CN106589169A - Preparation method of water-soluble high-molecular cyclodextrin polymer - Google Patents
Preparation method of water-soluble high-molecular cyclodextrin polymer Download PDFInfo
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- CN106589169A CN106589169A CN201710058194.4A CN201710058194A CN106589169A CN 106589169 A CN106589169 A CN 106589169A CN 201710058194 A CN201710058194 A CN 201710058194A CN 106589169 A CN106589169 A CN 106589169A
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- cyclodextrin
- water
- molecular
- cyclodextrin polymer
- polymer
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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
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
Abstract
The invention discloses a preparation method of a water-soluble high-molecular cyclodextrin polymer, and belongs to the field of chemical modification of cyclodextrin. The method comprises the following steps: activating hydroxyl groups in alkaline environment, and carrying out nucleophilic substitution on chloropropylene oxide and a hydroxyl group activated solution used as a nucleophilic agent; terminating the above reaction when the reaction time is reached; and adjusting the obtained reaction system to be neutral, carrying out alcohol precipitation and water washing purification on the obtained product, and drying the purified product to obtain the water-soluble high-molecular cyclodextrin polymer. The obtained cyclodextrin polymer has high weight average molecular weight reaching 10<7> Da, and has high water solubility of 500 g/L or above, so the cyclodextrin polymer obtained in the invention is better than reported cyclodextrin polymers. The cyclodextrin polymer structurally reserves the cavity of cyclodextrin, also has high-molecular effects, has strong inclusion capability to guests, and has high practical values in the field of insoluble substance solubilizing.
Description
Technical field
The present invention relates to Cyclodextrin Chemistry technical field of modification, reaches the water-soluble high score of 10E7 more particularly, to a kind of molecular weight
The preparation method of sub- cyclodextrin.
Background technology
Cyclodextrin has outer hydrophilic interior hydrophobic characteristic, can be widely used in solubilising, the micro encapsulation of indissoluble material
Etc. aspect.But mother body cyclodextrin forms internal hydrogen bond, cause the water solublity of itself relatively low, limit its application.It is main at present
Improve the water solublity of cyclodextrin by two Technology Ways, one is to add deriveding group on cyclodextrin parent to break inside
Hydrogen bond, such as hydroxypropyl cyclodextrin, sulphur butyl cyclodextrin etc..Two is to become polymer by beta-cyclodextrin cross-linked.
Cyclodextrin not only has polymer effect, while the Binding ability of mother body cyclodextrin cavity is also retains,
There is preferable inclusion characteristic in the case where guest molecule is larger.Cyclodextrin is prepared at present is broadly divided into linear polymer
With branch shaped polymer, wherein preparation method the most convenient be prepared with epoxychloropropane as cross-linking agent under alkaline environment it is poly-
Compound, gradually rising with the increase of crosslinking degree, molecular weight for the method, then forms insoluble after reaching crosslinking boundary
Cyclodextrin, it is impossible to be applied to the situations such as medicine increase-volume.Research shows that the molecular weight of polymer is more high more favourable again simultaneously
In inclusion medicine, the especially guest molecule larger to molecular weight, the molecular weight pole of the cyclodextrin that current technology is prepared
It is limited to 106.The present invention attempts to lift this boundary, and having polymer has preferable inclusion characteristic to larger guest molecule.
The content of the invention
For the problems referred to above that prior art is present, the applicant provides a kind of water soluble polymer cyclodextrin
Preparation method.This preparation method step is simple, and the polymer prepared by this method can be 107Still have under Da molecular weight
There is higher water solublity, while retaining cyclodextrin cavity, be in dendroid in structure.
