CN106674516B - Amino acid block copolymer, preparation method and temperature sensitive type water gel - Google Patents
Amino acid block copolymer, preparation method and temperature sensitive type water gel Download PDFInfo
- Publication number
- CN106674516B CN106674516B CN201710053711.9A CN201710053711A CN106674516B CN 106674516 B CN106674516 B CN 106674516B CN 201710053711 A CN201710053711 A CN 201710053711A CN 106674516 B CN106674516 B CN 106674516B
- Authority
- CN
- China
- Prior art keywords
- formula
- block
- acid
- ester
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
- C08G69/40—Polyamides containing oxygen in the form of ether groups
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2377/00—Characterised by the use of polyamides obtained by reactions forming a carboxylic amide link in the main chain; Derivatives of such polymers
Landscapes
- Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Polyamides (AREA)
Abstract
Block copolymer provided by the invention includes the first block that the polyethylene glycol of Amino End Group or the poly glycol monomethyl ether of Amino End Group are formed and the second block with formula (III) structure.The first block and the second block of block copolymer of the present invention all have the different degree of polymerization, it can be by adjusting block ratio, and the ratio of ethyl ester group and carboxyl or amino, obtain the block polymer with different structure, and the hydrogel of different phase transition temperatures.Block polymer provided by the invention has a variety of regulating measures, so that the controllability of the temperature sensitive type water gel formed is good, has expanded the regulating measure of temperature sensitive type hydrogel transformation behavior, has been conducive to the type temperature-sensitive hydrogel and further applies.
Description
Technical field
The present invention relates to a kind of technical field of polyamino acid more particularly to amino acid block copolymer, preparation method and
Temperature sensitive type water gel.
Background technique
Syringeability temperature-sensitive hydrogel in vitro or be high molecular aqueous solution under cryogenic conditions, and when being injected into
When internal, the gel of semisolid can be changed into rapidly, this characteristic is conducive to such material in the side such as drug delivery, organizational project
The application in face.Currently, the research to topical remedy's controlled release system based on syringeability hydrogel, it has also become current medicine controlled releasing
One of the research hotspot in field.
Polymer can formation temperature sensitive hydrogel, become one of research hotspot in recent years.The prior art discloses
The hydrogel of polyethylene glycol oxide-polypropylene oxide and polyalanine or polyalanine and phenylalanine random copolymer
(Macromalecule, 2008,41:8204~8209, Biomacromolecules, 2009,10:2476~2481.), it is this kind of
The biodegradable product of hydrogel is amino acid, does not have any injury to human body, still, forms the block copolymer of hydrogel only
The transformation behavior of hydrogel can be adjusted by unilaterally changing the molecular weight of polyalanine block or polyphenylalanine, it is adjustable
Section property is relatively simple, is unfavorable for the further application of temperature sensitive type water gel.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is that provide a kind of hydrogel, amino acid provided by the invention
The temperature sensitive type water gel transformation behavior controllability that block copolymer is formed is good.
The present invention provides a kind of block copolymers, comprising the first block with formula (I) or formula (II) structure and have
Second block of formula (III) structure:
Wherein, the R is independent is selected from-CH2COOH、-(CH2)2COOH、-(CH2)4NH2；
M, n, x, y are the degree of polymerization, 5≤m≤227,5≤n≤226,1≤x≤200,1≤y≤100.
Preferably, it is 30%~70% that second block, which accounts for the weight percent of the block copolymer,.
The present invention provides a kind of preparation methods of block copolymer, comprising the following steps:
The poly- second of the poly glycol monomethyl ether of Amino End Group with IV structure of formula or the Amino End Group with V structure of formula
Glycol is sent out with VI structure γ of formula-didodecyl l glutamic acid ethyl ester-N- carboxylic acid inner-acid anhydride and amino acid derivativges-N- carboxylic acid inner-acid anhydride
Raw polymerization reaction, deprotection obtain block polymer；
Wherein, m is the degree of polymerization, 5≤m≤227；
N is the degree of polymerization, 5≤n≤226.
Preferably, the amino acid derivativges-N- carboxylic acid inner-acid anhydride is selected from one of formula VII, formula VIII and formula Ⅸ；
Preferably, the poly glycol monomethyl ether of the Amino End Group with formula (IV) structure or with formula (V) structure
The polyethylene glycol of Amino End Group and γ-didodecyl l glutamic acid ethyl ester-N- carboxylic acid inner-acid anhydride molar ratio of VI structure of formula are 1:(5
~150).
Preferably, VI structure γ of the formula-didodecyl l glutamic acid ethyl ester-N- carboxylic acid inner-acid anhydride and amino acid derivativges-N-
It is 1:(0.01~10 that carboxylic acid inner-acid anhydride, which polymerize molar ratio).
Preferably, the polymeric reaction temperature is 20 DEG C~50 DEG C；The polymerization reaction time is for 24 hours~96h.
The present invention provides a kind of temperature sensitive type water gel, comprising block copolymer described in above-mentioned technical proposal and molten
Agent.
Preferably, the solvent is water, physiological saline, buffer solution, tissue culture medium or body fluid.
Preferably, the mass fraction of the block copolymer is 1%~50%.
Compared with prior art, block copolymer provided by the invention includes the polyethylene glycol or Amino End Group of Amino End Group
Poly glycol monomethyl ether formed the first block and with formula (III) structure the second block.Block copolymerization of the present invention
The first block and the second block of object all have the different degree of polymerization, can by adjust block ratio and ethyl ester group with
The ratio of carboxyl or amino obtains the block polymer with different structure, and the hydrogel of different phase transition temperatures.This hair
The block polymer of bright offer has a variety of regulating measures, so that the controllability of the temperature sensitive type water gel formed is good, expands
The regulating measure for having filled temperature sensitive type hydrogel transformation behavior is conducive to the type temperature-sensitive hydrogel and further answers
With.Meanwhile hydrogel material is in addition to containing other than ethyl glutamate segment, is also drawn by glutamic acid, lysine, aspartic acid
Enter, increase carboxyl, amino isoreactivity functional group, these groups can by electrostatic interaction between drug molecule, match
The interaction such as position effect and covalent bonding, realizes to the adjusting of the release behavior of water soluble drug, reduces the burst release of drug
Behavior；This is conducive to realize the adjustable sustained release to drug in vivo by the gel carrier.Temperature provided by the invention
Sensitive hydrogel has good biocompatibility and biodegradability, and degradation cycle is 3 weeks~15 weeks, is conducive to it
As the further application of pharmaceutical carrier in vivo, and the obtained product of degradation is amino acid, ethyl alcohol and polyethylene glycol, can quilt
Body is absorbed or is excreted by being metabolized in vivo, substantially harmless to human body；Therefore, before which has wide application
Scape.
Detailed description of the invention
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram for the block copolymer that the embodiment of the present invention 1 is prepared；
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram for the block copolymer that the embodiment of the present invention 2 is prepared；
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram for the block copolymer that the embodiment of the present invention 3 is prepared；
Fig. 4 is the phasor that the block polymer solution for the various concentration that the embodiment of the present invention 1 obtains varies with temperature；
Fig. 5 is the phasor that the block polymer solution for the various concentration that the embodiment of the present invention 2 obtains varies with temperature；
Fig. 6 is the result of study figure of the outer degradation experiment of gelinite of the embodiment of the present invention 13.
Specific embodiment
The present invention provides a kind of block copolymers, comprising the first block with formula (I) or formula (II) structure and have
Second block of formula (III) structure:
Wherein, the R is independent is selected from-CH2COOH、-(CH2)2COOH、-(CH2)4NH2；
M is the degree of polymerization, 5≤m≤227, preferably 20≤m≤185, more preferably 30≤m≤115；
N is the degree of polymerization, 5≤m≤226；Preferably 20≤n≤180, more preferably 30≤n≤112；
X is the degree of polymerization, 2≤x≤200；Preferably 5≤x≤80；More preferably 3≤x≤50；
Y is the degree of polymerization, 1≤y≤100；Preferably 1≤x≤50；More preferably 3≤x≤30.
In the present invention, the weight percent that second block accounts for the block copolymer is preferably 30%~70%；
More preferably 35%~65%；Most preferably 40%~60%.
The present invention provides a kind of preparation methods of block copolymer, comprising the following steps:
The poly- second of the poly glycol monomethyl ether of Amino End Group with IV structure of formula or the Amino End Group with V structure of formula
Glycol is sent out with VI structure γ of formula-didodecyl l glutamic acid ethyl ester-N- carboxylic acid inner-acid anhydride and amino acid derivativges-N- carboxylic acid inner-acid anhydride
Raw polymerization reaction, deprotection obtain block polymer；
Wherein, m is the degree of polymerization, 5≤m≤227；
N is the degree of polymerization, 5≤n≤226.
In the present invention, the poly glycol monomethyl ether of the Amino End Group with formula (IV) structure or have formula (V) structure
The polyethylene glycol of Amino End Group preferably prepare in accordance with the following methods:
To methylsufonyl chloride esterification occurs for poly glycol monomethyl ether or polyethylene glycol and potassium hydroxide, obtains methyl
Sulfonic acid poly glycol monomethyl ether ester or methane sulfonic acid macrogol ester；
The methane sulfonic acid poly glycol monomethyl ether ester or methane sulfonic acid macrogol ester and ammonium hydroxide carry out ammonolysis reaction, obtain
The poly- second two of poly glycol monomethyl ether to the Amino End Group with formula (IV) structure or the Amino End Group with formula (V) structure
Alcohol.
Firstly, will continue to remove toluene after poly glycol monomethyl ether or polyethylene glycol and toluene azeotropic water removing, then thereto
Organic solvent is added, obtains poly glycol monomethyl ether or polyglycol solution.Wherein, the poly glycol monomethyl ether or poly- second two
The number-average molecular weight of alcohol is 550~10000, preferably 1000~8000, more preferably 1500~5000, and the organic solvent is excellent
It is selected as methylene chloride, the volume ratio of the quality and organic solvent of the poly glycol monomethyl ether or polyethylene glycol is preferably 1g:(1
~20) mL, more preferably 1g:(3~18) mL, most preferably 1g:(5~15) mL.
Potassium hydroxide and methylsufonyl chloride are added into obtained poly glycol monomethyl ether or polyglycol solution, carries out ester
Change reaction, obtains methane sulfonic acid poly glycol monomethyl ether ester or methane sulfonic acid macrogol ester.Wherein, the potassium hydroxide and poly-
The molar ratio of glycol monoethyl ether is preferably (1~10): 1, more preferably (3~8): 1, most preferably (4~7): 1；The hydrogen
The molar ratio of potassium oxide and polyethylene glycol is preferably (2~20): 1, more preferably (5~18): 1, most preferably (8~14): 1；
The molar ratio of the potassium hydroxide and methylsufonyl chloride is preferably (1~10): (10~30), more preferably (3~8): (18~
26), most preferably (4~7): (15~24).
The present invention is preferably under -10 DEG C~10 DEG C, anhydrous condition, more preferably at -8 DEG C~8 DEG C, most preferably -5 DEG C~
At 5 DEG C, potassium hydroxide is added in Xiang Suoshu poly glycol monomethyl ether or polyglycol solution, while methylsufonyl chloride is added dropwise,
In obtained mixed solution, the poly glycol monomethyl ether or polyethylene glycol and triethylamine, methylsufonyl chloride carry out esterification,
Obtain methane sulfonic acid poly glycol monomethyl ether ester or methane sulfonic acid macrogol ester.Preferred reaction 0.5 hour at the temperature disclosed above
~4 hours, more preferably 1 hour~3.5 hours, most preferably 1.5 hours~2.5 hours, be then preferably warming up to 12 DEG C~
40 DEG C, more preferably 18 DEG C~35 DEG C, most preferably 15 DEG C~28 DEG C, preferably the reaction was continued under agitation 10 hours~72
Hour, more preferably 15 hours~60 hours, most preferably 20 hours~48 hours.
After esterification, obtained reaction solution is filtered, filters off sediment, it is preferably heavy with ether after filtrate concentration
Drop, is then filtered again, washs, be preferably dried in vacuo at a temperature of 10 DEG C~40 DEG C, more preferably 15 DEG C~38 DEG C,
Most preferably 20 DEG C~30 DEG C, the drying time is preferably 15 hours~35 hours, and more preferably 18 hours~30 hours, most
Preferably 22 hours~28 hours, obtain methane sulfonic acid poly glycol monomethyl ether ester or methane sulfonic acid macrogol ester.
Obtained methane sulfonic acid poly glycol monomethyl ether ester or methane sulfonic acid macrogol ester and ammonium chloride are dissolved in ammonium hydroxide
In, wherein the quality of the methane sulfonic acid poly glycol monomethyl ether ester or methane sulfonic acid macrogol ester, the quality of ammonium chloride with
The volume ratio of ammonium hydroxide is preferably 1g:(0.2~3.5) g:(30~70) mL, more preferably 1g:(0.5~3) g:(35~55) mL,
Most preferably 1g:(1~1.8) g:(40~50) mL.
In ammonium hydroxide, the methane sulfonic acid poly glycol monomethyl ether ester or methane sulfonic acid macrogol ester progress ammonolysis are anti-
It answers, obtain the poly glycol monomethyl ether with the Amino End Group of formula (IV) structure or there is the poly- of the Amino End Group of formula (V) structure
Ethylene glycol.The temperature of the aminating reaction is preferably 10 DEG C~40 DEG C, more preferably 15 DEG C~35 DEG C, most preferably 20 DEG C~30
DEG C, the aminating reaction time is preferably 40 hours~100 hours, and more preferably 50 hours~85 hours, most preferably 60 is small
When~75 hours.
After the completion of ammonolysis reaction, obtained reaction solution is preferably extracted with dichloromethane and then is washed with sodium-chloride water solution
It washs, anhydrous sodium sulfate drying, obtained filtrate is concentrated, is then settled with ether, obtained sediment is filtered, washed, it is excellent
It is dried in vacuo at a temperature of being selected in 10 DEG C~40 DEG C, more preferably 15 DEG C~35 DEG C, most preferably 20 DEG C~30 DEG C, it is described dry
The dry time is preferably 15 hours~35 hours, more preferably 18 hours~30 hours, most preferably 20 hours~28 hours, is obtained
The polyethylene glycol of the poly glycol monomethyl ether of Amino End Group with formula (IV) structure or the Amino End Group with (V) structure.
The present invention for the γ-didodecyl l glutamic acid ethyl ester-N- carboxylic acid inner-acid anhydride source without limiting, can be with
To be commercially available, preferably prepare in accordance with the following methods:
Esterification occurs for Pidolidone and alcohol compound, obtains γ-didodecyl l glutamic acid ester；
The γ-didodecyl l glutamic acid ester and bis- (trichloromethyl) carbonic esters carry out condensation reaction, obtain γ-alkyl-L-
Glutamate-N- carboxylic acid inner-acid anhydride.
