CN104558419B - A kind of preparation method of environment sensitive type cyclodextrine derivatives hydrogel - Google Patents
A kind of preparation method of environment sensitive type cyclodextrine derivatives hydrogel Download PDFInfo
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- CN104558419B CN104558419B CN201410504485.8A CN201410504485A CN104558419B CN 104558419 B CN104558419 B CN 104558419B CN 201410504485 A CN201410504485 A CN 201410504485A CN 104558419 B CN104558419 B CN 104558419B
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Abstract
The invention discloses a kind of preparation method of environment sensitive type cyclodextrine derivatives hydrogel, by cyclodextrin, methacrylic acid, 1, the reaction of 2 dicyclohexylcarbodiimides is obtained methacrylic acid cyclodextrin ester, then methacrylic acid cyclodextrin ester, methacrylic acid, crosslinking agent N, N' di-2-ethylhexylphosphine oxide isopropyl acrylamide, acrylamide are reacted in the presence of initiator ammonium persulfate solution and gel is obtained.Gel of the invention has pH sensitiveness and temperature sensitivity, and swelling ratio is high in the basic conditions, and swelling ratio is low under acid condition, is ideal for the carrier in controlled release drug to enteron aisle, and be advantageously implemented the insoluble drug release of responsive to temperature type.
Description
(1) technical field
The present invention relates to a kind of preparation of cyclodextrine derivatives hydrogel, more particularly, to a kind of pH/ temperature of Fast-swelling
Spend the preparation of responsive type cyclodextrine derivatives hydrogel.
(2) background technology
Environmental sensitive hydrogels material is the important biological medical polymer material of a class, and corresponding thing is produced by itself
Reason is micro- come (such as temperature, pH, pressure, electricity, light) in responding external environment with structure chemically and qualitative significant changes
Small change or the hydrogel of stimulation.More and more closed because environmental sensitive hydrogels have various potential applications
Note, such as immobilization of intellectual drug induction system, artificial-muscle, valve for chemical industry, enzyme and cell.(Huang J,Hastings
CL,Duffy GP,Kelly HM,Raeburn J,Adams DJ,Heise A.Biomacromolecules 2012,4,200-
206；Vermonden T,Censi R,Hennink WE.Chem Rev2012,112,2853-2888；Seliktar
D.Science 2012,336,1124-1128；Li Y,Rodrigues J,Tomas H.Chem Soc Rev 2012,41,
2193-2221；Qiu Y,Park K.Adv Drug Deliv Rev 2012,64,49-60；Siepmann J,Peppas
NA.Adv Drug Deliv Rev 2012,64,163-174；Josef E,Barat K,Barsht I,Zilberman M,
Bianco-Peled H.Acta Biomater 2013,9,8815-8822.)。
Used as hydrophilic polymer network, hydrogel can improve the solubility and bioavilability of medicine.However, water-setting
One weakness of glue is that xerogel has certain vitrifying property, discharges drug molecule in water diffusion to xerogel
The speed ratio come is slower.Therefore, the hydrogel of exploitation Fast-swelling type is necessary.
(3) content of the invention
The purpose carrier of this patent provides a kind of preparation of the temperature sensitive hydrogels of the pH/ of Fast-swelling, with cyclodextrin
And cyclodextrin derivative prepares hydrogel for base material, develops the pharmaceutical carrier with environment sensitive type, medicine is capable of achieving
Fixed point, the control release of quantitative and timing, improve the high efficiency and targeting of medicine-carried system.
The present invention relates to a kind of preparation of cyclodextrine derivatives hydrogel, more particularly, to a kind of pH/ temperature of Fast-swelling
Spend the preparation of responsive type cyclodextrine derivatives hydrogel.To realize the object of the invention, the technical solution adopted by the present invention is：
A kind of preparation method of environment sensitive type cyclodextrine derivatives hydrogel, the environment sensitive type cyclodextrine derivatives
Hydrogel has pH sensitiveness and temperature sensitivity, the described method comprises the following steps：
(1) cyclodextrin is dissolved in organic solvent A, and methacrylic acid (MAA) and 1,2- bis- are added under 0-10 DEG C of condition of ice bath
Cyclohexyl-carbonyl diimine (DCC), after 30~60min of stirring reaction, reacts 5-12h at being placed in 20-40 DEG C, reaction terminates rear institute
Obtain reaction solution A post processings and methacrylic acid-cyclodextrin ester (MAA-CD) is obtained；The cyclodextrin, methacrylic acid, the rings of 1,2- bis-
The ratio between amount of material of hexyl carbonyl diimine is 1：1~4：1~5；
(2) crosslinking agent N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide (BIS) are dissolved in solvent B, (preferably 0 DEG C at 0~5 DEG C
Under) stirring 3~5 hours after, in gained cross-linking agent solution add methacrylic acid (MAA), metering system obtained in step (1)
Acid-cyclodextrin ester and acrylamide (MBAA), and nitrogen exclusion air is passed through, 10 are stirred (at preferably 0 DEG C) at 0~5 DEG C
After~30 minutes, plus initiator ammonium persulfate solution, keep reaction solution to react 1.0- (at preferably 50~80 DEG C) at 25-80 DEG C
8.0 hours, gel crude product is prepared, after stopping reaction, will be dried after gained gel crude product distillation water washing, immersion, system
Obtain xerogel, as described environment sensitive type cyclodextrine derivatives hydrogel；The methacrylic acid-cyclodextrin ester, methyl-prop
Olefin(e) acid, crosslinking agent N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide, the mass ratio of acrylamide are 1：0.5~4.5：0.2~1.5：0.05
~0.88；The solvent B is dimethyl sulfoxide (DMSO) (DMSO) or dimethyl sulfoxide (DMSO) (DMSO) and distilled water volume than 1~10：1 mixing
Mixed solvent.
