WO2021007899A1 - 一种可注射水凝胶材料及其制备方法、应用 - Google Patents

一种可注射水凝胶材料及其制备方法、应用 Download PDF

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WO2021007899A1
WO2021007899A1 PCT/CN2019/100764 CN2019100764W WO2021007899A1 WO 2021007899 A1 WO2021007899 A1 WO 2021007899A1 CN 2019100764 W CN2019100764 W CN 2019100764W WO 2021007899 A1 WO2021007899 A1 WO 2021007899A1
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injectable hydrogel
hydrogel material
component
aldehyde
material according
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French (fr)
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王旭
陈思
王成
严森祥
吴凌云
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浙江工业大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
    • A61K49/0457—Semi-solid forms, ointments, gels, hydrogels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/12—Macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1803—Semi-solid preparations, e.g. ointments, gels, hydrogels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • 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
    • C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; 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
    • C08J2405/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00

Definitions

  • the invention relates to the technical field of medical polymer materials, in particular to an injectable hydrogel material and a preparation method and application thereof.
  • diagnosis and treatment is an emerging medical technology that organically combines the diagnosis and treatment of diseases.
  • diagnostic components and therapeutic components it is expected to realize accurate and timely treatment while discovering diseases to avoid further deterioration. This is especially important for cancer.
  • Cancer treatments are generally surgery, chemotherapy, and radiotherapy.
  • Chemotherapy and radiotherapy have serious side effects, and it is difficult to identify tumor tissues during surgery. Therefore, the targeted treatment of the lesions during the diagnosis period is expected to give timely and effective treatment when they are detected early to reduce the chance of deterioration and spread.
  • multi-modal visualization is related to the amount of information that the material can monitor in the body and directly affects the accuracy of diagnosis.
  • the difference between the hardness of the tumor and the surrounding tissue is small, there is no envelope and border, and the tumor tissue is easy to move, and it is difficult to have a fixed position. This makes it difficult to completely identify and remove the tumor site during surgery, causing hidden dangers. Therefore, in the diagnosis process, a visualizable substance is used to mark the diseased tissue, so that the lesion can be accurately identified during surgery and the purpose of precise treatment can be achieved.
  • the implanted imaging material can be degraded in the body, subsequent removal operations can be avoided.
  • the degradation time is controllable, it is expected to realize personalized and customized treatment, and design an appropriate body time for different patients.
  • the development of a diagnosis and treatment material that integrates marking, identification, protection and treatment has significant practical significance.
  • hydrogel materials have become an emerging material in the field of biomedicine. It has applications in the fields of drug delivery systems, tissue engineering, and environmentally responsive biomaterials.
  • Hydrogel is a polymer with a three-dimensional cross-linked network, with high water content and soft elastic properties. Injectable hydrogels use the sol-gel transition point. After a liquid sol is injected into the body, it uses temperature, pH, and other stimuli to respond to changes to form a gel in the body. It can avoid surgical implantation, greatly reduce the cost and relieve the suffering of patients.
  • the dual injection technology can deliver the matrix and the cross-linking agent into the body by two-component co-injection, forming a chemically cross-linked gel in situ in the body, which can solve the slow gel formation rate and weak gel strength of the physical gel The problem.
  • the Chinese patent document discloses "temperature-sensitive injectable hydrogel loaded with adipose stem cell exosomes and its preparation method and application", the application publication number is CN109568665A, the temperature-sensitive type of the invention loaded with adipose stem cell exosomes can be Injection hydrogels include temperature-sensitive injectable hydrogels and adipose stem cell exosomes.
  • the temperature-sensitive injectable hydrogels contain chitosan, nano-hydroxyapatite-collagen and sodium ⁇ -glycerophosphate.
  • the temperature-sensitive injectable hydrogel loaded with adipose stem cell exosomes has the disadvantages of slow coagulation and low strength, which is not conducive to the fixed-point molding of the gel after injection and long-term exercise tolerance.
  • the present invention provides a Injectable hydrogel material with good exercise tolerance, high biocompatibility and biodegradability, multi-modal imaging and controllable degradation functions.
  • the invention also provides a method for preparing an injectable hydrogel material.
  • the raw material biopolysaccharide has a wide range of sources and is low in cost.
  • the gel formed by cross-linking by Schiff base reaction has the advantage of fast gelling speed, simple steps and simple preparation. The obtained medicine is easy to store.
