CN100534532C - Medicine carrying nanometer particles and preparation method thereof - Google Patents
Medicine carrying nanometer particles and preparation method thereof Download PDFInfo
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- CN100534532C CN100534532C CNB2004100253726A CN200410025372A CN100534532C CN 100534532 C CN100534532 C CN 100534532C CN B2004100253726 A CNB2004100253726 A CN B2004100253726A CN 200410025372 A CN200410025372 A CN 200410025372A CN 100534532 C CN100534532 C CN 100534532C
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- nanometer particle
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Abstract
A medicine-carried nanoparticle (50-300 nm in diameter) is composed of the oridonin as its active component and the amphiphilic caprolactone-polyethanediol-caprolactone (ABA) block copolymer as its carrier. It is prepared by deposition method.
Description
Technical field
The present invention relates to a kind of drug-carrying nanometer particle, the invention still further relates to the preparation method of above-mentioned drug-carrying nanometer particle.
Background technology
The modern medicines therapeutics not only requires medicine to discharge with a kind of predetermined speed, and requires the medicine targeting moiety that concentrates as much as possible, thereby improves bioavailability of medicament and curative effect, reduces the toxic and side effects of medicine.And traditional medicine and pharmaceutical preparation (comprising slow releasing preparation) distribution in vivo is a zero difference, when lesions position is worked, the normal organ of human body has been brought certain toxic and side effects.Thereby, how to make medicine can arrive targeting (focus) position, and drug release is come out with predetermined speed, become the focus and the difficult point of current materia medica and pharmaceutical preparation.Drug-carried nanometer (Drug-loaded Nanoparticles) is just for solving the novel medicine-carried system that these two problems grow up.
Drug-carried nanometer generally is meant the solid-state or colloidal particle of particle diameter between 10nm-1000nm.Active component (medicine, bioactive substance etc.) is distributed in particle inside by dissolving, package action or is positioned at the surface of particle by adsorption.Nanoparticle is because itself distinctive character makes it have many distinctive advantages aspect drug conveying:
(1) owing to the dimensional effect of nanoparticle, nanoparticle distribution in vivo has specificity.The size of control nanoparticle can make nanoparticle arrive specific tissue, plays the effect of targeting.From blood, remove in the very fast phagocyte of the microsphere of 100nm-1000nm such as particle diameter, arrive in the abundant liver of reticuloendothelium, the spleen tissue, and particle diameter can arrive during bone marrow etc. organizes less than the nanoparticle of 100nm by reticuloendothelial system (RES).
(2) the drug-carried nanometer surface is modified, can be prolonged the half-life of nanoparticle in blood, perhaps make nanoparticle arrive some specific position.As passing through blood brain barrier (BBB), conduct drugs to brain with the paracyanogen base butyl acrylate nanoparticle of F-68 parcel.And the polylactide that the PEG modifies-poly-time of staying of Acetic acid, hydroxy-, bimol. cyclic ester nanoparticle in blood prolongs greatly, thereby can reduce administration number of times and dosage, improves the utilization rate of medicine.
(3), be scattered in the inside of nanoparticle or be adsorbed in the surface of nanometer, so drug-carried nanometer can slow releasing pharmaceutical, the action time of prolong drug because medicine is effect by chemistry or physics.
(4) can improve stability of drug, avoid medicine to be degraded before reaching lesions position, this point is to the medicine particular importance of genomic medicine and biologically active.
Based on some above characteristics, the drug-carried nanometer system is very promising drug delivery system, has caused people's extensive studies interest.
Summary of the invention
One object of the present invention is to provide a kind of drug-carrying nanometer particle that contains rubescensin;
Another object of the present invention is to provide a kind of preparation method of drug-carrying nanometer particle.
Above-mentioned purpose of the present invention is achieved by the following technical solution:
The invention discloses a kind of drug-carrying nanometer particle, the active component of described drug-carrying nanometer particle is a rubescensin, and used medicament-carried nano material is amphiphilic polycaprolactone-polyethylene glycol-polycaprolactone ABA block polymer, and described nanoparticle particle size range is 50nm～300nm.
Preferably, described drug-carrying nanometer particle drug loading is 1%～20%.
The present invention also provides a kind of sedimentation method to prepare the method for above-mentioned drug-carrying nanometer particle, this method comprises following step successively: raw material is by following weight ratio, 0～200 part of polycaprolactone-polyethylene glycol- polycaprolactone copolymer 1,1～50 part of rubescensin, 10～100 parts in acetone, 10～500 parts in water.According to the above ratio medicament-carried nano material and active component are dissolved in the organic solvent, form organic facies; The control temperature is added dropwise to water formation nano-micelle by stirring with organic facies at 20 ℃～40 ℃; Stirred 1～5 hour; Removing the organic facies solvent makes nanoparticle obtain solidifying.
Preferably, described stirring is a magnetic agitation, and speed is 20～90 rev/mins; The described organic facies of removing is that rotary evaporation is removed organic facies, and control rotary evaporation temperature is 60～95 ℃, and vacuum degree control is below 400mbar.
Compared with prior art, the present invention has following beneficial effect:
Rubescensin is an anticancer vegetable drug, and therefore the drug-carrying nanometer particle that contains rubescensin of the present invention can be used for treatment for cancer.Utilize the drug-carrying nanometer particle of method preparation of the present invention, realized higher drug loading, drug loading is 1%～20%.
Description of drawings
Fig. 1 is with the synthetic molecular weight of copolymer scattergram of different PEG molecular weight;
Fig. 2 is with the synthetic copolymer DSC figure of different PEG molecular weight (fusing point);
Fig. 3 is the infrared spectrogram with the synthetic copolymer of different PEG molecular weight;
Fig. 4 is pyrene I338/I335 fluorescence intensity ratio and LogC (logarithm of polymer concentration) figure;
Fig. 5 is the particle size distribution figure of PCL-PEG6000-PCL drug-carrying nanometer particle;
Fig. 6 is the particle size distribution figure of PCL-PEG2000-PCL drug-carrying nanometer particle;
Fig. 7 is the sem photograph of drug-carrying nanometer particle.
The specific embodiment
Below in conjunction with drawings and Examples the present invention is further described.
The preparation of PCL-PEO-PCL
Determine rate of charge according to design 50000 copolymer weight average molecular weight, caprolactone monomer, Polyethylene Glycol and the stannous octoate of purification placed polymerisation tube,, under vacuum state, melt the envelope reaction tube at last by three successive vacuum nitrogen fillings operations.This reaction tube is placed 150 ℃～200 ℃ high-temperature reactors, react and obtained head product in 12～36 hours.Head product is passed through repeatedly the purification step that chloroform dissolves methanol extraction, can remove the homopolymer of Polyethylene Glycol and not reacted caprolactone monomer, last 40 ℃ of vacuum dryings.
Physicochemical property to this copolymer is investigated: actual molecular weight is about 50000, and polydispersity is good; Fusing point is between 60 ℃～65 ℃, and the Infrared Characterization collection of illustrative plates has shown the characteristic peak of polycaprolactone and polyoxyethylated crystalline state, show synthetic polymer be our contemplated block copolymer.Sign is seen accompanying drawing.
Take by weighing 100mgPCL-PEO-PCL (PEG6000) polymer, be dissolved in 20ml acetone, place, treat the high molecular polymer swelling; Take by weighing about 10mg rubescensin and be dissolved in the acetone soln of polymer, as oil phase.Measure the 50ml redistilled water, magnetic agitation speed is 70～80 rev/mins, and oil phase is added dropwise to aqueous phase, and can obviously see has the opalescence phenomenon.
Rotary evaporation is removed acetone, and control rotary evaporation temperature is that 70 ℃ and vacuum degree control are below 200mbar; And the concentrated solution volume is to about 20ml, put cold, the water microporous filter membrane sucking filtration of usefulness 0.65um, lyophilization.
Freeze-dried products compares with standard curve method with its drug loading of high effective liquid chromatography for measuring, and recording drug loading is 1.05%.
Get 50mgPCL-PEO-PCL (PEG6000) polymer, be dissolved in 20ml acetone, place and treat the high molecular polymer swelling; Take by weighing about 5mg rubescensin and be dissolved in the acetone soln of polymer, as oil phase.Measure the 50ml ultra-pure water, temperature control is in 25 ℃, and magnetic agitation speed is 70～80 rev/mins.Oil phase is added dropwise to aqueous phase, can sees obviously that the opalescence phenomenon is arranged.Magnetic agitation 4h is with equilibrium system.
Rotary evaporation is removed acetone, and control rotary evaporation temperature is that 70 ℃ and vacuum degree control are below 200mbar; And the concentrated solution volume is to about 20ml, and controlling the rotary evaporation temperature at this moment is 95 ℃.Put cold, with the water microporous filter membrane sucking filtration of 0.65um, to remove the aggregation and the medicine of parcel not.Lyophilization.
Freeze-dried products is proofreaied and correct with two-point method with its drug loading of high effective liquid chromatography for measuring, and recording drug loading is 3.28%.
Embodiment 4
100mgPCL-PEO-PCL (PEG6000) polymer is dissolved in 20ml acetone, places, and treats the high molecular polymer swelling; Take by weighing about 10mg rubescensin and be dissolved in the acetone soln of polymer, as oil phase.Measure the 50ml ultra-pure water, temperature control is in 25 ℃, and magnetic agitation speed is 30～40 rev/mins.Oil phase is added dropwise to aqueous phase, can sees obviously that the opalescence phenomenon is arranged.Magnetic agitation 4h is with equilibrium system.
Rotary evaporation is removed acetone, and control rotary evaporation temperature is that 70 ℃ and vacuum degree control are below 400mbar; Control rotary evaporation temperature is 95 ℃, and the concentrated solution volume is to about 20ml.Put cold, with the water microporous filter membrane sucking filtration of 0.65um, to remove the aggregation and the medicine of parcel not.Lyophilization.
Freeze-dried products is proofreaied and correct with two-point method with its drug loading of high effective liquid chromatography for measuring, and recording drug loading is 9.58%.
Blank nanoparticle to this system is measured CMC (critical micelle concentration) with fluorescent method, obtains its value and is 0.008g/L; Medicine-carried system with its form of scanning electron microscopic observation, is found that particle is the sphere of rounding; Also respectively blank and drug-carrying nanometer particle have been made the mensuration of particle diameter and particle size distribution range, the particle diameter of finding time system all between 50～300nm, is seen Fig. 5.
100mgPCL-PEO-PCL (PEG2000) polymer is dissolved in 20ml acetone, places, and treats the high molecular polymer swelling; Take by weighing about 10mg rubescensin and be dissolved in the acetone soln of polymer, as oil phase.Measure the 400ml ultra-pure water, temperature control is in 25 ℃, and magnetic agitation speed is 30～40 rev/mins.Oil phase is added dropwise to aqueous phase, can sees obviously that the opalescence phenomenon is arranged.Magnetic agitation 4h is with equilibrium system.
Rotary evaporation is removed acetone, and control rotary evaporation temperature is that 70 ℃ and vacuum degree control are below 300mbar; And the concentrated solution volume is to about 20ml, and controlling the rotary evaporation temperature at this moment is 95 ℃.Put cold, with the water microporous filter membrane sucking filtration of 0.65um, to remove the aggregation and the medicine of parcel not.Lyophilization.
Freeze-dried products is proofreaied and correct with two-point method with its drug loading of high effective liquid chromatography for measuring, and recording drug loading is 9.95%.
Blank nanoparticle to this system is measured CMC (critical micelle concentration) with fluorescent method, obtains its value and is 0.002g/L; Medicine-carried system with its form of scanning electron microscopic observation, is found that particle is the sphere of rounding; Also respectively blank and drug-carrying nanometer particle have been made the mensuration of particle diameter and particle size distribution range, the particle diameter of finding this system is all about 200nm, and polydispersity is less.See Fig. 6.
Embodiment 6
200mgPCL-PEO-PCL (PEG2000) polymer is dissolved in 50ml acetone, places, and treats the high molecular polymer swelling; Take by weighing about 30mg rubescensin and be dissolved in the acetone soln of polymer, as oil phase.Measure the 500ml ultra-pure water, temperature control is in 25 ℃, and magnetic agitation speed is 30～40 rev/mins.Oil phase is added dropwise to aqueous phase, can sees obviously that the opalescence phenomenon is arranged.Magnetic agitation 4h is with equilibrium system.
