CN117398388A - Pharmaceutical preparation of ceftazidime avibactam sodium and preparation method thereof - Google Patents
Pharmaceutical preparation of ceftazidime avibactam sodium and preparation method thereof Download PDFInfo
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- CN117398388A CN117398388A CN202311556449.1A CN202311556449A CN117398388A CN 117398388 A CN117398388 A CN 117398388A CN 202311556449 A CN202311556449 A CN 202311556449A CN 117398388 A CN117398388 A CN 117398388A
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- Prior art keywords
- ceftazidime
- avibactam
- sodium
- avibactam sodium
- pharmaceutical preparation
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- 229960000484 ceftazidime Drugs 0.000 title claims abstract description 269
- 229960001496 avibactam sodium Drugs 0.000 title claims abstract description 246
- 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 235
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 106
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- 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 22
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 284
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 142
- 238000002156 mixing Methods 0.000 claims abstract description 89
- 239000000463 material Substances 0.000 claims abstract description 56
- 239000002994 raw material Substances 0.000 claims abstract description 28
- 238000007599 discharging Methods 0.000 claims abstract description 26
- 239000003381 stabilizer Substances 0.000 claims abstract description 26
- 230000001954 sterilising effect Effects 0.000 claims abstract description 26
- 238000004659 sterilization and disinfection Methods 0.000 claims abstract description 26
- 238000005303 weighing Methods 0.000 claims abstract description 26
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims abstract description 9
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 9
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims abstract description 9
- 229960000502 poloxamer Drugs 0.000 claims abstract description 9
- 229920001983 poloxamer Polymers 0.000 claims abstract description 9
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims abstract description 8
- 239000011261 inert gas Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 5
- 238000011049 filling Methods 0.000 claims description 72
- 239000002245 particle Substances 0.000 claims description 54
- 238000004806 packaging method and process Methods 0.000 claims description 27
- 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 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- 239000005660 Abamectin Substances 0.000 claims description 9
- 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 9
- 230000007613 environmental effect Effects 0.000 claims 1
- 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 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 8
- 239000012535 impurity Substances 0.000 abstract description 8
- 239000000203 mixture Substances 0.000 abstract description 3
- 239000002131 composite material Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- ORFOPKXBNMVMKC-DWVKKRMSSA-N ceftazidime Chemical compound 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 ORFOPKXBNMVMKC-DWVKKRMSSA-N 0.000 description 247
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 88
- 239000001569 carbon dioxide Substances 0.000 description 44
- 229910002092 carbon dioxide Inorganic materials 0.000 description 44
- 239000013078 crystal Substances 0.000 description 26
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 25
- 239000001301 oxygen Substances 0.000 description 25
- 229910052760 oxygen Inorganic materials 0.000 description 25
- 238000009455 aseptic packaging Methods 0.000 description 23
- 230000000052 comparative effect Effects 0.000 description 20
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 238000011835 investigation Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 108090000204 Dipeptidase 1 Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003781 beta lactamase inhibitor Substances 0.000 description 2
- 102000006635 beta-lactamase Human genes 0.000 description 2
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229960002379 avibactam Drugs 0.000 description 1
- NDCUAPJVLWFHHB-UHNVWZDZSA-N avibactam Chemical compound C1N2[C@H](C(N)=O)CC[C@@]1([H])N(OS(O)(=O)=O)C2=O NDCUAPJVLWFHHB-UHNVWZDZSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000005388 borosilicate glass Substances 0.000 description 1
- 229920005556 chlorobutyl Polymers 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- -1 polytetrafluoroethylene Polymers 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 1
- 229960005256 sulbactam Drugs 0.000 description 1
- 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 description 1
- 229960003865 tazobactam Drugs 0.000 description 1
- 125000000647 trehalose group Chemical group 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 150000003952 β-lactams Chemical class 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
- A61K31/55—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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application relates to the technical field of medicine preparation, and in particular discloses a ceftazidime avibactam sodium medicine preparation and a preparation method thereof. The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime and avibactam sodium containing sodium carbonate; the composition also comprises a stabilizer, wherein the stabilizer is prepared by mixing trehalose and poloxamer in a mass ratio of 2:1-5, and the formula is simple and the proportion is strict; the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps: s1, carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium respectively, weighing, uniformly mixing, and discharging to obtain a mixed material; s2, aseptic subpackaging is carried out on the mixed materials, and inert gas is filled to obtain the composite material; the method has simple steps and low cost, and is suitable for industrial production; the obtained pharmaceutical preparation has good stability, less impurities, good quality and wide market prospect.
