CN106620884A - Preparation method of EMPLGA/Gel-HA hydrogel-microsphere bionic composite support - Google Patents
Preparation method of EMPLGA/Gel-HA hydrogel-microsphere bionic composite support Download PDFInfo
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Abstract
The invention provides a preparation method of an EMPLGA/Gel-HA hydrogel-microsphere bionic composite support. The preparation method comprises the following steps: preparing high-molecular weight poly lactide-glycolide acid (PLGA) through melt polymerization under high vacuum, reducing the pressure and grafting maleic anhydride at a temperature of 100 DEG C to obtain maleinized poly lactide-glycolide acid (MPLGA); conducting reaction on quadrol and MPLGA for 30-60 minutes in a chloroform solution at a room temperature, precipitating, vacuum-drying to obtain a quadrol-modified MPLGA polymer and preparing a porous MPLGA hard support by using a pore-forming method; adding a prepared mixed aqueous solution of gelatin/hyaluronic acid into liquid paraffin containing span-80, performing glutaraldehyde cross-linking and solidifying into a sphere; respectively adding gelatin and hyaluronic acid into a glacial acetic acid solution for dissolution, uniformly mixing, and adding a Gel/HA microsphere into a mixed solution to obtain a composite system; soaking the EMPLGA hard support material in the composite system, vacuum-pumping for 20-30 minutes, taking out, freezing, drying, soaking with an ethanol solution containing carbodiimide and ethanol, and vacuum-drying to obtain the EMPLGA/Gel-HA hydrogel-microsphere bionic composite support. The bionic composite support prepared by the preparation method provided by the invention has a natural tissue environment and is good in mechanical strength.
Description
Technical field
The present invention relates to a kind of production technical field of degradable soft/hard bionical compound cartilage tissue scaffold material, specifically
It is related to a kind of preparation method for having class natural tissues environment and the bionical compound rest of good mechanical strength concurrently, it is expected to be applied to soft
Bone tissue engineering stent material field.
Background technology
Because the cartilage defect that mechanical damage or arthritis are caused is the problem that is medically difficult to for a long time overcome.Adult cartilage
Repair ability is limited, and cartilage defect diameter is less than the spontaneous reparation of 3mm energy, but when with diameter greater than 3mm, defect cannot be voluntarily
Repair.Organizational engineering technology provides new method for the reparation of Cranial defect, it have to for bulk damage is little, no antigen,
Can be made into 3 D stereo, the advantages of anatomical structure is accurate, thus have broad application prospects.
Being applied to the synthesized degradable polymeric main of cartilaginous tissue reparation will have PLA（PLA）, poly- third glycolide
（PLGA）Deng.Wherein PLGA due to the degradation rate with certain mechanical strength and easy-regulating, the advantages of easily macroscopical moulding,
It is widely used in the fields such as organizational project and medicament slow release, but its low hydrophily, active group and biogenic signaling molecule lack
The defects such as the accumulation of weary and internal acid degradation products cause its application to be restricted.
Carry out copolymerization to PLA or PLGA etc. at present or graft modification is one of the important method for improving its performance.As adopted
The controllable amine solution technology in surface, grafting-coating, coupling or layer-layer（LBL）Self-assembling technique by Compatible solute such as collagen,
Fibrin etc. is fixed to polylactic acid-based material surface, can improve the hydrophilicity and cell recognition ability of high polymer support.
Maleic anhydride be it is a kind of can eubolism in vivo polyfunctional group material, the carbon-to-carbon double bond in its acid anhydrides
May occur from being reacted by base.Maleic anhydride and aliphatic diamine are introduced by PLA or PLGA chains using Graft Method and prepares degradable polymerization
Thing, it is expected to effectively alleviate material while material hydrophilic performance is further improved in asking that degradation process middle acid substance is accumulated
Topic.This seminar adopts D, L- lactides, glycolide and maleic anhydride to obtain maleic anhydride grafting by direct melting copolymerization
Poly- third glycolide（MPLGA）, successfully apply for a patent（See ZL2013.10564511.1）, the method is simple to operate, and acquisition is total to
There is higher acid anhydrides percent grafting in polymers（2.0~10.0wt%）.Ethylenediamine is further introduced into MPLGA skeletons, can be obtained
Copolymer EMPLGA containing basic group（See patent ZL201410420672.8）, effectively alleviate material acid in degradation process
Property material accumulation problem.But because Direct melt copolycondensation prepares the molecular weight of copolymer during MPLGA by monomer and Malaysia
The impurities affect of acid anhydrides is very big, and the material for participating in reacting is more, and the influence factor of its molecular weight is more complicated, and experiment reappearance is got over
Difference, while the MPLGA molecular weights for obtaining（＜ 1.0 × 105Da）, it is impossible to meet the demand of different medical materials, limit
It is in the clinical application of bio-medical material.
Hydrogel is very much like with normal extracellular matrix on composition and performance, with superior bio compatibility：Carefully
Born of the same parents can be suspended in hydrogel and grow, and in natural spherical, be conducive to maintaining the normal phenotype of cell.Repair for cartilaginous tissue
Multiple natural hydrogel mainly includes collagen, Fibrin Glue, alginate, gelatin, hyaluronic acid and agar etc..But hydrogel
Porous material has that mechanical strength is little, shape retentivity is poor and the deficiency such as relatively difficult of sterilizing.
The present invention adopts D, L- lactides, glycolide melting copolymerization to obtain the PLGA of HMW, then straight with maleic anhydride
In being grafted to PLGA skeletons, PLGA molecular weight and molecular weights degree is little in grafting process, can obtain HMW MPLGA, further
Ethylenediamine is introduced, the HMW EMPLGA with basic functional group is obtained, HMW is prepared using pore creating material method
EMPLGA porous " hard " support.