Technical scheme is as follows：
A kind of preparation method of water soluble polymer cyclodextrin, comprises the following steps：
(A) 10～15g cyclodextrins are persistently stirred in the NaOH aqueous solutions that 16～25ml concentration is 20～30wt%
Mixing makes which be dissolved as clear solution for 12～15 hours, and hydroxyl is fully activated, and is subsequently adding 2～8ml dehydrated alcohol and stirs equal
It is even；
(B) cyclodextrin solution that step (A) is obtained is heated and maintains 30～40 DEG C, the amount for adding material is cyclodextrin
The epoxychloropropane that 5～8 times of mole, stirring 180～360min of sustained response；
(C) the acetone terminating reaction of gained 0.5～1 times of volume of reaction system in step B, 200～240rpm are subsequently poured into
Stand after 5～8min of lower stirring, the acetone on upper strata is removed after system layering；It is added dropwise over hydrochloric acid solution to adjust reaction system
To neutrality；Gained neutral products are poured into during volume is its 4～6 times dehydrated alcohol, and 10 are centrifuged under the conditions of 2000g～3000g
～20min, leaves and takes bottom viscous liquid；
(D) viscous liquid is diluted to into 50～100 times of volumes, the concentration time of 10～30kDa ultra-filtration centrifuge tubes with distilled water
To remove salt ion and small molecule product, by concentrated solution, under the conditions of 40～50 DEG C, drying water soluble polymer cyclodextrin gathers
Compound.
The cyclodextrin adopts alpha-cyclodextrin, beta-schardinger dextrin-, any one in gamma-cyclodextrin, or its mixture.
The present invention is beneficial to be had technical effect that：
Can be because the degree of cross linking be excessive when the reaction of traditional cyclodextrin epichlorohydrin polymer is carried out to a certain extent
Insoluble gel is formed, the water-soluble polymer obtained by high molecular needs the terminating reaction before into glue point, wayward
And molecular weight is low.The present invention affects nucleophilic displacement of fluorine by controlling the polarity of reaction system, and then can extend the response time and make
Reaction is easily controllable, and the molecular weight of water-soluble cyclodextrin reaches 107, while high water-soluble with more than 500g/L
Property, better than report before.Which remains the cavity of cyclodextrin in structure, while also having polymer effect.To object
Binding ability is strong, has higher practical value in indissoluble thing solubilising field.
On the same chain of cyclodextrin prepared by the present invention, adjacent cavity can include a guest molecule jointly, right
In molecular weight than it is larger, be not easy the guest molecule for being included and have good pardon.Such as taxane molecule, beta-carotene
Molecule.
Description of the drawings
The ESC elution curves of 1 sample of Fig. 1 embodiment of the present invention；
The microstructure under a scanning electron microscope of 1 sample of Fig. 2 embodiment of the present invention.
Fourier's infrared scan collection of illustrative plates of 1 sample of Fig. 3 embodiment of the present invention.
Specific embodiment
With reference to the accompanying drawings and examples, the present invention is specifically described.
Embodiment 1
1), in the NaOH aqueous solutions by 10g cyclodextrins to 16ml concentration for 20wt%, persistently stirring makes which in 12 hours
Clear solution is dissolved as, and hydroxyl is fully activated, be subsequently adding 2ml dehydrated alcohol and stir；
2) cyclodextrin solution that step (1) is obtained is heated and maintains 30 DEG C, the amount for adding material is cyclodextrin mole
The epoxychloropropane of 5～8 times of amount, stirring 180～360min of sustained response；
3) the acetone terminating reaction of gained 0.5～1 times of volume of reaction system in step (2) is subsequently poured into, is stirred under 200rpm
Stand after mixing 5min, the acetone on upper strata is removed after system layering；It is added dropwise over hydrochloric acid solution reaction system to be adjusted to neutrality；
Gained neutral products are poured into during volume is its 4 times dehydrated alcohol, and 10min is centrifuged, bottom is left and taken thick under the conditions of 2000g
Liquid；
4) viscous liquid is diluted to into 50 times of volumes with distilled water, the concentration time of 10kDa ultra-filtration centrifuge tubes with remove salt from
Son and small molecule product, by concentrated solution under the conditions of 40 DEG C drying water soluble polymer cyclodextrin.
