CN102772366B - Preparation method of water-soluble molecular microspheres encapsulated by biodegradable high molecules - Google Patents
Preparation method of water-soluble molecular microspheres encapsulated by biodegradable high molecules Download PDFInfo
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- CN102772366B CN102772366B CN201210224251.9A CN201210224251A CN102772366B CN 102772366 B CN102772366 B CN 102772366B CN 201210224251 A CN201210224251 A CN 201210224251A CN 102772366 B CN102772366 B CN 102772366B
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Abstract
The invention relates to a preparation method of water-soluble molecular microspheres encapsulated by biodegradable high molecules. According to the method, a mesoporous nano material is firstly added into a water solution containing water-soluble molecules so as to form an inner water phase, and initial emulsion is formed by high-speed dispersion after the inner water phase is mixed with a degradable high-molecular organic solution. Then, compound emulsion is formed by high-speed dispersion after the initial emulsion is mixed with a water solution containing a surfactant, and solidified degradable high-molecular microspheres are obtained by removing an organic solvent. The microspheres which can be used for releasing hydrophilic molecules are obtained after being washed, filtered and dried. Because the mesoporous nano material is added in the inner water phase, the encapsulation rate of the water-soluble molecules in hydrophobic degradable high molecules is greatly enhanced, and the period of slow release is also increased.
Description
Technical field
The present invention relates to biodegradable microspheres preparing technical field, be specifically related to the method for preparing microsphere that Biodegradable high-molecular is sealed water-soluble molecules.
Background technology
Microsphere refers to that micromolecule dissolves or is dispersed in the small spherical entity forming in macromolecular material substrate, and common particle diameter, at 1-500 μ m, belongs to matrix type skeleton microgranule.The microsphere that the degradable macromolecule of take is substrate has been subject to increasingly extensive attention and application with the superiority of its long-acting slow-release.Be widely used in nearly ten years micromolecule slow/controlled release system, transmit various micromolecule, the micromolecule relating at present comprises hormone, medicine, vitamin, protein, small peptide etc.Existing multiple micromolecule microball preparation goes on the market and sells now.
Generally speaking the preparation method of microsphere has following a few class, two emulsion seasonings, spray drying method, cold nebulization extraction method, phase separation method, supercritical fluid technology etc.The microsphere that wherein prepared by two emulsion seasonings, dashes forward when micromolecule disperses evenly in microsphere and microsphere discharges that it is smaller to release, thereby is most widely used.Two emulsion seasonings are prepared microsphere and first micromolecule are dissolved in to interior water, be added to again stirring and emulsifying in oil phase and form water/oily colostrum, this colostrum is added in outer water and again disperses to form water/oil/water Emulsion, treat just to form curing microsphere after the volatilization of intermediate layer.
While utilizing two emulsion seasonings to prepare microsphere parcel hydrophilic molecule, its envelop rate is difficult to improve, because water-soluble molecules and oil-soluble polymer-polymer miscibility are very poor, and then water-soluble molecules has the tendency being extracted by outer water.The method that tradition improves water-soluble molecules envelop rate is to improve polymeric oil phase concentration, thereby increase oil phase viscosity, makes water-soluble molecules be difficult to be extracted out.This method has certain effect to improving water-soluble molecules envelop rate, but polymeric oil phase concentration is difficult to after increasing disperse, and technique realizes difficulty, and the particle diameter of microsphere is difficult to control.
Mesoporous nano material is the new material with huge surface area and three-dimensional open-framework of a kind of aperture between micropore and macropore.The research and development of mesoporous material is all significant for theoretical research and actual production.It has the excellent specific property that other porous material does not have: the pore passage structure with high-sequential; The single distribution in aperture, and aperture size can change at relative broad range; Mesoporous shape is various, and hole wall forms and character can regulate and control; By optimizing synthesis condition, can obtain high thermal stability and hydrothermal stability etc.Simultaneously because mesoporous material has high-specific surface area and pore volume, thereby there is very strong adsorptivity, to playing fixing effect after the absorption such as small-molecule drug, protein.
Based on above-mentioned principle, mesoporous material is added after interior water adsorbed water soluble molecule, to water-soluble molecules play a part one fixing, then water-soluble molecules is difficult to be extracted while preparing microsphere with two emulsion solidification methods, thereby can greatly improve the envelop rate of water-soluble molecules.Avoided improving the variety of issue producing after polymer oil phase simultaneously, had broad application prospects.
Summary of the invention
The object of the invention is to overcome two lower problems of emulsion method water-soluble molecules envelop rate, the preparation method that provides Biodegradable high-molecular to seal water-soluble molecules microsphere, concrete technical scheme is as follows.
Biodegradable high-molecular is sealed the preparation method of water-soluble molecules microsphere, comprises the steps:
(1) mesoporous nano hole material is added and contain the interior water of formation in water-soluble molecules aqueous solution;
(2) interior water step (1) being obtained adds in degradable macromolecule organic solution, disperses to form colostric fluid under high speed dispersor;
(3) colostric fluid step (2) being obtained adds the aqueous solution that contains surfactant, and high speed dispersion forms emulsion;
(4) emulsion step (3) being obtained is added to the water stirring, desolvation solidifies rear filtration drying, obtains Biodegradable high-molecular and seals water-soluble molecules microsphere.
Further, the particle diameter of the described mesoporous nano material of step (1) is 2-500nm, and the mass ratio of mesoporous material and water-soluble molecules is 0.5 ~ 10 times.
Further, in step (1), aqueous solution also adds surfactant, improves colostric fluid stability, and surfactant concentration is 0.05%-5% (g/mL).
Further, the rate of dispersion of the described high speed dispersor of step (2) is 3000-60000rpm, and the volume ratio of interior water and degradable macromolecule organic solution is 1:2-1:10, and jitter time is 10min-2h.
Further, its surfactant concentration of aqueous solution in step (3) is 0.01%-5% (g/mL), and rate of dispersion is 2000-70000rpm, and in system, organic facies and watr-proportion are between 1:1.5-1:20, and jitter time is between 10min-5h.
Further, the described surfactant in step (1), (3) is anion or cation or the non-ionic surface active agent (being not limited to methylcellulose, Polyethylene Glycol, carboxymethyl cellulose or polyvinyl alcohol) with biocompatibility.
Further, in step (4), solvent removal temperature is 20-50 ℃, and the solvent removal time is 2h-12h, and baking temperature is 20-50 ℃.
Further, the mesoporous nano material using in step (1) is mesoporous silicon or mesoporous hydroxyapatite; Described water-soluble molecules comprises micromolecule or the macromole with treatment and trophic function.
Further, described water-soluble molecules comprises more than one in hormone or chemicals or vitamin or protein or small peptide.
Further, the degradable macromolecule that can use in step (2) is polyurethane or polyester or polylactic acid or polyglycolic acid or PLGA or above-mentioned high molecular complex, and molecular weight is 10000-100000.
Compare with current material, tool of the present invention has the following advantages and effect:
When traditional oils dissolubility degradable macromolecule is sealed water-soluble molecules, envelop rate is lower, and by mesoporous nano material is added in water-soluble molecules aqueous solution, adsorbed water soluble molecule, thereby when using two emulsion solidification methods to prepare microsphere, water-soluble molecules is difficult to be extracted by outer water, and then can greatly improve the envelop rate of water-soluble molecules.
The specific embodiment
Embodiment 1
The Poly(D,L-lactide-co-glycolide that is 17800 by 0.5 gram-molecular weight adds concussion dissolving in 5mL dichloromethane to obtain degradable macromolecule oil solution.(containing 0.1% methylcellulose, g/mL), adding 0.1g particle diameter is to obtain interior water after 25nm mesoporous silicon shakes up to get the aqueous solution of the ofloxacin of the 100mg/mL that 500 μ l prepare.Interior water is added in degradable macromolecule oil solution, with 7200rpm, disperse to obtain for 10 minutes colostrum.Get 30mg methylcellulose be dissolved in 50mL water (0.06%, g/mL), after colostrum is added, with 7200rpm, disperse to obtain for 10 minutes emulsion.Emulsion is added to 35 ℃ of precipitation 4h in 400mL water.Sucking filtration obtains after microsphere, 40 ℃ of dry 10h, and with not adding the microsphere of mesoporous silicon to compare, ofloxacin envelop rate is increased to 72% from 25%.
Embodiment 2
The polylactic acid that is 23000 by 0.4 gram-molecular weight adds concussion dissolving in 5mL dichloromethane to obtain degradable macromolecule oil solution.Get the TGF-β of the 50mg/mL that 600 μ l prepare
3(containing 1% Polyethylene Glycol, g/mL), add 0. 1mg particle diameter is to obtain interior water after 30nm mesoporous silicon shakes up to aqueous solution.Interior water is added in degradable macromolecule oil solution, with 9000rpm, disperse to obtain for 25 minutes colostrum.Get 300mg Polyethylene Glycol be dissolved in 30mL water (1%, g/mL), after colostrum is added, with 10000rpm, disperse to obtain for 30 minutes emulsion.Emulsion is added to 35 ℃ of precipitation 4h in 400mL water.Sucking filtration obtains after microsphere, 40 ℃ of dry 10h.TGF-β
3envelop rate is increased to 42% from 15%.
Embodiment 3
The polycaprolactone that is 38000 by 0.6 gram-molecular weight adds concussion dissolving in 4mL dichloromethane to obtain degradable macromolecule oil solution.The vitamin C aqueous solution of getting the 10mg/mL that 400 μ l prepare, adding 50mg particle diameter is to obtain interior water after the mesoporous hydroxyapatite of 25nm shakes up.Interior water is added in degradable macromolecule oil solution, with 10000rpm, disperse to obtain for 50 minutes colostrum.Get 30mg methylcellulose be dissolved in 40mL water (0.075%, g/mL), after colostrum is added, with 12000rpm, disperse to obtain for 20 minutes emulsion.Emulsion is added to 35 ℃ of precipitation 3h in 400mL water.Sucking filtration obtains after microsphere, 40 ℃ of dry 10h.Vitamin C envelop rate is increased to 45% from 15%.
Embodiment 4
The polylactic acid that is 50000 by 0.3 gram-molecular weight adds concussion dissolving in 6mL dichloromethane to obtain degradable macromolecule oil solution.(containing 0.5% carboxymethyl cellulose, g/mL), adding 0. 5mg particle diameter is to obtain interior water after the mesoporous hydroxyapatite of 200nm shakes up to get the serine aqueous solution of the 2mg/mL that 400 μ l prepare.Interior water is added in degradable macromolecule oil solution, with 8000rpm, disperse to obtain for 1 hour colostrum.Get 30mg methylcellulose be dissolved in 20mL water (0.15%, g/mL), after colostrum is added, with 9000rpm, disperse to obtain for 50 minutes emulsion.Emulsion is added to 35 ℃ of precipitation 7h in 400mL water.Sucking filtration obtains after microsphere, 40 ℃ of dry 10h.Serine envelop rate is increased to 67% from 22%.
Embodiment 5
The poly-valerolactone that is 90000 by 0.5 gram-molecular weight adds concussion dissolving in 4mL dichloromethane to obtain degradable macromolecule oil solution.(containing 2% polyvinyl alcohol, g/mL), adding 25mg particle diameter is to obtain interior water after the mesoporous hydroxyapatite of 100nm shakes up to get the ofloxacin aqueous solution of the 10mg/mL that 600 μ l prepare.Interior water is added in degradable macromolecule oil solution, with 8000rpm, disperse to obtain for 20 hours colostrum.Get 10mg methylcellulose be dissolved in 30mL water (0.03%, g/mL), after colostrum is added, with 10000rpm, disperse to obtain for 15 minutes emulsion.Emulsion is added to 35 ℃ of precipitation 3h in 400mL water.Sucking filtration obtains after microsphere, 40 ℃ of dry 10h.Ofloxacin envelop rate is increased to 76% from 28%.
Embodiment 6
The polyurethane that is 40000 by 0.3 gram-molecular weight adds concussion dissolving in 4mL dimethyl formamide to obtain degradable macromolecule oil solution.(containing 3% polyvinyl alcohol, g/mL), adding 32mg particle diameter is to obtain interior water after the mesoporous hydroxyapatite of 200nm shakes up to get the ofloxacin aqueous solution of the 10mg/mL that 800 μ l prepare.Interior water is added in degradable macromolecule oil solution, with 8000rpm, disperse to obtain for 30 hours colostrum.Get 0.6g methylcellulose be dissolved in 30mL water (2%, g/mL), after colostrum is added, with 10000rpm, disperse to obtain for 20 minutes emulsion.Emulsion is added to 35 ℃ of precipitation 3h in 400mL water.Sucking filtration obtains after microsphere, 40 ℃ of dry 10h.Ofloxacin envelop rate is increased to 68% from 35%.
