CN110433141A - A kind of preparation process of piperacillin sodium and tazobactam sodium for injection freeze dried powder - Google Patents
A kind of preparation process of piperacillin sodium and tazobactam sodium for injection freeze dried powder Download PDFInfo
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- CN110433141A CN110433141A CN201910563222.7A CN201910563222A CN110433141A CN 110433141 A CN110433141 A CN 110433141A CN 201910563222 A CN201910563222 A CN 201910563222A CN 110433141 A CN110433141 A CN 110433141A
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- Prior art keywords
- sodium
- tazobactam
- freeze
- piperacillin
- preparation process
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- TUPFOYXHAYOHIB-YCAIQWGJSA-M sodium;(2s,5r,6r)-6-[[(2r)-2-[(4-ethyl-2,3-dioxopiperazine-1-carbonyl)amino]-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate;(2s,3s,5r)-3-methyl-4,4,7-trioxo-3-(triazol-1-ylmethyl)-4$l^{6}-thia-1-azabicyclo[3.2.0]h Chemical compound [Na+].C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1.O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 TUPFOYXHAYOHIB-YCAIQWGJSA-M 0.000 title claims abstract description 68
- 238000002347 injection Methods 0.000 title claims abstract description 42
- 239000007924 injection Substances 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- 239000000843 powder Substances 0.000 title claims abstract description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 21
- 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 19
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229920001971 elastomer Polymers 0.000 claims abstract description 15
- 239000000243 solution Substances 0.000 claims abstract description 13
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 8
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 8
- 238000007689 inspection Methods 0.000 claims abstract description 8
- 239000000463 material Substances 0.000 claims abstract description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000004615 ingredient Substances 0.000 claims abstract description 6
- 239000001301 oxygen Substances 0.000 claims abstract description 6
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 6
- 238000003860 storage Methods 0.000 claims abstract description 6
- 239000011261 inert gas Substances 0.000 claims abstract description 4
- 238000004806 packaging method and process Methods 0.000 claims abstract description 4
- 239000007788 liquid Substances 0.000 claims description 32
- 238000001914 filtration Methods 0.000 claims description 23
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 239000003610 charcoal Substances 0.000 claims description 14
- 229960003865 tazobactam Drugs 0.000 claims description 12
- 239000004411 aluminium Substances 0.000 claims description 11
- 229910052782 aluminium Inorganic materials 0.000 claims description 11
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 238000004108 freeze drying Methods 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 230000003749 cleanliness Effects 0.000 claims description 8
- 238000012545 processing Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000012376 hot air sterilization Methods 0.000 claims description 7
- 230000001954 sterilising effect Effects 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 239000004695 Polyether sulfone Substances 0.000 claims description 6
- 229920006393 polyether sulfone Polymers 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229960000373 tazobactam sodium Drugs 0.000 claims description 6
- 239000008215 water for injection Substances 0.000 claims description 6
- 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 claims description 5
- 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 5
- 229960002292 piperacillin Drugs 0.000 claims description 5
- IVBHGBMCVLDMKU-GXNBUGAJSA-N piperacillin Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 IVBHGBMCVLDMKU-GXNBUGAJSA-N 0.000 claims description 5
- 238000004321 preservation Methods 0.000 claims description 5
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000011049 filling Methods 0.000 claims description 4
- 238000012859 sterile filling Methods 0.000 claims description 4
- 238000004659 sterilization and disinfection Methods 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000004140 cleaning Methods 0.000 claims description 3
- 230000018044 dehydration Effects 0.000 claims description 3
- 238000006297 dehydration reaction Methods 0.000 claims description 3
- 238000010790 dilution Methods 0.000 claims description 3
- 239000012895 dilution Substances 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 229910001220 stainless steel Inorganic materials 0.000 claims description 3
- 239000010935 stainless steel Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 238000009298 carbon filtering Methods 0.000 claims description 2
- 229910001873 dinitrogen Inorganic materials 0.000 claims description 2
- 239000003292 glue Substances 0.000 claims description 2