Description
Technical Field
The application relates to the technical field of medicine preparation, in particular to a pharmaceutical preparation of ceftazidime avibactam sodium and a preparation method thereof.
Background
The ceftazidime avibactam sodium for injection is a novel enzyme inhibitor compound preparation, belongs to beta-lactam/beta-lactamase inhibitor compound, can inhibit beta-lactamase activity, reduces hydrolysis of ceftazidime, has wider avibactam enzyme inhibition spectrum and stronger enzyme inhibition effect compared with the existing beta-lactamase inhibitors (sulbactam, tazobactam and the like), and can treat infections caused by drug-resistant gram-negative bacteria including CRE, multi-drug resistant pseudomonas aeruginosa, bacteria producing ultra-broad spectrum beta-lactamase and the like.
The ceftazidime and avibactam sodium pharmaceutical preparation is prepared by mixing and sterile packaging two raw material medicaments of ceftazidime and avibactam sodium, wherein the two raw material medicaments are easy to decompose under the conditions of light, heat and oxygen, so that the impurity of the product is increased, and the content of active ingredients is reduced.
At present, CN116606306A discloses a preparation process of ceftazidime avermectin sodium for injection, which comprises the following steps of: s1, refining ceftazidime and avibactam sodium respectively; s11, dissolving: dissolving ceftazidime and avibactam sodium respectively to obtain a ceftazidime solution and a avibactam sodium solution; s12, removing impurities; s13, crystallizing: firstly adding vitamin E and sodium sulfate into the solution, uniformly stirring, and then cooling for crystallization; s14, powdering: sequentially filtering and drying the solution after crystallization to obtain ceftazidime powder and avibactam sodium powder; s2, uniformly mixing the ceftazidime obtained in the step S1 with sodium carbonate according to a specified proportion; s3, mixing the avibactam sodium obtained in the step S1 and the ceftazidime containing sodium obtained in the step S2 according to a specified proportion; the preparation method improves the stability of the ceftazidime avibactam sodium pharmaceutical preparation to a certain extent, but still cannot meet higher clinical requirements, so that the ceftazidime avibactam sodium pharmaceutical preparation and the preparation method thereof are needed to be provided, and the stability of the ceftazidime avibactam sodium pharmaceutical preparation is further improved, so that the application market is enlarged.
Disclosure of Invention
In order to solve the problem of poor stability of the existing ceftazidime avibactam sodium pharmaceutical preparation, the application provides the ceftazidime avibactam sodium pharmaceutical preparation and a preparation method thereof.
The application is realized by the following technical scheme:
in a first aspect, the present application provides a pharmaceutical formulation of ceftazidime avibactam sodium, which adopts the following technical scheme:
the ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials in parts by weight: 1.8-2.5 parts of ceftazidime containing sodium carbonate and 0.7-0.9 part of avibactam sodium;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1-2.
Preferably, the average particle size of the ceftazidime containing sodium carbonate is 50-65 mu m, and the average particle size of the avibactam sodium is 160-178 mu m.
Preferably, the average particle size of the avibactam sodium is 2.5-3.5 times of that of ceftazidime containing sodium carbonate.
Preferably, the avibactam sodium is in a B crystal form.
Preferably, the ceftazidime avibactam sodium pharmaceutical preparation further comprises 0.1-0.2 part of stabilizer.
Preferably, the stabilizer is a mixture of trehalose and poloxamer.
Preferably, the stabilizer is prepared by mixing trehalose and poloxamer in a mass ratio of 2:1-5.
In a second aspect, the present application provides a method for preparing a pharmaceutical preparation of ceftazidime avibactam sodium, which adopts the following technical scheme:
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium respectively, weighing, uniformly mixing, and discharging to obtain a mixed material;
s2, sterile packaging is carried out on the mixed materials, and then inert gas is filled, so that the ceftazidime avibactam sodium pharmaceutical preparation is obtained.
Preferably, in the step S1, the mixing rotating speed is 30-69Hz, and the mixing time is 20-45min.
Preferably, the relative humidity of the environment in the split charging in the step S2 is less than or equal to 58%, and the split charging speed is 90-130 counts/min.
Preferably, the inert gas is filled in the step S2 at a flow rate of 65-70L/min, a filling pressure of 6-8MPa and a filling time of 2-3S.
