CN102631680B - 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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- 239000000648 calcium alginate Substances 0.000 title claims abstract description 39
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- OKHHGHGGPDJQHR-YMOPUZKJSA-L calcium;(2s,3s,4s,5s,6r)-6-[(2r,3s,4r,5s,6r)-2-carboxy-6-[(2r,3s,4r,5s,6r)-2-carboxylato-4,5,6-trihydroxyoxan-3-yl]oxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylate Chemical compound [Ca+2].O[C@@H]1[C@H](O)[C@H](O)O[C@@H](C([O-])=O)[C@H]1O[C@H]1[C@@H](O)[C@@H](O)[C@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@H](O2)C([O-])=O)O)[C@H](C(O)=O)O1 OKHHGHGGPDJQHR-YMOPUZKJSA-L 0.000 title claims abstract description 39
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- 238000003756 stirring Methods 0.000 claims description 12
- 239000003995 emulsifying agent Substances 0.000 claims description 9
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims description 8
- 239000007762 w/o emulsion Substances 0.000 claims description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 claims description 6
- 229960002918 doxorubicin hydrochloride Drugs 0.000 claims description 6
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 5
- 239000000661 sodium alginate Substances 0.000 claims description 5
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- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 4
- 239000001110 calcium chloride Substances 0.000 claims description 4
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 4
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims description 4
- 229960002179 ephedrine Drugs 0.000 claims description 4
- 229960000907 methylthioninium chloride Drugs 0.000 claims description 4
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims description 3
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- PRXRUNOAOLTIEF-WUOFIQDXSA-N sorbitan trioleate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C\CCCCCCCC)C1OCC(O)C1OC(=O)CCCCCCC\C=C\CCCCCCCC PRXRUNOAOLTIEF-WUOFIQDXSA-N 0.000 claims description 3
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- JZRWCGZRTZMZEH-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 claims description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 abstract description 5
- 229910001424 calcium ion Inorganic materials 0.000 abstract description 5
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- 238000002791 soaking Methods 0.000 abstract 2
- NWXMGUDVXFXRIG-WESIUVDSSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O NWXMGUDVXFXRIG-WESIUVDSSA-N 0.000 description 9
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- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 2
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- AEMOLEFTQBMNLQ-BZINKQHNSA-N D-Guluronic Acid Chemical compound OC1O[C@H](C(O)=O)[C@H](O)[C@@H](O)[C@H]1O AEMOLEFTQBMNLQ-BZINKQHNSA-N 0.000 description 1
- AEMOLEFTQBMNLQ-VANFPWTGSA-N D-mannopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H]1O AEMOLEFTQBMNLQ-VANFPWTGSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
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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 the sodium chloride solution that especially utilizes variable concentrations is processed the method for microsphere regulation and control microsphere drug loading.
Background technology
Polymer microsphere refer to diameter at micron order, be shaped as a spherical family macromolecule material.In recent years, because the polymer microsphere huge applications potential in fields such as medicine, biochemistry, electronic information is worth, therefore be widely studied.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 large, but the particle size distribution of obtained microsphere is mostly all very wide, so that be restricted in the application in some fields.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 outside stressed effect of decentralized photo by the inoranic membrane micropore, be pressed into and form emulsion in the continuous phase, by controlled pressure, emulsifying agent, continuous phase flow velocity and membrane aperture, realize the monodispersity of emulsion droplets, this is that the 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.The most normal use is a kind of inorganic porous glass-film---SPG film.
The natural polysaccharide polymer microsphere has good application prospect 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 of guluronic acid and two kinds of monomers of mannuronic acid.It derives from the abundant seaweed plant of reserves in the ocean, has the 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 the fields such as food, medical science.Calcium alginate microsphere is the excellent carrier of drug delivery, and its multiplex stirring and emulsifying method, gas atomization method or static drop formation legal system are standby to be obtained.The method for preparing at present the medicine carrying calcium alginate microsphere 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 then calcium ion crosslinking forms microsphere.The static method of formation is difficult to obtain the following microsphere of particle diameter 50 μ m, and the microspherulite diameter wider distribution that the stirring and emulsifying method obtains, prepare that method that the initial stage just mixes medicine and micro-sphere material exists 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 process 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 processed 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, preparation contains the isobutyltrimethylmethane. of 3% emulsifying agent as oil phase, wherein emulsifying agent is the by volume mixture of 9:1 of sorbester p37 and polysorbate85, water and oil phase by volume 1:12 pour in the membrane emulsifier that includes cylindrical SPG film, water and oil phase are respectively in the outside and the inboard of cylindrical SPG film, exert pressure with nitrogen under stirring, make water push through the SPG film and enter 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 at least 0.5h, then add isopropyl alcohol and continue to stir at least 1h, water-in-oil emulsion, the volume ratio of 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 processed of gained adds in the positively charged drug solution, at least 2h that vibrates, then eccentric cleaning is removed the drug molecule that is not adsorbed by calcium alginate microsphere, 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 processed.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 higher just to have more calcium ions replaced, and the carboxylate radical in the alginic acid changes free state into by the chelating attitude simultaneously.Calcium alginate microsphere immerses in the positively charged drug solution after cleaning, because alginic acid is electronegative in water, so calcium alginate microsphere can be by the drug molecule of electrostatic interaction adsorption band positive charge.Because only being in the carboxylate radical of free state could ionize in solution and be negative electricity, thereby the ability that possesses adsorption band positive charge drug molecule, 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.By 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: technique of the present invention is simple, raw material sources are extensive, the process controllability is good, it is even that final products have particle diameter, there is multiple particle diameter specification optional, drug loading is large and be easy to, characteristics that envelop rate is high, in fields such as medicine, biology, chemical industry good application prospect 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 microsphere.C) the light microscopic photo of microsphere.
The light microscopic photo of the calcium alginate microsphere of 15 μ m aperture SPG film preparations after Fig. 2 processes with the sodium chloride solution of variable concentrations.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 15 μ m aperture SPG film preparations after Fig. 3 processes with the sodium chloride solution of variable concentrations.Concentration of sodium chloride solution is respectively a) 0.45%, b) 0.9% and c) 1.8%.Insert the stereoscan photograph that little figure is cross section corresponding to microsphere.
The content of calcium ion and sodium ion in the microsphere that Fig. 4 has represented to process with the variable concentrations sodium chloride solution.
Fig. 5 is the infrared spectrum before and after microsphere is processed with sodium chloride solution.
The calcium alginate microsphere of 15 μ m aperture SPG film preparations after Fig. 6 processes with the sodium chloride solution of variable concentrations 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 laser co-focusing photo corresponding to 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 example, but these examples are not used for limiting the present invention.
1) the sodium alginate soln 10mL of preparation 2% is as water, preparation contains 3% emulsifying agent, and (sorbester p37: the isobutyltrimethylmethane. 120mL of polysorbate85=9:1) is as oil phase, water and oil phase are poured in the membrane emulsifier that includes cylindrical SPG film, water and oil phase are respectively in the outside and the inboard of cylindrical SPG film, exert pressure with nitrogen under stirring, make water push through the SPG film and enter 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, then add the 50mL isopropyl alcohol and continue to stir 1h, separatory, eccentric cleaning, obtain calcium alginate microsphere, its stereoscan photograph is seen Fig. 1 a, b, 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, then use the ultra-pure water centrifuge washing 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 then eccentric cleaning is removed the amycin that is not adsorbed, and 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 adopt the aperture in step 1), obtains loading the calcium alginate microsphere of amycin.
Embodiment 5
Step is the SPG film of 5 μ m with embodiment 1 but adopt the aperture in step 1), 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 adopts vitamin B in step 3)
1Replace doxorubicin hydrochloride, obtain having loaded vitamin B
1Microsphere.
Claims (3)
1. one kind is utilized sodium chloride solution to process 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, preparation contains the isobutyltrimethylmethane. of 3% emulsifying agent as oil phase, wherein emulsifying agent is the by volume mixture of 9:1 of sorbester p37 and polysorbate85, water and oil phase by volume 1:12 pour in the membrane emulsifier that includes cylindrical SPG film, water and oil phase are respectively in the outside and the inboard of cylindrical SPG film, exert pressure with nitrogen under stirring, make water push through the SPG film and enter 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 at least 0.5h, then add isopropyl alcohol and continue to stir at least 1h, water-in-oil emulsion, the volume ratio of 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 processed of gained adds in the positively charged drug solution, at least 2h that vibrates, then eccentric cleaning is removed the drug molecule that is not adsorbed by calcium alginate microsphere, obtains the calcium alginate microsphere of drug loading.
2. the sodium chloride solution that utilizes according to claim 1 is processed the method that calcium alginate microsphere is regulated and control the microsphere drug loading, it is characterized in that described 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 processed.
3. the sodium chloride solution that utilizes according to claim 1 is processed the method that calcium alginate microsphere is regulated and control the microsphere drug loading, it is characterized in that step 3) described in positively charged medicine be doxorubicin hydrochloride, methylene blue, ephedrine or vitamin B
1
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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 |
CN113350573B (en) * | 2021-06-07 | 2022-05-27 | 王健 | Porous microsphere adhesive with osteoinductive capacity and preparation method thereof |
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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 |
CN102357075A (en) * | 2011-09-30 | 2012-02-22 | 武汉平华生物医药科技有限公司 | Docetaxel nano preparation and preparation method thereof |
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