- 238000002372 labelling Methods 0.000 claims description 2
- 239000004408 titanium dioxide Substances 0.000 claims description 2
- 229920005549 butyl rubber Polymers 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 18
- 239000003814 drug Substances 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 8
- 238000011109 contamination Methods 0.000 abstract description 5
- 238000006243 chemical reaction Methods 0.000 abstract description 4
- 230000007774 longterm Effects 0.000 abstract description 4
- 229910021645 metal ion Inorganic materials 0.000 abstract description 3
- 230000000813 microbial effect Effects 0.000 abstract description 3
- 238000010525 oxidative degradation reaction Methods 0.000 abstract description 3
- 238000001556 precipitation Methods 0.000 abstract description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 238000012856 packing Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- NSOSGFJJXFKRDG-UUOKFMHZSA-N 9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-8-sulfanylidene-3,7-dihydropurin-6-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=S)NC2=C1NC=NC2=O NSOSGFJJXFKRDG-UUOKFMHZSA-N 0.000 description 2
- 238000012371 Aseptic Filling Methods 0.000 description 2
- 244000248349 Citrus limon Species 0.000 description 2
- 235000005979 Citrus limon Nutrition 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000012797 qualification Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 235000002710 Ilex cornuta Nutrition 0.000 description 1
- 241001310146 Ilex cornuta Species 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 235000010326 Osmanthus heterophyllus Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 241000588768 Providencia Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003781 beta lactamase inhibitor Substances 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 238000012372 quality testing Methods 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000005406 washing Methods 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
- A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
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- 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
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- General Health & Medical Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Engineering & Computer Science (AREA)
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- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Urology & Nephrology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Inorganic Chemistry (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention discloses a kind of preparation process of piperacillin sodium and tazobactam sodium for injection freeze dried powder, including cillin bottle preparation, rubber plug preparation, ingredient, it is aseptic subpackaged, roll lid lamp inspection packaging and other steps, wherein, the citric acid for adjusting pH is added when ingredient, with the EDTA for sufficiently chelating the metal ion of solution, so that product is kept pH value for a long time and contamination precipitation do not occur；Secondly, the inert gas being passed through in preparation process, can not only sufficiently drive the carbon dioxide in drug away, improve the rate and efficiency of reaction, the oxygen in air can also be driven away, prevent drug oxidative degradation, guarantee the stability of various content of material when the long-term storage of product；Most of all, all links of present invention process guarantee that sterile level is constantly in higher state, make the level of microbial contamination in acceptable criterion of acceptability, the quality of General Promotion final products and long-term stability.
Description
Technical field
The present invention relates to a kind of preparation processes of piperacillin sodium and tazobactam sodium for injection freeze dried powder, belong to medical skill
Art field.
Technical background
Piperacillin sodium and tazobactam sodium is a kind of compound antibiotic developed by Japanese Taiho Pharmaceutical Co. Ltd,
There are 8:1 and two kinds of 4:1 proportions.Wherein, piperacillin sodium and tazobactam sodium for injection (4:1) is by roc pharmaceutical industries strain formula meeting
Society, Toyama Chemical Co., Ltd. and the listing of big positive Fushan Mountain pharmaceuticals Co., Ltd. joint development by beta-lactamase
Inhibitor and wide spectrum semi-synthetic penicillins antibiotic group at compound preparation, listed in Japan in June, 2001, trade nameDosage form is freeze-dried powder injection, and specification is respectively 1.25g (C23H27N5O7S 1.0g and C10H12N4O5S
0.25g) and 2.5g (C23H27N5O7S 2.0g and C10H12N4O5S 0.5g), it is clinically used for being suitable for staphylococcus, coliform, lemon
What lemon acidfast bacilli category, Klebsiella, Enterobacter, Providencia, Pseudomonas aeruginosa category and beta-lactamase generated
It infects caused by the drug resistant bacterium of Piperacillin, septicemia, pyelonephritis, complexity cystitis etc..
