CN101724163B - Composite microsphere of chitosan derivative, preparing method and applications thereof - Google Patents
Composite microsphere of chitosan derivative, preparing method and applications thereof Download PDFInfo
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- CN101724163B CN101724163B CN2009102636449A CN200910263644A CN101724163B CN 101724163 B CN101724163 B CN 101724163B CN 2009102636449 A CN2009102636449 A CN 2009102636449A CN 200910263644 A CN200910263644 A CN 200910263644A CN 101724163 B CN101724163 B CN 101724163B
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Abstract
The invention belongs to the field of macromolecule material science, and particularly relates to a composite microsphere of a chitosan derivative, a preparing method and applications thereof. The preparing method comprises the following steps of: preparing a chitosan hydrophilic derivative from chitosan, and then preparing a chitosan derivative solution with the mass to volume ratio (g/ml) being 1-10%; adding the chitosan derivative solution into a cellulose solution with the mass to volume ratio of 1-10% to prepare W/O emulsion; slowly adding the W/O emulsion into a sodium polyphosphate solution with the mass concentration of 1-10%, stirring, solidifying and filtering to obtain the chitosan derivate microsphere. The composite microsphere of the chitosan derivative has good biocompatibility and good slow release property, and the preparing method has the advantages of convenient operation, stable process and low manufacture cost.
Description
(1) technical field
The invention belongs to macromolecular material and learn field, particularly a kind of chitosan derivatives complex microsphere and its production and application.
(2) background technology
Chitin (Chitin) claims poly-N-acetyl-D-Portugal amine sugar again, extensively is present in the cell walls of the shell of shrimp, crab and insect and mushroom and algae, and be that the occurring in nature growing amount is only second to cellulosic a kind of natural polysaccharide.Chitin molecule is sloughed part or all ethanoyl with highly basic hydrolysis or enzymolysis, and its product is called chitosan (Chitosan).Chitosan contains free amine group, can combine with acid molecule, is unique natural alkaline polysaccharide, has many special physicochemical character and physiological function.Because it is nontoxic, harmless to human body, good biocompatibility, advantage such as biodegradable, chitosan has been widely used in the slow-released carrier on the preparation medicine industry.Present existing carrier format comprises chitosan particle, chitosan sheet, chitosan microball and chitosan pearl etc., wherein the research of chitosan microball has caused people's extensive concern, can be used for preparing the carrier of various biologically active substances such as hormone, VITAMIN, albumen and enzyme.
Chitosan microball generally adopts emulsification chemical crosslink technique, solvent evaporated method, spray-drying process and the precipitator method to wait to prepare.Prepare DNA embedded type chitosan microball as usefulness glutaraldehyde chemical crosslink techniques such as Jameela, the chitosan solution that will contain medicine is scattered in the mixing oil phase of whiteruss and gasoline, add tensio-active agent, stirring and emulsifying, add the linking agent glutaraldehyde, prepared medicine carrying microballoons can prolong drug release time greatly.Usefulness W/O emulsified solvent method of evaporation such as Abd prepare fluorescent mark dextran chitosan microball, soon dextran is dissolved in and forms medicine/chitosan mixing solutions in the chitosan solution, add then and contain in the mineral oil of emulsifying agent, stir and form the W/O emulsion, constantly stir with 2000rpm, be heated to 80 ℃ simultaneously, stir, heat maintenance 4.5 hours, be evaporated fully until solvent and remove, chromatographic separation mineral oil is collected microballoon, cleans with normal hexane, filter, be drying to obtain the chitosan drug-loading microballoon that makes release 12% in 24 hours.He etc. are prepared by spray-dryer with chitosan microballs such as spray drying method for preparation cimetidine, and the microballoon that makes has good sphere and slick surface, and medicine is scattered in the chitosan microball with molecularity, but drug release rate is very fast, and burst effect is arranged; Huang etc. make modifier with spray drying method for preparation BTM chitosan microball, adding gelatin etc., and then prepared microballoon has excellent drug stability and higher medicine carrying efficient, simultaneously because the effect of gelatin can make medicament slow release reach 12h.
Yet the solvability of chitosan under acidic conditions makes chitosan microball rapidly disintegration in gastric juice, thereby the slow release effect of chitosan microball is affected; Chemical cross-linking agents such as adding formaldehyde, glutaraldehyde can improve the slow release effect of chitosan microball, but the toxic side effect of aldehydes has limited the application of chitosan microball; And the high temperature during the spray drying method for preparation microballoon can make institute's embedding active substance be damaged; The while chitosan only is dissolved in acidic solution also makes the embedding of acid labile drugs be restricted.
Therefore the novel chitosan microball with excellent biological compatibility and slow release effect of research preparation has great importance.
(3) summary of the invention
The object of the present invention is to provide a kind of chitosan derivatives complex microsphere and its production and application, described chitosan derivatives complex microsphere biocompatibility and slow release effect are good.
The technical solution used in the present invention is as follows:
A kind of chitosan derivatives complex microsphere is made by laxative remedy: utilize Preparation of Chitosan chitosan hydrophilic derivative, make mass volume ratio (g/ml) then and be the chitosan derivative solution of 1-10%; Chitosan derivative solution is added mass volume ratio (g/ml) make the W/O emulsion in the cellulose solution of 1-10%; The W/O emulsion is slowly added in the polyphosphoric acid sodium solution that mass concentration is 1-10%, stir and solidify, filter and promptly get described chitosan derivatives microballoon; The volume ratio of chitosan derivative solution, cellulose solution and polyphosphoric acid sodium solution is 1: 2-10: 3-20.
Preferred cm-chitosan of described chitosan hydrophilic derivative or chitosan quaternary ammonium salt hydrophilic derivatives.Specifically can utilize chitosan and Mono Chloro Acetic Acid, quaternary ammonium salt reagent etc. to be prepared.
The plain derivative of the preferred hydrophobic fibre of described Mierocrystalline cellulose is as cellulose acetate or ethyl cellulose.
Described cellulose solution is dissolved in the solution of methylene dichloride and dehydrated alcohol for the Mierocrystalline cellulose or derivatives thereof, and the volume ratio of methylene dichloride and dehydrated alcohol is 1: 4-4: 1.
This method is applicable to the chitosan of different performance; as part deacetylation chitosan, whole deacetylation chitosan, low-molecular weight chitoglycan, middle molecular weight chitosan or high molecular weight chitosan etc.; the molecular weight of chitosan is greater than 38KDa, and the deacetylation scope is 50-100%.
The emulsifying agent that need add when preparation W/O emulsion can be selected as required, as tween-80 etc., repeats no more.
Preparation temperature preferably carries out at 25-40 ℃; The stirring velocity that is adopted during mixing can be 2000-5000rpm.
Described chitosan derivatives complex microsphere has good application as active ingredient carriers.As it has the effect that the protection active substance is not destroyed for the sour environment labile drug.
Concrete, prepare chitosan derivatives loading microballoon by adsorption after active substance directly added chitosan derivative solution or preparation microballoon.
Described active substance can be hydrophilic medicament or hydrophobic drug, also can be protein, vaccine, enzyme isoreactivity material.The adding quality of active substance is 0.01-1 a times of chitosan mass.
Described is that model drug is added in the chitosan solution with active substance direct adding chitosan solution in the chitosan compound microsphere preparation process, dissolving fully, and then the method for preparing according to microballoon prepares the chitosan drug-loading complex microsphere, i.e. the method for elder generation's loading refabrication; Preparing the chitosan derivatives medicine carrying microballoons by adsorption behind the preparation complex microsphere is to prepare chitosan compound microsphere earlier, and adding active substance then is that model drug continues to stir, and makes medicine be adsorbed in microballoon, is applicable to water-soluble substances.
The present invention has extensive applicability to starting material, and the chitosan derivatives of all possess hydrophilic property substituted radicals all goes for the present invention.The present invention also has extensive applicability to Mierocrystalline cellulose, is applicable to have hydrophobic all derivatived celluloses.Therefore, raw material sources of the present invention are very extensive.
Significance of the present invention also is to adopt chitosan hydrophilic derivative and Mierocrystalline cellulose to make novel chitosan compound microsphere in the microballoon preparation, because the hud typed structure of complex microsphere possess hydrophilic property nuclear and hydrophobic film, it can make the slow-releasing of chitosan compound microsphere be improved, and performance is more stable; Can improve active agent stability, avoid its toxic side effect.The present invention is expected to become the desirable slow-released system of active substance, has good research and development application prospect.
The present invention has following advantage with respect to prior art:
Chitosan derivatives complex microsphere biocompatibility provided by the invention and sustained release performance are good, and that the preparation method has is easy and simple to handle, process stabilizing, advantage cheap for manufacturing cost.
(4) description of drawings
Fig. 1 is the release curve of the prepared medicine carrying microballoons of different concns chitosan quaternary ammonium salt and 2% cellulose acetate solution in the phosphoric acid buffer of pH6.8.
(5) embodiment:
Below with specific embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited thereto:
Embodiment 1
The 0.40g cm-chitosan added to make the quality concentration of volume percent in the 40ml deionized water be 1% carboxymethyl chitosan sugar soln, stir, add Zorubicin 0.10g,, add volumetric concentration and be 1% Tween-80 and stir fully with 3000rpm speed stirring and dissolving; The preparation quality volume percent is that (solvent is that methylene dichloride/dehydrated alcohol volume ratio is 1/4 mixed solvent, 80ml) for the ethyl cellulose solution of 2% (g/ml); The carboxymethyl chitosan sugar soln is slowly added ethyl cellulose solution, stirring and emulsifying; It is in 3% sodium polyphosphate (TPP) solution that the W/O emulsion is slowly added the 240ml mass concentration, slowly adds while stirring, stirs and solidifies, and leaves standstill suction filtration and promptly gets the chitosan drug-loading complex microsphere.
Embodiment 2
The 0.60g cm-chitosan is added in the 20ml deionized water, stir, add Zorubicin 0.20g,, add 1%Tween-80 and stir fully with 2000rpm speed stirring and dissolving; The preparation quality volume percent is 3% cellulose acetate solution (methylene dichloride/dehydrated alcohol=1/4) 80ml; The carboxymethyl chitosan sugar soln is slowly added cellulose acetate solution, stirring and emulsifying; It is in 3% the TPP solution that the W/O emulsion is slowly added the 300ml mass concentration, slowly adds while stirring, stirs and solidifies, and leaves standstill suction filtration and promptly gets chitosan derivatives medicine carrying complex microsphere.
Embodiment 3
The 0.40g chitosan quaternary ammonium salt is added in the 20ml deionized water, stir, add albumin 0.15g,, add 1%Tween-80 and stir fully with 4500rpm speed stirring and dissolving; The preparation quality volume percent is 3% cellulose butyrate solution (solvent: methylene dichloride/dehydrated alcohol=2/3) 60ml; The chitosan quaternary ammonium salts solution is slowly added cellulose butyrate solution, and stirring and emulsifying forms the W/O emulsion; It is among the 3%TPP solution 200ml that the W/O emulsion is slowly added mass concentration, slowly adds while stirring, stirs and solidifies, and leaves standstill suction filtration and promptly gets chitosan derivatives medicine carrying complex microsphere.
The 0.50g chitosan quaternary ammonium salt is added in the 20ml deionized water, stir, add 1%Tween-80 and stir fully; The preparation quality volume percent is 2% cellulose acetate solution (solvent: methylene dichloride/dehydrated alcohol=1/4) 60ml; The chitosan quaternary ammonium salts solution is slowly added cellulose acetate solution, stirring and emulsifying; It is in 3% the TPP solution that the W/O emulsion is slowly added the 250ml mass concentration, slowly adds while stirring, stirs and solidifies, and leaves standstill suction filtration and promptly gets chitosan compound microsphere.Then complex microsphere is suspended in water, add xitix 0.20g, 3000rpm whip attachment, preparation medicine carrying chitosan derivatives complex microsphere.The prepared release curve of medicine carrying microballoons in the phosphoric acid buffer of pH6.8 of different concns chitosan quaternary ammonium salt and 2% cellulose acetate solution seen Fig. 1.
Embodiment 5
The 0.30g sulfated chitosan is added in the 20ml deionized water, stir, add 1%Tween-80 and stir fully, add xitix 0.20g, stirring and dissolving; The preparation quality volume percent is 2% cellulose butyrate solution (two solvents: methyl chloride/dehydrated alcohol=2/3) 60ml; Sulfated chitosan solution is slowly added cellulose butyrate solution, stirring and emulsifying; It is in 5% the TPP solution that the W/O emulsion is slowly added the 400ml mass concentration, slowly adds while stirring, stirs and solidifies, and leaves standstill suction filtration and promptly gets sulfated chitosan medicine carrying complex microsphere.
Embodiment 6
The 0.50g hydroxyethyl chitosan is added in the 20ml deionized water, stir, add 1%Tween-80 and stir fully, add mercaptopurine 0.30g, stirring and dissolving; The preparation quality volume percent is 4% cellulose acetate butyric ester solution (solvent: methylene dichloride/dehydrated alcohol=4/1) 60ml; Hydroxyethyl chitosan solution is slowly added cellulose acetate butyric ester solution, stirring and emulsifying; It is in 6% the TPP solution that the W/O emulsion is slowly added the 180ml mass concentration, slowly adds while stirring, stirs and solidifies, and leaves standstill suction filtration and promptly gets hydroxyethyl chitosan medicine carrying complex microsphere.
Embodiment 7
The 1g cm-chitosan added to make the quality concentration of volume percent in the 10ml deionized water be 10% carboxymethyl chitosan sugar soln, stir, add Zorubicin 0.10g,, add volumetric concentration and be 1% Tween-80 and stir fully with 3000rpm speed stirring and dissolving; The preparation quality volume percent is that (solvent is that methylene dichloride/dehydrated alcohol volume ratio is 1/4 mixed solvent, 80ml) for the ethyl cellulose solution of 10% (g/ml); The carboxymethyl chitosan sugar soln is slowly added ethyl cellulose solution, stirring and emulsifying; It is in 10% the TPP solution that the W/O emulsion is slowly added the 90ml mass concentration, slowly adds while stirring, stirs and solidifies, and leaves standstill suction filtration and promptly gets the chitosan drug-loading complex microsphere.
Claims (10)
1. a chitosan derivatives complex microsphere is characterized in that, is made by laxative remedy: utilize Preparation of Chitosan chitosan hydrophilic derivative, make the chitosan derivative solution that mass volume ratio g/ml is 1-10% then; Chitosan derivative solution added in the cellulose solution that mass volume ratio g/ml is 1-10% make the W/O emulsion; The W/O emulsion is slowly added in the polyphosphoric acid sodium solution that mass concentration is 1-10%, stir and solidify, filter and promptly get described chitosan derivatives microballoon; The volume ratio of chitosan derivative solution, cellulose solution and polyphosphoric acid sodium solution is 1: 2-10: 3-20.
2. chitosan derivatives complex microsphere as claimed in claim 1 is characterized in that, described chitosan hydrophilic derivative is cm-chitosan or chitosan quaternary ammonium salt hydrophilic derivatives.
3. chitosan derivatives complex microsphere as claimed in claim 1 is characterized in that, described cellulose solution is dissolved in the solution of methylene dichloride and dehydrated alcohol for the Mierocrystalline cellulose or derivatives thereof, and the volume ratio of methylene dichloride and dehydrated alcohol is 1: 4-4: 1.
