CN112618486B - Suspension oil for injection and preparation method thereof - Google Patents
Suspension oil for injection and preparation method thereof Download PDFInfo
- Publication number
- CN112618486B CN112618486B CN202011546314.3A CN202011546314A CN112618486B CN 112618486 B CN112618486 B CN 112618486B CN 202011546314 A CN202011546314 A CN 202011546314A CN 112618486 B CN112618486 B CN 112618486B
- Authority
- CN
- China
- Prior art keywords
- piperacillin
- injection
- tazobactam
- oil
- lecithin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002347 injection Methods 0.000 title claims abstract description 56
- 239000007924 injection Substances 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 239000000725 suspension Substances 0.000 title claims abstract description 30
- 229960002292 piperacillin Drugs 0.000 claims abstract description 59
- 229960003865 tazobactam Drugs 0.000 claims abstract description 52
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 claims abstract description 52
- 239000003921 oil Substances 0.000 claims description 54
- 235000019198 oils Nutrition 0.000 claims description 54
- 238000011049 filling Methods 0.000 claims description 24
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 21
- 230000001954 sterilising effect Effects 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 19
- 235000012424 soybean oil Nutrition 0.000 claims description 18
- 239000003549 soybean oil Substances 0.000 claims description 18
- 238000005303 weighing Methods 0.000 claims description 18
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 17
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 17
- 239000002245 particle Substances 0.000 claims description 17
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 16
- 235000010445 lecithin Nutrition 0.000 claims description 16
- 239000000787 lecithin Substances 0.000 claims description 16
- 229940067606 lecithin Drugs 0.000 claims description 16
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 14
- 238000007789 sealing Methods 0.000 claims description 13
- 235000019438 castor oil Nutrition 0.000 claims description 10
- 239000004359 castor oil Substances 0.000 claims description 10
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 10
- 238000005070 sampling Methods 0.000 claims description 10
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 9
- 229920000053 polysorbate 80 Polymers 0.000 claims description 9
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 239000012528 membrane Substances 0.000 claims description 8
- -1 polyoxyethylene Polymers 0.000 claims description 8
- 229930003427 Vitamin E Natural products 0.000 claims description 7
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 7
- 229960004217 benzyl alcohol Drugs 0.000 claims description 7
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 7
- 235000019165 vitamin E Nutrition 0.000 claims description 7
- 229940046009 vitamin E Drugs 0.000 claims description 7
- 239000011709 vitamin E Substances 0.000 claims description 7
- 229930182555 Penicillin Natural products 0.000 claims description 6
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 6
- 229940049954 penicillin Drugs 0.000 claims description 6
- 239000003708 ampul Substances 0.000 claims description 5
- 238000003825 pressing Methods 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 3
- 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 12
- 239000002994 raw material Substances 0.000 claims 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 claims 1
- 229920000136 polysorbate Polymers 0.000 claims 1
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].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 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 abstract description 49
- 239000007788 liquid Substances 0.000 abstract description 16
- 238000000034 method Methods 0.000 abstract description 13
- 239000003963 antioxidant agent Substances 0.000 abstract description 11
- 230000003078 antioxidant effect Effects 0.000 abstract description 11
- 239000000375 suspending agent Substances 0.000 abstract description 8
- 238000004108 freeze drying Methods 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 150000003839 salts Chemical class 0.000 abstract description 5
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 238000010255 intramuscular injection Methods 0.000 abstract description 2
- 239000007927 intramuscular injection Substances 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 19
- 238000009472 formulation Methods 0.000 description 14
- 235000006708 antioxidants Nutrition 0.000 description 10
- 238000004659 sterilization and disinfection Methods 0.000 description 10
- 230000000202 analgesic effect Effects 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 238000009826 distribution Methods 0.000 description 5
- 229940102213 injectable suspension Drugs 0.000 description 5
- 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 description 5
- 239000000463 material Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 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 2
- 241000894006 Bacteria Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- 206010040047 Sepsis Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229960005264 piperacillin sodium Drugs 0.000 description 2
- 208000013223 septicemia Diseases 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000011146 sterile filtration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960000373 tazobactam sodium Drugs 0.000 description 2