Existing piperacillin sodium and tazobactam sodium for injection lyophilized preparation generallys use avocin is dissolved after plus
Enter sodium-tazobactam to be uniformly mixed, then adjusts pH with sodium bicarbonate, then prepared with the de- method of charcoal is carried out with active carbon.Anti-
It needs during answering or after the reaction was completed to open vacuum abstraction carbon dioxide gas, feed liquid need to be filtered, then clear to feed liquid
The inspection of clear degree and pH, then enters cillin bottle by filling pump sterile filling, is further lyophilized, and pressure half is filled in, and rolls lid and freeze-drying is made
Pulvis finished product.With piperacillin sodium and tazobactam sodium for injection (4:1) freeze dried powder of above-mentioned preparation after storage 24 months, piperazine
The content of XiLin sodium and sodium-tazobactam is drawn to be substantially reduced, degree of purity and pH have significant change, this is operated with preparation process
The control of environment cleanliness, sterilizing-drying technique, carbon dioxide gas abstraction in pouring process, in supplementary material between metal ion
Chelating degree, pH adjust the close relations such as auxiliary material additive amount.Therefore, it is necessary to be optimized to existing technique, to improve
The stability of product.
Summary of the invention
In view of the above-mentioned problems, the present invention proposes a kind of preparation work that piperacillin sodium and tazobactam sodium for injection is freeze-dried
Skill optimizes the auxiliary material and preparation process of addition, and then improves the stability of product.Specific technical solution is as follows:
A kind of preparation process that piperacillin sodium and tazobactam sodium for injection is freeze-dried, wherein avocin and his azoles bar
The mass ratio of smooth sodium is 4:1, specifically includes the following steps:
(1) cillin bottle prepares: the cillin bottle of packing is neatly sent into supersound washing through ultraviolet lamp sterilizing 15min final finishing
Device cleans up, spare after cooling then hot air sterilization 5 minutes or more at 350 DEG C；
(2) rubber plug prepares: rubber plug matched with drawing cillin bottle described in step (1) being placed under ultraviolet lamp and is sterilized
15min, then cleaning, F0Wet-hot steam sterilizes under the conditions of=15, then is dried in vacuo 1.5 hours, spare after cooling；
(3) ingredient: by avocin, sodium-tazobactam, auxiliary material and active carbon with ultraviolet lamp sterilize 30min, then
Each group is weighed by recipe quantity be placed in dense preparing tank and dense feed liquid is made, by the dense feed liquid of preparation except being introduced into dilute preparing tank after carbon filtering
Dilution, obtains the sterile feed liquid of piperacillin sodium and tazobactam sodium to be packed；
(4) aseptic subpackaged: the further refined filtration of the sterile feed liquid of piperacillin sodium and tazobactam sodium that will be prepared in step (3)
Afterwards, it is filled into cillin bottle described in step (1) as linear automatic filling machine, is filled with inert gas in bottle in the same direction, drives away
Carbon dioxide and oxygen in bottle；And rubber plug described in step (2) is filled in, it is put into freeze dryer freeze-drying, piperazine is obtained and draws west
Woods sodium-tazobactam sodium freeze dried powder；
(5) roll lid: through step (4) freeze-drying after, then give cillin bottle cover aluminium lid, cover before with 75% alcohol
Wiping packet disinfection in aluminium lid, aluminium lid is by 120 DEG C after high-temperature sterilization 2 hours, then rolls aluminium lid with capping machine and cover on rubber plug, and
Compress rubber plug.
(6) lamp inspection is packed: step (5) is rolled cover intact piperacillin sodium and tazobactam sodium freeze dried powder product respectively into
It is put in storage after being packed after portable lighter inspection, labeling.
