CN106943412A - Injection ceftaroline fosamil composition sterile powder and preparation method thereof - Google Patents
Injection ceftaroline fosamil composition sterile powder and preparation method thereof Download PDFInfo
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- CN106943412A CN106943412A CN201710281669.6A CN201710281669A CN106943412A CN 106943412 A CN106943412 A CN 106943412A CN 201710281669 A CN201710281669 A CN 201710281669A CN 106943412 A CN106943412 A CN 106943412A
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- Prior art keywords
- ceftaroline fosamil
- injection
- avm hereinafter
- acetic acid
- pharmaceutically acceptable
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- ZCCUWMICIWSJIX-NQJJCJBVSA-N ceftaroline fosamil Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OCC)C=2N=C(NP(O)(O)=O)SN=2)CC=1SC(SC=1)=NC=1C1=CC=[N+](C)C=C1 ZCCUWMICIWSJIX-NQJJCJBVSA-N 0.000 title claims abstract description 96
- 229960004828 ceftaroline fosamil Drugs 0.000 title claims abstract description 95
- 239000000203 mixture Substances 0.000 title claims abstract description 54
- 239000000843 powder Substances 0.000 title claims abstract description 54
- 239000007924 injection Substances 0.000 title claims abstract description 45
- 238000002347 injection Methods 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 239000004475 Arginine Substances 0.000 claims abstract description 10
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000012453 solvate Substances 0.000 claims abstract description 7
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 claims abstract description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052782 aluminium Inorganic materials 0.000 claims abstract description 3
- 239000004411 aluminium Substances 0.000 claims abstract description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 38
- 229930064664 L-arginine Natural products 0.000 claims description 38
- 235000014852 L-arginine Nutrition 0.000 claims description 38
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 34
- 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 30
- 229910052708 sodium Inorganic materials 0.000 claims description 30
- 239000011734 sodium Substances 0.000 claims description 30
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 claims description 28
- 239000011812 mixed powder Substances 0.000 claims description 11
- 235000009697 arginine Nutrition 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 4
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 claims 1
- 238000012856 packing Methods 0.000 abstract description 17
- 230000000694 effects Effects 0.000 abstract description 7
- 238000000034 method Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 34
- 239000002904 solvent Substances 0.000 description 17
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 11
- 229960003194 meglumine Drugs 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000003381 stabilizer Substances 0.000 description 9
- 239000003814 drug Substances 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 150000003952 β-lactams Chemical class 0.000 description 5
- 206010059866 Drug resistance Diseases 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003781 beta lactamase inhibitor Substances 0.000 description 3
- 102000006635 beta-lactamase Human genes 0.000 description 3
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 230000003381 solubilizing effect Effects 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 108090000204 Dipeptidase 1 Proteins 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- -1 Oxygen imine Cephalosporins Chemical class 0.000 description 2
- 206010034133 Pathogen resistance Diseases 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 108010059993 Vancomycin Proteins 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 229940125532 enzyme inhibitor Drugs 0.000 description 2
- 229940093181 glucose injection Drugs 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000008354 sodium chloride injection Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229960003165 vancomycin Drugs 0.000 description 2
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 2
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- NDIURPSCHWTXDC-UHFFFAOYSA-N 2-(4,5-dimethoxy-2-nitrophenyl)acetohydrazide Chemical compound COC1=CC(CC(=O)NN)=C([N+]([O-])=O)C=C1OC NDIURPSCHWTXDC-UHFFFAOYSA-N 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 101710202686 Penicillin-sensitive transpeptidase Proteins 0.000 description 1
- 201000005010 Streptococcus pneumonia Diseases 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 1
- 229960003324 clavulanic acid Drugs 0.000 description 1
- 230000009137 competitive binding Effects 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229960000373 tazobactam sodium Drugs 0.000 description 1
- 229940036731 teflaro Drugs 0.000 description 1
- 238000004154 testing of material Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—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
- 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
- A61K9/145—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 organic compounds
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of injection Ceftaroline Fosamil composition sterile powder and preparation method thereof, belong to pharmaceutical synthesis and preparation technique field.Described aseptic powdery includes Ceftaroline Fosamil or its pharmaceutically acceptable salt or solvate, AVM hereinafter Batan or its pharmaceutically acceptable salt, and free arginine or its pharmaceutically acceptable salt.Its preparation method is first to crush free arginine or its pharmaceutically acceptable salt under cryogenic sterile environment, sieve, it is mixed with Ceftaroline Fosamil or its pharmaceutically acceptable salt or solvate again, then mixed with AVM hereinafter Batan or its pharmaceutically acceptable salt, finally it is vacuum-packed with sterile aluminium plastic bag, packing is into sterile cillin bottle, and lid is rolled in tamponade.The present invention Ceftaroline Fosamil composition sterile powder can solve the problem that the problem of this product effectively dissolves and maintains enough chemical stabilities, the stability of products obtained therefrom is not less than original product, with solute effect it is good, it is solution-stabilized the characteristics of.