- 208000019206 urinary tract infection Diseases 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- LITBAYYWXZOHAW-QNWQYGOSSA-N (2s,5r,6r)-6-[[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-carboxylic acid;(2s,3s,5r)-3-methyl-4,4,7-trioxo-3-(triazol-1-ylmethyl)-4$l^{6}-thia-1-azabicyclo[3.2.0]heptane-2 Chemical compound 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)NC(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 LITBAYYWXZOHAW-QNWQYGOSSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- 208000034950 Acinetobacter Infections Diseases 0.000 description 1
- 201000010000 Agranulocytosis Diseases 0.000 description 1
- 206010061695 Biliary tract infection Diseases 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000588921 Enterobacteriaceae Species 0.000 description 1
- 208000034801 Enterobacteriaceae Infections Diseases 0.000 description 1
- 206010018687 Granulocytopenia Diseases 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 208000032536 Pseudomonas Infections Diseases 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940126575 aminoglycoside Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003781 beta lactamase inhibitor Substances 0.000 description 1
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229930003836 cresol Natural products 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 238000007731 hot pressing Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000012792 lyophilization process Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229940104666 zosyn Drugs 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- 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
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Biophysics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Biochemistry (AREA)
- Dermatology (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application provides a suspension oil for injection and a preparation method thereof, belonging to the technical field of medical preparations. The piperacillin and tazobactam injection comprises piperacillin and tazobactam, wherein the ratio of the piperacillin to the tazobactam is 8:1 or 4:1, and the piperacillin injection also comprises a liquid medium, a suspending agent and an antioxidant, wherein the liquid medium is injection oil: the liquid medium is 1:5-1:20, and the suspension oil for injection obtained by the application is used for intramuscular injection, so that the stability of the piperacillin and tazobactam preparation is improved, and the preparation has the advantages of simple process, short production period, lower energy consumption and the like compared with the salt forming and freeze-drying processes.
Description
Technical Field
The application relates to a suspension oil for injection and a preparation method thereof, belonging to the technical field of medical preparations.
Background
Piperacillin sodium is a semisynthetic beta-lactam broad-spectrum antibiotic with a molecular formula of C 23 H 27 N 5 O 7 S·H 2 O, molecular weight 535.58, and can be used for treating septicemia, upper urinary tract infection, complicated urinary tract infection, respiratory tract infection, biliary tract infection, abdominal cavity infection, and pelvic cavity infection caused by bacteria of the family Enterobacteriaceae, pseudomonas aeruginosa, and AcinetobacterInfection, skin, soft tissue infection, and the like. The product can be used in combination with aminoglycosides for treating infection of patients with granulocytopenia and immunodeficiency.
Tazobactam sodium is a beta-lactamase inhibitor of formula C 10 H 12 N 4 O 5 S, molecular weight 300.29, has better clinical application effect, wider enzyme inhibition spectrum, strong tissue penetrability and wide distribution. It has inhibiting effect on chromosome, plasmid mediated and various ultra-broad spectrum enzymes and penicillin enzymes.
The combination of piperacillin and tazobactam has better synergistic effect. The piperacillin sodium tazobactam sodium for injection, which is currently commercially available, is first marketed in france at 7 of 2 nd 1992 under the trade name "TAZOCILLINE" and then subsequently marketed in the united states, the european union, japan under the trade name "ZOSYN" and the european union under the trade name "Tazocin". There are two specifications of piperacillin and tazobactam in the current commercial variety, namely 8:1 and 4:1. Clinically, the composition is suitable for septicemia, complicated cystitis and pyelonephritis caused by staphylococcus, colibacillus, trifoliate-edge acid bacteria, klebsiella, enterobacter, general Luo Weide s and pseudomonas aeruginosa which are sensitive to the composition. The piperacillin sodium and tazobactam sodium for injection are prepared by reacting piperacillin and tazobactam with sodium bicarbonate to obtain piperacillin sodium and tazobactam sodium, and then preparing into powder for injection by freeze drying; however, piperacillin sodium and tazobactam sodium are poor in stability, the product impurities are increased due to higher alkalinity of sodium bicarbonate in the salifying process, and the freeze-dried preparation can improve the product stability to a certain extent, but the product is degraded at high temperature and still has a larger risk of hydrolysis after dissolution before clinical use.