The freeze-dried preparation process of piperacillin sodium and tazobactam sodium for injection above-mentioned, step (3) ingredient, concrete operations
Including following sub-step:
3-1: it prepares the dense feed liquid of piperacillin sodium and tazobactam sodium: the injection of dose volume 75% being added into dense preparing tank
Water cools the temperature to 5~10 DEG C, sequentially adds citric acid stirring and makes it completely dissolved, avocin is then added and continues to stir
10min is mixed to being completely dissolved, adds sodium-tazobactam and EDTA, continues stirring 30min and is all completely dissolved simultaneously to all substances
It is uniformly mixed, obtains the dense feed liquid of piperacillin sodium and tazobactam sodium；
3-2: it adjusts pH value: 10% medicine is added in the dense feed liquid of piperacillin sodium and tazobactam sodium obtained into step 3-1
With sodium bicarbonate solution, pH value is adjusted to 6.0~6.4, inert nitrogen gas (pressure is during which passed through into dense preparing tank
0.05Mpa), to drive the carbon dioxide of generation away；
3-3: it the de- processing of charcoal: was adjusted into step 3-2 in the dense feed liquid of piperacillin sodium and tazobactam sodium of pH and medicine is added
With active carbon, 5min is stirred, 15min is then allowed to stand and carries out the de- processing of charcoal, and coarse filtration removes active carbon；
3-4: dilution feed liquid: will de- treated that the dense feed liquid of piperacillin sodium and tazobactam sodium introduces is dilute through charcoal in rapid 3-3
Distribution tank, temperature remain 5~10 DEG C, water for injection are added again, make Piperacillin content range 158.3mg/ml~
175.0mg/ml, Tazobactam Sodium content range are 39.6mg/ml~43.7mg/ml, and adjust its pH value again to 6.2~6.6,
Obtain the sterile feed liquid of piperacillin sodium and tazobactam sodium to be packed.
As currently preferred technical solution, in step 3-1, the amount that citric acid is added be avocin and
The 5%~6% of sodium-tazobactam gross mass, preferably 5.5%~5.8%, most preferably 5.75%.
As currently preferred technical solution, in step 3-1, the amount that EDTA is added is avocin and he
The 0.4% of zababatin sodium gross mass.
As currently preferred technical solution, in step 3-3, the medicinal carbon amount that the de- processing of the charcoal is added is
The 2.0% of total dose.
The freeze-dried preparation process of piperacillin sodium and tazobactam sodium for injection above-mentioned, in step (3), the coarse filtration is
It is tentatively sterile filtered using 0.45 μm of stainless steel sheet frame and removes active carbon；The refined filtration is sterile to be carried out using secondary filtration mode
Filtering as first uses 0.45 μm of polyether sulfone pre-filtering, then carries out terminal aseptic filtration using 0.22 μm of polyether sulfone.
The freeze-dried preparation process of piperacillin sodium and tazobactam sodium for injection above-mentioned, in step (4), the freezing is dry
It is dry that be lyophilized by freeze-drying curve, first low-temperature setting 1 hour, then distillation dehydration distils and is dehydrated total 18 hours of used time, and
Slowly heating rises sample temperature afterwards, then residual moisture is sloughed in heat preservation and dryness evaporation, and freeze-drying terminates.Wherein, low-temperature setting
Temperature is -45 DEG C, protects and freezes 1 hour, 40 DEG C of the temperature of the heat preservation and dryness, and the time is 1.5 hours.
As a preferred technical scheme, the freeze-dried preparation work of piperacillin sodium and tazobactam sodium for injection above-mentioned
Skill, step (1) and step (5) purity requirements are D grades, and step (2) and step (3) purity requirements are C grades, and step (4) is clean
Cleanliness requires to be B grade, wherein use in refined filtration and step (5) in cillin bottle hot air sterilization and cooling, step (4) in step (1)
The purity requirements that capping machine rolls lid are A grades.
The beneficial effects of the present invention are:
For compared with the prior art, present invention process has following advantage:
Firstly, present invention process, the citric acid combination medicinal sodium bicarbonate solution of addition adjust pH, so that the pH of product
Can stable for extended periods of time, the metal ion of solution sufficiently chelates as chelating agent, keeps it for a long time not by the EDTA of addition
As for there is contamination precipitation；Secondly, the inert gas being passed through in preparation process, can not only sufficiently drive the titanium dioxide in drug away
Carbon improves the rate and efficiency of reaction, can also drive the oxygen in air away, prevent drug oxidative degradation, guarantees the length of product
The stability of phase various content of material when storing；Most of all, all links of present invention process guarantee high environment and medicine
Product purity requirements guarantee that sterile level is constantly in higher state, the aseptic filling process in freeze-dried powder production technology
Employed in various methods and regulation so that microbial contamination level in acceptable criterion of acceptability.And to desinfection chamber
Sterile filling personnel carry out qualification determine, it is ensured that the cleanliness operated in production process, the quality of General Promotion final products and
Long-term stability.