Embodiment 2
1), in the NaOH aqueous solutions by 13g cyclodextrins to 20ml concentration for 25wt%, persistently stirring makes which in 13 hours
Clear solution is dissolved as, and hydroxyl is fully activated, be subsequently adding 5ml dehydrated alcohol and stir；
2) cyclodextrin solution that step (1) is obtained is heated and maintains 35 DEG C, the amount for adding material is cyclodextrin mole
The epoxychloropropane of 6 times of amount, stirring sustained response 270min；
3) the acetone terminating reaction of gained 0.7 times of volume of reaction system in step (2) is subsequently poured into, is stirred under 220rpm
Stand after 6min, the acetone on upper strata is removed after system layering；It is added dropwise over hydrochloric acid solution reaction system to be adjusted to neutrality；Institute
Neutral products are poured into during volume is its 5 times dehydrated alcohol, 15min is centrifuged under the conditions of 2500g, the thick liquid of bottom is left and taken
Body；
4) viscous liquid is diluted to into 75 times of volumes with distilled water, the concentration time of 20kDa ultra-filtration centrifuge tubes with remove salt from
Son and small molecule product, by concentrated solution under the conditions of 45 DEG C drying water soluble polymer cyclodextrin.
Embodiment 3
1), in the NaOH aqueous solutions by 15g cyclodextrins to 25ml concentration for 30wt%, persistently stirring makes which in 15 hours
Clear solution is dissolved as, and hydroxyl is fully activated, be subsequently adding 8ml dehydrated alcohol and stir；
2) cyclodextrin solution that step (1) is obtained is heated and maintains 40 DEG C, the amount for adding material is cyclodextrin mole
The epoxychloropropane of 8 times of amount, stirring sustained response 360min；
3) the acetone terminating reaction of gained 1 times of volume of reaction system in step (2) is subsequently poured into, under 240rpm, 8min is stirred
After stand, the acetone on upper strata is removed after system layering；It is added dropwise over hydrochloric acid solution reaction system to be adjusted to neutrality；In gained
Property product is poured into during volume is its 6 times dehydrated alcohol, and 20min is centrifuged, bottom viscous liquid is left and taken under the conditions of 3000g；
4) viscous liquid is diluted to into 100 times of volumes with distilled water, the concentration time of 30kDa ultra-filtration centrifuge tubes with remove salt from
Son and small molecule product, by concentrated solution under the conditions of 50 DEG C drying water soluble polymer cyclodextrin.
Hydrochloric acid solution used by embodiment 1～3 can be 2mol/L concentration.
Performance test 1：
The aqueous solution that the polymer in a small amount of embodiment 1 is made into 5mg/ml is taken, its molecule is determined by size exclusion chromatography
Amount size.Chromatographic condition：Chromatographic column Shodex 806+804, column temperature 40C, flow velocity 0.5ml/min, pulullan standard specimen P-82 are painted
Standard curve processed, MALLS+RID detectors.As a result it is as shown in figure 1,18min or so is polymer peak, heavy respectively through calculating which
Son amount is 1.5*107。
Performance test 2：
Take the polymer samples in a small amount of embodiment 1 to be dissolved in distilled water, the lyophilization 72h after -80 DEG C of anxious jellies,
Observe under scanning electron microscope after sample preparation, as shown in Fig. 2 the microstructure of polymer is in dendroid.
Performance test 3：
Paclitaxel is dissolved in ethanol, the paclitaxel solution of 1mg/ml is configured to.It is diluted to series concentration solution and draws mark
Directrix curve.Take 1ml cyclodextrin aqueous solutions to be placed in centrifuge tube, instill 0.1ml paclitaxel mother solutions, in enzyme reactor
30C 1000r/min shake 24Hr.Being centrifuged and taking supernatant and absorbance is measured at 228nm wavelength, its value brings standard curve into
Calculate concentration.Cyclodextrin is high due to molecular weight, its skeleton effect and to face base effect notable.Big point this for paclitaxel
The inclusion effect is significant of sub- object.Its clathrate dissolubility in aqueous reaches 3mg/ml, is that monomer dissolves in aqueous
1000 times or so of degree, stability of solution is good within 48 hours.Its concentration can meet current paclitaxel 135 or 175mg/ completely
m2, the quantity of 500-1000ml transfusions.
