CN102631680A - Method of regulating microsphere drug-load rate by treating calcium alginate microspheres with sodium chloride solution - Google Patents
Method of regulating microsphere drug-load rate by treating calcium alginate microspheres with sodium chloride solution Download PDFInfo
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- CN102631680A CN102631680A CN201210115661XA CN201210115661A CN102631680A CN 102631680 A CN102631680 A CN 102631680A CN 201210115661X A CN201210115661X A CN 201210115661XA CN 201210115661 A CN201210115661 A CN 201210115661A CN 102631680 A CN102631680 A CN 102631680A
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Abstract
The invention discloses a method of regulating microsphere drug-load rate by treating calcium alginate microspheres with sodium chloride solution. The method comprises the following steps: preparing calcium alginate microspheres with uniform grain diameter by adopting a membrane emulsification-gelatinization method; soaking the microspheres with sodium chloride solutions with different concentrations to substitute sodium ions for part of calcium ions in the calcium alginate microspheres, and then cleaning with ultrapure water; and soaking the treated microspheres into medicinal solution with positive charges, and loading drugs by virtue of static effect to obtain the calcium alginate microspheres with different drug-load rates finally. The preparation method is easy and controllable, the material sources are wide, the drug-load rate of microspheres can be conveniently adjusted, and the method has the advantage of excellent application prospect.
Description
Technical field
The present invention relates to a kind of method for preparing microsphere and regulate and control its drug loading.Thereby especially utilize the method for different concentrations of sodium chloride solution-treated microsphere regulation and control microsphere drug loading.
Background technology
Polymer microsphere be meant diameter at micron order, be shaped as a spheric family macromolecule material.In recent years, potential huge applications is worth because polymer microsphere is in fields such as medicine, biochemistry, electronic information, therefore by broad research.Main method for preparing microsphere has spray drying method, squeezing and pressing method, interface and situ aggregation method, phase separation method and complex phase emulsion method at present.These method output are big, but the particle size distribution of obtained microsphere is all very wide mostly, makes that the application in some fields is restricted.The film emulsifying technology is a kind of new emulsifying manner that occurs in the later stage eighties 20th century, is considered to prepare the simple effective method of monodisperse emulsion.This technology is with under the stressed outside effect of decentralized photo through the inoranic membrane micropore; Be pressed into and form emulsion in the continuous phase; Through controlled pressure, emulsifying agent, continuous phase flow velocity and membrane aperture; Realize the monodispersity of emulsion droplets, this is that conventional emulsification methods such as mechanical agitation, ultrasonic emulsification are not available.The film emulsion process uses multiple aperture plasma membrane, requires the membrane aperture homogeneous, after the impressed pressure effect, can not deform, breakage and varying aperture.What the most often use is a kind of inorganic porous glass-film---SPG film.
The natural polysaccharide polymer microsphere has good application prospects owing to the performance with excellences such as good biocompatibility and degradabilities gets more and more people's extensive concerning in the bio-medical field.In recent years, adopt the film emulsion process successfully to prepare the monodispersed natural polysaccharide polymer microsphere of particle diameter.Alginic acid is a kind of natural polysaccharide macromolecular material commonly used, is made up of guluronic acid and two kinds of monomers of mannuronic acid.It derives from the abundant seaweed plant of reserves in the ocean, has advantages such as abundant raw material is easy to get, good biocompatibility.Alginic acid can form gel with multivalent metallic ion crosslinking, and this unique character is widely used in fields such as food, medical science.Calcium alginate microsphere is the excellent carrier of drug delivery, and how it prepares with stirring and emulsifying method, gas atomization method or static drop method of formation.The method for preparing the medicine carrying calcium alginate microsphere at present in the research is just mixed medicine and sodium alginate soln at the preparation initial stage mostly, adopts static method of formation or stirring and emulsifying method to form drop, and calcium ion is cross-linked to form microsphere then.The static method of formation is difficult to obtain the microsphere below the particle diameter 50 μ m; And the microspherulite diameter wider distribution that the stirring and emulsifying method obtains; The preparation initial stage just with medicine and micro-sphere material method of mixing have that drug loading and embedding rate are not high, the drug loading of the microsphere problem of easy-regulating not, more than these drawbacks limit its promotion and application.
Summary of the invention
The purpose of this invention is to provide a kind of easy controlled sodium chloride solution that utilizes and handle the method that calcium alginate microsphere is regulated and control the microsphere drug loading.
The sodium chloride solution that utilizes of the present invention is handled the method that calcium alginate microsphere is regulated and control the microsphere drug loading, may further comprise the steps:
1) sodium alginate soln of preparation mass concentration 2% is as water, and the isobutyltrimethylmethane. that preparation contains 3% emulsifying agent is as oil phase, and wherein emulsifying agent is sorbester p37 and the polysorbate85 mixture of 9:1 by volume; Water and oil phase by volume 1:12 pour in the membrane emulsifier that includes cylindrical SPG film, water and oil phase stir down and exert pressure with nitrogen respectively in the outside and the inboard of cylindrical SPG film; Make water push through the SPG film and get into oil phase, obtain water-in-oil emulsion, in water-in-oil emulsion, add the saline solution that contains 5% calcium chloride and 20% sodium chloride; Stir 0.5h at least; Add isopropyl alcohol then and continue to stir 1h at least, the volume ratio of water-in-oil emulsion, saline solution and isopropyl alcohol is 13:2:5, separatory, eccentric cleaning; Obtain calcium alginate microsphere, lyophilizing is preserved;
2) calcium alginate microsphere of step 1) gained being added mass fraction is that making its final concentration is 1mg/mL in 0.45% ~ 1.8% the sodium chloride solution, behind the 2h that vibrates at least, uses the ultra-pure water centrifuge washing;
3) with step 2) calcium alginate microsphere through sodium chloride solution is handled of gained adds in the positively charged drug solution, the 2h at least that vibrates, eccentric cleaning is removed not by the drug molecule of calcium alginate microsphere absorption then, obtains the calcium alginate microsphere of drug loading.
Among the present invention, said SPG film is a kind of inorganic porous glass-film, and it has multiple aperture, is respectively 0.3 μ m, 1 μ m, 2 μ m, 5 μ m, 10 μ m, 15 μ m, 20 μ m, 30 μ m and 50 μ m, and the surface of film is carried out hydrophobization with silane coupler and handled.Said positively charged medicine is doxorubicin hydrochloride, methylene blue, ephedrine or vitamin B
1
Principle of the present invention is: in the suspension of calcium alginate microsphere and sodium chloride; Calcium ion in the microsphere is replaced by the sodium ion in the solution; Solution concentration is high more just to have more calcium ions to be replaced, and the carboxylate radical in the alginic acid changes free state into by the chelating attitude simultaneously.Clean the back calcium alginate microsphere and immerse in the positively charged drug solution, because alginic acid is electronegative in water, so calcium alginate microsphere can be through the positively charged drug molecule of electrostatic interaction absorption.Could in solution, ionization be negative electricity because only be in the carboxylate radical of free state; Thereby the ability that possesses the positively charged drug molecule of absorption; Increase through the free state carboxylate radical content in the calcium alginate microsphere of sodium chloride processing, therefore can adsorb more drug molecule, improve drug loading.Through changing step 2) in the concentration of sodium chloride solution, just can regulate and control the final drug loading of calcium alginate microsphere.
Beneficial effect of the present invention is: technology of the present invention is simple; Raw material sources are extensive; Controllable process property is good, and it is even that final products have particle diameter, has multiple particle diameter specification optional; Drug loading is big and be easy to, characteristics that envelop rate is high, in fields such as medicine, biology, chemical industry good prospects for application is arranged.
Description of drawings
Fig. 1 is a) with the stereoscan photograph of the calcium alginate microsphere of 15 μ m aperture SPG film preparations.B) enlarged drawing of single microsphere wherein inserts the cross-sectional view that little figure is a microsphere.C) the light microscopic photo of microsphere.
The light microscopic photo of the calcium alginate microsphere of the 15 μ m aperture SPG film preparations of Fig. 2 after with the different concentrations of sodium chloride solution-treated.Concentration of sodium chloride solution is respectively a) 0.45%, b) 0.9% and c) 1.8%.
The stereoscan photograph of the calcium alginate microsphere of the 15 μ m aperture SPG film preparations of Fig. 3 after with the different concentrations of sodium chloride solution-treated.Concentration of sodium chloride solution is respectively a) 0.45%, b) 0.9% and c) 1.8%.Inserting little figure is the stereoscan photograph of the corresponding cross section of microsphere.
The content of calcium ion and sodium ion in the microsphere that Fig. 4 has represented to handle with the variable concentrations sodium chloride solution.
Fig. 5 is the infrared spectrum before and after microsphere is handled with sodium chloride solution.
The calcium alginate microsphere of the 15 μ m aperture SPG film preparations of Fig. 6 after with the different concentrations of sodium chloride solution-treated loads the light microscopic photo behind the amycin.Concentration of sodium chloride solution is respectively a) 0.45%, b) 0.9% and c) 1.8%.Inserting little figure is the corresponding laser co-focusing photo of medicine carrying microballoons.
Fig. 7 has represented the amycin content with the microsphere loading of variable concentrations sodium chloride solution processing.
The specific embodiment
Further specify the present invention below in conjunction with instance, but these instances are not used for limiting the present invention.
1) preparation 2% sodium alginate soln 10mL is as water, and preparation contains 3% emulsifying agent, and (sorbester p37: the isobutyltrimethylmethane. 120mL of polysorbate85=9:1) pours water and oil phase in the membrane emulsifier that includes cylindrical SPG film into as oil phase; Water and oil phase stir down and exert pressure with nitrogen respectively in the outside and the inboard of cylindrical SPG film, make water push through the SPG film and get into oil phase; Obtain water-in-oil emulsion; In water-in-oil emulsion, add the saline solution that 20mL contains 5% calcium chloride and 20% sodium chloride, stir 0.5h, add the 50mL isopropyl alcohol then and continue to stir 1h; Separatory, eccentric cleaning; Obtain calcium alginate microsphere, its stereoscan photograph is seen Fig. 1 a, b, and the light microscopic photo is seen Fig. 1 c;
2) it is 0.45% sodium chloride solution that the calcium alginate microsphere of getting 2mg step 1) gained adds the 2mL mass fraction; Vibration 2h; Use the ultra-pure water centrifuge washing then 3 times, its optical microscope photograph is seen Fig. 2 a, and the stereoscan photograph behind the microsphere critical point drying is seen Fig. 3 a;
3) get 2mg step 2) calcium alginate microsphere of gained adds vibration 2h in the 2mL doxorubicin hydrochloride solution (1.5mg/mL), and eccentric cleaning is removed the amycin that is not adsorbed then, obtains loading the calcium alginate microsphere of amycin, and its light microscopic photo is seen Fig. 6 a.
Embodiment 2
Step is with embodiment 1, but in step 2) in to adopt mass fraction be 0.9% sodium chloride solution, its optical microscope photograph is seen Fig. 2 b, dried stereoscan photograph is seen Fig. 3 b, loads behind the amycin light microscopic photo and the laser co-focusing photo of microsphere and sees Fig. 6 b.
Embodiment 3
Step is with embodiment 1, but in step 2) in to adopt mass fraction be 1.8% sodium chloride solution, its optical microscope photograph is seen Fig. 2 c, dried stereoscan photograph is seen Fig. 3 c, loads behind the amycin light microscopic photo of microsphere and sees Fig. 6 c.
Embodiment 4
Step is the SPG film of 2 μ m with embodiment 1 but in step 1), adopt the aperture, obtains loading the calcium alginate microsphere of amycin.
Embodiment 5
Step is the SPG film of 5 μ m with embodiment 1 but in step 1), adopt the aperture, obtains loading the calcium alginate microsphere of amycin.
Embodiment 6
Step is with embodiment 1, but in step 1), adopt concentration be 1% sodium alginate soln as water, the saline solution of adding contains 2.5% calcium chloride and 10% sodium chloride, obtains loading the calcium alginate microsphere of amycin.
Embodiment 7
Step is with embodiment 1, but the employing methylene blue replaces doxorubicin hydrochloride in step 3), has obtained loading the microsphere of methylene blue.
Embodiment 8
Step is with embodiment 1, but the employing ephedrine replaces doxorubicin hydrochloride in step 3), has obtained loading the microsphere of ephedrine.
Embodiment 9
Step is with embodiment 1, but in step 3), adopts vitamin B
1Replace doxorubicin hydrochloride, obtain having loaded vitamin B
1Microsphere.
Claims (3)
1. one kind is utilized sodium chloride solution to handle the method that calcium alginate microsphere is regulated and control the microsphere drug loading, may further comprise the steps:
1) sodium alginate soln of preparation mass concentration 2% is as water, and the isobutyltrimethylmethane. that preparation contains 3% emulsifying agent is as oil phase, and wherein emulsifying agent is sorbester p37 and the polysorbate85 mixture of 9:1 by volume; Water and oil phase by volume 1:12 pour in the membrane emulsifier that includes cylindrical SPG film, water and oil phase stir down and exert pressure with nitrogen respectively in the outside and the inboard of cylindrical SPG film; Make water push through the SPG film and get into oil phase, obtain water-in-oil emulsion, in water-in-oil emulsion, add the saline solution that contains 5% calcium chloride and 20% sodium chloride; Stir 0.5h at least; Add isopropyl alcohol then and continue to stir 1h at least, the volume ratio of water-in-oil emulsion, saline solution and isopropyl alcohol is 13:2:5, separatory, eccentric cleaning; Obtain calcium alginate microsphere, lyophilizing is preserved;
2) calcium alginate microsphere of step 1) gained being added mass fraction is that making its final concentration is 1mg/mL in 0.45% ~ 1.8% the sodium chloride solution, behind the 2h that vibrates at least, uses the ultra-pure water centrifuge washing;
3) with step 2) calcium alginate microsphere through sodium chloride solution is handled of gained adds in the positively charged drug solution, the 2h at least that vibrates, eccentric cleaning is removed not by the drug molecule of calcium alginate microsphere absorption then, obtains the calcium alginate microsphere of drug loading.