Detailed description of the invention
Fig. 1 is the freeze-dried preparation technology flow chart of piperacillin sodium and tazobactam sodium for injection of the present invention.
Specific embodiment
To make the object, technical solutions and advantages of the present invention clearer, below in conjunction with embodiment, to skill of the invention
Art scheme is clearly and completely described, the freeze-dried entire preparation work of piperacillin sodium and tazobactam sodium for injection of the present invention
Skill flow chart, referring to Fig.1.
Embodiment 1: prepare the cillin bottle of packing
After cillin bottle is placed under ultraviolet lamp the 15min that sterilizes, proper alignment station then is arranged with the mixed and disorderly bottle of bottle managing machine
It stands on the conveyor belt, is cleaned up to be sent into ultrasonic washer, then in F0Wet-hot steam sterilizing is carried out under the conditions of=15, so
It is dried in vacuo 1.5 hours afterwards, it is spare after cooling.Bottle, wash bottle, hot air sterilization and cooling procedure is wherein managed to be intended to guarantee the clean of environment
Cleanliness reaches D grades or more, and wherein hot air sterilization and cooling requirement reach A grades.
Embodiment 2: prepare rubber plug
Rubber plug matched with drawing cillin bottle described in embodiment 1 is placed under ultraviolet lamp the 15min that sterilizes, then clean,
F0The sterilizing of=15 wet-hot steams, then be dried in vacuo 1.5 hours, it is spare after dry cooling；Whole process needs to keep environment clean
Degree reaches C grades or more.
Embodiment 3: the sterile feed liquid of piperacillin sodium and tazobactam sodium is prepared, steps are as follows:
(1) weigh each component by recipe quantity: wherein the mass ratio of avocin and sodium-tazobactam is 4:1, citric acid
Amount be the amount of 5.76%, EDTA of avocin and sodium-tazobactam gross mass be that avocin and sodium-tazobactam are total
The 0.4% of quality, medicinal carbon amount are the 2.0% of total dose.
(2) water for injection of dose volume 75% is added into dense preparing tank, cools the temperature to 5~10, DEG C sequentially adds Chinese holly
The stirring of rafter acid makes it completely dissolved, and avocin is then added and continues to stir 10min to being completely dissolved, adds Tazobactam Sodium
Sodium and EDTA continue stirring 30min and are completely dissolved and are uniformly mixed to all substances, obtain piperacillin sodium and tazobactam sodium
Dense feed liquid.
(3) 10% medicinal sodium bicarbonate solution is added into the dense feed liquid of piperacillin sodium and tazobactam sodium obtained, adjusts
During which pH value is passed through nitrogen (pressure 0.05Mpa) into dense preparing tank, to drive the carbon dioxide of generation away, improves to 6.0~6.4
The rate and efficiency of reaction, can also drive the oxygen in air away, prevent drug oxidative degradation.
(4) medicine of main ingredient amount 2% the de- processing of charcoal: is added into the dense feed liquid of piperacillin sodium and tazobactam sodium for adjusting pH
With active carbon, 5min is stirred, 15min is then allowed to stand and carries out the de- processing of charcoal, and using 0.45 μm of stainless steel sheet frame coarse filtration except deactivation
Property charcoal.
(5) dilute feed liquid: will through charcoal de- treated that the dense feed liquid of piperacillin sodium and tazobactam sodium introduces dilute preparing tank, temperature
5~10 DEG C are remained, water for injection is added again, makes Piperacillin content range 158.3mg/ml~175.0mg/ml, he
Zababatin content range is 39.6mg/ml~43.7mg/ml, and adjusts its pH value again to 6.2~6.6, then uses second level
Filter type is sterile filtered, and as first uses 0.45 μm of polyether sulfone pre-filtering, then using 0.22 μm polyether sulfone into
Row terminal is sterile filtered, and obtains the sterile feed liquid of piperacillin sodium and tazobactam sodium to be filled.