Description
Technical field
The present invention relates to a kind of injection Ceftaroline Fosamil composition sterile powder and preparation method thereof, belong to pharmaceutical synthesis
And preparation technique field.
Background technology
Ceftaroline Fosamil (ceftaroline fosamil) trade name Teflaro, is opened by Japanese Takeda Pharmaceutical Company Limited
Hair, Forest Laboratories companies of the U.S. obtain to be authorized in the market in the U.S., in March, 2011 in U.S.'s Initial Public Offering.
Ceftaroline Fosamil is as Beta-lactam medicine, and its action target spot is PBP PBPs, by suppressing bacterial cell
The synthesis of wall and make bacterial death, but Ceftaroline Fosamil has higher affinity to PBP PBP2a, and has
Broad spectrum antibiotic activity, the medicine is to S. aureus L-forms [including Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin intermediate drug-resistant staphylococcus aureus
(VISA), Heterogeneous resistance VISA (hVISA) and drug resistance of vancomycin S. aureus L-forms (VRSA)], streptococcus pneumonia (including drug-fast bacteria
Strain) etc. gram positive bacteria and respiratory tract gram-negative bacteria [such as moraxelle catarrhalis and Hemophilus influenzae (including beta-lactam enzyme positive
Bacterium)] the preferable antibacterial activity of display, totally the drug resistance to gram positive bacteria is relatively low, to the drug resistance of gram-negative bacteria and other
Oxygen imine Cephalosporins are similar.
AVM hereinafter Batan is new non-beta-lactam β-lactamase inhibitor, and it presses down zymogram extensively, can suppress A in vitro
Class, C classes and some D classes beta-lactamases.Traditional β-lactamase inhibitor belongs to irreversible Suicide enzyme inhibitor, with β-
Lactamase competitive binding, forms stable non-covalent complex, and self structure is also destroyed in the process.And AVM hereinafter bar
Smooth to form stable amido bond with beta-lactamase covalent bond to reach inhibition, self structure can be recovered through back reaction,
Therefore with long-acting Inhibitory activity.And research is found, suppressing a beta-lactam enzyme molecule only needs 1~5 AVM hereinafter Batan point
Son, and Tazobactam Sodium and clavulanic acid then need 55~214 molecules, it is seen that the Inhibitory activity of AVM hereinafter Batan is stronger.
With antibacterials it is long-term, largely use, causing the drug resistance of bacterium gradually strengthens, increasingly the super wide spectrum of fecund
β-lactamase inhibitor (ESBLs), carbapenem enzyme negative bacillus occur, as influenceing these antibacterials clinical efficacies
One big threat, many problems are brought to clinical anti-infective therapy.Clinic tackles quagmire in the urgent need to new antimicrobial agent at present, Ah
Batan is tieed up as novel ss-lactam enzyme inhibitor, the antibacterial of Ceftaroline Fosamil can be recovered or strengthen by combining with Ceftaroline Fosamil
Activity, it is shown that overcome the potential of bacterial resistance problem.AVM hereinafter Batan is combined with Ceftaroline Fosamil has been enter into the second stage of clinical research
Stage, but do not have a kind of formulation of AVM hereinafter Batan and Ceftaroline Fosamil so far and disclose, so AVM hereinafter Batan and cephalo
The exploitation of Lorraine ester formulation is particularly urgent.
