CN106117547B - Using beta-cyclodextrin as the multi-arm polyglutamic acid of core, its injection aquagel and preparation method thereof - Google Patents
Using beta-cyclodextrin as the multi-arm polyglutamic acid of core, its injection aquagel and preparation method thereof Download PDFInfo
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- 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
- C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
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- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
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- C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
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- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
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- C08L77/00—Compositions of polyamides obtained by reactions forming a carboxylic amide link in the main chain; Compositions of derivatives of such polymers
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- C08L2205/00—Polymer mixtures characterised by other features
- C08L2205/02—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group
- C08L2205/025—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group containing two or more polymers of the same hierarchy C08L, and differing only in parameters such as density, comonomer content, molecular weight, structure
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- C08L2312/00—Crosslinking
Abstract
The present invention relates to a kind of using beta-cyclodextrin as the multi-arm polyglutamic acid of core, injectable hydrogel and preparation method thereof.The beta-cyclodextrin for synthesizing polyamino first introduces multiple graft reactions and causes site, and then causes Pidolidone-N- carboxylic acid anhydrides ring-opening polymerisation, and to multi-arm L-glutamic acid, it carries out aldehyde grouping modified the first component using as hydrogel.Two components are mixed in a certain proportion by L-glutamic acid amination modified simultaneously as the second component, are crosslinked to obtain glutamic acid based aquagel by schiff base reaction, gelation time is 20 ~ 400s.The characteristics of hydrogel, is there is good biocompatibility and biological degradability, can adapt to different shapes.In addition the introducing of beta-cyclodextrin can increase crosslinking points, be conducive to the mechanical strength for improving hydrogel, and can be loaded and be controlled release to dewatering medicament.Therefore the hydrogel has broad application prospects in the fields such as organizational project and regenerative medicine, medicine controlled releasing.
Description
Technical field
The present invention relates to a kind of polyglutamic acids with multi-arm structure, injectable hydrogel and preparation method thereof, especially
It is a kind of using beta-cyclodextrin as the multi-arm polyglutamic acid of core, injectable hydrogel and preparation method thereof.
Background technique
Hydrogel is made of tridimensional network macromolecule and the hydrone being included in, by chemically or physically
Cross-linked gel is formed, and has good biocompatibility, degradability.Wherein injection aquagel is obtained in field of tissue engineering technology
Extensive concern, injection aquagel can be used for the control release of bioactive molecule, embedding cell and as tissue branch
Frame material etc..Injection aquagel defect and in-situ solidifying molding in obturator by way of injection, can avoid surgical operation
Height wound, have the advantages that healing acceleration, reduce patient pain, reduce medical expense.Injection aquagel is because having certainly
Adaptability and tissue repair especially suitable for complicated defect shape；The drug not easy in inactivation of injection aquagel load simultaneously,
The effect that can reach and reduce administration number of times, extend the drug effect period, has good application prospect in medicine controlled releasing field.
L-glutamic acid is a kind of polyaminoacid with good biocompatibility, however poly-L-glutamic acid acid hydrogel is because of it
Hydrophily and be difficult to payload hydrophobic drug.And beta-cyclodextrin possesses hydrophobic cavity characteristic that be widely used in it hydrophobic
The load of drug.
Summary of the invention
One of the objects of the present invention is to provide a kind of using beta-cyclodextrin as the multi-arm polyglutamic acid of core.
The second object of the present invention is to use the aldehyde radical multi-arm polyglutamic acid for the first component, with amination polyglutamic
Acid is used as the second component, obtains injection aquagel by schiff base reaction.
The third object of the present invention is to provide the preparation method of the hydrogel.
In order to achieve the above objectives, the invention adopts the following technical scheme:
It is a kind of using beta-cyclodextrin as the multi-arm polyglutamic acid of core, it is characterised in that the multi-arm polyglutamic acid is by polyamino
Beta-cyclodextrin as initiator, cause Pidolidone-N- carboxylic acid anhydrides ring-opening polymerisation and form graft copolymer obtained from arm,
The number of middle arm is 3 ~ 5；The structural formula of the arm are as follows:
, 10≤n≤40.