By the human simulation to cartilaginous tissue extracellular matrix the Nomenclature Composition and Structure of Complexes, by gelatin/hyaluronic acid gel
" soft " support and gelatin/hyaluronate microspheres are compound in the EMPLGA of advance comprising " hard " support.Hydrogel " soft " support energy
For the growing environment that cartilage cell provides a class natural tissues, effectively to keep the natural form of cartilage cell, cell is guided
Normal proliferative, differentiation and functional expression, the gelatin/hyaluronate microspheres energy composite bio-active factor, it is expected to realize its substep
Controlled release, further gives the composite bionic support more superior biology performance.EMPLGA " hard " support can be in cartilage
Sufficiently high mechanical strength, controllable degradation rate and good shape retentivity are provided in repair process.This is bionical compound
Support has class natural tissues environment and good mechanical strength concurrently, it is expected to be applied to cartilage tissue engineered rack material field.
The content of the invention
It is an object of the invention to provide support has the bionical compound rest of class natural tissues environment and good mechanical strength concurrently
Preparation method.
The step of the inventive method, is as follows：
（1）D, L- lactides, glycolide are added in the ampoule bottle after dried process, a certain amount of stannous octoate (Sn is added
(Oct)2)；After 12 ~ 24 h of vacuum drying, at normal temperatures using the h of diffusion pump pumping high vacuum 0.5 ~ 1.0, pressure in ampoule bottle is made
Less than 5.0Pa, tube sealing.Ampoule bottle after tube sealing is put into insulating box, is taken after reacting 12 ~ 60 h at a temperature of 120 ~ 170 DEG C
Go out.Crude product is dissolved in chloroform, 1.0 ~ 5.0wt% solution is configured to, precipitating in the ethanol of 3 ~ 5 times of volumes is then instilled,
Precipitating 3 ~ 5 times repeatedly, by product vacuum drying to the constant weight after purification PLGA polymer is obtained final product.
（2）By PLGA after purification and a certain amount of maleic anhydride, dibenzoyl peroxide（BPO）Mixing, be placed in decompression,
24h is reacted in 100 DEG C of environment and obtains the thick polymers of MPLGA.Thick polymers is placed in Soxhelt extractors, with chloroform
For the h of solvent extraction 8,4 ~ 6 times are flowed back per hour to remove homopolymers, will be dried under vacuum to perseverance at 40 DEG C of copolymer after extracting
Weight.Copolymer is added in chloroform, 1 ~ 5wt% solution is configured to, precipitating in the ethanol of 3 ~ 5 times of volumes is instilled, is sunk repeatedly
Analysis 3 ~ 5 times, then will be dried under vacuum to constant weight at 40 DEG C of purification, obtain pure MPLGA.
（3）MPLGA after purification is dissolved in chloroform, the chloroform of the MPLGA of 20.0 ~ 30.0wt% is configured to
Solution.
（4）Ethylenediamine is dissolved in chloroform, the chloroform soln of the ethylenediamine that concentration is 38.0wt% is configured to.
（5）Under conditions of stirring, by step（4）The chloroform soln of gained ethylenediamine is added dropwise to step（3）Gained
In the chloroform soln of MPLGA, ice bath control temperature of reaction system is less than 10 DEG C, is incubated 5 ~ 10min, then temperature is risen into room
Temperature 30 ~ 60min of reaction, finally instills precipitating in excessive ethanol by product, precipitating 3 ~ 5 times repeatedly, be washed with deionized to
Neutrality, is dried under vacuum to constant weight, obtains poly- third co-glycolide polymers of ethylenediamine modified maleic anhydridization（EMPLGA）Solid.
（6）Weigh a certain amount of EMPLGA to dissolve in chloroform, fully by a certain amount of 300 ~ 450 μm after dissolving
Na2CO3Particle is added in polymer solution and stirred, and after a large amount of solvents are volatilized under room temperature, adds mixture to steel
It is compressing in mould.Sample is soaked 3 hours in dilute hydrochloric acid solution after being dried 6 hours under room temperature, again with distillation after washing
Water soaks 12 hours, and a water was changed per 3 ~ 4 hours, and the porous support for obtaining is dried 24 hours in atmosphere, and vacuum drying 48 is little
When.
（7）By gelatin（Gel）And hyaluronic acid（HA）, by weight 95:5, prepare gelatin/bright matter acid mixed aqueous solution.
Add atoleine to be heated to 60 DEG C in container, then a small amount of span-80, mechanical agitation are added in container.Take gelatin/transparent
Matter acid mixed solution is added in container, is stirred, and drop is uniformly scattered in oil phase, and the gelatin in the addition container/
The molten volume ratio with atoleine of hyaluronic acid mixing is 13:87.Then container is placed in ice-water bath, treats that system is cooled down, temperature
After degree is less than 4 DEG C, a small amount of glutaraldehyde is added as crosslinking agent, crosslinking, solidification balling-up.With acetone and water（Volume ratio 3:1）It is mixed
Close solution to wash 2 ~ 3 times, filter off atoleine and water, finally washed with pure acetone, suction filtration, natural airing, gained complex microsphere
Surface is smooth.
（8）A certain amount of glacial acetic acid is taken, with distilled water diluting to pH value 4.7 or so, by gelatin and hyaluronic acid, by weight
8:2 are separately added into dissolving, are configured to the solution of 5mg/mL.The gelatin solution for preparing and hyaluronic acid solution are uniformly mixed
Close.