The content of the invention
It is an object of the invention to provide a kind of injection Ceftaroline Fosamil composition sterile powder, solve because of bacterial resistance
Property enhancing and cause the reduction of Ceftaroline Fosamil antibacterial activity, the problem of its aqueous stability is poor, with solute effect is good, solution
The characteristics of good stability, present invention simultaneously provides its preparation method.
Injection Ceftaroline Fosamil composition sterile powder of the present invention, comprising Ceftaroline Fosamil or its pharmaceutically may be used
The salt or solvate of receiving, AVM hereinafter Batan or its pharmaceutically acceptable salt, and free arginine or its can pharmaceutically connect
The salt received.
Described aseptic powdery includes Ceftaroline Fosamil list acetic acid monohydrate.
Described aseptic powdery includes AVM hereinafter Batan sodium.
Described aseptic powdery includes L-arginine.
In the present invention：
Ceftaroline Fosamil is the stable crystalline shape prodrug of CPT, and CPT is active part.Under oral route, head
Spore Lorraine exposed amount is not enough, therefore can not use oral administration.Compared with oral formulations, injection has many advantages：Effect
It is rapid reliable, do not influenceed by pH, enzyme, food etc., no first pass effect, whole body or local positioning effect can be played, it is adaptable to unsuitable
Oral drugs and patient that can not be oral.Injection no matter with liquid injection or with powder pin, to during clinical practice with liquid
State is injected directly into the tissue of human body, blood vessel or organ.Therefore in order to coordinate Clinical practice, need to tie up active ingredient solubility
Hold within the specific limits.AVM hereinafter Batan sodium is readily soluble in water, but the dissolving of Ceftaroline Fosamil is in pH dependences.Ceftaroline Fosamil exists
Solubility increase between pH value 3-4, solubility is maintained between pH value 4-7>165.0mg/mL.The purpose of the present invention is offer one
Ceftaroline Fosamil, AVM hereinafter Batan composition are planted, the two solubility is maintained within a certain range, to meet clinical demand.
In view of Ceftaroline Fosamil solubility has pH dependences, present invention exploitation Ceftaroline Fosamil, AVM hereinafter Batan sodium, smart ammonia
Acid composition, by solubilizer of basic amino acid to reach invention effect.Arginine is a kind of a-amino acid, is 20 kinds universal
One of natural amino acid.Arginine can change ionic strength, and/or improve drug solubility by changing composition pH.
In the embodiment that applicant provides, arginine is compared with the close meglumine of property, with more excellent solubilizing effect.In addition, head
Spore Lorraine aqueous solution of ester is unstable, it is impossible to use lyophilized technique.The present invention provides aseptic subpackaged preparation method, in Clinical practice
When be configured to the finite concentration aqueous solution, now, arginine can by complexing and medicine formation complex compound so that in sample
During preparing and depositing, reduction principal component degraded increases composition stability.
Preferably, the aseptic powdery is made up of the component of following weight proportion：
300~800g of Ceftaroline Fosamil list acetic acid monohydrate (in terms of Ceftaroline Fosamil list acetic acid anhydride)
300~800g of AVM hereinafter Batan sodium (in terms of AVM hereinafter Batan)
50~600g of L-arginine.
It is highly preferred that the aseptic powdery is made up of the component of following weight proportion：
Ceftaroline Fosamil list acetic acid monohydrate 600g (in terms of Ceftaroline Fosamil list acetic acid anhydride)
AVM hereinafter Batan sodium 500g (in terms of AVM hereinafter Batan)
L-arginine 261g.