Pidolidone and alcohol compound are mixed and stirred for first, and the concentrated sulfuric acid is added dropwise thereto under agitation,
Under conditions of the concentrated sulfuric acid exists and stirs, Pidolidone and alcohol compound carry out esterification, obtain γ-alkyl-L- paddy
Propylhomoserin ester.The alcohol compound is preferably methanol, ethyl alcohol, normal propyl alcohol, isopropanol or n-butanol, the Pidolidone and alcohols
The molar ratio of compound is preferably 1:(0.8~8), more preferably 1:(1.5~6), most preferably 1:(3~4) and, the L- paddy ammonia
Acid and the molar ratio of the concentrated sulfuric acid are preferably 1:(0.5~5), more preferably 1:(0.8~3), most preferably 1:(1.2~2).It is described
The temperature that Pidolidone is mixed with alcohol compound is preferably 0 DEG C~30 DEG C, and more preferably 0 DEG C~20 DEG C, most preferably 0 DEG C~
10 DEG C, the temperature of the esterification is preferably 20 DEG C~50 DEG C, more preferably 25 DEG C~45 DEG C, most preferably 28 DEG C~40
DEG C, the reaction time of esterification is preferably 5 hours~35 hours, and more preferably 7 hours~33 hours, most preferably 10 hours~
30 hours.
After the completion of the esterification of Pidolidone and alcohol compound, preferably neutralized with the mixed solution of triethylamine and ethyl alcohol
Obtained reaction solution obtains γ-didodecyl l glutamic acid ester then by the centrifugation of obtained mixed solution, recrystallization, drying.This hair
In bright, the volume ratio of the triethylamine and ethyl alcohol is preferably 1:(0.5~1.5), more preferably 1:(0.7~1.3), most preferably
1:(0.8~1.2), the molar ratio of the triethylamine and the concentrated sulfuric acid is preferably (0.7~3): 1, more preferably (0.8~2.0): 1,
Most preferably (0.9~1.2): 1.
After obtaining γ-didodecyl l glutamic acid ester, preferably in anhydrous conditions, the γ-is dissolved with anhydrous organic solvent
Didodecyl l glutamic acid ester and bis- (trichloromethyl) carbonic esters, in organic solvent, γ-didodecyl l glutamic acid ester and bis- (trichlorines
Methyl) carbonic ester progress condensation reaction, obtain γ-didodecyl l glutamic acid ester-N- carboxylic acid inner-acid anhydride.The γ-alkyl-L- paddy
The molar ratio of propylhomoserin ester and bis- (trichloromethyl) carbonic esters is preferably 1:(0.1~1.2), more preferably 1:(0.3~1), optimal
It is selected as 1:(0.5~0.8), the organic solvent is preferably tetrahydrofuran, the γ-didodecyl l glutamic acid ester and bis- (three chloromethanes
Base) reaction temperature of carbonic ester is preferably 30 DEG C~80 DEG C, and more preferably 40 DEG C~70 DEG C, most preferably 50 DEG C~60 DEG C, institute
Stating condensation reaction time is preferably 0.1 hour~5 hours, more preferably 0.15 hour~3 hours, more preferably 0.2 hour~2
Hour.
After condensation reaction, obtained reaction solution is preferably settled with petroleum ether, obtained sediment is separated, then
By the washing of obtained separation product, recrystallization, drying, γ-didodecyl l glutamic acid ester-N- carboxylic acid inner-acid anhydride is obtained.
Amino acid derivativges-N- carboxylic acid inner-acid anhydride of the present invention includes but is not limited to one in formula VII, formula VIII and formula Ⅸ
Kind；
Above structure amino acid derivativges-N- carboxylic acid inner-acid anhydride can be phenyl as blocking group, be also possible to ability
Remaining blocking group known to field technique personnel, the present inventor are not limited thereto.
The present invention for the amino acid derivativges-N- carboxylic acid inner-acid anhydride of the formula VII, formula VIII and formula Ⅸ source without
It limits, it is commercially available.
In the present invention, the poly glycol monomethyl ether of the Amino End Group with IV structure of formula or end ammonia with V structure of formula
The polyethylene glycol of base, with VI structure γ of formula-didodecyl l glutamic acid ethyl ester-N- carboxylic acid inner-acid anhydride and amino acid derivativges-N- carboxylic
Polymerization reaction occurs for sour inner-acid anhydride, obtains reaction product；It is preferred that specifically includes the following steps:
By the poly glycol monomethyl ether of the Amino End Group with IV structure of formula or Amino End Group with V structure of formula
Polyethylene glycol be dissolved in the first organic solvent, obtain the first solution.It is preferred that specifically:
By the poly glycol monomethyl ether of the Amino End Group with IV structure of formula or Amino End Group with V structure of formula
Polyethylene glycol and dry toluene azeotropic water removing after continue remove toluene, be then dissolved in the first organic solvent, obtain first
Solution.
The present invention is not particularly limited the concentration of first solution.First organic solvent is preferably N, N- diformazan
Base formamide, n,N-dimethylacetamide or chloroform, more preferably n,N-Dimethylformamide.It is described that there is IV structure
The quality of the polyethylene glycol of the poly glycol monomethyl ether of Amino End Group or the Amino End Group with V structure of formula and first organic molten
The volume ratio of agent is preferably 1g:(10mL~50mL), more preferably 1g:(15mL~45mL), most preferably 1g:(25mL~
35mL), the temperature of the azeotropic is preferably 110 DEG C~150 DEG C, and more preferably 115 DEG C~140 DEG C, most preferably 125 DEG C~
135 DEG C, the time of the azeotropic is preferably 1 hour~10 hours, more preferably 1.5 hours~7.5 hours, most preferably 1.8
Hour~2.2 hours.
By the γ-didodecyl l glutamic acid ethyl ester-N- carboxylic acid inner-acid anhydride VI and amino acid derivativges-N- carboxylic acid inner-acid anhydride
(VII/VIII/IX) it is dissolved in the second organic solvent, obtains the second solution, the present invention is not special to the concentration of second solution
Limitation.Second organic solvent is preferably n,N-Dimethylformamide, n,N-dimethylacetamide or chloroform, more preferably
For N,N-dimethylformamide.
After obtaining the first solution and the second solution, in a nitrogen atmosphere, first solution is mixed simultaneously with the second solution
It is stirred continuously, in obtained mixed solution, the poly glycol monomethyl ether of the Amino End Group or the polyethylene glycol of Amino End Group
Polymerization reaction occurs with γ-didodecyl l glutamic acid ester-N- carboxylic acid inner-acid anhydride and amino acid derivativges-N- carboxylic acid inner-acid anhydride, obtains
Reaction product.The polyethylene glycol of the Amino End Group or the poly glycol monomethyl ether of Amino End Group and amino acid derivativges-N- carboxylic
The molar ratio of sour inner-acid anhydride is preferably 1:(5~150), more preferably 1:(10~50).The polymeric reaction temperature is preferably 10
DEG C~50 DEG C, more preferably 15 DEG C~45 DEG C, more preferably 20 DEG C~40 DEG C, the polymerization reaction time is preferably to arrive for 10 hours
120 hours, more preferably 20 hours to 90 hours, most preferably 24 hours to 72 hours.
