CN108815168B - Nano-emulsion preparation for resisting bacterial infection and preparation method and application thereof - Google Patents
Nano-emulsion preparation for resisting bacterial infection and preparation method and application thereof Download PDFInfo
- Publication number
- CN108815168B CN108815168B CN201810326723.9A CN201810326723A CN108815168B CN 108815168 B CN108815168 B CN 108815168B CN 201810326723 A CN201810326723 A CN 201810326723A CN 108815168 B CN108815168 B CN 108815168B
- Authority
- CN
- China
- Prior art keywords
- ceftiofur
- oil
- flunixin meglumine
- preparation
- nano
- 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.)
- Active
Links
- 239000007908 nanoemulsion Substances 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 208000022362 bacterial infectious disease Diseases 0.000 title claims abstract description 27
- 208000035143 Bacterial infection Diseases 0.000 title claims abstract description 23
- 238000003539 bacterial infection method Methods 0.000 title description 2
- 229960000469 flunixin meglumine Drugs 0.000 claims abstract description 63
- MGCCHNLNRBULBU-WZTVWXICSA-N flunixin meglumine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.C1=CC=C(C(F)(F)F)C(C)=C1NC1=NC=CC=C1C(O)=O MGCCHNLNRBULBU-WZTVWXICSA-N 0.000 claims abstract description 59
- 229960005229 ceftiofur Drugs 0.000 claims abstract description 46
- ZBHXIWJRIFEVQY-IHMPYVIRSA-N ceftiofur 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=1CSC(=O)C1=CC=CO1 ZBHXIWJRIFEVQY-IHMPYVIRSA-N 0.000 claims abstract description 46
- 235000015112 vegetable and seed oil Nutrition 0.000 claims abstract description 27
- 239000008158 vegetable oil Substances 0.000 claims abstract description 27
- 239000007864 aqueous solution Substances 0.000 claims abstract description 19
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 18
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000002156 mixing Methods 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003921 oil Substances 0.000 claims abstract description 6
- 235000019198 oils Nutrition 0.000 claims abstract description 6
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 6
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 8
- 238000009472 formulation Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000003549 soybean oil Substances 0.000 claims description 6
- 235000012424 soybean oil Nutrition 0.000 claims description 6
- 239000000839 emulsion Substances 0.000 claims description 4
- 235000019483 Peanut oil Nutrition 0.000 claims description 2
- 235000019484 Rapeseed oil Nutrition 0.000 claims description 2
- 239000010495 camellia oil Substances 0.000 claims description 2
- 239000003240 coconut oil Substances 0.000 claims description 2
- 235000019864 coconut oil Nutrition 0.000 claims description 2
- 235000005687 corn oil Nutrition 0.000 claims description 2
- 239000002285 corn oil Substances 0.000 claims description 2
- 235000012343 cottonseed oil Nutrition 0.000 claims description 2
- 239000002385 cottonseed oil Substances 0.000 claims description 2
- 239000004006 olive oil Substances 0.000 claims description 2
- 235000008390 olive oil Nutrition 0.000 claims description 2
- 239000000312 peanut oil Substances 0.000 claims description 2
- 239000008159 sesame oil Substances 0.000 claims description 2
- 235000011803 sesame oil Nutrition 0.000 claims description 2
- 235000020238 sunflower seed Nutrition 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 7
- 230000004054 inflammatory process Effects 0.000 abstract description 5
- 241000894006 Bacteria Species 0.000 abstract description 4
- 206010061218 Inflammation Diseases 0.000 abstract description 4
- 241001465754 Metazoa Species 0.000 abstract description 4
- 239000008267 milk Substances 0.000 abstract description 4
- 230000009471 action Effects 0.000 abstract description 3
- 235000013336 milk Nutrition 0.000 abstract description 3
- 210000004080 milk Anatomy 0.000 abstract description 3
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 241000699670 Mus sp. Species 0.000 description 12
- RFLHUYUQCKHUKS-JUODUXDSSA-M Ceftiofur sodium Chemical compound [Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC(=O)C1=CC=CO1 RFLHUYUQCKHUKS-JUODUXDSSA-M 0.000 description 11
- 229960004467 ceftiofur sodium Drugs 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- 239000002504 physiological saline solution Substances 0.000 description 6
- 229940124350 antibacterial drug Drugs 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 241000191967 Staphylococcus aureus Species 0.000 description 4
- 235000011187 glycerol Nutrition 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229940124599 anti-inflammatory drug Drugs 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 206010041925 Staphylococcal infections Diseases 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 210000000003 hoof Anatomy 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 208000015339 staphylococcus aureus infection Diseases 0.000 description 2