It is highly preferred that the aseptic powdery is made up of the component of following weight proportion：
Ceftaroline Fosamil list acetic acid monohydrate 600g (in terms of Ceftaroline Fosamil list acetic acid anhydride)
AVM hereinafter Batan sodium 600g (in terms of AVM hereinafter Batan)
L-arginine 350g.
It is highly preferred that the aseptic powdery is made up of the component of following weight proportion：
Ceftaroline Fosamil list acetic acid monohydrate 400g (in terms of Ceftaroline Fosamil list acetic acid anhydride)
AVM hereinafter Batan sodium 400g (in terms of AVM hereinafter Batan)
L-arginine 258g.
The preparation method of injection Ceftaroline Fosamil composition sterile powder of the present invention, comprises the following steps：
(1) under the gnotobasis no more than 20 DEG C, free arginine or its pharmaceutically acceptable salt are crushed,
Cross 60 mesh sieves；
(2) Ceftaroline Fosamil or its pharmaceutically acceptable salt or solvate are existed with the powder prepared by step (1)
Mixed under no more than 20 DEG C gnotobasis；
(3) by AVM hereinafter Batan or its pharmaceutically acceptable salt under the gnotobasis no more than 20 DEG C with step (2) institute
Obtained mixed-powder mixing；
(4) it is vacuum-packed after mixing terminates with sterile aluminium plastic bag, then will always mixes thing and dispense into sterile cillin bottle, tamponade
Roll lid.
Injection Ceftaroline Fosamil composition sterile powder of the present invention, is mainly used in treatment MRSA and pneumobacillus
Infection.
The aseptic powdery of the present invention has advantages below in practical application：
(1) solubility of Ceftaroline Fosamil or its pharmaceutically acceptable salt or solvate is effectively improved
It is embodied in：When solubilizer consumption is identical, injection sterile powder of the invention with use using meglumine as
The injection sterile powder of solubilizer is compared, and has more preferable solubilising power；
(2) when being configured to concentrated liquid form, there is preferable stability
It is embodied in：Ceftaroline Fosamil is unstable under solution state in itself, but when the injection cephalo to the present invention
Injected in the ester composition sterile powder of Lorraine after 20mL sterilizeds water for injection, impurity level is without significant changes in 1 hour, and this is carried
Show by the present invention injection sterile powder be configured to concentrated liquid form when, have preferable stability.
(3) when being configured to dilute liquid form, equally with preferable stability
It is embodied in：The injection sterile powder of the present invention is configured to concentrated liquid, then further with 250mL concentration
It is that 5% glucose injection is diluted to after dilute liquid for 0.9% sodium chloride injection or 250mL concentration, it is observed that in 6 hours
Impurity level has preferably without significant changes, the injection sterile powder of this prompting present invention when being configured to dilute liquid form
Stability.
Beneficial effects of the present invention are as follows：
The Ceftaroline Fosamil composition sterile powder of the present invention can solve the problem that this product effectively dissolves and maintains enough chemistry
The problem of stability, the stability of products obtained therefrom is not less than original product, with solute effect it is good, it is solution-stabilized the characteristics of.
Embodiment
The present invention is described further with reference to embodiments.
Embodiment 1
Using L-arginine as solubilizer and stabilizer, injection Ceftaroline Fosamil composition sterile powder is matched somebody with somebody by following weight
The component of ratio is made：
Ceftaroline Fosamil list acetic acid monohydrate 600g (in terms of Ceftaroline Fosamil list acetic acid anhydride)
AVM hereinafter Batan sodium 500g (in terms of AVM hereinafter Batan)
L-arginine 261g
Preparation method is as follows：
L-arginine is crushed under the aseptic condition no more than 20 DEG C, 60 eye mesh screens is crossed, weighs recipe quantity L-arginine
In 261g, Ceftaroline Fosamil list acetic acid monohydrate 600g, input three-dimensional mixer, mix 30 minutes, then weigh AVM hereinafter bar
In smooth sodium 500g, input three-dimensional mixer, mix 30 minutes, mixed-powder is fitted into sterile bag, be transferred to packing workshop and enter
Lid, batch 1000 are rolled in row packing, tamponade.