It after polymerization reaction, is preferably settled with ether, obtained sediment is filtered, is washed, vacuum is done
It is dry, obtain reaction product.
After obtaining reaction product HBr acetic acid removing benzyl, obtain through dialysis with comprising with Formulas I or Formula II structure
The block copolymer of first block and the second block with formula III structure.
It is described preferred with HBr acetic acid removing benzyl condition are as follows: reaction product is dissolved in dichloroacetic acid；The reactant with
The ratio of dichloroacetic acid is preferably 1g:1~50mL, more preferably 1g:5~30mL, most preferably 1g:8~12mL.It later will be anti-
System is answered to be warming up to specific temperature；The temperature is preferably 20~40 DEG C, more preferably 25~35 DEG C, most preferably 28~32
℃.The HBr acetum for being added 33% is reacted, and additional amount is preferably 1g:1~5mL, more preferably 1g:2.5~4.0mL,
Most preferably 2.8~3.2mL.Certain time is reacted in reaction under agitation, which is preferably 0.5~5h, more preferably
0.7~3h, most preferably 1~2h.Obtain block copolymer.
In the block copolymer that the present invention obtains, the weight percent that second block accounts for the block copolymer is preferred
It is 30%~70%；More preferably 35%~65%；Most preferably 40%~60%.
Block polymer of the present invention can also be prepared using following methods:
By the poly glycol monomethyl ether of the Amino End Group with IV structure of formula or Amino End Group with V structure of formula
Polyethylene glycol be dissolved in the first organic solvent, obtain the first solution.It is preferred that specifically:
By the poly glycol monomethyl ether of the Amino End Group with IV structure of formula or Amino End Group with V structure of formula
Polyethylene glycol and dry toluene azeotropic water removing after continue remove toluene, be then dissolved in the first organic solvent, obtain first
Solution.
The present invention is not particularly limited the concentration of first solution.First organic solvent is preferably N, N- diformazan
Base formamide, n,N-dimethylacetamide or chloroform, more preferably n,N-Dimethylformamide.It is described that there is IV structure
The quality of the polyethylene glycol of the poly glycol monomethyl ether of Amino End Group or the Amino End Group with V structure of formula and first organic molten
The volume ratio of agent is preferably 1g:(10mL~50mL), more preferably 1g:(15mL~45mL), most preferably 1g:(25mL~
35mL), the temperature of the azeotropic is preferably 110 DEG C~150 DEG C, and more preferably 115 DEG C~140 DEG C, most preferably 125 DEG C~
135 DEG C, the time of the azeotropic is preferably 1 hour~10 hours, more preferably 1.5 hours~7.5 hours, most preferably 1.8
Hour~2.2 hours.
The γ-didodecyl l glutamic acid ethyl ester-N- carboxylic acid inner-acid anhydride VI is dissolved in the second organic solvent, it is molten to obtain second
Liquid, the present invention are not particularly limited the concentration of second solution.Second organic solvent is preferably N, N- dimethyl methyl
Amide, n,N-dimethylacetamide or chloroform, more preferably n,N-Dimethylformamide.
Amino acid derivativges-N- carboxylic acid inner-acid anhydride (VII/VIII/IX) is dissolved in the second organic solvent, it is molten to obtain third
Liquid；
After obtaining the first solution and the second solution, in a nitrogen atmosphere, first solution is mixed simultaneously with the second solution
It is stirred continuously, reacts；The reaction temperature is preferably 10 DEG C~40 DEG C, and more preferably 15 DEG C~35 DEG C, more preferably 20 DEG C~
30 DEG C, the polymerization reaction time is preferably 10 hours to 60 hours, and more preferably 20 hours to 50 hours, most preferably 24 is small
When by 48 hours.Third solution is added under the protective condition of nitrogen again, the reaction was continued, obtains reaction product.The Amino End Group
The molar ratio of the poly glycol monomethyl ether and amino acid derivativges-N- carboxylic acid inner-acid anhydride of the polyethylene glycol or Amino End Group of change is preferred
For 1:(5~150), more preferably 1:(10~50).The polymeric reaction temperature is preferably 10 DEG C~50 DEG C, more preferably 15 DEG C
~45 DEG C, more preferably 20 DEG C~40 DEG C, the polymerization reaction time is preferably 10 hours to 120 hours, and more preferably 20 is small
When by 90 hours, most preferably 24 hours to 72 hours.
Operation after polymerization reaction is above-mentioned to be clearly described, and details are not described herein.
The present invention provides a kind of temperature sensitive type water gel, comprising block copolymer described in above-mentioned technical proposal and molten
Agent.
In the present invention, after the block copolymer is mixed with solvent, temperature sensitive type water gel is obtained.
The solvent is preferably water, physiological saline, buffer solution, tissue culture medium or body fluid；More preferably buffer solution
Or physiological saline, most preferably buffer solution.
The mass fraction of the block copolymer is preferably 1%~50%；More preferably 2%~45%；Most preferably 2%
~30%；It is the most preferably 3%~20%.
The present invention is tested phasor, the degradation property of the temperature sensitive type water gel using following methods:
The block polymer that above-mentioned technical proposal is obtained is dissolved in buffer solution, obtains block polymer solution.Institute
Stating buffer solution is preferably phosphate buffer solution, and the pH of the buffer solution is preferably 5.0~8.0, more preferably 6.5~
7.5.The gelling temperature that the above-mentioned polymer solution of various concentration is measured to polymer solution by test tube anastrophe, obtains material
Sol-gel transition phasor；Obtained block polymer solution is placed 15 minutes preferably in water bath with thermostatic control, the constant temperature
The temperature of water-bath is preferably 30 DEG C~45 DEG C, more preferably 35 DEG C~40 DEG C, obtains block polymer hydrogel.Then preferably will
The buffer solution of 3mL is slowly added in the block polymer hydrogel, preferably puts the block polymer hydrogel
It being placed in 30 DEG C~45 DEG C of constant temperature oscillation case, more preferably 35 DEG C~40 DEG C, the standing time is preferably 1 week~20 weeks,
More preferably 3 weeks~10 weeks, and degradation solution is replaced in different time；Gelatin degradation assay is studied using weight method.
Block copolymer provided by the invention includes the polyethylene glycol of Amino End Group or the polyethyleneglycol first of Amino End Group
The first block that ether is formed and the second block with formula (III) structure.First block of block copolymer of the present invention and
Second block all has the different degree of polymerization, furthermore, (γ-ethyl-L-glutamate poly- in block polymer provided by the invention
Ester) ratio of the second block that is formed is different, poly- (γ-ethyl-L-glutamate ester) the different block polymer of content is obtained, from
And the phase transition temperature of its adjustable temperature sensitive type water gel formed.Block polymer provided by the invention has a variety of tune
Section means have expanded temperature sensitive type hydrogel phase transformation row so that the controllability of the temperature sensitive type water gel formed is good
For regulating measure, be conducive to the type temperature-sensitive hydrogel and further apply.Meanwhile hydrogel material is in addition to containing paddy
Outside propylhomoserin ethyl ester segment, also passes through the introducing of glutamic acid, lysine, aspartic acid, increase carboxyl, amino isoreactivity function base
Group, these groups can be interacted by electrostatic interaction, coordination and the covalent bonding etc. between drug molecule, real
Now to the adjusting of the release behavior of water soluble drug, the burst release behavior of drug is reduced；This is conducive to realize by the gel carrier
To the adjustable sustained release of drug in vivo.Temperature sensitive type water gel provided by the invention has good biocompatibility
And biodegradability, degradation cycle are 3 weeks~15 weeks, are conducive to its further application as pharmaceutical carrier in vivo,
And the product that degradation obtains is amino acid, ethyl alcohol and polyethylene glycol, can be absorbed by organisms or by the body of metabolism discharge in vivo
Outside, substantially harmless to human body；Therefore, which has broad application prospects.
