CN103877029B - A kind of magnetic carries the preparation method of 5-fluorouracil PLGA material - Google Patents
A kind of magnetic carries the preparation method of 5-fluorouracil PLGA material Download PDFInfo
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- CN103877029B CN103877029B CN201410084089.4A CN201410084089A CN103877029B CN 103877029 B CN103877029 B CN 103877029B CN 201410084089 A CN201410084089 A CN 201410084089A CN 103877029 B CN103877029 B CN 103877029B
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Abstract
The present invention relates to the preparation method that a kind of novel magnetic carries 5-fluorouracil PLGA material.Joined by magnetic nanoparticle in the solution of PLGA, 5-fluorouracil is dissolved in dimethyl sulfoxide, joins in the solution of PLGA by the DMSO solution of 5-Fu, and supersound process obtains the oily O/O emulsion of oil bag.Joined in the aqueous solution with the saturated PVA of 5-Fu again, stir and solvent is volatilized, microsphere solidifies, and deionized water wash, namely lyophilization obtains the PLGA microsphere that magnetic carries 5-Fu.Gained medicine carrying microballoons particle diameter is comparatively even, and particle diameter is 100-500 μm.The drug loading of microsphere is higher, can reach 10%.By the rate of release regulating the ratio of both LA and GA in PLGA to carry out regulating drug.Due to the introducing of magnetic nanoparticle, under the control in magnetic field in vitro, medicine carrying microballoons can be made to concentrate on tumor region, improve the drug level of tumor region, make tumor cell rapid apoptosis, also tumour medicine be dropped to minimum to Normocellular injury simultaneously.Preparation method of the present invention is simple, and raw material can suitability for industrialized production, has good application value.
Description
Technical field
The invention belongs to the preparation field of macromolecular material and medicament-carried nano material, be specifically related to the preparation method that a kind of magnetic carries 5-fluorouracil PLGA (PLGA) material.
Background technology
PLGA (PLGA) is formed by two kinds of monomer-lactic acid and hydroxyacetic acid random copolymerization, is a kind of degradable functional polymer compound.There is good biocompatibility and biological degradability, nontoxic, it is degraded to carbon dioxide and water in vivo, and not easily accumulate in vivo, now be approved as pharmaceutic adjuvant by united states drug and food Surveillance Authority (FDA), be now widely used in pharmacy, medical engineering material and modernization industrial circle.Due to encystation and the filming performance of its excellence, existing multi-medicament adopts PLGA to prepare biodegradable microspheres realization to the gentle control of the slow release of medicine as framework material at present.
PLGA is the copolymer of lactic acid and hydroxyacetic acid, and lactic acid is more hydrophobic than hydroxyacetic acid, so the higher PLGA polymer of lactic acid content can be more hydrophobic, water absorption causes its degraded relatively slow at least.Therefore kind and copolymerization ratio by regulating two kinds of monomers (lactic acid and hydroxyacetic acid) in PLGA realize the effective control to micro-sphere degrades and slow release, and research discovery copolymerization ratio is the degradation rate of the PLGA of 50:50 is the fastest in all proportionings.
5-fluorouracil (5-Fu) is a kind ofly widely used in clinical spectrum cancer therapy drug, since nineteen fifty-seven, exploitation was come out, just in chemotherapy of tumors, occupied important position.The increment cycle of 5-Fu to cell is inhibited, its inhibitory action mechanism mainly suppresses thymidylate synthase, block deoxyribonucleotides nucleotide and convert thymidine core to, interference DNA synthesis, play antitumaous effect, and to mix in RNA thus the propagation of inhibition tumor cell with pseudo-metabolite again.5-Fu is widely used in clinical at present, and especially in treatment malignant tumor of digestive tract, there is no other drug so far can replace.But because it is to the poor selectivity of tumor cell, also comparatively large to Normocellular toxicity, especially when concentration is larger, it is more obvious to Normocellular toxic and side effects.And 5-Fu has again metabolism feature faster, and the half-life is in vivo short.Blood drug level that can not be continual and steady is for a long time to play its antitumaous effect.Take intravenous injection or persistent instillation administration when taking clinically more more, but often along with bone marrow depression and a series of toxicity.In order to extend the drug effect of 5-Fu, reducing its toxic and side effects, adopting carrier to prepare the method for medicine carrying microballoons in recent years more and more.But 5-Fu is one is insoluble in water, be insoluble in the white crystals of ethanol, methanol and acetone and other organic solvent, carry in 5-Fu microsphere in preparation and encounter an a lot of difficult problem, maximum method of current application makes pharmaceutical suspension prepare medicine carrying microballoons exactly in organic solution, and result makes the drug loading of microsphere extremely low and unstable.When room temperature, the dissolubility of 5-Fu in DMSO can reach 100mg/mL more greatly, and the present invention utilizes DMSO to dissolve 5-Fu, and the drug loading of the microsphere that the method then mixed with the organic solution of PLGA finally obtains can up to 10%.In addition magnetic nano-particle is incorporated into the drug-supplying system can making magnetic target in medicine carrying microballoons, under the guiding in magnetic field in vitro, MagneticphamaceuticaMicrophere Microphere in vivo displacement, location concentrates, and effectively can reduce the infringement of microsphere normal tissue.Meanwhile, microsphere can slow releasing antitumor drug, extends drug effect and reduces whole body toxic and side effects simultaneously.
The biocompatibility of PLGA and biological degradability is utilized to be prepared in medicine carrying microballoons, by the rate of release regulating the ratio of both lactic acid and hydroxyacetic acid to control medicine carrying microballoons, dissolving 5-Fu by DMSO can make the drug loading of microsphere be increased to 10%, the function of its magnetic target is given in the introducing of magnetic nano-particle, increase the drug level of tumor locus and also reduce it to Normocellular injury while extending action time simultaneously, in chemotherapy of tumors, having good application prospect.
Summary of the invention
A kind of magnetic is the object of the present invention is to provide to carry the preparation method of 5-fluorouracil PLGA (PLGA) microsphere.
Medicine 5-Fu is the object of the invention is to be dissolved in DMSO, and then mix with the dichloromethane solution of PLGA, the drug loading of final gained medicine carrying microballoons is increased with this, method simultaneously by adding magnetic nano-particle in the dichloromethane solution of PLGA introduces magnetic nanoparticle in medicine carrying microballoons, makes the microsphere finally obtained have the characteristic of magnetic target administration.
A kind of magnetic that the present invention proposes carries the preparation of 5-fluorouracil PLGA (PLGA) microsphere, and its concrete steps are as follows:
(1) PLGA (PLGA) is dissolved in dichloromethane, in solution, adds magnetic nanoparticle, then ultrasonicly make it dispersed; In described PLGA, lactic acid (LA) is any one in 75/25,50/50 or 80/20 with the copolymerization ratios of hydroxyacetic acid (GA);
(2) be dissolved in DMSO by 5-Fu, then joined in the dichloromethane solution of the PLGA in step (1), the ultrasonic oil that obtains wraps oily O/O emulsion;
(3) oil of gained in step (2) is wrapped oily O/O emulsion dropwise to join by the saturated PVA aqueous solution of 5-Fu, mechanical agitation 3 ~ 6h, makes dichloromethane volatilize, microsphere solidification;
(4) stop stirring, sedimentation, outwells supernatant liquid, collects lower floor microsphere, with deionized water wash three times;
(5) use buchner funnel sucking filtration, lyophilization, obtain MagneticphamaceuticaMicrophere Microphere.
In the present invention, the molecular weight of the PLGA in described step (1) is in 25000 ~ 30000 scopes;
In the present invention, in described step (1), magnetic nanoparticle comprises Fe
2o
3, MnFe
2o
4, CoFe
2o
4, particle diameter is within the scope of 5-20nm;
In the present invention, the concentration of the dichloromethane solution of PLGA is 80 ~ 120mg/mL;
In the present invention, ultrasonic power used is 250 ~ 300W;
In the present invention, the concentration of the DMSO solution of 5-Fu is 70 ~ 100mg/mL;
In the present invention, the concentration of PVA solution is 0.5 ~ 2%(mass fraction);
In the present invention, churned mechanically rotating speed is 280 ~ 420rpm;
In the present invention, lyophilization condition: temperature is-50 ~-55 DEG C, and sublimation drying is 12 ~ 24h.
The invention has the advantages that: raw material sources are extensive, and solvent used, emulsifying agent etc. all obtain by suitability for industrialized production, and synthetic method is simple.The medicine carrying microballoons particle diameter of gained is comparatively even, and particle diameter major control is within the scope of 100-500 μm.The drug loading of microsphere is higher, can reach 10%.By the Effective Regulation regulating the ratio of both lactic acid and hydroxyacetic acid in PLGA to realize slow release to MagneticphamaceuticaMicrophere Microphere and degraded.The drug loading being carried the PLGA microsphere gained of 5-Fu by the magnetic Nano prepared by this kind of method is higher, and can realize the characteristic of target administration, while improving cancerous cell position local drug concentration, also drops to minimum by cancer therapy drug to Normocellular injury.
Accompanying drawing explanation
Fig. 1: the structural representation of material of main part PLGA.
Detailed description of the invention
Be below further illustrating invention, instead of limit range of application of the present invention.
This magnetic Nano carries lactic acid and the ratio both hydroxyacetic acid in the material of main part of 5-Fu polylactic-co-glycolic acid microsphere and confirms by NMR.The particle diameter of gained magnetic Nano medicine carrying microballoons measures by dynamic laser light scattering instrument (DLS).The surface topography of magnetic Nano medicine carrying microballoons can utilize scanning electron microscope (SEM) to characterize.The elution profiles of magnetic Nano medicine carrying microballoons measures by ultraviolet spectrophotometer.Embodiment 1
Take PLGA (PLGA) 200mg, wherein: lactic acid (LA) is 75:25 with the copolymerization ratio of hydroxyacetic acid (GA).Then be dissolved in dichloromethane, in solution, added the magnetic nanoparticle Fe of 5mg
2o
3then ultrasonic 2min makes it dispersed; Be dissolved in the DMSO of 2mL by the 5-Fu of 200mg, then joined in the dichloromethane solution of PLGA, ultrasonic 2min obtains the oily O/O emulsion of oil bag; The emulsion of gained is dropwise joined 60mL by the saturated PVA aqueous solution of 5-Fu, mechanical agitation 3h, makes dichloromethane volatilize, and microsphere solidifies; Stop stirring, sedimentation, outwells supernatant liquid, collects lower floor microsphere, with deionized water wash three times; Use buchner funnel sucking filtration, namely lyophilization obtains MagneticphamaceuticaMicrophere Microphere.
Embodiment 2
Take PLGA (PLGA) 200mg, wherein: lactic acid (LA) is 50:50 with the copolymerization ratio of hydroxyacetic acid (GA).Then be dissolved in dichloromethane, in solution, added the magnetic nanoparticle MnFe of 10mg
2o
4then ultrasonic 2.5min makes it dispersed; Be dissolved in the DMSO of 2mL by the 5-Fu of 180mg, then joined in the dichloromethane solution of PLGA, ultrasonic 2.5min obtains the oily O/O emulsion of oil bag; The emulsion of gained is dropwise joined 70mL by the saturated PVA aqueous solution of 5-Fu, mechanical agitation 4h, makes dichloromethane volatilize, and microsphere solidifies; Stop stirring, sedimentation, outwells supernatant liquid, collects lower floor microsphere, with deionized water wash three times; Use buchner funnel sucking filtration, namely lyophilization obtains MagneticphamaceuticaMicrophere Microphere.
Embodiment 3
Take PLGA (PLGA) 250mg, wherein: lactic acid (LA) is 80:20 with the copolymerization ratio of hydroxyacetic acid (GA).Then be dissolved in dichloromethane, in solution, added the magnetic nanoparticle CoFe of 5mg
2o
4, then ultrasonic 1.5min makes it dispersed; Be dissolved in the DMSO of 2mL by the 5-Fu of 190mg, then joined in the dichloromethane solution of PLGA, ultrasonic 3min obtains the oily O/O emulsion of oil bag; The emulsion of gained is dropwise joined 70mL by the saturated PVA aqueous solution of 5-Fu, mechanical agitation 3.5h, makes dichloromethane volatilize, and microsphere solidifies; Stop stirring, sedimentation, outwells supernatant liquid, collects lower floor microsphere, with deionized water wash three times; Use buchner funnel sucking filtration, namely lyophilization obtains MagneticphamaceuticaMicrophere Microphere.
Embodiment 4
Take PLGA (PLGA) 250mg, wherein: lactic acid (LA) is 75:25 with the copolymerization ratio of hydroxyacetic acid (GA).Then be dissolved in dichloromethane, in solution, added the magnetic nanoparticle Fe of 5mg
2o
3, then ultrasonic 2min makes it dispersed; Be dissolved in the DMSO of 2.5mL by the 5-Fu of 250mg, then joined in the dichloromethane solution of PLGA, ultrasonic 2.5min obtains the oily O/O emulsion of oil bag; The emulsion of gained is dropwise joined 75mL by the saturated PVA aqueous solution of 5-Fu, mechanical agitation 4h, makes dichloromethane volatilize, and microsphere solidifies; Stop stirring, sedimentation, outwells supernatant liquid, collects lower floor microsphere, with deionized water wash three times; Use buchner funnel sucking filtration, namely lyophilization obtains MagneticphamaceuticaMicrophere Microphere.
Embodiment 5
Take PLGA (PLGA) 250mg, wherein: lactic acid (LA) is 50:50 with the copolymerization ratio of hydroxyacetic acid (GA).Then be dissolved in dichloromethane, in solution, added the magnetic nanoparticle MnFe of 10mg
2o
4, then ultrasonic 2.5min makes it dispersed; Be dissolved in the DMSO of 2mL by the 5-Fu of 250mg, then joined in the dichloromethane solution of PLGA, ultrasonic 2.5min obtains the oily O/O emulsion of oil bag; The emulsion of gained is dropwise joined 70mL by the saturated PVA aqueous solution of 5-Fu, mechanical agitation 5h, makes dichloromethane volatilize, and microsphere solidifies; Stop stirring, sedimentation, outwells supernatant liquid, collects lower floor microsphere, with deionized water wash three times; Use buchner funnel sucking filtration, namely lyophilization obtains MagneticphamaceuticaMicrophere Microphere.
Embodiment 6
Take PLGA (PLGA) 300mg, wherein: lactic acid (LA) is 80:20 with the copolymerization ratio of hydroxyacetic acid (GA).Then be dissolved in dichloromethane, in solution, added the magnetic nanoparticle CoFe of 15mg
2o
4, then ultrasonic 2min makes it dispersed; Be dissolved in the DMSO of 2.5mL by the 5-Fu of 250mg, then joined in the dichloromethane solution of PLGA, ultrasonic 3min obtains the oily O/O emulsion of oil bag; The emulsion of gained is dropwise joined 80mL by the saturated PVA aqueous solution of 5-Fu, mechanical agitation 4h, makes dichloromethane volatilize, and microsphere solidifies; Stop stirring, sedimentation, outwells supernatant liquid, collects lower floor microsphere, with deionized water wash three times; Use buchner funnel sucking filtration, namely lyophilization obtains MagneticphamaceuticaMicrophere Microphere.
Claims (5)
1. magnetic carries a preparation method for 5-fluorouracil PLGA material, it is characterized in that concrete steps are as follows:
(1) PLGA is dissolved in dichloromethane, in solution, adds magnetic nanoparticle, then ultrasonicly make it dispersed; In described PLGA, the copolymerization ratio of lactic acid and hydroxyacetic acid is any one in 75/25,50/50 or 80/20; The molecular weight of PLGA is 25000 ~ 30000; The concentration of the dichloromethane solution of PLGA is 80 ~ 120mg/mL;
(2) be dissolved in DMSO by 5-Fu, then joined in the dichloromethane solution of the PLGA in step (1), the ultrasonic oil that obtains wraps oily O/O emulsion;
(3) oil of gained in step (2) is wrapped oily O/O emulsion dropwise to join by the saturated PVA aqueous solution of 5-Fu, mechanical agitation 3 ~ 6h, makes dichloromethane volatilize, microsphere solidification; The concentration of the DMSO solution of 5-Fu is 70 ~ 100mg/mL; The concentration of PVA solution is 0.5 ~ 2%(mass fraction);
(4) stop stirring, sedimentation, outwells supernatant liquid, collects lower floor microsphere, with deionized water wash three times;
(5) use buchner funnel sucking filtration, lyophilization, obtain MagneticphamaceuticaMicrophere Microphere.
2. preparation method according to claim 1, is characterized in that, in described step (1), magnetic nanoparticle comprises Fe
2o
3, MnFe
2o
4or CoFe
2o
4in any one, particle diameter is 5-20nm.
3. preparation method according to claim 1, is characterized in that, in described step (1), (2), ultrasonic power is 250 ~ 300W.
4. preparation method according to claim 1, is characterized in that, in described step (3), churned mechanically rotating speed is 280 ~ 420rpm.
5. preparation method according to claim 1, is characterized in that, in described step (5), lyophilization condition: temperature is-50 ~-55 DEG C, sublimation drying is 12 ~ 24h.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106420757A (en) * | 2016-09-23 | 2017-02-22 | 西南科技大学 | 5-fluorouracil/methoxy grafted kaolinite complex and preparation method thereof |
| CN107890465A (en) * | 2017-08-11 | 2018-04-10 | 深圳市第二人民医院 | A kind of preparation method for the magnetic Nano carried medicine sustained-release microsphere for wrapping up 5 fluorouracils |
| DE102018222807B4 (en) | 2017-12-22 | 2022-10-13 | Shandong Rientech Medical Technology Co., Ltd. | Degradable embolic microspheres with high drug loading capacity and method for their manufacture |
| CN108114310B (en) | 2017-12-22 | 2022-11-25 | 张海军 | Degradable drug-loaded microsphere and preparation method 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 |
| CN111803449B (en) * | 2020-06-15 | 2023-06-30 | 广东省医疗器械研究所 | Polymer microsphere for immune regulation and control as well as preparation method and application thereof |
| CN113082297B (en) * | 2021-04-15 | 2022-02-25 | 漯河医学高等专科学校 | Preparation method of superparamagnetic bone repair material |
| CN113440472A (en) * | 2021-06-25 | 2021-09-28 | 南方科技大学 | Polymer micro-robot and preparation method and application thereof |
| CN115300466A (en) * | 2022-08-08 | 2022-11-08 | 青岛市肿瘤医院 | Magnetic particle for enhancing tumor drug sensitivity and application thereof |
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Patent Citations (3)
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| CN101299998A (en) * | 2005-08-19 | 2008-11-05 | 麦格霍斯奈米生技股份有限公司 | Method for encapsulating therapeutic substances in cells |
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