- RDEIXVOBVLKYNT-VQBXQJRRSA-N (2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(1-aminoethyl)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-5-methyl-4-(methylamino)oxane-3,5-diol;(2r,3r,4r,5r)-2-[(1s,2s,3r,4s,6r)-4,6-diamino-3-[(2r,3r,6s)-3-amino-6-(aminomethyl)oxan-2-yl]o Chemical compound OS(O)(=O)=O.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@@H](CN)O2)N)[C@@H](N)C[C@H]1N.O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC[C@H](O2)C(C)N)N)[C@@H](N)C[C@H]1N.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 RDEIXVOBVLKYNT-VQBXQJRRSA-N 0.000 description 1
- KKCMGMIPHDNPQL-YZPBMOCRSA-N (3r,4s,5s,6r,7r,9r,11r,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-7,12,13-trihydroxy-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione;2-hyd Chemical compound CC(O)C(O)=O.O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 KKCMGMIPHDNPQL-YZPBMOCRSA-N 0.000 description 1
- NRBJWZSFNGZBFQ-UHFFFAOYSA-N 1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-ylquinoline-3-carboxylic acid;2-hydroxypropanoic acid Chemical compound CC(O)C(O)=O.C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 NRBJWZSFNGZBFQ-UHFFFAOYSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 208000004145 Endometritis Diseases 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010039438 Salmonella Infections Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- FHNINJWBTRXEBC-UHFFFAOYSA-N Sudan III Chemical compound OC1=CC=C2C=CC=CC2=C1N=NC(C=C1)=CC=C1N=NC1=CC=CC=C1 FHNINJWBTRXEBC-UHFFFAOYSA-N 0.000 description 1
- 208000025609 Urogenital disease Diseases 0.000 description 1
- 206010046793 Uterine inflammation Diseases 0.000 description 1
- 206010046914 Vaginal infection Diseases 0.000 description 1
- 201000008100 Vaginitis Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- 229960001931 ampicillin sodium Drugs 0.000 description 1
- KLOHDWPABZXLGI-YWUHCJSESA-M ampicillin sodium Chemical compound [Na+].C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C([O-])=O)(C)C)=CC=CC=C1 KLOHDWPABZXLGI-YWUHCJSESA-M 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- FCPVYOBCFFNJFS-LQDWTQKMSA-M benzylpenicillin sodium Chemical compound [Na+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1 FCPVYOBCFFNJFS-LQDWTQKMSA-M 0.000 description 1
- 208000030270 breast disease Diseases 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- XMEVHPAGJVLHIG-FMZCEJRJSA-N chembl454950 Chemical compound [Cl-].C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H]([NH+](C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O XMEVHPAGJVLHIG-FMZCEJRJSA-N 0.000 description 1
- 229960004055 ciprofloxacin lactate Drugs 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000004815 dispersion polymer Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 231100000206 health hazard Toxicity 0.000 description 1
- POUMFISTNHIPTI-BOMBIWCESA-N hydron;(2s,4r)-n-[(1r,2r)-2-hydroxy-1-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]propyl]-1-methyl-4-propylpyrrolidine-2-carboxamide;chloride Chemical compound Cl.CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 POUMFISTNHIPTI-BOMBIWCESA-N 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229960001595 lincomycin hydrochloride Drugs 0.000 description 1
- 208000004396 mastitis Diseases 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000010773 plant oil Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 206010039447 salmonellosis Diseases 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Images
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
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives 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
- A61K47/44—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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a nano-emulsion preparation for resisting bacterial infection, which is prepared by the following steps: mixing Tween-80 and glycerol to obtain emulsifier; preparing ceftiofur-containing vegetable oil; preparing flunixin meglumine aqueous solution; the preparation method comprises the following steps of preparing a raw material of a milk preparation by using 8-15% of ceftiofur-containing vegetable oil, 35-45% of flunixin meglumine aqueous solution and the balance of an emulsifier, uniformly mixing the emulsifier and the ceftiofur-containing vegetable oil, and then adding the flunixin meglumine aqueous solution for mixing to obtain the bacterial infection resistant nano-milk preparation. The invention also provides the application of the nano-emulsion preparation in resisting bacterial infection. After the nano emulsion preparation is used for treating bacterial infection, flunixin meglumine in a water phase quickly enters a body to control inflammatory reaction caused by bacteria, ceftiofur in an oil phase is slowly released into an animal body to prolong the action time of an antibacterial agent, and the combination of the flunixin meglumine and the ceftiofur improves the treatment effect on bacterial infectious diseases.
Description
Technical Field
The invention relates to a nano-emulsion preparation for resisting bacterial infection and a preparation method thereof.
Background
Bacterial infections are a serious health hazard to humans and animals. According to foreign reports, the fatality rate of patients who live into ICU due to serious sepsis caused by bacterial infection reaches 18-50%. After pathogenic bacteria invade the body, inflammatory reaction is caused, and body tissues are damaged in the inflammatory process, so that various diseases are caused. For example, respiratory diseases (pneumonia, bronchitis, etc.), gastrointestinal diseases (diarrhea, enteritis, colibacillosis, salmonellosis), genitourinary diseases (cystitis, vaginitis, endometritis, metritis), soft tissue, skin and hoof diseases (hoof rot, wound, abscess, arthritis) and breast diseases (mastitis) and the like. For treating bacterial infectious diseases, anti-inflammatory drugs are used to inhibit inflammatory reactions and antibacterial drugs are used to eliminate invading bacteria. However, in practice, there are few therapeutic drugs having both anti-inflammatory and antibacterial effects. Moreover, for clinical convenience, drug molecules having antibacterial action are often modified into water-soluble salt molecules (e.g., penicillin sodium, ampicillin sodium, erythromycin lactate, ceftiofur sodium, tetracycline hydrochloride, gentamicin sulfate, lincomycin hydrochloride, ciprofloxacin lactate, etc.). But the salt antibacterial drug is absorbed and metabolized quickly after injection, the drug action time is short, and the clinical treatment effect is not ideal enough.
Disclosure of Invention
The invention aims to provide a nano-emulsion preparation for resisting bacterial infection and a preparation method and application thereof.
In order to solve the above technical problems, the present invention provides a method for preparing a nanoemulsion formulation (ceftiofur-flunixin meglumine nanoemulsion) against bacterial infection, comprising the following steps:
1) preparing an emulsifier: uniformly mixing tween-80 and glycerol in a weight ratio (W/W) of 2: 0.5-1.5 to obtain an emulsifier;
2) and preparing the ceftiofur-containing vegetable oil: dissolving ceftiofur in dimethyl sulfoxide, and then adding vegetable oil for mixing until the concentration of the dimethyl sulfoxide is adjusted to be 15-550 mg/mL, so as to obtain the vegetable oil containing ceftiofur;
remarking: the amount of dimethyl sulfoxide can only dissolve ceftiofur;
3) preparing a flunixin meglumine aqueous solution: dissolving flunixin meglumine in water to obtain a flunixin meglumine aqueous solution with the concentration of the flunixin meglumine of 65-325 mg/mL;
4) forming an emulsion preparation raw material by 8-15% of ceftiofur-containing vegetable oil, 35-45% of flunixin meglumine aqueous solution and the balance of emulsifier; the above% is volume%;
firstly, the emulsifier and the vegetable oil containing ceftiofur are mixed evenly, and then the aqueous solution of flunixin meglumine is added (slowly added) for mixing, thus obtaining the nano-emulsion preparation (which is clear and transparent nano-emulsion containing ceftiofur and flunixin meglumine) for resisting bacterial infection.
In the present invention: the content of the emulsifier is about 45-60%;
flunixin meglumine is a water-soluble anti-inflammatory drug, and ceftiofur is a water-insoluble antibacterial drug.
As an improvement of the preparation method of the nano-emulsion preparation for resisting bacterial infection of the invention: the vegetable oil is rapeseed oil, sesame oil, olive oil, sunflower seed oil, tea oil, coconut oil, cottonseed oil, soybean oil, corn oil or peanut oil.
The invention also provides a nano-emulsion preparation for resisting bacterial infection, which is prepared by the method.
The invention also provides the application of the nano-emulsion preparation prepared by the method in resisting bacterial infection; the bacteria are for example staphylococcus aureus.
The nanoemulsion preparation contains water-soluble anti-inflammatory drug flunixin meglumine and water-insoluble antibacterial drug ceftiofur, and also contains Tween-80 of 29-39%, glycerin of 12-22%, vegetable oil of 8-15% and water of 40-50%.
In the present invention, all the ingredients can be obtained by conventional commercial methods, for example, ceftiofur and flunixin meglumine are available from Wuhan Yuancheng Co-creation science and technology Co., Ltd, Qilu animal health products Co., Ltd, Tween-80, and glycerol are available from Shanghai Aladdin Biotechnology science and technology Co., Ltd.
The nano-emulsion preparation of the invention consists of two parts, namely an oil phase containing ceftiofur and a water phase containing flunixin meglumine. After the nano emulsion preparation is used for treating bacterial infection, flunixin meglumine in a water phase quickly enters a body to control inflammatory reaction caused by bacteria, ceftiofur in an oil phase is slowly released into an animal body to prolong the action time of an antibacterial agent, and the combination of the flunixin meglumine and the ceftiofur improves the treatment effect on bacterial infectious diseases. Moreover, after the antibacterial drugs are prepared into the nano-emulsion, the nano-emulsion is more uniformly distributed in vivo, and the treatment effect on bacterial infectious diseases is further improved.
Drawings
The following describes embodiments of the present invention in further detail with reference to the accompanying drawings.
FIG. 1 is a diagram showing the distribution of the particle size of ceftiofur-flunixin meglumine nanoemulsion.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
example 1 preparation of ceftiofur-flunixin meglumine nanoemulsion (nanoemulsion formulation against bacterial infections) the following steps were performed in sequence:
1) preparing an emulsifier: mixing Tween-80 and glycerol at a ratio of 2:1(W/W) to obtain emulsifier;
2) and preparing the ceftiofur-containing vegetable oil: dissolving ceftiofur in dimethyl sulfoxide (the amount of dimethyl sulfoxide can only dissolve ceftiofur), adding vegetable oil, and mixing until the concentration of ceftiofur is adjusted to 300mg/mL to obtain the vegetable oil containing ceftiofur;
the types of vegetable oils are specifically as described in table 1 below.
3) Preparing a flunixin meglumine aqueous solution: dissolving flunixin meglumine in water to obtain a flunixin meglumine aqueous solution with the concentration of the flunixin meglumine of 131.7 mg/mL;
4) forming an emulsion preparation raw material by 9% of ceftiofur-containing vegetable oil, 41% of flunixin meglumine aqueous solution and an emulsifier as the balance (namely, 50%); the above% is volume%;
namely, firstly, 50mL of emulsifier and 9mL of ceftiofur-containing vegetable oil are mixed uniformly to obtain 59mL of mixed liquid; then adding (slowly adding for about 2-3 minutes) 41mL of flunixin meglumine aqueous solution, and uniformly mixing (stirring for about 1-2 minutes); 100ml of nano-emulsion preparation (clear and transparent nano-emulsion containing ceftiofur and flunixin meglumine) for resisting bacterial infection is obtained.
Each milliliter of nanoemulsion contains 27mg of ceftiofur and 54mg of flunixin meglumine.
TABLE 1 ratio of ingredients contained in nanoemulsion (%)
The character detection result of the nano-emulsion (nano-emulsion preparation) is as follows:
the prepared nano-emulsion is a light yellow clear liquid. The hydrophilic dye methylene blue is diffused rapidly in the nano-emulsion, while the hydrophobic dye Sudan red III is not diffused basically in the nano-emulsion, which indicates that the emulsion is oil-in-water type; diluting the nano-emulsion by 5-40 times with water, and avoiding turbidity and layering; after being sterilized by high-pressure steam at the temperature of 121 ℃ for 15min, the liquid is placed at room temperature, the color of the liquid is obviously deepened and becomes turbid, which indicates that the high-pressure sterilization cannot be tolerated; after centrifugation at 12000rpm for 15min, the liquid has no demixing and precipitation; a viscosity of 371 mPa.S at 20 ℃ (NDJ-8S type rotational viscometer, geological instruments of Shanghai Changji Co., Ltd.); the mean particle size of the oil droplets in the nanoemulsion was found to be 60.14nm and the polymer dispersion coefficient (PDI) was 0.161(Nano ZS model nanosized potential Analyzer, Markov instruments, England) at 25 ℃ as shown in FIG. 1.
1. Staphylococcus aureus infected mice
Female ICR mice (18-22 g) were randomized into 7 groups of 30 mice each. Each mouse was injected intraperitoneally with 0.4mL of Staphylococcus aureus (ATCC 25923) suspension (5X 10)9CFU). After 3 hours, the mice had symptoms of lassitude, clattering, shortness of breath, rough mouse hair and the like.
2. Medicine
Liquid A: containing ceftiofur Sodium (SC) (molecular formula: C)19H16N5NaO7S3(ii) a Molecular weight: 545.54) and Flunixin Meglumine (FM) (molecular formula: c21H28F3N3O7(ii) a Molecular weight: 491.46) in saline. 140.7mg of ceftiofur sodium and 540mg of flunixin meglumine are dissolved in 100mL of physiological saline, mixed evenly and filtered (0.22 mu m) for sterilization to obtain a physiological saline solution containing ceftiofur sodium and flunixin meglumine, wherein each milliliter of the physiological saline solution contains 1.41mg of ceftiofur sodium (equivalent to 2.58 mu moL) and 5.4mg of flunixin meglumine (equivalent to 10.99 mu moL).
B, liquid B: a physiological saline solution containing ceftiofur Sodium (SC) and Flunixin Meglumine (FM). 281.3mg of ceftiofur sodium and 540mg of flunixin meglumine are dissolved in 100mL of physiological saline, mixed evenly and filtered (0.22 mu m) for sterilization, so that a physiological saline solution containing ceftiofur sodium and flunixin meglumine is obtained, and each milliliter of the solution contains 2.81mg of ceftiofur sodium (equivalent to 5.16 mu moL) and 5.4mg of flunixin meglumine (equivalent to 10.99 mu moL).
And C, liquid C: containing ceftiofur (molecular formula: C)19H17N5O7S3(ii) a Molecular weight: 523.56) and flunixin meglumine. Formulation method referring to example 1, the vegetable oil was soybean oil containing 1.35mg (equivalent to 2.58. mu. moL) of ceftiofur and 5.4mg (equivalent to 10.99. mu. moL) of flunixin meglumine per ml of nanoemulsion.
Namely: with respect to example 1: changing the step 4) into a method that 9 percent of vegetable oil containing ceftiofur (the concentration of ceftiofur is 15mg/mL), 41 percent of flunixin meglumine aqueous solution (the concentration of flunixin meglumine is 131.7mg/mL) and the balance (namely 50 percent) of emulsifier form milk preparation raw materials; the rest is equivalent to embodiment 1.
D, liquid: a nanoemulsion containing ceftiofur and flunixin meglumine. The preparation method is the same as that of example 1, the vegetable oil is soybean oil, and each milliliter of the nanoemulsion contains 2.7mg of ceftiofur (equivalent to 5.16 mu moL) and 5.4mg of flunixin meglumine (equivalent to 10.99 mu moL).
Namely: with respect to example 1: changing the step 4) into a method that 9 percent of plant oil containing ceftiofur (the concentration of ceftiofur is 30mg/mL), 41 percent of flunixin meglumine aqueous solution (the concentration of flunixin meglumine is 131.7mg/mL) and the balance (namely 50 percent) of emulsifier form milk preparation raw materials; the rest is equivalent to embodiment 1.
E, liquid E: comprising only ceftiofur (formula: C)19H17N5O7S3(ii) a Molecular weight: 523.56). Preparation method referring to example 1, the vegetable oil is soybean oil, and each milliliter of the nanoemulsion contains 38.20 mu moL of ceftiofur and 0 mu moL of flunixin meglumine.
Liquid preparation: nanoemulsion containing flunixin meglumine alone. Preparation method referring to example 1, the vegetable oil is soybean oil, and each milliliter of the nanoemulsion contains 0 mu moL of ceftiofur and 81.39 mu moL of flunixin meglumine.
3. Treatment of
3 hours after staphylococcus aureus infection, Ceftiofur Nanoemulsion (CNE) + Flunixin Meglumine (FM), ceftiofur Sodium (SC) + Flunixin Meglumine (FM) aqueous solution or normal saline (CS dosage is calculated according to CNE) is injected into each mouse 1 time, and the dosages of each group are shown in table 2. The mortality of each group of mice was recorded within 120h after infection.
TABLE 2 drug treatment methods for groups of mice
3. Therapeutic results
As shown in table 3, the survival rate of the mice in the saline group was only 2, 6.7%; in groups 1 and 3, although the dosages of the two groups of medicines are the same, the group 1 medicine is an aqua, 18 surviving mice survive, and the survival rate is 60 percent; the group 3 medicament is nanoemulsion, 22 mice survive, and the survival rate is 73.3%; the surviving mice of groups 2 and 4 were 21 and 26, respectively, and the survival rates were 70% and 86.6%, respectively. This result indicates that the effect of ceftiofur/flunixin meglumine nanoemulsion on treating staphylococcus aureus infection is superior to the effect of ceftiofur sodium/flunixin meglumine aqueous solution.
TABLE 3 surviving mice (only)
Finally, it is also noted that the above-mentioned lists merely illustrate a few specific embodiments of the invention. It is obvious that the invention is not limited to the above embodiments, but that many variations are possible. All modifications which can be derived or suggested by a person skilled in the art from the disclosure of the present invention are to be considered within the scope of the invention.
Claims (4)
1. The preparation method of the nano-emulsion preparation for resisting bacterial infection is characterized by comprising the following steps:
1) preparing an emulsifier: uniformly mixing tween-80 and glycerol in a weight ratio of 2: 0.5-1.5 to obtain an emulsifier;
2) and preparing the ceftiofur-containing vegetable oil: dissolving ceftiofur in dimethyl sulfoxide, and then adding vegetable oil for mixing until the concentration of the dimethyl sulfoxide is adjusted to be 15-550 mg/mL and the concentration of the ceftiofur is adjusted to be 300mg/mL, so as to obtain the vegetable oil containing ceftiofur;
3) preparing a flunixin meglumine aqueous solution: dissolving flunixin meglumine in water to obtain a flunixin meglumine aqueous solution with the concentration of the flunixin meglumine of 131.7 mg/mL;
4) forming an emulsion preparation raw material by 8-15% of ceftiofur-containing vegetable oil, 35-45% of flunixin meglumine aqueous solution and the balance of emulsifier; the above% is volume%;
firstly, the emulsifier and the vegetable oil containing ceftiofur are mixed evenly, and then the flunixin meglumine aqueous solution is added for mixing, thus obtaining the nano-emulsion preparation for resisting bacterial infection.
2. The method of preparing a nanoemulsion formulation for combating bacterial infections according to claim 1, wherein: the vegetable oil is rapeseed oil, sesame oil, olive oil, sunflower seed oil, tea oil, coconut oil, cottonseed oil, soybean oil, corn oil or peanut oil.
3. A nanoemulsion formulation against bacterial infections, prepared by the process according to claim 1 or 2.
4. Use of a nanoemulsion formulation prepared according to the method of claim 1 or 2 in the preparation of a medicament for combating bacterial infections.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810326723.9A CN108815168B (en) | 2018-04-12 | 2018-04-12 | Nano-emulsion preparation for resisting bacterial infection and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810326723.9A CN108815168B (en) | 2018-04-12 | 2018-04-12 | Nano-emulsion preparation for resisting bacterial infection and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108815168A CN108815168A (en) | 2018-11-16 |
| CN108815168B true CN108815168B (en) | 2021-02-12 |
Family
ID=64155380
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810326723.9A Active CN108815168B (en) | 2018-04-12 | 2018-04-12 | Nano-emulsion preparation for resisting bacterial infection and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108815168B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109568316A (en) * | 2018-12-19 | 2019-04-05 | 南京农业大学 | Compound long-acting injection and preparation method thereof containing Ceftiofur and Flunixin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1600371A (en) * | 2003-09-22 | 2005-03-30 | 王玉万 | Preparing pharmaceutics of medication containing antimicrobials by using silicone oil as medium |
| CN102106857A (en) * | 2009-12-29 | 2011-06-29 | 齐鲁动物保健品有限公司 | Compound ceftiofur sodium freeze-dried power injection used for injection |
-
2018
- 2018-04-12 CN CN201810326723.9A patent/CN108815168B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1600371A (en) * | 2003-09-22 | 2005-03-30 | 王玉万 | Preparing pharmaceutics of medication containing antimicrobials by using silicone oil as medium |
| CN102106857A (en) * | 2009-12-29 | 2011-06-29 | 齐鲁动物保健品有限公司 | Compound ceftiofur sodium freeze-dried power injection used for injection |
Non-Patent Citations (2)
| Title |
|---|
| EVALUATION OF HYPERTONIC SALINE SOLUTION IN COMBINATION WITH CEFTIOFUR HCL AND FLUNIXINMEGLUMINE IN THE TREATMENT OF HAEMORRHAGIC SEPTICAEMIA IN BUFFALOES;Zafar, MA等;《JOURNAL OF ANIMAL AND PLANT SCIENCES》;20121231;第22卷;第190-195页 * |
| 兽用抗菌药复方注射剂研制进展;董梦晓等;《中国抗生素杂志》;20171031;第42卷(第10期);第880-890页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108815168A (en) | 2018-11-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100861820B1 (en) | Propofol Formulation With Enhanced Microbial Characteristics | |
| AU2010310258B2 (en) | Pharmaceutical solution of taxanes comprising pH regulator and preparation method thereof | |
| JP6618475B2 (en) | Materials and methods related to stabilized polymeric silicate compositions | |
| CN102058821A (en) | Application of tsaoko oil in preparation of medicament for treating bacterial infection diseases | |
| CN101209307A (en) | Chinese medicinal oral liquid with heat-clearing and detoxication, dampness-eliminating and dysentery-stopping efficacy | |
| Ling et al. | Preparation, characterization, and pharmacokinetics of tilmicosin‐and florfenicol‐loaded hydrogenated castor oil‐solid lipid nanoparticles | |
| CN108815168B (en) | Nano-emulsion preparation for resisting bacterial infection and preparation method and application thereof | |
| CN102058660B (en) | Application of patchouli oil in preparing drugs for treating bacterial infectious diseases | |
| CN103142990B (en) | Medicine for treating animal bacterial diseases and preparation method thereof | |
| CN101987105A (en) | Compound preparation for treating diseases caused by poultry sensitive bacteria and preparation method thereof | |
| WO2014091078A1 (en) | Polymeric particles-based temozolomide dosage form | |
| CN111514157A (en) | Application of composition in preparation of veterinary anti-parasitic drug, veterinary anti-parasitic transdermal solution and preparation method thereof | |
| CN102600304A (en) | Nanoemulsion composition for treating mycoplasma pneumonia of livestock and preparation method of nanoemulsion composition | |
| CN101874774A (en) | Suspension composition containing lysozyme and florfenicol and preparation method thereof | |
| JP5568114B2 (en) | Pharmaceutical composition for preparing an infusion of an antibacterial preparation, and method for producing the same | |
| CN102697725B (en) | Veterinary ciprofloxacin lactate injection and preparation method thereof | |
| Ayoob et al. | Preparation, characterization and in vitro toxicity study of antiparasitic drugs loaded onto functionalized MWCNTs | |
| CA2706264C (en) | Propofol transparent anesthetic solution, with low venous irritation threshold | |
| CN108670948A (en) | A kind of nanoscale micro-capsule unimolecule Betagen Solution and preparation method thereof | |
| CN108403631A (en) | Ten thousand rhzomorph oil mixed suspension injections of tartaric acid Thailand and preparation method thereof | |
| CN109431999B (en) | Nano self-microemulsion, veterinary drug nano self-microemulsion and preparation method and application thereof | |
| CN102813909A (en) | Compound doxycycline hydrochloride composition for preventing and treating colibacillosis and chronic respiratory disease of poultry as well as preparation method thereof | |
| El-Sherbiny et al. | Nanoemulsion of cinnamon oil to combat colistin-resistant Klebsiella pneumoniae and cancer cells | |
| CN1151782C (en) | A medicinal injection for inducing and maintaining anesthesia and tranquilizing of mammals | |
| CN1278676C (en) | Curcumin injection and method for preparing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |