CN112353765B - Preparation method of ceftiofur microspheres - Google Patents
Preparation method of ceftiofur microspheres Download PDFInfo
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- 229960005229 ceftiofur Drugs 0.000 title claims abstract description 63
- 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 title claims abstract description 63
- 239000004005 microsphere Substances 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000003756 stirring Methods 0.000 claims abstract description 27
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 26
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 26
- 239000000839 emulsion Substances 0.000 claims abstract description 25
- 239000012876 carrier material Substances 0.000 claims abstract description 21
- 239000003960 organic solvent Substances 0.000 claims abstract description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 229920001400 block copolymer Polymers 0.000 claims abstract description 15
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 9
- 230000001804 emulsifying effect Effects 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 7
- 230000001502 supplementing effect Effects 0.000 claims abstract description 7
- 238000005406 washing Methods 0.000 claims abstract description 7
- 238000001291 vacuum drying Methods 0.000 claims abstract description 6
- 229920000136 polysorbate Polymers 0.000 claims description 18
- 239000004626 polylactic acid Substances 0.000 claims description 15
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 239000000273 veterinary drug Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 38
- 229940079593 drug Drugs 0.000 abstract description 21
- 239000002245 particle Substances 0.000 abstract description 10
- 238000013268 sustained release Methods 0.000 abstract description 9
- 239000012730 sustained-release form Substances 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 7
- 238000011068 loading method Methods 0.000 abstract description 6
- 238000005516 engineering process Methods 0.000 abstract description 4
- 239000006185 dispersion Substances 0.000 abstract description 2
- 230000000857 drug effect Effects 0.000 abstract description 2
- 230000002045 lasting effect Effects 0.000 abstract description 2
- 230000035515 penetration Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000000338 in vitro Methods 0.000 description 9
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 238000005538 encapsulation Methods 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- KEQFDTJEEQKVLM-JUODUXDSSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-(furan-2-carbonylsulfanylmethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydron;chloride Chemical compound Cl.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 KEQFDTJEEQKVLM-JUODUXDSSA-N 0.000 description 1
- 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 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229960001356 ceftiofur hydrochloride Drugs 0.000 description 1
- 229960004467 ceftiofur sodium Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000001261 hydroxy acids Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940041007 third-generation cephalosporins Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000002699 waste material Substances 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
- A61K9/14—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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- 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
- 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
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- 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)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of ceftiofur microspheres, which relates to the field of veterinary medicines and comprises the following steps: step 1, dissolving polylactic acid-polyethylene glycol block copolymer serving as a carrier material in an organic solvent; step 2, adding ceftiofur, stirring and mixing to prepare a dispersed phase; step 3, adding the dispersed phase into water, adding an emulsifier, and magnetically stirring and emulsifying to obtain an emulsion; step 4, rapidly stirring the emulsion for a period of time T1, supplementing water, and continuously stirring for a period of time T2 until the organic solvent is completely volatilized; and step 5, centrifuging, washing, collecting and vacuum drying to obtain the ceftiofur microsphere. The ceftiofur sustained-release microspheres enable the drug to be more uniformly dispersed in the carrier material, the drug loading is high, the nano-scale microsphere technology reduces the dispersion system of drug particles, and the ceftiofur sustained-release microspheres have better needle penetration, so that the drug has stronger sustained-release effect and longer lasting drug effect.
Description
Technical Field
The invention relates to the field of veterinary drugs, in particular to a preparation method of ceftiofur microspheres.
Background
Ceftiofur is a special 3 rd generation cephalosporin for animals, and has the characteristics of strong antibacterial activity, wide antibacterial spectrum, excellent pharmacokinetic characteristics, small toxic and side effects, low residue and the like, so the ceftiofur is widely applied all over the world.
