CN101633739B - Method for preparing chitosan nano-particles in water phase - Google Patents
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Abstract
The invention provides a method for preparing chitosan nano-particles in water phase, which comprises the following steps: (a) providing a chitosan solution of which the concentration is between about 0.05 and about 1 w/v percent; (b) adding water and acetic anhydride into the chitosan solution in turn to perform acetylization, wherein in terms of the volume of the entire solution, the concentration of the acetic anhydride is between about 10 and about 30 v/v percent; and (c) performing physical dispersion on the solution of the step (b).
Description
Technical field
The present invention relates to the manufacturing of chitosan nano particle, particularly a kind of method for preparing chitosan nano particle at aqueous phase.
Background technology
Nanotechnology focuses on the correlative study of medical prophylaxis, diagnosis, drug conveying and disease treatment in the application of field of medicaments now.Nano particle can be used as the carrier of delivery system, it possesses plurality of advantages, for example improve the stability of medicine at intestines and stomach, improve the absorptivity and the bioavailability of oral pharmaceutical, reduce the using dosage of medicine, thereby reduce the side effect that produces because of the use high dose medicament, and specificity ground dispensing.Yet, consider based on biological safety in utilization, often limit the range of application of nano particle such as factors such as material source and employed reagent.
Chitosan is the high (LD of present generally recognized as safe
50＞4g/kg) pharmaceutical carrier.Chitosan is made microsphere usually.For example, CN1698900 discloses a kind of preparation method of chitosan drug-loading microballoon, it is characterized in that hydrophilic medicament is dissolved in the acetic acid-sodium acetate buffer solution of chitosan, water is pressed in the oil phase by microporous membrane with pressure, obtain the emulsion droplet of size homogeneous, with two step solidification methods emulsion droplet is carried out crosslinking curing then.Aforementioned " two step solidification methods " is meant and uses ionic jelling agent (for example triphosphate (TPP)) to make the gathering of chitosan generation molecular chain agglomerating, utilize chemical cross-linking agent to make its crosslinking curing then.This method can not make nano level chitosan particle.
Because chitosan and adjacent molecule and such as can the strong hydrogen bond of generation between the organic acids such as lactic acid, so be difficult to be dissolved in the water.Therefore chitosan is the important factor that can its range of application of decision enlarge in the solubleness of aqueous phase.Known chitosan and the acid anhydrides of can making under special reaction condition and in organic phase carries out the acylations effect, produces the chitosan with different removal of acylation degree, thereby the control chitosan is water-soluble.In addition, the those skilled in the art also advises preparing the nano particle of chitosan.
US 2005/0226938 A1 discloses a kind of by the method for Preparation of Chitosan through crosslinked core and core-shell type nano particle polymkeric substance, described method is to make chitosan and at least a carboxylic acid reaction that has at least two carboxylic acid groups on it, preferably uses carbon imide (carbodiimide) as reacting movable agent.
US 2006/0013885 A1 disclose a kind of water-soluble chitosan nano particle that is used to carry cancer therapy drug with and preparation method thereof, described method be make chitosan molecule and methyl poly-(ethylene glycol) right-nitrogen base benzol carbonate links, become the amphipathic molecule chain, and then self-assembly forms chitosan nano particle.
JP 2006241321 discloses a kind of method for preparing chitosan nano particle, described method comprises chitosan is dissolved in a kind of aqueous peracid solution, to obtain the aqueous peracid solution of chitosan, and the aqueous peracid solution of this chitosan is added in a kind of alkaline aqueous solution, for example, the aqueous sodium hydroxide solution of 3N.
CN1686560 discloses a kind of preparation method of chitin tetra ammonium salt nano-particle, it is by making chitosan and propylene oxide-trimethylammonium-ammonia chloride reaction with the preparation chitosan quaternary ammonium salt, then this chitosan quaternary ammonium salt, the medicine for the treatment of embedding and tripoly phosphate sodium STPP are mixed and carry out crosslinkedly, and obtain chitin tetra ammonium salt nano-particle.
US 4; 996; 307 disclose a kind of preparation method of water-soluble acetylated chitosan sugar; described method comprises that the water-soluble chitosan that will be any multipolymer form and have at least 70% a deacetylation degree is dissolved in a kind of aqueous peracid solution; with water or for example the water miscible solvent of methyl alcohol dilute described solution; the acetylizing agent that adds acid anhydrides for example then is to described solution, to produce acetylization reaction.According to the embodiment of this patent, when carrying out above-mentioned acetylization reaction, add organic solvents such as methyl alcohol, ethanol or Virahol as organic phase.
JP 2000256403 discloses a kind of preparation method of partial acetylation chitosan particle, and described method comprises chitosan is dissolved in a kind of aqueous peracid solution, and this solution is dispersed in a kind of granulation with in the solvent, stirs aforementioned disperse phase and makes it to form particle.In addition,, form, add alkali and heating, make the products therefrom partial acetylation, make product stable by crosslinked action at last through acetylizad chitosan via in the organic phase of toluene or Virahol, carrying out acetylizing.
JP 62079201 discloses a kind of preparation method of porousness round shaped grain shape N-acetylated chitosan sugar; described method comprises low-molecular-weight chitosan is dissolved in a kind of aqueous peracid solution; this solution is splashed in a kind of basic solution; make chitosan solution produce agglutination, and then form described porousness round shaped grain shape N-acetylated chitosan sugar.Aforementioned acetylizing is for example to carry out in the organic phase such as methyl alcohol or benzene.
CN 1367183 discloses the preparation method of a kind Hyaluronic Acid chitosan, and described method comprises makes chitosan carry out acetylizing, carries out selective oxidation then, has the chitosan of the structure of similar Hyaluronic Acid with acquisition.Aforementioned acetylizing is to carry out in the organic phase of for example methyl alcohol.
In addition; open country numerous wide (Shigehiro Hirano) and mountain pass dragon two (Ryuji Yamaguchi) in being published in the 15th edition the 1685th to 1691 page of biological polymer (BIOPOLYMERS) in 1976, title is in the document (to call " document in 1976 " in the following text) of " N-acetylize gel: the polyhydrate of chitin (N-Acetylation Gel:A Polyhydrate of Chitin) ", compared chitosan-acetic acid solution and carried out acetylizing at methyl alcohol phase and aqueous phase respectively and produce difference between the gel.This document in 1976 is mainly being inquired into the gel phenomenon of chitosan through being produced after the acetylize, and further inquires into the basic physical properties of formed colloidal, for example be dissolvable in water in which kind of solvent with relevant solubleness how.But this document in 1976 only teaching add a certain amount of acetic anhydride at aqueous phase can be so that chitosan be owing to acetylizing is glueization, the colloidal solid that it produced is often excessive, even aggegation is agglomerating.The operational condition of this document in 1976 can't make chitosan nano particle.
Other pertinent literature comprises that also Li Dongyuan people such as (Dong-Won Lee) was published in 2004 in " carbohydrate polymer (Carbohydrate Polymers); 58 (2004) "; title is the document of " physicochemical property of shellglycan nano particle and blood compatibility (Physicochemical properties and blood compatibility ofacylated chitosan nanoparticles) "; and; quite Te Ruoa people such as (A.Portero) was published in 2002 in " micro encapsulation (MICROCAPSULATION), 19 (2002) "; title is the document of " being used for the reacetylation chitosan microball body (Reacetylated chitosan microspheres forcontrolled delivery of anti-microbial agents to the gastric mucosa) of biocide to the controlled release drug administration of stomach mucous membrane ".It is incorporated in the specification sheets of this patent case in full by reference.
The preparation method of above-mentioned known chitosan particle has one or more following shortcoming respectively: (1) fails to make the nano-scale chitosan particle, (2) relate to loaded down with trivial details chemically modified step, labor intensive again consuming time, (3) organic solvent that uses in the manufacturing processed can residue in the prepared chitosan particle, therefore, promptly allow to make the nano-scale chitosan particle, its security for medical applications is still troubling.
At present still need have the nano-scale chitosan particulate method that good biocompatibility meets the security consideration of medical applications again a kind of can the preparation.
Summary of the invention
The invention provides a kind of nano-scale chitosan particulate preparation method who satisfies the demand, it is the chemical modification of carrying out chitosan solution at aqueous phase, make chitosan molecule link become the amphipathic molecule chain, and then under the effect of physical property dispersion force, be self-assembled into and be chitosan nano particle.The present invention produces via acetylation modification in the colloidal process at chitosan to disperse to obtain nano level chitosan particle by the concentration of control chitosan and acetic anhydride and by physical property, and this can be avoided producing the megalump colloid as aforementioned 1976 as the document.
Particularly, the invention provides and a kind ofly prepare the method for chitosan nano particle at aqueous phase, it comprises following steps:
(a) providing concentration is the chitosan solution of about 0.05w/v% to about 1w/v%,
(b) water and acetic anhydride are added in the described chitosan solution in regular turn, to carry out acetylizing, wherein, with the volumeter of whole solution, the concentration of described acetic anhydride for about 10v/v% extremely about 30v/v% and
(c) make the solution of step (b) carry out the physical property dispersion.
Employed chitosan is meant β-[1 → 4]-2-amino-2-deoxidation-D-glucopyanosyl in step (a), has 10-1 usually, the molecular weight of 000kDa and the deacetylation degree between 70% and 90%.Chitosan can be obtained by any known source, includes but not limited to mollusk (for example cuttlefish), insect shell, algae, Crustacean and fungi.The Crustacean chitosan is preferably shrimp or crab shell chitosan, and the fungi chitosan is preferably the Actinomucortaiwanensis chitosan.Chitosan solution according to the present invention is meant chitosan is dissolved in formed solution behind the solvent, wherein said solvent can be any known solvent that can be used for dissolving chitosan, it includes but not limited to aqueous acetic acid, formic acid, propionic acid, oxysuccinic acid, succsinic acid and lactic acid, wherein is preferably the aqueous acetic acid of about 1v/v%; And the concentration of chitosan solution is preferably about 0.05w/v% to about 0.6w/v%, and more preferably about 0.1w/v% is to about 0.3w/v%.
Employed Glacial acetic acid acid anhydride can be buied by commercial activity in step (b).With the volumeter of whole solution, the concentration of described acetic anhydride is extremely about 30v/v% of about 10v/v%, is preferably about 12.5v/v% to about 25v/v%, and more preferably about 17.5v/v% is to about 25v/v%.
Acetylizing among the present invention is meant the reaction that the carboxyl of the amino of chitosan and acetic anhydride is formed ethanoyl, and it can carry out under the known proper temperature in any affiliated field.
Disperse to be meant the processing that makes solution molecule generation dissemination with physics mode in the physical property described in the step (c), it can use the known mode in any affiliated field to carry out, and it includes but not limited to stir and the ultrasonic oscillation processing with vibrator (Shaker), liquid sprinkler (Spray Sparger), mechanical type.As utilize alr mode to carry out physical property when disperseing, magnetite can be added in the described solution, and stir one section with agitation as appropriate speed and surpass about 24 hours time from step (b).Stir speed (S.S.) depends on the liquor capacity size of being reacted, and can be for example about 150rpm to about 1500rpm, is preferably about 175rpm to about 1300rpm.As utilize ultrasonic oscillation to carry out physical property when disperseing, according to a preferred embodiment of the present invention, be to utilize ultrasonic oscillator ((the Sonic ﹠amp of sound wave and Materials Co., Ltd; Materials Inc.) model: VC 134, power: 130W, capacity: 115V, 50/60Hz) carry out under following condition: the concussion time is about 5 minutes, pulse distance is about 4 seconds, and earthquake moves into solution in the ice bath after finishing immediately.
The physical property of step (c) is disperseed and can be carried out under the known proper temperature in any affiliated field, for example about 20 ℃ to about 40 ℃, use mechanical type to stir (stirring) and carry out the physical property dispersion as magnetite, preferably under about 37 ℃, carry out, as utilize ultrasonic oscillation to carry out physical property and disperse, preferably at room temperature carry out.
The chitosan nano particle that obtains according to the inventive method can have the median size of about 100nm to about 500nm, is preferably about 100nm to about 300nm, is most preferably about 100nm to about 200nm.
The inventive method can obtain down chitosan nano particle in mild conditions, and need not be with an organic solvent or loaded down with trivial details chemical modification step, and its operating method is quite simple.Because the inventive method whole process is carried out at aqueous phase, so can avoid the problem of organic solvent residual in the conventional chitosan particle.The chitosan nano particle that obtains according to the inventive method more meets the security consideration of medical applications, and has good biocompatibility.
Embodiment
Following examples are used for that the invention will be further described, but not are used for limiting the scope of the invention.Correction that the technician of any the technical field of the invention can reach easily and change are included within this case specification sheets disclosure and the appended claims.
The preparation of embodiment 1 chitosan nano particle (magnetite stirring)
(I) use the chitosan that obtains and have different molecular-weight average from the difference source
Respectively that weighing is good 0.2g (opens up (the Shin Era TechnologyCo. of company available from Taiwan generation available from shrimp and crab shells, and fungi (available from the Actinomucor taiwanensis bacterial strain of Foodstuff Industrial Development Inst. of Financial Group Legal Persons) and have the chitosan of different molecular weight Ltd)), add in the 1v/v% aqueous acetic acid of preparation in advance, so that its dissolving, then with it quantitatively to 100mL, and get the above-mentioned chitosan solution of 10mL and carry out subsequent reactions.In described 10mL chitosan solution, add earlier 5mL Milli Q pure water, add again 5mL 100% acetic anhydride (be pure water: the volume ratio of acetic anhydride=1: 1), to carry out acetylizing.In this reaction, the total reaction liquor capacity is 20mL, and with the volumeter of described W-response solution, the concentration of described acetic anhydride is 25v/v%.Magnetite is added in the above-mentioned solution, under 37 ℃, with the stir speed (S.S.) of 1300rpm stir one section surpass 24 hours time after, obtain the aqueous solution of chitosan nano particle.With nano particle size instrument analysis chitosan nano particle wherein, the result is as shown in table 1, and its average particle size range is 195～326nm.
Table 1
| The chitosan source | Molecular-weight average (kDa) | Median size (nm) |
| CC?68 | 68 | 233 |
| CC?72 | 72 | 243 |
| CC?95 | 95 | 247 |
| FC?24 | 24 | 195 |
| FC?190 | 190 | 299 |
| FC?340 | 340 | 326 |
Annotate: the CC representative is available from the chitosan of shrimp and crab shells, and the FC representative is available from the chitosan of fungi, and numerical portion is represented molecular-weight average (kDa)
(II) use different chitosan concentration and acetic anhydride concentration
The experiment condition that the center blendes together design (Central Composite Design (CCD)) experiment is according to Design-Expert 6.0.2 software design.At first, the experiment condition of giving according to this software carries out shake flask test (shaker test) with small vessels, then test-results is imported in the former the design's of this software the field as a result of experiment table,, just can be obtained the concrete conclusion of many discussion experimental variables via software analysis.The CCD contrived experiment that the present invention uses in experimentation can be in once inquiring into required a plurality of experimental variables (and once can only inquire into a variable unlike the traditional experiment design) simultaneously in the experiment, plan out according to Design-Expert 6.0.2 software again and inquire into the changeable factor, the reaction conditions and the group number that need experiment, the experimenter promptly carries out shake flask test according to the designed experiment condition of software, the shake flat experiment result data is imported the part that eases back again originally planned in the experimental group number, in blank field as a result.Via the software statistics analysis, can understand each unitary variant respectively for the influence degree of experimental result, perhaps also can inquire in twos between the variable interaction to the influence of experimental result.
(1) selects in this example that (available from Taiwan generation exhibition company (Shin Era Technology Co., Ltd)) and molecular weight is that the chitosan (CC 95) of 95kDa carries out above-mentioned CCD contrived experiment available from shrimp and crab shells.
The above-mentioned chitosan of 0.05 respectively that weighing is good～0.35g adds in the 1v/v% aqueous acetic acid of preparation in advance so that its dissolving, then with it quantitatively to 100mL, and get the above-mentioned chitosan solution of 5mL and carry out subsequent reactions.In described 5mL chitosan solution, add earlier 2.5mL Milli Q pure water, add again 2.5mL 100% acetic anhydride (be pure water: the volume ratio of acetic anhydride=1: 1), to carry out acetylizing.In this reaction, the total reaction liquor capacity is 10mL, and with the volumeter of described W-response solution, the concentration of described acetic anhydride is 25v/v%.Under the same terms described in above-mentioned (I), carry out acetylizing.The result confirms can make under these conditions the aqueous solution of chitosan nano particle.With nano particle size instrument analysis chitosan nano particle wherein, the result is as shown in table 2, and its average particle size range is 189～298nm.
Table 2
(2) selecting in this example available from fungi (available from the Actinomucortaiwanensis bacterial strain of Foodstuff Industrial Development Inst. of Financial Group Legal Persons) and molecular-weight average is that the chitosan (FC 24) of 24kDa carries out above-mentioned CCD contrived experiment.
The above-mentioned chitosan of respectively that weighing is good 0.4g and 0.6g adds in the 1v/v% aqueous acetic acid of preparation in advance so that its dissolving, then with it quantitatively to 100mL, and get the above-mentioned chitosan solution of 5mL and carry out subsequent reactions.In described 5mL chitosan solution, add earlier 2.5mL Milli Q pure water, add again 2.5mL 100% acetic anhydride (be pure water: the volume ratio of acetic anhydride=1: 1), to carry out acetylizing.In this reaction, the total reaction liquor capacity is 10mL, and with the volumeter of described W-response solution, the concentration of described acetic anhydride is 25v/v%.Magnetite is added in the above-mentioned solution, stir above after 24 hours time, obtain the aqueous solution of chitosan nano particle in the stir speed (S.S.) with 175rpm under 37 ℃.With nano particle size instrument analysis chitosan nano particle wherein, the result is as shown in table 3, and its average particle size range is 196～206nm.
Table 3
Table 2 and 3 result confirm that according to the inventive method, reaction density is the chitosan of 0.1w/v%～0.6w/v%, can make chitosan nano particle.
(3) the above-mentioned experiment method that continues, the 0.2g chitosan (CC 95) that weighing is good adds in the 1v/v% aqueous acetic acid of preparation in advance so that its dissolving, then with it quantitatively to 100mL, and get the above-mentioned chitosan solution of 5mL and carry out subsequent reactions.In described 5mL chitosan solution, add differential responses volume Milli Q pure water earlier, add 100% acetic anhydride again, to carry out acetylizing.In this reaction, the total reaction liquor capacity is 10mL, and with the volumeter of described W-response solution, the concentration of acetic anhydride is respectively 17.5v/v% and 25v/v%.Under the same terms described in above-mentioned (2), carry out acetylizing and obtain the aqueous solution of chitosan nano particle.With nano particle size instrument analysis chitosan nano particle wherein, the result is as shown in table 4, and its average particle size range is 170～245nm.Therefore in the methods of the invention, under being the condition of 17.5v/v%～25v/v%, the concentration of acetic anhydride can make chitosan nano particle.
Table 4
The preparation (ultrasonic oscillation) of embodiment 2 chitosan nano particles
(I) use the chitosan that obtains and have different molecular-weight average from the difference source
Respectively that weighing is good 0.2g (opens up (the Shin EraTechnology Co. of company available from Taiwan generation available from shrimp and crab shells, Ltd)) and fungi (available from the Actinomucor taiwanensis bacterial strain of Foodstuff Industrial Development Inst. of Financial Group Legal Persons) and chitosan with different molecular weight add in the 1v/v% aqueous acetic acid of preparation in advance, so that its dissolving, then with it quantitatively to 100mL, and get the above-mentioned chitosan solution of 3.6mL and carry out subsequent reactions.In described 3.6mL chitosan solution, add differential responses volume Milli Q pure water earlier, add 100% acetic anhydride (pure water: the volume ratio of acetic anhydride was respectively 1: 2,2: 3 and 1: 1) again, to carry out acetylizing.In this reaction, the total reaction liquor capacity is 7.2mL, and with the volumeter of described W-response solution, the concentration of described acetic anhydride is respectively 16.67v/v%, 20v/v% and 25v/v%.In reaction process, utilize ultrasonic oscillator ((the Sonic ﹠amp of sound wave and Materials Co., Ltd simultaneously; Materials Inc.) model: VC 134) output rating be 15W and pulse distance be under 4 seconds the condition under room temperature 5 minutes (oscillator is placed in the reaction unit (test tube)) of concussion, to obtain the aqueous solution of chitosan nano particle, after finishing, concussion immediately solution is moved in the ice bath.With nano particle size instrument analysis chitosan nano particle wherein, the result is as shown in table 5, and its average particle size range is 138～213nm.
Table 5
Annotate: in the sample number of table 5, the FC representative is available from the chitosan of fungi, and the CC representative is available from the chitosan of shrimp and crab shells, and numerical portion is represented molecular-weight average (kDa)
As shown in Table 5, according to the inventive method, use obtains and has the chitosan (for example shrimp and crab shells chitosan and fungi chitosan) of different molecular-weight average from the difference source, making the concentration of acetic anhydride in interpolation is under the condition of 16.67v/v%～25v/v%, by ultra-sonic oscillation, can obtain the chitosan nano particle that average particle size range is 138～213nm.
(II) use different acetic anhydride ultimate densities
Selection is that the chitosan (FC 340) of 340kDa carries out following experiment available from fungi (available from the Actinomucor taiwanensis bacterial strain of Foodstuff Industrial Development Inst. of Financial Group Legal Persons) and molecular-weight average.
With weighing is that the above-mentioned chitosan of 0.2g adds respectively in the 1v/v% aqueous acetic acid of preparation in advance so that its dissolving, then with it quantitatively to 100mL, and get the above-mentioned chitosan solution of 2mL and carry out subsequent reactions.In described 2mL chitosan solution, add earlier differential responses volume Milli Q pure water, add 100% acetic anhydride (pure water: the volume ratio of acetic anhydride was respectively 1: 1,3: 5,1: 3) again, to carry out acetylizing.In this reaction, the total reaction liquor capacity is 4mL, and with the volumeter of described W-response solution, the concentration of described acetic anhydride is respectively 25v/v%, 18.75v/v% and 12.5v/v%.React by ultrasonic oscillator with the same way as described in embodiment 2 (I) simultaneously, to obtain the aqueous solution of chitosan nano particle.With nano particle size instrument analysis chitosan nano particle wherein, the result is as shown in table 6, and its average particle size range is 153～170nm.