Preferably, the inert gas is one of carbon dioxide, nitrogen and helium.
Preferably, the residual oxygen content in the product bottle in the step S2 is controlled below 3%.
In summary, the present application has the following beneficial effects:
1. the ceftazidime and avibactam sodium pharmaceutical preparation comprises ceftazidime and avibactam sodium of sodium carbonate, and is prepared by controlling the weight parts of the ceftazidime and avibactam sodium, the grain size and the crystal form of avibactam sodium; meanwhile, the composition comprises a stabilizer, wherein the stabilizer is prepared by mixing trehalose and poloxamer; the ceftazidime avibactam sodium pharmaceutical preparation has high stability and enhances the medicinal curative effect.
2. The ceftazidime and avibactam sodium pharmaceutical preparation is prepared by mixing and aseptically packaging ceftazidime and avibactam sodium containing sodium carbonate, various process parameters are controlled, the impurity content of the product is remarkably reduced, the content of active ingredients is further enhanced, and the obtained pharmaceutical preparation has a wide application prospect.
Detailed Description
The present application is described in further detail below with reference to examples.
Examples 1-12 provide pharmaceutical formulations of ceftazidime avermectin sodium and methods of preparing the same.
Example 1
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g and avibactam sodium 0.7g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1;
ceftazidime containing sodium carbonate has an average particle size of 65 μm; the average particle size of the avibactam sodium is 178 mu m; and the average grain diameter of the avibactam sodium is 2.7 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 90 counts/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 65L/min, the filling pressure is 6MPa, the filling time is 2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Example 2
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: 2g of ceftazidime containing sodium carbonate and 0.75g of avibactam sodium;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1.2;
the ceftazidime containing sodium carbonate has an average particle size of 60 mu m; the average particle size of the avibactam sodium is 175 mu m; and the average particle size of the avibactam sodium is 3 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 25min at a mixing rotating speed of 35Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 100 pieces/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 66L/min, the filling pressure is 6.5MPa, the filling time is 2.2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Example 3
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: 2.2g of ceftazidime containing sodium carbonate and 0.8g of avibactam sodium;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1.5;
ceftazidime containing sodium carbonate has an average particle size of 58 μm; the average particle diameter of the avibactam sodium is 170 mu m; and the average particle size of the avibactam sodium is 3 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 30min at a mixing rotating speed of 40Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 110 counts/min, then filling carbon dioxide at a flow rate of 68L/min, filling the mixed materials at a pressure of 7MPa for 2.5S, and controlling the content of residual oxygen in a product bottle to be less than 3% to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Example 4
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: 2.4g of ceftazidime containing sodium carbonate and 0.85g of avibactam sodium;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1.7;
the average particle size of ceftazidime containing sodium carbonate is 53 μm; the average particle diameter of the avibactam sodium is 165 mu m; the average particle size of the avibactam sodium is 3.1 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 40min at a mixing rotating speed of 60Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 120 counts/min, then filling carbon dioxide, and controlling the flow rate of the carbon dioxide to be 68L/min, the filling pressure to be 7.5MPa, the filling time to be 2.8S, and controlling the content of residual oxygen in a product bottle to be less than 3% to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Example 5
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: 2.5g of ceftazidime containing sodium carbonate and 0.9g of avibactam sodium;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 5:1;
the ceftazidime containing sodium carbonate has an average particle size of 50 μm; the average particle diameter of the avibactam sodium is 160 mu m; and the average grain diameter of the avibactam sodium is 3.2 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 45min at a mixing rotating speed of 69Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 130 counts/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 70L/min, the filling pressure is 8MPa, the filling time is 3S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Example 6
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g containing sodium carbonate, avibactam sodium 0.7g and stabilizer 0.1g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1; the stabilizer is prepared by mixing trehalose and poloxamer in a mass ratio of 2:1;
ceftazidime containing sodium carbonate has an average particle size of 65 μm; the average particle size of the avibactam sodium is 178 mu m; and the average grain diameter of the avibactam sodium is 2.7 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, carrying out surface sterilization on ceftazidime containing sodium carbonate, avibactam sodium and a stabilizer respectively, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 90 counts/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 65L/min, the filling pressure is 6MPa, the filling time is 2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Example 7
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g containing sodium carbonate, avibactam sodium 0.7g and stabilizer 0.15g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1; the stabilizer is prepared by mixing trehalose and poloxamer in a mass ratio of 2:3;
ceftazidime containing sodium carbonate has an average particle size of 65 μm; the average particle size of the avibactam sodium is 178 mu m; and the average grain diameter of the avibactam sodium is 2.7 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, carrying out surface sterilization on ceftazidime containing sodium carbonate, avibactam sodium and a stabilizer respectively, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 90 counts/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 65L/min, the filling pressure is 6MPa, the filling time is 2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Example 8