  • the invention also provides an application of the injectable hydrogel material in the integration of diagnosis and treatment.
  • an injectable hydrogel material characterized in that, the injectable hydrogel material is produced in situ by equal volume injection of component A and component B using a dual injection process; the component A is carboxymethyl For chitosan, the B component is obtained by reacting a dialdehyde polysaccharide with an auxiliary cross-linking agent and an aldehyde-based contrast agent.
  • the present invention uses biopolysaccharide as raw material and modifies it so that the two components can be chemically cross-linked to prepare a pure natural biopolysaccharide-based injectable hydrogel; the degradation mechanism is studied, and different formulas are designed to predict the degradation of the gel , Realize customized treatment; load iodine contrast agent, liposome microbubbles, enhance the traceability in vivo, and build a multi-modal imaging system of MR, CT, and ultrasound.
  • the injectable hydrogel provided by the present invention is a gel formed by cross-linking of Schiff base reaction, which has the advantage of fast gelation speed, and the Schiff base bond is a dynamic reversible covalent bond, which gives the gel self-repair Performance, good resistance to sports fatigue.
  • the cross-linking network of macromolecular polyaldehydes has higher integrity and adjustability, thereby giving the gel better elasticity and gel strength.
  • the injectable hydrogel based on Schiff base reaction with biopolysaccharide as raw material has great application prospects in the integration of diagnosis and treatment.
  • prostate cancer radiotherapy can damage the normal tissues around the prostate. Even if the latest technologies such as intensity modulated radiation therapy (IMRT) and image guided radiation therapy (Image guided radiation therapy, IGRT) are used, the rectum can be better protected. Wait for the surrounding tissues, but as the radiation dose increases, the front wall of the rectum will still receive high doses of radiation. Therefore, radiation oncologists try to create a "temporary space" between the prostate and rectum with biologically inert substances to reduce the radiation dose received by the rectum, which is called "spacing" technology.
  • the injectable hydrogel has biocompatibility and biodegradability, can avoid surgical implantation of spacers, greatly simplifies the technology, and significantly reduces the suffering of patients.
  • hydrogel material has the function of multi-modal imaging, it will not only protect the rectum in the application of this technology, but also guide imaging diagnosis and monitor the position and shape of the gel during treatment.
  • the carboxymethyl chitosan is prepared according to the following method: chitosan suspension is swelled with sodium hydroxide at 50-80°C for 1 to 3 hours; monochloroacetic acid is dissolved in a In propanol, it is added dropwise to the chitosan suspension at 60-90°C, and after reacting for 3 to 4 hours, a crude product is obtained; after washing and drying, carboxymethyl chitosan is obtained.
  • the dialdehyde polysaccharide is prepared according to the following method: dissolve the biopolysaccharide in water, add sodium periodate solution dropwise in the dark, react at room temperature for 2-24 hours, centrifuge to obtain the clear liquid, and then use anhydrous The product is precipitated by ethanol and dried to obtain the dialdehyde polysaccharide.
  • Natural polysaccharides are rich in hydroxyl groups, amino groups and other groups.
  • the aldehyde groups and amino groups required for Schiff base reaction can be obtained through simple reaction treatment.
  • the biopolysaccharide is selected from one of sodium alginate, hyaluronic acid, heparin, chondroitin sulfate, dextran, guar gum, xanthan gum, starch, dextrin, gum arabic and carrageenan; Guar gum is preferred.
  • the aldehyde-based contrast agent is prepared by oxidizing and purifying the iodine-based contrast agent with an aldehyde-based oxidant.
  • the purification is separation and purification by column chromatography.
  • the iodine contrast agent is selected from one of iopromide, iopamidol, meglumine diatrizoate, iohexol, sodium diatrizoate, iodized oil and iodixanol; preferably iopamidol;
  • the aldehyde-based oxidant is selected from one of active manganese dioxide, sodium periodate, Swern reagent, DMP reagent, TEMPO reagent, Jones reagent and Collins reagent; preferably sodium periodate and active manganese dioxide .
  • the aldehyde-based oxidant is sodium periodate, and the oxidation time is controlled within 2-6 hours.
  • the aldehyde-based oxidant is active manganese dioxide, the oxidation temperature is 50-80°C, and the oxidation time is 6-12h.
  • a preparation method of injectable hydrogel material includes the following steps:
  • auxiliary crosslinking agent includes polyvinyl alcohol 1798 and polyvinyl alcohol 1788 , Polyvinyl alcohol 1750, PEG-200, PEG-400, PEG-600, PEG-1000, PEG4000, PEG-10000, etc.