A kind of hydrogel of injectable is made after aldehyde radical using above-mentioned by the multi-arm polyglutamic acid of core of beta-cyclodextrin
For the first component, using amination L-glutamic acid as the second component, it is characterised in that the hydrogel is the first component and second
Component is cross-linked to form the macromolecule hydrogel with three-dimensional crosslinking structure by schiff base reaction, and solid content is 1~10%；Institute
The ratio of the total mole number of the aldehyde radical of the total mole number of the amino for the second component stated and the first component are as follows: 1:1 ~ 3.
A method of preparing above-mentioned injection aquagel, it is characterised in that the specific steps of this method:
A. by beta-cyclodextrin and N', N- carbonyl dimidazoles are dissolved in dimethyl sulfoxide DMSO by the molar ratio of 1:8 ~ 15
In, it stirs 24 ~ 36 hours, is poured into ethyl alcohol under the conditions of room temperature and inert gas shielding, stirring is filtered to white solid is generated
After dry, the powder after drying is dissolved in a small amount of deionized water, and be freeze-dried to obtain polyamino after for 24 hours ~ 48h that dialyses
Change beta-cyclodextrin；
B. by polyamino beta-cyclodextrin, Pidolidone-N- carboxylic acid anhydrides obtained by step a with the molar ratio of 1:20 ~ 160
It is scattered in DMSO, 1 ~ 10mlDMSO is added according to every gram of Pidolidone-N- carboxylic acid anhydrides in dispersion concentration；It is stirred at 15~35 DEG C
Mix 48~72h of reaction, system becomes milky and sticky；Reaction solution is poured into dehydrated alcohol and is stirred, there is White Flocculus analysis
Out；Then filtering is washed with dehydrated alcohol, is dry, obtain the multi-arm poly benzyl glutamate using beta-cyclodextrin as core；
C. anhydrous methylene chloride is dissolved in by the multi-arm poly benzyl glutamate of core of beta-cyclodextrin by step b is resulting, prepare
The solution for being 0.01 ~ 0.05g/ml at concentration, is then added deprotection agent, every 0.5~1.0 g is using beta-cyclodextrin as the multi-arm of core
0.3~0.5mL deprotection agent is added in poly-L-glutamic acid acid benzyl ester；It is anti-under the conditions of being protected from light under inert gas protection in 35~40 DEG C
12~20h is answered, reaction solution is poured into petroleum ether and is settled, obtains white solid through suction filtration, petroleum ether, vacuum drying, i.e.,
For using beta-cyclodextrin as the multi-arm polyglutamic acid of core；
D. by step c it is resulting using beta-cyclodextrin as the multi-arm polyglutamic acid and amino-propanediol of core by 0.1g:(0.1 ~
0.5) mass volume ratio of mL is configured to aqueous solution, adds activator I-hydroxybenzotriazole HOBT or N- hydroxysuccinimidyl
Acid imide NHS, to activate the carboxyl on polyglutamic acid segment；Reaction 5~pass through the small molecule of deionized water dialysis removing afterwards for 24 hours
Impurity takes out the product that will be obtained after freeze-drying；It is described using beta-cyclodextrin as the polyglutamic on arm in the multi-arm polyglutamic acid of core
The ratio of the molal quantity of the molal quantity and activator of the constitutional repeating unit of acid is 1:1 ~ 5；
E. step d products therefrom is dissolved in deionized water, oxidant is added at room temperature, the molal quantity of oxidant is
The 10 ~ 20% of the carboxyl molal quantity being modified in step d, react 5 ~ 10min after dialyse again, be lyophilized after obtain required first
Component, i.e., after aldehyde radical using beta-cyclodextrin as the multi-arm polyglutamic acid of core；
F. L-glutamic acid is soluble in water, carbodiimide activating agent stirring and dissolving, the L-glutamic acid weight is added
The ratio of the molal quantity of the molal quantity and carbodiimide activating agent of complex structure unit is 1:1 ~ 5, to activate on polyglutamic acid segment