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g containing sodium carbonate, avibactam sodium 0.7g and stabilizer 0.2g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1; the stabilizer is prepared by mixing trehalose and poloxamer in a mass ratio of 2:5;
ceftazidime containing sodium carbonate has an average particle size of 65 μm; the average particle size of the avibactam sodium is 178 mu m; and the average grain diameter of the avibactam sodium is 2.7 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, carrying out surface sterilization on ceftazidime containing sodium carbonate, avibactam sodium and a stabilizer respectively, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 90 counts/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 65L/min, the filling pressure is 6MPa, the filling time is 2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Example 9
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g and avibactam sodium 0.7g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1;
ceftazidime containing sodium carbonate has an average particle size of 65 μm; the average particle size of the avibactam sodium is 178 mu m; and the average grain diameter of the avibactam sodium is 2.7 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 100 counts/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 65L/min, the filling pressure is 6MPa, the filling time is 2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Example 10
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g and avibactam sodium 0.7g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1;
ceftazidime containing sodium carbonate has an average particle size of 65 μm; the average particle size of the avibactam sodium is 178 mu m; and the average grain diameter of the avibactam sodium is 2.7 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 130 counts/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 65L/min, the filling pressure is 6MPa, the filling time is 2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Example 11
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g and avibactam sodium 0.7g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1;
ceftazidime containing sodium carbonate has an average particle size of 65 μm; the average particle size of the avibactam sodium is 178 mu m; and the average grain diameter of the avibactam sodium is 2.7 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 90 counts/min, then filling carbon dioxide at a flow rate of 68L/min, filling the mixed materials at a pressure of 6MPa for 2S, and controlling the content of residual oxygen in a product bottle to be less than 3% to obtain the ceftazidime avermectin sodium pharmaceutical preparation.
Example 12
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g and avibactam sodium 0.7g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1;
ceftazidime containing sodium carbonate has an average particle size of 65 μm; the average particle size of the avibactam sodium is 178 mu m; and the average grain diameter of the avibactam sodium is 2.7 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 90 counts/min, then filling carbon dioxide with the flow rate of 70L/min, filling the mixed materials under the pressure of 6MPa for 2S, and controlling the content of residual oxygen in a product bottle to be less than 3% to obtain the ceftazidime avermectin sodium pharmaceutical preparation.
To verify the performance of the pharmaceutical formulation of ceftazidime avibactam sodium provided herein, the applicant set comparative examples 1-11, wherein:
comparative example 1
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g and avibactam sodium 0.7g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1;
ceftazidime containing sodium carbonate has an average particle size of 65 μm; the average particle size of the avibactam sodium is 178 mu m; and the average grain diameter of the avibactam sodium is 2.7 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a crystal form A;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 90 counts/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 65L/min, the filling pressure is 6MPa, the filling time is 2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Comparative example 2
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g and avibactam sodium 0.7g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1;
ceftazidime containing sodium carbonate has an average particle size of 65 μm; the average particle size of the avibactam sodium is 178 mu m; and the average grain diameter of the avibactam sodium is 2.7 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a D crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 90 counts/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 65L/min, the filling pressure is 6MPa, the filling time is 2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Comparative example 3
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g and avibactam sodium 0.7g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1;
ceftazidime containing sodium carbonate has an average particle size of 65 μm; the average particle size of the avibactam sodium is 178 mu m; and the average grain diameter of the avibactam sodium is 2.7 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in the E crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 90 counts/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 65L/min, the filling pressure is 6MPa, the filling time is 2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Comparative example 4
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g and avibactam sodium 0.7g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1;
the average grain diameter of ceftazidime containing sodium carbonate is 40 mu m, and the average grain diameter of avibactam sodium is 190 mu m; and the average particle size of the avibactam sodium is 4.75 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 90 counts/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 65L/min, the filling pressure is 6MPa, the filling time is 2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Comparative example 5
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g and avibactam sodium 0.7g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1;
the average grain diameter of ceftazidime containing sodium carbonate is 80 mu m, and the average grain diameter of avibactam sodium is 150 mu m; and the average particle size of the avibactam sodium is 1.875 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 90 counts/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 65L/min, the filling pressure is 6MPa, the filling time is 2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Comparative example 6