  • polyvinyl alcohol 1798 is preferred; this step is mixed and reacted under normal temperature conditions;
  • the total volume is the benchmark, and the volume fraction of each component is: carboxymethyl chitosan 30%-50%; dialdehyde polysaccharide 20%-35%; auxiliary crosslinking agent 10%-15%; aldehyde-based contrast agent 5% ⁇ 10%;
  • the injectable hydrogel material can be generated in situ within a few seconds; the gel formed by the cross-linking of the Schiff base reaction has a gel forming The advantage of speed.
  • the present invention takes water-soluble modified chitosan as the first component, and aldehyde-modified biopolysaccharide, modified iodine contrast agent, liposome microbubbles, and auxiliary crosslinking solution as the second group
  • the amino group and the aldehyde group undergo a Schiff base cross-linking reaction to form a gel.
  • the contrast agent is grafted on the molecular chain of the gel in the form of a chemical reaction, so that the hydrogel spacer is loaded CT contrast agent and ultrasound contrast agent can realize multi-modal imaging, which provides a basis for flexible monitoring and tracking after implantation. As the entire treatment cycle progresses, it can play the role of imaging and tracing, which can realize the development time and degradation time Synchronicity.
  • An injectable hydrogel material is used in the integration of diagnosis and treatment.
  • the present invention has the following beneficial effects:
  • the injectable hydrogel material of the present invention has good exercise tolerance, meets the requirements of biocompatibility and biodegradability, and also has the functions of multi-modal development and controllable degradation to achieve integrated protection and display. Multi-functional effects such as tracking and customized treatment;
  • the raw material biopolysaccharide has a wide range of sources and low cost.
  • the gel formed by Schiff base reaction cross-linking has the advantages of fast gelation speed, simple steps, easy storage of the prepared medicine, and is expected to realize industrial production and clinical application;
  • Figure 1 is a low-magnification SEM image of the injectable hydrogel material prepared in Example 1.
  • Example 2 is a high-magnification SEM image of the injectable hydrogel material prepared in Example 1.
  • Figure 3 is a graph showing changes in storage modulus (G') and loss modulus (G") of the injectable hydrogel materials prepared in Examples 1-5 with frequency.
  • dialdehyde guar gum was prepared into 3.0 mL of a 2% mass fraction solution, and 1.5 mL of polyvinyl alcohol 1798 solution (2 wt%) and 0.5 mL of aldehyde-based iohexol injection were added to form group B Minute;
  • the time from the start of the injection to the end when the sol stops flowing is counted as the gel time.
  • the injectable hydrogel material has a dense pore structure , The pore diameter is about 5 ⁇ m, and the holes are perfect.
  • the pore structure can hold a large amount of water and provide the possibility for drug loading, and the density and perfection of the pores affect the strength of the gel body. This is the reason why the gel has higher drug-carrying capacity and gel strength.
  • Example 2- The difference between Example 5 and Example 1 is that in step (5), the formula of component B is different, see Table 1, and the rest of the process is completely the same.
  • Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that in step (5), the formula of component B is different, see Table 1, and the rest of the process is completely the same.
  • Example 1 5mL 1mL 3.5mL 76-106s
  • Example 2 5mL 2mL 2.5mL 23-42s
  • Example 3 5mL 3mL 1.5mL 8-15s
  • Example 4 5mL 4mL 0.5mL 25-36s
  • Example 5 5mL 4.5mL 0 32-39s Comparative example 1 5mL 10mL 0 72-96s
  • the gel time is related to the amount of crosslinking agent added. This is because the amount of crosslinking agent added affects the final concentration of the two components after mixing. The higher the concentration, the faster the reaction. However, since the amino group and the aldehyde group react equimolarly, the reaction activity is best when the group ratio is 1:1. Therefore, when the amount of addition exceeds the number of amino groups, the gel time will become longer.
  • the injectable hydrogel materials prepared in Examples 1-5 were placed in an advanced expansion rheometer, the scanning strain and temperature were fixed, and the relationship between the modulus and the frequency was tested. The results are shown in Fig. 3: As the added amount increases, the elastic modulus tends to rise, which means the elasticity of the gel increases. When the addition amount exceeds a certain range, the elasticity does not increase further, because the amino group is consumed and the degree of crosslinking does not continue to increase.
