CN1128167C - Nanometer microball of chitosan-polyacrylic acid composite and its producing method and use - Google Patents
Nanometer microball of chitosan-polyacrylic acid composite and its producing method and use Download PDFInfo
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- CN1128167C CN1128167C CN01113580.8A CN01113580A CN1128167C CN 1128167 C CN1128167 C CN 1128167C CN 01113580 A CN01113580 A CN 01113580A CN 1128167 C CN1128167 C CN 1128167C
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Abstract
The present invention relates to a nanometer microsphere of chitosan-polyacrylic acid compounds, the average particle diameter of which is from 200 to 300 nm, wherein the molecular weight of chitosan is from 10, 000 to 500, 000; the deacetylation degree is from 50 to 100%; the molecular weight of polyacrylic acid is from 20, 000 to 200, 000; the content of polyacrylic acid is from 20 to 50%. The nanometer microsphere can be used as a carrier of medicine, particularly a carrier of a magnetic resonance imaging and developing reinforcing agent. The present invention discloses a preparation method of the nanometer microsphere.
Description
The present invention relates to a kind of Biodegradable high-molecular Nano microsphere, can be used as medicine and proteic carrier, also can be used as the carrier of magnetic resonance contrast agent.
Adopt biocompatible polymer material to prepare the sustained release that medicine and genophore be used for them and received more and more many concerns.The degradable macromolecule Nano microsphere be late nineteen seventies grow up have slow controlled release put with body in the new drug carrier of target.The specificity that can distribute in vivo according to particle, conduct drugs to disease location after, slowly discharge, medicine is significantly increased in the concentration of lesions position, prolong action time, the result of treatment of medicine significantly improves; Alleviate the toxic side effect of medicine simultaneously, thereby make medicine reach the purpose of slow release of lesions position in vivo and target administration, clinical application is had great application value (J.Exp.Med.1988. (67) .440-451) human normal tissue.
As the biodegradable polymer of the general employing of the used material of the Nano microsphere of pharmaceutical carrier, mainly contain albumin, gelatin, polysaccharide and polyester compound etc.The polyester compound is to be recognized as the earliest to use the intravital synthetic materials in the people safely.As polylactide, poly-glycollide, polycaprolactone and their multipolymer (Contraception, 1976, (13), 275-384).Recently, a kind of novel multi-block polymer that is embedded with hydrophilic segment PEG has received concern.(Colloids and surfaces B:Biointerfaces, 2000,18:371-379) these materials come with some shortcomings, as: the medicine encapsulation ratio is too low, controlled delivery of pharmaceutical agents discharges restive, and polypeptide and other biologically active substance are easy to inactivation etc. in encapsulation process.And the chitosan that adopts among the present invention is because its excellent biological compatibility, biodegradable, hypotoxicity and excellent wetting ability become a kind of excellent material as pharmaceutical carrier.
Nuclear magnetic resonance MRI:Magnetic Resonance Imaging) technology has been one of last word in the medical imageology since the eighties.It is to utilize in the organism different tissues the different magnetic resonance signal of generation comes imaging under the influence of magnetic field adding.The power of magnetic resonance signal depends on the relaxation time of proton in the interior molecule of tissue.Paramagnetic metal ion is (as Gd
3+, Mn
2+, Fe
3+) the local magnetic field that produces of unpaired electron spin can shorten the relaxation time of proton in the contiguous water molecules, thereby increase the magnetic resonance signal intensity of adjacent domain, improve the contrast gradient of image.
Make a definite diagnosis the strength of signal at position for raising, must make developing promotor reach certain concentration, could improve the sensitivity and the accuracy of diagnosis at this position.And traditional mr developing promotor (as: DTPA-Gd DTPA-Gd) is a toughener between tissue, and the extracellular distributes, and biodistribution does not have specificity, can not be in the privileged site enrichment, thus, the consumption of toughener must be strengthened, better image could be obtained.Because DTPA-Gd has certain side effect, increased dosage amount must influence its practical security, thus, has limited mr imaging technique and has medically further used.
Adopting Nano microsphere or nanoparticle to come load mr developing promotor, is a newer field, has obtained great development in recent years.How passing through the characteristics of the target of nano-high molecule carrier, contrast medium is transported to interested position, improve the signal of lower concentration acceptor, is the focus of nuclear magnetic resonance contrast medium research.By having the high molecular nanometer control delivery of good biocompatibility, load DTPA-Gd contrast medium, the contrast medium that can make low concentration improve the contrast gradient of nuclear magnetic resonance image in Local enrichment.Simultaneously, it is long that nanoparticle contrast agent also has the body-internal-circulation time, the function of target, (collods andsurfaces B:Biointerfaces 1999, (16): 305-319) at medical blood pond radiography, fields such as liver, lung tumor diagnosis have fabulous application prospect.
The synthetic medicine carrying chitosan microball of prior art mainly contains the precipitator method, reversed phase method (W/O) and spray method etc., preparation technology's more complicated of this several method, and the purification step of gained chitosan microball is many and more loaded down with trivial details.The preparation method of the chitosan nano microballoon close with the present invention (referring to Polymer Bullitin, 1999, (43): be that poly-amino methyl propanesulfonic acid acid is added drop-wise in the dilute solution of chitosan 67-73), agitation condition forms the compound polyelectrolyte particle down.These class methods are that the particle diameter ratio of synthetic particle is bigger on the one hand, greater than 1 micron.Form in extremely dilute solution owing to this kind particle on the other hand, the finished product output capacity is lower, and the particle diameter heterogeneity of the particulate that forms.
And the prior art for preparing load has the approach of mr developing promotor microballoon to mainly contain: (1) is with liposome embedded developing promotor DTPA-Gd; (collods and surfaces B:Biointerfaces 2000, (18): 293-299), (2) connect some multi-functional parts in the surface of liposome modification, make Gd again
3+With the liposome coordination after this kind modification, form (collods and surfaces B:Biointerfaces 1999, (16): 305-319) such as polymer complex of gadolinium.There are some shortcomings in aforesaid method.In first method, micromolecular developing promotor can infiltrate in liposome, and the developing promotor that infiltrates can destroy liposome membrane.For second method, must guarantee that coordination takes place in the functional group of most of atoms metal and surface of liposome, just can guarantee the quick exchange of atoms metal and water molecules.In addition, be hydrophobicity as the liposome of DTPA-Gd carrier, this character has limited the exchange of gadolinium atom and water, and reinforced effects is not very desirable thus.The chemical process more complicated of the surface modification of liposome, the embedding process is also more loaded down with trivial details.
The objective of the invention is:
1. a kind of Nano microsphere of biodegradable hydrophilic chitosan-polyacrylic acid composite is provided;
2. a kind of preparation method of above-mentioned Nano microsphere is provided;
3. a kind of Nano microsphere that is loaded with the chitosan-polyacrylic acid composite of medicine is provided, particularly is loaded with the Nano microsphere of the chitosan-polyacrylic acid composite of nuclear magnetic resonance developing promotor.
Technical scheme of the present invention is as follows:
A kind of Nano microsphere of chitosan-polyacrylic acid composite, wherein the molecular weight of chitosan is in the 10000-500000 scope, deacetylation is 50-100%, polyacrylic molecular weight ranges is 20000-200000, the median size of Nano microsphere is 200-300nm, and polyacrylic content is 20-50%.
Above-mentioned Nano microsphere can be the Nano microsphere with the crosslinked chitosan-polyacrylic acid composite of glutaraldehyde cross-linking agent.Nano microsphere after crosslinked is more stable, and alkaline resistance properties is better.
A kind of method for preparing above-mentioned chitosan-polyacrylic acid composite Nano microsphere, it is that chitosan is dissolved in tart (for example can add acetate makes the acid) distilled water, stir and add the polyacrylic acid aqueous solution down, form microemulsion, filter the Nano microsphere that promptly gets chitosan-polyacrylic acid composite.
A kind of method for preparing above-mentioned chitosan-polyacrylic acid composite Nano microsphere, it is under 40-60 ℃ of stirring, in distilled water, add chitosan and vinylformic acid, after the dissolving fully, adding initiator reacts, initiator can be a Potassium Persulphate, forms microemulsion after reaction is finished, and filters the Nano microsphere that promptly gets chitosan-polyacrylic acid composite.
A kind of method for preparing above-mentioned crosslinked chitosan-polyacrylic acid composite Nano microsphere, it is that chitosan is dissolved in tart (for example can add acetate makes the acid) distilled water, stir and add the polyacrylic acid aqueous solution down, form microemulsion, adding concentration is the glutaraldehyde water solution of 1% (m%), be warming up to 40 ℃, reaction is finished, and filters the Nano microsphere that promptly gets crosslinked chitosan-polyacrylic acid composite.
Crosslinked chitosan-polyacrylic acid composite Nano microsphere also can adopt the laxative remedy preparation, at 40-60 ℃, stir down, in distilled water, add chitosan and vinylformic acid, dissolving back fully adds initiator potassium persulfate, after reaction is finished, forms microemulsion, add the linking agent glutaraldehyde water solution then and continue reaction, promptly get the Nano microsphere of crosslinked chitosan-polyacrylic acid composite after reaction is finished.
The linking agent glutaraldehyde water solution also can shift to an earlier date with initiator potassium persulfate and adds simultaneously, to not influence of crosslinking reaction.
Chitosan of the present invention-polyacrylic acid composite Nano microsphere can particularly can be made the carrier of mr developing promotor as the carrier of medicine.
Carrier as medicine, it can add medicine or the mr developing promotor of wanting load in chitosan-polyacrylic acid of the present invention, through standing adsorption, dialysis can obtain being enclosed with the Nano microsphere of the chitosan-polyacrylic acid composite of medicine or mr developing promotor.
Carrier as medicine, it also can (when promptly adding initiator) just add the medicament that needs load before acroleic acid polymerization, as mr developing promotor DTPA-Gd (DTPA-Gd) or 1,4,7,10-tetraazacyclododecanand-N, N, N, N-tetraacethyl gadolinium (DOTA-Gd), add initiator then, linking agent is after reacting completely, filter out Nano microsphere, with secondary water dialysis, remove inorganic salt small molecules and unreacted monomer in the system, can obtain being enclosed with the Nano microsphere of the chitosan-polyacrylic acid composite of mr photographic developer.
The invention provides a kind of median size is chitosan-polyacrylic acid composite Nano microsphere of 200-300nm, and it is hydrophilic, and stability is preferably arranged in PH3-8 buffered soln, biodegradable, good biocompatibility.Preparation method of the present invention has adopted the method for aqueous polymerization to prepare the Nano microsphere of chitosan.Do not use any organic reagent and tensio-active agent in the preparation process.The separation of chitosan microball and the problem of purifying have well been solved.The microsphere surface rule has certain intensity.DTPA-Gd or DOTA-Gd load factor height, chemical property is stable.Above-mentioned feature shows: this microballoon meets the application need in biomedical and biochemical engineering field as a kind of carrier on performance.
Description of drawings:
Fig. 1 has the model diagram of the Nano microsphere of the present invention of DTPA-Gd for load: 1 is polymer network; 2 is DTPA-Gd.
Fig. 2 is the electromicroscopic photograph (50000 times of magnifications) of crosslinking nano microballoon of the present invention.
Fig. 3 is the transmission electron microscope photo of the load DTPA-Gd Nano microsphere that adopts the inventive method and make, and particle diameter is less than 300 nanometers (50000 times of magnifications).
Fig. 4 is the size distribution statistical graph of the Nano microsphere of each embodiment gained, and wherein Fig. 4-1～4-5 is respectively the Nano microsphere of embodiment 1～5 gained.
Fig. 5 is the vitro drug release curve of the Nano microsphere of load Zorubicin.
Below by embodiment technical scheme of the present invention is further described.
Embodiment 1:
Adding molecular weight in the 100ml stirring reactor that fills 50ml distilled water is 80,000, and deacetylation is 90% chitosan 3 grams, adds 1 gram vinylformic acid again, under the agitation condition, is warming up to 60 ℃.After treating chitosan dissolving fully, to the initiator-Potassium Persulphate that wherein adds 40 milligrams, reaction is 2 hours under 60 ℃ of conditions, can get nanometer micro-emulsion.Stopped reaction after the filtration was poured microemulsion in the dialysis tubing dialysis 48 hours, with inorganic salt small molecules in the system of removing and unreacted monomer, can obtain the mixture Nano microsphere.
The content of nanoparticle is about 4 grams in the above-mentioned system, and polyacrylic molecular weight is 40,000, and the nanoparticle of transmission electron microscope observing chitosan is comparatively regular globosity, and median size is about 200nm, can stablize preservation in the pH3-7 scope.
Embodiment 2:
Adding molecular weight in the 100ml stirring reactor that fills 50ml distilled water is 80,000, and deacetylation is 85% chitosan 3 grams, adds 1 gram vinylformic acid again, under the agitation condition, is warming up to 60 ℃.After treating chitosan dissolving fully, to the initiator-Potassium Persulphate that wherein adds 40 milligrams, reaction is 2 hours under 60 ℃ of conditions, can get nanometer micro-emulsion.Add 10ml 1% linking agent glutaraldehyde again, reaction is 2 hours under 40 ℃ of conditions, reacts completely to guarantee glutaraldehyde.Stop reaction, after the filtration microemulsion poured in the dialysis tubing into dialysis 48 hours,, can obtain the mixture Nano microsphere with inorganic salt small molecules in the system of removing and unreacted monomer.
The content of nanoparticle is about 4 grams in the above-mentioned system, and polyacrylic molecular weight is 40,000.The nanoparticle of transmission electron microscope observing chitosan is comparatively regular globosity, and median size is about 200nm, can preserve for a long time in the pH3-8 scope.
Embodiment 3:
Adding molecular weight in the 100ml stirring reactor that fills 50ml distilled water is 80,000, and deacetylation is 70% chitosan 3 grams, adds 1 gram vinylformic acid again, under the agitation condition, is warming up to 60 ℃.After treating chitosan dissolving fully,, add 30 milligrams of Potassium Persulphates again as initiator to wherein adding 0.3 gram DTPA-Gd micromolecular compound.Reaction is 2 hours under 60 ℃ of conditions, can get nanometer micro-emulsion.Be cooled to 40 ℃, add 10ml 1% linking agent glutaraldehyde, reaction is 2 hours under 40 ℃ of conditions, reacts completely to guarantee glutaraldehyde.After stopping reaction, filter, microemulsion is poured in the dialysis tubing with dialysing more than 1 hour, with inorganic salt small molecules in the system of removing and unreacted monomer in the secondary water.Can obtain being enclosed with the mixture Nano microsphere of mr photographic developer.
The content of nanoparticle is 4 grams in the above-mentioned system, and polyacrylic molecular weight is 40,000, and the clad ratio of DTPA-Gd is approximately 60%.The nanoparticle of transmission electron microscope observing chitosan is comparatively regular globosity, and median size is about 210nm, can preserve for a long time in the pH3-8 scope.Nuclear magnetic resonance experiment is the result show: this nanoparticle has good in-vitro relaxation performance.
Embodiment 4:
Adding molecular weight in the 100ml stirring reactor that fills 50ml distilled water is 80,000, and deacetylation is 55% chitosan 1 gram, adds 1 gram vinylformic acid again, stirs.After treating chitosan dissolving fully, to the glutaraldehyde water solution that wherein adds 15 milligrams of Potassium Persulphates and 5ml (1%, wt%).Reaction is 4 hours under 50 ℃ of conditions, can get nanometer micro-emulsion.Under 40 ℃ of conditions, reacted 2 hours again, react completely to guarantee glutaraldehyde.After stopping reaction, after the filtration microemulsion poured in the dialysis tubing into dialysis more than 1 hour, with inorganic salt small molecules in the system of removing and unreacted monomer.After wherein adding the 0.1 DTPA-Gd compound that restrains, leaving standstill 48 hours, dialysis can obtain being enclosed with the mixture Nano microsphere of mr photographic developer more than 1 hour in the secondary water.
The content of nanoparticle is 2 grams in the above-mentioned system, and polyacrylic molecular weight is 60,000, and the clad ratio of DTPA-Gd is approximately 60%.The nanoparticle of transmission electron microscope observing chitosan is comparatively regular globosity, and median size is about 200nm, can preserve for a long time in the pH3-8 scope.Nuclear magnetic resonance experiment is the result show: this nanoparticle has good in-vitro relaxation performance.
Embodiment 5:
Adding molecular weight in the 100ml stirring reactor that fills 50ml distilled water is 80,000, and deacetylation is 60% chitosan 1 gram, adds 1 gram vinylformic acid again, stirs.After treating chitosan dissolving fully, to wherein adding 15 milligrams of Potassium Persulphates, the DTPA-Gd compound of 0.1 gram and the glutaraldehyde water solution of 5ml (1%, wt%).Reaction is 4 hours under 50 ℃ of conditions, can get nanometer micro-emulsion.Under 40 ℃ of conditions, reacted 2 hours again, react completely to guarantee glutaraldehyde.After stopping reaction, after the filtration microemulsion is poured in the dialysis tubing, dialysis is more than 1 hour, with inorganic salt small molecules in the system of removing and unreacted monomer in the secondary water., can obtain being enclosed with the mixture Nano microsphere of mr photographic developer.
The content of nanoparticle is 2 grams in the above-mentioned system, and polyacrylic molecular weight is 40,000, and the clad ratio of DTPA-Gd is approximately 60%.The nanoparticle of transmission electron microscope observing chitosan is comparatively regular globosity, and median size is about 230nm, can preserve for a long time in the pH3-8 scope.Nuclear magnetic resonance experiment is the result show: this nanoparticle has good in-vitro relaxation performance.
Embodiment 6:
The content of nanoparticle is 2 grams in the above-mentioned system, and the clad ratio of DTPA-Gd is approximately 60%.The nanoparticle of transmission electron microscope observing chitosan is comparatively regular globosity, and median size is about 290nm, broad particle distribution.In the pH3-8 scope, can preserve for a long time.Nuclear magnetic resonance experiment is the result show: this nanoparticle has good in-vitro relaxation performance.
Table 1 has illustrated the relaxation time (T1) of the different DTPA-Gd concentration that contain the DTPA-Gd Nano microsphere.
Embodiment 7:
The content of nanoparticle is 2 grams in the above-mentioned system, and the clad ratio of DTPA-Gd is approximately 60%.The nanoparticle of transmission electron microscope observing chitosan is comparatively regular globosity, and median size is about 280nm, broad particle distribution.In the pH3-8 scope, can preserve for a long time.Nuclear magnetic resonance experiment is the result show: this nanoparticle has good in-vitro relaxation performance.
Embodiment 8:
Adding molecular weight in the 100ml stirring reactor that fills 50ml distilled water is 20,000, and deacetylation is 90% chitosan 2 grams, adds 1 gram vinylformic acid again, under the agitation condition, is warming up to 60 ℃.After treating chitosan dissolving fully,, add 20 milligrams of Potassium Persulphates again as initiator to wherein adding 0.2 gram DTPA-Gd micromolecular compound.Reaction is 2 hours under 60 ℃ of conditions, can get nanometer micro-emulsion.Be cooled to 40 ℃, add 10ml 1% linking agent glutaraldehyde, reaction is 2 hours under 40 ℃ of conditions, reacts completely to guarantee glutaraldehyde.After stopping reaction, filter, microemulsion is poured in the dialysis tubing with dialysing more than 1 hour, with inorganic salt small molecules in the system of removing and unreacted monomer in the secondary water.Can obtain being enclosed with the mixture Nano microsphere of mr photographic developer.
The content of nanoparticle is 2.5 grams in the above-mentioned system, and polyacrylic molecular weight is 1.5 ten thousand, and the clad ratio of DTPA-Gd is approximately 50%.The nanoparticle of transmission electron microscope observing chitosan is comparatively regular globosity, and median size is about 210nm, can preserve for a long time in the pH3-8 scope.Nuclear magnetic resonance experiment is the result show: this nanoparticle has good in-vitro relaxation performance.
Embodiment 9:
Adding molecular weight in the 100ml stirring reactor that fills 50ml distilled water is 200,000, and deacetylation is 85% chitosan 2 grams, adds 1 gram vinylformic acid again, under the agitation condition, is warming up to 60 ℃.After treating chitosan dissolving fully,, add 20 milligrams of Potassium Persulphates again as initiator to wherein adding 0.2 gram DTPA-Gd micromolecular compound.Reaction is 2 hours under 60 ℃ of conditions, can get nanometer micro-emulsion.Be cooled to 40 ℃, add 10ml 1% linking agent glutaraldehyde, reaction is 2 hours under 40 ℃ of conditions, reacts completely to guarantee glutaraldehyde.After stopping reaction, filter, microemulsion is poured in the dialysis tubing with dialysing more than 1 hour, with inorganic salt small molecules in the system of removing and unreacted monomer in the secondary water.Can obtain being enclosed with the mixture Nano microsphere of mr photographic developer.
The content of nanoparticle is 2.0 grams in the above-mentioned system, and polyacrylic molecular weight is 80,000, and the clad ratio of DTPA-Gd is approximately 50%.The nanoparticle of transmission electron microscope observing chitosan is comparatively regular globosity, and median size is about 240nm, can preserve for a long time in the pH3-8 scope.Nuclear magnetic resonance experiment is the result show: this nanoparticle has good in-vitro relaxation performance.
Embodiment 10:
Adding molecular weight in the 100ml stirring reactor that fills 50ml distilled water is 450,000, and deacetylation is 85% chitosan 4 grams, adds 1.5 gram vinylformic acid again, under the agitation condition, is warming up to 60 ℃.After treating chitosan dissolving fully,, add 20 milligrams of Potassium Persulphates again as initiator to wherein adding 0.2 gram DTPA-Gd micromolecular compound.Reaction is 2 hours under 60 ℃ of conditions, can get nanometer micro-emulsion.Be cooled to 40 ℃, add 10ml 1% linking agent glutaraldehyde, reaction is 2 hours under 40 ℃ of conditions, reacts completely to guarantee glutaraldehyde.After stopping reaction, filter, microemulsion is poured in the dialysis tubing with dialysing more than 1 hour, with inorganic salt small molecules in the system of removing and unreacted monomer in the secondary water.Can obtain being enclosed with the mixture Nano microsphere of mr photographic developer.
The content of nanoparticle is 2.5 grams in the above-mentioned system, and polyacrylic molecular weight is 80,000, and the clad ratio of DTPA-Gd is approximately 50%.The nanoparticle of transmission electron microscope observing chitosan is comparatively regular globosity, and median size is about 260nm, and wider distribution can be preserved in the pH3-8 scope for a long time.Nuclear magnetic resonance experiment is the result show: this nanoparticle has good in-vitro relaxation performance.
Embodiment 11: the mensuration of mr toughener DTPA-Gd encapsulation ratio.
Accurately measure the prepared nanometer micro-emulsion of 10ml, place that (Ultra ProTM 80, Du Pont) ultracentrifugation separated after 1 hour in 50,000 rpms the ultracentrifuge, collect supernatant liquid.Measure Gd ionic concentration in the clear liquid with atomic absorption spectrometry (ICP), can calculate the encapsulation ratio of DTPA-Gd.
Embodiment 12: the mensuration of the vitro drug release curve of drug-carried nanometer
Get the nanoparticle 100mg that embodiment 2 makes, be scattered in the physiological saline, again to wherein adding anticarcinogen doxorubicin hydrochloride 10mg, after the dissolving, left standstill 24 hours, after ultracentrifugation separates, taking precipitate is measured its drug release curve in the physiological saline under 37 ℃ of conditions.With this understanding, the encapsulation ratio of medicine is 80%.
Table 1, the relaxation time (T1) of different DTPA-Gd content Nano microspheres
| Sample number into spectrum (embodiment six) | Concentration (mmol/mL) | T1，(ms) |
| 1 | 4.46 | 24.0 |
| 2 | 1.59 | 64.2 |
| 3 | 1.27 | 82.6 |
| 4 | 0.637 | 172.8 |
| 5 | 0.204 | 383.1 |
Claims (8)
1. the Nano microsphere of a chitosan-polyacrylic acid composite, the median size that it is characterized in that Nano microsphere is 200-300nm, wherein the molecular weight of chitosan is 10000-500000, deacetylation is 50-100%, polyacrylic molecular weight is 20000-200000, and polyacrylic content is 20-50%.
2. Nano microsphere according to claim 1 is characterized in that the Nano microsphere through the crosslinked chitosan-polyacrylic acid composite of glutaraldehyde cross-linking agent.
3. a method for preparing the described Nano microsphere of claim 1 is characterized in that chitosan is dissolved in the acid distilled water, stirs down to add the polyacrylic acid aqueous solution, forms microemulsion, filters the Nano microsphere that promptly gets chitosan-polyacrylic acid composite.
4. a method for preparing the described Nano microsphere of claim 1 is characterized in that under 40-60 ℃ of stirring, adds chitosan and vinylformic acid in distilled water, after the dissolving fully, add initiator and react, form microemulsion, filter the Nano microsphere that promptly gets chitosan-polyacrylic acid composite.
5. method for preparing the described Nano microsphere of claim 2, it is characterized in that chitosan is dissolved in the acid distilled water, stir and add the polyacrylic acid aqueous solution down, form microemulsion, add the linking agent glutaraldehyde water solution, be warming up to 40 ℃, reaction is finished, and filters the Nano microsphere that promptly gets crosslinked chitosan-polyacrylic acid composite.
6. method for preparing the described Nano microsphere of claim 2, it is characterized in that at 40-60 ℃, stir down, in distilled water, add chitosan and vinylformic acid, dissolving back adding initiator is fully reacted, and forms microemulsion, adds the linking agent glutaraldehyde water solution then, continue reaction, promptly get the Nano microsphere of crosslinked chitosan-polyacrylic acid composite after reacting completely.
7. the method for Nano microsphere according to claim 6 is characterized in that the linking agent glutaraldehyde water solution when adding initiator, adds simultaneously.
8. the purposes of Nano microsphere according to claim 1 and 2 is characterized in that the carrier as medicine or nuclear magnetic resonance developing promotor.
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| CN100374477C (en) * | 2005-07-07 | 2008-03-12 | 复旦大学 | Nano granules adhesive to mucous membrane, preparation method and application |
| CN100361657C (en) * | 2005-11-17 | 2008-01-16 | 中国人民解放军第二军医大学 | Fluorouracial nano particle formulation and its preparing method |
| CN100423831C (en) * | 2006-06-15 | 2008-10-08 | 南开大学 | Chromatographic fixed-phase for modified glycan substrate, its preparation and use |
| CN101903408B (en) * | 2007-10-30 | 2013-08-14 | 粘凝胶股份公司 | Chitosan composition |
| CN102552157B (en) * | 2010-12-17 | 2013-06-12 | 南京大学 | Chitosan-polyacrylic acid composite nanometer micro-sphere covered with precious metal on surface as well as preparation method and application thereof |
| CN102382207B (en) * | 2011-09-08 | 2012-11-14 | 江苏天竹化工科技有限公司 | Natural biomaterial acrylate derivative and preparation method thereof |
| CN102813931B (en) * | 2012-08-08 | 2015-01-21 | 华侨大学 | Chitosan nanoparticles and their preparation method and use |
| CN107537044B (en) * | 2017-08-29 | 2021-02-26 | 重庆医科大学 | Chitosan nano microbubble and preparation method and application thereof |
| CN107899025B (en) * | 2017-11-08 | 2020-12-11 | 上海交通大学 | Glucan-gadolinium MRI nano developer and preparation method thereof |
| CN108849998B (en) * | 2018-06-12 | 2020-12-15 | 滁州政通中小企业服务中心有限公司 | Composite nano germination accelerator |
| CN113350314B (en) * | 2021-06-25 | 2022-07-26 | 上海信谊天平药业有限公司 | Preparation method of sustained-release medicine |
| CN113680522B (en) * | 2021-08-30 | 2023-05-02 | 东北大学 | Method for preparing micro-nano magnetic material from carbonate-containing iron ore flotation tailings |
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