4. the preparation method of the described chitosan derivatives complex microsphere of claim 1 is characterized in that, utilizes Preparation of Chitosan chitosan hydrophilic derivative, makes the chitosan derivative solution that mass volume ratio g/ml is 1-10% then; Chitosan derivative solution added in the cellulose solution that mass volume ratio is 1-10% make the W/O emulsion; The W/O emulsion is slowly added in the polyphosphoric acid sodium solution that mass concentration is 1-10%, stir and solidify, filter and promptly get described chitosan derivatives microballoon; The volume ratio of chitosan derivative solution, cellulose solution and polyphosphoric acid sodium solution is 1: 2-10: 3-20.
5. the preparation method of chitosan derivatives complex microsphere as claimed in claim 4 is characterized in that, described chitosan hydrophilic derivative is cm-chitosan or chitosan quaternary ammonium salt hydrophilic derivatives.
6. the preparation method of chitosan derivatives complex microsphere as claimed in claim 4 is characterized in that, cellulose solution is dissolved in the solution of methylene dichloride and dehydrated alcohol for the Mierocrystalline cellulose or derivatives thereof, and the volume ratio of methylene dichloride and dehydrated alcohol is 1: 4-4: 1.
7. the preparation method of chitosan derivatives complex microsphere as claimed in claim 6 is characterized in that, derivatived cellulose is cellulose acetate or ethyl cellulose.
8. the described chitosan derivatives complex microsphere of claim 1 is as the application of active ingredient carriers.
9. chitosan derivatives complex microsphere as claimed in claim 8 is characterized in that as the application of active ingredient carriers, prepares chitosan derivatives loading microballoon by adsorption after active substance is directly added chitosan derivative solution or prepares microballoon.
10. chitosan derivatives complex microsphere as claimed in claim 9 is characterized in that as the application of active ingredient carriers the adding quality of active substance is 0.01-1 a times of chitosan mass.
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| CN102179236A (en) * | 2011-03-24 | 2011-09-14 | 南昌航空大学 | Method for preparing O-carboxymethyl chitosan quaternary ammonium salt nano particles |
| CN102579364B (en) * | 2012-03-05 | 2013-10-09 | 河北科技大学 | Sustained or controlled release microsphere of valnemulin/valnemulin salts and preparation method thereof |
| CN104812777A (en) * | 2012-10-24 | 2015-07-29 | 塞拉尼斯醋酸纤维有限公司 | Polysaccharide ester microspheres and methods and articles relating thereto |
| CN103611505B (en) * | 2013-12-06 | 2015-07-08 | 中国烟草总公司郑州烟草研究院 | Preparation method, product and application of copper ion functionalized porous cellulose composite microsphere |
| CN103628306B (en) * | 2013-12-09 | 2016-03-02 | 科凯精细化工（上海）有限公司 | A kind of preparation method of shitosan list guanidine hydrochloride load nano-titanium dioxide compound |
| CN108166313B (en) * | 2017-11-14 | 2019-08-02 | 孝感市锐思新材科技有限公司 | A kind of preparation method of paper grade (stock) anti-biotic material |
| CN110651895B (en) * | 2019-10-31 | 2022-12-20 | 上海耐威克宠物用品有限公司 | Functional food for solving tear stains of pets and preparation method thereof |
| CN111134119B (en) * | 2020-02-19 | 2020-11-20 | 湖南省植物保护研究所 | Nano chitosan-thiamethoxam water agent and preparation method and application thereof |
| CN112121162A (en) * | 2020-09-07 | 2020-12-25 | 四川康城生物科技有限公司 | Carboxymethyl chitosan microcapsule for carrying chemotherapy medicament and thermotherapy sensitizer for sustained release of novel embolism and preparation method and application thereof |
| CN113637188B (en) * | 2021-08-27 | 2022-07-15 | 中国科学院长春应用化学研究所 | Chitosan microsphere and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6207180B1 (en) * | 1997-04-03 | 2001-03-27 | Thomas B. Ottoboni | Intravesical drug delivery |
| CN1927912A (en) * | 2006-09-21 | 2007-03-14 | 上海大学 | Physical cross-linking hydrogel and preparation method thereof |
Non-Patent Citations (1)
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