Rotary evaporation is removed acetone, and control rotary evaporation temperature is that 70 ℃ and vacuum degree control are below 300mbar; And the concentrated solution volume is to about 50ml, and controlling the rotary evaporation temperature at this moment is 95 ℃.Put cold, with behind the water microporous filter membrane sucking filtration of 0.65um, lyophilization.
Freeze-dried products is proofreaied and correct with two-point method with its drug loading of high effective liquid chromatography for measuring, and recording drug loading is 19.5%.
Claims (5)
1. drug-carrying nanometer particle, it is characterized in that: the active component of described drug-carrying nanometer particle is a rubescensin, used medicament-carried nano material is amphiphilic polycaprolactone-polyethylene glycol-polycaprolactone ABA block polymer, and described nanoparticle particle size range is 50nm～300nm.
2. a kind of drug-carrying nanometer particle as claimed in claim 1 is characterized in that, described drug-carrying nanometer particle drug loading is 1%～20%.
3. the sedimentation method prepare the method for claim 1 or 2 described drug-carrying nanometer particles, it is characterized in that comprising successively following step: raw material is by following weight ratio, 0～200 part of polycaprolactone-polyethylene glycol-polycaprolactone copolymer 1,1～50 part of rubescensin, 10～100 parts in acetone, 10～500 parts in water is dissolved in medicament-carried nano material and active component in the organic solvent according to the above ratio, forms organic facies; The control temperature adds water formation nano-micelle by stirring with organic facies at 20 ℃～40 ℃; Stirred 1～5 hour; Removing the organic facies solvent makes nanoparticle obtain solidifying.
4. a kind of sedimentation method as claimed in claim 3 prepare the method for drug-carrying nanometer particle, it is characterized in that: described stirring is a magnetic agitation, and speed is 20～90 rev/mins.
5. a kind of sedimentation method as claimed in claim 3 prepare the method for drug-carrying nanometer particle, it is characterized in that: the described organic facies of removing is that rotary evaporation is removed organic facies, and control rotary evaporation temperature is 60～95 ℃, and vacuum degree control is below 400mbar.
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100371020C (en) * | 2006-01-27 | 2008-02-27 | 中山大学 | In situ quick preparation method of injectable supermolecular structure water gel and its uses |
| CN101333295B (en) * | 2007-06-27 | 2011-01-05 | 中国科学院化学研究所 | Biodegradable high molecular nanometer particles, special polymer thereof and preparation method thereof |
| CN101167718B (en) * | 2007-10-19 | 2010-07-14 | 浙江大学 | Rebescensine A powder injection and preparing process thereof |
| CN101328270B (en) * | 2008-07-31 | 2010-11-03 | 上海交通大学 | Synthetic method of non-linear structure polycaprolactone-block-polyethyleneglycol |
| CN101422615B (en) * | 2008-12-09 | 2013-01-23 | 沈阳药科大学 | Oridonin polymer micelle administration preparation and preparation method thereof |
| CN101810908B (en) * | 2009-02-25 | 2013-03-20 | 四川大学华西医院 | Rapid transdermal delivery system of local anesthetics |
| CN102846562B (en) * | 2012-09-28 | 2014-11-26 | 山东大学 | Galactose-mediated oridonin albumin nanoparticle and preparation method thereof |
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Non-Patent Citations (4)
| Title |
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| 冬凌草甲素硬脂酸固态类脂纳米粒的实验研究. 张典瑞，任天池，娄红祥，张君华.中国药学杂志，第39卷第2期. 2004 |
| 冬凌草甲素硬脂酸固态类脂纳米粒的实验研究. 张典瑞，任天池，娄红祥，张君华.中国药学杂志，第39卷第2期. 2004 * |
| 负载紫杉醇的两亲性共聚物纳米粒. 邓联东，董岸杰，张跃庭，霍建中，元英进，孙多先.天津大学学报，第37卷第1期. 2004 |
| 负载紫杉醇的两亲性共聚物纳米粒. 邓联东，董岸杰，张跃庭，霍建中，元英进，孙多先.天津大学学报，第37卷第1期. 2004 * |
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