Carboxyl；Addition aminating agent reaction 5~for 24 hours；The small molecular weight impurity removed again by deionized water dialysis obtains institute after taking out freeze-drying
The second component needed；The molar ratio of the carbodiimide activating agent and L-glutamic acid constitutional repeating unit number is 1~3:1；
The aminating agent be hexamethylene diamine, ethylenediamine, p-phenylenediamine, adipic dihydrazide, maleic hydrazide or sebacic dihydrazide,
The ratio of the molal quantity of the molal quantity and L-glutamic acid structural unit of aminating agent is 3~10:1；
G. by the multi-arm polyglutamic acid of aldehyde radical obtained by step e and the amidized poly- L- paddy of resulting second component of step f
Propylhomoserin is configured to aqueous solution respectively, and the concentration of solution is 1 ~ 10wt%, is cross-linked in situ after the mixing of two components by schiff base reaction
To injection aquagel；
Above-mentioned deprotection agent are as follows: Iodotrimethylsilane, trim,ethylchlorosilane, bromotrimethylsilane it is any.
Above-mentioned oxidant is sodium metaperiodate, potassium bichromate or hydrogen peroxide.
Hydrogel of the invention has good biocompatibility and biological degradability, can adapt to different shapes.Separately
The introducing of outer beta-cyclodextrin can increase crosslinking points, be conducive to improve hydrogel mechanical strength, and can to dewatering medicament into
Row load and control release.Therefore the hydrogel has wide application in the fields such as organizational project and regenerative medicine, medicine controlled releasing
Prospect.
Specific embodiment
Below with reference to example, the present invention will be described in detail.
Embodiment one:
1. taking a dry round-bottomed flask (100mL), DMSO(20mL is added) and beta-cyclodextrin (0.88 mmoL), stirring
After completely dissolution be added CDI (7.04mmoL), under inert gas protection react 12 ~ for 24 hours, then be added ethylenediamine (2.4mL)
And the reaction was continued 12 ~ for 24 hours, reaction solution is poured into after excessive dehydrated alcohol, a large amount of whiteness is precipitated, product is crossed and is filtered dry
It is dissolved in deionized water after dry, freeze-drying can obtain the white product of about 0.5g, as polyamino β-after deionized water dialysis
Cyclodextrin, structural formula are as follows:
The wherein structural formula of R are as follows:
。
2. being put into polyamino beta-cyclodextrin (0.5g) in an anhydrous round-bottomed flask (100mL), anhydrous DMSO is added
(125mL) is added Pidolidone-N- carboxylic acid anhydrides (3.2g) after dissolution, vacuumizes logical nitrogen, and reaction 72h is stirred at room temperature.?
Under glass bar stirring, this reaction solution is poured into dehydrated alcohol (500mL), there are a large amount of white flock substances to be precipitated.Filter and
The product obtained after vacuum drying is using beta-cyclodextrin as the multi-arm poly benzyl glutamate of core, structural formula are as follows:
The wherein structural formula of R are as follows:
, 10≤n≤40.
3. sloughing the benzyl of poly-L-glutamic acid acid benzyl ester using Iodotrimethylsilane prepares L-glutamic acid: at room temperature, take with
Beta-cyclodextrin is that 0.5 gram of multi-arm poly benzyl glutamate of core is dissolved in anhydrous methylene chloride, adds Iodotrimethylsilane
The ratio of (25mL) is added, 10 ~ 12h of reaction in 35 ~ 40 DEG C of heat collecting type blenders, after natural cooling, is added in petroleum ether
Sedimentation is filtered and is washed respectively three times with petroleum ether and distilled water repeatedly, and vacuum drying for 24 hours, obtains white chunks substance, as
Using beta-cyclodextrin as the multi-arm L-glutamic acid of core, average molecular weight is about 6600 dalton；Its structural formula are as follows:
The wherein structural formula of R are as follows:
, 10≤n≤40.