In order to further illustrate the present invention, with reference to embodiments to block copolymer provided by the invention, its preparation side
Method and temperature sensitive type water gel are described in detail.
Embodiment 1
By 3.0g, the poly glycol monomethyl ether for the Amino End Group that number-average molecular weight is 2000 and 100mL toluene at 130 DEG C
Azeotropic 2h is removed water, then the remaining toluene of decompressing and extracting；Obtained solid is dissolved in the dry N of 30mL, N- dimethyl formyl
In amine, the first solution is obtained；By the γ of 4.52g-ethyl-L-glutamate ester-N- carboxylic acid inner-acid anhydride and 0.59g γ-benzyl-L- paddy
Propylhomoserin ester-N- carboxylic acid inner-acid anhydride is dissolved in the dry n,N-Dimethylformamide of 60mL, obtains the second solution；In nitrogen atmosphere
In, first solution is mixed with the second solution, is stirred to react 72h under the conditions of room temperature, nitrogen protection；After reaction,
Then obtained solid is dissolved in chloroform, then is settled with ether by decompressing and extracting n,N-Dimethylformamide, filter,
After drying, poly glycol monomethyl ether-polyaminoacid ester block polymer is obtained.The polymer material 1 not being deprotected.It will be upper
It states resulting materials to be dissolved in the dichloroacetic acid of 50mL, 30 DEG C are completely dissolved material, and the HBr acetic acid that 20mL is then added is molten
Liquid, 30 DEG C are reacted 1 hour, which is added in ether and is settled, solid is obtained and is dissolved with DMF, and secondary heavy with ice ether
Drop, and be dried in vacuo；Crude product is dissolved with DMF, and distilled water is dialysed 3 days, and freeze-drying obtains the poly- γ-second of poly glycol monomethyl ether-
Base-Pidolidone ester-Pidolidone block copolymer.
Nuclear magnetic resonance spectroscopy is carried out to obtained block copolymer, as a result as shown in FIG. 1, FIG. 1 is the systems of the embodiment of the present invention 1
The hydrogen nuclear magnetic resonance spectrogram of standby obtained block copolymer；The result shows that polymer prepared by the embodiment of the present invention 1 includes 14
Pidolidone ethyl ester unit and 1.5 Pidolidone units, yield 87%.
Embodiment 2
By 3.0g, the poly glycol monomethyl ether for the Amino End Group that number-average molecular weight is 2000 and 100mL toluene at 130 DEG C
Azeotropic 2h is removed water, then the remaining toluene of decompressing and extracting；Obtained solid is dissolved in the dry N of 30mL, N- dimethyl formyl
In amine, the first solution is obtained；By the γ of 4.5g-ethyl-L-glutamate ester-N- carboxylic acid inner-acid anhydride and 1.18g γ-benzyl-L- paddy
Propylhomoserin ester-N- carboxylic acid inner-acid anhydride is dissolved in the dry n,N-Dimethylformamide of 60mL, obtains the second solution；In nitrogen atmosphere
In, first solution is mixed with the second solution, is stirred to react 72h under the conditions of room temperature, nitrogen protection；After reaction,
Then obtained solid is dissolved in chloroform, then is settled with ether by decompressing and extracting n,N-Dimethylformamide, filter,
After drying, poly glycol monomethyl ether-polyaminoacid ester block polymer is obtained.The polymer material 1 not being deprotected.It will be upper
It states resulting materials to be dissolved in the dichloroacetic acid of 55mL, 30 DEG C are completely dissolved material, and the HBr acetic acid that 15mL is then added is molten
Liquid, 30 DEG C are reacted 1 hour, which is added in ether and is settled, solid is obtained and is dissolved with DMF, and secondary heavy with ice ether
Drop, and be dried in vacuo；Crude product is dissolved with DMF, and distilled water is dialysed 3 days, and freeze-drying obtains the poly- γ-second of poly glycol monomethyl ether-
Base-Pidolidone ester-Pidolidone copolymer.
Nuclear magnetic resonance spectroscopy is carried out to obtained block copolymer, as a result as shown in Fig. 2, Fig. 2 is the system of the embodiment of the present invention 2
The hydrogen nuclear magnetic resonance spectrogram of standby obtained block copolymer；The result shows that polymer prepared by the embodiment of the present invention 2 includes 13
Pidolidone ethyl ester unit and 2.3 Pidolidone unit units, yield 85%.
Embodiment 3
By 3.0g, the poly glycol monomethyl ether for the Amino End Group that number-average molecular weight is 2000 and 100mL toluene at 130 DEG C
Azeotropic 2h is removed water, then the remaining toluene of decompressing and extracting；Obtained solid is dissolved in the dry N of 50mL, N- dimethyl formyl
In amine, the first solution is obtained；By the γ of 4.51g-ethyl-L-glutamate ester-N- carboxylic acid inner-acid anhydride and 2.37g γ-benzyl-L- paddy
Propylhomoserin ester-N- carboxylic acid inner-acid anhydride is dissolved in the dry n,N-Dimethylformamide of 80mL, obtains the second solution；In nitrogen atmosphere
In, first solution is mixed with the second solution, is stirred to react 72h under the conditions of room temperature, nitrogen protection；After reaction,
Then obtained solid is dissolved in chloroform, then is settled with ether by decompressing and extracting n,N-Dimethylformamide, filter,
After drying, poly glycol monomethyl ether-polyaminoacid ester block polymer is obtained.The polymer material 1 not being deprotected.It will be upper
It states resulting materials to be dissolved in the dichloroacetic acid of 60mL, 30 DEG C are completely dissolved material, and the HBr acetic acid that 18mL is then added is molten
Liquid, 30 DEG C are reacted 1.5 hours, which is added in ether and is settled, solid is obtained and is dissolved with DMF, and is secondary with ice ether
Sedimentation, and be dried in vacuo；Crude product is dissolved with DMF, and distilled water is dialysed 3 days, and freeze-drying obtains the poly- γ-second of poly glycol monomethyl ether-
Base-Pidolidone ester-Pidolidone copolymer.
Nuclear magnetic resonance spectroscopy is carried out to obtained block copolymer, as a result as shown in figure 3, Fig. 3 is the system of the embodiment of the present invention 3
The hydrogen nuclear magnetic resonance spectrogram of standby obtained block copolymer；The result shows that polymer prepared by the embodiment of the present invention 3 includes 13.8
A Pidolidone ethyl ester unit and 5.9 Pidolidone units, producing rate is 93%.
