CN105017495B - A kind of preparation of soybean protein base dual-sensitivity high molecule micropore gel and the application as pharmaceutical carrier - Google Patents
A kind of preparation of soybean protein base dual-sensitivity high molecule micropore gel and the application as pharmaceutical carrier Download PDFInfo
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Abstract
The invention discloses a kind of preparation of soybean protein base dual-sensitivity high molecule micropore gel, belong to biological technical field.The present invention is using the natural polymer soybean protein isolate with biocompatibility and biodegradability, functional monomer N N-isopropylacrylamides and acrylic acid as raw material, by cross-linked polymeric, obtain that there is pH and temperature dual-sensitivity and the micropore gel of good swelling and deswelling performance.Vitro drug release performance test shows that the high molecule micropore gel has preferable slow release effect to model drug especially small molecule model medicine, therefore can be applied as pharmaceutical carrier in drug controlled release.
Description
Technical field
The invention belongs to biological technical field, is related to a kind of preparation of dual-sensitivity high molecule micropore gel, more particularly to
A kind of preparation of soybean protein base dual-sensitivity high molecule micropore gel;The present invention also relates to the soybean protein base sensitive
Application of the property high molecule micropore gel as pharmaceutical carrier.
Background technology
Natural polymer aboundresources, renewable, nontoxic, good biocompatibility and it is degradable the advantages that obtained in each field
It is widely applied.As typical natural polymer, soybean protein isolate is a kind of multifunctional protein, is passed through by various amino acid
The polypeptide chain that peptide bond is formed by connecting, containing various active side base such as amino, carboxyl, hydroxyl and sulfydryl, it can occur with many materials
Chemical reaction, it has many important physiology and pharmacological effects.Simultaneously because with safe and non-toxic, non-immunogenicity, can
The advantages that biodegradation, good biocompatibility, usually as carrier and raw material in pharmaceutical carrier and organizational project.
There is hydrophilic acylamino- and hydrophobicity simultaneously on the macromolecular chain of poly-N-isopropyl acrylamide (PNIPAM)
Isopropyl so that the PNIPAM hydrogels after the line style PNIPAM aqueous solution and crosslinking all show temperature sensitive properties:
Undergone phase transition when the PNIPAM aqueous solution is warming up to about 33 DEG C or so, heterogeneous system is transformed into by homogeneous system, chemistry is handed over
The PNIPAM hydrogels of connection volume when being warming up to 32 DEG C is shunk suddenly, and volume diminishes.Therefore, poly-N-isopropyl acrylamide exists
The smart system of temperature-responsive " on-off " effect is required, in Intelligent chemical mechanical valve, intellectual drug release vehicle etc.
Research is very deep.Contain a large amount of carboxylated hydrophilic bases in other polyacrylic hydrogels, in different pH value, present not
Contraction or solvent swelling state with degree, it is typical pH sensitive hydrogels.However, as pharmaceutical carrier in use, it is in life
There is the defects of certain in thing compatibility and biodegradability.
The content of the invention
The purpose of the present invention is by with the characteristic of NIPA and poly-N-isopropyl acrylamide, to soybean point
From being crosslinked by N, N- methylene-bisacrylamides after protein modified, prepare soybean protein base pH and temperature dual-sensitivity is high
The method of molecule micropore gel;
It is another object of the present invention to the medicine releasability by studying above-mentioned soybean protein based high molecular microporous
Can, there is provided its application as pharmaceutical carrier in drug controlled release.
First, the preparation of dual-sensitivity high molecule micropore hydrogel
The preparation of soybean protein base dual-sensitivity high molecule micropore gel of the present invention, is with soybean protein isolate, feature
Monomer NIPA, acrylic acid are raw material, and urea is dispersion liquid, are obtained by cross-linked polymeric.Specific preparation technology
It is as follows:
0.1 ~ 2.0 g soybean protein isolates are scattered in 1 ~ 15 mL dispersion liquids, 3 ~ 24 h are stirred at room temperature;Add
0.1 ~ 5.0 g NIPAs stir, and add 5 ~ 50uL acrylic acid, 0.05 ~ 5 g crosslinking agents, stirring is instead
Answer 5 ~ 40 min;Then 30 ~ 85 DEG C are warming up under inert gas shielding, 0.01 ~ 0.5g initiators are added, after stirring
3 ~ 12 h are stood, obtain hydrogel;Hydrogel is freeze-dried after ethanol, water immersion, washing, and it is micro- to obtain dual-sensitivity macromolecule
Hole gel.
Wherein, the granularity of soybean separation protein white powder is 50 ~ 200 mesh;Dispersion liquid is that the mol/L of concentration 0.8 ~ 10 urea is molten
Liquid;Crosslinking agent uses N,N methylene bis acrylamide;Initiator uses ammonium persulfate or ammonium persulfate potassium;Inert gas is nitrogen
Gas, argon gas or carbon dioxide.
2nd, soybean protein base dual-sensitivity polymeric gel structure characterizes
1st, macro morphology
Fig. 1 is the macro morphology of soybean protein base dual-sensitivity high molecule micropore gel, it will be seen from figure 1 that of the invention
The soybean protein base dual-sensitivity high molecule micropore gel of preparation is loose porous solid material.
2nd, infared spectrum
Fig. 2 is the infared spectrum of soybean protein base dual-sensitivity high molecule micropore gel.In Fig. 2, in 1718 cm-1Near
There are C=O stretching vibration absworption peaks in NIPA and acrylic copolymer P (NIPAM-co-AA), simultaneously
In 1652 cm-1、1538 cm-1、1215 cm-1Nearby there is the characteristic absorption of acid amides I, II, III band of soybean protein isolate
Peak, illustrate that soybean protein isolate is effectively compound with copolymer.
3rd, thermogravimetric analysis
Fig. 3 is the thermogravimetric curve TG of soybean protein base dual-sensitivity high molecule micropore gel(Test condition:N2Protection;Rise
Warm scope:25~800℃;Programming rate:10℃/min).As a result show, soybean protein base dual-sensitivity high molecule micropore gel
Main weightless section is at 200 ~ 450 DEG C, and compared with raw soybeans protein isolate, its heat endurance is significantly improved.
4th, scanning electron microscope (SEM) photograph
Fig. 4 is the scanning electron microscope (SEM) photograph of soybean protein base dual-sensitivity high molecule micropore gel.It can be seen by ESEM
Go out, the aperture of soybean protein base dual-sensitivity high molecule micropore gel is 2 ~ 5um, and pore size differs, and can be very good not
Drug loading with molecular weight is in pore structure.In addition, the addition of soybean protein isolate, can improve the swellbility of gel, have
Beneficial to drug loading.
3rd, the performance of soybean protein base dual-sensitivity high molecule micropore gel
1st, swelling behavior
In order to evaluate adaptability of the soybean protein base dual-sensitivity high molecule micropore gel as biomaterial, test micro-
Swelling ratio of the hole gel in different simulation biological solutions(At lower 37 DEG C).As a result show:Soybean protein base dual-sensitivity is high
Swellbility of the molecule micropore gel in two water is more than NIPA and acrylic copolymer, illustrates soybean separation protein
White addition can improve the swelling behavior of gel.In addition, test under body temperature(37℃)Soybean protein base dual-sensitivity high score
Again swelling behavior of the sub- micropore gel in water, as a result as shown in Figure 5:Water suction and dried gel absorption ability for the first time
For for the first time in secondary water is gone equilibrium swelling ratio 89.47%, show soybean protein base dual-sensitivity polymer-network method secondary
Water can be repeatedly swelled, and be reused.
2nd, temperature, pH sensitiveness
In order to evaluate sensitiveness of the gel to temperature, the swelling ratio of test gel at different temperatures(See Fig. 6).It was found that
4 ~ 25 DEG C, gel swelling gradually increases, and 32 DEG C or so rear swellbilitys are begun to decline.Illustrate soybean protein base dual-sensitivity high score
Sub- micropore gel has temperature sensitivity.
In order to evaluate sensitiveness of the gel to pH value, the swelling ratio tested in different pH value changes(See Fig. 7).As a result
Show:Gel swelling performance is smaller in acid stronger environment, and as pH is raised, its swelling behavior gradually steps up.
3rd, vitro drug release performance
Using dual-sensitivity high molecule micropore gel as pharmaceutical carrier, from small molecule anticancer drug(Doxorubicin hydrochloride), examine
The vitro drug release performance of dual-sensitivity micropore gel is examined.In human body temperature(37℃)Under, investigate the ring of different pH value
Border(That is gastric juice(pH=1.2), blood(pH=7.4))The release performance of lower dual-sensitivity micropore gel, as a result as shown in Figure 8.Can
See under acid condition(pH=1.2)Rate of release is slow, and maximum release rate is 23.9% during 12h, and most of medicine retention is in water-setting
In glue;Under neutrallty condition(pH=7.4), drug releasing rate is most fast, and preparation is up to 51.77% after 12 h, with release
Time lengthening, preparation reach as high as 93.8%.Illustrate in neutral conditions(Blood environment)Rate of release is fast, and acid
In environment(Gastric juice)Rate of release is most slow, illustrates that gel has sensitivity to acid.In addition, other temperature are also investigated in experiment(25
℃、37℃、42℃)Under, as a result environmental pH is shown in Fig. 9 to the release performance of gel.It was found that at 40 DEG C, doxorubicin hydrochloride is tired out
Meter release rate is higher, and insoluble drug release reached balance at 36 hours, reached as high as 98.5%;And at 25 DEG C, the release of medicine compared with
To be steady, highest is accumulative to be released to 66.1%.This explanation gel has temperature sensitivity.
In summary, the present invention is with the natural polymer soybean separation protein with biocompatibility and biodegradability
In vain, functional monomer NIPA and acrylic acid are raw material, be prepared for it is a kind of have pH and temperature dual-sensitivity and
Good swelling and the micropore gel of deswelling performance, there is preferably sustained release to imitate to model drug especially small molecule model medicine
Fruit.Therefore, can be applied as pharmaceutical carrier in drug controlled release.
Brief description of the drawings
Fig. 1 is the macro morphology of soybean protein base sensitive high molecule micropore gel.
Fig. 2 is the infrared spectrogram of soybean protein base sensitive high molecule micropore gel.
Fig. 3 is the thermogravimetric analysis figure of soybean protein base sensitive high molecule micropore gel.
Fig. 4 is the scanning electron microscope (SEM) photograph of soybean protein base sensitive high molecule micropore gel.
Fig. 5 is again Swelling Dynamics of the soybean protein base sensitive high molecule micropore gel in water(37℃).
Fig. 6 is the swelling ratio of soybean protein base sensitive high molecule micropore gel at different temperatures.
Fig. 7 is swelling ratio of the soybean protein base sensitive high molecule micropore gel under different pH.
Release in vitro performances of the Fig. 8 for micropore gel under the conditions of different acidity to cancer therapy drug(37℃).
Release in vitro performances of the Fig. 9 for micropore gel under condition of different temperatures to cancer therapy drug(pH=7.4).
Embodiment
It is described further below by preparation of the specific embodiment to micropore gel of the present invention and performance.
Embodiment 1:The g of soybean separation protein white powder 0.1 of the mesh of granularity 50 ~ 200 is taken, being scattered in 1mL must disperse in urea liquid
(The concentration of urea liquid is 0.8 mol/L), 24 h are stirred at room temperature;0.1 g NIPAs are added to stir;
5uL acrylic acid is added, 0.05g crosslinking agents N, N- methylene-bisacrylamide, continues to stir 10 min or so;Then in nitrogen
30 DEG C are warming up under gas shielded;0.01g initiator ammonium persulfates are added to stir;Reaction solution is poured into reaction bulb, is placed in water
In bath, 12 h are stood at 30 DEG C, obtain hydrogel;Hydrogel, which is sequentially placed into ethanol, water, to be soaked, washs, and then freezing is dry
It is dry, obtain soybean protein base dual-sensitivity micropore gel.The gel is to small molecule anticancer drug doxorubicin hydrochloride(37℃)It is tired
And release rate is 76%.
Embodiment 2:Take the g of soybean separation protein white powder 0.5 of the mesh of granularity 50 ~ 200 to be scattered in 5 mL to disperse in urea liquid
(The concentration of urea liquid is 1.0 mol/L), 10 h are stirred at room temperature, adds 0.5 g NIPAs and stirs;
20 uL acrylic acid are added, 0.1 g crosslinking agents N, N- methylene-bisacrylamide, continue to stir 10 min;Then in nitrogen
50 DEG C are warming up under protection;0.02g initiator ammonium persulfates are added to stir;Reaction solution is poured into reaction bulb, is placed in water-bath
In pot, 10 h are stood at 50 DEG C, obtain hydrogel;Hydrogel, which is sequentially placed into ethanol, water, to be soaked, washs, and is then freeze-dried,
Obtain soybean protein base dual-sensitivity micropore gel.The gel is to small molecule anticancer drug doxorubicin hydrochloride(37℃)Involve and release
Rate is put as 88%.
Embodiment 3:Take the g of soybean separation protein white powder 1.0 of the mesh of granularity 50 ~ 200 to be scattered in 10 mL to disperse in urea liquid
(The concentration of urea liquid is 1.5 mol/L), 18 h are stirred at room temperature, adds 1.0 g NIPAs and stirs;
30uL acrylic acid is added, 0.5 g crosslinking agents N, N- methylene-bisacrylamide, continues to stir 30 min;Then in nitrogen
60 DEG C are warming up under protection;0.03g initiator ammonium persulfate potassium is added to stir;Reaction solution is poured into reaction bulb, is placed in water
In bath, 8h is stood at 60 DEG C, obtains hydrogel;Hydrogel is sequentially placed into ethanol, water and soaks, wash, then freezing is dry
It is dry, obtain soybean protein base dual-sensitivity micropore gel.The gel is to small molecule anticancer drug doxorubicin hydrochloride(37℃)It is tired
And release rate is 81%.
Embodiment 4:Take the g of soybean separation protein white powder 1.5 of the mesh of granularity 50 ~ 200 to be scattered in 10mL to disperse in urea liquid
(The concentration of urea liquid is 5 mol/L), 10 h are stirred at room temperature, adds 3.0 g NIPAs and stirs;Again
40uL acrylic acid is added, 1.5 g crosslinking agents N, N- methylene-bisacrylamides, continues to stir 15 min;Then protected in nitrogen
70 DEG C are warming up under shield;Add 0.4g initiator ammonium persulfates to stir, reaction solution is then poured into reaction bulb, is placed in water
In bath, 5 h are stood at 70 DEG C, obtain hydrogel;Hydrogel is sequentially placed into ethanol, water and soaks, wash, then freezing is dry
It is dry, obtain soybean protein base dual-sensitivity micropore gel.The gel is to small molecule anticancer drug doxorubicin hydrochloride(37℃)It is tired
And release rate is 71%.
Embodiment 5:Take the g of soybean separation protein white powder 2.0 of the mesh of granularity 50 ~ 200 to be scattered in 15 mL to disperse in urea liquid
(The concentration of urea liquid is 10 mol/L), 10 h are stirred at room temperature, adds 5.0 g NIPAs and stirs;Again
50uL acrylic acid is added, 5g crosslinking agents N, N- methylene-bisacrylamide, continues to stir 10 min;Then under nitrogen protection
It is warming up to 85 DEG C;0.5g initiator ammonium persulfate potassium is added to stir;Reaction solution is poured into reaction bulb, is placed in water-bath,
3 h are stood at 85 DEG C, obtain hydrogel;Hydrogel is sequentially placed into ethanol, water and soaks, wash, is then freeze-dried, obtains
Soybean protein base dual-sensitivity micropore gel.The gel is to small molecule anticancer drug doxorubicin hydrochloride(37℃)Involve release rate
For 65%.
Claims (5)
1. a kind of preparation method of soybean protein base dual-sensitivity high molecule micropore gel, is with soybean protein isolate, feature
Monomer NIPA, acrylic acid are raw material, and urea is dispersion liquid, are obtained by cross-linked polymeric;Its concrete technology is such as
Under:0.1 ~ 2.0 g soybean separation protein white powders are scattered in 1 ~ 15 mL dispersion liquids, 3 ~ 24 h are stirred at room temperature;Addition 0.1 ~
5.0 g NIPAs stir, and add 5 ~ 50uL acrylic acid, 0.05 ~ 5 g crosslinking agents, and stirring reaction 5 ~
40 min;Then 30 ~ 85 DEG C are warming up under inert gas shielding, 0.01 ~ 0.5g initiators is added, 3 is stood after stirring
~ 12 h, obtain hydrogel;Hydrogel is freeze-dried after ethanol, water immersion, washing, is obtained dual-sensitivity high molecule micropore and is coagulated
Glue;The crosslinking agent is N, and N- methylene-bisacrylamides, initiator is ammonium persulfate or ammonium persulfate potassium.
2. the preparation method of soybean protein base dual-sensitivity high molecule micropore gel as claimed in claim 1, it is characterised in that:
The granularity of soybean separation protein white powder is 50 ~ 200 mesh.
3. the preparation method of soybean protein base dual-sensitivity high molecule micropore gel as claimed in claim 1, it is characterised in that:
Dispersion liquid is the mol/L of concentration 0.8 ~ 10 urea liquid.
4. the preparation method of soybean protein base dual-sensitivity high molecule micropore gel as claimed in claim 1, it is characterised in that:
Hydrogel is dried using freeze-drying.
5. soybean protein base dual-sensitivity high molecule micropore gel prepared by method as claimed in claim 1 is as pharmaceutical carrier
Using.
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CN103524759A (en) * | 2013-09-27 | 2014-01-22 | 西北师范大学 | Method for preparing animal keratin base macromolecular hydrogel and application of hydrogel serving as medicine carrier |
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US4863613A (en) * | 1985-10-25 | 1989-09-05 | Regents Of The University Of Minnesota | Soy protein isolation process using swellable poly(N-isopropylacrylamide) gels |
CN103524764A (en) * | 2013-09-27 | 2014-01-22 | 西北师范大学 | Preparation method of isolated soy protein macromolecular interpenetrating network hydrogel and application of hydrogel serving as medicine controlled release carrier |
CN103524759A (en) * | 2013-09-27 | 2014-01-22 | 西北师范大学 | Method for preparing animal keratin base macromolecular hydrogel and application of hydrogel serving as medicine carrier |
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