CN105175756B - The preparation and application of keratin/methacrylic acid-beta-hydroxy ethyl ester composite hydrogel with inierpeneirating network structure - Google Patents
The preparation and application of keratin/methacrylic acid-beta-hydroxy ethyl ester composite hydrogel with inierpeneirating network structure Download PDFInfo
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- CN105175756B CN105175756B CN201510621974.6A CN201510621974A CN105175756B CN 105175756 B CN105175756 B CN 105175756B CN 201510621974 A CN201510621974 A CN 201510621974A CN 105175756 B CN105175756 B CN 105175756B
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Abstract
The present invention provides a kind of keratin/methacrylic acids with inierpeneirating network structureβThe preparation of hydroxyl ethyl ester composite hydrogel is with natural polymer keratin and functional monomer methacrylic acidβHydroxyl ethyl ester is raw material, the progress self-crosslinking polymerization under crosslinking agent, initiator effect, and macromolecular is mutually formed there through the network structure of intertexture in three dimensions with different mosaic modes in obtained compound water congealing xanthan polymer.The composite hydrogel has good swelling and deswelling performance, and with pH sensibility.Vitro drug release experiment shows the composite hydrogel to micromolecular compound rhodamine B, anticancer drug doxorubicin hydrochloride（Dox•HCl）And macromolecular compound bovine serum albumin(BSA) model drug is respectively provided with slow release effect.Therefore, pharmaceutical carrier can be used as to be applied in controlled drug delivery system.
Description
Technical field
Preparation more particularly to one kind the present invention relates to a kind of keratin macromolecule composite hydrogel have interpenetrating networks knot
Keratin/methacrylic acid of structure-βThe preparation of hydroxyl ethyl ester composite hydrogel；The present invention also relates to the keratin/methyl
Acrylic acid-βApplication of the hydroxyl ethyl ester plural gel as pharmaceutical carrier belongs to field of compound material and bio-medical material technology
Field.
Background technology
With scientific and technological progress, attention that the research of controlled drug delivery system has caused people more and more extensive.Pass through height
Molecular drug control delivery systme, make drug reach in carrier system the time or spatially control release, keep drug exist
To the optimum concentration needed for disease treatment in blood, avoid in conventional administration, be poisoned when blood concentration is higher, nothing is treated when relatively low
The problem of effect.
Interpenetrating polymer networks（IPN）It is a kind of novel high polymer material to grow up the 1970s, also referred to as
Interpenetrating net polymer, a kind of mixing being made of two or more different polymer with absolute construction and stand-alone nature
Object.Due in IPN materials two or more polymer network mutually tangle, interpenetrating it is intrinsic without losing original copolymer
Characteristic, so as to obtain the incomparable special performance of other polymer.Mutual compatibility is forced since it has, thus can be made not exclusively
The polymer of mutual tolerance can control phase separation degree by artificial from aerodynamic point, so as to generate special " synergistic effect ", cause
The properties such as its machinery, calorifics and damping is made extreme value occur under specific composition.Therefore, make the excellent of materials combine two kinds of polymer
Performance.The shortcomings of natural polymer is not brittle, water-fast can be changed in IPN structures, so as to which the modification for natural polymer provides new way
Diameter.
Hydrogel is a kind of macromolecule network system, and property is soft, can keep certain shape, can absorb a large amount of water.
It interpenetrating polymer networks hydrogel is prepared by different types of protein can effectively improve and synthesize the blood phase of high molecular material
Capacitive and bioactivity, thus attracted attention in the purposes of bio-medical field.CN102977534A discloses a kind of seaweed
The preparation of sour sodium and poly- Diacetone Acrylamide interpenetrating networks gel, and for pharmaceutical carrier, sodium alginate is overcome to hydrophobic
The shortcomings that property drug loading is not high.Disclosed in CN103113700, CN104004231, CN1757662A, CN102382267A
Hydrogel material with inierpeneirating network structure is with excellent mechanical strength, antibacterial and performance of keeping humidity, biocompatibility.
