CN114381014A - 一种可生物降解的水凝胶及其应用 - Google Patents
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Abstract
本发明公开了一种可生物降解的水凝胶及其应用，所述水凝胶是通过加入活化剂和交联剂氨基化聚乙二醇使羧甲基纤维素钠和羧甲基壳聚糖进行交联的方法制备。本发明的水凝胶能够在胃中保持适当时间，并且能够生物降解二不引起肠梗阻，并且水凝胶能够通过一步法制备减少了物料浪费，反应条件温和，不会造成污染和其他危害。
Description
技术领域
本发明涉及生物医学材料领域，具体涉及一种可生物降解的水凝胶及其应用。
背景技术
目前，治疗和预防肥胖症的主要方法有药物治疗、手术治疗，运动和饮食控制。例如：减肥药物治疗，胃部减肥手术，胃内水球减重行为治疗，运动+饮食治疗。这几种治疗都有不错的疗效，但是也有其缺点。减肥药物治疗，是常用的治疗手法，但是食用药物会带来一系列的副作用，例如食用之后会出现口干舌燥，失眠，还有一些出现精神恍惚，代谢不正常等等状况。胃部减肥手术，需要对患者的胃部进行切除或者束带，通过改变胃的容积，从根源上控制肥胖者的摄入量。但是，手术费用和风险，往往让患者望而却步。胃内水球，是指在患者的胃部，放置由硅胶制成的水球，在放置期间，水球能减少胃内容量和空腹感，但患者仍需控制饮食并增加运动量，以达至减重效果。一般六个月后，需要重新取出。其缺点是：存在水球破裂风险和需要二次手术取出。
利用水凝胶作为胃部填充剂，作为减肥的一种辅助材料，成为了近年的研究热点。国内外已经有相关的文献和专利，对此做了不同程度的研究和分析。水凝胶的特性让其成为胃填充剂的一种理想原材料，可以有效占据胃部空间并提供饱腹感，辅助使用者控制调节饮食，不会造成人体严重副作用，目前已有多种作为胃填充剂使的水凝胶被开发。但是胃填充剂水凝胶需要进行较复杂的合成或改性工艺，除了反应过程可能存在残留单体或助剂(例如有机溶剂)产生额外风险(如，不适用于口服，尤其是不适用于大量和长期使用)外，还提高了胃填充剂的生产成本，导致了胃填充剂在日益丰富的减肥治疗途径中并不占据竞争优势。另外，作为胃填充剂，要求材料在胃中保持适当的时间，并且能够被摄取或生物降解从而不会引起肠梗阻。这也是目前部分胃部填充剂不能达到的。
发明内容
本发明一方面提供一种可生物降解的水凝胶，所述水凝胶是通过加入活化剂和交联剂氨基化聚乙二醇(NH2-PEG-NH2)使羧甲基纤维素钠(Carboxymethylcellulose sodium，CMC-Na)和羧甲基壳聚糖(CM-chitosan，CMC)进行交联的方法制备。本发明的水凝胶能够在胃中保持适当时间，并且能够生物降解二不引起肠梗阻，并且水凝胶能够通过一步法制备减少了物料浪费，反应条件温和，不会造成污染和其他危害，无毒性。
在一些实施方式中，所述活化剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和N-羟基琥珀酰亚胺(NHS)。在一些实施方式中，所述羧甲基纤维素钠、NH2-PEG-NH2、羧甲基壳聚糖的质量比为甲基纤维素钠：氨基化聚乙二醇：羧甲基壳聚糖＝0.5～1:1:0.5～1。在一些实施方式中，所述羧甲基纤维素钠、NH2-PEG-NH2、羧甲基壳聚糖的质量比为羧甲基纤维素钠：氨基化聚乙二醇：羧甲基壳聚糖＝1:1:1、1:1:0.5或0.5:1:1。
在一些实施方式中，所述方法包括以下步骤：(1)称取羧甲基纤维素钠、NH2-PEG-NH2、羧甲基壳聚糖于去离子水中；(2)加入EDC和NHS，室温条件下，搅拌反应；(3)12h后，进行冷冻干燥，冷冻干燥条件为：-80℃/24h，得到冻干产物；以及(4)将所述冻干产物，用去离子水清洗后，再次冻干，即可得到所述水凝胶。本发明的水凝胶能够在胃中保持适当时间，并且能够生物降解二不引起肠梗阻，并且水凝胶能够通过一步法制备减少了物料浪费，反应条件温和，不会造成污染和其他危害，无毒性。