Table 6
| Acetic anhydride concentration (v/v%) | Median size (nm) |
| 25 | 170 |
| 18.75 | 165 |
| 12.5 | 153 |
As shown in Table 6, according to the inventive method, use fungi chitosan (FC 340), be respectively in the concentration that makes acetic anhydride under the condition of 12.5v/v%, 18.75v/v% and 25v/v%, by ultra-sonic oscillation, can obtain the chitosan nano particle that average particle size range is 153～170nm.
Comprehensive the foregoing description 1 and 2 result are as can be known, use is available from different sources and have the chitosan (for example available from the chitosan of shrimp and crab shells with available from the chitosan of fungi) of different molecular-weight average, in the concentration that makes acetic anhydride is under the condition of 12.5v/v%～25v/v%, disperse (for example stirring or ultra-sonic oscillation) by physical property, really can obtain chitosan nano particle.
Claims (14)
1. one kind prepares the method for chitosan nano particle at aqueous phase, and it comprises following steps:
(a) providing concentration is the chitosan solution of 0.05w/v% to 1w/v%,
(b) water and acetic anhydride are added in the described chitosan solution in regular turn, to carry out acetylizing, wherein, with the volumeter of whole solution, the concentration of acetic anhydride be 10v/v% to 30v/v% and
(c) make the solution of step (b) carry out the physical property dispersion.
2. the method for claim 1, wherein said chitosan is available from crustaceans or fungi.
3. the method for claim 1, wherein said chitosan solution are that chitosan is dissolved in formed solution behind the aqueous acetic acid of 1v/v%.
4. the method for claim 1, the concentration of wherein said chitosan solution is 0.05w/v% to 0.6w/v%.
5. method as claimed in claim 4, the concentration of wherein said chitosan solution are 0.1w/v% to 0.3w/v%.
6. the method for claim 1, the concentration of wherein said acetic anhydride is 12.5v/v% to 25v/v%.
7. method as claimed in claim 6, the concentration of wherein said acetic anhydride are 17.5v/v% to 25v/v%.
8. the method for claim 1, wherein to disperse be to stir or the mode of ultrasonic oscillation is carried out with mechanical type to the physical property of step (c).
9. method as claimed in claim 8, wherein said physical property dispersion is to carry out in the mode that mechanical type stirs, it is by magnetite being added in the described solution from step (b), and stirs one section with the stir speed (S.S.) of 150rpm to 1500rpm down in 37 ℃ and surpass 24 hours time and carry out.
10. method as claimed in claim 8, it is to carry out under room temperature in the mode of ultrasonic oscillation that wherein said physical property is disperseed.
11. the method for claim 1, wherein the dispersion of the physical property of step (c) is to carry out under 20 ℃ to 40 ℃.
12. the method for claim 1, wherein said chitosan nano particle has the median size of 100nm to 500nm.
13. method as claimed in claim 12, wherein said chitosan nano particle has the median size of 100nm to 300nm.
14. method as claimed in claim 13, wherein said chitosan nano particle has the median size of 100nm to 200nm.
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| CN1485346A (en) * | 2002-09-23 | 2004-03-31 | 广汉恒宇新材料有限公司 | Preparation of nanometer-sized cation polysaccharide |
| CN1712431A (en) * | 2004-12-13 | 2005-12-28 | 中国科学院上海应用物理研究所 | Chitose superfine powder and production thereof |
| CN1986608A (en) * | 2006-12-18 | 2007-06-27 | 武汉大学 | Preparing process and application of nano chitosan particle |
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| CN1485346A (en) * | 2002-09-23 | 2004-03-31 | 广汉恒宇新材料有限公司 | Preparation of nanometer-sized cation polysaccharide |
| CN1712431A (en) * | 2004-12-13 | 2005-12-28 | 中国科学院上海应用物理研究所 | Chitose superfine powder and production thereof |
| CN1986608A (en) * | 2006-12-18 | 2007-06-27 | 武汉大学 | Preparing process and application of nano chitosan particle |
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