Feather keratin has good biofacies as a kind of resourceful and cheap natural macromolecular material
Capacitive, degradability and hydrophobicity and cystine it is more and with physicochemical property, but it is easily by proteases for decomposing and machine
Tool poor-performing.Therefore, the application field of feather keratin can be widened by modified.The modified of feather keratin is led at present
If by adding in other high molecular materials to change its structure, so as to effectively improve its mechanical property and biocompatibility.
Methacrylic acid-βHydroxyl ethyl ester（HEMA）In contain hydrophilic radical（-OH）And hydrophobic group（-CH3）, it is one
The widely used functional monomer of kind.Polymethylacrylic acid-βHydroxyl ethyl ester（PHEMA）As a kind of traditional biological basis material
Material has good biocompatibility, is widely used in dentures, medicament slow release, burn coating, organ transplant, contact lense system
It makes, cell culture and biomolecule and enzyme immobilization etc..Therefore, with the natural polymer feather keratin of bio-compatible with
Functional monomer methacrylic acid-βHydroxyl ethyl ester is raw material, by controlling polymerization methods, technique and the form of product, is had
There is the polymer composite of inierpeneirating network structure, have both the excellent properties of two kinds of polymer, be expected to and become a kind of novel
Polymeric biomaterial.
Invention content
The present invention seeks to using keratin and methacrylic acid-βThe property of hydroxyl ethyl ester provides a kind of with interpenetrating net
Keratin/methacrylic acid of network structure-βThe preparation method of hydroxyl ethyl ester composite hydrogel；
Another object of the present invention be to provide keratin/methacrylic acid of the inierpeneirating network structure-βHydroxyl ethyl ester Compound Water
The application of gel --- it is applied in drug controlled release as pharmaceutical carrier.
First, there is the preparation of interpenetrating networks keratin composite hydrogel
The present invention has the preparation of inierpeneirating network structure keratin composite hydrogel, is with natural polymer keratin and work(
Energy property monomer methacrylic acid-βHydroxyl ethyl ester is raw material, carries out self-crosslinking polymerization under crosslinking agent, initiator effect and obtains.Tool
Preparation process is as follows：
Under inert gas shielding, 0.1~3.0 g feather keratins are scattered in the urea liquid or diluted alkaline of 5~30 mL
In solution, 50~85 DEG C are warming up to, stirring is completely dissolved keratin；Add in 10~100 mg of reducing agent, stirring 10~50
min；1~5 mL methacrylic acids of addition-βHydroxyl ethyl ester is stirred to react 1~5 h；It is equal to add in 50~200 mg crosslinking agents I mixing
It is even；10~150 mg initiators are added in, stir 20~50 min；0.1~1.0 mL crosslinking agent II are added, continue to be stirred to react
5~30 min；Then reaction solution is stood into 3~8 h at 40~100 DEG C；Impregnated with ethyl alcohol, water, washing, it is dry to get to
Keratin/methacrylic acid-βHydroxyl ethyl ester composite hydrogel.
Above-mentioned feather keratin is the feather keratin extracted from discarded poultry feather, and specific preparation process and performance are shown in
Patent ZL200810150653.2.
A concentration of 0.8~8 mol/L of the urea liquid or dilute alkaline soln.
The reducing agent is dithiothreitol (DTT) or mercaptoethanol.
The crosslinking agent I isN,NMethylene-bisacrylamide, crosslinking agent II are glutaraldehyde.
The initiator is ammonium persulfate or potassium peroxydisulfate.
Inert gas is nitrogen, argon gas or carbon dioxide gas.
The drying means is freeze-drying.
2nd, keratin/methacrylic acid-βThe structural characterization of hydroxyl ethyl ester composite hydrogel
1st, macro morphology
Keratin/methacrylic acid that Fig. 1 is prepared for the present invention-βThe macro morphology of hydroxyl ethyl ester composite hydrogel.By Fig. 1
As it can be seen that keratin composite hydrogel is the cellular solid material with inierpeneirating network structure.
2nd, infared spectrum
Fig. 2 is the infrared absorpting light spectra with inierpeneirating network structure keratin composite hydrogel prepared by the present invention.Fig. 2
In, in 1650 cm-1、1528 cm-1、1232 cm-1Nearby there is the characteristic absorption peak of albumen（Amide I, II, III band）,
1700 cm-1Nearby occur polymethylacrylic acid-βThe stretching vibration absworption peak of C=O, illustrates polymethyl in hydroxyl ethyl ester
Acid-βHydroxyl ethyl ester is effectively compound with keratin.
3rd, thermogravimetric analysis
Fig. 3 is the thermogravimetric curve with inierpeneirating network structure keratin composite hydrogel prepared by the present invention.The result of Fig. 3
It has been shown that, the weightless section of keratin composite hydrogel are 300 DEG C~430 DEG C, with raw material feather keratin, polymethylacrylic acid-βHydroxyl ethyl ester is compared, illustrate to synthesize polyphosphazene polymer methacrylic acid-βThe presence of hydroxyl ethyl ester, is greatly improved interpenetrating polymer
The thermal stability of network gel.
4th, scanning electron microscope
Fig. 4 is the scanning electron microscope (SEM) photograph of keratin composite hydrogel prepared by the present invention.It can be seen that, polymerize by scanning electron microscope
Macromolecular is inlayed in different ways in three dimensions in object, is mutually formed there through the network structure to interweave, and on reticular structure
The also inhomogenous cavernous structure of multilayer size.Illustrate keratin and polymethylacrylic acid-βThe interpenetrating networks that hydroxyl ethyl ester is formed
Composite hydrogel can be well by drug loading in network structure hole, and is conducive to the load of different molecular weight drug, has
Good drug carrying ability.
3rd, the performance test of keratin composite hydrogel
1st, swelling behavior
In order to evaluate with applicability of the inierpeneirating network structure keratin composite hydrogel as biomaterial, body is tested
Temperature（37℃）Under the conditions of, swelling ratio of the keratin composite hydrogel in different simulated solutions（Fig. 5）.Fig. 5 the result shows that：Keratin
Composite hydrogel water,DSwelling ratio in glucose solution and physiological saline than polymethylacrylic acid-βHydroxyl ethyl ester homopolymer
Height illustrates that the addition of feather keratin improves the swelling behavior of hydrogel.
In addition, test body temperature（37℃）Under the conditions of the swelling behavior again of keratin composite hydrogel in water.As a result
As shown in Figure 6：It absorbs water for the first time and dried hydrogel specific retention is 86.2%, show that keratin composite hydrogel can be in water
In be swollen again.
2nd, temperature, pH sensibility
Test the swelling ratio of composite hydrogel at a temperature of not in aqueous solution（Fig. 7）.Fig. 7 the result shows that, temperature pair
The influence unobvious of composite hydrogel swelling ratio.Swelling of the composite hydrogel in different pH value is tested in experiment again
Rate, the results are shown in Figure 8：Composite hydrogel swelling ratio is smaller in acidic environment；It is increased with pH, swelling ratio is gradually increased；
As pH=7.4, swelling ratio reaches maximum value；As pH ＞ 7.4, swelling ratio reduces instead, illustrates that the composite hydrogel has pH
Sensibility.
3rd, vitro drug release performance
Using composite hydrogel as pharmaceutical carrier, small molecule anticancer drug is selected（Doxorubicin hydrochloride）, investigated its external medicine
Object release performance.In human body temperature（37℃）Under, the release performance of composite hydrogel when having investigated different pH value：That is gastric juice（pH=
1.2）, intestinal juice（pH=8.4）, blood（pH=7.4）, the results are shown in Figure 9.It can be seen that rate of release is slower in pH=1.2,16 h
When release rate be 71.9%；Under weak basic condition（pH=8.4）, release rate is 90.3% during 16 h；Under neutrallty condition（pH=
7.4）, release rate during 16 h is 82.5%.Cumulative release rate in acid medium is slower, and the accumulation in alkaline medium is released
It is very fast to put rate, rate of release falls between in neutral medium, this may be due to a small amount of carboxylic on feather keratin
Caused by base.The above results show that cumulative release amount of the pharmaceutical carrier in the dissolution medium of different pH value is different, this also illustrates
With inierpeneirating network structure keratin composite hydrogel to pH with sensibility.
Further experiment proves, keratin composite hydrogel prepared by the present invention is to model drug small molecule rhodamine B, big
Molecule bovine serum albumin(BSA) is respectively provided with slow release effect.Therefore, pharmaceutical carrier can be used as to be applied in controlled drug delivery system.
Description of the drawings
Fig. 1 is the macro morphology with inierpeneirating network structure keratin composite hydrogel.
Fig. 2 is the infrared absorpting light spectra of keratin composite hydrogel.
Fig. 3 is the thermogravimetric curve of keratin composite hydrogel.
Fig. 4 is the scanning electron microscope (SEM) photograph of keratin composite hydrogel.
Fig. 5 is swelling ratio of the keratin composite hydrogel in different simulated solutions.
Fig. 6 is the swellability again of keratin composite hydrogel in water（37℃）.
Fig. 7 is swelling ratio of the composite hydrogel at a temperature of not in aqueous solution.
Fig. 8 is swelling ratio situation of change of the keratin composite hydrogel in different pH value.
Fig. 9 is keratin composite hydrogel to drug（Doxorubicin hydrochloride）Release in vitro performance.
Specific embodiment
Below by specific embodiment to the present invention have inierpeneirating network structure keratin/methacrylic acid-βHydroxyl ethyl ester
The preparation of composite hydrogel and medicine-releasing performance are described further.
Embodiment 1
Under inert gas shielding, 0.1 g feather keratins are dissolved in 5 mL, 0.8 mol/L urea liquids, in 50 DEG C
20 min of lower stirring, are completely dissolved keratin；10 mg of dithiothreitol (DTT) is added in, stirs 10 min；Add in 1 mL metering systems
Acid-βHydroxyl ethyl ester stirs 1 h；Add in 50 mgN,NMethylene-bisacrylamide is uniformly mixed；10 mg ammonium persulfates are added in,
Stir 20 min；0.1 mL glutaraldehydes are added to continue to be stirred to react 5 min；Then reaction solution is stood into 3 h at 40 DEG C；
It is impregnated with ethyl alcohol, water, washing, it is dry to get with inierpeneirating network structure keratin composite hydrogel.The composite hydrogel is in body
Warm environment（37℃）Under, the preparation to doxorubicin hydrochloride is 72.6%.
Embodiment 2
Under inert gas shielding, 0.3 g feather keratins are dissolved in 8mL 1mol/L sodium hydroxide solutions, in 60 DEG C of items
25 min are stirred under part, are completely dissolved keratin；20 mg of dithiothreitol (DTT) is added in, stirs 20 min；Add in 2 mL methyl-props
Olefin(e) acid-βHydroxyl ethyl ester stirs 2 h；Add in 100 mgN,NMethylene-bisacrylamide is uniformly mixed, and adds in 15 mg persulfuric acid
Ammonium stirs 30 min, adds 0.3 mL glutaraldehydes, continue to be stirred to react 10 min；Then reaction solution is stood at 50 DEG C
5 h；It impregnated with ethyl alcohol, water, dried after washing to get to inierpeneirating network structure keratin composite hydrogel.The Compound Water
Gel is in body temperature environment（37℃）Under, the preparation to doxorubicin hydrochloride is 84.4%.
Embodiment 3
Under inert gas shielding, 0.5 g feather keratins are disperseed in 10 mL, 5 mol/L urea, in 65 DEG C of conditions
35 min of lower stirring, are completely dissolved keratin；40 mg of mercaptoethanol is added in, stirs 30 min；Add in 3 mL metering systems
Acid-βHydroxyl ethyl ester stirs 3 h；Add in 100 mgN,NMethylene-bisacrylamide is uniformly mixed；Add in 30 mg persulfuric acid
Ammonium stirs 30 min；0.5 mL glutaraldehydes are added, continue to be stirred to react 20 min；Then reaction solution is stood 6 at 65 DEG C
h；It is impregnated, washing, is freeze-dried to get to inierpeneirating network structure keratin composite hydrogel with ethyl alcohol, water.The Compound Water
Gel is in body temperature environment（37℃）Under, the preparation to doxorubicin hydrochloride is 90.9%.
Embodiment 4
Under inert gas shielding, 1.0 g feather keratins are scattered in 20 mL, 8 mol/L urea liquids, in 70
40 min are stirred under the conditions of DEG C, are completely dissolved keratin；60 mg of mercaptoethanol is added in, stirs 40 min；Add in 4 mL methyl
Acrylic acid-βHydroxyl ethyl ester stirs 4 h；Add in 150 mgN,NMethylene-bisacrylamide is uniformly mixed；Add in 100 mg mistakes
Potassium sulfate stirs 40 min, adds 0.8 mL glutaraldehydes, continue to be stirred to react 30 min；Then by reaction solution at 80 DEG C
Stand 8 h；It is impregnated, washing, is freeze-dried to get to inierpeneirating network structure keratin composite hydrogel with ethyl alcohol, water.It should
Composite hydrogel is in body temperature environment（37℃）Under, the preparation to doxorubicin hydrochloride is 86.9%.
Embodiment 5
Under inert gas shielding, 3.0 g feather keratins are scattered in 30 mL, 4 mol/L urea liquids, in 85
50 min are stirred under the conditions of DEG C, are completely dissolved keratin；100 mg of dithiothreitol (DTT) is added in, stirs 50 min；Add in 5 mL
Methacrylic acid-βHydroxyl ethyl ester stirs 5 h；Add in 200 mgN,NMethylene-bisacrylamide is uniformly mixed；Add in 150
Mg potassium peroxydisulfates stir 50 min；1.0 mL glutaraldehydes are added, continue to be stirred to react 30 min；Then by reaction solution in 100
8 h are stood at DEG C；It is impregnated, washing, is freeze-dried to get to inierpeneirating network structure keratin compound water congealing with ethyl alcohol, water
Glue.The composite hydrogel is in body temperature environment（37℃）Under, the preparation to doxorubicin hydrochloride is 84.4%.
Claims (2)
1. a kind of keratin/methacrylic acid with inierpeneirating network structure-βThe preparation of hydroxyl ethyl ester composite hydrogel, in inertia
Under gas shield, 0.5 g feather keratins are disperseed in 10 mL, 5 mol/L urea, 35 min are stirred under the conditions of 65 DEG C, are made
Keratin is completely dissolved；40 mg of mercaptoethanol is added in, stirs 30 min；Add in 3 mL methacrylic acids-βHydroxyl ethyl ester, stirring 3
h；Add in 100 mgN,NMethylene-bisacrylamide is uniformly mixed；30 mg ammonium persulfates are added in, stir 30 min；It adds
0.5 mL glutaraldehydes continue to be stirred to react 20 min；Then reaction solution is stood into 6 h at 65 DEG C；It is impregnated, washed with ethyl alcohol, water
It washs, is freeze-dried to get to inierpeneirating network structure keratin composite hydrogel；The composite hydrogel is in 37 DEG C of body temperature environment
Under, the preparation to doxorubicin hydrochloride is 90.9%.
2. keratin/methacrylic acid with inierpeneirating network structure prepared by method as described in claim 1-βHydroxyl ethyl ester is multiple
Application of the Heshui gel as pharmaceutical carrier.
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| CN107693483A (en) * | 2017-11-02 | 2018-02-16 | 巴斯特医药科技（常州）有限公司 | Long-acting controlled release composite membrane and its preparation method with gel state pressure transmission key-course |
| CN107827573A (en) * | 2017-11-26 | 2018-03-23 | 来安县杭姑娘生态农业有限公司 | A kind of cucumber soilless culture substrate preparation method of service life length |
| CN107827496A (en) * | 2017-11-26 | 2018-03-23 | 来安县杭姑娘生态农业有限公司 | A kind of preparation method of retain water and nutrients cucumber soilless culture substrate |
| CN109111580B (en) * | 2018-06-11 | 2021-08-03 | 温州生物材料与工程研究所 | Platelet-rich lysate plasma-based hydrogel with micron porous structure |
| CN113603528B (en) * | 2021-08-05 | 2023-02-03 | 四川大学 | Method for preparing keratin-based hydrogel slow-release fertilizer by using tanning cattle hair |
| CN113861357A (en) * | 2021-11-12 | 2021-12-31 | 天水师范学院 | High-strength feather keratin double-network hydrogel and preparation method thereof |
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| CN104892864B (en) * | 2015-06-03 | 2017-09-22 | 西北师范大学 | The preparation and the application as pharmaceutical carrier of a kind of composite microporous gel of keratin sodium alginate |
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