WO2018232856A1 - 一种可注射水凝胶及其制备方法与应用 - Google Patents

一种可注射水凝胶及其制备方法与应用 Download PDF

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WO2018232856A1
WO2018232856A1 PCT/CN2017/096207 CN2017096207W WO2018232856A1 WO 2018232856 A1 WO2018232856 A1 WO 2018232856A1 CN 2017096207 W CN2017096207 W CN 2017096207W WO 2018232856 A1 WO2018232856 A1 WO 2018232856A1
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xanthan gum
injectable hydrogel
aqueous solution
carboxymethyl chitosan
hydroformylated
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PCT/CN2017/096207
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English (en)
French (fr)
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任建安
吴秀文
黄金健
陈国璞
王革非
顾国胜
黎介寿
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中国人民解放军南京军区南京总医院
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Publication of WO2018232856A1 publication Critical patent/WO2018232856A1/zh

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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

Definitions

  • the invention relates to the field of injectable hydrogels, in particular to an injectable hydrogel and a preparation method and application thereof.
  • porcine-derived fibrin glue is usually used for the closure of intestinal fistula, so that a part of patients with intestinal fistula can restore the continuity of the intestine through conservative treatment, and avoid the treatment of intestinal fistula.
  • this fibrin glue is expensive due to its origin, and in addition, the bio-material has poor anti-enzymatic ability, so that its application process is quickly digested by the intestinal juice, making some patients unsatisfactory.
  • the object of the present invention is to provide an injectable hydrogel and a preparation method and application thereof, aiming at solving the problem that the existing fibrin glue is expensive and has poor anti-enzymatic ability.
  • the invention provides a preparation method of an injectable hydrogel, comprising:
  • Step A suspending 10-20 g of chitosan in 50-100 ml of isopropanol, adding 20-40 ml of 5-15 mol/L NaOH aqueous solution, stirring at room temperature for 20-40 min, and adding 20-30 g of monochloroacetic acid dropwise. After heating to 55-65 ° C for 2 to 4 hours, filtering, washing, and drying to obtain carboxymethyl chitosan;
  • Step B according to the molar ratio of xanthan gum and sodium periodate is 1:1 to 3, the sodium periodate aqueous solution is added dropwise to the xanthan gum aqueous solution, and the reaction is stirred in a dark room for 2 to 4 hours, and then the second solution is added. The alcohol is continuously stirred for 1 to 2 hours, and then the reaction solution is purified by dialysis to obtain a hydroformylated xanthan gum;
  • Step C Cross-linking the hydroformylated xanthan gum with the carboxymethyl chitosan to form an injectable hydrogel.
  • the method for preparing an injectable hydrogel wherein the step of filtering, washing and drying in the step A comprises: after filtering, filtering the residue in a volume ratio of 70 to 90% of methanol/water.
  • the mixed solution was washed 3 to 5 times, then washed 2 to 4 times with ethanol, and finally the carboxymethyl chitosan was obtained by vacuum drying.
  • the method for preparing an injectable hydrogel wherein, in the step B, the mass to volume ratio of the xanthan gum aqueous solution is 0.5 to 2.0%, and the mass ratio of the sodium periodate aqueous solution is 5 to 20%.
  • the preparation method of the injectable hydrogel wherein, in the step B, when dialysis and purification of the reaction solution, the purified reaction solution is dialyzed against distilled water using a dialysis bag, dialyzed for 2 to 4 days, and water is updated at least 5 times a day.
  • the present invention provides an injectable hydrogel which is produced by the preparation method described in any of the above.
  • the invention further provides an injectable hydrogel comprising a hydroformylated xanthan gum and a carboxymethyl chitosan, wherein the structural formula of the hydroformylated xanthan gum is:
  • n is an integer greater than one.
  • the invention also provides an injectable hydrogel, wherein the injectable hydrogel has the structural formula:
  • n and n are integers greater than one.
  • the invention also provides an injectable hydrogel for use in the preparation of an intestinal fistula occluding material.
  • the invention provides an injectable hydrogel and a preparation method and application thereof, and the injectable hydrogel synthesized by the functional group modification by using the natural polysaccharide is safe, non-toxic, low in cost and remarkable in anti-enzymatic ability.
  • Figure 1 is a reaction equation for synthesizing a hydroformylated xanthan gum of the present invention, wherein a is xanthan gum, b is a hydroformylated xanthan gum, and n is an integer greater than 1.
  • Figure 3 is a reaction equation for synthesizing the injectable hydrogel of the present invention, wherein e is the injectable hydrogel m and n are integers greater than one.
  • Figure 5 is a graph showing the results of in vitro toxicity test of the injectable hydrogel of the present invention.
  • Figure 6 is a graph showing the results of an anti-enzymatic test of the injectable hydrogel of the present invention, wherein P ⁇ 0.001 indicates a significant statistical difference.