Embodiment 2
Using L-arginine as solubilizer and stabilizer, injection Ceftaroline Fosamil composition sterile powder is matched somebody with somebody by following weight
The component of ratio is made：
Ceftaroline Fosamil list acetic acid monohydrate 600g (in terms of Ceftaroline Fosamil list acetic acid anhydride)
AVM hereinafter Batan sodium 600g (in terms of AVM hereinafter Batan)
L-arginine 350g
Preparation method is as follows：
L-arginine is crushed under the aseptic condition no more than 20 DEG C, 60 eye mesh screens is crossed, weighs recipe quantity L-arginine
In 350g, Ceftaroline Fosamil list acetic acid monohydrate 600g, input three-dimensional mixer, mix 30 minutes, then weigh AVM hereinafter bar
In smooth sodium 600g, input three-dimensional mixer, mix 30 minutes, mixed-powder is fitted into sterile bag, be transferred to packing workshop and enter
Lid, batch 1000 are rolled in row packing, tamponade.
Embodiment 3
Using L-arginine as solubilizer and stabilizer, injection Ceftaroline Fosamil composition sterile powder is matched somebody with somebody by following weight
The component of ratio is made：
Ceftaroline Fosamil list acetic acid monohydrate 800g (in terms of Ceftaroline Fosamil list acetic acid anhydride)
AVM hereinafter Batan sodium 800g (in terms of AVM hereinafter Batan)
L-arginine 600g
Preparation method is as follows：
L-arginine is crushed under the aseptic condition no more than 20 DEG C, 60 eye mesh screens is crossed, weighs recipe quantity L-arginine
In 600g, Ceftaroline Fosamil list acetic acid monohydrate 800g, input three-dimensional mixer, mix 30 minutes, then weigh AVM hereinafter bar
In smooth sodium 800g, input three-dimensional mixer, mix 30 minutes, mixed-powder is fitted into sterile bag, be transferred to packing workshop and enter
Lid, batch 1000 are rolled in row packing, tamponade.
Embodiment 4
Using L-arginine as solubilizer and stabilizer, injection Ceftaroline Fosamil composition sterile powder is matched somebody with somebody by following weight
The component of ratio is made：
Ceftaroline Fosamil list acetic acid monohydrate 300g (in terms of Ceftaroline Fosamil list acetic acid anhydride)
AVM hereinafter Batan sodium 300g (in terms of AVM hereinafter Batan)
L-arginine 50g
Preparation method is as follows：
L-arginine is crushed under the aseptic condition no more than 20 DEG C, 60 eye mesh screens is crossed, weighs recipe quantity L-arginine
In 50g, Ceftaroline Fosamil list acetic acid monohydrate 300g, input three-dimensional mixer, mix 30 minutes, then weigh AVM hereinafter Batan
In sodium 300g, input three-dimensional mixer, mix 30 minutes, mixed-powder is fitted into sterile bag, be transferred to packing workshop and carry out
Lid, batch 1000 are rolled in packing, tamponade.
Embodiment 5
Using L-arginine as solubilizer and stabilizer, injection Ceftaroline Fosamil composition sterile powder is matched somebody with somebody by following weight
The component of ratio is made：
Ceftaroline Fosamil list acetic acid monohydrate 600g (in terms of Ceftaroline Fosamil list acetic acid anhydride)
AVM hereinafter Batan sodium 500g (in terms of AVM hereinafter Batan)
L-arginine 395g
Preparation method is as follows：
L-arginine is crushed under the aseptic condition no more than 20 DEG C, 60 eye mesh screens is crossed, weighs recipe quantity L-arginine
In 395g, Ceftaroline Fosamil list acetic acid monohydrate 600g, input three-dimensional mixer, mix 30 minutes, then weigh AVM hereinafter bar
In smooth sodium 500g, input three-dimensional mixer, mix 30 minutes, mixed-powder is fitted into sterile bag, be transferred to packing workshop and enter
Lid, batch 1000 are rolled in row packing, tamponade.