Disclosure of Invention
In view of the above, the present application first provides a suspension oil for injection comprising a combination of piperacillin and tazobactam
Specifically, the application is realized through the following scheme:
the suspension oil for injection comprises piperacillin and tazobactam, wherein the mass ratio of the piperacillin to the tazobactam is 8:1 or 4:1, and the suspension oil for injection further comprises a liquid medium and an antioxidant, wherein the liquid medium is oil for injection, and the piperacillin is as follows: the liquid medium is 1:5-1:20.
In the suspension oil agent, piperacillin and tazobactam are isolated in a solid form by a liquid medium of oil for injection, and are not contacted with acid, alkali, water, oxygen and the like, so that degradation can not occur basically, and the stability is better than that of piperacillin sodium and tazobactam sodium for injection. The stability of piperacillin and tazobactam preparations is improved by matching with an antioxidant for intramuscular injection.
Further, as preferable:
the liquid medium is any one of soybean oil for injection, medium chain oil (namely triglyceride) and castor oil; the main function is to isolate water and air as a suspending medium, so that the stability is improved.
The piperacillin: the liquid medium is 1:7-1:9.
The suspension adjuvant is any one of lecithin, polyoxyethylene castor oil and Tween 80, not only meets the suspension effect, but also is an auxiliary material which can be dissolved in oil and matched with a liquid medium so as to realize the effect.
The antioxidant is any one of vitamin E, tert-butyl p-hydroxy anisole (BHA) and di-tert-butyl hydroxy cresol (BHT). The antioxidant can prevent unsaturated fatty acid in grease, especially vegetable oil from being oxidized, and is oil-soluble and has good compatibility with liquid medium.
The injection also comprises an analgesic agent for relieving local irritation, and the irritation of the oily solvent and the suspension agent is larger than that of a common injection, so the analgesic agent adopts benzyl alcohol.
Meanwhile, the application also provides a preparation method of the suspension oil for injection, which comprises the following steps: adding a suspending agent and an antioxidant into a liquid medium, stirring and dissolving, and after hot-pressing sterilization or sterile filtration, crushing sterile piperacillin and tazobactam, adding the crushed piperacillin: the solvent is 1:5-1:20.
The production environment is a sterile production environment, a suspending agent, an antioxidant and a local analgesic are added into a liquid medium to be stirred and dissolved, sterile assurance is met through hot press sterilization or sterile filtration, piperacillin and tazobactam are added into a solvent to be stirred and dispersed uniformly, and the mixture is encapsulated after being detected to be qualified.
Further, as preferable:
the piperacillin and tazobactam are crushed mechanically or through air flow, and the particle size is required to be smaller than 40 μm, preferably smaller than 15 μm in D90 (equivalent diameter of the largest particle when the cumulative distribution in the particle size distribution curve is 90%). The piperacillin and tazobactam with the particle size range are beneficial to reducing the sedimentation of suspension solid, so that particles are easier to suspend and disperse, and the uniformity of the content of the preparation is improved.
The piperacillin: the liquid medium is 1:7-1:9.
The preparation method also comprises the step of adding an analgesic, a suspending agent and an antioxidant into a liquid medium to be stirred and dissolved, wherein the analgesic is benzyl alcohol.
In the above scheme, the antioxidant, the suspending agent and the analgesic are all commonly used dosage ranges specified by industry.
Meanwhile, the application also provides a preparation method of the suspension oil for injection, which comprises the following steps: sterile piperacillin and tazobactam are crushed and added to a liquid medium, piperacillin: the solvent is 1:5-1:20, and then suspending agent and antioxidant are added to form suspension oil.
Further, as preferable:
the piperacillin and tazobactam are crushed mechanically or through air flow, and the particle size is required to be smaller than 40 μm, preferably smaller than 15 μm in D90 (equivalent diameter of the largest particle when the cumulative distribution in the particle size distribution curve is 90%).
The piperacillin: the solvent is 1:7-1:9.
The preparation also comprises an analgesic, wherein the analgesic, the suspending agent and the antioxidant are added to form a suspension, and the analgesic is benzyl alcohol.
The above statement provides two preparation schemes with different addition sequences at normal temperature, and has the advantages of simple process, short production period, lower energy consumption and the like compared with the salt forming and freeze-drying processes.