Claims (8)
1. Biodegradable high-molecular is sealed the preparation method of water-soluble molecules microsphere, it is characterized in that comprising the steps:
(1) mesoporous nano material is added and contain the interior water of formation in water-soluble molecules aqueous solution; The particle diameter of described mesoporous nano material is 2-500nm, and the mass ratio of mesoporous material and water-soluble molecules is 0.5 ~ 10 times;
(2) interior water step (1) being obtained adds in degradable macromolecule organic solution, disperses to form colostric fluid under high speed dispersor; The rate of dispersion of described high speed dispersor is 3000-60000rpm, and the volume ratio of interior water and degradable macromolecule organic solution is 1:2-1:10, and jitter time is 10min-2h;
(3) colostric fluid step (2) being obtained adds the aqueous solution that contains surfactant, and high speed dispersion forms emulsion;
(4) emulsion step (3) being obtained is added to the water stirring, desolvation solidifies rear filtration drying, obtains Biodegradable high-molecular and seals water-soluble molecules microsphere.
2. preparation method according to claim 1, is characterized in that in step (1), aqueous solution also adds surfactant, and surfactant concentration is 0.05%-5%g/mL.
3. preparation method according to claim 1, it is characterized in that its surfactant concentration of aqueous solution in step (3) is 0.01%-5% g/mL, rate of dispersion is 2000-70000rpm, and in system, organic facies and watr-proportion are between 1:1.5-1:20, and jitter time is between 10min-5h.
4. preparation method according to claim 2, is characterized in that the described surfactant in step (1), (3) is anion or cation or the non-ionic surface active agent with biocompatibility.
5. preparation method according to claim 1, is characterized in that in step (4), solvent removal temperature is 20-50 ℃, and the solvent removal time is 2h-12h, and baking temperature is 20-50 ℃.
6. preparation method according to claim 1, is characterized in that the mesoporous nano material using in step (1) is mesoporous silicon or mesoporous hydroxyapatite; Described water-soluble molecules comprises micromolecule or the macromole with treatment and trophic function.
7. preparation method according to claim 6, is characterized in that described water-soluble molecules comprises more than one in hormone or chemicals or vitamin or protein or small peptide.
8. preparation method according to claim 1, it is characterized in that the degradable macromolecule that can use in step (2) is polyurethane or polyester or polylactic acid or polyglycolic acid or PLGA or above-mentioned high molecular complex, molecular weight is 10000-100000.
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| CN102961780B (en) * | 2012-12-17 | 2014-07-23 | 江苏科技大学 | Preparation method of bone repair material with slow-release performance |
| CN103656651A (en) * | 2013-11-22 | 2014-03-26 | 深圳清华大学研究院 | Drug-loaded composite microsphere and preparation method thereof |
| CN103830112B (en) * | 2014-02-28 | 2017-01-18 | 华南理工大学 | Emulsion with functions of persistently moisturizing and removing wrinkles and preparation method thereof |
| EP3612164A1 (en) * | 2017-04-19 | 2020-02-26 | Nanomi B.V. | Method and system for producing substantially mono-disperse particles of a substance |
| CN110302172A (en) * | 2019-07-18 | 2019-10-08 | 广东省医疗器械研究所 | A kind of polymer composite microsphere, preparation method and application |
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| CN1463696A (en) * | 2002-06-14 | 2003-12-31 | 中国科学院成都有机化学研究所 | Biological active control release microsphere and method for preparing same |
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| CN1463696A (en) * | 2002-06-14 | 2003-12-31 | 中国科学院成都有机化学研究所 | Biological active control release microsphere and method for preparing same |
| CN102110506A (en) * | 2010-11-17 | 2011-06-29 | 安徽工业大学 | Carbon-based magnetic mesoporous composite microsphere and preparation method thereof |
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