CN107417801A - A kind of injection aquagel and preparation method and application - Google Patents

A kind of injection aquagel and preparation method and application Download PDF

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Publication number
CN107417801A
CN107417801A CN201710467784.2A CN201710467784A CN107417801A CN 107417801 A CN107417801 A CN 107417801A CN 201710467784 A CN201710467784 A CN 201710467784A CN 107417801 A CN107417801 A CN 107417801A
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xanthans
injection aquagel
hydroformylation
preparation
carboxymethyl chitosan
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CN107417801B (en
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任建安
黄金健
吴秀文
陈国璞
王革非
顾国胜
黎介寿
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Nanjing General Hospital of Nanjing Command PLA
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Nanjing General Hospital of Nanjing Command PLA
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Priority to PCT/CN2017/096207 priority patent/WO2018232856A1/en
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • 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
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0033—Xanthan, i.e. D-glucose, D-mannose and D-glucuronic acid units, saubstituted with acetate and pyruvate, with a main chain of (beta-1,4)-D-glucose units; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/042—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/145—Hydrogels or hydrocolloids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0003—General processes for their isolation or fractionation, e.g. purification or extraction from biomass
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • 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
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
    • C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • 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
    • C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
    • 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
    • C08J2405/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00
    • C08J2405/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

The present invention discloses a kind of injection aquagel and preparation method and application, and the preparation method includes step：10~20g chitosans are suspended in 50~100ml isopropanols, add 20~40ml, 5~15mol/L NaOH aqueous solution and stir 20~40min at room temperature, then 20~30g chloroacetic acids are added dropwise, after being heated to 55~65 DEG C of 2~4h of stirring, filtration washing is dried, and obtains carboxymethyl chitosan；By the mol ratio 1 of xanthans and sodium metaperiodate:1~3 is added drop-wise to the sodium metaperiodate aqueous solution in xanthan gum solution, 2~4h of stirring reaction in darkroom, adds ethylene glycol and stirs 1~2h, dialysis purification reaction solution, obtains hydroformylation xanthans；By hydroformylation xanthans and carboxymethyl chitosan reaction generation injection aquagel.The injection aquagel that the present invention by using natural polysaccharide synthesize after modified with functional group, safe and non-toxic, cost is cheap, and resistance to enzymolysis ability is notable.

Description

A kind of injection aquagel and preparation method and application
Technical field
The present invention relates to injection aquagel field, more particularly to a kind of injection aquagel and preparation method thereof is with answering With.
Background technology
In clinical position, the Occlusion therapy of intestinal fistula is carried out usually using the pig source property Fibrin Glue of commercialization so that A part of patients with intestinal fistula can recover the continuity of enteron aisle by expectant treatment, avoid intestinal fistula operative treatment.It is but this Fibrin Glue due to its from biology and price is high, in addition, the resistance to enzymolysis ability of this biomaterial so that its should Digested completely by intestinal juice quickly during so that some patientss therapeutic effect is unsatisfied with.
Therefore, prior art has yet to be improved and developed.
The content of the invention
In view of above-mentioned the deficiencies in the prior art, it is an object of the invention to provide a kind of injection aquagel and its preparation side Method and application, it is intended to it is high to solve existing Fibrin Glue price, and the problem of resistance to enzymolysis ability.
Technical scheme is as follows：
The present invention provides a kind of preparation method of injection aquagel, including：
Step A, 10~20g chitosans are suspended in 50~100ml isopropanols, add 20~40ml, 5~15mol/L The NaOH aqueous solution, 20~40min is stirred at room temperature, then 20~30g chloroacetic acids is added dropwise, be heated to 55~65 DEG C stirring 2~ After 4h, filtering, washing, dry, obtain carboxymethyl chitosan；
Step B, it is 1 according to the mol ratio of xanthans and sodium metaperiodate:1~3, the sodium metaperiodate aqueous solution is added drop-wise to xanthan In glue solution, 2~4h of stirring reaction in darkroom, add ethylene glycol and continue 1~2h of stirring, then dialysis purification reaction is molten Liquid, obtain hydroformylation xanthans；
Step C, the hydroformylation xanthans and the carboxymethyl chitosan are subjected to cross-linking reaction generation injection aquagel.