The test method of its average molecular weight uses viscosimetry, detailed process are as follows: prepares NaCl and NaH2PO4Mixing it is molten
Liquid.NaCl and NaH2PO4Concentration be respectively 0.4mol/L and 0.01mol/L.It is by solvent compound concentration of above-mentioned mixed solution
The weak solution of the multi-arm L-glutamic acid of 1mg/mL.Experimental temperature is 25 DEG C, pH=6.8, and molecular weight calculation formula is [η]=2.93
×10-5M0.923。
3. pouring into deionized water (20mL) by using beta-cyclodextrin as the multi-arm L-glutamic acid (0.1g) of core and hydrogen being added dropwise
Sodium hydroxide solution (3M) obtains its aqueous solution, and 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride is added
(0.42g), I-hydroxybenzotriazole (0.18g) react 12 hours with amino-propanediol (0.1mL), dialysis freeze-drying, obtained production
Object is dissolved in deionized water (20mL), is added after sodium metaperiodate (0.15g) is protected from light oxidation 5min and ethylene glycol (2 μ L) is added, anti-
Reaction solution is dialysed after answering 12h and is lyophilized to obtain the multi-arm L-glutamic acid of aldehyde radical；Its structural formula are as follows:
The wherein structural formula of R are as follows:
, 10≤n+m≤40.
4. weigh 0.1g L-glutamic acid, pours into deionized water (20mL) and sodium hydroxide solution (3M) is added dropwise and obtain it
1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (0.42g), I-hydroxybenzotriazole is added in aqueous solution
(0.18g) and adipyl dihydrazide (0.4g) takes out dialysis freeze-drying and obtains amination L-glutamic acid.
5. the multi-arm polyglutamic acid of aldehyde radical and amination L-glutamic acid to be configured to the solution of 6wt% respectively, bodies are waited
Product mixing, obtains hydrogel, gelation time 75s, which is that the solidification of self-control liquid is not being flowed after two components mix
The required time.Storage modulus be 78Pa(rotational rheometer, 37 DEG C, shear strain: 1%, angular frequency range: 0.1 ~
500rad-1).
Embodiment two:
The preparation of the multi-arm L-glutamic acid of the aldehyde radical of the present embodiment is basically the same as the first embodiment, except that:
In step 2, polyamino beta-cyclodextrin (1.0g) is added, is added DMSO (125mL), Pidolidone-N- carboxylic acid is added after dissolution
Acid anhydride (3.2g).Finally obtained multi-arm L-glutamic acid, average molecular weight are about 2200 dalton.Other reagent dosages and operation
Condition is constant.The injection aquagel finally obtained, gelation time 81s, storage modulus 81Pa.
Embodiment three:
The preparation of the multi-arm L-glutamic acid of the aldehyde radical of the present embodiment is basically the same as the first embodiment, except that:
In step 2, polyamino beta-cyclodextrin (0.25g) is added, is added DMSO (125mL), Pidolidone-N- carboxylic acid is added after dissolution
Acid anhydride (3.2g).Finally obtained multi-arm L-glutamic acid, average molecular weight are about 11000 dalton.Other reagent dosages and behaviour
It is constant to make condition.The injection aquagel finally obtained, gelation time 86s, storage modulus 196Pa.
Example IV:
The present embodiment and embodiment two are essentially identical, except that: it in steps of 5, respectively will the modified poly- L- paddy of multi-arm
Propylhomoserin and modified L-glutamic acid are configured to the solution of 7wt%, isometric to mix, and obtain hydrogel, gelation time 88s, energy storage mould
Amount is 446Pa.
Embodiment five:
The present embodiment and embodiment two are essentially identical, except that: it in steps of 5, respectively will the modified poly- L- paddy of multi-arm
Propylhomoserin and modified L-glutamic acid are configured to the solution of 8wt%, isometric to mix, and obtain hydrogel, gelation time 73s, energy storage mould
Amount is 576Pa.
Embodiment two, embodiment three will provide the preparation process of the different multi-arm polyglutamic acid micella of arm number respectively, and give
Out using beta-cyclodextrin as the characterization parameter of the multi-arm polyglutamic acid of core.Not change the poly- L- paddy of multi-arm in embodiment 2 and embodiment 3
The arm number of propylhomoserin but change the number of repeat unit on brachium, that is, arm, this regulation is only needed by adjusting polyamino ring
The molar ratio of dextrin and Pidolidone-N- carboxylic acid anhydrides can realize that other experimental procedures are constant.
Viscosimetry, detailed process are used by the test method of the multi-arm polyglutamic acid average molecular weight of core of beta-cyclodextrin
Are as follows: prepare NaCl and NaH2PO4Mixed solution.NaCl and NaH2PO4Concentration be respectively 0.4mol/L and 0.01mol/L.With
Above-mentioned mixed solution is the weak solution for the multi-arm L-glutamic acid that solvent compound concentration is 1mg/mL.Experimental temperature is 25 DEG C, pH=
6.8, molecular weight calculation formula is [η]=2.93 × 10-5M0.923。
Claims (4)
1. a kind of hydrogel of injectable, after aldehyde radical using beta-cyclodextrin be the multi-arm L-glutamic acid of core as first
Component, using amidized L-glutamic acid as the second component, which is characterized in that the hydrogel is the first component and the second component
It is cross-linked to form the macromolecule hydrogel with three-dimensional crosslinking structure by schiff base reaction, solid content is 1~10%；Described
The ratio of the total mole number of the total mole number of the amino of second component and the aldehyde radical of the first component are as follows: 1:1~3；
The amidized L-glutamic acid is the beta-cyclodextrin by polyamino as initiator, causes Pidolidone-N- carboxylic
Acid anhydrides ring-opening polymerisation forms graft copolymer obtained from arm, and wherein the number of arm is 3~5；The structural formula of the arm are as follows:
After aldehyde radical using beta-cyclodextrin as the structural formula of the arm of the multi-arm L-glutamic acid of core are as follows:
2. a kind of method for the hydrogel for preparing injectable according to claim 1, it is characterised in that the tool of this method
Body step:
A. by beta-cyclodextrin and N', N- carbonyl dimidazoles are dissolved in dimethyl sulfoxide DMSO by the molar ratio of 1:8~15, in room
It is stirred 24~36 hours under the conditions of temperature and inert gas shielding, ethylenediamine, stirring to generation white solid, after filtering is then added
It is dry, the powder after drying is dissolved in a small amount of deionized water, and be freeze-dried to obtain polyamino after for 24 hours~48h that dialyses
The beta-cyclodextrin of change；
B. by the beta-cyclodextrin of polyamino obtained by step a, Pidolidone benzyl ester-N- carboxylic acid anhydrides with the molar ratio of 1:20~160
It is scattered in DMSO, 1~10mL DMSO is added according to every gram of Pidolidone benzyl ester-N- carboxylic acid anhydrides in dispersion concentration；At 15~35 DEG C
Under be stirred to react 48~72h, system becomes milky and sticky；Reaction solution is poured into dehydrated alcohol and is stirred, there is white flock
Object is precipitated；Then filtering is washed with dehydrated alcohol, is dry, obtain the multi-arm poly-L-glutamic acid acid benzyl ester using beta-cyclodextrin as core；
C. anhydrous methylene chloride is dissolved in by the multi-arm poly-L-glutamic acid acid benzyl ester of core of beta-cyclodextrin by step b is resulting, be configured to