Embodiment 6
Using L-arginine as solubilizer and stabilizer, injection Ceftaroline Fosamil composition sterile powder is matched somebody with somebody by following weight
The component of ratio is made：
Ceftaroline Fosamil list acetic acid monohydrate 400g (in terms of Ceftaroline Fosamil list acetic acid anhydride)
AVM hereinafter Batan sodium 600g (in terms of AVM hereinafter Batan)
L-arginine 172g
Preparation method is as follows：
L-arginine is crushed under the aseptic condition no more than 20 DEG C, 60 eye mesh screens is crossed, weighs recipe quantity L-arginine
In 172g, Ceftaroline Fosamil list acetic acid monohydrate 400g, input three-dimensional mixer, mix 30 minutes, then weigh AVM hereinafter bar
In smooth sodium 600g, input three-dimensional mixer, mix 30 minutes, mixed-powder is fitted into sterile bag, be transferred to packing workshop and enter
Lid, batch 1000 are rolled in row packing, tamponade.
Embodiment 7
Using L-arginine as solubilizer and stabilizer, injection Ceftaroline Fosamil composition sterile powder is matched somebody with somebody by following weight
The component of ratio is made：
Ceftaroline Fosamil list acetic acid monohydrate 400g (in terms of Ceftaroline Fosamil list acetic acid anhydride)
AVM hereinafter Batan sodium 400g (in terms of AVM hereinafter Batan)
L-arginine 258g
Preparation method is as follows：
L-arginine is crushed under the aseptic condition no more than 20 DEG C, 60 eye mesh screens is crossed, weighs recipe quantity L-arginine
In 258g, Ceftaroline Fosamil list acetic acid monohydrate 400g, input three-dimensional mixer, mix 30 minutes, then weigh AVM hereinafter bar
In smooth sodium 400g, input three-dimensional mixer, mix 30 minutes, mixed-powder is fitted into sterile bag, be transferred to packing workshop and enter
Lid, batch 1000 are rolled in row packing, tamponade.
Comparative example 1
Using meglumine as solubilizer and stabilizer, injection Ceftaroline Fosamil composition sterile powder is by following weight proportion
Component be made：
Ceftaroline Fosamil list acetic acid monohydrate 600g (in terms of Ceftaroline Fosamil list acetic acid anhydride)
AVM hereinafter Batan sodium 500g (in terms of AVM hereinafter Batan)
Meglumine 445g
Preparation method is as follows：
Meglumine is crushed under the aseptic condition no more than 20 DEG C, cross 60 eye mesh screens, weigh recipe quantity meglumine 445g,
In Ceftaroline Fosamil list acetic acid monohydrate 600g, input three-dimensional mixer, mix 30 minutes, then weigh AVM hereinafter Batan sodium
In 500g, input three-dimensional mixer, mix 30 minutes, mixed-powder is fitted into sterile bag, be transferred to packing workshop and divided
Dress, tamponade roll lid, batch 1000.
Comparative example 2
Using meglumine as solubilizer and stabilizer, injection Ceftaroline Fosamil composition sterile powder is by following weight proportion
Component be made：
Ceftaroline Fosamil list acetic acid monohydrate 600g (in terms of Ceftaroline Fosamil list acetic acid anhydride)
AVM hereinafter Batan sodium 500g (in terms of AVM hereinafter Batan)
Meglumine 261g
Preparation method is as follows：
Meglumine is crushed under the aseptic condition no more than 20 DEG C, cross 60 eye mesh screens, weigh recipe quantity meglumine 261g,
In Ceftaroline Fosamil list acetic acid monohydrate 600g, input three-dimensional mixer, mix 30 minutes, then weigh AVM hereinafter Batan sodium
In 500g, input three-dimensional mixer, mix 30 minutes, mixed-powder is fitted into sterile bag, be transferred to packing workshop and divided
Dress, tamponade roll lid, batch 1000.