（9）To step（8）In mixed solution in add a certain amount of step（7）Obtained Gel/HA microballoons obtain complex
System, added colloidal sol is 10 with the mass ratio of microballoon:1.The compound system of Gel/HA colloidal sols and microballoon is placed in and is connected with vacuum plant
Flask in, then cylindrical shape EMPLGA porous " hard " timbering material is soaked in compound system, vacuumize 20 ~
30min.Compound rest is taken out to be put into freeze drier and freezes 12h, be dried 48h.After taking-up, carbodiimides is used（EDC）
Alcohol solution dipping 24h, then use alcohol solution dipping 12h, change a water per 4h.By soaked compound support frame material
Air drying 48h is put into, is vacuum dried, obtain EMPLGA/Gel-HA hydrogels-bionical compound rest of microballoon.
Step（1）In, the D, L- lactides, glycolide, the weight ratio of stannous octoate are：D, L- lactide 70.0 ~
80.0wt%, 20.0 ~ 30.0wt% of glycolide, 0.01 ~ 0.03wt% of stannous octoate, and stannous octoate Jing processeds.
Step（1）In, the chloroform soln（1.0~5.0wt%）Concentration it is directly relevant with PLGA molecular size ranges,
Molecular weight is bigger, and the chloroform soln concentration of preparation should be less.
Step（2）In, the amount of the maleic anhydride is D, L- lactides, 5 ~ 10 wt% of glycolide monomer total amount, peroxide
Change 1 ~ 5 wt% of the addition for maleic anhydride weight of benzoyl.Described reduced pressure atmosphere is that pressure is less than 0.09MPa.
Step（5）In, the addition of the ethylenediamine is the 20.0 ~ 30.0% of MPLGA mass.
Step（6）EMPLGA is 1.0 ~ 5.0wt% with the concentration of chloroform, and the concentration of hydrochloric acid is 5.0-10.0wt%,
EMPLGA and Na2CO3Mass ratio be 1:5.
Step（7）In, the concentration of gelatin/hyaluronic acid mixed solution is 20.0 ~ 25.0wt%, and the concentration of span-80 is
0.016 ~ 0.020g/L, 200 ~ 800r/min of stir speed (S.S.), the concentration of glutaraldehyde is 0.3mL/g.
Step（9）Middle vacuum is 0.07 ~ 0.09MPa, and the ethanol solution concentration of carbodiimides is 0.1wt%.
Successful design of the present invention has gone out to have concurrently class natural tissues environment with good mechanical strength by HMW EMPLGA
The degradable bionic compound support frame material constituted with gelatin/hyaluronic acid gel-microballoon, is the preparation of the bionical compound rest
Method provides detailed description.
EMPLGA/ hydrogels obtained by the present invention-bionical compound rest of microballoon has advantages below：
（1）Using the PLGA molecular weight of Direct melt copolycondensation preparation up to 1.0 ~ 2.0 × 105Da, covalently introduces maleic anhydride
And ethylenediamine, the HMW EMPLGA containing maleic anhydride and amido active group is obtained, expand the regulation and control of its degradation property
Scope, while can effectively alleviate material accumulating in degradation process middle acid substance.
（2）Have devised the bionical compound rest for having class natural tissues environment and good mechanical strength concurrently, EMPLGA " hard "
Support can provide sufficiently high mechanical strength, controllable degradation rate and good shape retentivity.Hydrogel " soft " support
The growing environment of one class natural tissues can be provided for cartilage cell, the gelatin/hyaluronate microspheres energy composite bio-active factor,
It is expected to realize its step-wise controllable release, further gives the composite bionic support more superior biology performance.
Specific embodiment
Below by specific embodiment, the present invention is described in further detail, and described raw material number is removed especially to be said
It is bright outer, it is parts by weight.
Embodiment 1：
The dried D of 78.0g, L- lactides, 22.0g glycolides are added in the ampoule bottle after dried process, added
Stannous octoate (the Sn (Oct) of 0.015g Jing processeds2)；After being vacuum dried 12 h, alcohol blast burner is used under conditions of 4.0Pa
Tube sealing.Ampoule bottle after tube sealing is put into insulating box, 24 h are reacted at a temperature of 140 DEG C, break ampoule bottle into pieces, take out slightly to produce
Thing PLGA.Products obtained therefrom Mw=1.76×105Da, Mw/Mn=1.21。
Crude product is dissolved in chloroform, 2.0wt% solution is configured to, precipitating 3 times in the ethanol of 3 times of volumes is instilled, very
Sky is dried.PLGA after purification is mixed with 6.0g maleic anhydrides, 0.20g dibenzoyl peroxides, in being placed in three-neck flask,
Pressure is 0.084MPa, 24h is reacted under conditions of 100 DEG C obtains the thick polymers of MPLGA.Thick polymers after by grafting is placed in Soxhelt
In extractor, with chloroform as the h of solvent extraction 8, will be dissolved in chloroform after the residue vacuum drying of extracting, prepare
Into 2.0wt% solution, precipitating 3 times in the ethanol of 3 times of volumes are instilled, then purification is dried under vacuum into constant weight, obtain faint yellow
Pure graft copolymer MPLGA.Products obtained therefrom Mw=1.71×105Da, Mw/Mn=1.24, percent grafting is 1.11%.
10.0g MPLGA are dissolved in 20mL chloroforms the chloroform soln for preparing 20.0wt% MPLGA, equal-volume
Ethylenediamine and chloroform mixed preparing 38.0wt% ethylenediamine chloroform soln.The chloroform of MPLGA is added into dress
In having the there-necked flask of agitator and thermometer, the chloroform soln of 2mL ethylenediamines, ice bath control are added dropwise under conditions of stirring
System temperature processed is less than 10 DEG C.Completion of dropping, after insulation 5min, then is warmed to room temperature 60 min of reaction by temperature.Product is instilled
Precipitation in excessive ethanol solution, is washed with deionized in neutrality, and 40 DEG C of product is dried under vacuum to constant weight, obtains yellow
EMPLGA solids.
Weigh 2.0gEMPLGA to dissolve in 25mL chloroforms, by 10.0g particle diameters be 300 ~ 450 μm fully after dissolving
Na2CO3Particle is added in polymer solution and stirred, and after a large amount of solvents are volatilized under room temperature, adds mixture to steel
It is compressing in mould.Sample is soaked 3 hours in 5.0wt% solution after being dried 6 hours under room temperature, again with distillation after washing
Water soaks 12 hours, and a water was changed per 4 hours, and the porous support for obtaining is dried 24 hours in atmosphere, is vacuum dried 48 hours.
15.8g gelatin and 0.83g hyaluronic acids are taken, 20.0% gelatin/hyaluronic acid mixed solution is configured to；To 250mL
50mL atoleines are added in round-bottomed flask, heating water bath adds the span- that 0.8g concentration is 0.012g/L to after 60 DEG C
80, with 200r/min mechanical agitations 30min, after forming stable emulsion, add 10mL gelatin/hyaluronic acid mixed solution, breast
Change 10min, it is to be emulsified completely after be rapidly cooled to less than 4 DEG C, add the glutaraldehyde cross-linking solidification of 200 μ L 2 hours.
10mL glacial acetic acid is taken, with distilled water diluting to pH value 4.7 or so, acetum is obtained.By 8.0g gelatin and 2.0g
Hyaluronic acid, is separately added into dissolving, is configured to the solution of 5mg/mL.The gelatin solution for preparing and hyaluronic acid solution is equal
Even mixing.
20.0mgGel/HA microballoons are added in 40mL gelatin/hyaluronic acid mixed sols.By Gel/HA colloidal sols and microballoon
Compound system be placed in the flask for being connected with vacuum plant, then cylinder EMPLGA porous " hard " timbering material is soaked in
In compound system, 20 ~ 30min is vacuumized under conditions of 0.082MPa.Compound rest taking-up is put into cold in freeze drier
Freeze 12h, be dried 48h.After taking-up, with the alcohol solution dipping 24h of 0.1% carbodiimides, alcohol solution dipping is then used
12h, per 4h a water is changed.Soaked compound support frame material is put into air drying 48h, is vacuum dried.
Embodiment 2：
The dried D of 76.0g, L- lactides, 24.0g glycolides are added in the ampoule bottle after dried process, added
Stannous octoate (the Sn (Oct) of 0.022g Jing processeds2)；After being vacuum dried 12 h, alcohol blast burner is used under conditions of 5.0Pa
Tube sealing.Ampoule bottle after tube sealing is put into insulating box, 36 h are reacted at a temperature of 120 DEG C, break ampoule bottle into pieces, take out slightly to produce
Thing PLGA.Products obtained therefrom Mw=1.45×105Da, Mw/Mn=1.31。
Crude product is dissolved in chloroform, 3.0wt% solution is configured to, precipitating 4 times in the ethanol of 4 times of volumes is instilled, very
Sky is dried.PLGA after purification is mixed with 6.5g maleic anhydrides, 0.25g dibenzoyl peroxides, in being placed in three-neck flask,
Pressure is 0.065MPa, 24h is reacted under conditions of 100 DEG C obtains the thick polymers of MPLGA.Thick polymers after by grafting is placed in Soxhelt
In extractor, with chloroform as the h of solvent extraction 8, will be dissolved in chloroform after the residue vacuum drying of extracting, prepare
Into 3.0wt% solution, precipitating 4 times in the ethanol of 4 times of volumes are instilled, then purification is dried under vacuum into constant weight, obtain faint yellow
Pure graft copolymer MPLGA.Products obtained therefrom Mw=1.39×105Da, Mw/Mn=1.35, percent grafting is 0.98%.
10g MPLGA are dissolved in 20mL chloroforms the chloroform soln for preparing 25.0wt% MPLGA, it is isopyknic
The chloroform soln of ethylenediamine and chloroform mixed preparing 38.0wt% ethylenediamine.The chloroform of MPLGA is added and is equipped with
In the there-necked flask of agitator and thermometer, the chloroform soln of 2mL ethylenediamines, ice bath control are added dropwise under conditions of stirring
System temperature is less than 10 DEG C.Completion of dropping, after insulation 5min, then is warmed to room temperature 60 min of reaction by temperature.Product was instilled
Precipitation in the ethanol solution of amount, is washed with deionized in neutrality, and 40 DEG C of product is dried under vacuum to constant weight, obtains yellow
EMPLGA solids.
Weigh 3.0gEMPLGA to dissolve in 37.5mL chloroforms, by 15.0g particle diameters be 300 ~ 450 μm fully after dissolving
Na2CO3Particle is added in polymer solution and stirred, and after a large amount of solvents are volatilized under room temperature, adds mixture to steel
It is compressing in mould.Sample is soaked 3 hours in 7.5wt% solution after being dried 6 hours under room temperature, again with distillation after washing
Water soaks 12 hours, and a water was changed per 4 hours, and the porous support for obtaining is dried 24 hours in atmosphere, is vacuum dried 48 hours.
15.8g gelatin and 0.83g hyaluronic acids are taken, 22.5% gelatin/hyaluronic acid mixed solution is configured to；To 250mL
50mL atoleines are added in round-bottomed flask, heating water bath adds the span- that 0.8g concentration is 0.016g/L to after 60 DEG C
80, with 300r/min mechanical agitations 30min, after forming stable emulsion, add 10mL gelatin/hyaluronic acid mixed solution, breast
Change 10min, it is to be emulsified completely after be rapidly cooled to less than 4 DEG C, add the glutaraldehyde cross-linking solidification of 200 μ L 2 hours.
10mL glacial acetic acid is taken, with distilled water diluting to pH value 4.7 or so, acetum is obtained.By 7.0g gelatin and 1.75g
Hyaluronic acid, is separately added into dissolving, is configured to the solution of 5mg/mL.The gelatin solution for preparing and hyaluronic acid solution is equal
Even mixing.
25.0mgGel/HA microballoons are added in 50mL gelatin/hyaluronic acid mixed sols.By Gel/HA colloidal sols and microballoon
Compound system be placed in the flask for being connected with vacuum plant, then cylinder EMPLGA porous " hard " timbering material is soaked in
In compound system, 20 ~ 30min is vacuumized under conditions of 0.085MPa.Compound rest taking-up is put into cold in freeze drier
Freeze 12h, be dried 48h.After taking-up, with the alcohol solution dipping 24h of 0.1% carbodiimides, alcohol solution dipping is then used
12h, per 4h a water is changed.Soaked compound support frame material is put into air drying 48h, is vacuum dried.
Embodiment 3：
The dried D of 73.0g, L- lactides, 27.0g glycolides are added in the ampoule bottle after dried process, added
Stannous octoate (the Sn (Oct) of 0.025g Jing processeds2)；After being vacuum dried 12 h, alcohol blast burner is used under conditions of 6.0Pa
Tube sealing.Ampoule bottle after tube sealing is put into insulating box, 36 h are reacted at a temperature of 130 DEG C, break ampoule bottle into pieces, take out slightly to produce
Thing PLGA.Products obtained therefrom Mw=1.85×105Da, Mw/Mn=1.23。
Crude product is dissolved in chloroform, 4.0wt% solution is configured to, precipitating 5 times in the ethanol of 5 times of volumes is instilled, very
Sky is dried.PLGA after purification is mixed with 6.8g maleic anhydrides, 0.18g dibenzoyl peroxides, in being placed in three-neck flask,
Pressure is 0.076MPa, 24h is reacted under conditions of 100 DEG C obtains the thick polymers of MPLGA.Thick polymers after by grafting is placed in Soxhelt
In extractor, with chloroform as the h of solvent extraction 8, will be dissolved in chloroform after the residue vacuum drying of extracting, prepare
Into 4.0wt% solution, precipitating 5 times in the ethanol of 5 times of volumes are instilled, then purification is dried under vacuum into constant weight, obtain faint yellow
Pure graft copolymer MPLGA.Products obtained therefrom Mw=1.80×105Da, Mw/Mn=1.27, percent grafting is 0.89%.
10.0g MPLGA are dissolved in 20mL chloroforms the chloroform soln for preparing 30.0wt% MPLGA, equal-volume
Ethylenediamine and chloroform mixed preparing 38wt% ethylenediamine chloroform soln.The chloroform of MPLGA is added and is equipped with
In the there-necked flask of agitator and thermometer, the chloroform soln of 2mL ethylenediamines, ice bath control are added dropwise under conditions of stirring
System temperature is less than 10 DEG C.Completion of dropping, after insulation 5min, then is warmed to room temperature 60 min of reaction by temperature.Product was instilled
Precipitation in the ethanol solution of amount, is washed with deionized in neutrality, and 40 DEG C of product is dried under vacuum to constant weight, obtains yellow
EMPLGA solids.
Weigh 2.5gEMPLGA to dissolve in 31mL chloroforms, by 12.5g particle diameters be 300 ~ 450 μm fully after dissolving
Na2CO3Particle is added in polymer solution and stirred, and after a large amount of solvents are volatilized under room temperature, adds mixture to steel
It is compressing in mould.Sample is soaked 3 hours in 6.0wt% solution after being dried 6 hours under room temperature, again with distillation after washing
Water soaks 12 hours, and a water was changed per 4 hours, and the porous support for obtaining is dried 24 hours in atmosphere, is vacuum dried 48 hours.
15.8g gelatin and 0.83g hyaluronic acids are taken, 25.0% gelatin/hyaluronic acid mixed solution is configured to；To 250mL
50mL atoleines are added in round-bottomed flask, heating water bath adds the span- of the concentration for 0.02g/L of 0.8g to after 60 DEG C
80, with 400r/min mechanical agitations 30min, after forming stable emulsion, add 10mL gelatin/hyaluronic acid mixed solution, breast
Change 10min, it is to be emulsified completely after be rapidly cooled to less than 4 DEG C, add the glutaraldehyde cross-linking solidification balling-up in 2 hours of 200 μ L.
10mL glacial acetic acid is taken, with distilled water diluting to pH value 4.7 or so, acetum is obtained.By 6.0g gelatin and 1.5g
Hyaluronic acid, is separately added into dissolving, is configured to the solution of 5mg/mL.The gelatin solution for preparing and hyaluronic acid solution is equal
Even mixing.
22.5mgGel/HA microballoons are added in 45mL gelatin/hyaluronic acid mixed sols.By Gel/HA colloidal sols and microballoon
Compound system be placed in the flask for being connected with vacuum plant, then cylinder EMPLGA porous " hard " timbering material is soaked in
In compound system, 20 ~ 30min is vacuumized under conditions of 0.078MPa.Compound rest taking-up is put into cold in freeze drier
Freeze 12h, be dried 48h.After taking-up, with the alcohol solution dipping 24h of 0.1% carbodiimides, alcohol solution dipping is then used
12h, per 4h a water is changed.Soaked compound support frame material is put into air drying 48h, is vacuum dried.
Embodiment 4：
The dried D of 75.0g, L- lactides, 25.0g glycolides are added in the ampoule bottle after dried process, added
Stannous octoate (the Sn (Oct) of 0.026g Jing processeds2)；After being vacuum dried 12 h, alcohol blast burner is used under conditions of 7.0Pa
Tube sealing.Ampoule bottle after tube sealing is put into insulating box, 36 h are reacted at a temperature of 150 DEG C, break ampoule bottle into pieces, take out slightly to produce
Thing PLGA.Products obtained therefrom Mw=1.54×105Da, Mw/Mn=1.35。
Crude product is dissolved in chloroform, 5.0wt% solution is configured to, precipitating 3 times in the ethanol of 3 times of volumes is instilled, very
Sky is dried.PLGA after purification is mixed with 7.0g maleic anhydrides, 0.15g dibenzoyl peroxides, in being placed in three-neck flask,
Pressure is 0.086MPa, 24h is reacted under conditions of 100 DEG C obtains the thick polymers of MPLGA.Thick polymers after by grafting is placed in Soxhelt
In extractor, with chloroform as the h of solvent extraction 8, will be dissolved in chloroform after the residue vacuum drying of extracting, prepare
Into 5.0wt% solution, precipitating 3 times in the ethanol of 3 times of volumes are instilled, then purification is dried under vacuum into constant weight, obtain faint yellow
Pure graft copolymer MPLGA.Products obtained therefrom Mw=1.48×105Da, Mw/Mn=1.38, percent grafting is 1.05%.
10.0g MPLGA are dissolved in 20mL chloroforms the chloroform soln for preparing 22.5wt% MPLGA, equal-volume
Ethylenediamine and chloroform mixed preparing 38.0wt% ethylenediamine chloroform soln.The chloroform of MPLGA is added into dress
In having the there-necked flask of agitator and thermometer, the chloroform soln of 2mL ethylenediamines, ice bath control are added dropwise under conditions of stirring
System temperature processed is less than 10 DEG C.Completion of dropping, after insulation 5min, then is warmed to room temperature 60 min of reaction by temperature.Product is instilled
Precipitation in excessive ethanol solution, is washed with deionized in neutrality, and 40 DEG C of product is dried under vacuum to constant weight, obtains yellow
EMPLGA solids.
Weigh 3.0gEMPLGA to dissolve in 37.5mL chloroforms, by 15.0g particle diameters be 300 ~ 450 μm fully after dissolving
Na2CO3Particle is added in polymer solution and stirred, and after a large amount of solvents are volatilized under room temperature, adds mixture to steel
It is compressing in mould.Sample is soaked 3 hours in 8.0wt% solution after being dried 6 hours under room temperature, again with distillation after washing
Water soaks 12 hours, and a water was changed per 4 hours, and the porous support for obtaining is dried 24 hours in atmosphere, is vacuum dried 48 hours.
15.8g gelatin and 0.83g hyaluronic acids are taken, 21.0% gelatin/hyaluronic acid mixed solution is configured to；To 250mL
50mL atoleines are added in round-bottomed flask, heating water bath adds the span- of the concentration for 0.012g/L of 0.8g to after 60 DEG C
80, with 500r/min mechanical agitations 30min, after forming stable emulsion, add 10mL gelatin/hyaluronic acid mixed solution, breast
Change 10min, it is to be emulsified completely after be rapidly cooled to less than 4 DEG C, add the glutaraldehyde cross-linking solidification balling-up in 2 hours of 200 μ L.
10mL glacial acetic acid is taken, with distilled water diluting to pH value 4.7 or so, acetum is obtained.By 5.0g gelatin and 1.25g
Hyaluronic acid, is separately added into dissolving, is configured to the solution of 5mg/mL.The gelatin solution for preparing and hyaluronic acid solution is equal
Even mixing.
17.5mgGel/HA microballoons are added in 35mL gelatin/hyaluronic acid mixed sols.By Gel/HA colloidal sols and microballoon
Compound system be placed in the flask for being connected with vacuum plant, then cylinder EMPLGA porous " hard " timbering material is soaked in
In compound system, 20 ~ 30min is vacuumized under conditions of 0.086MPa.Compound rest taking-up is put into cold in freeze drier
Freeze 12h, be dried 48h.After taking-up, with the alcohol solution dipping 24h of 0.1% carbodiimides, alcohol solution dipping is then used
12h, per 4h a water is changed.Soaked compound support frame material is put into air drying 48h, is vacuum dried.
Embodiment 5：
The dried D of 80.0g, L- lactides, 20.0g glycolides are added in the ampoule bottle after dried process, added
Stannous octoate (the Sn (Oct) of 0.030g Jing processeds2)；After being vacuum dried 12 h, alcohol blast burner is used under conditions of 8.0Pa
Tube sealing.Ampoule bottle after tube sealing is put into insulating box, 36 h are reacted at a temperature of 160 DEG C, break ampoule bottle into pieces, take out slightly to produce
Thing PLGA.Products obtained therefrom Mw=1.32×105Da, Mw/Mn=1.38。
Crude product is dissolved in chloroform, 4.0wt% solution is configured to, precipitating 3 times in the ethanol of 3 times of volumes is instilled, very
Sky is dried.PLGA after purification is mixed with 6.2g maleic anhydrides, 0.18g dibenzoyl peroxides, in being placed in three-neck flask,
Pressure is 0.068MPa, 24h is reacted under conditions of 100 DEG C obtains the thick polymers of MPLGA.Thick polymers after by grafting is placed in Soxhelt
In extractor, with chloroform as the h of solvent extraction 8, will be dissolved in chloroform after the residue vacuum drying of extracting, prepare
Into 1 ~ 5wt% solution, precipitating 3 times in the ethanol of 3 times of volumes are instilled, then purification is dried under vacuum into constant weight, obtain faint yellow
Pure graft copolymer MPLGA.Products obtained therefrom Mw=1.27×105Da, Mw/Mn=1.43, percent grafting is 0.95%.
10.0g MPLGA are dissolved in 20mL chloroforms the chloroform soln for preparing 27.5wt% MPLGA, equal-volume
Ethylenediamine and chloroform mixed preparing 38.0wt% ethylenediamine chloroform soln.The chloroform of MPLGA is added into dress
In having the there-necked flask of agitator and thermometer, the chloroform soln of 2mL ethylenediamines, ice bath control are added dropwise under conditions of stirring
System temperature processed is less than 10 DEG C.Completion of dropping, after insulation 5min, then is warmed to room temperature 60 min of reaction by temperature.Product is instilled
Precipitation in excessive ethanol solution, is washed with deionized in neutrality, and 40 DEG C of product is dried under vacuum to constant weight, obtains yellow
EMPLGA solids.
Weigh 2.0gEMPLGA to dissolve in 25mL chloroforms, by 10.0g particle diameters be 300 ~ 450 μm fully after dissolving
Na2CO3Particle is added in polymer solution and stirred, and after a large amount of solvents are volatilized under room temperature, adds mixture to steel
It is compressing in mould.Sample is soaked 3 hours in 10.0wt% solution after being dried 6 hours under room temperature, again with steaming after washing
Distilled water is soaked 12 hours, and a water was changed per 4 hours, and the porous support for obtaining is dried 24 hours in atmosphere, and vacuum drying 48 is little
When.
15.8g gelatin and 0.83g hyaluronic acids are taken, 23.5% gelatin/hyaluronic acid mixed solution is configured to；To 250mL
50mL atoleines are added in round-bottomed flask, heating water bath adds the span- of the concentration for 0.020g/L of 0.8g to after 60 DEG C
80, with 600r/min mechanical agitations 30min, after forming stable emulsion, add 10mL gelatin/hyaluronic acid mixed solution, breast
Change 10min, it is to be emulsified completely after be rapidly cooled to less than 4 DEG C, add the glutaraldehyde cross-linking solidification balling-up in 2 hours of 200 μ L.
10mL glacial acetic acid is taken, with distilled water diluting to pH value 4.7 or so, acetum is obtained.By 4.0g gelatin and 1.0g
Hyaluronic acid, is separately added into dissolving, is configured to the solution of 5mg/mL.The gelatin solution for preparing and hyaluronic acid solution is equal
Even mixing.
20.0mgGel/HA microballoons are added in 40mL gelatin/hyaluronic acid mixed sols.By Gel/HA colloidal sols and microballoon
Compound system be placed in the flask for being connected with vacuum plant, then cylinder EMPLGA porous " hard " timbering material is soaked in
In compound system, 20 ~ 30min is vacuumized under conditions of 0.075MPa.Compound rest taking-up is put into cold in freeze drier
Freeze 12h, be dried 48h.After taking-up, with the alcohol solution dipping 24h of 0.1% carbodiimides, alcohol solution dipping is then used
12h, per 4h a water is changed.Soaked compound support frame material is put into air drying 48h, is vacuum dried.
Claims (8)
1. the preparation method of a kind of EMPLGA/Gel-HA hydrogels-bionical compound rest of microballoon, it is characterised in that including following
Step：
（1）D, L- lactides, glycolide are added in the ampoule bottle after dried process, a certain amount of stannous octoate (Sn is added
(Oct)2)；After 12 ~ 24 h of vacuum drying, at normal temperatures using the h of diffusion pump pumping high vacuum 0.5 ~ 1.0, pressure in ampoule bottle is made
Less than 5.0Pa, tube sealing；Ampoule bottle after tube sealing is put into insulating box, is taken after reacting 12 ~ 60 h at a temperature of 120 ~ 170 DEG C
Go out；Crude product is dissolved in chloroform, 1.0 ~ 5.0wt% solution is configured to, precipitating in the ethanol of 3 ~ 5 times of volumes is then instilled,
Precipitating 3-5 time repeatedly, by product vacuum drying to the constant weight after purification PLGA polymer is obtained final product；
（2）By PLGA after purification and a certain amount of maleic anhydride, dibenzoyl peroxide（BPO）Mixing, be placed in decompression, 100
DEG C environment in react 24h obtain the thick polymers of MPLGA；Thick polymers is placed in Soxhelt extractors, with chloroform as molten
Agent extracts 8 h, and 4 ~ 6 times are flowed back per hour to remove homopolymers, will be dried under vacuum to constant weight at 40 DEG C of copolymer after extracting；Will
Copolymer is added in chloroform, is configured to 1 ~ 5wt% solution, instills precipitating in the ethanol of 3 ~ 5 times of volumes, repeatedly precipitating 3 ~ 5
It is secondary, then constant weight will be dried under vacuum at 40 DEG C of purification, obtain pure MPLGA；
（3）MPLGA after purification is dissolved in chloroform, the chloroform soln of the MPLGA of 20.0 ~ 30.0wt% is configured to；
（4）Ethylenediamine is dissolved in chloroform, the chloroform soln of the ethylenediamine that concentration is 38.0wt% is configured to；
（5）Under conditions of stirring, by step（4）The chloroform soln of gained ethylenediamine is added dropwise to step（3）Gained MPLGA
Chloroform soln in, ice bath control temperature of reaction system is less than 10 DEG C, is incubated 5 ~ 10min, then temperature is warmed to room temperature instead
30 ~ 60min is answered, finally product precipitating in excessive ethanol is instilled into, precipitating 3 ~ 5 times repeatedly is washed with deionized to neutrality,
