CN1927169A - Norcantharidin magnetic nano microsphere and its preparing process - Google Patents
Norcantharidin magnetic nano microsphere and its preparing process Download PDFInfo
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Abstract
The invention belongs to the field of composite materials and biomedical technology, specifically involves Norcantharidin-magnetic nanoparticles and their preparation methods. The invention take the biodegradable polymers as carriers, nanometer Fe304 as magnetic seeds, use hybrid emulsion -solvent volatilixation method (water-oil-water) to preparation packing parcels Norcantharidin magnetic nanoparticles. The main technological process includes the preparation, admixture and re- emulsification of two colostric fluid, solvent removal, removal of non-encapsulationed drug and free magnetic particles, magnetic microspheres washing cryodesiccation and so on. The Microspheres have smooth roundness surface, no adhesion, diameter below 400 nm, 6-9% Fe3O4 content, 8-15%drug encapsulation, and has a good biodegradable character. The magnetic microspheres have a broad prospect in experimental research and future clinical cancer therapy. The invention is characterized in simple process, good reproducibility, and low cost.
Description
Technical field
The invention belongs to composite and biological medicine technology field, be specifically related to a kind of norcantharidin magnetic nano microsphere and preparation method thereof.
Background technology
Norcantharidin is the at first synthetic new type antineoplastic medicine of China; improve leukocyte, protection hepatocyte, regulate effect such as immunity and come into one's own day by day because have simultaneously; believe the development along with Protocols in Molecular Biology, the molecular mechanism of its antitumaous effect will progressively be illustrated.Yet, because norcantharidin still has certain internal organs toxicity, limited the dosage of its clinical use, influenced anticancer effect; So developing new high-efficiency low-toxicity derivant or developing the efficacy enhancing and toxicity reducing novel form is the effective way that norcantharidin is further promoted the use of.
At present, to the norcantharidin preparation research more be to be the simple medicine carrying microballoons of carrier with the high molecular polymer, the degradable polylactic acid-polyglycolic acid copolymer of employings such as Sun Ming (PLGA) material is made adjuvant, make norcantharidin antitumor drug intravenous formulations (Sun Ming with the supersound method and the solidification method that desolvates, Zhang Li etc. oncology's magazine [J] .2001,7 (6): 321-325); Zhang Aiguo etc. make the norcantharidin/polylactic acid microsphere (Zhang Aiguo with the effect of lung target slow-release with solvent evaporation method, Yang Jinju. distribute [J] in the preparation of norcantharidin targeting microsphere and the mice body thereof. Shandong medical industry .2000,19 (3): 10-11).Reports such as Cheng Yuhui with the emulsifying solidification method prepared norcantharidin/albumin microsphere (Cheng Yuhui, Li Li etc. the research [J] of norcantharidin acid sodium albumin microsphere. Acta Pharmaceutica Sinica, 1995,28 (5): 384-388).Chinese patent (application number: 200510027776.3) provide a kind of preparation method of utilizing emulsion-solvent evaporation method to prepare slow-releasing micro-balls of demethyl cantharidine.Wherein the norcantharidin nano microsphere preparations has the characteristic of targeting and controlled release, can prolong drug action time, reduce dosage, thereby alleviate or reduce or remit toxicity.But nanoparticle enters behind the blood circulation easily by reticuloendothelial system phagocytic, thereby forms the passive target effect to the liver spleen, and the drug microparticles that is distributed in pathological tissues is then less.For overcoming this defective, must give initiatively targeting of medicine microspheres, so introducing magnetic medicinal microglobule, Pilwat and Widder etc. have proposed magnetic control target since the notion of drug delivery system from the seventies, the research of magnetic medicinal microglobule is one of current medicine new formulation most active fields always, and it is to introduce the material (Fe with magnetic responsiveness in medicine microspheres
3O
4), magnetic medicinal microglobule is injected in the body, apply the external magnetic field of certain field intensity simultaneously at diseased region, utilize magnetic and medicated mobile performance and induced by magnetic field performance, magnetic medicine carrier is oriented to the target area, and medicine is slowly location release in a controlled manner, concentrates the performance drug effect, the corresponding systemic drug level that reduced has advantage efficient, quick-acting, low toxicity.
Do not see the pertinent literature report of norcantharidin magnetic microsphere up to now.
Summary of the invention
The objective of the invention is to propose that a kind of technology is simple, good reproducibility, norcantharidin magnetic nano microsphere that cost is low and preparation method thereof.
The norcantharidin magnetic nano microsphere that the present invention proposes, the medicine of its parcel is a norcantharidin, magnetic seeds is Fe
3O
4Nano-particle, carrier material are biodegradable polymer.
Among the present invention, described biodegradable polymer is polylactide, polylactide-ethylene glycol copolymer, polylactide-poly-glycolide copolymer, polylactide-polycaprolactone copolymer, polyhydroxy-alkanoate, gathers a kind of of beta-hydroxy-butanoic acid ester.
Among the present invention, described polymer weight average molecular weight is 5000～65000.
Among the present invention, described Fe
3O
4Nano particle diameter is 10～25nm, and the surface is hydrophilic.
The preparation method of the norcantharidin magnetic nano microsphere that the present invention proposes, concrete steps are as follows:
As oil phase, the aqueous solution of norcantharidin that contains surfactant is as interior water, with Fe with the dichloromethane of polymer or ethyl acetate solution
3O
4The nano-particle ultra-sonic dispersion is in interior aqueous phase, and biphase mixing is stirred, and forms colostrum; This colostrum is joined in the aqueous solution that contains polyvinyl alcohol, stir or evaporation, obtain double emulsion; Again double emulsion is dialysed and centrifugalize repeatedly, remove not entrapped drug and free Fe
3O
4, washing, lyophilization promptly obtain norcantharidin magnetic nano microsphere at last.
Actual conditions is:
The concentration of polymer in dichloromethane is 1～25mg/ml, and the concentration in ethyl acetate is 1～30mg/ml;
Interior aqueous phase, the concentration of norcantharidin are 2～15mg/ml;
Interior aqueous phase, surfactant concentrations are 10～60mg/ml;
Interior aqueous phase, Fe
3O
4The magnetic powder inventory is 0.1～1.5mg/ml;
When forming colostrum, oil phase and interior water volume ratio are 2: 1～10: 1;
When forming emulsion, mixing speed is 5000～30000 rev/mins, and the time is 5～30min;
The concentration of polyvinyl alcohol water solution is 0.05～0.5g/mi;
The volume ratio of colostrum and polyvinyl alcohol water solution 1: 3～1: 30.
Among the present invention, the surfactant of interior aqueous phase is a kind of of sorbitan fatty acid ester class, polyoxyethylene (20), sorbitan fatty acid ester class, polyvinyl alcohol, is specifically as follows class of department 80, Tween 80, polyvinyl alcohol etc.
Among the present invention, the polyvinyl alcohol molecular weight is 7000～14000.
The present invention is carrier with the biodegradable polymer, nanometer Fe
3O
4Make magnetic seeds, utilize the magnetic Nano microsphere of complex emulsions one solvent evaporation method (W/O/W) preparation parcel norcantharidin.Thus obtained microsphere smooth surface rounding, no adhesion, particle diameter below 400nm, Fe
3O
4Content is 6～9%, and entrapment efficiency is 8～15%, this magnetic medicinal microglobule aspect experimentation and the future clinical cancer therapy aspect have broad application prospects.Wherein the microsphere pattern utilizes transmission electron microscope observing, and particle diameter adopts laser particle size analyzer to measure Fe
3O
4Content adopts the simultaneous thermal analysis instrument to measure, and entrapment efficiency adopts ultraviolet spectrophotometer to measure.
It is simple that the present invention has technology, good reproducibility, characteristics such as cost is low.
The specific embodiment
Be described further below in conjunction with example, be to be understood that the example of being lifted just in order to explain the present invention, does not comprise all the elements of the present invention.
Embodiment 1
Polymer adopts polylactide-ethylene glycol copolymer (PLA-PEG), and wherein the PEG molecular weight is 5000, and the copolymerization ratio is 6/1.0.237g PLA-PEG is dissolved in the 60ml dichloromethane forms oil phase, the 30mg norcantharidin is dissolved in the 20ml deionized water, add the 0.2g Tween 80 and form interior water, with 25mg magnetic powder ultra-sonic dispersion in interior aqueous phase, biphase mixing, temperature are controlled at 25 ℃, 10000 rev/mins of high-speed stirred, mixing time 20 minutes forms colostrum; With colostrum impouring 150ml concentration is in polyvinyl alcohol (PVA) aqueous solution of 0.02g/ml, stirs, and obtains emulsion; Dialysis and centrifugalize repeatedly, washing, lyophilization at last obtains the magnetic drug-carrying microsphere.The thus obtained microsphere mean diameter is 234nm, Fe
3O
4Content is 7.3%, and entrapment efficiency is 12.1%.
Embodiment 2
Polymer adopts polylactide-ethylene glycol copolymer (PLA-PEG), and wherein the PEG molecular weight is 5000, and the copolymerization ratio is 6/1.0.681g PLA-PEG is dissolved in the 60ml dichloromethane forms oil phase, the 30mg norcantharidin is dissolved in the 20ml deionized water, add the 0.2g Tween 80 and form interior water, with 25mg magnetic powder ultra-sonic dispersion in interior aqueous phase, biphase mixing, temperature are controlled at 25 ℃, 10000 rev/mins of high-speed stirred, mixing time 20 minutes forms colostrum; With colostrum impouring 150ml concentration is in polyvinyl alcohol (PVA) aqueous solution of 0.02g/ml, stirs, and obtains emulsion; Dialysis and centrifugalize repeatedly, washing, lyophilization at last obtains the magnetic drug-carrying microsphere.The thus obtained microsphere mean diameter is 251nm, Fe
3O
4Content is 7.8%, and entrapment efficiency is 14.3%.
Embodiment 3
Polymer adopts polylactide-ethylene glycol copolymer (PLA-PEG), and wherein the PEG molecular weight is 8000, and the copolymerization ratio is 5/1.0.681g PLA-PEG is dissolved in the 60ml dichloromethane forms oil phase, the 30mg norcantharidin is dissolved in the 20ml deionized water, add the 0.2g Tween 80 and form interior water, with 25mg magnetic powder ultra-sonic dispersion in interior aqueous phase, biphase mixing, temperature are controlled at 25 ℃, 10000 rev/mins of high-speed stirred, mixing time 20 minutes forms colostrum; With colostrum impouring 150ml concentration is in polyvinyl alcohol (PVA) aqueous solution of 0.02g/ml, stirs, and obtains emulsion; Dialysis and centrifugalize repeatedly, washing, lyophilization at last obtains the magnetic drug-carrying microsphere.The thus obtained microsphere mean diameter is 243nm, Fe
3O
4Content is 7.4%, and entrapment efficiency is 12.5%.
Embodiment 4
Dichloromethane is replaced with ethyl acetate, and other condition is with embodiment 1, and the mean diameter that obtains microsphere is 218nm, Fe
3O
4Content is 6.5%, and entrapment efficiency is 11.4%.
Embodiment 5
Aqueous phase magnetic powder inventory is 40mg in getting, and other condition is with embodiment 1, and the mean diameter that obtains microsphere is 236nm, Fe
3O
4Content is 8.3%, and entrapment efficiency is 10.5%.
Embodiment 6
The aqueous phase drug dose is 50mg in getting, and other condition is with embodiment 1, and the mean diameter that obtains microsphere is 247nm, Fe
3O
4Content is 6.3%, and entrapment efficiency is 14.6%.
Embodiment 7
Get in the aqueous phase dosage of surfactant be 0.5g, for other condition with embodiment 1, the mean diameter that obtains microsphere is 218nm, Fe
3O
4Content is 7.4%, and entrapment efficiency is 11.5%.
Embodiment 8
The class of surfactant employing department 80 of interior water, other condition is with embodiment 1, and the mean diameter that obtains microsphere is 225nm, Fe
3O
4Content is 6.2%, and entrapment efficiency is 9.4%.
Embodiment 9
The water volume is 5ml in getting, and other condition is with embodiment 1, and the mean diameter that obtains microsphere is 241nm, Fe
3O
4Content is 6.3%, and entrapment efficiency is 12.6%.
Embodiment 10
Getting outer aqueous phase PVA concentration is 0.06g/ml, and other condition is with embodiment 1, and the mean diameter that obtains microsphere is 217nm, Fe
3O
4Content is 6.5%, and entrapment efficiency is 11.1%.
Embodiment 11
Polymer employing polylactide (PLLA, Mw=30000), other condition is with embodiment 1, and the mean diameter that obtains microsphere is 209nm, Fe
3O
4Content is 6.1%, and entrapment efficiency is 8.5%.
Embodiment 12
Polymer employing polylactide-(PLGA, LA/GA=85: 15), other condition is with embodiment 1, and the mean diameter that obtains microsphere is 211nm, Fe for poly-glycolide copolymer
3O
4Content is 6.2%, and entrapment efficiency is 8.8%.
Embodiment 13
Polymer adopts poly-beta-hydroxy-butanoic acid ester (Mw=25000), and other condition is with embodiment 1, and the mean diameter that obtains microsphere is 228nm, Fe
3O
4Content is 6.2%, and entrapment efficiency is 9.5%.
Claims (7)
1, a kind of norcantharidin magnetic nano microsphere is characterized in that the medicine that wraps up is a norcantharidin, and magnetic seeds is a nanometer Fe
3O
4, carrier material is a biodegradable polymer.
2, norcantharidin magnetic nano microsphere according to claim 1 is characterized in that described biodegradable polymer is polylactide, polylactide-ethylene glycol copolymer, polylactide-poly-glycolide copolymer, polylactide-polycaprolactone copolymer, polyhydroxy-alkanoate, gathers a kind of of beta-hydroxy-butanoic acid ester.
3, norcantharidin magnetic nano microsphere according to claim 1 and 2 is characterized in that described polymer weight average molecular weight is 5000～65000.
4, norcantharidin magnetic nano microsphere according to claim 1 and 2 is characterized in that described Fe
3O
4Nano particle diameter is 10～25nm, and the surface is hydrophilic.
5, a kind of preparation method of norcantharidin magnetic nano microsphere as claimed in claim 1 is characterized in that concrete steps are as follows:
As oil phase, the aqueous solution of norcantharidin that contains surfactant is as interior water, with Fe with the dichloromethane of polymer or ethyl acetate solution
3O
4The nano-particle ultra-sonic dispersion is in interior aqueous phase, and biphase mixing is stirred, and forms colostrum; This colostrum is joined in the aqueous solution that contains polyvinyl alcohol, stir or evaporation, obtain double emulsion; Again double emulsion is dialysed and centrifugalize repeatedly, remove not entrapped drug and free Fe
3O
4, washing, lyophilization at last obtains norcantharidin magnetic nano microsphere; Wherein, actual conditions is:
The concentration of polymer in dichloromethane is 1～20mg/ml, and the concentration in ethyl acetate is 1～30mg/ml;
Interior aqueous phase, the concentration of norcantharidin are 2～15mg/ml;
Interior aqueous phase, surfactant concentrations are 15～60mg/ml;
Interior aqueous phase, Fe
3O
4The magnetic powder inventory is 0.1～1.5mg/ml;
When forming colostrum, oil phase and interior water volume ratio are 2: 1～10: 1;
When forming emulsion, mixing speed is 5000～30000 rev/mins, and the time is 5～30min;
The concentration of polyvinyl alcohol water solution is 0.05～0.5g/ml;
The volume ratio of colostrum and polyvinyl alcohol water solution 1: 3～1: 30.
6, the preparation method of norcantharidin magnetic nano microsphere according to claim 5, it is characterized in that described in the surfactant of aqueous phase be a kind of of sorbitan fatty acid ester class, polyoxyethylene, sorbitan fatty acid ester class, polyvinyl alcohol.
7, the preparation method of norcantharidin magnetic nano microsphere according to claim 5 is characterized in that described polyvinyl alcohol molecular weight is 7000～14000.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102688494A (en) * | 2011-03-23 | 2012-09-26 | 卢世璧 | Preparation method of protein drug-carrying magnetic composite nano-material and application thereof |
| CN112791226A (en) * | 2019-11-14 | 2021-05-14 | 美国发现集团有限公司 | Nano robot with anti-tumor function and preparation method thereof |
| CN114249909B (en) * | 2020-09-24 | 2024-05-03 | 中国科学院理化技术研究所 | Micro-nano magnetic polymer microsphere with surface topological structure and preparation method thereof |
-
2006
- 2006-09-28 CN CN 200610116646 patent/CN1927169A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102688494A (en) * | 2011-03-23 | 2012-09-26 | 卢世璧 | Preparation method of protein drug-carrying magnetic composite nano-material and application thereof |
| CN112791226A (en) * | 2019-11-14 | 2021-05-14 | 美国发现集团有限公司 | Nano robot with anti-tumor function and preparation method thereof |
| CN114249909B (en) * | 2020-09-24 | 2024-05-03 | 中国科学院理化技术研究所 | Micro-nano magnetic polymer microsphere with surface topological structure and preparation method thereof |
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