Above-mentioned each step is both needed to guarantee the cleanliness of environment at C grades or more, and especially refined filtration needs to guarantee drug
Class's height reach A grades.
Embodiment 4: it is freeze-dried to prepare piperacillin sodium and tazobactam sodium for injection
The sterile feed liquid of piperacillin sodium and tazobactam sodium to be packed that will be prepared in embodiment 3, by linear automatic filling
Installation is filled into cillin bottle described in embodiment 1, needs the cleanliness for guaranteeing environment up to B grades or more at this time, while to bottle
In be filled with nitrogen, drive carbon dioxide and oxygen in bottle away；And rubber plug described in embodiment 2 is filled in, freeze dryer is put by jelly
Stem curve is lyophilized, i.e. first -45 DEG C low-temperature setting 1 hour, then distillation 18 hours of dehydration, and then slowly heating makes sample
Temperature rises to 40 DEG C, then the heat preservation and dryness time is that residual moisture is sloughed in evaporation in 1.5 hours, obtains piperacillin sodium and tazobactam
Sodium freeze dry agent；Will be after freeze-drying, then cillin bottle is given to cover aluminium lid, at this time the clean degree of environment need at C grades and
More than, it is sterilized before covering with packet in 75% alcohol wipe aluminium lid, then aluminium lid is rolled with capping machine and is covered on rubber plug, and compresses glue
Plug obtains the freeze-dried finished product of piperacillin sodium and tazobactam sodium for injection.The aseptic filling process in freeze-dried powder production technology
Employed in various methods and regulation so that the level of microbial contamination is in acceptable criterion of acceptability, and to desinfection chamber
Sterile filling personnel carry out qualification and determine, it is ensured that the cleanliness operated in production process, with the quality of General Promotion final products
With long-term stability.
Embodiment 5: lamp inspection packaging
Lamp inspection is carried out respectively by the piperacillin sodium and tazobactam sodium for injection prepared in embodiment 4 is freeze-dried, strictly handle
Gate of the quality monitoring is controlled, it is then labelled to be fitted into packing box, while it being equipped with corresponding specification and exterior and interior packing box, and coding is indicated
Date of manufacture and correlated identities, then whole flow process is as shown in Figure 1, could be put in storage.
Embodiment 6: the freeze-dried quality testing of piperacillin sodium and tazobactam sodium for injection
Piperacillin sodium and tazobactam sodium for injection freeze-dried 6 batches of Example 1-5 preparation measure Piperacillin respectively
(C23H27N5O7) and Tazobactam Sodium (C S10H12N4O5S content), pH value, clarity and color, related content of material, water content
And the drug standards set quota such as bacterial endotoxin, it is as a result as follows:
The freeze-dried quality measurements of 1. piperacillin sodium and tazobactam sodium for injection of table
1 testing result of table shows the freeze-dried items of piperacillin sodium and tazobactam sodium for injection of present invention process preparation
Quality index meets the regulation of " Chinese Pharmacopoeia " (version two in 2015).
Embodiment 7: the freeze-dried Detection of Stability of piperacillin sodium and tazobactam sodium for injection under hot and humid environment
The piperacillin sodium and tazobactam sodium for injection of Example 1-5 preparation is freeze-dried to be placed in 40 ± 2 DEG C of temperature, opposite
It under the conditions of humidity RH75% ± 5%, places 6 months, 1st month during test, 2 months, 3 months, 6 the end of month samplings one
It is secondary, it is detected by stability high spot reviews project, compared with 0 month.As a result as follows:
The freeze-dried high temperature and humidity stability inferior of 2. piperacillin sodium and tazobactam sodium for injection of table
As can be seen from Table 2, the piperacillin sodium and tazobactam sodium for injection of present invention process preparation is freeze-dried in high temperature
Under high humidity environment, indices are more stable.