For the injection sterile powder of the present invention, using it with using meglumine as the injection sterile powder of solubilizer
Contrasted by the following aspects：
(1) solubilizing effect
20mL sterilizeds water for injection are injected into the gained sample of embodiment 1 and the gained sample of comparative example 2 respectively, are shaken, are seen
Character is examined, 1 is shown in Table.
The embodiment 1 of table 1 and the gained sample aqueous solution character pair ratio of comparative example 2
| Embodiment 1 | Comparative example 2 | |
| Character | Clear yellow solution | A small amount of drug powder is not molten |
It can be derived that by table 1, injection sterile powder of the invention and the injection sterile powder using other solubilizer
Compare, under same amount, solubilizing effect is more preferable.
(2) stability of solution after diluting
20mL sterilizeds water for injection are injected first into sample, concentrated solution is made into and is detected, be then injected into 250mL concentration
Sodium chloride injection or 5% glucose injection liquid for 0.9% are detected that its character, relevant material testing method are as follows：
It is measured with reference to high performance liquid chromatography (Chinese Pharmacopoeia version general rule 0512 in 2015)：Chromatographic column is C18 posts；Stream
Dynamic phase A is 0.1mol/L ammonium acetate buffers-acetonitrile (960:65), Mobile phase B is 0.1mol/L ammonium acetate buffers-acetonitrile
(96:416), gradient elution program is shown in Table 2；Flow velocity is 1.0mL/min, and Detection wavelength is 254nm, 30 DEG C of column temperature.Testing result
It is shown in Table 3.
The gradient elution program of table 2
The embodiment 1 of table 3, embodiment 2 and the concentrated solution Detection of Stability result of comparative example 1
The embodiment 1 of table 4, embodiment 2 and the concentrated solution Detection of Stability result of comparative example 1
Wherein, the molecular structural formula of impurity A is as follows：
The molecular structural formula of impurity B is as follows：
By table 3, it can be seen that the injection sterile powder of the present invention is under concentrated solution state, relevant material, which is better than, to be used
The injection sterile powder of other solubilizer, and 1 hour internal stability is good.
By table 4, it can be seen that the injection sterile powder of the present invention is under weak solution state, relevant material, which is better than, to be used
The injection sterile powder of other solubilizer, and 6 hours internal stabilities are good.
(3) acceleration, long-time stability
Embodiment 1, embodiment 2 and the gained sample of comparative example 1 are placed in 25 DEG C, RH60% normal temperature condition, and 40 DEG C,
Placed 6 months under the conditions of RH75% accelerated test, it is shown in Table 5 about the situation of change of material.
The embodiment 1 of table 5, embodiment 2 and the Detection of Stability result of comparative example 1
By table 5, it can be seen that the injection sterile powder of the present invention is under acceleration, long-term conditions, relevant material is better than
Use the injection sterile powder of other solubilizer.
Claims (9)
1. a kind of injection Ceftaroline Fosamil composition sterile powder, it is characterised in that：The aseptic powdery includes CPT
Ester or its pharmaceutically acceptable salt or solvate, AVM hereinafter Batan or its pharmaceutically acceptable salt, and free arginine
Or its pharmaceutically acceptable salt.
2. injection Ceftaroline Fosamil composition sterile powder according to claim 1, it is characterised in that：The aseptic powder
End includes Ceftaroline Fosamil list acetic acid monohydrate.
3. injection Ceftaroline Fosamil composition sterile powder according to claim 1, it is characterised in that：The aseptic powder
End includes AVM hereinafter Batan sodium.