Two preparation methods can be summarized as follows: crushing materials, preparing an oil solvent, sterilizing, or sterilizing, preparing a suspension, detecting and filling; the bulk drugs cannot resist high temperature and cannot be sterilized at the terminal, and the suspension is not suitable for final sterilization and filtration, so that the sterilization and the sterilization are carried out on auxiliary materials such as injection oil, and the two procedures can be implemented.
Detailed Description
Specific embodiments of the present application are described in detail below to facilitate a further understanding of the present invention.
All experimental methods used in the following examples are conventional methods unless otherwise specified. Materials, reagents and the like used in the following examples were commercially available unless otherwise specified.
Example 1
Table 1 shows the formulation of the suspension oil for injection in this example.
TABLE 1 formulation of suspension oil for injection in this example
The preparation process is as follows:
(1) Crushing piperacillin and tazobactam respectively by a high-speed crusher, wherein the particle size D90 is smaller than 40 mu m for later use;
(2) Respectively weighing the BHA, the BHT and the medium chain oil for injection according to the prescription, adding the BHA and the BHT into the medium chain oil for injection, stirring and dissolving;
(3) Filling the oil solution into a sealing container pressure-resistant device (such as an infusion bottle), performing hot-press sterilization at 121 ℃ for 15 minutes, taking out and cooling;
(4) Weighing crushed piperacillin and tazobactam according to the prescription, adding the crushed piperacillin and tazobactam into the sterilized oil solution, and stirring for 2 hours;
(5) And (5) after sampling and detecting the content, filling the sample into ampoule bottles, filling 11 ml/bottle, and sealing to obtain the product.
Example 2
Table 2 shows the formulation of the injectable suspension oil in this example.
TABLE 2 formulation of suspension oil for injection in this example
The preparation process is as follows:
(1) Crushing piperacillin and tazobactam respectively by a high-speed crusher, wherein the particle size D90 is smaller than 40 mu m for later use;
(2) Respectively weighing the BHA, the BHT, the polyoxyethylene castor oil and the medium-chain oil for injection according to the prescription, adding the BHA, the BHT and the polyoxyethylene castor oil into the medium-chain oil for injection, stirring and dissolving;
(3) Filling the oil solution into a sealing container pressure-resistant device (such as an infusion bottle), performing hot-press sterilization at 121 ℃ for 15 minutes, taking out and cooling;
(4) Weighing crushed piperacillin and tazobactam according to the prescription, adding the crushed piperacillin and tazobactam into the sterilized oil solution, and stirring for 2 hours;
(5) And (5) after sampling and detecting the content, filling the sample into ampoule bottles, filling about 7.7 ml/bottle, and sealing to obtain the product.
Example 3
Table 3 shows the formulations of the injectable suspension oils in this example.
TABLE 3 formulation of suspension oil for injection in this example
The preparation process is as follows:
(1) Crushing piperacillin and tazobactam respectively by a high-speed crusher, wherein the particle size D90 is smaller than 40 mu m for later use;
(2) Respectively weighing the BHA, BHT, polyoxyethylene castor oil, tween 80 and soybean oil for injection according to the prescription, adding the BHA, BHT, tween 80 and polyoxyethylene castor oil into the soybean oil for injection, stirring and dissolving;
(3) Filling the oil solution into a sealing container pressure-resistant device (such as an infusion bottle), performing hot-press sterilization at 121 ℃ for 15 minutes, taking out and cooling;
(4) Weighing crushed piperacillin and tazobactam according to the prescription, adding the crushed piperacillin and tazobactam into the sterilized oil solution, and stirring for 2 hours;
(5) And (5) after sampling and detecting the content, filling the sample into ampoule bottles, filling about 6.8 ml/bottle, and sealing to obtain the product.
Example 4
Table 4 shows the formulations of the injectable suspension oils in this example.
TABLE 4 formulation of suspension oil for injection in this example
The preparation process is as follows:
(1) Crushing piperacillin and tazobactam respectively by an airflow crusher, wherein the particle size D90 is smaller than 15 mu m for later use;
(2) Weighing the BHA, BHT, tween 80, lecithin and soybean oil for injection respectively, adding the BHA, BHT, tween 80 and lecithin into the soybean oil for injection, stirring and dissolving;
(3) Sterilizing and filtering the oil solution with a microporous filter membrane of 0.22 μm;
(4) Weighing crushed piperacillin and tazobactam according to the prescription, adding the crushed piperacillin and tazobactam into the sterilized oil solution, and stirring for 2 hours;
(5) And (5) after sampling and detecting the content, filling the sample into ampoule bottles, filling about 9.9 ml/bottle, and sealing to obtain the product.