Embodiment 8: the freeze-dried Detection of Stability of piperacillin sodium and tazobactam sodium for injection under normal environment
Example 1-5 preparation piperacillin sodium and tazobactam sodium for injection it is freeze-dried be placed in merging 25 ± 2 DEG C of room temperature,
It under the conditions of relative humidity RH60% ± 10%, places 24 months, with 3rd month, 6 months, 9 months, 12 months, 18 during this
The moon, 24 the end of month samplings are primary, are detected by stability high spot reviews project, compared with 0 month.As a result as follows:
The freeze-dried normal environment stability inferior of 3. piperacillin sodium and tazobactam sodium for injection of table
As can be seen from Table 3, the piperacillin sodium and tazobactam sodium for injection of present invention process preparation is freeze-dried normal
Storage condition under, stability is very good,.
It is obvious to a person skilled in the art that invention is not limited to the details of the above exemplary embodiments, Er Qie
In the case where without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, the present embodiments are to be considered as illustrative and not restrictive.Although in addition, it should be understood that originally
Specification is described in terms of embodiments, but only includes not one technical solution, and this narrating mode of specification is only
It is only for clarity that the skilled in the art should refer to the specification as a whole, the technical solution in embodiment can also
To be properly combined, form other embodiments that can be understood by those skilled in the art.
Claims (10)
1. a kind of preparation process that piperacillin sodium and tazobactam sodium for injection is freeze-dried, wherein avocin and Tazobactam Sodium
The mass ratio of sodium is 4:1, it is characterised in that: the following steps are included:
Cillin bottle prepares: by filling cillin bottle after ultraviolet lamp sterilizes 15min, arranging neat feeding ultrasonic washer cleaning
Completely, hot air sterilization is then carried out, the condition of hot air sterilization is 350 DEG C of temperature, the time 5 minutes or more, spare after cooling；
Rubber plug prepares: rubber plug matched with drawing cillin bottle as described in step (1) being placed under ultraviolet lamp the 15min that sterilizes, then
Butyl rubber plug is cleaned with filtering water for injection to no trichobothrium, then through F with rubber plug cleaning machine0The sterilizing of=15 wet-hot steams, then very
Sky is 1.5 hours dry, and cooling is spare；
Ingredient: by avocin, sodium-tazobactam, auxiliary material and active carbon with ultraviolet lamp sterilizing 30min, recipe quantity is then pressed
It weighs each group and is placed in dense preparing tank and dense feed liquid is made, the dense feed liquid of preparation is gone forward side by side except being introduced into dilute in dilute preparing tank after carbon filtering
After one step refined filtration, the sterile feed liquid of piperacillin sodium and tazobactam sodium to be packed is obtained；
Sterile filling: after the sterile feed liquid refined filtration of piperacillin sodium and tazobactam sodium prepared in step (3), by linear automatic
Bottle placer is filled into cillin bottle as described in step (1), is filled with inert gas in bottle in the same direction, drive away carbon dioxide in bottle and
Oxygen；And rubber plug described in step (2) is filled in, it is put into freeze dryer freeze-drying, piperacillin sodium and tazobactam sodium is obtained and freezes
Dry powder doses；
Roll lid: through step (4) freeze-drying after, then give cillin bottle cover aluminium lid, cover before with 75% alcohol wipe aluminium lid
The disinfection of interior packet, aluminium lid is by 120 DEG C after high-temperature sterilization 2 hours, then rolls aluminium lid with capping machine and cover on rubber plug, and compress glue
Plug；
Lamp inspection packaging: step (5) is rolled cover intact piperacillin sodium and tazobactam sodium freeze dried powder product carry out respectively lamp inspection,
It is put in storage after labeling and packaging.