Embodiment 4
By 3.0g, polyethylene glycol and 100mL toluene the azeotropic 2h at 130 DEG C for the Amino End Group that number-average molecular weight is 1500
It removes water, then the remaining toluene of decompressing and extracting；Obtained solid is dissolved in the dry n,N-Dimethylformamide of 30mL, is obtained
To the first solution；By the γ of 6.05g-ethyl-L-glutamate ester-N- carboxylic acid inner-acid anhydride and 1.57g γ-benzyl-Pidolidone ester-
N- carboxylic acid inner-acid anhydride is dissolved in the dry n,N-Dimethylformamide of 70mL, obtains the second solution；In nitrogen atmosphere, by institute
It states the first solution to mix with the second solution, is stirred to react 72h under the conditions of room temperature, nitrogen protection；After reaction, decompressing and extracting
Then obtained solid is dissolved in chloroform, then is settled with ether by n,N-Dimethylformamide, filter, and after dry, obtains
To poly glycol monomethyl ether-polyaminoacid ester block polymer.The polymer material 1 not being deprotected.By above-mentioned gained material
Material is dissolved in the dichloroacetic acid of 60mL, and 30 DEG C are completely dissolved material, and the HBr acetum of 20mL is then added, and 30 DEG C anti-
It answers 1 hour, which is added in ether and is settled, obtain solid and dissolved with DMF, and with ice ether secondary settlement, and vacuum
It is dry；Crude product is dissolved with DMF, and distilled water is dialysed 3 days, and freeze-drying obtains polyethylene glycol γ-ethyl-L-glutamate ester-L-
Glutamic.
Nuclear magnetic resonance spectroscopy is carried out to obtained block copolymer, the results showed that, polymer prepared by the embodiment of the present invention 4
Include 13 Pidolidone ethyl ester units and 2.8 Pidolidone units, yield 88%.
Embodiment 5
By 3.0g, the poly glycol monomethyl ether for the Amino End Group that number-average molecular weight is 5000 and 100mL toluene at 130 DEG C
Azeotropic 3h is removed water, then the remaining toluene of decompressing and extracting；Obtained solid is dissolved in the dry N of 30mL, N- dimethyl formyl
In amine, the first solution is obtained；1.21g γ-benzyl-Pidolidone ester-N- carboxylic acid inner-acid anhydride is dissolved in the dry N, N- of 12mL
In dimethylformamide, the second solution is obtained；In nitrogen atmosphere, first solution is mixed with the second solution, room temperature,
It is stirred to react for 24 hours under the conditions of nitrogen protection；The γ of 4.50g-ethyl-L-glutamate ester-N- carboxylic acid inner-acid anhydride is dissolved in 45mL and done
In dry DMF, third solution is obtained, third solution is added in reaction under conditions of nitrogen protection, it is 48 small that the reaction was continued
When.After, then obtained solid is dissolved in chloroform by decompressing and extracting n,N-Dimethylformamide, then carried out with ether
Sedimentation filters, and after dry, obtains poly glycol monomethyl ether-polyaminoacid ester block polymer.The polymer not being deprotected
Material 1.Above-mentioned resulting materials are dissolved in the dichloroacetic acid of 60mL, 30 DEG C are completely dissolved material, are then added 18mL's
HBr acetum, 30 DEG C are reacted 1.2 hours, which is added in ether and is settled, solid is obtained and is dissolved with DMF, and use ice
Ether secondary settlement, and be dried in vacuo；Crude product is dissolved with DMF, and distilled water is dialysed 3 days, and freeze-drying obtains polyethyleneglycol first
The poly- γ of ether-- ethyl-L-glutamate ester-Pidolidone copolymer.
Nuclear magnetic resonance spectroscopy is carried out to obtained block copolymer, the results showed that, polymer prepared by the embodiment of the present invention 5
Include 20 Pidolidone ethyl ester units and 3.3 Pidolidone units, conversion ratio 86%.
Embodiment 6
By 3.0g, polyethylene glycol and 100mL the toluene azeotropic at 130 DEG C for the Amino End Group that number-average molecular weight is 1000
2.5h is removed water, then the remaining toluene of decompressing and extracting；Obtained solid is dissolved in the dry N,N-dimethylformamide of 30mL
In, obtain the first solution；5g γ-ethyl-L-glutamate ester-N- carboxylic acid inner-acid anhydride is dissolved in the dry N of 50mL, N- dimethyl
In formamide, the second solution is obtained；In nitrogen atmosphere, first solution is mixed with the second solution, is protected in room temperature, nitrogen
30h is stirred to react under the conditions of shield；γ-benzyl of 1.53g-Pidolidone ester-N- carboxylic acid inner-acid anhydride is dissolved in the dry DMF of 15mL
In, third solution is obtained, third solution is added to reaction under conditions of nitrogen protection, and the reaction was continued 72 hours.After,
Then obtained solid is dissolved in chloroform, then is settled with ether by decompressing and extracting n,N-Dimethylformamide, filter,
After drying, poly glycol monomethyl ether-polyaminoacid ester block polymer is obtained.The polymer material 1 not being deprotected.It will be upper
It states resulting materials to be dissolved in the dichloroacetic acid of 60mL, 30 DEG C are completely dissolved material, and the HBr acetic acid that 20mL is then added is molten
Liquid, 30 DEG C are reacted 1.2 hours, which is added in ether and is settled, solid is obtained and is dissolved with DMF, and is secondary with ice ether
Sedimentation, and be dried in vacuo；Crude product is dissolved with DMF, and distilled water is dialysed 3 days, and freeze-drying obtains polyethylene glycol γ-ethyl-L-
Glutamate-Pidolidone copolymer.
Nuclear magnetic resonance spectroscopy is carried out to obtained block copolymer, the results showed that, polymer prepared by embodiment 6 includes
7.7 Pidolidone ethyl ester units and 1.8 Pidolidone units, conversion ratio 92%.
Embodiment 7
By 3.0g, the poly glycol monomethyl ether for the Amino End Group that number-average molecular weight is 2000 and 100mL toluene at 130 DEG C
Azeotropic 3h is removed water, then the remaining toluene of decompressing and extracting；Obtained solid is dissolved in the dry N of 30mL, N- dimethyl formyl
In amine, the first solution is obtained；The γ of 4.55g-ethyl-L-glutamate ester-N- carboxylic acid inner-acid anhydride and 1.37g ε-benzyl-L- are relied
Propylhomoserin ester-N- carboxylic acid inner-acid anhydride is dissolved in the dry n,N-Dimethylformamide of 50mL, obtains the second solution；In nitrogen atmosphere
In, first solution is mixed with the second solution, is stirred to react 96h under the conditions of room temperature, nitrogen protection；After reaction,
Then obtained solid is dissolved in chloroform, then is settled with ether by decompressing and extracting n,N-Dimethylformamide, filter,
After drying, poly glycol monomethyl ether-polyaminoacid ester block polymer is obtained.The polymer material 1 not being deprotected.It will be upper
It states resulting materials to be dissolved in the dichloroacetic acid of 60mL, 30 DEG C are completely dissolved material, and the HBr acetic acid that 12mL is then added is molten
Liquid, 30 DEG C are reacted 1.2 hours, which is added in ether and is settled, solid is obtained and is dissolved with DMF, and is secondary with ice ether
Sedimentation, and be dried in vacuo；Crude product is dissolved with DMF, and distilled water is dialysed 3 days, and freeze-drying obtains the poly- γ-second of poly glycol monomethyl ether-
Base-Pidolidone ester-L-lysine copolymer.
