity content and the like, and the investigation results are shown in the following table 2:
table 2 review of the results list of the project
The long-term test results show that ceftazidime, anhydrous sodium carbonate and avibactam sodium for injection with the uniformity meeting the requirement are obtained through the steps of premixing and total mixing, and the ceftazidime avibactam sodium for injection is packaged in a penicillin bottle and then filled with the ceftazidime avibactam sodium with the volume ratio of 6:1:3, after the mixed gas of nitrogen, helium and nitrogen dioxide is accelerated for 6 months and placed, the main medicine components of ceftazidime, avibactam sodium content, total impurity content and medicine color measurement result in the ceftazidime avibactam sodium for injection have no obvious change compared with the initial result. After being placed for 6 months at the same time, the medicine is not layered by visual observation. After the ceftazidime sodium for injection is placed for 6 months in the comparative example, the content of main medicine components and the total impurity content are obviously changed, the total magazine content is increased, the medicine is oxidized, and the medicine is found to have layering, so that the ceftazidime sodium for injection obtained by the preparation method is more stable and has better uniformity.
Example 6
In the actual production process of ceftazidime avibactam sodium for injection, the preparation process further comprises the steps of bottle washing, rubber plug cleaning, cap binding and the like, as shown in fig. 2, and the specific process flow is as follows:
s1: weighing, namely weighing 2.36 parts by weight of ceftazidime, 0.55 parts by weight of avibactam sodium and 0.24 parts by weight of anhydrous sodium carbonate according to the mass ratio of 75:7.5:17.5 of ceftazidime, anhydrous sodium carbonate to avibactam sodium, and marking; the weighing step is performed in a class A laminar flow zone;
s2: premixing, namely sucking ceftazidime and anhydrous sodium carbonate into a mixer in vacuum to obtain an intermediate mixed material, setting the premixing time to be 20min, and setting the mixing rotating speed to be 35Hz;
s3: total mixing, namely sucking the avibactam sodium into the mixer in vacuum, mixing the avibactam sodium with the intermediate mixture to obtain ceftazidime avibactam sodium for injection, setting the total mixing time to be 30min, and setting the mixing rotating speed to be 35Hz;
s4: performing qualification test, namely performing mixing uniformity test on ceftazidime avibactam sodium for injection obtained in the step S3, transferring the materials into a sterilized and dried aluminum barrel after the inspection is qualified, temporarily storing the materials in a class A area, and ensuring that the stacking height of the materials is not more than 280mm;
s5: washing the bottle, and sterilizing and cleaning the penicillin bottle by using a tunnel oven dry heat, wherein the sterilization temperature is 325-350 ℃, the mesh belt speed is 70%, and the pressure difference is 10Pa.
S6: and cleaning the rubber plug, cleaning the brominated butyl rubber plug coated with the polyethylene tetrafluoroethylene film by using a full-automatic wet air-flushing type rubber plug cleaning machine, and sterilizing for 30min at 121 ℃.
S7: and (3) carrying out aseptic packaging, namely carrying out aseptic packaging on qualified ceftazidime avibactam sodium for injection in the step (S5) into penicillin bottles by using a screw packaging machine, and filling nitrogen, helium and carbon dioxide in a volume ratio of 6:1:3, removing the gas in the bottle, covering the rubber plug, wherein the charging flow rate of the gas mixture is 55L/min, the charging time is 4s, and the charging amount of the gas mixture is controlled to +/-5 percent, so as to obtain the ceftazidime avibactam sodium product for injection.
S8: and (5) capping, lamp inspection, labeling and packaging to obtain the final ceftazidime avermectin sodium product for injection.
The above embodiments are merely for illustrating the technical solution of the present application, and not for limiting the same; although the present application has been described in detail with reference to the foregoing embodiments, it should be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the corresponding technical solutions.
Claims (4)
1. The preparation method of ceftazidime avibactam sodium for injection is characterized by comprising the following steps of:
s1, weighing ceftazidime, avibactam sodium and anhydrous sodium carbonate according to a prescription amount, and marking, wherein the mass ratio of the ceftazidime, the anhydrous sodium carbonate and the avibactam sodium in the prescription amount is 75:7.5:17.5;
s2, premixing, namely vacuum sucking the ceftazidime and the anhydrous sodium carbonate into a three-dimensional motion mixer to obtain an intermediate mixed material, wherein the premixing time is 20min, and the mixing rotating speed is 30-40 Hz;
s3: the avibactam sodium is sucked into the three-dimensional motion mixer in vacuum and mixed with the intermediate mixture to obtain ceftazidime avibactam sodium for injection, the total mixing time is 25-35 min, and the mixing rotating speed is 30-40 Hz;
s4: qualified inspection, namely inspecting ceftazidime avermectin sodium for injection obtained in the step S3;
s5: sterile packaging, namely sterile packaging the qualified ceftazidime avibactam sodium for injection in the step S4 into a penicillin bottle, and filling mixed gas to obtain a ceftazidime avibactam sodium product for injection, wherein the mixed gas is nitrogen, helium and carbon dioxide, and the volume ratio of the nitrogen, the helium and the carbon dioxide is 6:1:3, a step of; the aeration flow rate of the mixed gas is 50-60L/min, and the aeration time is 3-5s.
2. The method for preparing ceftazidime avibactam sodium for injection according to claim 1, wherein the ceftazidime avibactam sodium for injection obtained in the step S3 is subjected to mixing uniformity inspection.
3. The method for preparing ceftazidime avibactam sodium for injection according to claim 2, wherein the RSD obtained by the mixing uniformity test is less than 3%.
4. The preparation method of ceftazidime avibactam sodium for injection according to claim 1, wherein the filling amount of the mixed gas is controlled to be +/-5%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211018268.9A CN115252561B (en) | 2022-08-24 | 2022-08-24 | Preparation method of ceftazidime avibactam sodium for injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211018268.9A CN115252561B (en) | 2022-08-24 | 2022-08-24 | Preparation method of ceftazidime avibactam sodium for injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115252561A CN115252561A (en) | 2022-11-01 |
| CN115252561B true CN115252561B (en) | 2024-02-02 |
Family
ID=83751973
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211018268.9A Active CN115252561B (en) | 2022-08-24 | 2022-08-24 | Preparation method of ceftazidime avibactam sodium for injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115252561B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016116788A1 (en) * | 2015-01-24 | 2016-07-28 | Wockhardt Limited | Nitrogen containing bicyclic compounds and their use in treatment of bacterial infections |
| CN110396104A (en) * | 2018-07-26 | 2019-11-01 | 赛法洛抗生素有限公司 | The new indication of Tai Siting cefotaxime pharmaceutical preparation treatment gynecological infection |
| CN113350511A (en) * | 2021-03-01 | 2021-09-07 | 郎俊娜 | Novel sterile powder filling mixed protective gas for injection |
-
2022
- 2022-08-24 CN CN202211018268.9A patent/CN115252561B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016116788A1 (en) * | 2015-01-24 | 2016-07-28 | Wockhardt Limited | Nitrogen containing bicyclic compounds and their use in treatment of bacterial infections |
| CN110396104A (en) * | 2018-07-26 | 2019-11-01 | 赛法洛抗生素有限公司 | The new indication of Tai Siting cefotaxime pharmaceutical preparation treatment gynecological infection |
| CN113350511A (en) * | 2021-03-01 | 2021-09-07 | 郎俊娜 | Novel sterile powder filling mixed protective gas for injection |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115252561A (en) | 2022-11-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111686072B (en) | Linezolid injection and preparation method thereof | |
| EP1349580B2 (en) | Process to improve stability of a pharmaceutical composition | |
| EP3919395B1 (en) | Initial bacteria confirmation method in content filling system, method for verifying content filling system, and culture method | |
| CN110638751A (en) | Stable sugammadex sodium injection and preparation method thereof | |
| CN115252561B (en) | Preparation method of ceftazidime avibactam sodium for injection | |
| CN110123745B (en) | Preparation method of paclitaxel injection resistant to terminal sterilization | |
| CN113350511B (en) | Novel sterile powder filling mixed shielding gas for injection | |
| CN111204487B (en) | Control method for residual oxygen amount in filled medicine package | |
| US7678828B2 (en) | Methods for the formulation and manufacture of artesunic acid for injection | |
| AU2017215419B2 (en) | Process of manufacturing a stable, ready to use infusion bag for an oxidation sensitive formulation | |
| CN108066338A (en) | New antibiotic composition when prevention and treatment aerobic bacteria and anaerobic bacteria mixed infection and preparation method thereof | |
| CN102579430A (en) | Composition of meropenem and L-arginine | |
| CN107050476A (en) | A kind of donkey-hide gelatin block sterilization process | |
| JP2001114339A (en) | Sterilized culture medium packaging product | |
| CN114601806A (en) | Preparation method of nicorandil freeze-dried preparation | |
| CN110664739A (en) | Ornidazole sodium chloride injection and preparation process thereof | |
| CN103432121A (en) | Preparation method of amoxicillim sodium and sulbactam sodium for injection | |
| CN104188916B (en) | Amoxicillin sodium potassium clavulanate composition | |
| CN110433140A (en) | A kind of production technology of mezlocillin for injection sulbactam powder-injection | |
| WO2021162094A1 (en) | Method for measuring hydrogen peroxide content on container inner surface | |
| KR100292227B1 (en) | Tak, Yakju manufacturing method that can be stored for a long time | |
| JP2553955B2 (en) | Method for sterilizing petri dishes made of synthetic resin for culture medium | |
| CN114056618A (en) | Packaging system of aseptic powder for injection | |
| Murty | Aseptic packaging and labeling | |
| RU2089183C1 (en) | Antibacterial preparation and a method of its preparing |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |