CN107915787A - A kind of preparation method of pH temperature dual-sensitivity chitosan nano particle - Google Patents
A kind of preparation method of pH temperature dual-sensitivity chitosan nano particle Download PDFInfo
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- CN107915787A CN107915787A CN201610884478.4A CN201610884478A CN107915787A CN 107915787 A CN107915787 A CN 107915787A CN 201610884478 A CN201610884478 A CN 201610884478A CN 107915787 A CN107915787 A CN 107915787A
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- deoxycholic acid
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
- C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
- C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/12—Powdering or granulating
- C08J3/14—Powdering or granulating by precipitation from solutions
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
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Abstract
The invention belongs to medical material production technical field, specifically discloses a kind of preparation method of pH temperature dual-sensitivity chitosan nano particle, its making step is:The hydroxyl butyl chitosan (patent No. is synthesized by published method first：ZL201110214776.X), the deoxycholic acid activated is added dropwise in hydroxyl butyl chitosan solution, hydroxyl butyl/deoxycholic acid chitosan is obtained after Carbodiimide reaction；Hydroxyl butyl/deoxycholic acid chitosan is dissolved in dimethyl sub-maple, is added dropwise under stirring condition in distilled water, obtains hydroxyl butyl/deoxycholic acid chitosan nano.Preparation process of the present invention is simple, and cost is low, and hydrophobic grouping substitution value is controllable, safe without toxic side effect.Hydroxyl butyl/deoxycholic acid chitosan nano of synthesis has pH temperature dual-sensitivities, and sensitiveness is controllable, has good research and development prospect in fields such as biological medicine, organizational projects.
Description
Technical field
A kind of preparation method of pH- temperature dual-sensitivity chitosan nano particle, belongs to native biopolymer material neck
Domain, falls within biomedical materials field.
Background technology
Chitosan (chitosan) is a kind of glycosaminoglycan for being widely present in nature, has biocompatibility, nothing
Poison, biodegradable, are easy to the advantageous properties such as modification and antibiotic property, are widely used in biomedical sector.The knot of chitosan
Crystalline substance is higher, dissolubility is poor, significantly limit its development and application, and water-solubility chitosan derivative is prepared by chemical modification
It is to improve one of chitosan performance, the important channel for widening its application range.Research to chitosan it has been found that carry out hydroxyl butylation
Modification（ZL201110214776. X）, its modified product is easily soluble in water, and biological tissue's compatibility is good, has the temperature quick
Perception and pH sensitiveness, have huge in the application aspect such as tissue engineering bracket, minimally invasive injection, topical remedy's sustained release, beautifying technique
Potentiality, by as the active material of research and development.It is related in the world in the report of hydroxyl butyl chitosan at present, Thermo-sensitive
Hydrogel is the Main way of its research.In order to further expand the research and application and development of hydroxyl butyl chitosan, the present invention exists
Deoxycholic acid is introduced by Carbodiimide reaction on the basis of hydroxyl butyl chitosan, hydroxyl butyl/deoxycholic acid shell of formation gathers
Sugar can be self-assembly of nanoparticle in aqueous, nanoparticle uniform particle sizes, stable structure, and have temperature and pH sensitives
Property, have a good application prospect in the delivering of dewatering medicament and sustained release etc..
The content of the invention
The object of the present invention is to provide a kind of preparation method of pH- temperature dual-sensitivity chitosan nano particle.
The present invention specifically comprises the steps of：
（1）Hydroxyl butyl chitosan is dissolved in distilled water（750-1700 kDa of molecular weight ranges of chitosan, according to special
Profit number：ZL201110214776. X methods synthesize）, 0.01% -1 % of mass fraction of hydroxyl butyl chitosan, uses methanol dilute afterwards
Release, the ratio of methanol and water is 1:0.1-0.5.
（2）By deoxycholic acid, EDC, NHS is dissolved in dimethyl sub-maple, deoxycholic acid, the molal weight of EDC, NHS
Than for 1: 0.1:0.1 to 1: 5 :5,5 min -300 min are persistently stirred under room temperature, are activated in deoxycholic acid
γ-COOH。
（3）Hydroxyl butyl chitosan solution is added dropwise in the deoxycholic acid mixed solution activated under lasting stirring condition
In, the mass ratio of hydroxyl butyl chitosan and deoxycholic acid is 1: 0.1 – 1 :10, reaction temperature is 0-25 oC, reaction
After, it is transferred in the mixed solution of methanol and water and dialyses, the ratio of methanol and water is 1：0-0.5, after it is saturating with distilled water again
Analysis.Solution after dialysis is freezed, obtains hydroxyl butyl/deoxycholic acid chitosan.
（4）Hydroxyl butyl/deoxycholic acid chitosan is dissolved in dimethyl sub-maple, after being completely dissolved, this solution is being stirred
Under the conditions of be added dropwise in distilled water
（5）The mixed solution that step (4) obtains is dialysed with distilled water, is freeze-dried, obtains hydroxyl butyl/deoxycholic acid chitosan
Nano particle, the nano particle have pH- temperature dual-sensitivities.
Brief description of the drawings
Fig. 1：The nuclear magnetic spectrum of hydroxyl butyl/deoxycholic acid chitosan
Fig. 2：The electron microscopic picture of hydroxyl butyl/deoxycholic acid chitosan nano particle
Fig. 3：The pH and temperature double responsiveness of hydroxyl butyl/deoxycholic acid chitosan nano particle.
Embodiment
Embodiment 1
The hydroxyl butyl chitosan of 10 mg is weighed, molecular weight is 750 kDa, and deacetylation 85%, is dissolved in 100 mL distilled water
In, use 300mL methanol dilutions afterwards;The deoxycholic acid of 100 mg, 5.8mgEDC are weighed, 3.5 mg NHS are dissolved in 10mL bis-
In the maple of methyl Asia, 5 min are persistently stirred under room temperature, activate the γ-COOH in deoxycholic acid;The deoxycholic acid that will have been activated
Mixed solution is added dropwise under persistently being stirred in 0 oC in hydroxyl butyl chitosan solution, and after reacting 24h, reaction mixture is turned
Enter methanol and water（Volume ratio is 1：0.5）Mixed solution in, dialyse 24 h, after again with distilled water dialyse 48 h；After dialysing
Solution freezes, and obtains hydroxyl butyl/deoxycholic acid chitosan；4 mg hydroxyls butyl/deoxycholic acid chitosan is dissolved in 1 mL diformazans
In the maple of base Asia, after being completely dissolved, this solution is added dropwise in 3ml distilled water under agitation, persistently stirs 10 min；
Then 24 h that dialyse are transferred in bag filter, and freeze-drying obtains hydroxyl butyl/deoxycholic acid chitosan nano.
Embodiment 2
The hydroxyl butyl chitosan of 100 mg is weighed, molecular weight 1500kDa, deacetylation 90%, is dissolved in 100 mL distillations
In water, rear 200 mL methanol dilutions;The deoxycholic acid of 10 mg is weighed, 25 mg EDC, 17.5 mg NHS are dissolved in 3
In mL dimethyl sub-maple, 300 min are persistently stirred under room temperature, activate the γ-COOH in deoxycholic acid;It is de- by what is activated
Oxycholic acid mixed solution is being added dropwise in hydroxyl butyl chitosan solution under 15 oC are persistently stirred, after reacting 24 h, reaction is mixed
Compound is transferred in methanol, dialyse 24 h, after again with distilled water dialyse 48 h；Solution after dialysis is freezed, obtains hydroxyl butyl/de-
Oxycholic acid chitosan, 1mg hydroxyls butyl/deoxycholic acid chitosan is dissolved in 1 mL dimethyl sulfoxide (DMSO)s, after being completely dissolved, by this
Solution is added dropwise in 9mL distilled water under agitation, persistently stirs 10 min；Then 24 h that dialyse are transferred in bag filter,
Freeze-drying obtains hydroxyl butyl/deoxycholic acid chitosan nano.
Embodiment 3
The hydroxyl butyl chitosan of 50 mg is weighed, molecular weight is 1700 kDa, and deacetylation 90%, is dissolved in 50 mL distilled water
In, rear 500 mL methanol dilutions;The deoxycholic acid of 25 mg is weighed, 2.9 mg EDC, 1.75 mg NHS are dissolved in 1
In mL dimethyl sub-maple, 30 min are persistently stirred under room temperature, activate the γ-COOH in deoxycholic acid;The deoxidation that will have been activated
Cholic acid mixed solution is added dropwise under persistently being stirred in 25oC in hydroxyl butyl chitosan solution, after reacting 24 h, reaction is mixed
Compound is transferred to methanol and water（Volume ratio is 15:1）Mixed solution in, dialyse 24 h, after again with distilled water dialyse 48 h；Will
Solution freezes after dialysis, obtains hydroxyl butyl/deoxycholic acid chitosan；20mg hydroxyls butyl/deoxycholic acid chitosan is dissolved in 2
In mL dimethyl sub-maple, after being completely dissolved, this solution is added dropwise in 2 mL distilled water under agitation, lasting stirring
10 min；Then 24 h that dialyse are transferred in bag filter, and freeze-drying obtains hydroxyl butyl/deoxycholic acid chitosan nano.
Claims (7)
1. a kind of preparation method of pH- temperature dual-sensitivity chitosan nano particle, it is concretely comprised the following steps：
Step 1：Hydroxyl butyl chitosan is dissolved in distilled water, after use methanol dilution；By deoxycholic acid, EDC, NHS dissolving
In dimethyl sub-maple, lasting stirring a period of time, the γ-COOH in deoxycholic acid are activated.
