WO2014005471A1 - 一种温敏型可注射壳聚糖水凝胶产品及其应用 - Google Patents

一种温敏型可注射壳聚糖水凝胶产品及其应用 Download PDF

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WO2014005471A1
WO2014005471A1 PCT/CN2013/076362 CN2013076362W WO2014005471A1 WO 2014005471 A1 WO2014005471 A1 WO 2014005471A1 CN 2013076362 W CN2013076362 W CN 2013076362W WO 2014005471 A1 WO2014005471 A1 WO 2014005471A1
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solution
temperature
product
drugs
chitosan hydrogel
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French (fr)
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马小军
添美
于炜婷
谢红国
刘袖洞
谢威杨
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中国科学院大连化学物理研究所
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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
    • 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
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; 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
    • 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
    • C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Definitions

  • the present invention relates to a temperature sensitive hydrogel product, and more particularly to a Genipin crosslinked temperature sensitive injectable chitosan gel product. Background technique
  • Thermosensitive hydrogels are smart materials that respond to changes in temperature and provide a solution-gel transition. By controlling the phase change temperature to match the body temperature, a temperature-sensitive injectable hydrogel can be obtained: a liquid that can flow when it is cold, and when it is injected into a target position, it will rapidly solidify in a physiological environment to form a hydrogel. .
  • the temperature-sensitive properties of the temperature sensitive hydrogel have the following characteristics: 1) The solution is easy to be mixed with drugs or cells at low temperature, and the gel can fix the drug or cells after heating; 2) The solution mixed with the drug or the cell can be transferred by injection or the like. Into the body tissue; 3) can achieve sustained release of the drug (Li Z, Guan J. Thermo sensitive hydrogels for drug delivery.
  • the temperature-sensitive gel also has the common feature of hydrogels, that is, its high water-containing properties make it "soft” similar to the extracellular matrix (a hydrogel system composed of macromolecules such as collagen, polysaccharides, glycoproteins, etc.). "Wet" environment, viscoelasticity and material delivery characteristics (Chen YM, Ogawa R, Kakugo A, et al. Dynamic cell behavior on synthetic hydrogels with different charge densities. Soft Matter, 2009, 5:1804 - 1811). Based on the above characteristics, temperature-sensitive hydrogels have been widely used in biomedical fields such as drug delivery and tissue engineering scaffolds in recent years (Hoffman AS.
  • the materials for preparing temperature-sensitive hydrogels can be classified into natural and synthetic types according to their sources. Among them, natural polymer hydrogels are more similar to extracellular matrices in physical structure and chemical behavior, and become biomaterials in biomedical engineering (Drury JL, Mooney DJ. Hydrogels for tissue engineering: scaffold design variables) And applications. Biomaterials, 2003, 24(24): 4337-4351
  • the preparation methods of temperature sensitive hydrogels are mainly chemical and physical methods. Chemical methods include chemical crosslinking and graft modification. Chemical methods due to crosslinkers or The graft modification catalyst is toxic or difficult to remove for the organism and its application is limited (Huh KM, Cho YW, Chung H, et al.
  • thermosensitive injectable chitosan hydrogel which is invented with a natural crosslinker, genipin cross-linked natural cationic polysaccharide chitosan, which is isolated from genipin. Under the premise of hydrogel strength, the problem of cross-linking toxicity is solved.
  • the temperature-sensitive injectable chitosan hydrogel product of the invention has the shelf life of the two solutions (solution A and solution B) separately, and the volume ratio of the two solutions A and B is 5 at room temperature before use.
  • the ratio of 1-1 :1 is mixed.
  • the mixed solution is in a solution state at room temperature (temperature below 25 ° C). When the temperature rises to 28-42 ° C, it becomes a gel state within 1 hour.