  • the present invention provides an injectable hydrogel, a preparation method and application thereof, and the present invention will be further described in detail below in order to make the objects, technical solutions and effects of the present invention more clear and clear. It is understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
  • the reaction equation for synthesizing carboxymethyl chitosan is as shown in FIG. 2, and the steps of filtering, washing and drying specifically include: filtering the residue after filtration.
  • the mixture was washed 3 to 5 times with a methanol/water mixed solution having a volume ratio of 70 to 90% (v/v), and then washed 2 to 4 times with ethanol, and finally the carboxymethyl chitosan was obtained by vacuum drying.
  • 10 g of chitosan can be suspended in 75 ml of isopropanol and then stirred at room temperature; 25 ml of 10 mol/L aqueous NaOH solution is divided into 5 parts, and the interval is 5 min. After the addition to the stirred slurry; the resulting slurry was stirred for 30 min, then 20 g of monochloroacetic acid was added dropwise, heated to 60 ° C, and stirred at this temperature for 3 h; then, the reaction mixture was filtered, and the residue was filtered.
  • the % (v/v) methanol/water mixture was thoroughly washed 3 times, washed twice with ethanol, and vacuum-dried to obtain the final product NOCC, and the obtained NOCC had a degree of substitution of 85%, showing good hydrophilicity.
  • reaction equation for reacting xanthan gum with sodium periodate to form a hydroformylated xanthan gum is shown in FIG. 1 , and in the step S200, according to the mole of xanthan gum and sodium periodate The ratio of 1:1 to 3, the sodium periodate aqueous solution is added dropwise to the xanthan gum aqueous solution, and the reaction is stirred in a dark room for 2 to 4 hours, in order to cut the carbon-carbon bond of the substrate group, and in the molecular chain. A reactive aldehyde group is produced in the xanthan gum unit to obtain a hydroformylated xanthan gum (Xan-CHO).
  • the mass to volume ratio (w/v) of the xanthan gum aqueous solution is 0.5 to 2.0%, for example, 0.5%, 0.6%, 1.0%, and 2.0%.
  • the mass ratio (w/v) of the aqueous sodium periodate solution is 5 to 20%, and may be, for example, 5%, 8%, 15%, or 20%.
  • the purpose of adding ethylene glycol and stirring for 1 to 2 hours is to neutralize the unreacted sodium periodate, wherein the ethylene glycol may be added in an amount of 1 to 3 ml, for example, Add 1 ml, 2 ml, 3 ml.
  • the purified reaction solution is dialyzed against distilled water using a dialysis bag, dialyzed for 2 to 4 days, and water is updated at least 5 times a day to obtain a Xan-CHO product.
  • a dialysis bag preferably uses MWCO 12000-14000.
  • the Xan-CHO product is freeze dried in a freeze dryer and then stored in a sealed plastic bag at 4 °C.
  • a 0.6% aqueous solution of xanthan gum and an aqueous solution of 8% NaIO 4 are prepared, and 80 ml of an aqueous solution of xanthan gum is poured into a beaker and 2 ml of an aqueous solution of NaIO 4 is added dropwise (xanthan gum and NaIO 4 mol). The ratio was 1:1.5); the mixture was then stirred for 3 h in the dark room; 1 ml of ethylene glycol was added to neutralize the unreacted NaIO 4 , the reaction was stirred for an additional 1 h, and the solution was purified using distilled water for 3 days using a dialysis bag. The water was updated 5 times a day during the dialysis; finally, the Xan-CHO product was freeze-dried in a freeze dryer and stored in a sealed plastic bag at 4 °C.
  • the hydroformyl xanthan gum and the carboxymethyl chitosan are dissolved in water in a predetermined ratio (weight percentage) to form a gel in the orifice plate.
  • a predetermined ratio weight percentage
  • the reaction equation of the gel, Xan-CHO and NOCC to form a hydroformylated xanthan gum/carboxymethyl chitosan hydrogel is shown in Fig. 3, wherein the predetermined ratio of Xan-CHO to NOCC is 1%: (0.1 ⁇ 0.5%) may be, for example, 1%:0.1%, 1%:0.33%, 1%:0.5%.
  • An embodiment of the present invention also provides an injectable hydrogel which is produced by the preparation method described in any of the above.
  • the injectable hydrogel prepared by the invention is a hydroformylated xanthan gum/carboxymethyl chitosan hydrogel, comprising a hydroformylated xanthan gum and a carboxymethyl chitosan, wherein the hydroformyl xanthan gum and the solution
  • the structural formulas of the hydroformylated xanthan gum/carboxymethyl chitosan hydrogel are:
  • n and n are integers greater than one.
  • Embodiments of the present invention also provide an injectable hydrogel for applying the injectable hydrogel described above to a material for the preparation of intestinal fistula.
  • the injectable hydrogel synthesized by the functional group modification by using the natural polysaccharide is safe, non-toxic, low in cost, remarkable in anti-enzymatic ability, and superior in superiority to fibrin glue.
  • Synthesis of hydroformylated xanthan gum prepare 0.6% (w/v) xanthan gum aqueous solution and 8% (w/v) NaIO 4 aqueous solution, then pour 80 ml of xanthan gum aqueous solution into a beaker and add 2 ml of NaIO. 4 aqueous solution (the molar ratio of xanthan gum to NaIO 4 is 1:1.5); after that, the mixture is further stirred in a dark room for 3 h; then 1 ml of ethylene glycol is added to neutralize unreacted NaIO 4 , and the reaction is stirred again.
  • the solution was purified with distilled water for 3 days using a dialysis bag, and water was updated 5 times a day during the dialysis; finally, the Xan-CHO product was freeze-dried in a freeze dryer and then stored in a sealed plastic bag at 4 °C.
  • the degree of oxidation of Xan-CHO (the ratio of oxidized xanthogen repeat units) was determined by hydroxylamine hydrochloride titration. 5 ml of xanthan gum CHO aqueous solution (0.2% w/v) was dissolved in 15 ml of hydroxylamine hydrochloride solution (2.3% w/v), pH 1 was recorded by a pH meter, and then the mixed solution was stirred for 24 hours, and pH 2 was measured.
  • the relevant reactions and calculation formulas are as follows:
  • 993 is the molecular weight of the Xan-CHO repeating unit in units of g/mol. 20 represents the total volume of the reaction solution (15 ml + 5 ml). W refers to the weight of Xan-CHO in g. The degree of oxidation of the prepared Xan-CHO was calculated to be 44.1%.
  • Infrared spectroscopy was used to detect chitosan, carboxymethyl chitosan, xanthan gum, hydroformylated xanthan gum and the final cross-linked product of hydroformylated xanthan gum/carboxymethyl chitosan hydrogel. Infrared spectroscopy features. A Nicolet-6700 spectrometer was used at room temperature. The powder of each polymer was ground, placed on a dry KBr disk, and subjected to 32 scan recording spectra at a resolution of 4 cm -1 . Infrared spectroscopy results are shown in Figure 4.
  • In vitro toxicity test The safety of the hydrogel was evaluated by the extract method. First, Xan-CHO/NOCC hydrogel (1%: 0.33%) was fully prepared in a 24-well plate, followed by extraction with DMEM (medium) of 10% FBS (fetal calf serum) at 37 ° C for 24 h, then Serial dilutions of the stock solution were performed to obtain different concentrations of the leachate (100%, 50%, 25%, 12.5%); fibroblasts were co-cultured with the extract (200 ⁇ L) for 48 h, then 10 ⁇ L of LCCK-8 was added to each well, 37 ° C After incubation for 4 h, after the solution was homogenized, the absorbance at 450 nm was measured.
  • DMEM medium
  • FBS fetal calf serum
  • Anti-digestive enzyme enzymatic test Three X-CHO/NOCC hydrogels (1%: 0.33%) and fibrin gel were prepared in a 6-well plate and then immersed in fresh duodenal juice at 37 °C. . The duodenal juice is replaced every six hours. After 6h, 12h, 24h, 48h and 72h, the hydrogel block was removed and the surface moisture was immediately wiped off with a tissue. The weight of the hydrogel was then measured and then placed back into the 6-well plate. The results of the anti-digestive enzyme digestion test are shown in Fig. 6. The results in Fig. 6 show that the anti-enzymatic ability of the hydroformylated xanthan gum/carboxymethyl chitosan hydrogel prepared by the present invention is more remarkable than that of the commercial fibrin glue. The advantages.
  • Synthesis of hydroformylated xanthan gum Prepare 0.5% (w/v) xanthan gum aqueous solution and 5% (w/v) NaIO 4 aqueous solution, then pour xanthan gum aqueous solution into the beaker and add NaIO 4 aqueous solution dropwise. (The molar ratio of xanthan gum to NaIO 4 was 1:1); after that, the mixture was further stirred in a dark room for 2 h; then 1 ml of ethylene glycol was added to neutralize unreacted NaIO 4 , and the reaction was further stirred for 1 h.
  • the solution was purified using distilled water for 2 days using a dialysis bag, and water was updated 8 times per day during the dialysis; finally, the Xan-CHO product was freeze-dried in a freeze dryer and then stored in a sealed plastic bag at 4 °C.
  • the hydroformyl xanthan gum/carboxymethyl chitosan hydrogel prepared in this example was subjected to the same infrared spectrum detection, in vitro toxicity test, and anti-digestive enzyme enzymatic hydrolysis test as in Example 1, and as a result, it was found that the preparation of the present invention was carried out.
  • the hydroformylated xanthan gum/carboxymethyl chitosan hydrogel also has non-toxic and significant anti-enzymatic ability.
  • Synthesis of hydroformylated xanthan gum prepare 2% (w/v) xanthan gum aqueous solution and 20% (w/v) NaIO 4 aqueous solution, then pour xanthan gum aqueous solution into beaker and add NaIO 4 aqueous solution dropwise. (The molar ratio of xanthan gum to NaIO 4 was 1:3); after that, the mixture was further stirred in a dark room for 4 h; then 3 ml of ethylene glycol was added to neutralize unreacted NaIO 4 , and the reaction was stirred for another 2 h.
  • the solution was purified using distilled water for 4 days using a dialysis bag, and water was updated 5 times a day during the dialysis; finally, the Xan-CHO product was freeze-dried in a freeze dryer and then stored in a sealed plastic bag at 4 °C.
  • the hydroformyl xanthan gum/carboxymethyl chitosan hydrogel prepared in this example was subjected to the same infrared spectrum detection, in vitro toxicity test, and anti-digestive enzyme enzymatic hydrolysis test as in Example 1, and as a result, it was found that the preparation of the present invention was carried out.
  • the hydroformylated xanthan gum/carboxymethyl chitosan hydrogel also has non-toxic and significant anti-enzymatic ability.
  • the present invention provides an injectable hydrogel, a preparation method and application thereof, and the injectable hydrogel synthesized by using a natural polysaccharide for functional group modification is safe, non-toxic and low in cost. The anti-enzymatic ability is remarkable.

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Abstract

一种可注射水凝胶及其制备方法与应用，所述制备方法包括步骤：将10～20g壳聚糖悬浮于50～100ml异丙醇中，加入20～40ml 5～15mol/L NaOH水溶液室温下搅拌20～40min，再滴加20～30g一氯乙酸，加热至55～65℃搅拌2～4h后，过滤洗涤干燥，得到羧甲基壳聚糖；按黄原胶和高碘酸钠的摩尔比1∶1～3将高碘酸钠水溶液滴加到黄原胶水溶液中，暗室中搅拌反应2～4h，再加入乙二醇搅拌1～2h，透析纯化反应溶液，得到醛化黄原胶；将醛化黄原胶与羧甲基壳聚糖反应生成可注射水凝胶。通过利用天然多糖进行官能团修饰后合成的可注射水凝胶，安全无毒，成本低廉，抗酶解能力显著。

Description

一种可注射水凝胶及其制备方法与应用 技术领域
本发明涉及可注射水凝胶领域，尤其涉及一种可注射水凝胶及其制备方法与应用。
背景技术
在临床工作中，通常使用商品化的猪源性纤维蛋白胶进行肠瘘的封堵治疗，使得一部分肠瘘患者可以通过保守治疗而恢复肠道的连续性，避免了肠瘘手术治疗。但是这种纤维蛋白胶由于其来源于生物而价格高昂，此外，这种生物材料的抗酶解能力差，使得其应用过程中很快被肠液完全消化，使得部分患者治疗效果不满意。
因此，现有技术还有待于改进和发展。
技术问题
鉴于上述现有技术的不足，本发明的目的在于提供一种可注射水凝胶及其制备方法与应用，旨在解决现有的纤维蛋白胶价格高昂，且抗酶解能力差的问题。
问题的解决方案
技术解决方案
本发明的技术方案如下：
本发明提供一种可注射水凝胶的制备方法，包括：
步骤A、将10～20g壳聚糖悬浮于50～100ml异丙醇中，加入20～40ml 5～15mol/L NaOH水溶液，在室温下搅拌20～40min，再滴加20～30g一氯乙酸，加热至55～65℃搅拌2～4h后，过滤、洗涤、干燥，得到羧甲基壳聚糖；
步骤B、按照黄原胶和高碘酸钠的摩尔比为1∶1～3，将高碘酸钠水溶液滴加到黄原胶水溶液中，在暗室中搅拌反应2～4h，再加入乙二醇继续搅拌1～2h，然后透析纯化反应溶液，得到醛化黄原胶；
步骤C、将所述醛化黄原胶与所述羧甲基壳聚糖进行交联反应生成可注射水凝胶。
所述的可注射水凝胶的制备方法，其中，所述步骤A中，过滤、洗涤、干燥的步骤具体包括：过滤后，将过滤的残余物用体积比为70～90％的甲醇/水混合溶液洗涤3～5次，然后用乙醇洗涤2～4次，最后通过真空干燥得到所述羧甲基壳聚糖。
所述的可注射水凝胶的制备方法，其中，所述步骤B中，所述黄原胶水溶液的质量体积比为0.5～2.0％，所述高碘酸钠水溶液的质量体积比为5～20％。
所述的可注射水凝胶的制备方法，其中，所述步骤B中，透析纯化反应溶液时，使用透析袋用蒸馏水透析纯化反应溶液，透析2～4天，每天至少更新5次水。
本发明提供一种可注射水凝胶，采用以上任一项所述的制备方法制成。
本发明又提供一种可注射水凝胶，包括醛化黄原胶和羧甲基壳聚糖，其中，所述醛化黄原胶的结构式为：
Figure PCTCN2017096207-appb-000001
，n为大于1的整数。
本发明还提供一种可注射水凝胶，其中，所述可注射水凝胶的结构式为：
Figure PCTCN2017096207-appb-000002
，其中，m、n均为大于1的整数。
本发明还提供一种可注射水凝胶的应用，将以上任一项所述的可注射水凝胶应用于制备肠瘘封堵的材料。
发明的有益效果
有益效果
本发明提供了一种可注射水凝胶及其制备方法与应用，本发明通过利用天然多糖进行官能团修饰后合成的可注射水凝胶，安全无毒，成本低廉，抗酶解能力显著。
对附图的简要说明
附图说明
图1为本发明合成醛化黄原胶的反应方程式，图中a为黄原胶，b为醛化黄原胶，n为大于1的整数。
图2为本发明合成羧甲基壳聚糖的反应方程式，图中c为壳聚糖，d为羧甲基壳聚糖，m为大于1的整数。
图3为本发明合成所述可注射水凝胶的反应方程式，图中e为所述可注射水凝胶 ，m、n均为大于1的整数。
图4为本发明所述羧甲基壳聚糖、所述醛化黄原胶、所述可注射水凝胶的红外光谱结果图。
图5为本发明所述可注射水凝胶的体外毒性测试结果图。
图6为本发明所述可注射水凝胶的抗酶解试验结果图，图中P＜0.001表示具有明显的统计学差异。
实施该发明的最佳实施例
本发明的最佳实施方式 具体实施方式
本发明提供一种可注射水凝胶及其制备方法与应用，为使本发明的目的、技术方案及效果更加清楚、明确，以下对本发明进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
本发明较佳实施例的可注射水凝胶的制备方法，包括步骤：
S100、将10～20g壳聚糖(CS)悬浮于50～100ml异丙醇中，加入20～40ml5～15mol/L的NaOH水溶液，在室温下搅拌20～40min，再滴加20～30g一氯乙酸，加热至55～65℃搅拌2～4h后，过滤、洗涤、干燥，得到羧甲基壳聚糖(NOCC)；
S200、按照黄原胶和高碘酸钠(NaIO4)的摩尔比为1∶1～3，将高碘酸钠水溶液滴加到黄原胶水溶液中，在暗室中搅拌反应2～4h，再加入乙二醇继续搅拌1～2h，然后透析纯化反应溶液，得到醛化黄原胶；
S300、将所述醛化黄原胶与所述羧甲基壳聚糖进行交联反应生成可注射水凝胶，即醛化黄原胶/羧甲基壳聚糖水凝胶。
进一步的，本实施例中，所述步骤S100中，合成羧甲基壳聚糖的反应方程式如图2所示，所述过滤、洗涤、干燥的步骤具体包括：过滤后，将过滤的残余物用体积比为70～90％(v/v)的甲醇/水混合溶液洗涤3～5次，然后用乙醇洗涤2～4次，最后通过真空干燥得到所述羧甲基壳聚糖。
优选的，所述步骤S100具体实施时，可以将10g壳聚糖悬浮于75ml异丙醇中，然后在室温下搅拌；将25ml 10mol/L NaOH水溶液等分成5份，并以5min间隔依 次加入到搅拌的浆液中；之后，将所得浆液搅拌30min，然后滴加20g一氯乙酸，加热至60℃，并在该温度下搅拌3h；随后，将反应混合物过滤，过滤的残余物用80％(v/v)甲醇/水混合物彻底洗涤3次，用乙醇洗涤2次，通过真空干燥得到最终产物NOCC，制得的NOCC的取代度为85％，显示出良好的亲水性。
进一步的，本实施例中，将黄原胶与高碘酸钠反应生成醛化黄原胶的反应方程式如图1所示，所述步骤S200中，按照黄原胶和高碘酸钠的摩尔比为1∶1～3，将高碘酸钠水溶液滴加到黄原胶水溶液中，在暗室中搅拌反应2～4h，目的是为了切割底物基团的碳-碳键，并在分子链的黄原胶单元中产生反应性醛基，得到醛化黄原胶(Xan-CHO)。
进一步的，本实施例中，所述步骤S200中，所述黄原胶水溶液的质量体积比(w/v)为0.5～2.0％，例如，可以为0.5％、0.6％、1.0％、2.0％；所述高碘酸钠水溶液的质量体积比(w/v)为5～20％，例如，可以为5％、8％、15％、20％。
进一步的，本实施例中，所述步骤S200中，加入乙二醇继续搅拌1～2h的目的是为了中和未反应的高碘酸钠，其中，乙二醇可以加入1～3ml，例如可以加入1ml、2ml、3ml。
进一步的，本实施例中，所述步骤S200中，透析纯化反应溶液时，使用透析袋用蒸馏水透析纯化反应溶液，透析2～4天，每天至少更新5次水，得到Xan-CHO产品。例如，可以透析2天，每天更新8次水，或者可以透析3天，每天更新5次水。所述透析袋优选使用MWCO 12000-14000。优选的，将Xan-CHO产品在冷冻干燥机中冷冻干燥，然后在4℃的密封塑料袋中储存。
优选的，所述步骤S200具体实施时，制备0.6％黄原胶水溶液和8％NaIO4水溶液，将80ml黄原胶水溶液倒入烧杯中并滴加2ml NaIO4水溶液(黄原胶与NaIO4摩尔比为1∶1.5)；之后将混合液在暗室中继续搅拌3h；再加入1ml乙二醇以中和未反应的NaIO4，将反应物再搅拌1h，并使用透析袋用蒸馏水纯化溶液3天，在透析过程中每天更新5次水；最后将Xan-CHO产品在冷冻干燥机中冷冻干燥并在4℃的密封塑料袋中储存。
进一步的，本实施例中，所述步骤S300具体实施时，将所述醛化黄原胶与羧甲基壳聚糖按预定比例(重量百分比)溶于水中在孔板中成胶生成所述可注射水 凝胶，Xan-CHO与NOCC反应生成醛化黄原胶/羧甲基壳聚糖水凝胶的反应方程式如图3所示，其中，Xan-CHO与NOCC的预定比例为1％∶(0.1～0.5％)，例如可以为1％∶0.1％、1％∶0.33％、1％∶0.5％。
本发明实施例还提供了一种可注射水凝胶，其采用以上任一项所述的制备方法制成。本发明制备的可注射水凝胶即醛化黄原胶/羧甲基壳聚糖水凝胶，包括醛化黄原胶和羧甲基壳聚糖，其中，所述醛化黄原胶和所述醛化黄原胶/羧甲基壳聚糖水凝胶的结构式分别为：
Figure PCTCN2017096207-appb-000003
Figure PCTCN2017096207-appb-000004
其中，m、n均为大于1的整数。
本发明实施例还提供一种可注射水凝胶的应用，将以上所述的可注射水凝胶应用于制备肠瘘封堵的材料。
本发明通过利用天然多糖进行官能团修饰后合成的可注射水凝胶，安全无毒，成本低廉，抗酶解能力显著，比纤维蛋白胶性质显著优越。
下面以具体实施例对本发明做详细说明：
实施例1
1、醛化黄原胶的合成：制备0.6％(w/v)黄原胶水溶液和8％(w/v)NaIO4水溶液，然后将80ml黄原胶水溶液倒入烧杯中并滴加2ml NaIO4水溶液(黄原胶与NaIO4的摩尔比为1∶1.5)；之后，将混合液在暗室中继续搅拌3h；然后加入1ml乙二醇以中和未反应的NaIO4，将反应物再搅拌1h，并使用透析袋用蒸馏水纯化溶液3天，在透析过程中每天更新5次水；最后，将Xan-CHO产品在冷冻干燥机中冷冻干燥，然后在4℃的密封塑料袋中储存。
通过羟胺盐酸盐滴定法测定Xan-CHO的氧化度(氧化黄原酸重复单元的比例)。将5ml黄原胶CHO水溶液(0.2％w/v)溶于15ml盐酸羟胺溶液(2.3％w/v)中，通过pH计记录pH1，然后将混合溶液搅拌24h，测量pH2。相关的反应和计算公式如下：
Xan-(CHO)n+nH2N·HCl＝Xan-(CH＝N-OH)n+nH2O+nHCl  (1)
C1(H+)＝10-pH1        (2)
C2(H+)＝10-pH2        (3)
ΔC＝C2(H+)-C1(H+)         (4)
氧化度(％)＝993×ΔC×20×10-3/(2×W)(5)
在式(5)中，993是Xan-CHO重复单元的分子量，单位为g/mol。20表示反应溶液的总体积(15ml+5ml)。W指Xan-CHO的重量，单位为g。经计算，制备的Xan-CHO的氧化度为44.1％。
2、羧甲基壳聚糖的合成：将10g壳聚糖悬浮于75ml异丙醇中，然后在室温下搅拌，将25ml 10mol/L NaOH水溶液等分成5份，并以5min间隔依次加入到搅拌浆液中；之后，将所得浆液搅拌30min，滴加20g一氯乙酸，然后加热至60℃搅拌3h；随后，将反应混合物过滤后，再将过滤残余物用80％(v/v)甲醇/水混合物彻底洗涤3次，用乙醇循环2次，最后通过真空干燥得到羧甲基壳聚糖。
3、醛化黄原胶/羧甲基壳聚糖水凝胶的合成：将所述醛化黄原胶与羧甲基壳聚糖按重量百分比1％∶0.33％溶于水中在孔板中成胶生成醛化黄原胶/羧甲基壳聚糖水凝胶，即所述可注射水凝胶。
红外光谱检测：应用FTIR红外光谱检测壳聚糖、羧甲基壳聚糖、黄原胶、醛化黄原胶以及最终的交联产物醛化黄原胶/羧甲基壳聚糖水凝胶的红外光谱特点。在室温下使用Nicolet-6700光谱仪。将每种聚合物的粉末研磨后放置在干燥KBr盘，并以4cm-1的分辨率进行32次扫描记录光谱。红外光谱结果如图4所示，通过图4所示的FTIR证实了羧甲基壳聚糖和醛化黄原胶的成功制备。壳聚糖和羧甲基壳聚糖均显示了1340cm-1附近的多糖结构的特征吸收带(C-C-H和O-C-H振荡)和1100cm-1(C-O振荡)。与壳聚糖相比，由于COO-基团的不对称和对称伸缩振动，羧甲基壳聚糖在1610cm-1和1432cm-1处具有特征吸收带。在黄原胶和醛 化黄原胶中，也观察到多糖结构的典型吸收带。此外，在1740cm-1处是C＝O组伸缩振动，其在醛化黄原胶中比在黄原胶中更明显。上述结果表明，对黄原胶的醛化和对壳聚糖的羧甲基化成功。
体外毒性检测：通过浸提液法评估水凝胶的安全性。首先，在24孔板中充分制备了Xan-CHO/NOCC水凝胶(1％∶0.33％)，随后用10％FBS(胎牛血清)的DMEM(培养基)在37℃下提取24h，然后进行原液的连续稀释，得到浸出液的不同浓度(100％，50％，25％，12.5％)；将成纤维细胞与浸提液(200μL)共培养48h，接着，每孔加入10μLCCK-8，37℃孵育4h，待溶液均质后，测定450nm处的吸光度。体外毒性检测结果如图5所示，通过图5可以发现，无论浸提液与新鲜培养基以何种比例混合，都不会影响细胞的增殖，因此，本发明制备的醛化黄原胶/羧甲基壳聚糖水凝胶是安全无毒的。
抗消化酶酶解试验：在6孔板中制备了三块X-CHO/NOCC水凝胶(1％∶0.33％)和纤维蛋白凝胶，然后在37℃下浸入新鲜的十二指肠液中。十二指肠液每六h更换一次。6h，12h，24h，48h和72h后，取出水凝胶块，并用薄纸立即擦去表面水分。然后测量水凝胶的重量，之后将它们放回6孔板中。抗消化酶酶解试验结果如图6所示，图6结果显示本发明制备的醛化黄原胶/羧甲基壳聚糖水凝胶的抗酶解能力相比商品化的纤维蛋白胶具体显著的优势。
实施例2
1、醛化黄原胶的合成：制备0.5％(w/v)黄原胶水溶液和5％(w/v)NaIO4水溶液，然后将黄原胶水溶液倒入烧杯中并滴加NaIO4水溶液(黄原胶与NaIO4的摩尔比为1∶1)；之后，将混合液在暗室中继续搅拌2h；然后加入1ml乙二醇以中和未反应的NaIO4，将反应物再搅拌1h，并使用透析袋用蒸馏水纯化溶液2天，在透析过程中每天更新8次水；最后，将Xan-CHO产品在冷冻干燥机中冷冻干燥，然后在4℃的密封塑料袋中储存。
2、羧甲基壳聚糖的合成：将10g壳聚糖悬浮于50ml异丙醇中，然后在室温下搅拌，将20ml 5mol/L NaOH水溶液等分成5份，并以5min间隔依次加入到搅拌浆液中；之后，将所得浆液搅拌20min，滴加20g一氯乙酸，然后加热至55℃搅拌2h 。随后，将反应混合物过滤后，再将过滤残余物用70％(v/v)甲醇/水混合物彻底洗涤5次，用乙醇循环4次，最后通过真空干燥得到羧甲基壳聚糖。
3、醛化黄原胶/羧甲基壳聚糖水凝胶的合成：将所述醛化黄原胶与羧甲基壳聚糖按重量百分比1％∶0.33％溶于水中在孔板中成胶生成醛化黄原胶/羧甲基壳聚糖水凝胶。
将本实施例制备的醛化黄原胶/羧甲基壳聚糖水凝胶，进行与实施例1同样的红外光谱检测、体外毒性检测、以及抗消化酶酶解试验，结果发现本实施制备的醛化黄原胶/羧甲基壳聚糖水凝胶，同样具有无毒性和显著的抗酶解能力。
实施例3
1、醛化黄原胶的合成：制备2％(w/v)黄原胶水溶液和20％(w/v)NaIO4水溶液，然后将黄原胶水溶液倒入烧杯中并滴加NaIO4水溶液(黄原胶与NaIO4的摩尔比为1∶3)；之后，将混合液在暗室中继续搅拌4h；然后加入3ml乙二醇以中和未反应的NaIO4，将反应物再搅拌2h，并使用透析袋用蒸馏水纯化溶液4天，在透析过程中每天更新5次水；最后，将Xan-CHO产品在冷冻干燥机中冷冻干燥，然后在4℃的密封塑料袋中储存。
2、羧甲基壳聚糖的合成：将20g壳聚糖悬浮于100ml异丙醇中，然后在室温下搅拌，将40ml 15mol/L NaOH水溶液等分成5份，并以5min间隔依次加入到搅拌浆液中；之后，将所得浆液搅拌40min，滴加30g一氯乙酸，然后加热至65℃搅拌4h。随后，将反应混合物过滤后，再将过滤残余物用90％(v/v)甲醇/水混合物彻底洗涤3次，用乙醇循环2次，最后通过真空干燥得到羧甲基壳聚糖。
3、醛化黄原胶/羧甲基壳聚糖水凝胶的合成：将所述醛化黄原胶与羧甲基壳聚糖按重量百分比1％∶0.33％溶于水中在孔板中成胶生成醛化黄原胶/羧甲基壳聚糖水凝胶。
将本实施例制备的醛化黄原胶/羧甲基壳聚糖水凝胶，进行与实施例1同样的红外光谱检测、体外毒性检测、以及抗消化酶酶解试验，结果发现本实施制备的醛化黄原胶/羧甲基壳聚糖水凝胶，同样具有无毒性和显著的抗酶解能力。
综上所述，本发明提供了一种可注射水凝胶及其制备方法与应用，本发明通过利用天然多糖进行官能团修饰后合成的可注射水凝胶，安全无毒，成本低廉， 抗酶解能力显著。
应当理解的是，本发明的应用不限于上述的举例，对本领域普通技术人员来说，可以根据上述说明加以改进或变换，所有这些改进和变换都应属于本发明所附权利要求的保护范围。

Claims (8)

  1. 一种可注射水凝胶的制备方法，其特征在于，包括：
    步骤A、将10～20g壳聚糖悬浮于50～100ml异丙醇中，加入20～40ml 5～15mol/L NaOH水溶液，在室温下搅拌20～40min，再滴加20～30g一氯乙酸，加热至55～65℃搅拌2～4h后，过滤、洗涤、干燥，得到羧甲基壳聚糖；
    步骤B、按照黄原胶和高碘酸钠的摩尔比为1∶1～3，将高碘酸钠水溶液滴加到黄原胶水溶液中，在暗室中搅拌反应2～4h，再加入乙二醇继续搅拌1～2h，然后透析纯化反应溶液，得到醛化黄原胶；
    步骤C、将所述醛化黄原胶与所述羧甲基壳聚糖进行交联反应生成可注射水凝胶。
  2. 根据权利要求1所述的可注射水凝胶的制备方法，其特征在于，所述步骤A中，过滤、洗涤、干燥的步骤具体包括：过滤后，将过滤的残余物用体积比为70～90％的甲醇/水混合溶液洗涤3～5次，然后用乙醇洗涤2～4次，最后通过真空干燥得到所述羧甲基壳聚糖。
  3. 根据权利要求1所述的可注射水凝胶的制备方法，其特征在于，所述步骤B中，所述黄原胶水溶液的质量体积比为0.5～2.0％，所述高碘酸钠水溶液的质量体积比为5～20％。
  4. 根据权利要求1所述的可注射水凝胶的制备方法，其特征在于，所述步骤B中，透析纯化反应溶液时，使用透析袋用蒸馏水透析纯化反应溶液，透析2～4天，每天至少更新5次水。
  5. 一种可注射水凝胶，其特征在于，采用如权利要求1～4任一项所述的制备方法制成。
  6. 一种可注射水凝胶，其特征在于，包括醛化黄原胶和羧甲基壳聚糖，其中，所述醛化黄原胶的结构式为：
    Figure PCTCN2017096207-appb-100001
    ，n为大于1的整数。
  7. 一种可注射水凝胶，其特征在于，所述可注射水凝胶的结构式为：
    Figure PCTCN2017096207-appb-100002
    ，其中，m、n均为大于1的整数。
  8. 一种可注射水凝胶的应用，其特征在于，将如权利要求5～7任一项 所述的可注射水凝胶应用于制备肠瘘封堵的材料。
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