At present, ceftiofur related preparations on the market in China mainly comprise ceftiofur injection, ceftiofur sodium powder injection, ceftiofur hydrochloride injection and the like, and because ceftiofur is not well absorbed by oral administration, the use method is mainly injection, and multiple injections are needed for achieving effective treatment concentration, generally one time a day and 3 to 5 days for continuous use, so that great inconvenience exists in the clinical application process. In order to reduce the animal stress reaction caused by frequent injection of ceftiofur and reduce the waste of manpower and financial resources in a farm, it is necessary to develop a high-efficiency and long-acting ceftiofur preparation with convenient administration.
The new technology of microencapsulation as a medicinal preparation has been widely researched, and the new dosage form prepared by applying the microspheres to a carrier of a medicament has many incomparable advantages compared with the traditional preparation, and has obvious effects on covering bad smell and taste of the medicament, prolonging medicament effect, reducing toxicity, and improving activity and bioavailability. Polyesters are the most studied and widely used biodegradable synthetic polymers to date, and they are essentially polymers of hydroxy acids or lactones thereof. The biodegradable medical polymer auxiliary material refers to various medical polymer materials which can be biodegraded but are not easy to dissolve in water, and includes but is not limited to one or a mixture of two or more of polylactic acid, polylactic acid-glycolic acid copolymer, polylactic acid-polyethylene glycol block copolymer (PLA-PEG), polyethylene glycol, polyhydroxybutyrate-hydroxyvalerate copolymer, polyglycolic acid-polyethylene glycol, and the like. Polylactic acid (PLA) and polylactic glycolic acid (PLGA) are widely used polymers at present, and a microsphere drug delivery system is used for encapsulating drugs such as hormone, analgesia, anti-tumor, antibiotic, protein, polypeptide and the like, so that the obvious clinical curative effect is obtained.
The PLA microspheres are not favorable for the release of insoluble drugs due to strong hydrophobicity. For the above reasons, the applicant modified the chemical structure of PLA, increasing the hydrophilicity of the polymer, and decreasing the concentration of lactic acid and its oligomers in the microenvironment in direct contact with the drug.
Disclosure of Invention
The invention adopts the following technical scheme: a preparation method of ceftiofur microspheres comprises the following steps:
step 1, dissolving polylactic acid-polyethylene glycol block copolymer serving as a carrier material in an organic solvent;
step 2, adding ceftiofur, stirring and mixing to prepare a dispersed phase;
step 3, adding the dispersed phase into water, adding an emulsifier, and magnetically stirring and emulsifying to obtain an emulsion;
step 4, rapidly stirring the emulsion for a period of time T1, supplementing water, and continuously stirring for a period of time T2 until the organic solvent is completely volatilized;
and step 5, centrifuging, washing, collecting and vacuum drying to obtain the ceftiofur microsphere.
Preferably, the mass percentage of the carrier material to ceftiofur is 1:1 to 10.
Preferably, the emulsifier comprises tween and/or mono decanoate.
Preferably, the volume ratio of the dispersed phase to the continuous phase of the emulsion is 1:5 to 10.
Preferably, the T1 is 0.5-1 h, and the T2 is 2-4 h.
Preferably, the room-temperature vacuum drying time is 10-12 h.
Preferably, the molecular weight of the polylactic acid in the polylactic acid-polyethylene glycol block copolymer is 5000-10000.
Preferably, the molecular weight of polyethylene glycol in the polylactic acid-polyethylene glycol block copolymer is 750-1000.
Preferably, the weight ratio of the polyethylene glycol to the polylactic acid block in the polylactic acid-polyethylene glycol block copolymer is 1:5 to 10.
Preferably, the continuous phase of the emulsion is a mixed aqueous solution of tween and monodecanoate, the concentration of tween is 0.1-3.5% (g/ml), and the concentration of monodecanoate is 0.01-0.5% (g/ml).