  • the product mainly contains three major components:
  • Component 1 is chitosan, and the concentration of chitosan in the product is 2.0-25.0 g/L;
  • Component 2 is a sodium salt, and the sodium salt concentration in the product is 0.5-10.0 g/L ;
  • Component 3 is genipin, and the concentration of genipin in the product is 0.5-5.0 g/L;
  • Solution A is an acid solution of pH 6.0-7.4, physiological saline or distilled water;
  • Solution B is physiological saline or distilled water
  • component 1 is dissolved in solution A
  • component 3 is dissolved in solution B
  • component 2 is dissolved in solution A or dissolved in solution B.
  • the solution pH of solution A and solution B is between 6.0 and 7.4.
  • the mixed solution was dissolved at 4-25 ° C, and when the temperature rose to 28-42 ° C, it became a gel state for 2 minutes - 1 hour.
  • the chitosan in the product has a molecular weight of 10-1000 kDa and a degree of deacetylation of 50-98%. Chitosan is partially hydrophilic and partially hydrophobic.
  • the sodium salt in the product may be one or more of sodium hydrogencarbonate, sodium phosphate, sodium sulfate or sodium sulfite.
  • the acid solution for dissolving chitosan in the product is an aqueous acetic acid solution, an acetic acid-sodium acetate buffer solution or a hydrochloric acid solution.
  • the product When the product is in use, it can be directly injected into the biological tissue, organ or body cavity of the body or in vivo by means of instillation, injection, or endoscope introduction at a solution state at 4-25 °C.
  • the product can be used as an embedding carrier for cells or drugs for tissue engineering or drug delivery systems.
  • the cells are chondrocytes, fibrocartilage cells, ligament fibroblasts, skin fibroblasts, tendon cells, myofibroblasts, mesenchymal stem cells, or keratinocytes of animal or human origin.
  • the medicine is analgesic, anesthetic, antibacterial, antibiotic, anti-scald, antidepressant, anti-dermatitis, antifungal, antihistamine, anti-keratitis, anti-inflammatory, anti-irritation Agent, antibacterial, antifungal, antioxidant, antiparasitic, antipruritic, antipsoriatic, anti-seborrhoe, antiviral, cardiovascular, chemotherapeutic, corticosteroid, enzyme inhibitor, hormone , steroids, non-organic anti-inflammatory agents, progestins or vitamins.
  • the injectable thermosensitive hydrogel of the present invention is in a solution state at 4-25 ° C, and forms a gel in situ when the temperature is raised to 28-42 ° C. 2.
  • the invention utilizes a natural cross-linking agent and a natural polysaccharide to prepare a temperature-sensitive injectable hydrogel, and the prepared hydrogel can be used as a drug carrier and a tissue engineering scaffold.
  • the invention adopts natural cross-linking agent and natural polysaccharide material, and the prepared hydrogel is biodegradable and biocompatible.
  • Figure 1 is a schematic diagram of the gel mechanism of a temperature sensitive injectable chitosan hydrogel.
  • Figure 2 is a photograph of a temperature-sensitive injectable chitosan hydrogel before and after heating, where a is a solution and b is a hydrogel (after warming).
  • Figure 3 shows the gel time of a temperature-sensitive injectable chitosan hydrogel at 25 °C, 37 °C, and 45 °C.
  • Figure 4 shows the rheological properties of a temperature sensitive injectable chitosan hydrogel.
  • the rheological properties of the temperature sensitive gel were determined using an Anton Paar MCR301 rheometer (equipped with a 25 mm lamina with a cone angle of 1 °). The mixed solution was placed in a cone and covered with mineral oil to prevent evaporation of water. The linear viscoelastic properties of the temperature-sensitive gel (angular frequency range 100 - 0.1 rad/s) were measured at 37 ° C. The results are shown in Fig. 4.
  • the gel time of the temperature sensitive gel at 25 ° C, 37 ° C, and 45 ° C is shown in Figure 3B.
  • the rheological properties are shown in Figure 4. 1.
  • the chitosan having a molecular weight of 1000 kDa and a deacetylation degree of 80% is dissolved in a 10.0 mL/L acetic acid solution at 20.0 g/L, and then the pH is adjusted to 6.2 with 40.0 g/L NaOH to obtain a solution A;

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Abstract

本发明涉及一种温敏型可注射壳聚糖水凝胶。采用天然交联剂京尼平交联天然阳离子多糖壳聚糖制备得到温度低于25℃时为溶液态，温度升至28-42℃时，1小时内变为凝胶的温敏型可注射水凝胶。制备的水凝胶可作为药物载体及组织工程支架使用。

Description

种温敏型可注射壳聚糖水凝胶产品及其应用 技术领域
本发明涉及一种温敏型水凝胶产品，具体地说是一种京尼平交联的温敏型可注射 壳聚糖凝胶产品。 背景技术
温敏水凝胶是一种能够对温度变化做出溶液 -凝胶转变响应的智能材料。 通过控 制其相变温度与人体体温匹配， 即可得到温敏型可注射水凝胶： 低温时是可流动的液 体， 当注射到人体目标位置后， 在生理环境中会快速固化形成水凝胶。温敏水凝胶的 温敏特性使其具有如下特点 1 )低温时溶液易于药物或细胞混合， 升温后凝胶可将药 物或细胞固定； 2)可通过注射等方式将混有药物或细胞的溶液转入体内组织； 3 )可 实现药物的缓控释 (Li Z, Guan J. Thermo sensitive hydrogels for drug delivery. Expert Opin Drug Deliv. 2011, 8(8): 991-1007)。 除此之外， 温敏凝胶还具有水凝胶共有的特 点， 即高含水特性使其具有与细胞外基质 (由胶原、 多糖、 糖蛋白等大分子构成的水 凝胶体系)类似的 "软" "湿"环境、 粘弹性和物质递送等特性 （Chen YM， Ogawa R, Kakugo A, et al. Dynamic cell behavior on synthetic hydrogels with different charge densities. Soft Matter, 2009, 5:1804 - 1811 )。 基于以上特性， 温敏水凝胶近年来被广泛 应用药物传递、 组织工程支架等生物医学领域（Hoffman AS. Hydrogels for biomedical applications. Adv Drug Deliv Rev. 2002, 54(1):3-12. Nicodemus GD, Bryant SJ. Cell encapsulation in biodegradable hydrogels for tissue engineering applications. Tissue Eng Part B Rev. 2008, 14(2): 149-65. Balakrishnan B, Banerjee R. Biopolymer-based hydrogels for cartilage tissue engineering. Chem Rev. 2011, lll(8):4453-74. )。
制备温敏水凝胶的材料按其来源可分为天然和合成两大类。其中， 天然高分子水 凝胶在物理结构和化学行为上与细胞外基质更相似，而成为在生物医学工程中备受瞩 目的生物材料 (Drury JL, Mooney DJ. Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials, 2003, 24(24):4337-4351 温敏水凝胶的制备方 法主要有化学法和物理法两种。化学法又包括化学交联和接枝修饰。化学法由于交联 剂或接枝修饰催化剂对生物体有毒或难以除去而使其应用受到限制 （Huh KM, Cho YW， Chung H, et al. Supramolecular hydro gel formation based on inclusion complexation between poly(ethylene glycol)-modified chitosan and alpha-cyclodextrin. Macro mo 1 Biosci. 2004, 4(2):92-99 物理法主要是通过氢键、 疏水相互作用等成凝胶。 物理法凝胶因 强度低而使其应用受到限制 （Bao G. and Suresh S.， Cell and molecular mechanics of biological materials 2003: Nat Mater. 2(ll):715-25)。 发明内容
针对上述问题，本发明提出用从京尼平甙中分离获得的天然交联剂京尼平交联天 然阳离子多糖壳聚糖，发明了一种温敏可注射型壳聚糖水凝胶，在保证水凝胶强度的 前提下， 解决了交联剂毒性的问题。
技术方案
本发明的温敏型可注射壳聚糖水凝胶产品， 该产品货架期是由两种溶液（溶液 A 与溶液 B) 分别保存， 使用前在室温下将 A、 B两种溶液按体积比 5:1-1 :1 的比例混 合， 混合后的溶液在室温下 （温度低于 25°C ) 为溶液态， 当温度升至 28-42 °C时， 1 小时内变为凝胶态。 其中， 产品中主要含有三大类组分：
组分 1 为壳聚糖， 产品中壳聚糖浓度为 2.0-25.0g/L;
组分 2 为钠盐， 产品中钠盐浓度为 0.5-10.0g/L;
组分 3 为京尼平， 产品中京尼平浓度为 0.5-5.0g/L;
溶液 A为 pH 6.0-7.4 的酸溶液、 生理盐水或蒸馏水；
溶液 B 为生理盐水或蒸馏水；
其中， 组分 1 溶于溶液 A中， 组分 3 溶于溶液 B 中， 组分 2 溶于溶液 A中或 溶于溶液 B 中。
溶液 A与溶液 B混合后的溶液 pH介于 6.0-7.4。 混合后的溶液在 4-25 °C下为溶 液态， 当温度升至 28-42 °C时， 2分钟 -1 小时变为凝胶态。
产品中的壳聚糖分子量为 10-1000 kDa，脱乙酰度为 50-98%。壳聚糖为部分亲水、 部分疏水。
产品中的钠盐可以是碳酸氢钠、磷酸钠、硫酸钠或亚硫酸钠中的一种或二种以上。 产品中溶解壳聚糖用的酸溶液为乙酸水溶液、 乙酸-乙酸钠缓冲液或盐酸溶液。 产品在使用时， 4-25°C下以溶液态通过滴入、 注射、 或内窥镜引入等方式直接注 入离体或在体的生物组织、 器官或体腔中。
产品可作为细胞或药物的包埋载体， 用于组织工程领域或药物释放系统。
所述的细胞是动物来源或人源的软骨细胞、 纤维软骨细胞、韧带成纤维细胞、 皮 肤成纤维细胞、 肌腱细胞、 肌纤维母细胞、 间质干细胞、 或角质细胞。
所述的药物是止痛药、 麻醉药、 抗菌药物、 抗生素、 抗烫烧伤药、 抗抑郁药、 抗 皮炎药、 抗霉菌药物、 抗组胺药、 抗角化症药、 抗炎药， 抗刺激剂， 抗菌剂， 抗真菌 剂、 抗氧化药、 抗寄生虫药、 止痒剂、 抗牛皮癣药物、 抗皮脂溢剂、 抗病毒药物、 心 血管药物、 化疗药物、 皮质类固醇、 酶抑制剂、 激素、 类固醇、 非 体类抗炎剂、 孕 激素或维生素。
本发明的有益效果：
1、 本发明可注射型温敏水凝胶在 4-25°C下为溶液态， 当温度升至 28-42°C时， 原位定形成凝胶。 2、 本发明利用天然交联剂及天然多糖制备温敏型可注射水凝胶， 制备的水凝胶 可作为药物载体及组织工程支架使用。