  • the material implanted in the body needs to have a modulus similar to that of human tissue. The modulus of most soft tissues is 2000-5000Pa, and the modulus of this gel can be located in this area, which is suitable for use as an integrated material for diagnosis and treatment.

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Abstract

一种可注射水凝胶材料，由A组分和B组分采用双联注射工艺等体积注射原位生成；所述A组分为羧甲基壳聚糖，所述B组分由双醛化多糖与辅助交联剂、醛基化造影剂反应得到。所述可注射水凝胶材料用于医用高分子材料技术领域，解决了现有可注射型水凝胶凝结慢、强度低、生物相容性和生物可降解性差，不利于注射后凝胶的定点成型和长期运动耐受性的问题；获得的可注射水凝胶材料运动耐受性好、满足生物相容和生物可降解的要求之上，还具备多模态显影、可控降解的功能，达到集保护、示踪、定制化治疗等多功能于一体的效果，在诊疗一体化领域具有广阔的应用前景。

Description

一种可注射水凝胶材料及其制备方法、应用 技术领域
本发明涉及医用高分子材料技术领域，尤其涉及一种可注射水凝胶材料及其制备方法、应用。
背景技术
诊疗一体化是一种将疾病的诊断和治疗有机结合起来的新兴医学技术，通过诊断组份和治疗组分的结合，有望实现在发现疾病的同时，精准、及时治疗，避免进一步恶化。这对于癌症而言尤为重要。癌症的治疗手段一般是手术、化疗、放疗。化疗、放疗的副作用大，手术过程中肿瘤组织难以识别。因此在诊断期间对病灶进行定点治疗，有望在早期发现时给予及时有效的治疗，减少恶化、扩散的几率。
在诊疗一体化材料开发过程中，多模态显影关系到材料在体内可监控的信息量，直接影响到诊断的精准性。肿瘤在软硬度上和周边组织的差异性小，没有包膜和边界，且肿瘤组织易活动，难有固定位置。这就使得在手术时难以完整的识别和切除肿瘤部位，造成隐患。因此，在诊断过程中，用一种可显影物质对病变组织进行标记，使手术时可以准确识别病灶，达到精准治疗的目的。另一方面，植入的显影物质若可在体内降解，则可避免后续取出手术。理想情况下，根据不同病人的治疗周期需求不同，若降解的时间可控，则有望实现个性化定制治疗，针对不同病患，设计合适的体内存在时间。鉴于现今肿瘤的发病率逐年上升，开发一款集标记、识别、保护、治疗于一体的诊疗材料具有显著的现实意义。
近年来，水凝胶材料已成为生物医用领域的新兴材料，它在药物递送系统、组织工程学和环境响应性生物材料领域都有所应用。水凝胶是一种具有三维交联网络的聚合物，具有高含水量、软弹的性质。可注射型水凝胶是利用溶胶-凝胶转变点，将液态的溶胶注射入体内后，利用温度、pH值等刺激响应发生转变，在体内形成凝胶。它可以避免手术植入，极大的降低了成本，减轻病患痛苦。
传统的可注射水凝胶多为温敏型凝胶，利用体温完成溶胶-凝胶转变。但温敏凝胶本质上是一种物理交联型凝胶，存在凝结慢、强度低等缺点，不利于注射 后凝胶的定点成型和长期运动耐受性。采用双联注射技术可以将基体和交联剂以两组分共注射的方式送入体内，在体内原位形成化学交联型凝胶，可以解决物理凝胶成胶速率慢和凝胶强度弱的问题。但大多数化学交联剂具有生物毒性，而生物交联剂京尼平交联反应时间过长，无法满足注射后凝胶的定点成型效果。因此开发具有生物安全性的化学交联凝胶体系尤为重要。本世纪初，采用辐照交联的聚乙烯醇(PVA)水凝胶和聚乙烯吡咯烷酮(PVP)水凝胶用作人工玻璃体的研究已经十分成熟。它们被证实具有可靠的生物安全性，但因是人工合成高分子而难以降解。近年来，研究发现以天然的生物高分子材料作为凝胶基体，可兼得生物相容性和生物可降解性，如海藻酸钠、透明质酸、黄原胶、葡聚糖等。
