CN102370612A - 壳聚糖-单甲氧基聚乙二醇凝胶给药系统及其制备方法 - Google Patents
壳聚糖-单甲氧基聚乙二醇凝胶给药系统及其制备方法 Download PDFInfo
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Abstract
本发明公开了壳聚糖-单甲氧基聚乙二醇凝胶给药系统及其制备方法，包含重量比2.0％-2.5％壳聚糖、3.5％-4.0％单甲氧基聚乙二醇及胶原蛋白。该凝胶系统具有温度敏感性，能够在常温保持液态，37℃时转变为固态。本发明同时公开了其制备方法，包括：配制浓度为30％单甲氧基聚乙二醇溶液；使用醋酸配制壳聚糖溶液；将胶原蛋白溶于0.1M的氢氧化钠；将三种溶液冰浴后搅拌混合制备凝胶溶液系统。本发明还公开了一种肿瘤坏死因子α的凝胶给药系统和一种瘦素的凝胶给药系统。本发明所述的凝胶给药系统，温度敏感性好、制备条件温和，可以广泛的应用于药物载体领域。
Description
技术领域
本发明涉及一种给药缓释系统。具体而言，本发明公开了壳聚糖-单甲氧基聚乙二醇凝胶给药系统及其制备方法。本发明还涉及壳聚糖-单甲氧基聚乙二醇凝胶为载体的肿瘤坏死因子α与瘦素的给药缓释系统。本发明凝胶具有温度敏感性好，在医疗领域具有良好的应用前景。
背景技术
壳聚糖(chitosan)是一类甲壳素的脱乙酰衍生物，它具有良好的生物相容性和生物降解性。壳聚糖具有生物黏附性能，可起到控制药物释放的作用，具有独特的性质，因此壳聚糖已经被广泛地应用于药物载体的研究中[Chitosansodium alginate nanoparticles as submicroscopic reservoirs for oculardelivery：Formulation，optimization and in vitro characterization.Euro J PharmBio.2008，66(3)：513-525.Ever G，Jean C L.In situ-forming hydrogels reviewof temperature-sensitive systems.Euro J Pharm Bio.2004，58(2)：409-426.Sanjaykm，Shruti C，Sushma T et al.]。壳聚糖属于天然碱性多糖，不溶于水，但是壳聚糖含有游离氨基，在酸性条件下可以结合氢离子，从而使壳聚糖成为带正电荷的电解质。单甲氧基聚乙二醇(Methoxy Polyethylene Glycol，mPEG)具有良好的水溶性、润湿性、润滑性、生理惰性、对人体无刺激、温和，在化妆品和制药工业中应用广泛，分子量为2KD。胶原蛋白是细胞外最重要的水不溶性纤维蛋白，是构成细胞外基质的骨架。胶原在细胞外基质中形成半晶体的纤维，给细胞提供抗张力和弹性，并在细胞的迁移和发育中起作用。胶原在各种动物中都有存在，脊椎动物中腱、软骨和骨中的胶原非常丰富，几乎占了蛋白总重的一半。胶原经酸或碱部分水解或在水中煮沸，可以形成溶液。
在壳聚糖的酸溶液中加入适量的单甲氧基聚乙二醇不会立刻中和壳聚糖的质子而使壳聚糖沉淀下来，可使壳聚糖溶液的pH值升至生理范围即pH7.0左右。在低温条件下，壳聚糖与水的作用阻止了壳聚糖链的聚集；温度升高时，单甲氧基聚乙二醇与水的结构化作用(该作用能减弱壳聚糖与水的作用)加强，使壳聚糖链脱水，水分子的区域被聚乙二醇的羟基集团取代，壳聚糖链聚集。壳聚糖/单甲氧基聚乙二醇温敏凝胶的形成有两个重要因素，一个是壳聚糖游离氨基的存在，它将使壳聚糖在溶液中带正电荷。第二是单甲氧基聚乙二醇的加入，它赋予凝胶系统稳定在pH中性的环境且具有温敏特性。这个特点，使得壳聚糖温敏凝胶在形成凝胶前可以非常方便加载药物[Back，J.F.，Oakenfull，D.，Smith，M.B.Increased thermal stability of proteins inthe presence of sugars and polyols.Biochem.1979，18(23)：5191-5196.]
肿瘤坏死因子α(Tumor Necrosis Factor α，TNF-α)是一种多功能的细胞因子，她对细胞的增殖、分化、炎症反应与免疫功能等具有调节作用，特别是是其免疫调节功能更为重要[Smyth，M.J.，Johnstone，R.W.，Role of TNF inlymphocyte-mediated cytotoxicity.Microsc.Res.Technol.2000，50：196-208.]。TNF-α主要由激活的单核细胞/巨噬细胞、T淋巴细胞分泌，其它如中性粒细胞、肥大细胞及内皮细胞在一定条件下也能产生[Pennica D，Nedwin GE，Hayflick JS，et al.Human tumour necrosis factor：precursor structure，expression and homology to lymphotoxin.Nature，1984，312(5996)：724-729.Sherry B，Cerami A.Cachectin/tumor necrosis factor exerts endocrine，paracrine，and autocrine control of inflammatory responses.J Cell Biol，1988，107(4)：1269-1277.]。成熟的TNF-α(17kD)由膜型TNF-α(26kD)切割而产生，两种形式的TNF-α都具有生物活性[6]。TNF-α有三个与受体结合的主要活性表位，即29～36、84～91和143～146位。TNF-α以活性三聚体的形式与细胞表面的TNF-α受体(TNFR)结合，从而启动信号通路，发挥生物学功能[Boone E，Vanden Berghe T，Van Loo G，et al.Structure/Function analysis ofp55 tumor necrosis factor receptor and fas-associated death domain.Effect onnecrosis in L929sA cells.J Biol Chem，2000，275(48)：37596-37603.]。
TNF-α的过表达与类风湿性关节炎(rheumatoid arthritis，RA)、Crohn’s病、多发性硬化症(multiple sclerosis)等自身免疫性疾病的密切关系已得到证实[Xanthoulea S，Pasparakis M，Kousteni S，et al.Tumor necrosis factor(TNF)receptor shedding controls thresholds of innate immune activation thatbalance opposing TNF functions in infectious and inflammatory diseases.J ExpMed，2004，200(3)：367-376.Kollias G，Douni E，Kassiotis G，et al.On the roleof tumor necrosis factor and receptors in models of multiorgan failure，rheumatoid arthritis，multiple sclerosis and inflammatory bowel disease.Immunol Rev，1999，169：175-194.]。TNF-α还是一个重要的前炎性细胞因子，可以介导多种炎性因子的释放，如IL-1、IL-6、GM-CSF[B.J.Scallon，M.A.Moore，H.Trinh，D.M.Knight，J.Ghrayeb，Chimeric anti-TNF-alphamonoclonal antibody cA2 binds recombinant transmembrane TNF-alpha andactivates immune effector functions.Cytokine 7(1995)251-259.]。越来越多的疾病被发现与TNF-α的过量分泌有关，TNF-α已经成为治疗这类疾病的一个有效靶标[Camussi G，Lupia E.The future role of anti-tumour necrosis factor(TNF)products in the treatment of rheumatoid arth ritis.Drugs，1998，55(5)：613-620.Feldmann M and Maini RN.Development of anti-TNF therapy forrheumatoid arthritis.Nat.Rev Immunol，2002，2：364-371.]。
1994年，Zhang等利用定位克隆的方法获得“Obese”基因。ob基因编码脂肪组织特异性mRNA，翻译成167个氨基酸的蛋白质，N端21个氨基酸为分泌信号肽，在被分泌入血的过程中去除N端的信号肽成瘦素[Cohen SL，Halaas JL，Friedman JM，et al.Human leptin characterization.Nature，1996，382(6592)：589.]。血液循环中的瘦素为146个氨基酸的多肽类激素，其活性部位含146个氨基酸残基，相对分子质量为16KD，亲水性强，以单体形式存在于血浆中。与其他激素的分泌相似，瘦素的分泌也呈脉冲式。瘦素mRNA表达呈日周期变化，夜间表达量最高，半衰期为9.4±3.0min其分泌具有一定的节律性。瘦素在血液中的运输有游离和结合2种形式在人血清中2种形式各占50％，在肥胖的人和鼠中该比例发生变化。分泌到血中的瘦素大部分通过与血清蛋白结合来运输。在人类至少有两种瘦素结合蛋白，相对分子质量分别为176KD和240KD，只有游离的瘦素才具有生物活性。
在体内，瘦素的功能呈现多样性。能量代谢方面：瘦素与下丘脑的瘦素受体结合后可能通过下丘脑2神经肽通路，抑制NPY的合成与释放，增加交感神经系统活性，引起食欲降低，能量消耗增加，从而减轻体质量。生殖和发育方面：瘦素可作用于下丘脑-垂体性腺这一生殖轴的各个层次。瘦素通过位于下丘脑的长型受体调节性行为和促性腺激素释放激素(GnRH)释放；在性腺水平，瘦素可直接作用于卵巢，恢复雌性ob/ob小鼠的生育能力；瘦素对胎儿的生长发育也有一定的促进作用。骨代谢方面：瘦素可通过中枢途径增强成骨细胞功能，影响骨重建，抑制骨形成，但对破骨细胞分化功能无明显影响。心血管系统方面：瘦素能提高大鼠交感神经兴奋性而升高动脉压，可影响心肌细胞的代谢和功能血液系统方面：瘦素能刺激造血干细胞的分裂和分化，提高细胞数量，血小板有瘦素受体(OB-R)表达，瘦素能诱导血小板聚集。OB和ObR在多种肿瘤组织中均有表达，如乳腺癌、结肠癌、胃癌、前列腺癌和肝癌等[Cecilia G，Eva S.Leptin and Cancer.Journal of Cellular.Physiology，2006，207：12-22.Ambrosini G，Nath AK，Sierra Honigmann MR，etal.Transcriptional activation of the human leptin gene in response to hypoxia.Involvement of hypoxia-inducible factor 1.J Biol Chem，277(37)：34601-34609.Artwoh M，Roden M，Holzenbein T，et al.Modulation by leptin of proliferationand apoptosis in vascular endothelial cells.Int J Obes Relat MetabDisord，2002，26(4)：577-580.]。近年来发现瘦素还有影响水盐代谢，致使饮水增加、尿液稀释、肾脏排钾减少，增加机体免疫应答能力的作用。
根据壳聚糖和单甲氧基聚乙二醇的理化性质，本发明经过多次尝试改进了壳聚糖和单甲氧基聚乙二醇制备水凝胶系统，为TNF-α与瘦素给药提供了高性能的缓释系统。
发明内容
本发明公开了壳聚糖-单甲氧基聚乙二醇凝胶给药系统及其制备方法。
本发明所述的壳聚糖凝胶给药系统，是由壳聚糖和单甲氧基聚乙二醇所组成。本发明确定了壳聚糖和单甲氧基聚乙二醇混合比例，即为按照重量比的2.0％-2.5％的壳聚糖、3.5％-4.0％的单甲氧基聚乙二醇以及0.1％胶原蛋白。
本发明还公开了一种温度敏感的壳聚糖水凝胶的制备方法，包括以下步骤：
1)单甲氧基聚乙二醇溶液的配制：称取单甲氧基聚乙二醇，溶于双蒸水，振荡搅拌器上持续震荡15min，使其彻底溶解，制成浓度为30％单甲氧基聚乙二醇溶液(w/v)，滤膜过滤，4℃低温储存备用。
2)壳聚糖溶液的配制：使用0.1M的醋酸配制壳聚糖溶液，搅拌2天后将获得的壳聚糖溶液高温高压消毒20min，冷却至室温后使用。
3)将胶原溶于0.1M的氢氧化钠中，形成重量1％的胶原溶液，并调节pH值至7.0-7.4.
4)壳聚糖-单甲氧基聚乙二醇凝胶的制备：将三种溶液冰浴30min后，吸取壳聚糖醋酸溶液到容器中，滴加1％的胶原溶液后，快速搅拌同时逐滴加入单甲氧基聚乙二醇溶液，并持续搅拌20min。获得的壳聚糖-单甲氧基聚乙二醇凝胶系统中，壳聚糖质量浓度为2.0％-2.5％，单甲氧基聚乙二醇浓度为3.5％-4.0％、0.1％胶原蛋白。
本发明所研制的凝胶给药系统与以往文献与专利文件更具有技术的精确性。在壳聚糖和单甲氧基聚乙二醇混合系统中，2％以下浓度的壳聚糖在生理温度下很难凝固，而超过4.0％的浓度则难以溶解；本发明同时也确定了在重量比的2.0％-2.5％的壳聚糖下，温度敏感水凝胶系统中，单甲氧基聚乙二醇的精确浓度。
本发明公开了一种TNF-α的凝胶给药系统，含有浓度为10-7M的TNF-α、重量百分比2.5％的壳聚糖、3.5％单甲氧基聚乙二醇以及0.1％胶原蛋白。
本发明还公开了一种瘦素的凝胶给药系统，含有浓度为10-7M的瘦素、重量百分比2.0％的壳聚糖、4.0％单甲氧基聚乙二醇以及0.1％胶原蛋白。
附图说明
图1TNF-α与瘦素的SDS-PAGE电泳图。其中泳道1为TNF-α，泳道2为瘦素蛋白。
图24.0％单甲氧基聚乙二醇浓度下，壳聚糖不同浓度对凝胶系统胶凝时间的影响。
图32.5％壳聚糖浓度下，单甲氧基聚乙二醇浓度百分比对于凝胶系统胶凝时间的影响。
图4TNF-α在壳聚糖-单甲氧基聚乙二醇水凝胶系统与在磷酸盐缓冲液在体外释放比较。
图5瘦素在壳聚糖-单甲氧基聚乙二醇水凝胶系统与在磷酸盐缓冲液在体外释放比较。
具体实施方式
实验材料
壳聚糖(Promega，美国)、单甲氧基聚乙二醇(Sigma，美国)、胶原蛋白(Sigma，美国)、TNF-α(实验室自制)、瘦素(实验室自制)、冰醋酸(北京化学试剂公司)、乙腈(北京化学试剂公司)、氢氧化钠(北京化学试剂公司)、丙稀酰胺&甲叉双丙稀酰胺(Sigma，美国)、磷酸氢二钠(北京化学试剂公司)、磷酸二氢钠(北京化学试剂公司)。
实验方法
1)TNF-α与瘦素的蛋白表达
采用大肠杆菌原核表达系统，两种带有组氨酸标签。
2)壳聚糖-单甲氧基聚乙二醇凝胶给药系统的制备
①壳聚糖脱乙酰度的测定：依照文献对本发明所用壳聚糖进行了脱乙酰度测定，脱乙酰度为86％。
②单甲氧基聚乙二醇溶液的配制：称取单甲氧基聚乙二醇，溶于双蒸水，振荡搅拌器上持续震荡10min，使其彻底溶解。制成浓度为30％单甲氧基聚乙二醇溶液(w/v)，0.22μm滤膜过滤，低温放置备用。
③壳聚糖溶液的配制：0.1M的醋酸溶液配制4％的壳聚糖溶液。先将醋酸加入双蒸水混匀后，称取壳聚糖放入烧杯中，加入0.1M的醋酸溶液，搅拌24小时将获得的壳聚糖溶液121℃高温高压消毒，冷却至室温后使用。
④胶原蛋白溶液的配制：称取一定量的胶原蛋白，溶于0.1M的氢氧化钠中，配制重量1％的胶原溶液，并用稀盐酸调节pH值至7.0-7.4.
⑤壳聚糖-单甲氧基聚乙二醇的凝胶合成：三种溶液冰浴后，吸取壳聚糖醋酸溶液到新烧杯中，滴加1％的胶原溶液后，快速搅拌同时逐滴加入单甲氧基聚乙二醇溶液，并持续搅拌。最终获得壳聚糖质量浓度为2.0％-2.5％，单甲氧基聚乙二醇终浓度为3.5％-4.0％的壳聚糖-单甲氧基聚乙二醇溶液。
⑥凝胶粘度测定：将样品转移到盛样器中，4℃以及37℃水浴中恒温，分别采用10与100rpm转速测量胶凝前后壳聚糖-单甲氧基聚乙二醇水凝胶的粘度。
3)TNF-α给药凝胶系统体外释药实验
将含TNF-α(10-7M)壳聚糖-单甲氧基聚乙二醇给药缓释溶液在37℃恒温孵育箱胶凝后立即取出1ml分别置于透析袋(截留分子量5KD)中，放入小玻璃瓶内，在瓶中加入pH7.4的PBS，于37℃恒温振荡器中振摇(转速60rpm)。在5min，15min，45min，2h，5h，10h分别将溶出液全部取出，补加同样的37℃的PBS，高效液相色谱法测定制剂在各时间点的累积释放量。同样的方式，将TNF-α(10-7M)在PBS溶液下进行高效液相色谱法测定在各时间点的累积释放量。在所有实验均在室内温度20±3℃条件下完成。流动相经过0.45μm微孔滤膜真空负压过滤、超声排气。将析出的液体经0.22μm滤膜过滤后依次进行HPLC检测，观察TNF-α体外释药的情况。
4)瘦素给药凝胶系统体外释药实验
将含瘦素(10-7M)壳聚糖-单甲氧基聚乙二醇给药缓释溶液在37℃恒温孵育箱胶凝后立即取出1ml分别置于透析袋(截留分子量5KD)中，放入小玻璃瓶内，在瓶中加入pH7.4的PBS，于37℃恒温振荡器中振摇(转速100rpm)。在5min，10min，15min，30min，45min，60min分别将溶出液全部取出，补加37℃的PBS，高效液相色谱法测定制剂在各时间点的累积释放量。同样方式，将瘦素(10-7M)在PBS溶液下进行高效液相色谱法测定在各时间点的累积释放量。在所有实验均在室内温度20±3℃条件下完成。流动相经过0.45μm微孔滤膜真空负压过滤、超声排气。将析出的液体经0.22μm滤膜过滤后依次进行HPLC检测，观察瘦素体外释药。
结果与讨论
1)TNF-α与瘦素的蛋白表达
TNF-α与瘦素的纯度都较高，满足了实验的要求，其纯化的电泳图见图1。TNF-α与瘦素的纯度都达到了90％左右。
2)壳聚糖含量对对于胶凝时间的影响
在4.0％的单甲氧基聚乙二醇下，含量浓度1.0％的凝胶时间过长达到3h，1.5％-3.0％浓度的壳聚糖凝胶时间比较合适。终含量为2.0％单甲氧基聚乙二醇、4.0％单甲氧基聚乙二醇组胶凝时间为10-15min(图2)。而含量高于4％壳聚糖几乎难以搅拌溶解于0.1M的醋酸溶液中。
3)单甲氧基聚乙二醇含量对于胶凝时间的影响
在2.0％的壳聚糖下，单甲氧基聚乙二醇含量浓度2％的凝胶时间过长达到80min，3.0％-6.0％浓度的单甲氧基聚乙二醇凝胶时间比较合适。终含量为3.5％单甲氧基聚乙二醇、4.0％单甲氧基聚乙二醇组胶凝时间约为15-20min，终含量8％、10％单甲氧基聚乙二醇组胶凝时间为3min以下，随着单甲氧基聚乙二醇逐滴加入局部就立刻胶凝(图3)。单甲氧基聚乙二醇含量的变化致使单甲氧基聚乙二醇分子中的磷酸根基团与壳聚糖分子中氨基之间的静电作用增强，促进系统胶凝时间。本发明过程中也证实了单甲氧基聚乙二醇含量对于壳聚糖-单甲氧基聚乙二醇凝固时间的影响。当单甲氧基聚乙二醇在系统终含量大于8％或低于2％时系统胶凝形态均不理想，单甲氧基聚乙二醇终含量3.5％-4.0％时胶凝时间、胶凝形态最为适宜。这是因为随着单甲氧基聚乙二醇用量比的增加，单甲氧基聚乙二醇会夺取更多NH3+质子，加速了壳聚糖链间静电斥力减弱，使壳聚糖-单甲氧基聚乙二醇溶液凝胶化时间减少，或在较低的温度下就可以凝胶化，37℃时加速了这种过程。因为中和电荷、溶液碱性提高及溶解达到饱和等诸多因素的影响使混合液中的壳聚糖沉淀析出。研究发现，通过流变学和电子顺磁共振光谱学的方法对壳聚糖温敏凝胶的性质进行研究，羟基的浓度决定了壳聚糖温敏凝胶的粘稠度及pH值，并观察了壳聚糖温敏凝胶对瘦素的缓释作用[K.Gekko，S.N.Timasheff.Mechanism of protein stabilization by glycerol：Preferentialhydratation in glycerol-water mixtures.Biochem.1981，20：(16)：4667-4676.]。
3)TNF-α给药凝胶系统体外释药实验
将含10-7M TNF-α的壳聚糖-单甲氧基聚乙二醇给药缓释溶液在37℃恒温孵育箱胶凝后透析得到的蛋白，用高效液相色谱法测定在各时间点的累积释放量，与相同浓度TNF-α在PBS系统中透析释放的比较见图4。图中发现，在前5小时之内，TNF-α在壳聚糖-单甲氧基聚乙二醇给药缓释系统中，释放的速度基本成线性关系，而TNF-α在PBS系统在45min内可以成线性关系；由此可见，壳聚糖-单甲氧基聚乙二醇给药缓释大大降低了TNF-α的分解速度。
4)瘦素给药凝胶系统体外释药实验
将含10-7M瘦素的壳聚糖-单甲氧基聚乙二醇给药缓释溶液在37℃恒温孵育箱胶凝后透析得到的蛋白，用高效液相色谱法测定在各时间点的累积释放量，与相同浓度瘦素在PBS系统中透析释放的比较见图5。
本发明明显降低蛋白质药物的分解速度，通过药物凝胶缓释系统改善蛋白质药物的半衰期，提高蛋白质药物的效力。本发明壳聚糖-单甲氧基聚乙二醇凝胶缓释系统，具有温度敏感的良好特性。本发明还提出了TNF-α与瘦素的凝胶缓释系统，为壳聚糖-单甲氧基聚乙二醇凝胶系统在其他蛋白类药物与多肽类药物的缓释应用提供了一定的基础。
Claims (4)
1.壳聚糖-单甲氧基聚乙二醇凝胶给药系统及其制备方法，含有重量百分比2.0％-2.5％的壳聚糖、3.5％-4.0％的单甲氧基聚乙二醇以及0.1％胶原蛋白。
2.根据权利要求1所述的壳聚糖-单甲氧基聚乙二醇凝胶给药系统，其制备方法包括以下过程：
1)单甲氧基聚乙二醇溶液的配制：称取单甲氧基聚乙二醇，溶于双蒸水，振荡搅拌器上持续震荡15min，使其彻底溶解，制成浓度为30％单甲氧基聚乙二醇溶液(w/v)，滤膜过滤，4℃低温储存备用。
2)壳聚糖溶液的配制：使用0.1M的醋酸配制的壳聚糖溶液，搅拌2天后将获得的壳聚糖溶液经高温高压消毒20min，冷却至室温后使用。
3)将胶原溶于0.1M的氢氧化钠中，形成重量1％的胶原溶液，并调节pH值至7.0-7.4.
4)壳聚糖-单甲氧基聚乙二醇凝胶的制备：将三种溶液冰浴30min后，吸取壳聚糖醋酸溶液到容器中，滴加1％的胶原溶液后，快速搅拌同时逐滴加入单甲氧基聚乙二醇溶液，并持续搅拌20min。获得的壳聚糖-单甲氧基聚乙二醇凝胶系统中，壳聚糖质量浓度为2.0％-2.5％，单甲氧基聚乙二醇浓度为3.5％-4.0％、0.1％胶原蛋白。
3.一种肿瘤坏死因子α的给药缓释系统，其特征在于，所述的缓释系统含有浓度为10-7M的肿瘤坏死因子α、重量百分比2.5％的壳聚糖、3.5％的单甲氧基聚乙二醇以及0.1％胶原蛋白。
4.一种瘦素的给药缓释系统，其特征在于，所述的缓释系统含有浓度为10-7M的瘦素、重量百分比2.0％的壳聚糖、4.0％的单甲氧基聚乙二醇以及0.1％胶原蛋白。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105125420A (zh) * | 2015-10-09 | 2015-12-09 | 固安博健生物技术有限公司 | 一种用于缓解常规皮肤问题的药物凝胶系统及其制备方法 |
| CN109481732A (zh) * | 2018-12-29 | 2019-03-19 | 中国科学院理化技术研究所 | 一种基于peg化壳聚糖-明胶体系的3d细胞打印材料及其应用 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6602952B1 (en) * | 1999-06-11 | 2003-08-05 | Shearwater Corporation | Hydrogels derived from chitosan and poly(ethylene glycol) or related polymers |
| WO2005014698A1 (en) * | 2003-08-08 | 2005-02-17 | Mcmaster University | Methods for the preparation of cross-linked polymer networks using coacervation and in situ cross-linking |
| CN1954817A (zh) * | 2005-10-28 | 2007-05-02 | 中国科学院过程工程研究所 | 一种可注射型pH及葡萄糖敏感水凝胶的制备方法 |
-
2010
- 2010-08-24 CN CN 201010261118 patent/CN102370612B/zh not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6602952B1 (en) * | 1999-06-11 | 2003-08-05 | Shearwater Corporation | Hydrogels derived from chitosan and poly(ethylene glycol) or related polymers |
| WO2005014698A1 (en) * | 2003-08-08 | 2005-02-17 | Mcmaster University | Methods for the preparation of cross-linked polymer networks using coacervation and in situ cross-linking |
| CN1954817A (zh) * | 2005-10-28 | 2007-05-02 | 中国科学院过程工程研究所 | 一种可注射型pH及葡萄糖敏感水凝胶的制备方法 |
Non-Patent Citations (3)
| Title |
|---|
| NARAYAN BHATTARAI ET AL: "PEG-grafted chitosan as an injectable thermosensitive hydrogel for sustained protein release", 《JOURNAL OF CONTROLLED RELEASE》 * |
| 井波 等: "温敏性壳聚糖水凝胶研究进展", 《国际骨科学杂志》 * |
| 孙佳丽 等: "壳聚糖-mPEG温敏水凝胶载药系统的制备及释药行为", 《清华大学学报(自然科学版)》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105125420A (zh) * | 2015-10-09 | 2015-12-09 | 固安博健生物技术有限公司 | 一种用于缓解常规皮肤问题的药物凝胶系统及其制备方法 |
| CN105125420B (zh) * | 2015-10-09 | 2018-05-18 | 固安博健生物技术有限公司 | 一种用于缓解常规皮肤问题的药物凝胶系统及其制备方法 |
| CN109481732A (zh) * | 2018-12-29 | 2019-03-19 | 中国科学院理化技术研究所 | 一种基于peg化壳聚糖-明胶体系的3d细胞打印材料及其应用 |
| CN109481732B (zh) * | 2018-12-29 | 2021-07-27 | 中国科学院理化技术研究所 | 一种基于peg化壳聚糖-明胶体系的3d细胞打印材料及其应用 |
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