3、 本发明采用天然交联剂及天然多糖材料， 制备的水凝胶生物可降解、 生物相 容性好。 附图说明
图 1为温敏型可注射壳聚糖水凝胶的凝胶机理示意图。
图 2为升温前后的温敏型可注射壳聚糖水凝胶照片， 其中 a为溶液， b为水凝胶 (升温后）。
图 3为温敏型可注射壳聚糖水凝胶在 25 °C、 37°C、 45 °C的凝胶时间。
图 4为温敏型可注射壳聚糖水凝胶的流变性能。 具体实施方式
实施例 1
1、 将分子量为 60 kDa、 脱乙酰度为 50%的壳聚糖按 25.0g/L溶于蒸馏水中， 并 按 12.5g/L加入 Na2S04， 搅拌 30 min， 得溶液 A保存；
2、 将京尼平按 12.5g/L溶于蒸馏水中， 搅拌 2 h得溶液 B保存；
3、 使用前将溶液 A与溶液 B于 4°C下按体积比 4: 1混合， 搅拌 lOmin, 升温至 37 °C , 50min后成凝胶， 凝胶中壳聚糖浓度为 20.0g/L， Na2S04浓度为 10.0g/L， 京尼 平浓度为 2.5g/L (附图 2中的 A组）。
4、 将混合后的溶液置于 25 °C、 37°C、 45 °C水浴中， 一定时间后将装有混合溶液 的容器旋转 90°， 没有液体流出视为凝胶形成， 记录凝胶时间。 结果见图 3A。
用安东帕 MCR301流变仪（配备 25 mm椎板， 锥角 1° )测定温敏凝胶的流变性 能。将混合溶液置于锥桶内， 表面覆盖矿物油以防止水分挥发， 37°C下测定温敏凝胶 的线性粘弹性能 （角频率范围 100 - 0.1 rad/s)， 结果见图 4。
实施例 2
1、 将分子量为 10 kDa、 脱乙酰度为 90%的壳聚糖按 30.0g/L溶于 0.1 mL/L盐酸 溶液， 并按 6.0 g/L加入 NaHC03和 Na2S04， 搅拌 30 min， 然后用 40.0g/L NaOH 调 pH至 4.0， 得溶液 A保存；
2、 将京尼平按 30.0 g/L溶于蒸馏水中， 搅拌 2 h得溶液 B保存；
3、 使用前将溶液 A与溶液 B于室温 20°C下按体积比 5: 1混合， 搅拌 lOmin, 升 温至 30°C， 30min后成凝胶， 凝胶中壳聚糖浓度为 25.0g/L， NaHC03和 Na2S04浓度 为 5.0g/L， 京尼平浓度为 5.0g/L (附图 2中的 B组）。
4、 温敏凝胶在 25 °C、 37°C、 45 °C的凝胶时间见图 3B。 流变性能见图 4。 1、将分子量为 1000 kDa、脱乙酰度为 80%的壳聚糖按 20.0g/L溶于 10.0mL/L乙 酸溶液， 然后用 40.0g/L NaOH调 pH至 6.2， 得溶液 A保存；
2、将京尼平按 1.0 g/L溶于蒸馏水中，搅拌 2 h，并按 2.0g/L加入 Na3P04和 Na2S03， 搅拌 30 min， 得溶液 B保存；
3、 使用前将溶液 A与溶液 B于室温 4°C下按体积比 1 : 1混合， 搅拌 lOmin, 升 温至 42°C， 20min后成凝胶， 凝胶中壳聚糖浓度为 10.0g/L， Na3P04和 Na2S03浓度 为 1.0g/L， 京尼平浓度为 0.5g/L (附图 2中的 C组）。
4、 温敏凝胶在 25 °C、 37°C、 45 °C的凝胶时间见图 3C。 流变性能见图 4。
实施例 4
1、将分子量为 300 kDa、脱乙酰度为 60%的壳聚糖按 2.4g/L溶于 10.0mL/L乙酸 溶液， 然后用 40.0g/L NaOH调 pH至 6.0， 得溶液 A保存；
2、 将京尼平按 18.0 g/L溶于蒸馏水中， 搅拌 2 h， 并按 3.0g/L加入 Na2S03， 搅 拌 30 min， 得溶液 B保存；
