技术领域technical field
一种关于海藻酸钠与聚双丙酮丙烯酰胺互穿网络凝胶的制备方法，属于生物医用材料技术领域。The invention relates to a preparation method of interpenetrating network gel of sodium alginate and polydiacetone acrylamide, which belongs to the technical field of biomedical materials.
背景技术Background technique
海藻酸钠是从褐藻中提取的高分子化合物，原料来源丰富，具有良好的生物相容性，对生物组织无免疫原性，可生物降解，而且降解产物无毒；与其他聚合物相比，价格低、来源丰富、具有更好的亲水性，易于细胞吸附，营养物质易于渗透等特点；与其它天然高分子相比，与二价钙阳离子在温和条件下可形成符合多种性能要求的凝胶，因此在食品业、化妆品行业及医药业中具有广泛的应用。其中，在医药行业中，海藻酸钠作为药物载体多年来被广泛地用作制备丸剂、粉剂、片剂等多种药物输送系统。但在包埋疏水性药物方面，上述剂型无论从缓释效果、包埋率，还是在药物稳定性增加方面都存在很大缺陷，使得总的生物利用度较小。Sodium alginate is a high-molecular compound extracted from brown algae. It has rich sources of raw materials, good biocompatibility, no immunogenicity to biological tissues, biodegradability, and non-toxic degradation products; compared with other polymers, Low price, rich sources, better hydrophilicity, easy cell adsorption, easy penetration of nutrients, etc.; compared with other natural polymers, it can form a variety of performance requirements with divalent calcium cations under mild conditions. Gel, so it has a wide range of applications in the food industry, cosmetic industry and pharmaceutical industry. Among them, in the pharmaceutical industry, sodium alginate has been widely used as a drug carrier for many years to prepare various drug delivery systems such as pills, powders, and tablets. However, in terms of embedding hydrophobic drugs, the above-mentioned dosage forms have great defects in terms of sustained release effect, embedding rate, and increase in drug stability, resulting in a low overall bioavailability.
然而，许多优良的疏水性药物如布洛芬、阿霉素、伊曲康唑等在治疗疾病方面都是相当优良的药物，但它们在海藻酸钠凝胶中溶解性小，利用度较低，应用受到限制。为了提高利用度人们采取了多种研究方法，如：通过研磨增加总的比表面积从而增加溶解度、微粒结晶法、喷雾干燥法等等，但这些方法都有各自的缺点，如分散性差、稳定性差、粒度分布过宽等。However, many excellent hydrophobic drugs such as ibuprofen, doxorubicin, itraconazole, etc. are quite good drugs in the treatment of diseases, but they have low solubility in sodium alginate gel and low availability , the application is limited. In order to improve the availability, people have adopted a variety of research methods, such as: increasing the total specific surface area by grinding to increase solubility, particle crystallization, spray drying, etc., but these methods have their own shortcomings, such as poor dispersion and poor stability. , the particle size distribution is too wide, etc.
双丙酮丙烯酰胺简称双胺(DAAM)，分子式C9H15NO2，分子量169.2。常温下为白色粉状或片状结晶体，可溶于水，甲醇、乙醇、丙酮、四氢呋喃、醋酸乙酯、丙烯腈、苯乙烯等有机溶剂，极易于多种单体共聚，形成聚合物，有较强吸水性，已广泛应用于日用化工、感光树脂助剂、纺织助剂、医疗卫生等领域中。此外，它的生物相容性很好，与疏水性药物相互作用强，可极大地提高疏水性药物的负载量，同时可以减缓药物的释放速度。Diacetone acrylamide is referred to as diamine (DAAM) with a molecular formula of C9 H15 NO2 and a molecular weight of 169.2. It is white powder or flaky crystal at room temperature, soluble in water, organic solvents such as methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, acrylonitrile, styrene, etc. It is very easy to copolymerize various monomers to form polymers. With strong water absorption, it has been widely used in daily chemical industry, photosensitive resin auxiliary agent, textile auxiliary agent, medical and health care and other fields. In addition, it has good biocompatibility and strong interaction with hydrophobic drugs, which can greatly increase the loading capacity of hydrophobic drugs, and at the same time slow down the release rate of drugs.
本发明充分利用双丙酮丙烯酰胺-海藻酸钠具有的无毒、水溶性好、生物相容性较好等优点，将其制成互穿网络结构，合成一种新型的材料作为药物载体。The invention makes full use of the advantages of diacetone acrylamide-sodium alginate in non-toxicity, good water solubility, good biocompatibility, etc., makes it into an interpenetrating network structure, and synthesizes a novel material as a drug carrier.
发明内容Contents of the invention
本发明的目的在于通过制备海藻酸钠与聚双丙酮丙烯酰胺互穿网络结构，使海藻酸钠疏水改性。本发明所涉及物质是海藻酸钠与双丙酮丙烯酰胺，将二者混合均匀制成水溶液，然后采用液滴法制成海藻酸钙凝胶，再对海藻酸钙凝胶内的双丙酮丙烯酰胺进行UV引发，形成互穿网络的结构。结果表明：该互穿网络结构凝胶可以有效地提高药物负载量，并且具有较好的缓释效果。The purpose of the present invention is to modify sodium alginate hydrophobically by preparing interpenetrating network structure of sodium alginate and polydiacetone acrylamide. The substances involved in the present invention are sodium alginate and diacetone acrylamide, which are uniformly mixed to make an aqueous solution, and then calcium alginate gel is prepared by the liquid drop method, and then diacetone acrylamide in the calcium alginate gel is processed Initiated by UV, a structure of an interpenetrating network is formed. The results show that the interpenetrating network structure gel can effectively increase the drug loading capacity and has a good sustained release effect.
本发明的优点：Advantages of the present invention:
1.所用原料为天然产物海藻酸钠，生物相容性、降解性好且价格低廉。合成的互穿网络小球含有海藻酸钙与双丙酮丙烯酰胺，无毒、无刺激性并具有良好的生物相容性。1. The raw material used is sodium alginate, a natural product, which has good biocompatibility, good degradability and low price. The synthetic interpenetrating network spheres contain calcium alginate and diacetone acrylamide, are non-toxic, non-irritating and have good biocompatibility.
2.采用液滴法制的水凝胶，方法简单易操作，形态均为圆形较规整，且大小一致。制备过程不用有机溶剂，环境友好。2. The hydrogel prepared by the droplet method is simple and easy to operate, and the shape is round and regular, and the size is consistent. The preparation process does not use organic solvents and is environmentally friendly.
3.能够增加疏水性药物在海藻酸钠中的包埋率，延缓释放速度，因此可以作为药物载体，用于多种药物尤其疏水性药物的包埋和释放。3. It can increase the embedding rate of hydrophobic drugs in sodium alginate and delay the release rate, so it can be used as a drug carrier for the embedding and release of various drugs, especially hydrophobic drugs.
附图说明Description of drawings
图1(a)纯海藻酸钠凝胶的SEM照片；Fig. 1 (a) SEM photo of pure sodium alginate gel;
(b)海藻酸钠与聚双丙酮丙烯酰胺互传网络凝胶的切面SEM照片(b) Cross-sectional SEM photographs of sodium alginate and polydiacetone acrylamide intertransfer network gel
图2药物布洛芬在37℃，200mL pH 7.2磷酸盐缓冲液条件下的释放曲线。a未疏水改性凝胶；b实例3凝胶Fig. 2 release curve of drug ibuprofen at 37°C, 200mL pH 7.2 phosphate buffered saline condition. a non-hydrophobic modified gel; b example 3 gel
图3药物布洛芬的在37℃，0.9％氯化钠溶液条件下释放曲线。c未疏水改性凝胶；d实例4凝胶Fig. 3 is the release curve of drug ibuprofen at 37°C and 0.9% sodium chloride solution. c non-hydrophobically modified gel; d example 4 gel
具体实施方式Detailed ways
实施例1Example 1
取一定量的双丙酮丙烯酰胺与水溶性光引发剂溶于水中，在高速搅拌下滴入50mL质量分数为2％的海藻酸钠水溶液中，并继续搅拌20分钟，取其混合溶液，用6#医用针头滴入到双丙酮丙烯酰胺的浓度为30％、CaCl2浓度为3％的溶液中，得到海藻酸钠微球，凝胶用蒸馏水冲洗3次，低温干燥。Dissolve a certain amount of diacetone acrylamide and a water-soluble photoinitiator in water, and drop them into 50 mL of a 2% sodium alginate aqueous solution under high-speed stirring, and continue to stir for 20 minutes. Take the mixed solution and use 6 #Medical needles were dropped into a solution with a concentration of 30% diacetone acrylamide and a concentration of 3% CaCl2 to obtain sodium alginate microspheres. The gel was washed 3 times with distilled water and dried at low temperature.
实施例2Example 2
将实施例1中的改性海藻酸钠小球置于培养皿中铺开，放置在1000W的紫外灯下照射3分钟，取出得到具有互穿网络结构的小球。用蒸馏水冲洗3次，低温干燥即制得具有互穿网络结构的小球。The modified sodium alginate pellets in Example 1 were spread out in a petri dish, placed under a 1000W ultraviolet lamp and irradiated for 3 minutes, and taken out to obtain pellets with an interpenetrating network structure. Rinse three times with distilled water and dry at low temperature to obtain small balls with interpenetrating network structure.
实施例3Example 3
称取一定质量实例2制备的微球样品，放置在事先配置好的布洛芬的乙醇溶液中溶胀1天，在37℃，200mL pH 7.2磷酸盐缓冲液条件下，测定药物释放速度，绘制释放曲线。Weigh a certain mass of the microsphere sample prepared in Example 2, place it in the pre-configured ethanol solution of ibuprofen to swell for 1 day, and measure the drug release rate at 37°C, 200mL pH 7.2 phosphate buffer, and draw the release curve.
实施例4Example 4
称取一定质量实例2制备的微球样品，在37℃，0.9％氯化钠溶液条件下，测定药物释放速度，绘制释放曲线。Weigh a certain mass of the microsphere sample prepared in Example 2, measure the drug release rate at 37°C and 0.9% sodium chloride solution, and draw the release curve.
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| CN201110262866.6ACN102977534B (en) | 2011-09-07 | 2011-09-07 | Preparation method for sodium alginate and poly (diacetone acrylamide) interpenetrating network gel |
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| CN1757662A (en)* | 2005-07-07 | 2006-04-12 | 复旦大学 | Interpenetrating network polymer type super porous aquogel, its prepn. method and application |
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