在一些实施方式中，所述羧甲基纤维素钠、NH2-PEG-NH2、羧甲基壳聚糖的质量比为甲基纤维素钠：氨基化聚乙二醇：羧甲基壳聚糖＝0.5～1:1:0.5～1。在一些实施方式中，所述羧甲基纤维素钠、NH2-PEG-NH2、羧甲基壳聚糖的质量比为羧甲基纤维素钠：氨基化聚乙二醇：羧甲基壳聚糖＝1:1:1、1:1:0.5或0.5:1:1。
本发明另一方面提供一种用于控制体重的胃填充剂，所述胃填充剂包括上述任一种水凝胶。
在一些实施方式中，所述胃填充剂的剂型为粉末、片剂、或胶囊。
本发明另一方面提供一种药物组合物，所述药物组合物包括上述任一种水凝胶和药学上可接受的载体。本发明的水凝胶能够在胃中保持适当时间，并且能够生物降解二不引起肠梗阻，并且水凝胶能够通过一步法制备减少了物料浪费，反应条件温和，不会造成污染和其他危害，无毒性。
本发明再一方面提供上述任一种水凝胶在制备增加饱腹感、降低食欲、控制体重、防治肥胖的药物中的应用。
本发明再一方面提供一种食品，所述食品包含上述任一种水凝胶。
本发明凝胶的有益效果为下述中任一项或多项：(1)采用一步法制备三元水凝胶，通过羧甲基纤维素钠、NH2-PEG-NH2、羧甲基壳聚糖的配比，控制三元水凝胶的性能和防止物料浪费。(2)反应条件温和，而且使用水剂，不会造成污染和其他危害，通过化学交联的方法制得无毒性凝胶。(3)在胃中保持适当的时间，并且可以摄取或生物降解而不会引起肠梗阻。
附图说明
图1为不同实施例三元水凝胶的溶胀性能。
图2为不同实施例三元水凝胶的体外降解性能。
具体实施方式
术语“增加饱腹感”，意为经本领域技术人员所知的经临床认知的方法测定的饱腹感增强。更具体地说，它是指在使用本发明的水凝胶或含有水凝胶产品(例如，食物或药物)食物后至少两小时内或下一餐时摄食量的减少。在发明中，“增加饱腹感”是指个体热量摄入的净减少。
术语“控制体重”指为了维持或获得“期望体重”而调节体重的所有方面。与“期望体重”相对应的，词语“超重”和“肥胖症”用来表示超过该“期望体重”的体重。
对于人的“期望体重”、“正常体重”或“理想体重”可以根据如身体质量指数(BMI)的标准来定义，期望的BMI水平可以随年龄而变化，但是认为“标准”的BMI是在18.5-24.9kg/m2的范围内。
术语“肥胖”是一种医学病症，其中过多的身体脂肪已经聚集到其对健康可能具有不良影响的程度，导致缩短的预期寿命和/或增加的健康问题。超重被理解为以身体质量指数(BMI)为特征的临界状况为25至小于30。当受试者的体质指数(BMI)为30kg/m2或更大时，受试者被认为肥胖，所述体质指数(BMI)是通过将人的以千克计的体重除以该人的以米计的身高的平方获得的量度。
本发明水凝胶的制备
按照表1的配比，取一定量的羧甲基纤维素钠、NH2-PEG-NH2、羧甲基壳聚糖于100ml的去离子水中，然后加入50mmol EDC和25mmol NHS。室温条件下，搅拌反应，12h后，随后进行冷冻干燥，冷冻干燥条件为：-80℃/24h。将得到冻干产物，用去离子清洗三遍后，再次冻干，便可得到本发明的三元水凝胶。
表1.三元水凝胶配比
| 分组 | 羧甲基纤维素钠 | NH<sub>2</sub>-PEG-NH<sub>2</sub> | 羧甲基壳聚糖 |
| 对比例1 | 1 | 1 | 0 |
| 实施例1 | 1 | 1 | 0.5 |
| 实施例2 | 1 | 1 | 1 |
| 实施例3 | 0.5 | 1 | 1 |
| 对比例2 | 0 | 1 | 1 |
将不同实施例及对比例所制备的水凝胶，干燥称重后，记为W1，放置于人工胃液中，24h后，取出，称量重量，记为W2，根据以下的公式1，便可以得到不同实施例及对比例水凝胶的溶胀性能。
由图1可以得知，在三元水凝胶体系中，实施例1-3，其溶胀比都大于22.5，而对比例2，其溶胀比为12，其中实施例2的溶胀比最大为32。因此，可以得知，本发明的三元水凝胶体系各组分间协同提供了凝胶的溶胀能力。
本发明水凝胶的体外性能
为了考察三元水凝胶的体外性能，将不同实施例及对比例所制备的水凝胶，分别置于含有胃蛋白酶的人工胃液中，其中胃蛋白酶的浓度为1000U/mL，在设定的时间点，更换降解液体，同时检测水凝胶的残留量。人工胃液的配置参考2020版《中国药典》的规定配置人工胃液。人工胃液：取稀盐酸16.4ml，加水约800ml与胃蛋白酶10g，摇匀后，加水稀释成1000ml，最终pH值约为1.5。
由图2可以得知，本发明的水凝胶能够在胃液条件下实现溶胀。所有的实施例及对比例制备的水凝胶，都具有可降解性能，其中对比例2的降解速度最快，7天便可完全降解。实施例2的降解时间最慢，长达21天，而且其他实施例及对比例所制备的水凝胶，降解时间都在10-14天。
本发明水凝胶的生物安全性
为了检测本专利所制备的三元水凝胶的生物安全性，取了实施例32所制备的三元水凝胶，按照《GB/T 16886.11-2011医疗器械生物学评价第11部分：全身毒性试验》，进行急性毒性测试。具体方法如下：测试样品在0.9％的氯化钠注射液(生理盐水)和大豆油中浸提，浸提浓度为0.2g/mL。
将测试样品浸提液以单次剂量注射给一组5只动物，对应的一组五只动物给予对应的浸提溶剂。随后，观察受试动物在注射后即刻、4小时、24小时、48小时和72小时的全身毒性反应或死亡情况并在注射前，1天、2天和3天称体重。试验结束时仍存活的动物安乐死。所用的动物为SPF级昆明小鼠(购买自南方医科大学)。
由表2和表3可以得知，所有动物在整个试验过程中有所变化，没有发现体重减少超过10％，所有动物在整个测试中临床表现正常。说明实施例3所制备的三元水凝胶，在急性毒性测试中，没有观察到明显的毒性或病理变化。因此，虽然本发明的水凝胶通过化学交联方式制备，但是本发明的水凝胶具有较好的生物安全性，无毒性。
表2.生理盐水组体重数据
表3.大豆油组体重数据
Claims (10)
1.一种可生物降解的水凝胶，其特征在于，所述水凝胶是通过加入活化剂和交联剂氨基化聚乙二醇使羧甲基纤维素钠和羧甲基壳聚糖进行交联的方法制备。
2.根据权利要求1所述的水凝胶，其特征在于，所述活化剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺。
3.根据权利要求1所述的水凝胶，其特征在于，所述羧甲基纤维素钠、氨基化聚乙二醇、羧甲基壳聚糖的质量比为甲基纤维素钠：氨基化聚乙二醇：羧甲基壳聚糖＝0.5～1:1:0.5～1。
4.根据权利要求3所述的水凝胶，其特征在于，所述羧甲基纤维素钠、氨基化聚乙二醇、羧甲基壳聚糖的质量比为羧甲基纤维素钠：氨基化聚乙二醇：羧甲基壳聚糖＝1:1:1、1:1:0.5或0.5:1:1。
5.根据权利要求1-4中任一项所述的水凝胶，其特征在于，所述方法包括以下步骤：
(1)称取羧甲基纤维素钠、氨基化聚乙二醇、羧甲基壳聚糖置于去离子水中；
(2)加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺，室温条件下，搅拌反应；
(3)12h后，进行冷冻干燥，冷冻干燥条件为：-80℃/24h，得到冻干产物；以及
(4)将所述冻干产物，用去离子水清洗后，再次冻干，即可得到所述水凝胶。
6.一种用于控制体重的胃填充剂，其特征在于，所述胃填充剂包括权利要求1-5中任一项所述的水凝胶。
7.根据权利要求6所述的胃填充剂，其特征在于，所述胃填充剂的剂型为粉末、片剂、或胶囊。
8.一种药物组合物，其特征在于，所述药物组合物包括权利要求1-5中任一项所述的水凝胶和药学上可接受的载体。
9.权利要求1-5中任一项所述的水凝胶在制备进饱腹感、降低食欲、控制体重、防治肥胖的药物中的应用。
10.一种食品，其特征在于，所述食品包含权利要求1-5中任一项所述的水凝胶。
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