2. the freeze-dried preparation process of piperacillin sodium and tazobactam sodium for injection according to claim 1, feature exist
In: step (3) ingredient, including following sub-step:
3-1: it prepares the dense feed liquid of piperacillin sodium and tazobactam sodium: the water for injection of dose volume 75% being added into dense preparing tank, it will
Temperature is down to 5~10 DEG C, sequentially adds citric acid stirring and makes it completely dissolved, avocin is then added and continues to stir
10min adds sodium-tazobactam and EDTA to being completely dissolved, and continues stirring 30min and is all completely dissolved and mixes to all substances
It closes uniformly, obtains the dense feed liquid of piperacillin sodium and tazobactam sodium；
3-2: it adjusts pH value: 10% medicinal carbonic acid is added in the dense feed liquid of piperacillin sodium and tazobactam sodium obtained into step 3-1
Hydrogen sodium solution adjusts pH value to 6.0~6.4, is passed through inert nitrogen gas, into dense preparing tank during which to drive the titanium dioxide of generation away
Carbon；
3-3: it the de- processing of charcoal: was adjusted into step 3-2 in the dense feed liquid of piperacillin sodium and tazobactam sodium of pH and medicinal work is added
Property charcoal, stir 5min, be then allowed to stand 15min and carry out the de- processing of charcoal, and coarse filtration removes active carbon；
3-4: dilution feed liquid: will through charcoal in rapid 3-3 it is de- treated that the dense feed liquid of piperacillin sodium and tazobactam sodium introduces dilute preparing tank,
Temperature remains 5~10 DEG C, and water for injection is added again, makes Piperacillin content range 158.3mg/ml~175.0mg/
Ml, Tazobactam Sodium content range are 39.6mg/ml~43.7mg/ml, and adjust its pH value again to 6.2~6.6, are obtained wait divide
The sterile feed liquid of the piperacillin sodium and tazobactam sodium of dress.
3. the freeze-dried preparation process of piperacillin sodium and tazobactam sodium for injection according to claim 2, feature exist
In: in step 3-1, the amount that citric acid is added is the 5%~6% of avocin and sodium-tazobactam gross mass.
4. the freeze-dried preparation process of piperacillin sodium and tazobactam sodium for injection according to claim 2, feature exist
In: in step 3-1, the amount that EDTA is added is the 0.4% of avocin and sodium-tazobactam gross mass.
5. the freeze-dried preparation process of piperacillin sodium and tazobactam sodium for injection according to claim 2, feature exist
In: in step 3-3, the medicinal carbon amount that the de- processing of the charcoal is added is the 2.0% of total dose.
6. the freeze-dried preparation process of piperacillin sodium and tazobactam sodium for injection according to claim 1, feature exist
In: in step (3), the coarse filtration is to remove active carbon using 0.45 μm of stainless steel sheet frame coarse filtration.
7. the freeze-dried preparation process of piperacillin sodium and tazobactam sodium for injection according to claim 1, feature exist
In: in step (3), the refined filtration is to be sterile filtered using secondary filtration mode, as first uses 0.45 μm of polyether sulfone
Then pre-filtering carries out terminal aseptic filtration using 0.22 μm of polyether sulfone.
8. the freeze-dried preparation process of piperacillin sodium and tazobactam sodium for injection according to claim 1, feature exist
In: in step (4), the freeze-drying is is lyophilized by freeze-drying curve, first low-temperature setting 1 hour, then distillation dehydration 18
Hour, then slowly heating rises sample temperature, then residual moisture is sloughed in heat preservation and dryness evaporation, and freeze-drying terminates.
9. the freeze-dried preparation process of piperacillin sodium and tazobactam sodium for injection according to claim 8, feature exist
In: the temperature of the low-temperature setting is -45 DEG C, protects and freezes the time as 1 hour, and the temperature of the heat preservation and dryness is 40 DEG C, the time
It is 1.5 hours.
10. the freeze-dried preparation process of piperacillin sodium and tazobactam sodium for injection according to claim 1, feature exist
It is D grade in: step (1) and step (5) purity requirements, step (2) and step (3) purity requirements are C grades, and step (4) is clean
Cleanliness requires to be B grade, wherein use in refined filtration and step (5) in cillin bottle hot air sterilization and cooling, step (4) in step (1)
The purity requirements that capping machine rolls lid are A grades.
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Application publication date: 20191112 |