CN100553756C - A kind of preparation method of core-shell structure nano microcapsule - Google Patents
A kind of preparation method of core-shell structure nano microcapsule Download PDFInfo
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- CN100553756C CN100553756C CNB2007101917253A CN200710191725A CN100553756C CN 100553756 C CN100553756 C CN 100553756C CN B2007101917253 A CNB2007101917253 A CN B2007101917253A CN 200710191725 A CN200710191725 A CN 200710191725A CN 100553756 C CN100553756 C CN 100553756C
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Abstract
A kind of preparation method of core-shell structure nano microcapsule is a kind of good dispersion, stable storage and nano-microcapsule and the technology of preparing thereof with slow release effect.It is template that this method adopts polymer particles, and the polyelectrolyte that will have opposite charges by the layer upon layer electrostatic self-assembling method is assembled into template surface, again with the template particle dissolution, obtains having core-shell structure nano microcapsule.The wall thickness of micro-capsule can accurately be controlled at nanoscale, the polyelectrolyte of inwall and drug interaction, thus medicine is wrapping in the micro-capsule.The drug release rate that is wrapped up is controlled.The present invention is simple to operate, good reproducibility, and release rate of drugs is controlled effectively, and has a good application prospect at the packaging field of slow releasing pharmaceutical.
Description
Technical field
The present invention is specifically related to a kind of new type structure of hud nano-microcapsule preparation method, especially a kind of good dispersion, stable storage and have the nano-microcapsule and the technology of preparing thereof of slow release effect.
Background technology
Core-shell structure nano microcapsule and core-shell structure nano microcapsule are piled up the porous material that forms all has very big potential value in the parcel protection of bioactive macromolecules such as the simulation of the packing of catalytic field, slow releasing pharmaceutical, artificial cell and protein, enzyme, DNA and as each big fields such as coating or pigment, becomes one of noticeable direction in the investigation of materials field.
The template electrostatic self-assembly method is one of main method of preparation spherical shell structure nano-microcapsule.It is that template is combined with self assembling process, utilize the electrostatic adsorption between zwitterion to have opposite charges in the absorption of the surface of nano particle kernel, to form film, again kernel is got rid of, generally can adopt solvent that kernel is dissolved, thereby obtain hollow granule, its advantage is the size of nuclear particle in can selecting to use, particle shell layer thickness and composition are to satisfy different demands.
At present, how the research that has had both at home and abroad a lot of empty nuclear nanocapsules to use aspect medical improves the matter of utmost importance that medicine carrying amount and control slow-release time have become empty nuclear nanocapsule to use.Therefore, finding a kind of medicine carrying amount height, the regulatable pharmaceutical carrier of sustained release performance, is to have challenging work.
Adopt the template electrostatic self-assembly method to prepare core-shell structure nano microcapsule, its micro-capsule size can accurately be controlled by template, and its wall thickness can be controlled in the nanoscale, by adjusting the medicine carrying amount and the sustained release performance thereof of the adjustable nano-microcapsule of its preparation environment.
Summary of the invention
Technical problem: the purpose of this invention is to provide a kind of core-shell structure nano microcapsule preparation method, medicine is wrapped in the nano-microcapsule, and have higher medicine carrying amount and excellent drug sustained release performance.
Technical scheme: the new type structure of hud nano-microcapsule of proposition of the present invention is to adopt dispersion copolymerization method to prepare melamine resin (MF) Nano microsphere earlier; Be template with the MF microballoon again, wrap up the electronegative polyelectrolyte of one deck on the surface of above-mentioned MF Nano microsphere by the template electrostatic self-assembly method; Again by Electrostatic Absorption at the above-mentioned positively charged polyelectrolyte of surface parcel one deck that has wrapped up the MF Nano microsphere of the electronegative polyelectrolyte of one deck; Remove MF by the method for acid etch at last, prepare stable core-shell structure nano microcapsule as template.This core-shell structure nano microcapsule has nanoscale.
Above-mentioned core-shell structure nano microcapsule preparation method is as follows:
(1) in there-necked flask, adds 2～5g melamine and 4～10ml formalin, under 40～70 ℃ water-bath, stirred 0.5～2 hour, obtain the prepolymer melamine methylol.With 0.2～2.0g polyvinyl alcohol, being dissolved under 40～70 ℃ the water-bath in 50～150g ultra-pure water then, is 3～5 with the pH value of acetate regulator solution.Above-mentioned polyvinyl alcohol is joined in the prepolymer melamine methylol, after reacting 0.5～1.0 hour under 40～70 ℃ the water-bath, 40～70 ℃ of ultrasonic dispersion 5～10min, frozen water cooling fast.Products therefrom is centrifugal under the 4000rpm condition, remove and add ultra-pure water again after the supernatant and disperse again, centrifugal again, repeat this process 3～5 times, vacuum drying obtains the MF powder, and low temperature is preserved.
(2) be 0.3～0.6mol/L in concentration, pH is in 3～5 the NaCl solution, with concentration is that the electronegative polyelectrolyte of 0.5～1.5mg/ml and step (1) gained MF nanoparticle are mixed, the centrifugal supernatant of removing, adding ultra-pure water again disperses the MF nanoparticle again, the centrifugal again supernatant of removing, like this cyclic washing obtains the MF nanoparticle of the polyelectrolyte of ground floor wrap negative electrical charge; Be 0.3～0.6mol/L in concentration again, pH is in 3～5 the NaCl solution, the MF nanoparticle is joined the positively charged polyelectrolyte that concentration is 0.5～1.5mg/ml, the centrifugal supernatant of removing, so use the ultra-pure water cyclic washing, obtain the MF nanoparticle of the polyelectrolyte of second layer wrap positive charge; Repeat above process, respectively will be positively charged and polyelectrolyte self assembly layer by layer negative electrical charge by the number of plies of expection, obtain the nuclear shell structure nano particulate, remove MF by the method for acid etch as template, obtain the nano-microcapsule of hollow.
(3) under 20～70 ℃ of temperature, be 0.5～5 with the nano-microcapsule of the hollow of step (2) gained in the pH value, concentration is to hatch 0.5～3 hour in the pharmaceutical aqueous solution of 0.01～100mg/ml, and medicine is embedded in the nano-microcapsule, obtains the medicament-carried nano micro-capsule.
Among the present invention, said electronegative polyelectrolyte is sodium alginate (ALG); Positively charged polyelectrolyte is gelatin (GEL).Said medicine is Licardipine Hydrochloride or Olopatadine hydrochloride.
By changing the number of plies and the preparation condition of poly-electrolysis self assembly, can regulate and control the micro-structural and the thickness of nano-microcapsule cyst wall at nanoscale, thereby improve medicine carrying amount and sustained release performance.
Beneficial effect: the invention has the advantages that: adopt the template electrostatic self-assembly method to prepare a kind of new type structure of hud nano-microcapsule, not only simple to operate, good reproducibility, nano-microcapsule size are even, and its size can be regulated by preparation condition.This core-shell structure nano microcapsule stability is higher, as self-assembled material, has excellent biological compatibility with poisonless biological degradable material sodium alginate and gelatin.
Description of drawings
Fig. 1 is the transmission electron microscope picture of empty nuclear nanocapsule,
Fig. 2 is a Licardipine Hydrochloride cumulative in vitro releasing curve diagram.
The specific embodiment
Following example further specifies the present invention, but these examples are not used for limiting the present invention.
Example 1
In there-necked flask, add 2g melamine and 5ml formalin, under 50 ℃ water-bath, stir 30min, obtain the prepolymer melamine methylol.With the 0.5g polyvinyl alcohol, being dissolved under 50 ℃ the water-bath in the 100g ultra-pure water then, is 3.5 with the pH value of acetate regulator solution.Above-mentioned polyvinyl alcohol is joined in the prepolymer melamine methylol, after reacting 0.5 hour under 50 ℃ the water-bath, 50 ℃ of ultrasonic dispersion 5min, frozen water cooling fast.Products therefrom is centrifugal under the 4000rpm condition, remove and add ultra-pure water again after the supernatant and disperse again, centrifugal again, repeat this process 3 times, vacuum drying obtains the MF powder, and low temperature is preserved.
In 5ml concentration is 0.3mol/L, pH is in 3.5 the NaCl solution, with concentration is that the sodium alginate of 0.5mg/ml and 1ml concentration are that 5% MF nanoparticle suspension is mixed, the centrifugal supernatant of removing, at the adding ultra-pure water MF nanoparticle is disperseed again, the centrifugal again supernatant of removing, so cyclic washing obtains the MF nanoparticle that ground floor wraps up sodium alginate; Be 0.3mol/L in 5ml concentration again, pH in 3.5 the NaCl solution, joins the MF nanoparticle in the gelatin that concentration is 0.5mg/ml, and the centrifugal supernatant of removing is so used the ultra-pure water cyclic washing, obtains the MF nanoparticle of second layer wrap gelatin; Repeat above process, until obtaining MF/ (ALG/GEL)
4The nuclear shell structure nano particulate.
Then this nuclear shell structure nano particulate is joined in the hydrochloric acid solution of pH=1.2, reaction 10min removes the MF template.With the hydrochloric acid solution cyclic washing of pH=1.2 2 times, centrifugal removal supernatant with ultra-pure water washing 3 times, obtains the nano-microcapsule of hollow.Fig. 1 is the transmission electron microscope picture of empty nuclear nanocapsule.
Under 30 ℃ of temperature, it is 1.0 that the nano-microcapsule solution of 50 μ l hollows of gained is joined the 10mlpH value, concentration is hatching 1 hour in the Licardipine Hydrochloride aqueous solution of 0.04mg/ml, and Licardipine Hydrochloride is embedded in the nano-microcapsule, obtains the medicament-carried nano micro-capsule.
With the medicament-carried nano micro-capsule, disperse with a little ultra-pure water, place bag filter, be dissolution medium with the PBS of pH=6.8, temperature is 30 ℃, carries out the release experiment of medicine.And pure Licardipine Hydrochloride placed bag filter, do control experiment.Fig. 2 is a Licardipine Hydrochloride cumulative in vitro release profiles.
Example 2
Identical with example 1, but dissolution medium becomes the hydrochloric acid solution of pH=1.2.Prepared core-shell structure nano microcapsule discharged less than 10% of medicine carrying amount in the dissolution medium of the hydrochloric acid solution of pH=1.2 in preceding 2 hours.Fig. 2 is a Licardipine Hydrochloride cumulative in vitro release profiles.
Example 3
Identical with example 1, be 5.0 but Licardipine Hydrochloride solution becomes the pH value, concentration is 50mg/ml.
Example 4
Identical with example 1, but the medicine carrying temperature becomes 60 ℃.
The core-shell structure nano microcapsule that above-mentioned example 3,4 is prepared, its structure comes to the same thing with example 1 with performance or is similar, all has sustained release performance preferably.
Claims (4)
1. the preparation method of a core-shell structure nano microcapsule is characterized in that this method may further comprise the steps:
1) in there-necked flask, adds 2～5g melamine and 4～10ml formalin, under 40～70 ℃ water-bath, stirred 0.5～2 hour, obtain the prepolymer melamine methylol; With 0.2～2.0g polyvinyl alcohol, being dissolved under 40～70 ℃ the water-bath in 50～150g ultra-pure water then, is 3～5 with the pH value of acetate regulator solution; Above-mentioned polyvinyl alcohol is joined in the prepolymer melamine methylol, after reacting 0.5～1.0 hour under 40～70 ℃ the water-bath, 40～70 ℃ of ultrasonic dispersion 5～10min, frozen water cooling fast; Products therefrom is centrifugal under the 4000rpm condition, remove and add ultra-pure water again after the supernatant and disperse again, centrifugal again, repeat this process 3～5 times, vacuum drying obtains the MF powder, and low temperature is preserved;
2) be 0.3～0.6mol/L in concentration, pH is in 3～5 the NaCl solution, with concentration is that the electronegative polyelectrolyte of 0.5～1.5mg/ml and the described MF powder of step 1) are mixed, the centrifugal supernatant of removing, at the adding ultra-pure water MF nanoparticle is disperseed again, the centrifugal again supernatant of removing, like this cyclic washing obtains the MF nanoparticle of the polyelectrolyte of ground floor wrap negative electrical charge; Be 0.3～0.6mol/L in concentration again, pH is in 3～5 the NaCl solution, the MF nanoparticle is joined the positively charged polyelectrolyte that concentration is 0.5～1.5mg/ml, the centrifugal supernatant of removing, so use the ultra-pure water cyclic washing, obtain the MF nanoparticle of the polyelectrolyte of second layer wrap positive charge; Repeat above process, respectively will be positively charged and polyelectrolyte self assembly layer by layer negative electrical charge by the number of plies of expection, obtain the nuclear shell structure nano particulate, remove MF by the method for acid etch as template, obtain the nano-microcapsule of hollow;
3) under 20～70 ℃ of temperature, with step 2) nano-microcapsule of the hollow of gained is 0.5～5 in the pH value, concentration is to hatch 0.5～3 hour in the pharmaceutical aqueous solution of 0.01～100mg/ml, and medicine is embedded in the nano-microcapsule, obtains the medicament-carried nano micro-capsule.
2. the preparation method of core-shell structure nano microcapsule according to claim 1 is characterized in that described electronegative polyelectrolyte is a sodium alginate.
3. the preparation method of core-shell structure nano microcapsule according to claim 1 is characterized in that described positively charged polyelectrolyte is a gelatin.
4. the preparation method of core-shell structure nano microcapsule according to claim 1 is characterized in that the medicine that micro-capsule is suitable for is Licardipine Hydrochloride or Olopatadine hydrochloride.
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| CN101747512B (en) * | 2009-12-22 | 2012-07-11 | 浙江大学 | Electrostatic driving bionic super-molecule assembling body, preparation method thereof and purposes |
| CN101773483B (en) * | 2010-01-20 | 2011-06-22 | 华东理工大学 | Preparation method of water-insoluble drug microcapsule |
| CN101792118B (en) * | 2010-03-12 | 2012-10-03 | 浙江大学 | Method for preparing one-dimensional nanometer materials by using polyelectrolyte to adjust and control 1-pyrene formaldehyde |
| US8992660B2 (en) * | 2012-05-11 | 2015-03-31 | Lg Chem, Ltd. | Method for fabricating hollow metal nano particles and hollow metal nano particles fabricated by the method |
| CN104959085A (en) * | 2015-05-07 | 2015-10-07 | 温州生物材料与工程研究所 | Size and shape controllable polyelectrolyte hollow microcapsule and application thereof |
| CN104923133A (en) * | 2015-05-07 | 2015-09-23 | 温州生物材料与工程研究所 | Preparation method of polyelectrolyte microcapsules with independently controllable dimension and shape |
| CN105561901A (en) * | 2016-01-12 | 2016-05-11 | 南京工程学院 | Preparation method of mono-dispersed melamine resin microsphere |
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