CN114053226A - Pharmaceutical preparation of cefminox sodium compound and preparation method thereof - Google Patents
Pharmaceutical preparation of cefminox sodium compound and preparation method thereof Download PDFInfo
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- CN114053226A CN114053226A CN202111366463.6A CN202111366463A CN114053226A CN 114053226 A CN114053226 A CN 114053226A CN 202111366463 A CN202111366463 A CN 202111366463A CN 114053226 A CN114053226 A CN 114053226A
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- China
- Prior art keywords
- proliposome
- weight ratio
- cefminox
- parts
- cefminox sodium
- Prior art date
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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 51
- 238000002360 preparation method Methods 0.000 title abstract description 19
- 239000000825 pharmaceutical preparation Substances 0.000 title abstract description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 62
- 239000002245 particle Substances 0.000 claims abstract description 45
- 239000007787 solid Substances 0.000 claims abstract description 43
- 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 abstract description 32
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 31
- 235000017557 sodium bicarbonate Nutrition 0.000 claims abstract description 31
- 239000000787 lecithin Substances 0.000 claims abstract description 19
- 229940067606 lecithin Drugs 0.000 claims abstract description 19
- 235000010445 lecithin Nutrition 0.000 claims abstract description 19
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 18
- 229930195725 Mannitol Natural products 0.000 claims abstract description 18
- 239000000594 mannitol Substances 0.000 claims abstract description 18
- 235000010355 mannitol Nutrition 0.000 claims abstract description 18
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 claims abstract description 16
- 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 16
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 16
- 239000011975 tartaric acid Substances 0.000 claims abstract description 16
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 7
- QCIJKKRQPRMHOX-IJARWDBPSA-M sodium;(6r,7s)-7-[[2-(2-amino-2-carboxyethyl)sulfanylacetyl]amino]-7-methoxy-3-[(1-methyltetrazol-5-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].S([C@@H]1[C@@](C(N1C=1C([O-])=O)=O)(NC(=O)CSCC(N)C(O)=O)OC)CC=1CSC1=NN=NN1C QCIJKKRQPRMHOX-IJARWDBPSA-M 0.000 claims abstract description 7
- 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 6
- 229960002246 beta-d-glucopyranose Drugs 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 6
- XEPXGZZWVKNRGS-RGCYKPLRSA-N n-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]octanamide Chemical compound CCCCCCCC(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O XEPXGZZWVKNRGS-RGCYKPLRSA-N 0.000 claims description 5
- LTHCSWBWNVGEFE-UHFFFAOYSA-N octanamide Chemical compound CCCCCCCC(N)=O LTHCSWBWNVGEFE-UHFFFAOYSA-N 0.000 claims description 4
- 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 3
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 18
- 229940079593 drug Drugs 0.000 abstract description 14
- 238000005538 encapsulation Methods 0.000 abstract description 9
- 238000003860 storage Methods 0.000 abstract description 6
- 230000007774 longterm Effects 0.000 abstract description 4
- 239000002502 liposome Substances 0.000 description 19
- 239000000843 powder Substances 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- MSFSPUZXLOGKHJ-UHFFFAOYSA-N Muraminsaeure Natural products OC(=O)C(C)OC1C(N)C(O)OC(CO)C1O MSFSPUZXLOGKHJ-UHFFFAOYSA-N 0.000 description 4
- 108010013639 Peptidoglycan Proteins 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 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 3
- 101001105486 Homo sapiens Proteasome subunit alpha type-7 Proteins 0.000 description 3
- 102100021201 Proteasome subunit alpha type-7 Human genes 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 3
- 239000004299 sodium benzoate Substances 0.000 description 3
- 235000010234 sodium benzoate Nutrition 0.000 description 3
- -1 (6R,7S) -7- [ (S) -2- [ 2-amino-2-hydroxyethylmercapto ] -acetylamino ] -7-methoxy-3- [ [ (1-methyl-1H-tetrazol-5-yl) -mercapto ] -methyl ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic Chemical group 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 241000588747 Klebsiella pneumoniae Species 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 102000006635 beta-lactamase Human genes 0.000 description 2
- 210000002421 cell wall Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 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
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- 229930186147 Cephalosporin Natural products 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
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 229930195710 D‐cysteine Natural products 0.000 description 1
- JACXUEYJJKTYSW-UHFFFAOYSA-N O.O.O.O.O.O.O.[Na] Chemical compound O.O.O.O.O.O.O.[Na] JACXUEYJJKTYSW-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 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 description 1
- 108700020474 Penicillin-Binding Proteins Proteins 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 238000000703 high-speed centrifugation Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- 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
Abstract
Discloses a pharmaceutical preparation of cefminox sodium compound, which comprises the following raw materials: cefminox sodium; n- (β -D-glucopyranose) octanoamide; octadecylamine; 1-palmitoyl-2-stearoyl lecithin; mannitol; cholesterol; tartaric acid; solid sodium bicarbonate particles. In addition, also discloses a preparation method of the medicinal preparation. The pharmaceutical preparation of the cefminox sodium compound has better fluidity; while the drug encapsulation efficiency remains substantially unchanged after long-term storage (e.g., more than 3 months).