The paclitaxel for clinically using at present is dissolved in ethoxylate castor oil, and its side effect is 24 hours steady
It is qualitative bad, and need to carry out desensitization process before injection.The present invention can be issued in aqueous environment and require concentration, non-
Often convenient, good stability can keep settled solution at 48 hours, and the nephrotoxicity of cyclodextrin is lower.
Claims (2)
1. a kind of preparation method of water soluble polymer cyclodextrin, it is characterised in that comprise the following steps：
(A) 10～15g cyclodextrins are persistently stirred into 12 in the NaOH aqueous solutions that 16～25ml concentration is 20～30wt%
Make within～15 hours which be dissolved as clear solution, and hydroxyl is fully activated, be subsequently adding 2～8ml dehydrated alcohol and stir；
(B) cyclodextrin solution that step (A) is obtained is heated and maintains 30～40 DEG C, the amount for adding material is cyclodextrin mole
The epoxychloropropane of 5～8 times of amount, stirring 180～360min of sustained response；
(C) the acetone terminating reaction of gained 0.5～1 times of volume of reaction system in step B is subsequently poured into, is stirred under 200～240rpm
Stand after mixing 5～8min, the acetone on upper strata is removed after system layering；It is added dropwise over hydrochloric acid solution reaction system to be adjusted into
Property；Gained neutral products are poured into during volume is its 4～6 times dehydrated alcohol, under the conditions of 2000g～3000g centrifugation 10～
20min, leaves and takes bottom viscous liquid；
(D) viscous liquid is diluted to into 50～100 times of volumes with distilled water, 10～30kDa ultra-filtration centrifuge tubes concentrate secondary to wash
Except salt ion and small molecule product, the drying water soluble polymer cyclodextrin polymerization under the conditions of 40～50 DEG C by concentrated solution
Thing.
2. method according to claim 1, it is characterised in that：The cyclodextrin adopts alpha-cyclodextrin, beta-schardinger dextrin-, and γ-
Any one in cyclodextrin, or its mixture.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201710058194.4A CN106589169A (en) | 2017-01-23 | 2017-01-23 | Preparation method of water-soluble high-molecular cyclodextrin polymer |
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| CN201710058194.4A CN106589169A (en) | 2017-01-23 | 2017-01-23 | Preparation method of water-soluble high-molecular cyclodextrin polymer |
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| CN106589169A true CN106589169A (en) | 2017-04-26 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107364939A (en) * | 2017-09-04 | 2017-11-21 | 谭永超 | It is a kind of using plant extracts as sewage flocculant of main component and preparation method thereof |
| CN113651901A (en) * | 2021-08-20 | 2021-11-16 | 成都工业学院 | Preparation method of water-soluble polymer cyclodextrin |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58171404A (en) * | 1982-03-31 | 1983-10-08 | Agency Of Ind Science & Technol | Production of polycyclodextrin beads |
| JPH06145204A (en) * | 1991-04-08 | 1994-05-24 | Mercian Corp | Etherified cyclodextrin polymer |
| CN1879887A (en) * | 2006-05-11 | 2006-12-20 | 沈阳药科大学 | Insoluble drug delivery system based on water-soluble cyclodextrin |
-
2017
- 2017-01-23 CN CN201710058194.4A patent/CN106589169A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS58171404A (en) * | 1982-03-31 | 1983-10-08 | Agency Of Ind Science & Technol | Production of polycyclodextrin beads |
| JPH06145204A (en) * | 1991-04-08 | 1994-05-24 | Mercian Corp | Etherified cyclodextrin polymer |
| CN1879887A (en) * | 2006-05-11 | 2006-12-20 | 沈阳药科大学 | Insoluble drug delivery system based on water-soluble cyclodextrin |
Non-Patent Citations (1)
| Title |
|---|
| 王智平等: "高分子水溶性β-环糊精聚合物的制备", 《中国科技论文在线》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107364939A (en) * | 2017-09-04 | 2017-11-21 | 谭永超 | It is a kind of using plant extracts as sewage flocculant of main component and preparation method thereof |
| CN113651901A (en) * | 2021-08-20 | 2021-11-16 | 成都工业学院 | Preparation method of water-soluble polymer cyclodextrin |
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