Example 5
Table 5 shows the formulation of the injectable suspension oil in this example.
TABLE 5 formulation of suspension oil for injection of this example
The preparation process is as follows:
(1) Crushing piperacillin and tazobactam respectively by an airflow crusher, wherein the particle size D90 is smaller than 15 mu m for later use;
(2) Respectively weighing the BHA, BHT, polyoxyethylene castor oil, lecithin and soybean oil for injection according to the prescription, adding the BHA, BHT, tween 80 and lecithin into the soybean oil for injection, stirring and dissolving;
(3) Sterilizing and filtering the oil solution through a microporous filter membrane with the diameter of 0.22 mu m;
(4) Weighing crushed piperacillin and tazobactam according to the prescription, adding the crushed piperacillin and tazobactam into the sterilized oil solution, and stirring for 2 hours;
(5) And (5) after sampling and detecting the content, filling the sample into a penicillin bottle, filling about 10 ml/bottle, pressing a plug, and sealing.
Example 6
Table 6 shows the formulations of the injectable suspension oils in this example.
TABLE 6 formulation of suspension oil for injection of this example
The preparation process is as follows:
(1) Crushing piperacillin and tazobactam respectively by an airflow crusher, wherein the particle size D90 is smaller than 15 mu m for later use;
(2) Weighing the vitamin E, lecithin, benzyl alcohol and soybean oil for injection according to the prescription amount respectively, adding the vitamin E, lecithin and benzyl alcohol into the soybean oil for injection, stirring and dissolving;
(3) Sterilizing and filtering the oil solution through a microporous filter membrane with the diameter of 0.22 mu m;
(4) Weighing crushed piperacillin and tazobactam according to the prescription, adding the crushed piperacillin and tazobactam into the sterilized oil solution, and stirring for 2 hours;
(5) And (5) after sampling and detecting the content, filling the sample into a penicillin bottle, filling about 10 ml/bottle, pressing a plug, and sealing.
Comparative example: salt forming freeze-drying process
The formulation and preparation of the lyophilization process are shown in table 7.
TABLE 7 formulation of the reagents of the comparative examples
The preparation process is as follows:
(1) Taking 100ml of water for injection, adding the piperacillin and tazobactam with the prescribed amount, and stirring and dispersing;
(2) Slowly adding sodium bicarbonate with a prescription amount, reacting to generate a large amount of bubbles, and continuously stirring until the bubbles disappear, so that piperacillin and tazobactam are completely dissolved;
(3) Adjusting the pH value to 5.5-6.7 by using 0.1mol/L hydrochloric acid or sodium hydroxide, and adding water for injection to a volume of 500ml;
(4) Sterilizing and filtering the solution through a microporous filter membrane with the diameter of 0.22 mu m;
(5) After sampling and detecting the content, filling the sample into a penicillin bottle, and filling about 5 ml/bottle, and half-pressing the bottle plug;
(6) The samples were freeze dried in a freeze dryer:
(1) pre-freezing: the temperature of the plate layer is-50 ℃ and kept for 4 hours;
(2) sublimation: the temperature of the plate layer is raised to-10 ℃ and kept for 28 hours;
(3) and (5) analysis and drying: the temperature of the plate layer is raised to 30 ℃ and kept for 8 hours;
(7) And (5) after the freeze-drying procedure is finished, vacuum plugging, taking out of the box, and sealing.
The stability of the agents prepared in the above examples and comparative examples was demonstrated and analyzed as shown in table 8.
Table 8 comparison of test results for different examples
The results show that:
(1) Stability aspects: samples of each example of the composition containing piperacillin and tazobactam in the invention are placed at 40 ℃ for 30 days, the related substances slightly rise, and the content is basically unchanged; the related substances are obviously increased and the content is reduced after the comparative example is placed at 40 ℃ for 30 days; the stability of the suspension oil for injection comprising the piperacillin and tazobactam composition in this example is a significant advantage.
(2) The process comprises the following steps: the salt forming freeze-drying process of the comparative example not only involves dispersion and dissolution, but also needs salt forming and freeze-drying, needs to be switched among different reaction vessels, has complex operation, needs to consume a large amount of heat energy to realize state change, and can only produce one to two tens of thousands of bottles in one batch, and the production period exceeds 3 days in each batch. The preparation process of the suspension oil for injection only relates to the processes of crushing, mixing, sterilizing or degerming, and has simple process; the production period is short, the batch is large, the time consumed by one production process is generally not more than 12 hours, and the batch can reach hundreds of thousands of bottles; the preparation process only needs to provide mechanical energy for crushing and mixing, and the energy consumption in the sterilization process or the necessary filter membrane treatment for sterilization is low.
Claims (3)
1. The suspension oil for injection is characterized by comprising the following components in parts by mass:
100g of piperacillin, and the like,
25g of tazobactam, and the like,
10g of Tween 80, wherein the weight of the Tween is 10,
20g of lecithin, which is prepared from the following raw materials,
BHA 3g，
BHT 2g，
800g of soybean oil for injection,
the preparation process is as follows:
(1) Crushing piperacillin and tazobactam respectively by an airflow crusher, wherein the particle size D90 is smaller than 15 mu m for later use;
(2) Weighing the BHA, BHT, tween 80, lecithin and soybean oil for injection respectively, adding the BHA, BHT, tween 80 and lecithin into the soybean oil for injection, stirring and dissolving;
(3) Sterilizing and filtering the oil solution with a microporous filter membrane of 0.22 μm;
(4) Weighing crushed piperacillin and tazobactam according to the prescription, adding the crushed piperacillin and tazobactam into the sterilized oil solution, and stirring for 2 hours;
(5) And (5) after sampling and detecting the content, filling the sample into ampoule bottles, filling about 9.9 ml/bottle, and sealing to obtain the product.
2. The suspension oil for injection is characterized by comprising the following components in parts by mass:
100g of piperacillin, and the like,
25g of tazobactam, and the like,
50g of polyoxyethylated castor oil,
20g of lecithin, which is prepared from the following raw materials,
BHA 3g，
BHT 2g，
800g of soybean oil for injection,
the preparation process is as follows:
(1) Crushing piperacillin and tazobactam respectively by an airflow crusher, wherein the particle size D90 is smaller than 15 mu m for later use;
(2) Respectively weighing the BHA, the BHT, the polyoxyethylene castor oil, the lecithin and the soybean oil for injection according to the prescription, adding the BHA, the BHT, the polyoxyethylene castor oil and the lecithin into the soybean oil for injection, and stirring for dissolution;
(3) Sterilizing and filtering the oil solution through a microporous filter membrane with the diameter of 0.22 mu m;
(4) Weighing crushed piperacillin and tazobactam according to the prescription, adding the crushed piperacillin and tazobactam into the sterilized oil solution, and stirring for 2 hours;
(5) And (5) after sampling and detecting the content, filling the sample into a penicillin bottle, filling about 10 ml/bottle, pressing a plug, and sealing.
3. The suspension oil for injection is characterized by comprising the following components in parts by mass:
100g of piperacillin, and the like,
12.5g of tazobactam,
22.5g of lecithin,
10g of benzyl alcohol, which is prepared from the following components,
20g of vitamin E, and the total weight of the vitamin E,
800g of soybean oil for injection,
the preparation process is as follows:
(1) Crushing piperacillin and tazobactam respectively by an airflow crusher, wherein the particle size D90 is smaller than 15 mu m for later use;
(2) Weighing the vitamin E, lecithin, benzyl alcohol and soybean oil for injection according to the prescription amount respectively, adding the vitamin E, lecithin and benzyl alcohol into the soybean oil for injection, stirring and dissolving;
(3) Sterilizing and filtering the oil solution through a microporous filter membrane with the diameter of 0.22 mu m;
(4) Weighing crushed piperacillin and tazobactam according to the prescription, adding the crushed piperacillin and tazobactam into the sterilized oil solution, and stirring for 2 hours;
(5) And (5) after sampling and detecting the content, filling the sample into a penicillin bottle, filling about 10 ml/bottle, pressing a plug, and sealing.
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| CN101632670B (en) * | 2009-08-26 | 2010-12-15 | 海南永田药物研究院有限公司 | Suspension powder injection of piperacillin sodium and tazobactam sodium pharmaceutical composition and new application thereof |
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