In the step (1), the organic solvent A is DMF (DMF) or dimethyl sulfoxide (DMSO) (DMSO).
The volumetric usage of the organic solvent A is generally calculated as 5~15mL/g with the quality of cyclodextrin.
In the step (1), the cyclodextrin, methacrylic acid, the amount of the material of 1,2- dicyclohexylcarbodiimides
The ratio between be preferably 1：2~3：3~4.
In the step (1), the cyclodextrin is alpha-cyclodextrin, beta-schardinger dextrin or gamma-cyclodextrin, preferably beta-schardinger dextrin.
In the step (1), the reaction solution A post-processing approach is：After reaction terminates, reaction solution A vacuum filtrations are removed
Solid, gained filtrate a adds isopropanol, there is Precipitation, filters to obtain crude product, is dissolved with the ethanol solution of volume fraction 50%
Crude product, after filtering, gained filtrate b adds isopropanol again, there is Precipitation, filtering, filter cake vacuum drying, obtains white powder
End, as methacrylic acid-cyclodextrin ester (MAA-CD).
In the step (2), the volumetric usage of the solvent B is generally calculated as with the quality of methacrylic acid-cyclodextrin ester
15~40mL/g.
The solvent B is preferably dimethyl sulfoxide (DMSO) (DMSO) or dimethyl sulfoxide (DMSO) (DMSO) and distilled water volume than 1~4：1
The mixed solvent of mixing, most preferably DMSO.
In the step (2), the methacrylic acid-cyclodextrin ester, methacrylic acid, crosslinking agent N, N'- di-2-ethylhexylphosphine oxide
Isopropyl acrylamide, the mass ratio of acrylamide are preferably 1：4：1：0.25.
In the step (2), dried after gel crude product distillation water washing, immersion, the environment sensitive type is obtained
Cyclodextrine derivatives hydrogel, can specifically operate according to the following steps：After gel crude product is with distillation water washing 3-5 time, then with distilling
Water is soaked, and first water was changed every 24 hours, is soaked 2~8 days, and then the gel after immersion is done in 30~50 DEG C of vacuum
Dry or freeze-drying, is obtained the environment sensitive type cyclodextrine derivatives hydrogel.
In the step (2), ammonium persulfate and methacrylic acid-cyclodextrin ester in the initiator ammonium persulfate solution
Mass ratio be 0.06~0.63：1.0, preferably 0.25：1.0.Initiator is ammonium persulfate solution, wherein the concentration of ammonium persulfate
Usually 0.05~5g/mL.
Further, preferably the method for the invention is carried out according to the following steps：
(1) cyclodextrin is dissolved in organic solvent A, and methacrylic acid and 1,2- dicyclohexyl are added under 0-10 DEG C of condition of ice bath
Carbonyl diimine, after 30~60min of stirring reaction, reacts 5-12h at being placed in 20-40 DEG C, gained reaction solution A is true after reaction terminates
Empty suction filtration removes solid, and gained filtrate a adds isopropanol, there is Precipitation, crude product is filtered to obtain, with the second of volume fraction 50%
Alcoholic solution dissolves crude product, and after filtering, gained filtrate b adds isopropanol again, there is Precipitation, filtering, filter cake vacuum drying,
White powder is obtained, as methacrylic acid-cyclodextrin ester；The cyclodextrin, methacrylic acid, 1,2- dicyclohexyls carbonyl two
The ratio between amount of material of imines is 1：2~3：3~4；The organic solvent A is N,N-dimethylformamide or dimethyl sulfoxide (DMSO)；
(2) crosslinking agent N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide are dissolved in solvent B, after stirring 3~5 hours at 0 DEG C,
Methacrylic acid, methacrylic acid-cyclodextrin ester and acrylamide obtained in step (1) are added in gained cross-linking agent solution,
And nitrogen exclusion air is passed through, after being stirred 10~30 minutes at 0 DEG C, plus initiator ammonium persulfate solution, keep reaction solution to exist
Reacted 1.0-8.0 hours at 50~80 DEG C, prepare gel crude product, after stopping reaction, by gained gel crude product distilled water
After washing 3-5 times, then with distilled water immersion, first water was changed every 24 hours, soaked 2~8 days, then by after immersion
Gel is obtained xerogel, as described environment sensitive type cyclodextrine derivatives in 30~50 DEG C of vacuum drying or freeze-drying
Hydrogel；The methacrylic acid-cyclodextrin ester, methacrylic acid, crosslinking agent N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide, propylene
The mass ratio of acid amides is 1：0.5~4.5：0.2~1.5：0.05~0.88；The solvent B is that dimethyl sulfoxide (DMSO) or dimethyl are sub-
Sulfone and distilled water volume are than 1~4：The mixed solvent of 1 mixing；Ammonium persulfate and methyl in the initiator ammonium persulfate solution
The mass ratio of acrylic acid-cyclodextrin ester is 0.06~0.63：1.0.
The beneficial effects of the present invention are：The cyclodextrin hydrogel of one class Fast-swelling type is provided, is accelerated hydrone and is expanded
The speed in xerogel is dissipated to, is conducive to short time interior discharge drug molecule to reach therapeutic dose, can be to a certain degree
It is upper to solve the problems, such as that existing hydrogel xerogel initial release rate is relatively unable to quick acting slowly.And it is therefore of the invention solidifying
Glue has obviously pH sensitiveness, and swelling ratio is very low in acid condition, therefore is used for carrying medicine using gel of the invention
When, the amount that medicine is discharged in stomach can be fewer, while be also possible to prevent some produces the oral of stimulation to stomach lining
Injury of the medicine to stomach.In addition, the gel swellability preferably, is suitable to intestinal environment in the basic conditions, therefore the present invention is provided
Hydrogel be a kind of ideal for the carrier in controlled release drug to enteron aisle.The gel of the application is in not equality of temperature
Swelling behavior in degree environment is different, and swelling rate is smaller at room temperature, but its swelling behavior is gradually carried with the rising of temperature
Height, is advantageously implemented the insoluble drug release of responsive to temperature type.