Concentration is the solution of 0.01~0.05g/mL, and deprotection agent is then added, and every 0.5~1.0g is poly- by the multi-arm of core of beta-cyclodextrin
0.3~0.5mL deprotection agent is added in Pidolidone benzyl ester；12 are reacted under the conditions of being protected from light under inert gas protection in 35~40 DEG C
~20h, reaction solution is poured into petroleum ether and is settled, and obtains white solid through suction filtration, petroleum ether, vacuum drying, as with
Beta-cyclodextrin is the multi-arm L-glutamic acid of core；
D. by step c it is resulting using beta-cyclodextrin as the multi-arm L-glutamic acid and amino-propanediol of core by 0.1g:(0.1~
0.5) mass volume ratio of mL is configured to aqueous solution, adds activator I-hydroxybenzotriazole HOBT or N- hydroxysuccinimidyl acyl
Imines NHS, to activate the carboxyl on multi-arm L-glutamic acid segment；Reaction 5~remove small point by deionized water dialysis afterwards for 24 hours
Sub- impurity obtains product after taking out freeze-drying；Described is poly- as the multi-arm on arm in the multi-arm L-glutamic acid of core using beta-cyclodextrin
The ratio of the molal quantity of the molal quantity and activator of the constitutional repeating unit of Pidolidone is 1:1~5；
E. step d products therefrom is dissolved in deionized water, oxidant is added at room temperature, the molal quantity of oxidant is step d
In be modified the 10~20% of carboxyl molal quantity, react dialysed after 5~10min again, be lyophilized after obtain required first group
Point, i.e., after aldehyde radical using beta-cyclodextrin as the multi-arm L-glutamic acid of core；
F. L-glutamic acid is soluble in water, carbodiimide activating agent stirring and dissolving is added, the L-glutamic acid repeats to tie
The ratio of the molal quantity of the molal quantity and carbodiimide activating agent of structure unit is 1:1~5, to activate the carboxylic on L-glutamic acid segment
Base；Addition aminating agent reaction 5~for 24 hours；Small molecular weight impurity is removed by deionized water dialysis again, is obtained after taking-up freeze-drying required
Second component；The molar ratio of the carbodiimide activating agent and L-glutamic acid constitutional repeating unit number is 1~3:1；It is described
Aminating agent be hexamethylene diamine, ethylenediamine, p-phenylenediamine, adipic dihydrazide, maleic hydrazide or sebacic dihydrazide, ammonification
The ratio of the molal quantity of the molal quantity and L-glutamic acid structural unit of agent is 3~10:1；
G. by aldehyde radical obtained by step e using beta-cyclodextrin as the multi-arm L-glutamic acid of core and resulting second component of step f
Amidized L-glutamic acid is configured to aqueous solution respectively, and the concentration of solution is 1~10wt%, passes through Schiff after the mixing of two components
Alkali reaction is cross-linked in situ to obtain injection aquagel.
3. according to the method described in claim 2, it is characterized in that the deprotection agent are as follows: Iodotrimethylsilane, trimethyl
Chlorosilane, bromotrimethylsilane it is any.
4. according to the method described in claim 2, it is characterized in that the oxidant is sodium metaperiodate, potassium bichromate or dioxygen
Water.
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| CN110283321B (en) * | 2019-06-20 | 2021-05-04 | 常州大学 | Preparation method of polymer capable of forming self-pore structure |
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| JP4104556B2 (en) * | 2002-03-06 | 2008-06-18 | 伸彦 由井 | Tissue regeneration substrate, transplantation material, and production method thereof |
| CN103146002A (en) * | 2013-03-04 | 2013-06-12 | 上海大学 | Injectable polyglutamic acid chemical crosslinking hydrogel and preparation method thereof |
| CN105482104A (en) * | 2016-01-14 | 2016-04-13 | 上海大学 | Star-shaped polyglutamic acid as well as injectable hydrogel and preparation method thereof |
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