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g containing sodium carbonate, avibactam sodium 0.7g and stabilizer 0.1g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1; the stabilizer is trehalose only;
ceftazidime containing sodium carbonate has an average particle size of 65 μm; the average particle size of the avibactam sodium is 178 mu m; and the average grain diameter of the avibactam sodium is 2.7 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, carrying out surface sterilization on ceftazidime containing sodium carbonate, avibactam sodium and a stabilizer respectively, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 90 counts/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 65L/min, the filling pressure is 6MPa, the filling time is 2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Comparative example 7
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g containing sodium carbonate, avibactam sodium 0.7g and stabilizer 0.1g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1; the stabilizer is poloxamer only;
ceftazidime containing sodium carbonate has an average particle size of 65 μm; the average particle size of the avibactam sodium is 178 mu m; and the average grain diameter of the avibactam sodium is 2.7 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, carrying out surface sterilization on ceftazidime containing sodium carbonate, avibactam sodium and a stabilizer respectively, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 90 counts/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 65L/min, the filling pressure is 6MPa, the filling time is 2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Comparative example 8
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g and avibactam sodium 0.7g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1;
ceftazidime containing sodium carbonate has an average particle size of 65 μm; the average particle size of the avibactam sodium is 178 mu m; and the average grain diameter of the avibactam sodium is 2.7 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 60 counts/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 65L/min, the filling pressure is 6MPa, the filling time is 2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Comparative example 9
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g and avibactam sodium 0.7g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1;
ceftazidime containing sodium carbonate has an average particle size of 65 μm; the average particle size of the avibactam sodium is 178 mu m; and the average grain diameter of the avibactam sodium is 2.7 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 150 pieces/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 65L/min, the filling pressure is 6MPa, the filling time is 2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Comparative example 10
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g and avibactam sodium 0.7g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1;
ceftazidime containing sodium carbonate has an average particle size of 65 μm; the average particle size of the avibactam sodium is 178 mu m; and the average grain diameter of the avibactam sodium is 2.7 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 90 counts/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 60L/min, the filling pressure is 6MPa, the filling time is 2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Comparative example 11
The ceftazidime avibactam sodium pharmaceutical preparation comprises the following raw materials: ceftazidime 1.8g and avibactam sodium 0.7g;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1;
ceftazidime containing sodium carbonate has an average particle size of 65 μm; the average particle size of the avibactam sodium is 178 mu m; and the average grain diameter of the avibactam sodium is 2.7 times of that of ceftazidime containing sodium carbonate; the avibactam sodium is in a B crystal form;
the preparation method of the ceftazidime avibactam sodium pharmaceutical preparation comprises the following steps:
s1, respectively carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium, weighing according to a formula, uniformly mixing for 20min at a mixing rotating speed of 30Hz, and discharging to obtain a mixed material;
s2, carrying out aseptic packaging on the mixed materials, controlling the relative humidity of the environment to be less than or equal to 58%, controlling the packaging speed to be 90 counts/min, then filling carbon dioxide, wherein the flow rate of the carbon dioxide is 80L/min, the filling pressure is 6MPa, the filling time is 2S, and the content of residual oxygen in a product bottle is controlled to be less than 3%, so as to obtain the ceftazidime avibactam sodium pharmaceutical preparation.
Performance test
The performance of the pharmaceutical formulations of ceftazidime avermectin sodium in examples 1-12 and comparative examples 1-11, respectively, of the present application was examined.
The package form of the ceftazidime avibactam sodium pharmaceutical preparation is a medium borosilicate glass tube injection bottle, a local polytetrafluoroethylene film chlorinated butyl rubber plug for sterile powder for injection and an aluminum plastic combined cover for an antibiotic bottle. Stability investigation according to the principle of stability test guidance for crude drugs and pharmaceutical preparations in four annex of ceftazidime avibactam sodium quality Standard for injection A05-2019 and Chinese pharmacopoeia 2020 edition, accelerated test investigation is carried out: the temperature is 40+/-2 ℃ and the relative humidity is 75+/-5%; after 6 months, stability investigation is carried out, quality change is evaluated, investigation projects comprise calibration amounts and total impurity content of ceftazidime and avibactam sodium, and test results are shown in table 1:
table 1:
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as can be seen from the data of table 1, the ceftazidime, the avibactam sodium and the total impurities of the pharmaceutical preparation of the ceftazidime avibactam sodium obtained in examples 1-12 have small changes, which fully demonstrates that the pharmaceutical preparation of the ceftazidime avibactam sodium obtained in the application has excellent stability; in comparative examples 1 to 3, the excellent effect of the present application could not be achieved by adopting different crystal forms of avibactam sodium; meanwhile, the average particle sizes of the avibactam sodium and the ceftazidime containing sodium carbonate are changed in comparative examples 4 and 5, so that the stability of the pharmaceutical preparation is not facilitated.
Meanwhile, the ceftazidime, the avibactam sodium and the total impurities of the pharmaceutical preparation of the ceftazidime avibactam sodium obtained in the examples 6-8 are smaller in change, which indicates that the stability of the pharmaceutical preparation can be obviously improved by adding the stabilizer in the preparation process; and compared with the prior art, the single stabilizer component is adopted in the comparative examples 6 and 7, so that the stability of the pharmaceutical preparation is improved to be lower than that of the bistable component, and the clinical application prospect of the pharmaceutical preparation of ceftazidime avibactam sodium obtained by the application is further broad.
In addition, comparative examples 1, 9 and 10 and comparative examples 8 and 9 show that the split charging speed of the mixed materials is controlled between 90 and 130 counts/min, which is more beneficial to improving the stability of the pharmaceutical preparation; comparative examples 11, 12 and comparative examples 1, 10, 11 show that controlling the inert gas filling flow rate can enhance the stability of the pharmaceutical formulation of ceftazidime avibactam sodium, reducing the generation of total impurities.
The preferred embodiments of the present application have been described in detail above, but the present application is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solutions of the present application within the scope of the technical concept of the present application, and all the simple modifications belong to the protection scope of the present application. Moreover, any combination of the various embodiments of the present application may be made without departing from the spirit of the present application, which should also be considered as disclosed herein.
Claims (10)
1. The ceftazidime avibactam sodium pharmaceutical preparation is characterized by comprising the following raw materials in parts by weight: 1.8-2.5 parts of ceftazidime containing sodium carbonate and 0.7-0.9 part of avibactam sodium;
the ceftazidime containing sodium carbonate is prepared by mixing sodium carbonate and ceftazidime in a mass ratio of 10:1-2.
2. The pharmaceutical formulation of ceftazidime avibactam sodium according to claim 1, wherein the average particle size of ceftazidime containing sodium carbonate is 50-65 μm and the average particle size of avibactam sodium is 160-178 μm.
3. The pharmaceutical formulation of ceftazidime avibactam sodium according to claim 1, wherein the avibactam sodium has an average particle size of 2.5-3.5 times that of ceftazidime containing sodium carbonate.
4. The pharmaceutical formulation of ceftazidime avibactam sodium according to claim 1, wherein said avibactam sodium is in form B.
5. The pharmaceutical formulation of ceftazidime avibactam sodium according to claim 1, further comprising 0.1-0.2 parts of a stabilizer.
6. The pharmaceutical preparation of ceftazidime avermectin sodium according to claim 5, wherein the stabilizer is prepared by mixing trehalose and poloxamer in a mass ratio of 2:1-5.
7. A process for the preparation of a pharmaceutical formulation of ceftazidime avibactam sodium as claimed in any one of claims 1 to 6, comprising the steps of:
s1, carrying out surface sterilization on ceftazidime containing sodium carbonate and avibactam sodium respectively, weighing, uniformly mixing, and discharging to obtain a mixed material;
s2, sterile packaging is carried out on the mixed materials, and then inert gas is filled, so that the ceftazidime avibactam sodium pharmaceutical preparation is obtained.
8. The pharmaceutical preparation of ceftazidime avermectin sodium according to claim 7, wherein the mixing speed in the step S1 is 30-69Hz, and the mixing time is 20-45min.
9. The pharmaceutical preparation of ceftazidime avermectin sodium according to claim 7, wherein the environmental relative humidity is less than or equal to 58% during split charging in the step S2, and the split charging speed is 90-130 counts/min.
10. The pharmaceutical preparation of ceftazidime avermectin sodium according to claim 7, wherein the filling flow rate of the inert gas in the step S2 is 65-70L/min, the filling pressure is 6-8MPa, and the filling time is 2-3S.
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