中国专利文献上公开了“负载脂肪干细胞外泌体的温敏型可注射水凝胶及其制备方法和应用”，申请公布号为CN109568665A，该发明的负载脂肪干细胞外泌体的温敏型可注射水凝胶包括温敏型可注射水凝胶和脂肪干细胞外泌体，所述温敏型可注射水凝胶含有壳聚糖、纳米羟基磷灰石-胶原和β-甘油磷酸钠。但是，该负载脂肪干细胞外泌体的温敏型可注射水凝胶存在凝结慢、强度低等缺点，不利于注射后凝胶的定点成型和长期运动耐受性。
发明内容
本发明为了克服现有可注射型水凝胶凝结慢、强度低、生物相容性和生物可降解性差，不利于注射后凝胶的定点成型和长期运动耐受性的问题，提供了一种运动耐受性好、生物相容和生物可降解性高，具备多模态显影、可控降解功能的可注射水凝胶材料。
本发明还提供了一种可注射水凝胶材料的制备方法，原料生物多糖来源广泛，成本低廉，利用席夫碱反应交联形成的凝胶，具有成胶速度快的优势，步骤简便，制得的药剂易保存。
本发明还提供了一种可注射水凝胶材料在诊疗一体化中的应用。
为了实现上述目的，本发明采用以下技术方案：
一种可注射水凝胶材料，其特征在于，所述可注射水凝胶材料由A组分和B组分采用双联注射工艺等体积注射原位生成；所述A组分为羧甲基壳聚糖，所述B组分由双醛化多糖与辅助交联剂、醛基化造影剂反应得到。
本发明以生物多糖为原料，对其改性，使两组分可发生化学交联，制备成纯天然生物多糖基可注射水凝胶；研究其降解机理，设计不同配方使凝胶降解可预期，实现定制化治疗；负载碘造影剂、脂质体微泡，增强体内示踪性，构筑MR、CT、超声多模态显影体系。本发明所提供的可注射水凝胶是利用席夫碱反应交联形成的凝胶，具有成胶速度快的优势，且席夫碱键是一种动态可逆共价键，赋予凝胶自修复性能，耐运动疲劳性好。而且，相比于戊二醛等小分子醛基交联剂，大分子多元醛的交联网络具有更高的完整性和可调节性，从而赋予凝胶更好的弹性和凝胶强度。此外，生物多糖链上存有的大量羟基活性位点，为药物负载带来可能。因此，以生物多糖为原料，基于席夫碱反应的可注射型水凝胶在诊疗一体化上具有很大的应用前景。
例如，前列腺癌放疗会给前列腺周边正常组织带来损伤，即便采用最新技术如调强放疗(Intensity modulated radiation therapy，IMRT)和影像引导放疗(Image guided radiation therapy，IGRT)等，能较好保护直肠等周围组织，但随着放疗剂量的增加，直肠前壁仍会受到高剂量辐射。因此，放射肿瘤学家尝试以生物惰性物质在前列腺和直肠间创造一个“临时空间”以减少直肠受到的辐射剂量，称为“间隔”(“Spacing”)技术。可注射水凝胶具有生物相容性和生物可降解性，能避免手术植入间隔物，将该项技术大幅简化，显著降低患者痛苦，且对于熟悉近距离治疗的放射肿瘤学家而言，注射操作容易掌握。若水凝胶材料具有多模态显影的功能，则在该项技术应用中不仅具有保护直肠的作用，还可以指导影像诊断，在治疗过程中监控凝胶位置、形态。
作为优选，所述羧甲基壳聚糖按照以下方法制得：将壳聚糖用氢氧化钠在50～80℃下溶胀1～3h的壳聚糖混悬液；将一氯乙酸溶解在异丙醇中，于60～90℃下滴加到壳聚糖混悬液中，反应3～4h后，得到粗产物；经洗涤，干燥，得到羧甲基壳聚糖。
作为优选，所述双醛化多糖按照以下方法制得：将生物多糖溶于水中，于黑暗中滴加高碘酸钠溶液，在室温下反应2～24h，离心取清液，再用无水乙醇沉淀出产物，干燥即得双醛化多糖。
天然多糖中多含有丰富的羟基、氨基等集团，可经过简单的反应处理获得席夫碱反应所需的醛基、氨基。
作为优选，所述生物多糖选自海藻酸钠、透明质酸、肝素、硫酸软骨素、葡聚糖、瓜尔胶、黄原胶、淀粉、糊精、阿拉伯胶和卡拉胶中的一种；优选瓜尔胶。
作为优选，所述醛基化造影剂由碘造影剂经醛基化氧化剂氧化、提纯制得。所述提纯为柱色谱分离提纯。
作为优选，所述碘造影剂选自碘普罗胺、碘帕醇、泛影葡胺、碘海醇、泛影酸钠、碘化油和碘克沙醇中的一种；优选碘帕醇；
作为优选，所述醛基化氧化剂选自活性二氧化锰、高碘酸钠、Swern试剂、DMP试剂、TEMPO试剂、Jones试剂和Collins试剂中的一种；优选高碘酸钠和活性二氧化锰。
作为优选，所述醛基化氧化剂为高碘酸钠，氧化时间控制在2～6h。
作为优选，所述醛基化氧化剂为活性二氧化锰，氧化温度为50～80℃，氧化时间为6～12h。
一种可注射水凝胶材料的制备方法，包括以下步骤：
(1)配置1～5wt％的羧甲基壳聚糖溶液，得A组分；
(2)在1～5wt％的双醛化多糖溶液中，加入辅助交联剂溶液和醛基化造影剂，得到B组分；所述辅助交联剂包含聚乙烯醇1798、聚乙烯醇1788、聚乙烯醇1750、PEG-200、PEG-400、PEG-600、PEG-1000、PEG4000、PEG-10000等，本专利中优选聚乙烯醇1798；该步骤于常温条件混合反应；以混合后的总体积为基准，各组分的体积分数为：羧甲基壳聚糖30％～50％；双醛化多糖20％～35％；辅助交联剂10％～15％；醛基化造影剂5％～10％；
(3)采用双联注射工艺将A组分和B组分，等体积注射，即可数秒内原位生成可注射水凝胶材料；利用席夫碱反应交联形成的凝胶，具有成胶速度快的优势。
本发明以水溶化改性后的壳聚糖为第一组分，以醛基化改性后的生物多糖、改性的碘造影剂、脂质体微泡、辅助交联溶液为第二组份，两组分通过双联注射形式混合后氨基和醛基发生席夫碱交联反应形成凝胶，造影剂以化学反应的形式接枝在凝胶分子链上，使得水凝胶间隔物负载CT造影剂、超声造影剂，可实现多模态显影，为植入后的灵活监测、跟踪提供基础，随着整个治疗周期的进行，都能发挥显影示踪作用，可实现显影时长与降解时长的同步性。
一种可注射水凝胶材料在诊疗一体化中的应用。
因此，本发明具有如下有益效果：
(1)本发明的可注射水凝胶材料的运动耐受性好、满足生物相容和生物可降解的要求之上，还具备多模态显影、可控降解的功能，达到集保护、示踪、定制化治疗等多功能于一体的效果；
(2)原料生物多糖来源广泛，成本低廉，利用席夫碱反应交联形成的凝胶，具有成胶速度快的优势，步骤简便，制得的药剂易保存，有望实现工业化生产和临床应用；
(3)凝胶降解可预期，实现定制化治疗，负载碘造影剂、脂质体微泡，增强体内示踪性，构筑MR、CT、超声多模态显影体系，能够为该类天然高分子的生物医学应用提供理论指导和实验基础，以注射的形式植入水凝胶间隔物，避免手术植入带来的痛苦和成本，且具有相对较快的学习曲线，对临床转化意义重大，在诊疗一体化领域具有广阔的应用前景。
附图说明
图1是实施例1制得的可注射水凝胶材料的低倍率SEM图。
图2是实施例1制得的可注射水凝胶材料的高倍率SEM图。
图3是实施例1-5制得的可注射水凝胶材料的储能模量(G’)、损耗模量(G”)随频率变化图。
具体实施方式
下面通过具体实施例，并结合附图，对本发明的技术方案作进一步具体的说明。
在本发明中，若非特指，所有设备和原料均可从市场购得或是本行业常用的，下述实施例中的方法，如无特别说明，均为本领域常规方法。
实施例1
(1)精确称量10.0g壳聚糖、10g氢氧化钠于三口烧瓶中，加入100mL异丙醇溶剂，50℃下溶胀3小时；精确称量10.0g一氯乙酸并溶解在20mL异丙醇中。将氯乙酸溶液缓慢滴加至壳聚糖碱液中反应12h；倒入200mL无水乙醇洗涤产物，过滤、干燥即得到羧甲基壳聚糖；
(2)精确称量1.0g瓜尔胶，溶解在100mL水中，室温下于黑暗中滴加10ml高碘酸钠溶液(0.1g/mL)反应2h。离心去渣，乙醇沉淀出产物，干燥得双醛瓜尔胶；
(3)量取10mL碘海醇注射液，室温下于黑暗中滴加1mL高碘酸钠溶液(0.1g/mL)反应1h；经柱色谱分离纯化后得到醛基化碘海醇溶液；
(4)将上述羧甲基壳聚糖配置成5.0mL质量分数为2％的溶液，即得A组分；
(5)将上述双醛瓜尔胶配成3.0mL质量分数为2％的溶液，并加入1.5mL聚乙烯醇1798溶液(2wt％)、0.5mL醛基化的碘海醇注射液形成B组分；
(6)分别吸取等量的A、B两组分混合液，通过双联注射得到水凝胶间隔物，即为可注射水凝胶材料。
从开始注射时计时，到溶胶停止流动时结束，计为凝胶时间。
将凝胶冻住后，置于冷冻干燥机中抽干，制成干凝胶。对干凝胶表面喷金处理，与扫描电镜下观察其表面形貌，其SEM图如图1和图2所示，从图中可以看出，该可注射水凝胶材料具有密集的孔洞结构，孔径在5μm左右，孔洞完善。孔洞结构可以保持大量水分，为药物负载提供可能性，且孔洞的密集程度和完善程度影响着其凝胶本体的强度。这是该凝胶具有较高的载药能力和凝胶强度的原因。
实施例2-实施例5
实施例2-实施例5与实施例1的区别在于，步骤(5)中，B组分的配方不同，参见表1，其余工艺完全相同。
对比例1
对比例1与实施例1的区别在于，步骤(5)中，B组分的配方不同，参见表1，其余工艺完全相同。
表1.实施例1-5和对比例1的B组分配方及凝胶时间
编号 羧甲基壳聚糖 醛基多糖 辅助交联剂 凝胶时间
实施例1 5mL 1mL 3.5mL 76-106s
实施例2 5mL 2mL 2.5mL 23-42s
实施例3 5mL 3mL 1.5mL 8-15s
实施例4 5mL 4mL 0.5mL 25-36s
实施例5 5mL 4.5mL 0 32-39s
对比例1 5mL 10mL 0 72-96s
由表1可以看出，凝胶时间与交联剂添加量有关，这是因为交联剂的加入量影响最终的两组分混合后的浓度，浓度越高反应越快。但由于氨基和醛基是等摩尔反应，当基团比为1∶1时反应活性最佳。因此，当添加量超过氨基的基团数后会出现凝胶时间变长。
将实施例1-5制得的可注射水凝胶材料置于高级拓展流变仪，固定扫描应变和温度，测试模量与频率的关系，结果如图3所示：随着醛基多糖的加入量增加，弹性模量呈现上升的趋势，这意味着凝胶弹性的增加。当添加量超过一定范围后，弹性不再进一步增加，这是因为氨基被消耗完，交联度不再继续增加。对植入体内的材料而言，需要具有与人体组织相近的模量。大部分软体组织的模量在2000-5000Pa，本凝胶的模量恰好可处在该区域，适合用作诊疗一体化材料。
以上所述仅为本发明的较佳实施例，并非对本发明作任何形式上的限制，在不超出权利要求所记载的技术方案的前提下还有其它的变体及改型。

Claims (10)

  1. 一种可注射水凝胶材料，其特征在于，所述可注射水凝胶材料由A组分和B组分采用双联注射工艺等体积注射原位生成；所述A组分为羧甲基壳聚糖，所述B组分由双醛化多糖与辅助交联剂、醛基化造影剂反应得到。
  2. 根据权利要求1所述的一种可注射水凝胶材料，其特征在于，所述羧甲基壳聚糖按照以下方法制得：将壳聚糖用氢氧化钠在50～80℃下溶胀1～3h的壳聚糖混悬液；将一氯乙酸溶解在异丙醇中，于60～90℃下滴加到壳聚糖混悬液中，反应3～4h后，得到粗产物；经洗涤，干燥，得到羧甲基壳聚糖。
  3. 根据权利要求1所述的一种可注射水凝胶材料，其特征在于，所述双醛化多糖按照以下方法制得：将生物多糖溶于水中，于黑暗中滴加高碘酸钠溶液，在室温下反应2～24h，离心取清液，再用无水乙醇沉淀出产物，干燥即得双醛化多糖。
  4. 根据权利要求3所述的一种可注射水凝胶材料，其特征在于，所述生物多糖选自海藻酸钠、透明质酸、肝素、硫酸软骨素、葡聚糖、瓜尔胶、黄原胶、淀粉、糊精、阿拉伯胶和卡拉胶中的一种。
  5. 根据权利要求1所述的一种可注射水凝胶材料，其特征在于，所述醛基化造影剂由碘造影剂经醛基化氧化剂氧化、提纯制得。
  6. 根据权利要求5所述的一种可注射水凝胶材料，其特征在于，所述碘造影剂选自碘普罗胺、碘帕醇、泛影葡胺、碘海醇、泛影酸钠、碘化油和碘克沙醇中的一种；所述醛基化氧化剂选自活性二氧化锰、高碘酸钠、Swern试剂、DMP试剂、TEMPO试剂、Jones试剂和Collins试剂中的一种。
  7. 根据权利要求6所述的一种可注射水凝胶材料，其特征在于，所述醛基化氧化剂为高碘酸钠，氧化时间控制在2～6h。
  8. 根据权利要求6所述的一种可注射水凝胶材料，其特征在于，所述醛基化氧化剂为活性二氧化锰，氧化温度为50～80℃，氧化时间为6～12h。
  9. 一种如权利要求1-8任一所述的可注射水凝胶材料的制备方法，其特征在于，包括以下步骤：
    (1)配置1～5wt％的羧甲基壳聚糖溶液，得A组分；
    (2)在1～5wt％的双醛化多糖溶液中，加入辅助交联剂溶液和醛基化造影剂，得到B组分；
    (3)采用双联注射工艺将A组分和B组分，等体积注射，即可原位生成可注射水凝胶材料。
  10. 一种如权利要求1-8任一所述的可注射水凝胶材料在诊疗一体化中的应用。
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CN114230678A (zh) * 2021-12-13 2022-03-25 珠海通桥医疗科技有限公司 一种用于血管内治疗的光交联水凝胶栓塞系统及使用方法
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CN115887742A (zh) * 2022-03-15 2023-04-04 四川大学 抗菌功能性胶原基可注射自修复水凝胶的制备方法
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CN113754794A (zh) * 2021-08-10 2021-12-07 武汉纺织大学 抗菌性好耐高温可加工的羧甲基壳聚糖流体及其制备方法
CN113754794B (zh) * 2021-08-10 2022-12-23 武汉纺织大学 抗菌性好耐高温可加工的羧甲基壳聚糖流体及其制备方法
CN114230812A (zh) * 2021-12-07 2022-03-25 广东省科学院健康医学研究所 一种功能性水凝胶及其制备方法和应用
CN114230678A (zh) * 2021-12-13 2022-03-25 珠海通桥医疗科技有限公司 一种用于血管内治疗的光交联水凝胶栓塞系统及使用方法
CN114230678B (zh) * 2021-12-13 2023-09-01 珠海通桥医疗科技有限公司 一种用于血管内治疗的光交联水凝胶栓塞系统及使用方法
CN115887742A (zh) * 2022-03-15 2023-04-04 四川大学 抗菌功能性胶原基可注射自修复水凝胶的制备方法
CN115887742B (zh) * 2022-03-15 2024-02-02 四川大学 抗菌功能性胶原基可注射自修复水凝胶的制备方法
CN114796620A (zh) * 2022-04-24 2022-07-29 广东顺德工业设计研究院(广东顺德创新设计研究院) 一种用作医用植入材料的互穿网络水凝胶及其制备方法和应用
CN114796620B (zh) * 2022-04-24 2023-09-29 广东顺德工业设计研究院(广东顺德创新设计研究院) 一种用作医用植入材料的互穿网络水凝胶及其制备方法和应用
CN114939098B (zh) * 2022-05-19 2023-09-26 明德南加(成都)生物技术有限公司 一种负载外泌体的水凝胶及其制备方法和应用
CN114939098A (zh) * 2022-05-19 2022-08-26 明德南加(成都)生物技术有限公司 一种负载外泌体的水凝胶及其制备方法和应用
CN115177748A (zh) * 2022-08-01 2022-10-14 北京大学口腔医学院 碘佛醇在制备体表造影剂中的应用和体表造影剂
CN115651220A (zh) * 2022-10-28 2023-01-31 合肥师范学院 普鲁士蓝/壳聚糖/海藻酸钠复合水凝胶及制备方法与应用
CN116421745A (zh) * 2023-06-14 2023-07-14 中国人民解放军总医院第一医学中心 一种腹腔出血点延时显像造影剂
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