Constant weight is dried under vacuum to, poly- third co-glycolide polymers of ethylenediamine modified maleic anhydridization are obtained（EMPLGA）Solid；
（6）Weigh a certain amount of EMPLGA to dissolve in chloroform, fully by a certain amount of 300 ~ 450 μm of Na after dissolving2CO3Grain
Son is added in polymer solution and stirred, after a large amount of solvents are volatilized under room temperature, in adding mixture to steel die,
It is compressing；Sample is soaked 3 hours in dilute hydrochloric acid solution after being dried 6 hours under room temperature, uses distilled water immersion after washing again
12 hours, a water was changed per 3 ~ 4 hours, the porous support for obtaining is dried 24 hours in atmosphere, is vacuum dried 48 hours；
（7）By gelatin（Gel）And hyaluronic acid（HA）, by weight 95:5, prepare gelatin/bright matter acid mixed aqueous solution；Xiang Rong
Add atoleine to be heated to 60 DEG C in device, then a small amount of span-80, mechanical agitation are added in container；Take gelatin/hyaluronic acid
Mixed solution is added in container, stirring, drop is uniformly scattered in oil phase, the gelatin in the addition container/transparent
The molten volume ratio with atoleine of matter acid mixing is 13:87；Then container is placed in ice-water bath, treats that system is cooled down, temperature is low
After 4 DEG C, a small amount of glutaraldehyde is added as crosslinking agent, crosslinking, solidification balling-up；With acetone and water（Volume ratio 3:1）Mixing it is molten
Liquid is washed 2 ~ 3 times, filters off atoleine and water, is finally washed with pure acetone, suction filtration, natural airing, gained complex microsphere surface
It is smooth；
（8）A certain amount of glacial acetic acid is taken, with distilled water diluting to pH value 4.7 or so, by gelatin and hyaluronic acid, by weight 8:2
Dissolving is separately added into, the solution of 5mg/mL is configured to；The gelatin solution for preparing uniformly is mixed with hyaluronic acid solution；
（9）To step（8）In mixed solution in add a certain amount of step（7）Obtained Gel/HA microballoons obtain compound system,
Added colloidal sol is 10 with the mass ratio of microballoon:1；The compound system of Gel/HA colloidal sols and microballoon is placed in and is connected with vacuum plant
In flask, then cylindrical shape EMPLGA porous " hard " timbering material is soaked in compound system, vacuumizes 20 ~ 30min；
Compound rest is taken out to be put into freeze drier and freezes 12h, be dried 48h；After taking-up, carbodiimides is used（EDC）Ethanol
Solution soaks 24h, then uses alcohol solution dipping 12h, and per 4h a water is changed；Soaked compound support frame material is put into sky
48h is dried in gas, is vacuum dried, obtain EMPLGA/Gel-HA hydrogels-bionical compound rest of microballoon.
2. the preparation method of EMPLGA/Gel-HA hydrogels according to claim 1-bionical compound rest of microballoon, it is special
Levy and be, step（1）In, the D, L- lactides, glycolide, the weight ratio of stannous octoate are：D, L- lactide 70.0 ~
80.0wt%, 20.0 ~ 30.0wt% of glycolide, 0.01 ~ 0.03wt% of stannous octoate, and stannous octoate Jing processeds.
3. the preparation method of EMPLGA/Gel-HA hydrogels according to claim 1-bionical compound rest of microballoon, it is special
Levy and be, step（1）In, the chloroform soln（1.0~5.0wt%）Concentration it is directly relevant with PLGA molecular size ranges,
Molecular weight is bigger, and the chloroform soln concentration of preparation should be less.
4. the preparation method of EMPLGA/Gel-HA hydrogels according to claim 1-bionical compound rest of microballoon, it is special
Levy and be, step（2）In, the amount of the maleic anhydride is D, L- lactides, 5 ~ 10 wt% of glycolide monomer total amount, peroxidating
The addition of benzoyl is 1 ~ 5 wt% of maleic anhydride weight；Described reduced pressure atmosphere is that pressure is less than 0.09MPa.
5. the preparation method of EMPLGA/Gel-HA hydrogels according to claim 1-bionical compound rest of microballoon, it is special
Levy and be, step（5）In, the addition of the ethylenediamine is the 20.0 ~ 30.0% of MPLGA mass.
6. the preparation method of EMPLGA/Gel-HA hydrogels according to claim 1-bionical compound rest of microballoon, it is special
Levy and be, step（6）EMPLGA is 1.0 ~ 5.0wt% with the concentration of chloroform, and the concentration of hydrochloric acid is 5.0-10.0wt%,
EMPLGA and Na2CO3Mass ratio be 1:5.
7. the preparation method of EMPLGA/Gel-HA hydrogels according to claim 1-bionical compound rest of microballoon, it is special
Levy and be, step（7）In, the concentration of gelatin/hyaluronic acid mixed solution is 20.0 ~ 25.0wt%, and the concentration of span-80 is
0.016 ~ 0.020g/L, 200 ~ 800r/min of stir speed (S.S.), the concentration of glutaraldehyde is 0.3mL/g.
8. the preparation method of EMPLGA/Gel-HA hydrogels according to claim 1-bionical compound rest of microballoon, it is special
Levy and be, step（9）Middle vacuum is 0.07 ~ 0.09MPa, and the ethanol solution concentration of carbodiimides is 0.1wt%.
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| CN112587505A (en) * | 2020-10-16 | 2021-04-02 | 长春斯菲尔生物科技有限公司 | Olanzapine pamoate sustained-release microparticle preparation and preparation method thereof |
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