2. the sodium chloride solution that utilizes according to claim 1 is handled the method that calcium alginate microsphere is regulated and control the microsphere drug loading; It is characterized in that said SPG film has multiple aperture specification; The aperture is respectively 0.3 μ m, 1 μ m, 2 μ m, 5 μ m, 10 μ m, 15 μ m, 20 μ m, 30 μ m and 50 μ m, and the surface of film is carried out hydrophobization with trim,ethylchlorosilane and handled.
3. the sodium chloride solution that utilizes according to claim 1 is handled the method that calcium alginate microsphere is regulated and control the microsphere drug loading, it is characterized in that said positively charged medicine is doxorubicin hydrochloride, methylene blue, ephedrine or vitamin B in the step 3)
1
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| CN103157413A (en) * | 2013-03-28 | 2013-06-19 | 湖南农业大学 | Method for preparing sodium alginate microcapsule-supported nanoscale zero-valent iron particles |
| CN103285375A (en) * | 2013-05-09 | 2013-09-11 | 中国药科大学 | Phycocyanin microsphere preparation and preparation method thereof |
| CN104861946A (en) * | 2015-03-30 | 2015-08-26 | 山东大学 | Flexible controlled-release microsphere disperse system formed by natural water-soluble polymer and preparation thereof and application of system in reinforcement of oil extraction |
| CN110693725A (en) * | 2019-10-31 | 2020-01-17 | 厦门大学附属中山医院 | Calcium alginate gel tooth root canal filling material and preparation method thereof |
| CN111773428A (en) * | 2020-08-05 | 2020-10-16 | 华中科技大学 | Medicine sustained-release alginic acid embolism microsphere and preparation method thereof |
| CN113350573A (en) * | 2021-06-07 | 2021-09-07 | 王健 | Porous microsphere adhesive with osteoinductive capacity and preparation method thereof |
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| CN101905040A (en) * | 2010-07-23 | 2010-12-08 | 重庆大学 | Method for preparing three-dimensional cell scaffold from elastic microsphere pore-forming agent |
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Patent Citations (3)
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| CN101675996A (en) * | 2008-09-19 | 2010-03-24 | 中国科学院过程工程研究所 | Chitosan nano-microspheres product and preparation method thereof |
| CN101905040A (en) * | 2010-07-23 | 2010-12-08 | 重庆大学 | Method for preparing three-dimensional cell scaffold from elastic microsphere pore-forming agent |
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Cited By (9)
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| CN103157413A (en) * | 2013-03-28 | 2013-06-19 | 湖南农业大学 | Method for preparing sodium alginate microcapsule-supported nanoscale zero-valent iron particles |
| CN103285375A (en) * | 2013-05-09 | 2013-09-11 | 中国药科大学 | Phycocyanin microsphere preparation and preparation method thereof |
| CN104861946A (en) * | 2015-03-30 | 2015-08-26 | 山东大学 | Flexible controlled-release microsphere disperse system formed by natural water-soluble polymer and preparation thereof and application of system in reinforcement of oil extraction |
| CN104861946B (en) * | 2015-03-30 | 2017-06-23 | 山东大学 | A kind of flexible control-release microsphere dispersion formed by natural water-soluble copolymer and its preparation and the application in intensified oil reduction |
| CN110693725A (en) * | 2019-10-31 | 2020-01-17 | 厦门大学附属中山医院 | Calcium alginate gel tooth root canal filling material and preparation method thereof |
| CN111773428A (en) * | 2020-08-05 | 2020-10-16 | 华中科技大学 | Medicine sustained-release alginic acid embolism microsphere and preparation method thereof |
| CN113350573A (en) * | 2021-06-07 | 2021-09-07 | 王健 | Porous microsphere adhesive with osteoinductive capacity and preparation method thereof |
| CN115057741A (en) * | 2022-07-04 | 2022-09-16 | 西南交通大学 | Preparation method of calcium alginate-chitosan microbead slow-release fertilizer difficult to swell |
| CN115057741B (en) * | 2022-07-04 | 2023-06-20 | 西南交通大学 | Preparation method of calcium alginate-chitosan microsphere slow-release fertilizer not easy to swell |
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