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations; relates to a medicinal preparation of a cefminox sodium compound and a preparation method thereof, in particular to a proliposome of the cefminox sodium compound and a preparation method thereof.
Background
Cefminox sodium is (6R,7S) -7- [ (S) -2- [ 2-amino-2-hydroxyethylmercapto ] -acetylamino ] -7-methoxy-3- [ [ (1-methyl-1H-tetrazol-5-yl) -mercapto ] -methyl ] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid sodium salt heptahydrate, having a molecular weight of 667.66 daltons; belongs to beta-lactam cephalosporins.
The cefminox sodium is mainly prepared into powder for injection, has strong antibacterial activity and wide distribution in vivo, is mainly clinically used for treating symptoms such as respiratory system infection, urinary system infection, abdominal cavity infection, septicemia and the like caused by sensitive bacteria, and has higher competitive advantage in similar medicines.
Cefminox sodium is highly stable to beta-lactamases and has a high affinity for penicillin binding proteins, binding of which prevents synthesis of bacterial cell walls. The cefminox sodium also has a specific action on a mechanism of peptidoglycan, the D-cysteine at the tail end of a side chain at the 7 beta position of a drug molecule is combined with the peptidoglycan, and the combination of the peptidoglycan and the outer membrane combined protein is inhibited to combine with the peptidoglycan, so that the cell wall forms spherical protrusions, thereby forming a strong bacteriolysis effect and achieving the effect of quick sterilization. A large number of clinical tests prove that the product has wide distribution range in vivo, quick response, less adverse reaction and higher safety.
Chinese patent application CN101623263A discloses a cefminox sodium liposome preparation. The cefminox sodium liposome preparation is a powder injection, wherein cefminox sodium is wrapped in a liposome in the form of liposome and is prepared from the following components in parts by weight: 0.1-15 parts of cefminox sodium, 1-50 parts of soybean lecithin, 0.1-40 parts of cholesterol, 0.1-20 parts of antioxidant and 1-60 parts of support agent. The cefminox sodium preparation has good preparation stability, liposome can not be cracked due to dehydration, fusion, ice crystal generation and the like in the freeze-drying process, and the liposome can also keep good entrapment rate after hydration and redissolution.
Chinese patent application CN103550171A discloses a cefminox sodium composition freeze-dried powder injection for injection, which relates to the technical field of medicines and medicine manufacturing and comprises the following raw material components in parts by weight: 7.26-9.17 parts of cefminox sodium, 7.02-8.97 parts of chitosan nanoparticles and 81.38-87.10 parts of water for injection. The advantages are that: 1) the antibacterial agent has good antibacterial effect on Klebsiella pneumoniae, the sensitivity rate is 91.9%, and the advantages in the production of ESBLs Klebsiella pneumoniae are obvious; 2) the concentration of the effective components of the composition in the central chamber is increased and the circulation time is prolonged, so that the medicine can better play the role of whole body treatment and enhance the curative effect of the medicine at the target position of the focus; 3) the stability of the beta-lactamase generated by gram negative bacteria is increased, and the in vivo distribution is good; 4) the enhancement of the activity shortens the medication period of a patient, and reduces the possibility of adverse reaction caused by accumulation of cefminox sodium; 5) the chitosan nanoparticles can replace mannitol to be used as a freeze-drying skeleton agent of the freeze-dried powder injection, and the activity effect of the mannitol on a human body is eliminated.