(4) illustrate
The infared spectrum of raw material and product in Fig. 1 embodiments 1, wherein a is beta-schardinger dextrin, and b is methacrylic acid-β-ring paste
Smart ester (MAA- β-CD), c is product xerogel.
The outward appearance photo of the gel that Fig. 2 is prepared in different solvents.(Gel-1,VDMSO：VH2O=2.0:2.0；Gel-2,
VDMSO：VH2O=3.0:1.0；Gel-3,VDMSO：VH2O=3.5:0.5；Gel-4, solvent is DMSO).
Swelling ratio curve maps of Fig. 3 gels Gel-4 in the cushioning liquid of different pH value.
The swelling ratio curve map that Fig. 4 gels Gel-4 is varied with temperature in pH=8.0 cushioning liquid.
(5) specific embodiment
With reference to specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in
This：
Embodiment 1
The beta-schardinger dextrin (β-CD) for weighing 1.135g (0.001mol) is dissolved in 12mL N,N-dimethylformamides (DMF)
Stirring is separately added into 0.172g (0.002mol) methacrylic acid (MAA) and 0.618g to dissolving under 5 DEG C of condition of ice bath
1, the 2- dicyclohexylcarbodiimides (DCC) of (0.003mol), after stirring 30min, 5h are reacted at being placed in 35 DEG C.Reaction terminates
Afterwards, vacuum filtration removes solid, and filtrate is separated out with isopropanol precipitating, and filter cake is crude product, and the ethanol solution with 50% is again molten
Solution crude product, after filtering, filtrate adds isopropanol precipitating to separate out again, and filtering, filtration cakes torrefaction obtains white powder solid product first
Base senecioate-cyclodextrin ester (MAA- β-CD).
0.8g crosslinking agents N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide (BIS) are dissolved in 20mL dimethyl sulfoxide (DMSO)s (DMSO),
After stirring 3 hours at 0 DEG C, during monomer MAA 3.2g and MAA- β-CD 0.8g added into reaction system, while in reaction system
In add 0.2g acrylamides (MBAA) and lead to air in nitrogen exclusion system afterwards, after stirring 10min at 0 DEG C, add 0.2g mistakes
Ammonium sulfate is dissolved in the ammonium persulfate solution that 2mL distilled water is obtained, and 6h is reacted at going to 50 DEG C, you can obtain clear gel, such as Fig. 2
Shown in Gel-4.With distilled water cyclic washing gel 5 times, unnecessary DMSO is removed, finally use distilled water immersion gel, Mei Geyi
It changes first water, soaks 2 days, and freeze-drying obtains product xerogel, as environment sensitive type cyclodextrine derivatives water-setting
Glue.Its swelling ratio is determined, step is as follows.
The measure of swelling behavior rate：
Swelling behavior rate (Sr) can be determined with weight method.At a constant temperature, dry glue being weighed, it is slow be immersed in after (Wo)
In fliud flushing, treat that its is swelling, timing sampling sucks the unnecessary moisture of hydrogel surface with filter paper, weighs (Ws).Different swelling times
Swelling behavior rate Sr according to below equation calculate：Sr=(Ws-Wo)/Wo.
Xerogel Gel-4 be have studied in an experiment at a temperature of 25 DEG C, different pH value cushioning liquid (pH=1.04,
2.43rd, 3.84,6.67,8.86, swelling behavior acquired results 10.34) are shown in Fig. 3.Xerogel Gel-4 is investigated in pH=
Under the conditions of 8.0, different temperatures (25 DEG C, 30 DEG C, 35 DEG C, 37 DEG C, 40 DEG C, 45 DEG C (± 0.5 DEG C)) under the conditions of swelling behavior,
Acquired results are shown in Fig. 4.
Fig. 3 shows that the gel shows good swelling behavior in different pH cushioning liquid, when pH is less than 3.84,
Gel swelling is slow, and in pH=6.67, gel Fast-swelling, swellbility can reach 115.9, as pH increases to 8.86
When, gel is further swelling, and it is 252.5% that swellbility reaches a maximum, but when pH continues to increase to 10.34, gel
Swelling ratio reduction, but remain above the swelling ratio under acid condition.Therefore gel of the invention has obviously pH sensitiveness,
Swelling ratio is very low in acid condition, therefore when being used for carrying medicine using gel of the invention, medicine is in stomach (pH<3) release in
Amount out can be fewer, while being also possible to prevent some produces injury of the oral drugs for stimulating to stomach to stomach lining.In addition,
Swellability is preferable in the basic conditions for the gel, swelling ratio highest of the gel in the range of pH6.67-8.86, and small intestine
PH7.6-7.8, the pH8.3-8.4 of large intestine, it is seen that swellability is preferable under the conditions of pH of the gel in small intestine, therefore present invention offer
Hydrogel be a kind of ideal for the carrier in controlled release drug to enteron aisle.From the point of view of Fig. 4, gel is in difference
Swelling behavior in temperature environment is different, and swelling rate is smaller at room temperature, but with the rising of temperature its swelling behavior gradually
Improve, be advantageously implemented the insoluble drug release of responsive to temperature type.
Embodiment 2
The beta-schardinger dextrin (β-CD) for weighing 1.135g (0.001mol) is dissolved in 12mL N,N-dimethylformamides (DMF)
Stirring is separately added into the rings of 1,2- bis- of 0.002mol methacrylic acids (MAA) and 0.003mol to dissolving under 5 DEG C of condition of ice bath
Hexyl carbonyl diimine (DCC), after stirring 30min, 5h is reacted at being placed in 35 DEG C.After reaction terminates, vacuum filtration removes solid,
Filtrate separates out crude product with isopropanol precipitating, and crude product is dissolved again with 50% ethanol solution, and after filtering, filtrate is again with different
Propyl alcohol Precipitation, vacuum drying obtains white powder solid product methacrylic acid-beta-schardinger dextrin ester (MAA- β-CD).
0.8g crosslinking agents N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide (BIS) are dissolved in the distilled water and dimethyl sulfoxide (DMSO) of 20mL
(DMSO) mixed liquor (VDMSO：VH2O=3.50：0.5) in, after stirring 3 hours at 0 DEG C, by monomer MAA 3.2g and MAA-
β-CD 0.8g are added in reaction system, are excluded while adding 0.2g acrylamides (MBAA) in reaction system and leading to nitrogen afterwards
Air in system, after stirring 10mins at 0 DEG C, adds 0.2g ammonium persulfates (being dissolved in 2mL distilled water) again, goes to 50 DEG C
Lower reaction 6h, you can obtain clear gel as shown in Fig. 2 Gel-3, with distilled water cyclic washing gel 5 times, it is unnecessary to remove
DMSO, finally uses distilled water immersion gel, every other day changes first water, soaks 2 days, and it is dry solidifying that freeze-drying obtains product
Glue.In pH=8.86, gel maximum swelling rate is 110.6% to the gel.
Embodiment 3
The beta-schardinger dextrin (β-CD) for weighing 1.135g (0.001mol) is dissolved in 12mL N,N-dimethylformamides (DMF)
Stirring is separately added into the rings of 1,2- bis- of 0.002mol methacrylic acids (MAA) and 0.003mol to dissolving under 5 DEG C of condition of ice bath
Hexyl carbonyl diimine (DCC), after stirring 30min, 5h is reacted at being placed in 35 DEG C.After reaction terminates, vacuum filtration removes solid,
Filtrate separates out crude product with isopropanol precipitating, and crude product is dissolved again with 50% ethanol solution, after filtering, isopropanol is used again
Precipitation, vacuum drying obtains white powder solid product methacrylic acid-beta-schardinger dextrin ester (MAA- β-CD).
0.8g crosslinking agents N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide (BIS) are dissolved in the distilled water and dimethyl sulfoxide (DMSO) of 20mL
(DMSO) mixed liquor (VDMSO：VH2O=3.0：1.0) in, after stirring 3 hours at 0 DEG C, by monomer MAA3.2g and MAA- β-
CD 0.8g are added in reaction system, and body is excluded while adding 0.2g acrylamides (MBAA) in reaction system and leading to nitrogen afterwards
Air in system, after stirring 10mins at 0 DEG C, adds 0.2g ammonium persulfates (being dissolved in 2mL distilled water) again, goes at 50 DEG C
Reaction 6h, you can obtain the translucent gel of milky, as shown in Fig. 2 Gel-2, with distilled water cyclic washing gel 5 times, removes
Unnecessary DMSO, finally uses distilled water immersion gel, every other day changes first water, soaks 2 days, and freeze-drying obtains product
Xerogel.In pH=8.86, the maximum swelling rate of gel is 98.9% to the gel.
Embodiment 4
The beta-schardinger dextrin (β-CD) for weighing 1.135g (0.001mol) is dissolved in the middle stirring of 12mL dimethyl sulfoxide (DMSO)s (DMSO) extremely
Dissolving, is separately added into 1, the 2- dicyclohexyl carbonyls of 0.002mol methacrylic acids (MAA) and 0.003mol under 5 DEG C of condition of ice bath
Base diimine (DCC), after stirring 30min, 5h is reacted at being placed in 35 DEG C.After reaction terminates, vacuum filtration removes solid, and filtrate is used
Isopropanol precipitating separates out crude product, and crude product is dissolved again with 50% ethanol solution, after filtering, is analysed with isopropanol precipitating again
Go out, vacuum drying obtains white powder solid product methacrylic acid-beta-schardinger dextrin ester (MAA- β-CD).
0.8g crosslinking agents N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide (BIS) are dissolved in the distilled water and dimethyl sulfoxide (DMSO) of 20mL
(DMSO) mixed liquor (VDMSO：VH2O=1.0：1.0) in, after stirring 3 hours at 0 DEG C, by monomer MAA3.2g and MAA- β-
CD 0.8g are added in reaction system, and body is excluded while adding 0.2g acrylamides (MBAA) in reaction system and leading to nitrogen afterwards
Air in system, after stirring 10mins at 0 DEG C, adds 0.2g ammonium persulfates (being dissolved in 2mL distilled water) again, goes at 50 DEG C
Reaction 6h, you can obtain the opaque gel of milky, as shown in Fig. 2 Gel-1, with distilled water cyclic washing gel 5 times, removes many
Remaining DMSO, finally uses distilled water immersion gel, every other day changes first water, soaks 2 days, and freeze-drying obtains product and does
Gel.In pH=8.86, the maximum swelling rate of gel is 78.1% to the gel.
Embodiment 5
The beta-schardinger dextrin (β-CD) for weighing 1.135g (0.001mol) is dissolved in 10mL N,N-dimethylformamides (DMF)
Stirring is separately added into the rings of 1,2- bis- of 0.004mol methacrylic acids (MAA) and 0.005mol to dissolving under 0 DEG C of condition of ice bath
Hexyl carbonyl diimine (DCC), after stirring 30min, is placed under room temperature (25 DEG C) and reacts 12h.After reaction terminates, vacuum filtration is removed
Solid is removed, filtrate separates out crude product, dissolves crude product again with 50% ethanol solution, after filtering, again with isopropanol precipitating
Separated out with isopropanol precipitating, vacuum drying obtains white powder solid product methacrylic acid-beta-schardinger dextrin ester (MAA- β-CD).
0.15g crosslinking agents N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide (BIS) are dissolved in the distilled water and dimethyl sulfoxide (DMSO) of 20mL
(DMSO) mixed liquor (VH2O：VDMSO=1.0：1.0) in, after stirring 3 hours at 0 DEG C, by monomer MAA0.4g and MAA- β-
CD 0.8g are added in reaction system, and body is excluded while adding 0.04g acrylamides (MBAA) in reaction system and leading to nitrogen afterwards
Air in system, after stirring 10mins at 0 DEG C, adds 0.05g ammonium persulfates (being dissolved in 1mL distilled water) again, goes to 70 DEG C
Lower reaction 3h, you can obtain the opaque gel of milky, with distilled water cyclic washing gel 5 times, removes unnecessary DMSO, finally
Distilled water immersion gel is used, first water is every other day changed, soaked 2 days, freeze-drying obtains product xerogel.
Embodiment 6
The beta-schardinger dextrin (β-CD) for weighing 1.135g (0.001mol) is dissolved in the middle stirring of 10mL dimethyl sulfoxide (DMSO)s (DMSO) extremely
Dissolving, is separately added into 1, the 2- dicyclohexyls of 0.001mol methacrylic acids (MAA) and 0.001mol under 10 DEG C of condition of ice bath
Carbonyl diimine (DCC), after stirring 30min, 8h is reacted at being placed in 20 DEG C.After reaction terminates, vacuum filtration removes solid, filtrate
Crude product is separated out with isopropanol precipitating, crude product is dissolved again with 50% ethanol solution, after filtering, isopropanol precipitating is used again
Separate out, vacuum drying obtains white powder solid product methacrylic acid-beta-schardinger dextrin ester (MAA- β-CD).
0.3g crosslinking agents N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide (BIS) are dissolved in the distilled water and dimethyl sulfoxide (DMSO) of 20mL
(DMSO) mixed liquor (VDMSO：VH2O=2.0：1.0) in, after stirring 3 hours at 0 DEG C, by monomer MAA0.6g and MAA- β-
CD 0.8g are added in reaction system, and body is excluded while adding 0.1g acrylamides (MBAA) in reaction system and leading to nitrogen afterwards
Air in system, after stirring 10mins at 0 DEG C, adds 0.1g ammonium persulfates (being dissolved in 2mL distilled water) again, goes at 80 DEG C
Reaction 1h, you can obtain translucent gels, with distilled water cyclic washing gel 5 times, removes unnecessary DMSO, finally uses distilled water
Immersion gel, every other day changes first water, soaks 2 days, and freeze-drying obtains product xerogel.
Embodiment 7
The beta-schardinger dextrin (β-CD) for weighing 1.135g (0.001mol) is dissolved in 10mL N,N-dimethylformamides (DMF)
Stirring is separately added into the rings of 1,2- bis- of 0.002mol methacrylic acids (MAA) and 0.003mol to dissolving under 5 DEG C of condition of ice bath
Hexyl carbonyl diimine (DCC), after stirring 30min, 7h is reacted at being placed in 30 DEG C.After reaction terminates, vacuum filtration removes solid,
Filtrate separates out crude product with isopropanol precipitating, and crude product is dissolved again with 50% ethanol solution, after filtering, isopropanol is used again
Precipitation, vacuum drying obtains white powder solid product methacrylic acid-beta-schardinger dextrin ester (MAA- β-CD).
0.6g crosslinking agents N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide (BIS) are dissolved in the distilled water and dimethyl sulfoxide (DMSO) of 20mL
(DMSO) mixed liquor (VDMSO：VH2O=2.0：1.0) in, after stirring 3 hours at 0 DEG C, by monomer MAA1.8g and MAA- β-
CD 0.8g are added in reaction system, and body is excluded while adding 0.3g acrylamides (MBAA) in reaction system and leading to nitrogen afterwards
Air in system, after stirring 10mins at 0 DEG C, adds 0.2g ammonium persulfates (being dissolved in 2mL distilled water) again, goes at 60 DEG C
Reaction 3h, you can obtain translucent gels, with distilled water cyclic washing gel 5 times, removes unnecessary DMSO, finally uses distilled water
Immersion gel, every other day changes first water, soaks 2 days, and freeze-drying obtains product xerogel.
Embodiment 8
The beta-schardinger dextrin (β-CD) for weighing 1.135g (0.001mol) is dissolved in 12mL N,N-dimethylformamides (DMF)
Stirring is separately added into the rings of 1,2- bis- of 0.003mol methacrylic acids (MAA) and 0.004mol to dissolving under 5 DEG C of condition of ice bath
Hexyl carbonyl diimine (DCC), after stirring 30min, 5h is reacted at being placed in 40 DEG C.After reaction terminates, vacuum filtration removes solid,
Filtrate separates out crude product with isopropanol precipitating, and crude product is dissolved again with 50% ethanol solution, after filtering, isopropanol is used again
Precipitation, vacuum drying obtains white powder solid product methacrylic acid-beta-schardinger dextrin ester (MAA- β-CD).
0.6g crosslinking agents N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide (BIS) are dissolved in the distilled water and dimethyl sulfoxide (DMSO) of 20mL
(DMSO) mixed liquor (VH2O：VDMSO=1.0：1.0) in, after stirring 3 hours at 0 DEG C, by monomer MAA2.2g and MAA- β-
CD 0.8g are added in reaction system, and body is excluded while adding 0.4g acrylamides (MBAA) in reaction system and leading to nitrogen afterwards
Air in system, after stirring 10mins at 0 DEG C, adds 0.3g ammonium persulfates (being dissolved in 2mL distilled water) again, goes at 60 DEG C
Reaction 4h, you can obtain the opaque gel of milky, with distilled water cyclic washing gel 5 times, removes unnecessary DMSO, finally uses
Distilled water immersion gel, every other day changes first water, soaks 2 days, and freeze-drying obtains product xerogel.
Embodiment 9
The beta-schardinger dextrin (β-CD) for weighing 1.135g (0.001mol) is dissolved in 12mL N,N-dimethylformamides (DMF)
Stirring is separately added into the rings of 1,2- bis- of 0.004mol methacrylic acids (MAA) and 0.005mol to dissolving under 0 DEG C of condition of ice bath
Hexyl carbonyl diimine (DCC), after stirring 30min, 6h is reacted at being placed in 36 DEG C.After reaction terminates, vacuum filtration removes solid,
Filtrate separates out crude product with isopropanol precipitating, and crude product is dissolved again with 50% ethanol solution, after filtering, isopropanol is used again
Precipitation, vacuum drying obtains white powder solid product methacrylic acid-beta-schardinger dextrin ester (MAA- β-CD).
0.6g crosslinking agents N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide (BIS) are dissolved in the distilled water and dimethyl sulfoxide (DMSO) of 20mL
(DMSO) mixed liquor (VDMSO：VH2O=3.0：1.0) in, after stirring 3 hours at 0 DEG C, by monomer MAA2.6g and MAA- β-
CD 0.8g are added in reaction system, and body is excluded while adding 0.7g acrylamides (MBAA) in reaction system and leading to nitrogen afterwards
Air in system, after stirring 10mins at 0 DEG C, adds 0.3g ammonium persulfates (being dissolved in 2mL distilled water) again, goes at 50 DEG C
Reaction 5h, you can obtain translucent gels, with distilled water cyclic washing gel 5 times, removes unnecessary DMSO, finally uses distilled water
Immersion gel, every other day changes first water, soaks 2 days, and freeze-drying obtains product xerogel.
Embodiment 10
The beta-schardinger dextrin (β-CD) for weighing 1.135g (0.001mol) is dissolved in 12mL N,N-dimethylformamides (DMF)
Stirring is separately added into the rings of 1,2- bis- of 0.003mol methacrylic acids (MAA) and 0.004mol to dissolving under 0 DEG C of condition of ice bath
Hexyl carbonyl diimine (DCC), after stirring 30min, 6h is reacted at being placed in 35 DEG C.After reaction terminates, vacuum filtration removes solid,
Filtrate separates out crude product with isopropanol precipitating, and crude product is dissolved again with 50% ethanol solution, after filtering, isopropanol is used again
Precipitation, vacuum drying obtains white powder solid product methacrylic acid-beta-schardinger dextrin ester (MAA- β-CD).
0.8g crosslinking agents N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide (BIS) are dissolved in the distilled water and dimethyl sulfoxide (DMSO) of 20mL
(DMSO) mixed liquor (VDMSO：VH2O=2.0：1.0) in, after stirring 3 hours at 0 DEG C, by monomer MAA3.6g and MAA- β-
CD 0.8g are added in reaction system, and body is excluded while adding 0.7g acrylamides (MBAA) in reaction system and leading to nitrogen afterwards
Air in system, after stirring 10mins at 0 DEG C, adds 0.5g ammonium persulfates (being dissolved in 2mL distilled water) again, goes at 25 DEG C
Reaction 8h, you can obtain the opaque gel of milky, with distilled water cyclic washing gel 5 times, removes unnecessary DMSO, finally uses
Distilled water immersion gel, every other day changes first water, soaks 2 days, and freeze-drying obtains product xerogel.
Embodiment 11
The beta-schardinger dextrin (β-CD) for weighing 1.135g (0.001mol) is dissolved in 12mL N,N-dimethylformamides (DMF)
Stirring is separately added into the rings of 1,2- bis- of 0.002mol methacrylic acids (MAA) and 0.003mol to dissolving under 5 DEG C of condition of ice bath
Hexyl carbonyl diimine (DCC), after stirring 30min, 5h is reacted at being placed in 35 DEG C.After reaction terminates, vacuum filtration removes solid,
Filtrate separates out crude product with isopropanol precipitating, and crude product is dissolved again with 50% ethanol solution, after filtering, isopropanol is used again
Precipitation, vacuum drying white powder solid product methacrylic acid-beta-schardinger dextrin ester (MAA- β-CD).
1.2g crosslinking agents N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide (BIS) are dissolved in the distilled water and dimethyl sulfoxide (DMSO) of 20mL
(DMSO) mixed liquor (VDMSO：VH2O=4.0：1.0) in, after stirring 3 hours at 0 DEG C, by monomer MAA3.6g and MAA- β-
CD 0.8g are added in reaction system, and body is excluded while adding 0.5g acrylamides (MBAA) in reaction system and leading to nitrogen afterwards
Air in system, after stirring 10mins at 0 DEG C, adds 0.5g ammonium persulfates (being dissolved in 2mL distilled water) again, goes at 50 DEG C
Reaction 6h, you can obtain clear gel, with distilled water cyclic washing gel 5 times, removes unnecessary DMSO, finally with distillation water logging
Foaming gel, every other day changes first water, soaks 2 days, and freeze-drying obtains product xerogel.
Embodiment 12
The beta-schardinger dextrin (β-CD) for weighing 1.135g (0.001mol) is dissolved in 12mL N,N-dimethylformamides (DMF)
Stirring is separately added into the rings of 1,2- bis- of 0.002mol methacrylic acids (MAA) and 0.003mol to dissolving under 5 DEG C of condition of ice bath
Hexyl carbonyl diimine (DCC), after stirring 30min, 5h is reacted at being placed in 35 DEG C.After reaction terminates, vacuum filtration removes solid,
Filtrate separates out crude product with isopropanol precipitating, and crude product is dissolved again with 50% ethanol solution, after filtering, isopropanol is used again
Precipitation, vacuum drying obtains white powder solid product methacrylic acid-beta-schardinger dextrin ester (MAA- β-CD).
0.8g crosslinking agents N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide (BIS) are dissolved in the distilled water and dimethyl sulfoxide (DMSO) of 20mL
(DMSO) mixed liquor (VDMSO：VH2O=4.0：1.0) in, after stirring 3 hours at 0 DEG C, by monomer MAA3.2g and MAA- β-
CD 0.8g are added in reaction system, and body is excluded while adding 0.2g acrylamides (MBAA) in reaction system and leading to nitrogen afterwards
Air in system, after stirring 10min at 0 DEG C, adds 0.2g ammonium persulfates (being dissolved in 2mL distilled water) again, goes at 50 DEG C
Reaction 6h, you can obtain clear gel, with distilled water cyclic washing gel 5 times, removes unnecessary DMSO, finally with distillation water logging
Foaming gel, every other day changes first water, soaks 2 days, and freeze-drying obtains product xerogel.
Embodiment 13
The alpha-cyclodextrin (α-CD) for weighing 0.973g (0.001mol) is dissolved in the middle stirring of 10mL dimethyl sulfoxide (DMSO)s (DMSO) extremely
Dissolving, is separately added into 1, the 2- dicyclohexyl carbonyls of 0.002mol methacrylic acids (MAA) and 0.003mol under 5 DEG C of condition of ice bath
Base diimine (DCC), after stirring 30min, 4h is reacted at being placed in 35 DEG C.After reaction terminates, vacuum filtration removes solid, and filtrate is used
Isopropanol precipitating separates out crude product, and crude product is dissolved again with 50% ethanol solution, after filtering, is analysed with isopropanol precipitating again
Go out, vacuum drying obtains white powder solid product methacrylic acid-alpha-cyclodextrin ester (MAA- β-CD).
0.8g crosslinking agents N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide (BIS) are dissolved in the distilled water and dimethyl sulfoxide (DMSO) of 20mL
(DMSO) mixed liquor (VDMSO：VH2O=3.0：1.0) in, after stirring 3 hours at 0 DEG C, by monomer MAA3.0g and MAA- α-
CD 0.7g are added in reaction system, and body is excluded while adding 0.2g acrylamides (MBAA) in reaction system and leading to nitrogen afterwards
Air in system, after stirring 10mins at 0 DEG C, adds 0.2g ammonium persulfates (being dissolved in 2mL distilled water) again, goes at 60 DEG C
Reaction 6h, you can obtain clear gel, with distilled water cyclic washing gel 5 times, removes unnecessary DMSO, finally with distillation water logging
Foaming gel, every other day changes first water, soaks 2 days, and freeze-drying obtains product xerogel.
Embodiment 14
The gamma-cyclodextrin (γ-CD) for weighing 1.3g (0.001mol) is dissolved in the middle stirring of 15mL dimethyl sulfoxide (DMSO)s (DMSO) extremely
Dissolving, is separately added into 1, the 2- dicyclohexyl carbonyls of 0.002mol methacrylic acids (MAA) and 0.003mol under 5 DEG C of condition of ice bath
Base diimine (DCC), after stirring 30min, 5h is reacted at being placed in 40 DEG C.After reaction terminates, vacuum filtration removes solid, and filtrate is used
Isopropanol precipitating separates out crude product, and crude product is dissolved again with 50% ethanol solution, after filtering, is analysed with isopropanol precipitating again
Go out, vacuum drying obtains white powder solid product methacrylic acid-gamma-cyclodextrin ester (MAA- γ-CD).
0.8g crosslinking agents N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide (BIS) are dissolved in the distilled water and dimethyl sulfoxide (DMSO) of 20mL
(DMSO) mixed liquor (VDMSO：VH2O=3.5：0.5) in, after stirring 3 hours at 0 DEG C, by monomer MAA3.2g and MAA- γ-
CD 0.9g are added in reaction system, and body is excluded while adding 0.2g acrylamides (MBAA) in reaction system and leading to nitrogen afterwards
Air in system, after stirring 10mins at 0 DEG C, adds 0.2g ammonium persulfates (being dissolved in 2mL distilled water) again, goes at 70 DEG C
Reaction 6h, you can obtain clear gel, with distilled water cyclic washing gel 5 times, removes unnecessary DMSO, finally with distillation water logging
Foaming gel, every other day changes first water, soaks 2 days, and freeze-drying obtains product xerogel.