4. injection Ceftaroline Fosamil composition sterile powder according to claim 1, it is characterised in that：The free essence
Propylhomoserin is L-arginine.
5. injection Ceftaroline Fosamil composition sterile powder according to claim 1, it is characterised in that：The aseptic powder
End is made up of the component of following weight proportion：
300~800g of Ceftaroline Fosamil list acetic acid monohydrate (in terms of Ceftaroline Fosamil list acetic acid anhydride)
300~800g of AVM hereinafter Batan sodium (in terms of AVM hereinafter Batan)
50~600g of L-arginine.
6. injection Ceftaroline Fosamil composition sterile powder according to claim 5, it is characterised in that：The aseptic powder
End is made up of the component of following weight proportion：
Ceftaroline Fosamil list acetic acid monohydrate 600g (in terms of Ceftaroline Fosamil list acetic acid anhydride)
AVM hereinafter Batan sodium 500g (in terms of AVM hereinafter Batan)
L-arginine 261g.
7. injection Ceftaroline Fosamil composition sterile powder according to claim 5, it is characterised in that：The aseptic powder
End is made up of the component of following weight proportion：
Ceftaroline Fosamil list acetic acid monohydrate 600g (in terms of Ceftaroline Fosamil list acetic acid anhydride)
AVM hereinafter Batan sodium 600g (in terms of AVM hereinafter Batan)
L-arginine 350g.
8. injection Ceftaroline Fosamil composition sterile powder according to claim 5, it is characterised in that：The aseptic powder
End is made up of the component of following weight proportion：
Ceftaroline Fosamil list acetic acid monohydrate 400g (in terms of Ceftaroline Fosamil list acetic acid anhydride)
AVM hereinafter Batan sodium 400g (in terms of AVM hereinafter Batan)
L-arginine 258g.
9. a kind of preparation method of any described injection Ceftaroline Fosamil composition sterile powders of claim 1-8, it is special
Levy and be：Comprise the following steps：
(1) under the gnotobasis no more than 20 DEG C, free arginine or its pharmaceutically acceptable salt is crushed, 60 are crossed
Mesh sieve；
(2) Ceftaroline Fosamil or its pharmaceutically acceptable salt or solvate are not being surpassed with the powder prepared by step (1)
Mixed under the gnotobasis for crossing 20 DEG C；
(3) by AVM hereinafter Batan or its pharmaceutically acceptable salt under the gnotobasis no more than 20 DEG C with step (2) obtained by
Mixed-powder mixing；
(4) it is vacuum-packed after mixing terminates with sterile aluminium plastic bag, then will always mixes thing and dispense into sterile cillin bottle, tamponade is rolled
Lid.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106491537A (en) * | 2016-12-02 | 2017-03-15 | 瑞阳制药有限公司 | Injectable sterile powder comprising Ceftaroline Fosamil and preparation method thereof |
| CN114917223A (en) * | 2022-06-02 | 2022-08-19 | 成都倍特药业股份有限公司 | Oxacillin sodium pharmaceutical composition for injection and preparation method thereof |
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| CN104870457A (en) * | 2012-12-20 | 2015-08-26 | 桑多斯股份公司 | Novel crystalline forms of ceftaroline fosamil |
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| CN104870457A (en) * | 2012-12-20 | 2015-08-26 | 桑多斯股份公司 | Novel crystalline forms of ceftaroline fosamil |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106491537A (en) * | 2016-12-02 | 2017-03-15 | 瑞阳制药有限公司 | Injectable sterile powder comprising Ceftaroline Fosamil and preparation method thereof |
| CN114917223A (en) * | 2022-06-02 | 2022-08-19 | 成都倍特药业股份有限公司 | Oxacillin sodium pharmaceutical composition for injection and preparation method thereof |
| CN114917223B (en) * | 2022-06-02 | 2023-10-27 | 成都倍特药业股份有限公司 | Oxacillin sodium pharmaceutical composition for injection and preparation method thereof |
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