Chinese patent application CN102973569A discloses a pharmaceutical composition in the form of cefminox sodium sterile mixed powder, wherein the pharmaceutical composition consists of cefminox sodium, anhydrous sodium carbonate and sodium benzoate, and the mass ratio of the cefminox sodium to the anhydrous sodium carbonate to the sodium benzoate in the pharmaceutical composition is 100 g: 0.1-0.5 g: 0.1 to 1.0 g. The pharmaceutical composition greatly improves the thermal stability of cefminox sodium by the combined application of cefminox sodium, anhydrous sodium carbonate and sodium benzoate, and simultaneously improves the stability of cefminox sodium in a solution state, thereby improving the safety of clinical use. Meanwhile, the invention also relates to a preparation method of the pharmaceutical composition, and the preparation method is simple and feasible in process and suitable for industrial mass production.
Chinese patent application CN110420184A discloses a cefminox sodium pharmaceutical preparation, the raw materials include cefminox sodium as the medicine, N- (beta-D-glucopyranose) octanamide, film-forming lipid material; tartaric acid and solid sodium bicarbonate particles are also further included. In addition, a preparation method and a using method of the proliposome are also disclosed. The proliposome pharmaceutical preparation is prepared by using solid dispersion, and the liposome suspension is prepared by combining the effervescent technology, so that the stability of the proliposome during long-time storage can be exerted, the consistency of the liposome form can be well kept, the particle size distribution is narrow, and the entrapment rate is not obviously reduced.
However, the physicochemical properties of the cefminox sodium liposome preparation or the freeze-dried powder in the prior art are not stable enough, and the fluidity is not good; meanwhile, the drug encapsulation efficiency is reduced after long-term storage (for example, more than 3 months).
In view of the above-mentioned drawbacks of the prior art, there is a strong need to find an improved liposome precursor of cefminox sodium compound and a preparation method thereof.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides an improved precursor liposome of a cefminox sodium compound and a preparation method thereof.
In order to achieve the above object, in one aspect, the present invention provides a proliposome of cefminox sodium compound, which is characterized in that the raw materials comprise:
cefminox sodium;
n- (β -D-glucopyranose) octanoamide;
octadecylamine;
1-palmitoyl-2-stearoyl lecithin (HSPC);
mannitol;
cholesterol;
tartaric acid;
solid sodium bicarbonate particles.
The proliposome provided by the invention is characterized in that the weight ratio of N- (beta-D-glucopyranose) caprylamide to octadecylamine is (2-4): 1.
preferably, the weight ratio of N- (β -D-glucopyranosyl) octanoyl amide to octadecylamine is (2.2-3.8): 1; more preferably, the weight ratio of N- (β -D-glucopyranosyl) octanamide to octadecylamine is (2.5-3.5): 1; and, most preferably, the weight ratio of N- (β -D-glucopyranosyl) octanamide to octadecylamine is (2.8-3.2): 1.
in a specific embodiment, the weight ratio of N- (β -D-glucopyranosyl) octanamide to octadecylamine is 3: 1.
the proliposome provided by the invention is characterized in that the weight ratio of cefminox sodium to N- (beta-D-glucopyranose) octanamide is 1: (3.5-5.5).
Preferably, the weight ratio of the cefminox sodium to the N- (beta-D-glucopyranose) octanamide is 1: (3.8-5.2); more preferably, the weight ratio of cefminox sodium to N- (beta-D-glucopyranose) octanamide is 1: (4-5); and, most preferably, the weight ratio of cefminox sodium to N- (. beta. -D-glucopyranosyl) octanamide is 1: (4.2-4.8).