2. step 2：Continue under stirring condition, the deoxycholic acid solution activated be added dropwise in hydroxyl butyl chitosan solution,
After reaction, it is transferred in the mixed solution of methanol and water and dialyses.
3. solution after dialysis is freezed, hydroxyl butyl/deoxycholic acid chitosan is obtained.
4. step 3：Hydroxyl butyl/deoxycholic acid chitosan is dissolved in dimethyl sub-maple, after being completely dissolved, it is being stirred
Under the conditions of be added dropwise in distilled water；By dialysis, after freeze-drying, pH- temperature dual-sensitivity hydroxyls butyl/deoxidation courage had both been obtained
Sour chitosan nano particle.
5. a kind of preparation method of pH- temperature dual-sensitivity chitosan nano particle according to claim 1, its feature
It is the 750-1700kDa of molecular weight ranges of the chitosan；The volume ratio of methanol and water is 1: 0.1 - 0.5；Hydroxyl fourth
The mass fraction 0.01% -1% of base enclosure glycan.
6. a kind of preparation method of the chitosan nano particle of pH- temperature dual-sensitivity as described in claim 1, it is special
Levy in the deoxycholic acid in step 1, the molar concentration rate of EDC, NHS are 1:0.1:0.1 to 1: 5: 5.
7. a kind of preparation method of the chitosan nano particle of pH- temperature dual-sensitivity as described in claim 1, it is special
Sign in step 2 the mass ratio of hydroxyl butyl chitosan and deoxycholic acid be 1：0.1 to 1：10；Reaction temperature is 0- 25oC,
The ratio of methanol and water is 1：0- 1：0.5.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108822232A (en) * | 2018-05-03 | 2018-11-16 | 青岛大学 | A kind of preparation method of cholic acid grafting selenizing chitosan oligosaccharide |
| CN109589317A (en) * | 2018-12-10 | 2019-04-09 | 中国海洋大学 | It is a kind of to have both the preparation method for inhibiting the nano particle of histamine release and histamine receptor antagonism function |
| CN109776630A (en) * | 2019-02-26 | 2019-05-21 | 佛山科学技术学院 | Lactose base mercaptopropionic acid root or galactosyl mercaptopropionic acid root and its preparation method and application |
| CN109908105A (en) * | 2018-12-30 | 2019-06-21 | 浙江中医药大学 | A kind of nano-complex of deoxycholic acid modification and its preparation and application |
| CN114075427A (en) * | 2020-08-19 | 2022-02-22 | 上海微创惟美医疗科技(集团)有限公司 | Composite antifreezing agent and preparation method thereof |
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| JPH09188705A (en) * | 1995-11-07 | 1997-07-22 | Seikagaku Kogyo Co Ltd | Glycosaminoglycan derivative and production thereof |
| CN102260357A (en) * | 2011-07-14 | 2011-11-30 | 济南大学 | Amphipathic chitosan-bile acid derivatives and preparation method thereof |
| CN102276756A (en) * | 2011-07-29 | 2011-12-14 | 中国海洋大学 | Preparation method of chitosan hydroxybutyl derivative |
| CN102319436A (en) * | 2011-08-17 | 2012-01-18 | 山东大学 | O-carboxymethyl chitosan-deoxycholic acid complex of modified with folic acid and preparation method thereof and application |
| CN102775515A (en) * | 2012-06-12 | 2012-11-14 | 中国科学院化学研究所 | Amphiphilic chitosan derivatives, and preparation method and application thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108822232A (en) * | 2018-05-03 | 2018-11-16 | 青岛大学 | A kind of preparation method of cholic acid grafting selenizing chitosan oligosaccharide |
| CN109589317A (en) * | 2018-12-10 | 2019-04-09 | 中国海洋大学 | It is a kind of to have both the preparation method for inhibiting the nano particle of histamine release and histamine receptor antagonism function |
| CN109908105A (en) * | 2018-12-30 | 2019-06-21 | 浙江中医药大学 | A kind of nano-complex of deoxycholic acid modification and its preparation and application |
| CN109908105B (en) * | 2018-12-30 | 2021-05-28 | 浙江中医药大学 | Deoxycholic acid modified nano compound and preparation and application thereof |
| CN109776630A (en) * | 2019-02-26 | 2019-05-21 | 佛山科学技术学院 | Lactose base mercaptopropionic acid root or galactosyl mercaptopropionic acid root and its preparation method and application |
| CN114075427A (en) * | 2020-08-19 | 2022-02-22 | 上海微创惟美医疗科技(集团)有限公司 | Composite antifreezing agent and preparation method thereof |
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