Claims (11)
1. a kind of preparation method of environment sensitive type cyclodextrine derivatives hydrogel, it is characterised in that methods described includes following step
Suddenly：
(1) cyclodextrin is dissolved in organic solvent A, and methacrylic acid and 1,2- dicyclohexyl carbonyl are added under 0-10 DEG C of condition of ice bath
Diimine, after 30~60min of stirring reaction, reacts 5-12h at being placed in 20-40 DEG C, gained reaction solution A is post-processed after reaction terminates
Methacrylic acid-cyclodextrin ester is obtained；The cyclodextrin, methacrylic acid, the material of 1,2- dicyclohexylcarbodiimides
The ratio between amount is 1：1~4：1~5；
(2) crosslinking agent N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide are dissolved in solvent B, after stirring 3~5 hours at 0~5 DEG C, institute
Addition methacrylic acid, methacrylic acid-cyclodextrin ester and acrylamide obtained in step (1) in cross-linking agent solution are obtained, and
It is passed through nitrogen and excludes air, after being stirred 10~30 minutes at 0~5 DEG C, plus initiator ammonium persulfate solution, keep reaction solution to exist
Reacted 1.0-8.0 hours at 25-80 DEG C, prepare gel crude product, after stopping reaction, gained gel crude product washed with distillation
Wash, soak after dry, be obtained xerogel, as described environment sensitive type cyclodextrine derivatives hydrogel；The methacrylic acid-
Cyclodextrin ester, methacrylic acid, crosslinking agent N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide, the mass ratio of acrylamide are 1：0.5~
4.5：0.2~1.5：0.05~0.88；The solvent B is dimethyl sulfoxide (DMSO) or dimethyl sulfoxide (DMSO) and distilled water volume than 1~10：
The mixed solvent of 1 mixing.
2. the method for claim 1, it is characterised in that in the step (1), the organic solvent A is N, N- dimethyl
Formamide or dimethyl sulfoxide (DMSO).
3. the method for claim 1, it is characterised in that in the step (1), the cyclodextrin, methacrylic acid, 1,
The ratio between amount of material of 2- dicyclohexylcarbodiimides is 1：2~3：3~4.
4. the method for claim 1, it is characterised in that in the step (1), the cyclodextrin is beta-schardinger dextrin.
5. the method for claim 1, it is characterised in that in the step (1), the reaction solution A post-processing approach is：
After reaction terminates, reaction solution A vacuum filtrations remove solid, and gained filtrate a adds isopropanol, there is Precipitation, filters slightly to produce
Thing, crude product is dissolved with the ethanol solution of volume fraction 50%, and after filtering, gained filtrate b adds isopropanol again, has precipitation to analyse
Go out, filter, filter cake vacuum drying obtains white powder, as methacrylic acid-cyclodextrin ester.
6. the method for claim 1, it is characterised in that in the step (2), the solvent B is dimethyl sulfoxide (DMSO) or two
Methyl sulfoxide and distilled water volume are than 1~4：The mixed solvent of 1 mixing.
7. the method for claim 1, it is characterised in that in the step (2), the volumetric usage of the solvent B is with methyl
The quality of acrylic acid-cyclodextrin ester is calculated as 15~40mL/g.
8. the method for claim 1, it is characterised in that in the step (2), the methacrylic acid-cyclodextrin ester,
Methacrylic acid, crosslinking agent N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide, the mass ratio of acrylamide are 1：4：1：0.25.
9. the method for claim 1, it is characterised in that in the step (2), gel crude product distillation water washing
After 3-5 times, then with distilled water immersion, first water was changed every 24 hours, soaked 2~8 days, then by the gel after immersion
In 30~50 DEG C of vacuum drying or freeze-drying, the environment sensitive type cyclodextrine derivatives hydrogel is obtained.
10. the method for claim 1, it is characterised in that in the step (2), in the initiator ammonium persulfate solution
The mass ratio of ammonium persulfate and methacrylic acid-cyclodextrin ester be 0.06~0.63：1.0.
11. the method for claim 1, it is characterised in that methods described is carried out according to the following steps：
(1) cyclodextrin is dissolved in organic solvent A, and methacrylic acid and 1,2- dicyclohexyl carbonyl are added under 0-10 DEG C of condition of ice bath
Diimine, after 30~60min of stirring reaction, reacts 5-12h at being placed in 20-40 DEG C, gained reaction solution A vacuum is taken out after reaction terminates
Solid is filtered, gained filtrate a adds isopropanol, there is Precipitation, filters to obtain crude product, and the ethanol with volume fraction 50% is molten
Liquid dissolves crude product, and after filtering, gained filtrate b adds isopropanol again, there is Precipitation, filtering, filter cake vacuum drying, obtains
White powder, as methacrylic acid-cyclodextrin ester；The cyclodextrin, methacrylic acid, 1,2- dicyclohexylcarbodiimides
The ratio between the amount of material be 1：2~3：3~4；The organic solvent A is N,N-dimethylformamide or dimethyl sulfoxide (DMSO)；
(2) crosslinking agent N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide are dissolved in solvent B, after stirring 3~5 hours at 0 DEG C, gained
Methacrylic acid, methacrylic acid-cyclodextrin ester and acrylamide obtained in step (1) are added in cross-linking agent solution, and is led to
Enter nitrogen and exclude air, at 0 DEG C after stirring 10~30 minutes, plus initiator ammonium persulfate solution, keep reaction solution 50~
Reacted 1.0-8.0 hours at 80 DEG C, prepare gel crude product, after stopping reaction, by gained gel crude product distillation water washing
After 3-5 times, then with distilled water immersion, first water was changed every 24 hours, soaked 2~8 days, then by the gel after immersion
In 30~50 DEG C of vacuum drying or freeze-drying, xerogel, as described environment sensitive type cyclodextrine derivatives water-setting is obtained
Glue；The methacrylic acid-cyclodextrin ester, methacrylic acid, crosslinking agent N, N'- di-2-ethylhexylphosphine oxide isopropyl acrylamide, acrylamide
Mass ratio be 1：0.5~4.5：0.2~1.5：0.05~0.88；The solvent B be dimethyl sulfoxide (DMSO) or dimethyl sulfoxide (DMSO) and
Distilled water volume is than 1~4：The mixed solvent of 1 mixing；Ammonium persulfate and metering system in the initiator ammonium persulfate solution
The mass ratio of acid-cyclodextrin ester is 0.06~0.63：1.0.
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