The preparation method of described injection aquagel, wherein, in the step A, filtering, washing, the step tool dried Body includes：After filtering, the residue of filtering is washed 3~5 times with the methanol/water mixed solution that volume ratio is 70~90%, so Washed 2~4 times with ethanol afterwards, the carboxymethyl chitosan is obtained finally by vacuum drying.
The preparation method of described injection aquagel, wherein, in the step B, the quality of the xanthan gum solution Volume ratio is 0.5~2.0%, and the mass volume ratio of the sodium metaperiodate aqueous solution is 5~20%.
The preparation method of described injection aquagel, wherein, in the step B, during dialysis purification reaction solution, use Bag filter distilled water dialysis purification reaction solution, dialyse 2~4 days, at least update 5 water daily.
The present invention provides a kind of injection aquagel, is made of the preparation method described in any of the above item.
The present invention provides a kind of injection aquagel, including hydroformylation xanthans and carboxymethyl chitosan again, wherein, the aldehyde Change xanthans structural formula be：N is the integer more than 1.
The present invention also provides a kind of injection aquagel, wherein, the structural formula of the injection aquagel is：
Wherein, m, n are the integer more than 1.
The present invention also provides a kind of application of injection aquagel, by the injection aquagel application described in any of the above item In the material for preparing intestinal fistula closure.
Beneficial effect：The invention provides a kind of injection aquagel and preparation method and application, the present invention passes through profit The injection aquagel synthesized after carrying out modified with functional group with natural polysaccharide, safe and non-toxic, cost is cheap, and resistance to enzymolysis ability shows Write.
Brief description of the drawings
Fig. 1 synthesizes the reaction equation of hydroformylation xanthans for the present invention, and a is xanthans in figure, and b is hydroformylation xanthans, and n is Integer more than 1.
Fig. 2 synthesizes the reaction equation of carboxymethyl chitosan for the present invention, and c is chitosan in figure, and d is carboxymethyl chitosan Sugar, m are the integer more than 1.
Fig. 3 synthesizes the reaction equation of the injection aquagel for the present invention, and e is the injection aquagel in figure, M, n is the integer more than 1.
Fig. 4 is carboxymethyl chitosan of the present invention, the hydroformylation xanthans, the infrared spectrum of the injection aquagel Result figure.
Fig. 5 is the in vitro toxicity test result figure of injection aquagel of the present invention.
Fig. 6 is the resistance to enzymolysis result of the test figure of injection aquagel of the present invention, P in figure<0.001 represents have substantially Significant difference.
Embodiment
The present invention provides a kind of injection aquagel and preparation method and application, to make the purpose of the present invention, technical side Case and effect are clearer, clear and definite, and the present invention is described in more detail below.It is it should be appreciated that described herein specific real Example is applied only to explain the present invention, is not intended to limit the present invention.
The preparation method of the injection aquagel of present pre-ferred embodiments, including step：
S100,10~20g chitosans (CS) are suspended in 50~100ml isopropanols, add 20~40ml 5~ The 15mol/L NaOH aqueous solution, is stirred at room temperature 20~40min, then 20~30g chloroacetic acids are added dropwise, and is heated to 55~65 DEG C stirring 2~4h after, filtering, washing, dry, obtain carboxymethyl chitosan (NOCC)；
S200, according to xanthans and sodium metaperiodate (NaIO4) mol ratio be 1:1~3, the sodium metaperiodate aqueous solution is added dropwise Into xanthan gum solution, 2~4h of stirring reaction in darkroom, add ethylene glycol and continue 1~2h of stirring, then dialysis purification Reaction solution, obtain hydroformylation xanthans；
S300, the hydroformylation xanthans and the carboxymethyl chitosan are carried out to cross-linking reaction generation injection aquagel, That is hydroformylation xanthans/carboxymethyl chitosan hydrogel.
Further, in the present embodiment, in the step S100, reaction equation such as Fig. 2 of carboxymethyl chitosan is synthesized Shown, the filtering, washing, dry step specifically include：It is 70~90% by the residue volume ratio of filtering after filtering (v/v) methanol/water mixed solution washs 3~5 times, is then washed 2~4 times with ethanol, institute is obtained finally by vacuum drying State carboxymethyl chitosan.
Preferably, 10g chitosans when it is implemented, can be suspended in 75ml isopropanols, then by the step S100 It is stirred at room temperature；The 25ml 10mol/L NaOH aqueous solution is divided into 5 parts, and stirring is added sequentially to 5min intervals In slurries；Afterwards, gained slurries are stirred into 30min, 20g chloroacetic acids is then added dropwise, are heated to 60 DEG C, and stir at such a temperature Mix 3h；Then, reactant mixture is filtered, the residue of filtering is thoroughly washed 3 times with 80% (v/v) methanol/water mixture, is used Ethanol washs 2 times, and the substitution value that final product NOCC, obtained NOCC are obtained by vacuum drying is 85%, shows good Hydrophily.
Further, in the present embodiment, by the reaction equation of xanthans and sodium metaperiodate reaction generation hydroformylation xanthans It is 1 according to the mol ratio of xanthans and sodium metaperiodate as shown in figure 1, in the step S200:1~3, sodium metaperiodate is water-soluble Drop is added in xanthan gum solution, 2~4h of stirring reaction in darkroom, in order to the carbon-carbon bond of substrate group is cut, And reactive aldehyde groups are produced in the xanthans unit of strand, obtain hydroformylation xanthans (Xan-CHO).
Further, in the present embodiment, in the step S200, the mass volume ratio (w/v) of the xanthan gum solution For 0.5~2.0%, for example, can be 0.5%, 0.6%, 1.0%, 2.0%；The quality volume of the sodium metaperiodate aqueous solution It is 5~20% than (w/v), for example, can be 5%, 8%, 15%, 20%.
Further, in the present embodiment, in the step S200, add ethylene glycol continue 1~2h of stirring purpose be for The unreacted sodium metaperiodate of neutralization, wherein, ethylene glycol can add 1~3ml, such as can add 1ml, 2ml, 3ml.
Further, in the present embodiment, in the step S200, during dialysis purification reaction solution, bag filter is used to steam Distilled water dialysis purification reaction solution, dialyse 2~4 days, at least update 5 water daily, obtain Xan-CHO products.For example, can be saturating Analysis 2 days, 8 water are updated daily, or can dialysed 3 days, update 5 water daily.The bag filter preferably uses MWCO 12000-14000.Preferably, Xan-CHO products are freeze-dried in freeze drier, then in 4 DEG C of sealed plastic bag Middle storage.
Preferably, the step S200 is when it is implemented, prepare 0.6% xanthan gum solution and 8%NaIO4The aqueous solution, 80ml xanthan gum solutions are poured into beaker and 2ml NaIO are added dropwise4The aqueous solution (xanthans and NaIO4Mol ratio is 1:1.5)； Mixed liquor is continued in darkroom afterwards to stir 3h；1ml ethylene glycol is added to neutralize unreacted NaIO4, by reactant again 1h is stirred, and distillation water purification solutions are used 3 days using bag filter, 5 water of daily renewal in dialysis procedure；Finally by Xan- CHO products are freeze-dried in freeze drier and stored in 4 DEG C of sealed plastic bag.
Further, in the present embodiment, the step S300 is when it is implemented, by the hydroformylation xanthans and carboxymethyl shell Glycan generates the injection aquagel by predetermined ratio (percentage by weight) plastic in the orifice plate soluble in water, Xan-CHO with The reaction equation of NOCC reaction generations hydroformylation xanthans/carboxymethyl chitosan hydrogel as shown in figure 3, wherein, Xan-CHO with NOCC predetermined ratio is 1%：(0.1~0.5%), such as can be 1%：0.1%th, 1%：0.33%th, 1%：0.5%.
The embodiment of the present invention additionally provides a kind of injection aquagel, and it uses the preparation method system described in any of the above item Into.The i.e. hydroformylation xanthans/carboxymethyl chitosan hydrogel, including hydroformylation xanthans and carboxylic of injection aquagel prepared by the present invention Methyl chitosan, wherein, the structural formula difference of the hydroformylation xanthans and hydroformylation xanthans/carboxymethyl chitosan hydrogel For：
Wherein, m, n are the integer more than 1.
The embodiment of the present invention also provides a kind of application of injection aquagel, by above-described injection aquagel application In the material for preparing intestinal fistula closure.
The injection aquagel that the present invention by using natural polysaccharide synthesize after modified with functional group, it is safe and non-toxic, into This is cheap, and resistance to enzymolysis ability is notable, significantly more superior than Fibrin Glue property.
The present invention is elaborated with specific embodiment below：
Embodiment 1
1st, the synthesis of hydroformylation xanthans：Prepare 0.6% (w/v) xanthan gum solution and 8% (w/v) NaIO4The aqueous solution, so 80ml xanthan gum solutions are poured into beaker afterwards and 2ml NaIO are added dropwise4The aqueous solution (xanthans and NaIO4Mol ratio be 1: 1.5)；Afterwards, mixed liquor is continued in darkroom to stir 3h；Then 1ml ethylene glycol is added to neutralize unreacted NaIO4, will Reactant is stirred for 1h, and updates 5 water daily in dialysis procedure with water purification solutions are distilled 3 days using bag filter；Most Afterwards, Xan-CHO products are freeze-dried in freeze drier, then stored in 4 DEG C of sealed plastic bag.
Pass through hydroxylamine hydrochloride titration measuring Xan-CHO oxidizability (ratio of oxidation xanthic acid repeat unit).Will The 5ml xanthans CHO aqueous solution (0.2%w/v) is dissolved in 15ml hydroxylamine hydrochloride solutions (2.3%w/v), and pH1 is recorded by pH meter, Then mixed solution is stirred into 24h, measures pH2.Related reaction and calculation formula is as follows：
Xan-(CHO)n+nH2NHCl=Xan- (CH=N-OH)n+nH2O+nHCl (1)
C1(H+)=10-pH1 (2)
C2(H+)=10-pH2 (3)
Δ C=C2(H+)-C1(H+) (4)
Oxidizability (%)=993 × Δ C × 20 × 10-3/(2×W) (5)
In formula (5), 993 be the molecular weight of Xan-CHO repeat units, unit g/mol.20 represent the total of reaction solution Volume (15ml+5ml).W refers to Xan-CHO weight, unit g.It is computed, the Xan-CHO of preparation oxidizability is 44.1%.
2nd, the synthesis of carboxymethyl chitosan：10g chitosans are suspended in 75ml isopropanols, are then stirred at room temperature, The 25ml 10mol/L NaOH aqueous solution is divided into 5 parts, and is added sequentially to stir in slurries with 5min intervals；Afterwards, by institute Slurries stirring 30min is obtained, 20g chloroacetic acids are added dropwise, is then heated to 60 DEG C of stirring 3h；Then, after reactant mixture is filtered, Filtration residue is thoroughly washed 3 times with 80% (v/v) methanol/water mixture again, circulated 2 times with ethanol, finally by vacuum It is dried to obtain carboxymethyl chitosan.
3rd, the synthesis of hydroformylation xanthans/carboxymethyl chitosan hydrogel：By the hydroformylation xanthans and carboxymethyl chitosan By weight percentage 1%：The 0.33% generation hydroformylation of plastic in the orifice plate xanthans/carboxymethyl chitosan hydrogel soluble in water, I.e. described injection aquagel.
Infrared spectrum detects：Using FTIR infrared spectrums detection chitosan, carboxymethyl chitosan, xanthans, hydroformylation xanthan The infrared spectrum feature of glue and final cross-linking products hydroformylation xanthans/carboxymethyl chitosan hydrogel.Use at room temperature Nicolet-6700 spectrometers.Dry KBr disks will be placed on after the powder mull of every kind of polymer, and with 4cm-1Resolution ratio enter 32 scanning spectra re-recordeds of row.The results of FT-IR by the FTIR shown in Fig. 4 as shown in figure 4, confirm carboxymethyl chitosan With the successful preparation of hydroformylation xanthans.Chitosan and carboxymethyl chitosan show 1340cm-1The spy of neighbouring polysaccharide structures Levy absorption band (C-C-H and O-C-H vibrations) and 1100cm-1(C-O vibrations).It is not right due to COO- groups compared with chitosan Title and symmetrical stretching vibration, carboxymethyl chitosan is in 1610cm-1And 1432cm-1Place has characteristic absorption band.In xanthans and aldehyde Change in xanthans, also observe the typical absorption band of polysaccharide structures.In addition, in 1740cm-1Place is C=O group stretching vibrations, its Ratio becomes apparent from xanthans in hydroformylation xanthans.The above results show, the hydroformylation to xanthans and the carboxymethyl to chitosan It is melted into work(.
In vitro toxicity detects：The security of hydrogel is assessed by leaching liquor method.First, fully it is prepared in 24 orifice plates Xan-CHO/NOCC hydrogels (1%：0.33%), then with the DMEM (culture medium) of 10%FBS (hyclone) at 37 DEG C 24h is extracted, the serial dilution of stoste is then carried out, obtains the various concentrations (100%, 50%, 25%, 12.5%) of leachate； Fibroblast and leaching liquor (200 μ L) are co-cultured into 48h, then, 10 μ LCCK-8 is added per hole, 37 DEG C of incubation 4h, treat solution After homogeneous, the absorbance at 450nm is determined.In vitro toxicity testing result is as shown in figure 5, by Fig. 5 it can be found that no matter extracting Liquid and fresh culture are mixed with which kind of ratio, all without the propagation for influenceing cell, therefore, hydroformylation xanthan prepared by the present invention Glue/carboxymethyl chitosan hydrogel is safe and non-toxic.
Anti- digestive ferment proteolysis assay：Three blocks of X-CHO/NOCC hydrogels (1% are prepared in 6 orifice plates：0.33%) it is and fine Fibrillarin gel, then immersed at 37 DEG C in fresh duodenal juice.Every six h of duodenal juice is changed once.6h, 12h, After 24h, 48h and 72h, water-setting blob is taken out, and surface moisture is wiped immediately with thin paper.Then the weight of hydrogel is measured, it They are put back in 6 orifice plates afterwards.Anti- digestive ferment proteolysis assay result is as shown in fig. 6, hydroformylation prepared by Fig. 6 results display present invention The resistance to enzymolysis ability of xanthans/carboxymethyl chitosan hydrogel compares the specific significant advantage of Fibrin Glue of commercialization.
Embodiment 2
1st, the synthesis of hydroformylation xanthans：Prepare 0.5% (w/v) xanthan gum solution and 5% (w/v) NaIO4The aqueous solution, so Xanthan gum solution is poured into beaker afterwards and NaIO is added dropwise4The aqueous solution (xanthans and NaIO4Mol ratio be 1:1)；Afterwards, Mixed liquor is continued to stirring 2h in darkroom；Then 1ml ethylene glycol is added to neutralize unreacted NaIO4, reactant is stirred again 1h is mixed, and 8 water are updated daily in dialysis procedure with water purification solutions are distilled 2 days using bag filter；Finally, by Xan-CHO Product is freeze-dried in freeze drier, is then stored in 4 DEG C of sealed plastic bag.
2nd, the synthesis of carboxymethyl chitosan：10g chitosans are suspended in 50ml isopropanols, are then stirred at room temperature, The 20ml 5mol/L NaOH aqueous solution is divided into 5 parts, and is added sequentially to stir in slurries with 5min intervals；Afterwards, by institute Slurries stirring 20min is obtained, 20g chloroacetic acids are added dropwise, is then heated to 55 DEG C of stirring 2h.Then, after reactant mixture is filtered, Filtration residue is thoroughly washed 5 times with 70% (v/v) methanol/water mixture again, circulated 4 times with ethanol, finally by vacuum It is dried to obtain carboxymethyl chitosan.
3rd, the synthesis of hydroformylation xanthans/carboxymethyl chitosan hydrogel：By the hydroformylation xanthans and carboxymethyl chitosan By weight percentage 1%：The 0.33% generation hydroformylation of plastic in the orifice plate xanthans/carboxymethyl chitosan hydrogel soluble in water.
By hydroformylation xanthans/carboxymethyl chitosan hydrogel manufactured in the present embodiment, similarly to Example 1 infrared is carried out Spectral detection, in vitro toxicity detection and anti-digestive ferment proteolysis assay, as a result find hydroformylation xanthans/carboxylic prepared by this implementation Methyl chitosan hydrogel, equally with non-toxic and significant resistance to enzymolysis ability.
Embodiment 3
1st, the synthesis of hydroformylation xanthans：Prepare 2% (w/v) xanthan gum solution and 20% (w/v) NaIO4The aqueous solution, so Xanthan gum solution is poured into beaker afterwards and NaIO is added dropwise4The aqueous solution (xanthans and NaIO4Mol ratio be 1:3)；Afterwards, Mixed liquor is continued to stirring 4h in darkroom；Then 3ml ethylene glycol is added to neutralize unreacted NaIO4, reactant is stirred again 2h is mixed, and 5 water are updated daily in dialysis procedure with water purification solutions are distilled 4 days using bag filter；Finally, by Xan-CHO Product is freeze-dried in freeze drier, is then stored in 4 DEG C of sealed plastic bag.
2nd, the synthesis of carboxymethyl chitosan：20g chitosans are suspended in 100ml isopropanols, are then stirred at room temperature, The 40ml 15mol/L NaOH aqueous solution is divided into 5 parts, and is added sequentially to stir in slurries with 5min intervals；Afterwards, by institute Slurries stirring 40min is obtained, 30g chloroacetic acids are added dropwise, is then heated to 65 DEG C of stirring 4h.Then, after reactant mixture is filtered, Filtration residue is thoroughly washed 3 times with 90% (v/v) methanol/water mixture again, circulated 2 times with ethanol, finally by vacuum It is dried to obtain carboxymethyl chitosan.
3rd, the synthesis of hydroformylation xanthans/carboxymethyl chitosan hydrogel：By the hydroformylation xanthans and carboxymethyl chitosan By weight percentage 1%：The 0.33% generation hydroformylation of plastic in the orifice plate xanthans/carboxymethyl chitosan hydrogel soluble in water.
By hydroformylation xanthans/carboxymethyl chitosan hydrogel manufactured in the present embodiment, similarly to Example 1 infrared is carried out Spectral detection, in vitro toxicity detection and anti-digestive ferment proteolysis assay, as a result find hydroformylation xanthans/carboxylic prepared by this implementation Methyl chitosan hydrogel, equally with non-toxic and significant resistance to enzymolysis ability.
In summary, the invention provides a kind of injection aquagel and preparation method and application, the present invention passes through profit The injection aquagel synthesized after carrying out modified with functional group with natural polysaccharide, safe and non-toxic, cost is cheap, and resistance to enzymolysis ability shows Write.
It should be appreciated that the application of the present invention is not limited to above-mentioned citing, for those of ordinary skills, can To be improved or converted according to the above description, all these modifications and variations should all belong to the guarantor of appended claims of the present invention Protect scope.

Claims (8)

  1. A kind of 1. preparation method of injection aquagel, it is characterised in that including：
    Step A, 10~20g chitosans are suspended in 50~100ml isopropanols, add 20~40ml5~15mol/L NaOH The aqueous solution, 20~40min is stirred at room temperature, then 20~30g chloroacetic acids are added dropwise, after being heated to 55~65 DEG C of 2~4h of stirring, Filtering, washing, dry, obtain carboxymethyl chitosan；
    Step B, it is 1 according to the mol ratio of xanthans and sodium metaperiodate:1~3, the sodium metaperiodate aqueous solution is added drop-wise to xanthan glue In solution, 2~4h of stirring reaction in darkroom, add ethylene glycol and continue 1~2h of stirring, then dialysis purification reaction solution, Obtain hydroformylation xanthans；
    Step C, the hydroformylation xanthans and the carboxymethyl chitosan are subjected to cross-linking reaction generation injection aquagel.
  2. 2. the preparation method of injection aquagel according to claim 1, it is characterised in that in the step A, filtering, Washing, the step dried specifically include：After filtering, the methanol/water that the residue volume ratio of filtering is 70~90% is mixed Solution washs 3~5 times, is then washed 2~4 times with ethanol, the carboxymethyl chitosan is obtained finally by vacuum drying.
  3. 3. the preparation method of injection aquagel according to claim 1, it is characterised in that in the step B, the Huang The mass volume ratio of the virgin rubber aqueous solution is 0.5~2.0%, and the mass volume ratio of the sodium metaperiodate aqueous solution is 5~20%.
  4. 4. the preparation method of injection aquagel according to claim 1, it is characterised in that in the step B, dialysis is pure When changing reaction solution, using bag filter distilled water dialysis purification reaction solution, dialyse 2~4 days, at least update 5 water daily.
  5. 5. a kind of injection aquagel, it is characterised in that be made of the preparation method as described in any one of Claims 1 to 4.
  6. A kind of 6. injection aquagel, it is characterised in that including hydroformylation xanthans and carboxymethyl chitosan,
    Wherein, the structural formula of the hydroformylation xanthans is：
    N is the integer more than 1.
  7. 7. a kind of injection aquagel, it is characterised in that the structural formula of the injection aquagel is：
    Wherein, m, n are the integer more than 1.
  8. 8. a kind of application of injection aquagel, it is characterised in that by the injectable water as described in any one of claim 5~7 Gel application is in the material for preparing intestinal fistula closure.
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