The ceftiofur sustained-release microsphere has high stability, reduces a dispersion system of drug particles and has better needle penetration. The nano-scale microsphere technology enables the drug to have stronger sustained-release effect and longer lasting drug effect. Has targeting affinity for lung cells, and has higher drug concentration in lung compared with similar drugs after entering into body. Thereby being applicable to the sterilization and the inflammation diminishing of respiratory diseases of livestock and pets. The technology of the invention enables the medicine to be more uniformly dispersed in the carrier material, and the medicine carrying amount is high. The preparation method is simple, low in energy consumption and suitable for mass production. The degradation product of the polylactic acid-polyethylene glycol block copolymer in vivo has good biocompatibility, and is finally discharged out of the body completely without accumulation after long-term use.
Detailed Description
The present invention will be further described with reference to the following examples.
The components, materials and the like referred to in the following examples are, unless otherwise specified, conventional components, materials and the like known in the art, and are commercially available in normal forms.
The first embodiment is as follows: a preparation method of ceftiofur microspheres comprises the steps of dissolving polylactic acid-polyethylene glycol block copolymer serving as a carrier material in an organic solvent, dispersing medicine ceftiofur in a carrier material solution, and fully mixing the medicine ceftiofur in an ultrasonic wave manner to prepare a dispersed phase, wherein the mass percentages of the carrier material and the medicine ceftiofur are 1: 5. adding the dispersed phase into water at 25 ℃, adding Tween as an emulsifier, stirring at constant temperature and magnetic force, fully emulsifying at the rotating speed of 3000rpm to obtain O/W (O: represents oil phase; W: represents water phase) type emulsion, wherein the volume ratio of the dispersed phase to the continuous phase is 1: 10; and quickly stirring the emulsion at the temperature of 40 ℃ for 1 hour to evaporate part of the organic solvent, supplementing a proper amount of water into the emulsion to quickly extract the primarily dried microspheres to form hard films, continuously stirring the emulsion for 3 hours at the temperature of 25 ℃ until the organic solvent is completely volatilized, and then centrifuging, washing, collecting and drying in vacuum at room temperature for 12 hours to obtain the ceftiofur sustained-release microspheres.
The polylactic acid-polyethylene glycol block copolymer is composed of blocks, the Molecular Weight (MW) of the polylactic acid is 5000-10000, the MW of the polyethylene glycol is 750-1000, and the weight ratio of the polyethylene glycol to the polylactic acid blocks is 1:5 to 10.
The organic solvent is ethyl acetate, dichloromethane mixed solution and methanol, and the volume percentage is 80: 20.
the continuous phase is Tween aqueous solution, wherein the concentration of Tween is 2% (g/ml), and the dropping speed of the dispersed phase to the continuous phase is 10 ml/min.
The indexes of the ceftiofur microsphere prepared by the method are determined as follows: the average particle size of the microspheres is 12.75 microns, and the particle size of more than 90% of the microspheres is 10-18 microns. The electron microscope shows that the cefathilofur sustained-release tablet is of a regular spherical structure, the drug loading rate reaches 81.3 percent, the encapsulation rate reaches 24.8 percent, and the in vitro drug release rate is determined, so that the ceftiofur can be slowly released in vitro for 17 days.
Example two: a preparation method of ceftiofur microspheres comprises the steps of dissolving polylactic acid-polyethylene glycol block copolymer serving as a carrier material in an organic solvent, dispersing medicine ceftiofur in a carrier material solution, and fully mixing the medicine ceftiofur in an ultrasonic wave manner to prepare a dispersed phase, wherein the mass percentages of the carrier material and the medicine ceftiofur are 1: 10. adding the dispersed phase into water at the temperature of 25 ℃, adding Tween and monodecanoate serving as an emulsifier, stirring by magnetic force at constant temperature, fully emulsifying at the rotating speed of 2000rpm to obtain O/W (O: represents an oil phase; W: represents a water phase) type emulsion, wherein the volume ratio of the dispersed phase to the continuous phase is 1: 5; and quickly stirring the emulsion at the temperature of 40 ℃ for 1 hour to evaporate part of the organic solvent, supplementing a proper amount of water into the emulsion to quickly extract the primarily dried microspheres to form hard films, continuously stirring the emulsion for 3 hours at the temperature of 25 ℃ until the organic solvent is completely volatilized, and then centrifuging, washing, collecting and drying in vacuum at room temperature for 10 hours to obtain the ceftiofur sustained-release microspheres.
PLA-PEG each block constitutes, and polylactic acid MW is 5000 ~ 10000, and polyethylene glycol MW is 750 ~ 1000, and polyethylene glycol and polylactic acid block weight ratio is 1:5 to 10.
The organic solvent is ethyl acetate, dichloromethane mixed solution and methanol, and the volume percentage is 80: 20.
the continuous phase is mixed aqueous solution of tween and monodecanoate, wherein the concentration of tween is 1.5% (g/ml) and the concentration of monodecanoate is 0.2% (g/ml). The dropping speed of the dispersed phase to the continuous phase was 10 ml/min.
The indexes of the ceftiofur microsphere prepared by the method are determined as follows: the average particle size of the microspheres is 11.13 microns, and the particle size of more than 95 percent of the microspheres is 7-15 microns. The electron microscope shows that the cefathilofur has a regular spherical structure, the drug loading rate reaches 84.7 percent, the encapsulation rate reaches 26.8 percent, and the in vitro drug release rate is determined, so that the ceftiofur can be slowly released in vitro for 17 days.
Example three: a preparation method of ceftiofur microspheres comprises the steps of dissolving polylactic acid-polyethylene glycol block copolymer serving as a carrier material in an organic solvent, dispersing medicine ceftiofur in a carrier material solution, and fully mixing the medicine ceftiofur in an ultrasonic wave manner to prepare a dispersed phase, wherein the mass percentages of the carrier material and the medicine ceftiofur are 1: 10. adding the dispersed phase into water at the temperature of 25 ℃, adding Tween as an emulsifier, stirring at constant temperature without magnetic machinery, and fully emulsifying at the rotating speed of 3000rpm to obtain O/W (O: represents an oil phase; W: represents a water phase) type emulsion, wherein the volume ratio of the dispersed phase to the continuous phase is 1: 5; and quickly stirring the emulsion at the temperature of 40 ℃ for 1 hour to evaporate part of the organic solvent, supplementing a proper amount of water into the emulsion to quickly extract the primarily dried microspheres to form hard films, continuously stirring the emulsion for 3 hours at the temperature of 25 ℃ until the organic solvent is completely volatilized, and then centrifuging, washing, collecting and drying in vacuum at room temperature for 10 hours to obtain the ceftiofur sustained-release microspheres.
PLA-PEG each block constitutes, and polylactic acid MW is 5000 ~ 10000, and polyethylene glycol MW is 750 ~ 1000, and polyethylene glycol and polylactic acid block weight ratio is 1:5 to 10.
The organic solvent is ethyl acetate, dichloromethane mixed solution and methanol, and the volume percentage is 80: 20.
the continuous phase is Tween aqueous solution, wherein the concentration of Tween is 3% (g/ml), and the dripping speed of the disperse phase to the continuous phase is 10 ml/min.
The indexes of the ceftiofur microsphere prepared by the method are determined as follows: the average particle size of the microspheres is 12.67 microns, and the particle size of more than 90% of the microspheres is 7-18 microns. The electron microscope shows that the ceftiofur is a regular spherical structure, the drug loading rate reaches 80.9 percent, the encapsulation rate reaches 24.6 percent, and the ceftiofur can be slowly released in vitro for 17 days by in vitro drug release rate measurement.
Comparative example: a preparation method of ceftiofur microspheres comprises the steps of dissolving PLA (MW is 20000) as a carrier material in an organic solvent, dispersing medicine ceftiofur in a carrier material solution, and fully mixing the medicine ceftiofur by ultrasonic waves to prepare a dispersed phase, wherein the mass percentage of the carrier material to the medicine ceftiofur is 1: 10. adding the dispersed phase into water at the temperature of 25 ℃, adding Tween and monodecanoate serving as an emulsifier, stirring by magnetic force at constant temperature, fully emulsifying at the rotation speed of 5000rpm to obtain O/W (O: represents an oil phase; W: represents a water phase) type emulsion, wherein the volume ratio of the dispersed phase to the continuous phase is 1: 5; and rapidly stirring the emulsion for 1h at the temperature of 40 ℃ until the microspheres are rapidly extracted to form hard films, then continuously stirring the emulsion for 2h at the temperature of 25 ℃ until the organic solvent is completely volatilized, and then centrifuging, washing, collecting and vacuum-drying at room temperature for 10h to obtain the ceftiofur sustained-release microspheres.
The organic solvent is ethyl acetate, dichloromethane mixed solution and methanol, and the volume percentage is 80: 20.
the continuous phase is mixed aqueous solution of tween and monodecanoate, wherein the concentration of tween is 1.5% (g/ml) and the concentration of monodecanoate is 0.2% (g/ml). The dropping speed of the dispersed phase to the continuous phase was 10 ml/min.
The indexes of the ceftiofur microsphere prepared by the method are determined as follows: the average particle size of the microspheres is 13.98 microns, and the particle size of more than 90% of the microspheres is 8-20 microns. The electron microscope shows that the ceftiofur is a regular spherical structure, the drug loading rate reaches 22.5 percent, the encapsulation rate reaches 78.2 percent, and the ceftiofur can be slowly released for 15 days in vitro by in vitro drug release rate measurement.
From the test results of the above examples and comparative examples, it can be seen that the drug loading and encapsulation efficiency of the ceftiofur microsphere prepared by using the polylactic acid-polyethylene glycol block copolymer as the carrier material are significantly improved compared with that of using PLA as the carrier material, and the magnetic stirring and the mixed aqueous solution of Tween and monodecanoate as the continuous phase are particularly preferred. Meanwhile, compared with the mode of stirring and drying all the time, the mode of stirring, water supplementing and stirring intermittent drying is adopted to obtain the microspheres with better balling performance and longer in-vitro release time.
Claims (8)
1. A preparation method of ceftiofur microspheres is characterized by comprising the following steps:
step 1, taking polylactic acid-polyethylene glycol block copolymer as a carrier material to be dissolved in an organic solvent;
step 2, adding ceftiofur, stirring and mixing to prepare a dispersed phase;
step 3, adding the dispersed phase into water, adding an emulsifier, wherein the emulsifier comprises Tween and monodecanoate, and magnetically stirring and emulsifying to obtain an emulsion; the continuous phase of the emulsion is a mixed aqueous solution of tween and monodecanoate;
step 4, rapidly stirring the emulsion for a period of time T1, supplementing water, and continuously stirring for a period of time T2 until the organic solvent is completely volatilized;
and step 5, centrifuging, washing, collecting and vacuum drying to obtain the ceftiofur microsphere.
2. The method for preparing ceftiofur microspheres according to claim 1, wherein the mass percentage of the carrier material to ceftiofur is 1:1 to 10.
3. The method of preparing ceftiofur microspheres according to claim 1, wherein the volume ratio of the dispersed phase to the continuous phase of the emulsion is 1:5 to 10.
4. The method for preparing ceftiofur microspheres according to claim 1, wherein T1= 0.5-1 h and T2= 2-4 h.
5. The method for preparing ceftiofur microspheres according to claim 1, wherein the vacuum drying time is 10-12 h.
6. The method for preparing ceftiofur microspheres according to claim 1, wherein the molecular weight of the polylactic acid in the polylactic acid-polyethylene glycol block copolymer is 5000-10000.
7. The method for preparing ceftiofur microspheres according to claim 1, wherein the molecular weight of the polyethylene glycol in the polylactic acid-polyethylene glycol block copolymer is 750-1000.
8. Use of ceftiofur microspheres prepared by the method of preparing ceftiofur microspheres according to any one of claims 1 to 7 in the preparation of veterinary drugs.
Priority Applications (1)
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