Nuclear magnetic resonance spectroscopy is carried out to obtained block copolymer, the results showed that, polymer prepared by embodiment 7 includes
13.9 Pidolidone ethyl ester units and 2.5 lysine acid units, conversion ratio 91%.
Embodiment 8
By 3.0g, polyethylene glycol and 100mL the toluene azeotropic at 130 DEG C for the Amino End Group that number-average molecular weight is 10000
5h is removed water, then the remaining toluene of decompressing and extracting；Obtained solid is dissolved in the dry n,N-Dimethylformamide of 30mL,
Obtain the first solution；By the γ of 6.2g-ethyl-L-glutamate ester-N- carboxylic acid inner-acid anhydride and 1.81g β-benzyl-L-aspartate
Ester-N- carboxylic acid inner-acid anhydride is dissolved in the dry n,N-Dimethylformamide of 52mL, obtains the second solution；In nitrogen atmosphere,
First solution is mixed with the second solution, is stirred to react 120h under the conditions of 40 DEG C, nitrogen protection；After reaction, subtract
Pressure drains n,N-Dimethylformamide, and then obtained solid is dissolved in chloroform, then is settled with ether, filters, and does
After dry, poly glycol monomethyl ether-polyaminoacid ester block polymer is obtained.The polymer material 1 not being deprotected.It will be above-mentioned
Resulting materials are dissolved in the dichloroacetic acid of 60mL, and 30 DEG C are completely dissolved material, and the HBr acetum of 20mL is then added,
30 DEG C are reacted 1.2 hours, which is added in ether and is settled, solid is obtained and is dissolved with DMF, and secondary heavy with ice ether
Drop, and be dried in vacuo；Crude product is dissolved with DMF, and distilled water is dialysed 3 days, and freeze-drying obtains polyethylene glycol γ-ethyl-L- paddy
Propylhomoserin ester-L-Aspartic acid copolymer.
Nuclear magnetic resonance spectroscopy is carried out to obtained block copolymer, the results showed that, polymer prepared by embodiment 8 includes
90.5 Pidolidone ethyl ester units and 15.1 L-Aspartic acid units, conversion ratio 81%.
Embodiment 9
By 4.0g, polyethylene glycol and 100mL toluene the azeotropic 5h at 130 DEG C for the Amino End Group that number-average molecular weight is 400
It removes water, then the remaining toluene of decompressing and extracting；Obtained solid is dissolved in the dry n,N-Dimethylformamide of 40mL, is obtained
To the first solution；By the γ of 8.5g-ethyl-L-glutamate ester-N- carboxylic acid inner-acid anhydride and 2.3g β-benzyl-L-aspartate ester-
N- carboxylic acid inner-acid anhydride is dissolved in the dry n,N-Dimethylformamide of 65mL, obtains the second solution；In nitrogen atmosphere, by institute
It states the first solution to mix with the second solution, is stirred to react 72h under the conditions of 30 DEG C, nitrogen protection；After reaction, decompressing and extracting
Then obtained solid is dissolved in chloroform, then is settled with ether by n,N-Dimethylformamide, filter, and after dry, obtains
To poly glycol monomethyl ether-polyaminoacid ester block polymer.The polymer material 1 not being deprotected.By above-mentioned gained material
Material 1 is dissolved in the dichloroacetic acid of 60mL, and 30 DEG C are completely dissolved material, and the HBr acetum of 30mL is then added, and 30 DEG C anti-
It answers 1.2 hours, which is added in ether and is settled, obtain solid and dissolved with DMF, and with ice ether secondary settlement, and is true
Sky is dry；Crude product is dissolved with DMF, and distilled water is dialysed 3 days, and freeze-drying obtains polyethylene glycol γ-ethyl-L-glutamate ester-
L-Aspartic acid copolymer.
Nuclear magnetic resonance spectroscopy is carried out to obtained block copolymer, the results showed that, polymer prepared by embodiment 9 includes
3.9 Pidolidone ethyl ester units and 0.9 L-Aspartic acid unit, conversion ratio 94%.
Embodiment 10
By 5.0g, the poly glycol monomethyl ether for the Amino End Group that number-average molecular weight is 5000 and 100mL toluene at 130 DEG C
Azeotropic 5h is removed water, then the remaining toluene of decompressing and extracting；Obtained solid is dissolved in the dry N of 50mL, N- dimethyl formyl
In amine, the first solution is obtained；By the γ of 4.0g-ethyl-L-glutamate ester-N- carboxylic acid inner-acid anhydride and 4.7g β-benzyl-L- asparagus fern
Propylhomoserin ester-N- carboxylic acid inner-acid anhydride is dissolved in the dry n,N-Dimethylformamide of 100mL, obtains the second solution；In nitrogen atmosphere
In enclosing, first solution is mixed with the second solution, is stirred to react 48h under the conditions of 30 DEG C, nitrogen protection；Reaction terminates
Afterwards, then obtained solid is dissolved in chloroform, then is settled with ether by decompressing and extracting n,N-Dimethylformamide, take out
Filter obtains poly glycol monomethyl ether-polyaminoacid ester block polymer after dry.The polymer material 1 not being deprotected.
Above-mentioned resulting materials 1 are dissolved in the dichloroacetic acid of 100mL, 30 DEG C are completely dissolved material, and the HBr vinegar of 80mL is then added
Acid solution, 30 DEG C are reacted 1.1 hours, which is added in ether and is settled, solid is obtained and is dissolved with DMF, and with ice ether
Secondary settlement, and be dried in vacuo；Crude product is dissolved with DMF, and distilled water is dialysed 3 days, and it is poly- to obtain poly glycol monomethyl ether-for freeze-drying
γ-ethyl-L-glutamate ester-L-Aspartic acid copolymer.
Nuclear magnetic resonance spectroscopy is carried out to obtained block copolymer, the results showed that, polymer prepared by embodiment 10 includes
16.5 Pidolidone ethyl ester units and 17.1 L-Aspartic acid units, conversion ratio 83%.
Embodiment 11
It is molten that block polymer prepared by the embodiment of the present invention 1 is configured to the phosphoric acid buffer that mass concentration is 4%~20%
Liquid observes its viscosity change at 5 DEG C~60 DEG C using tubule anastrophe, and it is solidifying that flowing does not occur when being inverted with tubule, in 30s
Gelatinization judgment criteria.10min is balanced at each temperature, heating rate is 2 DEG C/min.
As a result referring to fig. 4, Fig. 4 is that the block polymer solution for the various concentration that the embodiment of the present invention 1 obtains becomes with temperature
The phasor of change.As shown in Figure 4, the solution of the block polymer can form hydrogel when the temperature rises；The block polymer
Solution is 10 DEG C~40 DEG C by the temperature that solution forms hydrogel, therefore may be used as injection-type hydrogel, as pharmaceutical carrier
Or timbering material application.
Embodiment 12
It is molten that block polymer prepared by the embodiment of the present invention 2 is configured to the phosphoric acid buffer that mass concentration is 4%~20%
Liquid observes its viscosity change at 5 DEG C~60 DEG C using tubule anastrophe, and it is solidifying that flowing does not occur when being inverted with tubule, in 30s
Gelatinization judgment criteria.10min is balanced at each temperature, heating rate is 2 DEG C/min.
It as a result is that the block polymer solution for the various concentration that the embodiment of the present invention 2 obtains becomes with temperature referring to Fig. 5, Fig. 5
The phasor of change.As shown in Figure 5, the solution of the block polymer can form hydrogel when the temperature rises；The block polymer
Solution is 5 DEG C~35 DEG C by the temperature that solution forms hydrogel, therefore may be used as injection-type hydrogel, as pharmaceutical carrier or
Timbering material application.
Embodiment 13
It is molten that block polymer prepared by the embodiment of the present invention 2 is configured to the phosphoric acid buffer that mass concentration is 4%~20%
Liquid.And the polymer solution of 500 microlitres of various concentrations is taken to be placed in the vial of diameter 1cm, it is placed in 37 DEG C of water-baths
30min makes solution gels；3mLPBS (pH 7.4) is added later, and the outer degradation experiment of gelinite is carried out by weight method
Research.