In a particular embodiment, the weight ratio of cefminox sodium to N- (β -D-glucopyranose) octanamide is 1: 4.5.
the proliposome provided by the invention is characterized in that the weight ratio of 1-palmitoyl-2-stearoyl lecithin to cholesterol is (0.4-2.6): 1.
preferably, the weight ratio of 1-palmitoyl-2-stearoyl lecithin to cholesterol is (0.6-2.4): 1; more preferably, the weight ratio of 1-palmitoyl-2-stearoyl lecithin to cholesterol is (0.8-2.2): 1; and, most preferably, the weight ratio of 1-palmitoyl-2-stearoyl lecithin to cholesterol is (1-2): 1.
in a specific embodiment, the weight ratio of 1-palmitoyl-2-stearoyl lecithin to cholesterol is 1.5: 1.
the proliposome provided by the invention is characterized in that the weight ratio of 1-palmitoyl-2-stearoyl lecithin to mannitol is (4.2-5.8): 1.
preferably, the weight ratio of 1-palmitoyl-2-stearoyl lecithin to mannitol is (4.5-5.5): 1; more preferably, the weight ratio of 1-palmitoyl-2-stearoyl lecithin to mannitol is (4.5-5.2): 1; and, most preferably, the weight ratio of 1-palmitoyl-2-stearoyl lecithin to mannitol is (4.8-5): 1.
in a specific embodiment, the weight ratio of 1-palmitoyl-2-stearoyl lecithin to mannitol is 4.93: 1.
the proliposome provided by the invention is characterized in that the weight ratio of tartaric acid to solid sodium bicarbonate particles is (3-7): 1.
preferably, the weight ratio of tartaric acid to solid sodium bicarbonate particles is (3.5-6.5): 1; more preferably, the weight ratio of tartaric acid to solid sodium bicarbonate particles is (4-6): 1; and, most preferably, the weight ratio of tartaric acid to solid sodium bicarbonate particles is (4.5-5.5): 1.
in a particular embodiment, the weight ratio of tartaric acid to solid sodium bicarbonate particles is 5: 1.
the proliposome provided by the invention is characterized in that the weight ratio of cefminox sodium to solid sodium bicarbonate particles is 1: (1-3).
Preferably, the weight ratio of cefminox sodium to solid sodium bicarbonate particles is 1: (1.2-2.8); more preferably, the weight ratio of cefminox sodium to solid sodium bicarbonate particles is 1: (1.5-2.5); and, most preferably, the weight ratio of cefminox sodium to solid sodium bicarbonate particles is 1: (1.8-2.2).
In a particular embodiment, the weight ratio of cefminox sodium to solid sodium bicarbonate particles is 1: 1.94.
the proliposome provided by the invention has the advantages that the particle size of solid sodium bicarbonate particles is 200-400 meshes, and the water content is less than 3.5%.
Preferably, the particle size of the solid sodium bicarbonate particles is 220-380 meshes, and the water content is less than 3 percent; more preferably, the particle size of the solid sodium bicarbonate particles is 240-360 meshes, and the water content is less than 2.5 percent; and, most preferably, the particle size of the solid sodium bicarbonate particles is 260-340 meshes, and the water content is less than 2%.
In one specific embodiment, the solid sodium bicarbonate particles have a particle size of 280-320 mesh and a water content of 1.7%.
In the present invention, the a-b mesh means that the solid particles can pass through the mesh of a mesh but cannot pass through the mesh of b mesh. For example, 200-400 mesh indicates that the solid particles can pass through a 200 mesh screen, but cannot pass through a 400 mesh screen.
The proliposome according to the present invention, wherein the raw materials comprise:
10 parts of cefminox sodium;
45 parts of N- (beta-D-glucopyranose) caprylamide;
15 parts of octadecylamine;
178.75 parts of 1-palmitoyl-2-stearoyl lecithin;
36.25 parts of mannitol;
118.75 parts of cholesterol;
96.875 parts of tartaric acid;
19.375 parts of solid sodium bicarbonate particles.
In another aspect, the present invention also provides a method for preparing the proliposome of the cefminox sodium compound, which comprises the following steps:
dissolving 1-palmitoyl-2-stearoyl lecithin, mannitol and cholesterol in a chloroform-ethanol mixed solvent;
adding cefminox sodium, N- (beta-D-glucopyranose) octanamide, octadecylamine and tartaric acid, and dissolving by ultrasonic;
adding solid sodium bicarbonate particles, and reacting for a certain time;
removing the solvent to obtain a solid substance;
curing the solid substance in a vacuum drier for 12-48h to obtain the proliposome.
The preparation method comprises the following steps of (2-4): 1.
the preparation method of the invention is characterized in that the reaction temperature is 35-65 DEGoAnd C, the reaction time is 30-150 min.
Preferably, the reaction temperature is 40-60 deg.CoC, the reaction time is 60-130 min; more preferably, the reaction temperature is from 45 to 55 deg.CoAnd C, the reaction time is 80-120 min.
In one embodiment, the reaction temperature is 50 deg.CoAnd C, the reaction time is 90 min.
Compared with the prior art, the liposome precursor of the cefminox sodium compound has better fluidity; while the drug encapsulation efficiency remains substantially unchanged after long-term storage (e.g., more than 3 months).
Detailed Description
It should be understood that the detailed description of the invention is merely illustrative of the spirit and principles of the invention and is not intended to limit the scope of the invention.
Example 1:
weighing raw materials of precursor liposome of cefminox sodium compound, which comprises the following steps:
80mg of cefminox sodium;
360mg of N- (. beta. -D-glucopyranose) octanoamide;
120mg of octadecylamine;
HSPC 1430mg；
290mg of mannitol;
cholesterol 950 mg;
775mg of tartaric acid; and the number of the first and second groups,
155mg of solid sodium bicarbonate particles. And crushing and classifying the solid sodium bicarbonate particles by using a medicinal ball mill to obtain solid sodium bicarbonate particles with the particle size of 280-320 meshes, and drying until the water content is less than 1.7%.
Prescribed amounts of HSPC, mannitol, and cholesterol were dissolved in 35mL volumes of 3: 1, chloroform-ethanol mixed solvent; adding cefminox sodium, N- (beta-D-glucopyranose) octanamide, octadecylamine and tartaric acid, and dissolving by ultrasonic.
Adding solid sodium bicarbonate particles to react for a certain time; the reaction temperature was 50 deg.CoAnd C, the reaction time is 90 min. Distilling under reduced pressure to remove the solvent to obtain a solid substance; the solid material was cured in a vacuum desiccator for 24h to give proliposomes.
The proliposome is accurately weighed and then placed in a penicillin bottle at 4oAnd C, storing in dark.
Comparative example 1:
no mannitol was added and the other conditions were the same as in example 1.
Comparative example 2:
the same procedure as in example 1 was repeated except that octadecylamine was replaced with the same weight of N- (. beta. -D-glucopyranosyl) octanamide.
Application examples
The fluidity is evaluated by adopting an angle of repose; the magnitude of the angle of repose was determined by the fixed cone method. A funnel is placed on an iron support, then solid powder is added into the funnel, the solid powder is injected into the center of a disc with a certain limited diameter until a product on the inclined edge of a solid powder accumulation layer automatically flows out along the edge of the disc, the solid powder addition is stopped, and at the moment, the included angle between a stack formed by the solid powder and a plane is the angle of repose (degree).
The proliposomes of cefminox sodium compound of example 1 and comparative examples 1-2 were precisely weighed and, after storage for 0 days and 3 months (90 days), respectively, according to a 1: 10 weight volume percent of 5wt% sodium bicarbonate solution is added; the solid substance was completely dissolved by sufficient shaking, and the pH was adjusted to 6.0 to obtain liposome suspensions of example 1 and comparative examples 1-2. The liposome suspensions obtained on day 0 and day 90 were tested for encapsulation efficiency and mean particle size, respectively.
Wherein, the encapsulation efficiency is calculated by adopting a high-speed centrifugation method according to the following formula: encapsulation efficiency = (total amount of drug-free drug weight)/total amount of drug × 100%. Wherein, the weight of the free drug is measured as follows: precisely measuring 0.1mL liposome suspension, placing in a centrifuge tube, adding 0.2mL physiological saline for dilution, centrifuging at 15000rpm for 30min, taking 0.1mL supernatant, diluting to reasonable times, taking physiological saline as blank, measuring absorbance at 215nm, and calculating free drug weight. The determination of the total amount of the drug is: precisely measuring 0.1mL of liposome suspension, placing in a centrifuge tube, adding 0.9mL, diluting with normal saline to a reasonable multiple, performing the same method operation for blank liposome, measuring absorbance, and calculating to obtain the total amount of the drug.
The particle size test was performed using a laser particle size analyzer.
The results of the relevant tests are shown in tables 1 and 2 below:
TABLE 1 Performance index at day 0
| Angle of repose/° | Encapsulation efficiency/% | Average particle diameter/. mu.m | |
| Example 1 | 34.8±1.1 | 70.5 | 0.98±0.15 |
| Comparative example 1 | 36.7±1.4 | 69.2 | 1.07±0.14 |
| Comparative example 2 | 40.3±1.2 | 71.6 | 1.05±0.11 |
TABLE 2 Performance index at day 90
| Encapsulation efficiency/% | Average particle diameter/. mu.m | |
| Example 1 | 68.9 | 1.06±0.19 |
| Comparative example 1 | 67.1 | 1.17±0.25 |
| Comparative example 2 | 69.3 | 1.19±0.23 |
As can be seen, the liposome precursor of the cefminox sodium compound of the embodiment of the invention has better fluidity (smaller angle of repose); while the drug encapsulation efficiency remains substantially unchanged after long-term storage (e.g., more than 3 months).
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention shall fall within the protection scope of the present invention.
Claims (10)
1. A proliposome of cefminox sodium compound is characterized in that the raw materials comprise:
cefminox sodium;
n- (β -D-glucopyranose) octanoamide;
octadecylamine;
1-palmitoyl-2-stearoyl lecithin;
mannitol;
cholesterol;
tartaric acid;
solid sodium bicarbonate particles.
2. The proliposome of claim 1, wherein the weight ratio of N- (β -D-glucopyranosyl) octanoamide to octadecylamine is (2-4): 1.
3. the proliposome of claim 1, wherein the weight ratio of cefminox sodium to N- (β -D-glucopyranose) octanamide is 1: (3.5-5.5).
4. The proliposome of claim 1, wherein the weight ratio of 1-palmitoyl-2-stearoyl lecithin to cholesterol is (0.4-2.6): 1.
5. the proliposome of claim 1, wherein the weight ratio of 1-palmitoyl-2-stearoyl lecithin to mannitol is (4.2-5.8): 1.
6. proliposome according to claim 1, wherein the weight ratio of tartaric acid to solid sodium bicarbonate particles is (3-7): 1.
7. the proliposome of claim 1, wherein the weight ratio of cefminox sodium to solid sodium bicarbonate particles is 1: (1-3).
8. The proliposome of claim 1, wherein the particle size of the solid sodium bicarbonate particles is 200-400 mesh, and the water content is less than 3.5%.
9. The proliposome of claim 1, wherein the starting material comprises:
10 parts of cefminox sodium;
45 parts of N- (beta-D-glucopyranose) caprylamide;
15 parts of octadecylamine;
178.75 parts of 1-palmitoyl-2-stearoyl lecithin;
36.25 parts of mannitol;
118.75 parts of cholesterol;
96.875 parts of tartaric acid;
19.375 parts of solid sodium bicarbonate particles.
10. A method for preparing a proliposome of the cefminox sodium compound of claim 1-9, which comprises:
dissolving 1-palmitoyl-2-stearoyl lecithin, mannitol and cholesterol in a chloroform-ethanol mixed solvent;
adding cefminox sodium, N- (beta-D-glucopyranose) octanamide, octadecylamine and tartaric acid, and dissolving by ultrasonic;
adding solid sodium bicarbonate particles, and reacting for a certain time;
removing the solvent to obtain a solid substance;
curing the solid substance in a vacuum drier for 12-48h to obtain the proliposome.
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