3、 使用前将溶液 A与溶液 B于室温 4°C下按体积比 5: 1混合， 搅拌 lOmin, 升 温至 28°C， 50min后成凝胶， 凝胶中壳聚糖浓度为 2.0g/L， Na2S03浓度为 0.5g/L， 京 尼平浓度为 3.0g/L (附图 2中的 D组）。
4、 温敏凝胶在 25 °C、 37°C、 45 °C的凝胶时间见图 3D。 流变性能见图 4。

Claims

权 利 要 求 书
1 . 一种温敏型可注射壳聚糖水凝胶产品， 其特征在于： 该产品是采用溶液 A与 溶液 B 两种溶液分别保存， 其中， 产品中主要含有三大类组分：
组分 1 为壳聚糖， 产品中壳聚糖浓度为 2.0-25.0g/L;
组分 2 为钠盐， 产品中钠盐浓度为 0.5-10.0g/L;
组分 3 为京尼平， 产品中京尼平浓度为 0.5-5.0g/L;
溶液 A为 pH 6.0-7.4 的酸溶液、 生理盐水或蒸馏水；
溶液 B 为生理盐水或蒸馏水；
其中， 组分 1 溶于溶液 A中， 组分 3 溶于溶液 B 中， 组分 2 溶于溶液 A中或 溶于溶液 B 中。
2. 按照权利要求 1 所述的温敏型可注射壳聚糖水凝胶， 其特征在于： 使用前在 4-25 °C下将 A、 B 两种溶液按体积比 5: 1-1 : 1 的比例混合。
3. 按照权利要求 1 或 2 所述的温敏型可注射壳聚糖水凝胶， 其特征在于： 混合 后的溶液 pH介于 6.0-7.4。
4. 按照权利要求 1 或 2 所述的温敏型可注射壳聚糖水凝胶， 其特征在于： 混合 后的溶液在 4-25 °C下为溶液态， 当温度升至 28-42 °C时， 2分钟 -1 小时变为凝胶态。
5. 按照权利要求 1 所述的温敏型可注射壳聚糖水凝胶， 其特征在于： 产品中的 壳聚糖分子量为 10-1000 kDa， 脱乙酰度为 50-98%。
6. 按照权利要求 1 所述的温敏型可注射壳聚糖水凝胶， 其特征在于： 产品中的 壳聚糖为部分亲水、 部分疏水。
7. 按照权利要求 1 所述的温敏型可注射壳聚糖水凝胶， 其特征在于： 产品中的 钠盐可以是碳酸氢钠、 磷酸钠、 硫酸钠或亚硫酸钠中的一种或二种以上。
8. 按照权利要求 1 所述的温敏型可注射壳聚糖水凝胶， 其特征在于： 产品中溶 解壳聚糖用的酸溶液为乙酸水溶液、 乙酸-乙酸钠缓冲液或盐酸溶液。
9. 按照权利要求 1 所述的温敏型可注射壳聚糖水凝胶， 其特征在于： 产品在使 用时， 4-25 °C下以溶液态通过滴入、 注射、 或内窥镜引入等方式直接注入离体或在体 的生物组织、 器官或体腔中。
10. 一种权利要求 1 所述的温敏型可注射壳聚糖水凝胶的应用， 其特征在于： 产品可作为细胞或药物的包埋载体， 用于组织工程领域或药物释放系统。
11 . 按照权利要求 10 所述的应用， 其特征在于： 温敏型可注射壳聚糖水凝胶用 于细胞的包埋， 所述的细胞是动物来源或人源的软骨细胞、 纤维软骨细胞、韧带成纤 维细胞、 皮肤成纤维细胞、 肌腱细胞、 肌纤维母细胞、 间质干细胞、 或角质细胞。
12. 按照权利要求 10 所述的应用， 其特征在于： 所述的温敏型可注射壳聚糖水 凝胶用于药物的包埋与缓释， 所述的药物是止痛药、 麻醉药、 抗菌药物、 抗生素、 抗 烫烧伤药、 抗抑郁药、 抗皮炎药、 抗霉菌药物、 抗组胺药、 抗角化症药、 抗炎药， 抗 刺激剂， 抗菌剂， 抗真菌剂、 抗氧化药、 抗寄生虫药、 止痒剂、 抗牛皮癣药物、 抗皮 脂溢剂、 抗病毒药物、 心血管药物、 化疗药物、 皮质类固醇、 酶抑制剂、 激素、 类固 醇、 非 体类抗炎剂、 孕激素或维生素。
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