Fig. 6 is the result of study figure of the outer degradation experiment of gelinite of the embodiment of the present invention 13；It will be appreciated from fig. 6 that gel rubber material
Can degrade at any time in PBS, as polymer concentration be 6% gel, at 28 days, degradation 50% or so.Meanwhile material
Degradation time can be adjusted by material concentration, such as: material concentration be 8% gel rubber material exist in 28 days degradation amounts
10% or so, degradation rate is significantly lower than 6% experimental group.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (9)
1. a kind of block copolymer, comprising the first block with formula (I) or formula (II) structure and have the of formula (III) structure
Diblock:
Wherein, the R is independent is selected from-CH2COOH、-(CH2)2COOH、-(CH2)4NH2；
M, n, x, y are the degree of polymerization, 5≤m≤227,5≤n≤226,1≤x≤200,1≤y≤100；
The weight percent that second block accounts for the block copolymer is 30%~70%.
2. a kind of preparation method of block copolymer, comprising the following steps:
The polyethylene glycol of the poly glycol monomethyl ether of Amino End Group with IV structure of formula or the Amino End Group with V structure of formula,
Occur with VI structure γ of formula-didodecyl l glutamic acid ethyl ester-N- carboxylic acid inner-acid anhydride and amino acid derivativges-N- carboxylic acid inner-acid anhydride poly-
Reaction is closed, deprotection obtains block polymer；
Wherein, m is the degree of polymerization, 5≤m≤227；
N is the degree of polymerization, 5≤n≤226.
3. preparation method according to claim 2, which is characterized in that the amino acid derivativges-N- carboxylic acid inner-acid anhydride choosing
From one of formula VII, formula VIII and formula Ⅸ；
4. preparation method according to claim 2, which is characterized in that the Amino End Group with formula (IV) structure gathers
γ-didodecyl l glutamic acid second of the polyethylene glycol and VI structure of formula of glycol monoethyl ether or the Amino End Group with formula (V) structure
The molar ratio of ester-N- carboxylic acid inner-acid anhydride is 1:(5~150).
5. preparation method according to claim 2, which is characterized in that VI structure γ of the formula-didodecyl l glutamic acid second
It is 1:(0.01~10 that ester-N- carboxylic acid inner-acid anhydride, which polymerize molar ratio with amino acid derivativges-N- carboxylic acid inner-acid anhydride).
6. preparation method according to claim 2, which is characterized in that the polymeric reaction temperature is 20 DEG C~50 DEG C；Institute
Stating polymerization reaction time is for 24 hours~96h.
7. a kind of temperature sensitive type water gel includes block copolymer described in claim 1~6 any one and solvent.
8. temperature sensitive type water gel according to claim 7, which is characterized in that the solvent is water, physiological saline, delays
Rush solution, tissue culture medium or body fluid.
9. temperature sensitive type water gel according to claim 7, which is characterized in that the mass fraction of the block copolymer
It is 1%~50%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710053711.9A CN106674516B (en) | 2017-01-22 | 2017-01-22 | Amino acid block copolymer, preparation method and temperature sensitive type water gel |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710053711.9A CN106674516B (en) | 2017-01-22 | 2017-01-22 | Amino acid block copolymer, preparation method and temperature sensitive type water gel |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106674516A CN106674516A (en) | 2017-05-17 |
| CN106674516B true CN106674516B (en) | 2019-03-08 |
Family
ID=58859828
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710053711.9A Active CN106674516B (en) | 2017-01-22 | 2017-01-22 | Amino acid block copolymer, preparation method and temperature sensitive type water gel |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106674516B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112029092B (en) * | 2020-09-08 | 2021-08-17 | 中国科学院长春应用化学研究所 | Cinnamic aldehyde modified polyethylene glycol-polyamino acid block copolymer, preparation method thereof and hydrogel |
| CN112341621A (en) * | 2020-11-05 | 2021-02-09 | 中国科学院长春应用化学研究所 | Polyethylene glycol-polyamino acid block copolymer, preparation method thereof and temperature-sensitive hydrogel |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102408561B (en) * | 2011-11-14 | 2013-03-27 | 中国科学院长春应用化学研究所 | Segmented copolymer and preparation method thereof, and temperature sensitive type hydrogel |
| CN102977362B (en) * | 2012-11-28 | 2015-01-21 | 中国科学院长春应用化学研究所 | Poly-amino acid block copolymer, preparation method thereof and temperature-sensitive hydrogel |
| CN105418916B (en) * | 2016-01-11 | 2018-04-10 | 中国科学院长春应用化学研究所 | Block copolymer, its preparation method and hydrogel and preparation method thereof |
-
2017
- 2017-01-22 CN CN201710053711.9A patent/CN106674516B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN106674516A (en) | 2017-05-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102408561B (en) | Segmented copolymer and preparation method thereof, and temperature sensitive type hydrogel | |
| Yang et al. | Penicillin V-conjugated PEG-PAMAM star polymers | |
| CN104892871B (en) | A kind of hydrogel with self-repair function and preparation method thereof | |
| CN104829830B (en) | A kind of methionine block copolymer, its preparation method and hydrogel | |
| CN102977362B (en) | Poly-amino acid block copolymer, preparation method thereof and temperature-sensitive hydrogel | |
| US10039837B2 (en) | Multi-arm polyethylene glycol-azido derivative | |
| CN106674516B (en) | Amino acid block copolymer, preparation method and temperature sensitive type water gel | |
| CN106589355B (en) | Non-viral gene transfection carrier material of the one kind based on cationic helical polypeptide | |
| CN102186507A (en) | Biodegradable proline-based polymers | |
| CN103755955B (en) | A kind of Cationic polyamino acid group carrier material and preparation method thereof | |
| CN107556497B (en) | A kind of preparation method and application of hybridized hydrogel material | |
| CN109880021B (en) | Polymer and preparation method thereof, ROS response type siRNA nano micelle and application thereof | |
| CN103772712B (en) | The preparation method of a kind of poly-peptide and polytetrahydrofuran multipolymer | |
| CN102167818A (en) | Poly(gamma-propynyl-L-glutamate) block copolymer and preparation method and hydrogel thereof | |
| CN109824890A (en) | Polyaminoacid, preparation method and application | |
| CN106700528B (en) | Supermolecule assembly and preparation and shape regulation and control method thereof | |
| CN105418916B (en) | Block copolymer, its preparation method and hydrogel and preparation method thereof | |
| CN103804685A (en) | Polyethylene glycol-polysarcosine double hydrophilic block copolymer and synthesis method thereof | |
| CN101357990B (en) | Tadpole polymer with controllable molecular weight and good biocompatibility and preparation method thereof | |
| CN105820332B (en) | A kind of star polyaminoacid and star polyaminoacid medicament-carried nano micelle and preparation method | |
| Abtew et al. | Glycopeptides derived from glucosaminic acid | |
| CN108558705B (en) | Aryl carbamate monomer containing phenolic hydroxyl amino acid, preparation method and application | |
| CN111072954A (en) | Polytetrahydrofuran-polyamino acid block copolymer and synthetic method thereof | |
| CN106083634B (en) | A kind of peptide amphiphile molecule and its preparation method and application | |
| CN110713596A (en) | PH-reduction dual-response polymer embolic agent for tumor ductless embolization and synthesis thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |