CN110420184A - A kind of cefminox sodium for injection preparation and its preparation and application - Google Patents
A kind of cefminox sodium for injection preparation and its preparation and application Download PDFInfo
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- CN110420184A CN110420184A CN201910871493.9A CN201910871493A CN110420184A CN 110420184 A CN110420184 A CN 110420184A CN 201910871493 A CN201910871493 A CN 201910871493A CN 110420184 A CN110420184 A CN 110420184A
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- Prior art keywords
- proliposome
- drug
- sodium bicarbonate
- solid
- particle
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- JSDXOWVAHXDYCU-VXSYNFHWSA-N cefminox Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSC[C@@H](N)C(O)=O)OC)CC=1CSC1=NN=NN1C JSDXOWVAHXDYCU-VXSYNFHWSA-N 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title abstract description 22
- 238000002347 injection Methods 0.000 title description 6
- 239000007924 injection Substances 0.000 title description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 98
- 239000002245 particle Substances 0.000 claims abstract description 65
- 239000007787 solid Substances 0.000 claims abstract description 65
- 235000017557 sodium bicarbonate Nutrition 0.000 claims abstract description 49
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 49
- 239000003814 drug Substances 0.000 claims abstract description 46
- 229940079593 drug Drugs 0.000 claims abstract description 42
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims abstract description 27
- 229960002246 beta-d-glucopyranose Drugs 0.000 claims abstract description 27
- LTHCSWBWNVGEFE-UHFFFAOYSA-N octanamide Chemical compound CCCCCCCC(N)=O LTHCSWBWNVGEFE-UHFFFAOYSA-N 0.000 claims abstract description 27
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 24
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 24
- 239000011975 tartaric acid Substances 0.000 claims abstract description 24
- 239000002502 liposome Substances 0.000 claims abstract description 21
- 239000011159 matrix material Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000000725 suspension Substances 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 23
- 235000012000 cholesterol Nutrition 0.000 claims description 11
- 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 9
- 229910052708 sodium Inorganic materials 0.000 claims description 9
- 239000011734 sodium Substances 0.000 claims description 9
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 238000002604 ultrasonography Methods 0.000 claims description 5
- 230000010355 oscillation Effects 0.000 claims description 3
- 229930182558 Sterol Natural products 0.000 claims description 2
- 210000000232 gallbladder Anatomy 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 150000003432 sterols Chemical class 0.000 claims description 2
- 235000003702 sterols Nutrition 0.000 claims description 2
- 238000005538 encapsulation Methods 0.000 abstract description 14
- 238000009826 distribution Methods 0.000 abstract description 13
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 11
- 230000003247 decreasing effect Effects 0.000 abstract description 7
- 239000007962 solid dispersion Substances 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 9
- 235000010469 Glycine max Nutrition 0.000 description 7
- 235000013339 cereals Nutrition 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 6
- 101001105486 Homo sapiens Proteasome subunit alpha type-7 Proteins 0.000 description 6
- 102100021201 Proteasome subunit alpha type-7 Human genes 0.000 description 6
- 239000011258 core-shell material Substances 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- -1 beta-lactam cephalosporin Chemical class 0.000 description 5
- XDZKBRJLTGRPSS-BGZQYGJUSA-N cefodizime Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(C)=C(CC(O)=O)S1 XDZKBRJLTGRPSS-BGZQYGJUSA-N 0.000 description 5
- 229960001958 cefodizime Drugs 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 229930186147 Cephalosporin Natural products 0.000 description 4
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 4
- 229940124587 cephalosporin Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000004676 glycans Chemical class 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 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 description 3
- 229960002025 cefminox Drugs 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 2
- 240000007594 Oryza sativa Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 description 2
- 229960004261 cefotaxime Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 2
- 229960002182 imipenem Drugs 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000004260 plant-type cell wall biogenesis Effects 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 150000003952 β-lactams Chemical group 0.000 description 2
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 1
- PZNPLUBHRSSFHT-UHFFFAOYSA-N (3-hexadecanoyloxy-2-octadecanoyloxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- OMAFFHIGWTVZOH-UHFFFAOYSA-N 1-methyltetrazole Chemical compound CN1C=NN=N1 OMAFFHIGWTVZOH-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-UWTATZPHSA-N D-Cysteine Chemical compound SC[C@@H](N)C(O)=O XUJNEKJLAYXESH-UWTATZPHSA-N 0.000 description 1
- 101710116957 D-alanyl-D-alanine carboxypeptidase Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- GRTOGORTSDXSFK-XJTZBENFSA-N ajmalicine Chemical compound C1=CC=C2C(CCN3C[C@@H]4[C@H](C)OC=C([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 GRTOGORTSDXSFK-XJTZBENFSA-N 0.000 description 1
- WQZGKKKJIJFFOK-UHFFFAOYSA-N alpha-D-glucopyranose Natural products OCC1OC(O)C(O)C(O)C1O WQZGKKKJIJFFOK-UHFFFAOYSA-N 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- HVFLCNVBZFFHBT-ZKDACBOMSA-N cefepime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 HVFLCNVBZFFHBT-ZKDACBOMSA-N 0.000 description 1
- 229960002100 cefepime Drugs 0.000 description 1
- SNBUBQHDYVFSQF-HIFRSBDPSA-N cefmetazole Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSCC#N)OC)CC=1CSC1=NN=NN1C SNBUBQHDYVFSQF-HIFRSBDPSA-N 0.000 description 1
- 229960003585 cefmetazole Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000003631 expected effect Effects 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 210000002706 plastid Anatomy 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—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
- 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
- A61K9/127—Liposomes
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
-
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Dispersion Chemistry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of cefminox sodium pharmaceutical preparation, raw material includes the cefminox sodium as drug, and N- (β-D- glucopyranose) caprylamide, form a film matrix material；Still further comprise tartaric acid and solid sodium bicarbonate particle.In addition, also disclosing the preparation method and application method of above-mentioned proliposome.Proliposome pharmaceutical preparation is prepared by using solid dispersion, liposome suspension is prepared in conjunction with effervescent technique, the long time stored stability of proliposome can either be played, and can preferably keep liposome consistency, particle diameter distribution is relatively narrow, and encapsulation rate is without being decreased obviously.
Description
Technical field
The invention belongs to field of pharmaceutical preparations；It is related to the pharmaceutical preparation more particularly to a kind of cephalo of a kind of cefminox sodium
Minot preparation of sodium and its preparation and application, more particularly relate to a kind of cefminox sodium of injection proliposome and its
Preparation and application.
Background technique
Cefminox sodium is (6R, 7S) -7- [(S) -2- [2- amino -2- ethoxy sulfydryl]-acetylamino] -7- methoxy
Base -3- [[(1- methyl-1 H- tetrazolium -5- base)-sulfydryl]-methyl] -8- oxo -5- thia -1- azabicyclo [4.2.0] octyl- 2-
Alkene -2- formic acid sodium salt heptahydrate, molecular weight are 667.66 dalton；Belong to beta-lactam cephalosporin.
Cefminox sodium is the powder ampoule agent for injection of Japanese MingZhi fruit Co., Ltd's exploitation, property and third generation cephalo bacterium
Element is similar.Cefminox sodium and penicillin binding protein have high affinity, in combination to prevent bacteria cell wall
Synthesis.The also peculiar mechanism for acting on peptide glycan of cefminox sodium, the D-Cys and peptide of 7 β side chain terminal of drug molecule
Glycan combines, inhibit albumen of the peptide glycan with outer membrane in conjunction with peptide glycan in conjunction with, make cell wall formation bulbous protrusion, to be formed
Very strong bacteriolysis, achievees the effect that quick sterilization.
Cefminox sodium is active to most bacteriums especially Gram-negative bacteria and anaerobic bacteria, and vivo potency is higher than body
Outer test expected effect.Have the Escherichia coli and Klebsiella pneumoniae for producing ESBL compared with high inhibition effect, does not find
The bacterial strain of imipenem-resistant, Cefminox than other beta-lactam cephalosporin, gentamicin and fluoroquinolones have compared with
High antibacterial activity in vitro；To the bacterial strain for not producing ESBL, Cefminox, cefmetazole, cefotaxime, cefotaxime, cephalo are bent
Pine, Cefepime and Imipenem have identical antibacterial activity.
Cefminox sodium raw materials be powder or crystalline powder white or yellowish, it is soluble easily in water；It not yet records at present
In Chinese Pharmacopoeia.
Cefminox sodium is similar with other lactams cephalosporins, more sensitive to environmental factor, makees in light and heat
Degradation, oxidation or polymerization reaction are easy to happen under, generating related substance I(after a long time placement is mainly Cefminox thioether)
Be mainly high molecular polymer with related substance II() etc. impurity, to influence its drug safety.
In order to solve the stability problem that cefminox sodium is long time stored and places, people have attempted various new drug
Preparation type.Among these, liposome is one of most commonly used novel dosage forms of research.It was verified that by Cephalosporins
Liposome is made for improving its environmental sensitivity significant effect.
Chinese patent application CN201710263114.X discloses a kind of liposomal pharmaceutical preparation of Cefodizime Sodium, the medicine
Object preparation uses film forming matter stabilizer of the D- glucopyranose amide as liposome, its own is with parents' surface-active
Matter substantially improves the phenomenon of osmosis of drug.Particle diameter distribution in gained drug suspension is smaller and uniform；It is store in long-time
Generated impurity content is still within allowed band after depositing and being acted on after placing by environmental factor.
However, it is found by the inventors that when said medicine suspension is at long time stored (such as 3 months or more), liposome
It is easy to happen aggregation or fusion, causes particle diameter distribution wider；Entrapment efficiency will appear decline by a relatively large margin simultaneously, thus difficult
To meet the requirement of drug preparation stability.
The problem of prior art is by that can significantly improve above-mentioned storage stability to liposome freeze-drying.In for example,
State patent application CN200910016147.9 discloses a kind of Cefodizime sodium proliposome preparation.The Cefodizime Sodium
Proliposome preparation calculates by weight, is made of the following components: 1-20 parts of Cefodizime Sodium, 5-50 parts of egg yolk lecithin,
2-30 parts of cholesterol, 0.5-20 parts of antioxidant and 3-50 parts of supporting agent, and during the preparation process, using special solvent system
The stable, Cefodizime sodium proliposome with good encapsulation rate is made in system.However, the repeatability of this method is not ideal enough,
80% or more encapsulation rate is extremely difficult in practice；Meanwhile particle diameter distribution is also extremely difficult to 10 nm ranges of average grain diameter or more
Compared with narrow particle diameter distribution.In addition, the proliposome preparation is at long time stored (such as 3 months or more), entrapment efficiency is same
Sample will appear decline by a relatively large margin, it is difficult to meet the requirement of drug preparation stability.
For above-mentioned various deficiencies of the prior art, there is an urgent need to find a kind of long time stored (such as 3 months or more)
Liposome consistency is preferable, and particle diameter distribution is relatively narrow, and encapsulation rate is without the Cefminox sodium proliposome being decreased obviously
Pharmaceutical preparation and its preparation and application.
Summary of the invention
The object of the invention first is that overcoming the deficiencies of the prior art and provide a kind of long time stored (such as 3 months or more)
Liposome consistency is preferable, and particle diameter distribution is relatively narrow, and encapsulation rate is without the Cefminox sodium proliposome being decreased obviously
Pharmaceutical preparation.
The second object of the present invention is to providing a kind of method for preparing above-mentioned Cefminox sodium proliposome pharmaceutical preparation.It should
Preparation method is simple, reproducible.
The three of the object of the invention are to provide a kind of method using above-mentioned Cefminox sodium proliposome pharmaceutical preparation.
To achieve the above object, on the one hand, the present invention provides a kind of Cefminox sodium proliposome, the preceding body fat
The raw material of plastid includes the cefminox sodium as drug, and N- (β-D- glucopyranose) caprylamide, form a film matrix material；It is special
Sign is that raw material further comprises tartaric acid and solid sodium bicarbonate particle.
No. CAS of N- (β-D- glucopyranose) caprylamide is 134403-86-4, and molecular weight 329, purity is greater than 98%.
Proliposome according to the present invention, wherein the drug and N- (β-D- glucopyranose) caprylamide
Weight ratio is 1:(3.5-8.5).
Preferably, the weight ratio of the drug and N- (β-D- glucopyranose) caprylamide is 1:(4-8)；It is highly preferred that
The weight ratio of the drug and N- (β-D- glucopyranose) caprylamide is 1:(4.5-7.5)；And most preferably, the medicine
The weight ratio of object and N- (β-D- glucopyranose) caprylamide is 1:(5-7).
In a specific embodiment, the weight ratio of the drug and N- (β-D- glucopyranose) caprylamide is 1:
6。
Proliposome according to the present invention, wherein the film forming matrix material is by hydrogenated soy phosphatidyl choline and gallbladder
Sterol composition.
As hydrogenated soy phosphatidyl choline, the entitled 1- palmityl -2- stearyl lecithin of chemistry, abbreviation HSPC, No. CAS
For 92128-87-5, molecular weight 784, purity is injection stage.
HSPC phase transition temperature is high, and human tolerance is more preferable than soybean lecithin；But HSPC molecular rigidity is big, it is difficult to independent shape
At stable bimolecular lipid membrane.
As cholesterol, No. CAS is 57-88-5, and molecular weight 387, purity is similarly injection stage.
Proliposome according to the present invention, wherein the weight ratio of hydrogenated soy phosphatidyl choline and cholesterol is 1:
(0.4-2.6)。
Preferably, the weight ratio of hydrogenated soy phosphatidyl choline and cholesterol is 1:(0.6-2.4)；It is highly preferred that hydrogenated soybean
The weight ratio of lecithin and cholesterol is 1:(0.8-2.2)；And most preferably, the weight of hydrogenated soy phosphatidyl choline and cholesterol
Amount is than being 1:(1-2).
In a specific embodiment, the weight ratio of hydrogenated soy phosphatidyl choline and cholesterol is 1:1.5.
Proliposome according to the present invention, wherein the drug and the weight ratio for forming a film matrix material are
1:(14-46).
Preferably, the weight ratio of the drug and the film forming matrix material is 1:(16-44)；It is highly preferred that the medicine
The weight ratio of object and the film forming matrix material is 1:(18-42)；And most preferably, the drug and described at membrane lipid
The weight ratio of material is 1:(20-40).
In a specific embodiment, the weight ratio of the drug and the film forming matrix material is 1:30.
Proliposome according to the present invention, wherein the weight ratio of the tartaric acid and solid sodium bicarbonate particle
For (2.5-8.5): 1.
Preferably, the weight ratio of the tartaric acid and solid sodium bicarbonate particle is (2-8): 1；It is highly preferred that the wine
The weight ratio of stone acid and solid sodium bicarbonate particle is (2.5-7.5): 1；And most preferably, the tartaric acid and solid carbon
The weight ratio of sour hydrogen sodium particle is (3-7): 1.
In a specific embodiment, the weight ratio of the tartaric acid and solid sodium bicarbonate particle is 5:1.
Proliposome according to the present invention, wherein the weight ratio of the drug and solid sodium bicarbonate particle is
(0.9-3.1): 1.
Preferably, the weight ratio of the tartaric acid and solid sodium bicarbonate particle is (1.1-2.9): 1；It is highly preferred that institute
The weight ratio for stating tartaric acid and solid sodium bicarbonate particle is (1.3-2.7): 1；And most preferably, the tartaric acid and solid
The weight ratio of body sodium bicarbonate particle is (1.5-2.5): 1.
In a specific embodiment, the weight ratio of the tartaric acid and solid sodium bicarbonate particle is 2:1.
Proliposome according to the present invention, wherein the partial size of solid sodium bicarbonate particle is 200-400 mesh, is contained
Water rate is less than 3.5%.
Preferably, the partial size of solid sodium bicarbonate particle is 220-380 mesh, and moisture content is less than 3%；It is highly preferred that solid carbon
The partial size of sour hydrogen sodium particle is 240-360 mesh, and moisture content is less than 2.5%；And most preferably, the grain of solid sodium bicarbonate particle
Diameter is 260-340 mesh, and moisture content is less than 2%.
In a specific embodiment, the partial size of solid sodium bicarbonate particle is 280-320 mesh, and moisture content is
1.7%。
In the present invention, a-b mesh indicates that solid particle can be leaked through from the sieve of a mesh, but cannot leak from the sieve of b mesh
It crosses.For example, 200-400 mesh indicates that solid particle can be leaked through from the sieve of 200 mesh, but cannot be leaked through from the sieve of 400 mesh.
On the other hand, the present invention also provides the methods for preparing above-mentioned Cefminox sodium proliposome pharmaceutical preparation, should
Method includes:
Film forming matrix material is dissolved in chloroform-ethanol in the mixed solvent；
Drug is added, N- (β-D- glucopyranose) caprylamide and tartaric acid, ultrasound make it dissolve；
Solid sodium bicarbonate particle is added, reacts certain time；
Solvent is removed, solid matter is obtained；
Solid matter is solidified into 12-48h in vacuum desiccator, obtains proliposome.
Preparation method according to the present invention, wherein the solid sodium bicarbonate particle is crushed using medicinal ball mill
And it is classified and obtains the solid sodium bicarbonate particle that partial size is 200-400 mesh, and dry to moisture content less than 3.5%.
Preferably, the partial size of solid sodium bicarbonate particle is 220-380 mesh, and moisture content is less than 3%；It is highly preferred that solid carbon
The partial size of sour hydrogen sodium particle is 240-360 mesh, and moisture content is less than 2.5%；And most preferably, the grain of solid sodium bicarbonate particle
Diameter is 260-340 mesh, and moisture content is less than 2%.
In a specific embodiment, the partial size of solid sodium bicarbonate particle is 280-320 mesh, and moisture content is
1.7%。
Preparation method according to the present invention, wherein the volume ratio of chloroform-ethanol is (2-4): 1.
Preparation method according to the present invention, wherein reaction temperature 45-65oC, reaction time 30-150min.
Preferably, reaction temperature 45-60oC, reaction time 60-130min；It is highly preferred that reaction temperature is 50-
60oC, reaction time 80-120min.
In a specific embodiment, reaction temperature 55oC, reaction time 90min.
Another aspect, the present invention also provides the methods for using above-mentioned Cefminox sodium proliposome pharmaceutical preparation, should
Method includes:
By Cefminox sodium proliposome precise weighing, 5% sodium bicarbonate solution is added according to constant weight volume ratio；Sufficiently
Oscillation, until solid matter is completely dissolved, and adjusting pH value is 4.5-7.0, obtains liposome suspension.
Preferably, pH value 5.0-7.0；It is highly preferred that pH value is 5.5-7.0；And most preferably, pH value 5.5-
6.5。
In one preferred embodiment, pH value 6.0.
Application method according to the present invention, wherein the w/v is 1:10.
Inventors have found that preparing proliposome by using solid dispersion, liposome is prepared in conjunction with effervescent technique and is suspended
Liquid, can either play the stability of proliposome long time stored (such as 3 months or more), and can preferably keep liposome
Form consistency, particle diameter distribution is relatively narrow, and encapsulation rate is without being decreased obviously.
It is not intended to limited to any theory, drug and film forming matrix material and N- (β-D- glucopyranose) caprylamide is uniform
Ground is scattered in tartaric acid and solid sodium bicarbonate particle, and N- (β-D- glucopyranose) caprylamide itself is living with parents surface
Property property, with film forming matrix material and drug beta-lactam structure fragment generate synergistic effect, be distributed evenly in them
On solid sodium bicarbonate particle surface, more uniform core-shell structure is formed, the diameter of the core-shell structure and pass through effervescent technique
Forming liposomal particle size, there are specific proportionate relationships.After sodium bicarbonate solution is added, tartaric acid and solid sodium bicarbonate are fast
Instant solution is collapsed, and is reacted and is occurred in the interface of core-shell structure, results in the more uniform carbon dioxide micron bubble of diameter,
The latter makes drug and the matrix material cephalo rice relatively narrow with N- (β-D- glucopyranose) caprylamide formation particle diameter distribution that forms a film
Promise sodium lipidosome suspension, and encapsulation rate is higher.
Compared with prior art, the present invention has following advantageous effects:
I) high stability of Cefminox sodium proliposome of the invention long time stored (such as 3 months or more), can be compared with
Liposome consistency is kept well, and particle diameter distribution is relatively narrow, and encapsulation rate is without being decreased obviously.
Ii) preparation method is simple for Cefminox sodium proliposome of the invention, reproducible.
Iii) Cefminox sodium proliposome of the invention is easy to use, can comparatively fast be converted into liposome suspension；
Without other auxiliary materials；Equipment cost is low and pollution-free, and popularity is suitble to use.
Specific embodiment
It should be understood that a specific embodiment of the invention is only used for illustrating the spirit and principles in the present invention, rather than limitation
The scope of the present invention.In addition, it should also be understood that, after reading the contents of the present invention, those skilled in the art can be to of the invention
Technical solution make it is various change, replace, delete, correct or adjust, these equivalents thereofs equally fall within right of the present invention
Claim limited range.
Embodiment 1:
Cefminox sodium 80mg, N- (β-D- glucopyranose) caprylamide 480mg as drug is weighed, as at membrane lipid material
The HSPC 1430mg and cholesterol 950mg and tartaric acid 775mg and solid sodium bicarbonate particle 155mg of material.The solid carbon
Sour hydrogen sodium particle is crushed using medicinal ball mill and is classified the solid sodium bicarbonate particle for obtaining partial size as 280-320 mesh, and is done
It is dry to moisture content less than 1.7%.It is 3:1 chloroform-ethanol in the mixed solvent that film forming matrix material, which is dissolved in 30mL volume,；It is added
Drug, N- (β-D- glucopyranose) caprylamide and tartaric acid, ultrasound make it dissolve；Solid sodium bicarbonate particle, reaction is added
Certain time；Reaction temperature is 55oC, reaction time 90min.Vacuum distillation removes solvent, obtains solid matter；By solid
Substance solidifies for 24 hours in vacuum desiccator, obtains proliposome.By proliposome accurate weighing be placed in cillin bottle in
4oC condition is kept in dark place.
Embodiment 2:
Cefminox sodium 60mg, N- (β-D- glucopyranose) caprylamide 420mg as drug is weighed, as at membrane lipid material
The HSPC 1590mg and cholesterol 435mg and tartaric acid 145mg and solid sodium bicarbonate particle 145mg of material.The solid carbon
Sour hydrogen sodium particle is crushed using medicinal ball mill and is classified the solid sodium bicarbonate particle for obtaining partial size as 280-320 mesh, and is done
It is dry to moisture content less than 1.7%.It is 3:1 chloroform-ethanol in the mixed solvent that film forming matrix material, which is dissolved in 30mL volume,；It is added
Drug, N- (β-D- glucopyranose) caprylamide and tartaric acid, ultrasound make it dissolve；Solid sodium bicarbonate particle, reaction is added
Certain time；Reaction temperature is 45oC, reaction time 80min.Vacuum distillation removes solvent, obtains solid matter；By solid
Substance solidifies 12h in vacuum desiccator, obtains proliposome.By proliposome accurate weighing be placed in cillin bottle in
4oC condition is kept in dark place.
Embodiment 3:
Cefminox sodium 120mg, N- (β-D- glucopyranose) caprylamide 600mg as drug is weighed, as at membrane lipid
The HSPC 1190mg and cholesterol 1190mg and tartaric acid 1260mg and solid sodium bicarbonate particle 180mg of material.It is described solid
Body sodium bicarbonate particle is crushed using medicinal ball mill and is classified to obtain the solid sodium bicarbonate particle that partial size is 280-320 mesh,
And it dries to moisture content less than 1.7%.It is 3:1 chloroform-ethanol in the mixed solvent that film forming matrix material, which is dissolved in 30mL volume,；
Drug is added, N- (β-D- glucopyranose) caprylamide and tartaric acid, ultrasound make it dissolve；Solid sodium bicarbonate particle is added,
React certain time；Reaction temperature is 65oC, reaction time 120min.Vacuum distillation removes solvent, obtains solid matter；It will
Solid matter solidifies 48h in vacuum desiccator, obtains proliposome.Proliposome accurate weighing is placed on cillin bottle
In in 4oC condition is kept in dark place.
Comparative example 1:
It is added without N- (β-D- glucopyranose) caprylamide, remaining condition is the same as embodiment 1.
Comparative example 2:
N- (β-D- glucopyranose) caprylamide is replaced with to the octadecylamine of same weight, remaining condition is the same as embodiment 1.
Comparative example 3:
Solid sodium bicarbonate particle is replaced with to the solid sodium bicarbonate particle of 80-120 mesh, and drying to moisture content is less than
1.7%。
Application Example 1-3 and application comparative example 1-3
By the Cefminox sodium proliposome precise weighing of embodiment 1-3 and comparative example 1-3, respectively in storage 0 day and 3 months
5wt% sodium bicarbonate solution is added according to the w/v of 1:10 after (90 days)；Sufficiently oscillation, until solid matter is completely dissolved,
And adjusting pH value is 6.0, the embodiment that is applied 1-3 and application comparative example 1-3 liposome suspension.It tests 0 day and 90 respectively
The encapsulation rate and average grain diameter of its gained liposome suspension.
Wherein, using supercentrifugal process computational envelope rate according to the following formula: encapsulation rate=(drug total amount-free drug weight
Amount)/drug total amount × 100%.Wherein, the measurement of free drug weight are as follows: precision measures the liposome suspension of 0.1mL, is placed in
In centrifuge tube, add 0.2mL normal saline dilution, be centrifuged 30min under 15000rpm revolving speed, take supernatant 0.1mL, is diluted to rationally
Multiple measures absorbance at 215nm, calculates free drug weight using physiological saline as blank.The measurement of drug total amount
Are as follows: precision measures the liposome suspension of 0.1mL, is placed in centrifuge tube, adds 0.9mL, with normal saline dilution to reasonable multiple,
Blank liposome is operated with method, as blank, measures absorbance, drug total amount is calculated.
Partial size test is carried out using laser particle size analyzer.
Shown in the following Tables 1 and 2 of dependence test result:
The 0th day performance indexes of table 1
| Encapsulation rate/% | Average grain diameter/μm | |
| Embodiment 1 | 71.9 | 0.93±0.12 |
| Embodiment 2 | 68.7 | 0.97±0.14 |
| Embodiment 3 | 69.5 | 1.03±0.16 |
| Comparative example 1 | 27.6 | 1.98±0.59 |
| Comparative example 2 | 39.6 | 2.55±0.73 |
| Comparative example 3 | 42.0 | 6.75±2.36 |
The 90th day performance indexes of table 2
| Encapsulation rate/% | Average grain diameter/nm | |
| Embodiment 1 | 69.3 | 1.02±0.17 |
| Embodiment 2 | 65.7 | 1.07±0.19 |
| Embodiment 3 | 63.1 | 1.14±0.23 |
| Comparative example 1 | 8.1 | 2.62±0.94 |
| Comparative example 2 | 24.7 | 2.91±1.02 |
| Comparative example 3 | 30.9 | 8.63±3.18 |
As can be seen from Table 1 and Table 2, it is added without N- (β-D- glucopyranose) caprylamide with comparative example 1 and comparative example 2 is added together
The octadecylamine of sample weight is compared, and the Cefminox sodium proliposome of the embodiment of the present application 1-3 long time stored (such as 3 months
More than) high stability, can preferably keep liposome consistency, particle diameter distribution is relatively narrow and partial size is smaller, and wraps
Envelope rate is without being decreased obviously.Compared with comparative example 3 is using the solid sodium bicarbonate particle of 80-120 mesh, the embodiment of the present application 1-3's
Cefminox sodium proliposome average grain diameter is smaller, while narrow distribution, and encapsulation rate is without being decreased obviously.
It is not intended to limited to any theory, drug and film forming matrix material and N- (β-D- glucopyranose) caprylamide is uniform
Ground is scattered in tartaric acid and solid sodium bicarbonate particle, and N- (β-D- glucopyranose) caprylamide itself is living with parents surface
Property property, with film forming matrix material and drug beta-lactam structure fragment generate synergistic effect, be distributed evenly in them
On solid sodium bicarbonate particle surface, more uniform core-shell structure is formed, the diameter of the core-shell structure and pass through effervescent technique
Forming liposomal particle size, there are specific proportionate relationships.After sodium bicarbonate solution is added, tartaric acid and solid sodium bicarbonate are fast
Instant solution is collapsed, and is reacted and is occurred in the interface of core-shell structure, results in the more uniform carbon dioxide micron bubble of diameter,
The latter makes drug and the matrix material cephalo rice relatively narrow with N- (β-D- glucopyranose) caprylamide formation particle diameter distribution that forms a film
Promise sodium lipidosome, and encapsulation rate is higher.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any to repair
Change, equivalent replacement, improvement etc., is all included in the scope of protection of the present invention.
Claims (10)
1. a kind of Cefminox sodium proliposome, the raw material of the proliposome includes the cefminox sodium as drug,
N- (β-D- glucopyranose) caprylamide, form a film matrix material；It is characterized in that, raw material further comprises tartaric acid and solid carbon
Sour hydrogen sodium particle.
2. proliposome according to claim 1, the weight of the drug and N- (β-D- glucopyranose) caprylamide
Than for 1:(3.5-8.5).
3. proliposome according to claim 1, wherein the film forming matrix material is by hydrogenated soy phosphatidyl choline and gallbladder
Sterol composition.
4. proliposome according to claim 3, wherein the weight ratio of hydrogenated soy phosphatidyl choline and cholesterol is 1:
(0.4-2.6)。
5. proliposome according to claim 1, wherein the drug and the weight ratio for forming a film matrix material are
1:(14-46).
6. proliposome according to claim 1, wherein the weight ratio of the tartaric acid and solid sodium bicarbonate particle
For (2.5-8.5): 1.
7. proliposome according to claim 1, wherein the weight ratio of the drug and solid sodium bicarbonate particle is
(0.9-3.1): 1.
8. proliposome according to claim 1, wherein the partial size of the solid sodium bicarbonate particle is 200-400
Mesh, moisture content is less than 3.5%.
9. a kind of method for preparing any one of claim 1-8 proliposome, this method comprises:
Film forming matrix material is dissolved in chloroform-ethanol in the mixed solvent；
Drug is added, N- (β-D- glucopyranose) caprylamide and tartaric acid, ultrasound make it dissolve；
Solid sodium bicarbonate particle is added, reacts certain time；
Solvent is removed, solid matter is obtained；Solid matter is solidified into 12-48h in vacuum desiccator, obtains proliposome.
10. a kind of method using any one of the claim 1-8 proliposome, this method comprises:
By Cefminox sodium proliposome precise weighing, 5% sodium bicarbonate solution is added according to constant weight volume ratio；
Sufficiently oscillation, until solid matter is completely dissolved, and adjusting pH value is 4.5-7.0, obtains liposome suspension.
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| CN114053226A (en) * | 2021-11-18 | 2022-02-18 | 上海欣峰制药有限公司 | Pharmaceutical preparation of cefminox sodium compound and preparation method thereof |
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Application publication date: 20191108 |