技术领域technical field
本发明属高分子材料技术领域，具体涉及一种互穿网络聚合物超多孔水凝胶及其制备方法和在药剂学中的应用。The invention belongs to the technical field of polymer materials, and in particular relates to an interpenetrating network polymer superporous hydrogel, a preparation method thereof and an application in pharmacy.
背景技术Background technique
水凝胶是含有网络结构的交联的亲水性高分子聚合物。它在水中不溶，但能吸收大量的水分。水凝胶的研究始于二十世纪六十年代，由于其具有生物相容性及生物可降解性等性质，可广泛用于医学、生物学以及药学领域，到目前为止已发明了多种水凝胶。Hydrogels are cross-linked hydrophilic polymers containing a network structure. It is insoluble in water but absorbs large amounts of water. The study of hydrogel began in the 1960s. Due to its biocompatibility and biodegradability, it can be widely used in the fields of medicine, biology and pharmacy. So far, a variety of hydrogels have been invented. gel.
互穿网络聚合物(Interpenetrating Polymer Networks，IPN)，是一类多相多组分高分子材料，由两种或两种以上分别形成的聚合物网络通过大分子链之间的永久缠结(或互穿)形成的独特聚合物合金，其聚合物网络之间交联，或既聚合又交联。按照聚合物网络形成的先后顺序，可将IPN分为两类：同时互穿网络聚合物(SIN)和分步互穿网络聚合物。两种聚合物网络同时产生则为同时互穿网络聚合物；而一种单体在另一种聚合物中聚合，所形成的聚合物则为分步互穿网络聚合物。按照聚合物的交联与否可将IPN分为全IPN和半IPN两种，聚合物均为交联的，称为全IPN；两种聚合物中一个组分是交联的，另一组分是线性的，称为半IPN。聚合物的互穿网络结构使其具有多种独特性能，如机械强度较高且柔韧性好。Interpenetrating Polymer Networks (IPN) is a class of heterogeneous multi-component polymer materials, composed of two or more polymer networks formed by permanent entanglement between macromolecular chains (or Interpenetrating) to form unique polymer alloys whose polymer networks are cross-linked with each other, or both polymerized and cross-linked. According to the sequence of polymer network formation, IPNs can be divided into two categories: simultaneous interpenetrating network polymers (SIN) and stepwise interpenetrating network polymers. The simultaneous generation of two polymer networks is a simultaneous interpenetrating network polymer; while one monomer is polymerized in another polymer, and the formed polymer is a step-by-step interpenetrating network polymer. According to whether the polymer is cross-linked or not, IPN can be divided into two types: full IPN and semi-IPN. The polymers are all cross-linked, which is called full IPN; The score is linear and is called semi-IPN. The interpenetrating network structure of the polymer endows it with several unique properties, such as high mechanical strength and good flexibility.
1998年，Chen等合成了超多孔水凝胶(Superporous Hydrogels，即SPH)(Synthesis andcharacterization of superporous hydrogel composites，J.Contr.Rel.，2002，65：73-82)。其为一种含有大量大孔的新型的水凝胶。同传统水凝胶相比，其具有快速溶胀的性能，但机械强度较差。Chen和Dorkoosh等合成了第二代超多孔水凝胶-超多孔水凝胶复合物(SPHC)(Synthesis and characterization of superporous hydrogel composites，J.Contr.Rel.，2002，65：73-82；Preparation and NMR characterization of superporous hydrogels(SPH)and SPHcomposites，Polymer，2000，41：8213-8220)。即在SPH原有的聚丙烯酸-丙烯酰胺骨架中加入亲水性聚合物交联羧甲基纤维素钠。使其既具有超多孔水凝胶的快速膨胀的性质，同时因该材料的加入，机械强度增加。SPH和SPHC具有抑酶、促渗及同小肠黏膜紧密接触的作用，可作为蛋白质多肽类药物口服给药的载体。In 1998, Chen et al. synthesized Superporous Hydrogels (SPH) (Synthesis and characterization of superporous hydrogel composites, J.Contr.Rel., 2002, 65:73-82). It is a new type of hydrogel containing a large number of macropores. Compared with traditional hydrogels, it has the property of rapid swelling, but the mechanical strength is poorer. Chen and Dorkoosh et al. synthesized the second generation superporous hydrogel-superporous hydrogel composite (SPHC) (Synthesis and characterization of superporous hydrogel composites, J.Contr.Rel., 2002, 65: 73-82; Preparation and NMR characterization of superporous hydrogels (SPH) and SPHcomposites, Polymer, 2000, 41: 8213-8220). That is, the hydrophilic polymer cross-linked sodium carboxymethyl cellulose is added to the original polyacrylic acid-acrylamide skeleton of SPH. It not only has the property of rapid expansion of the superporous hydrogel, but also increases the mechanical strength due to the addition of the material. SPH and SPHC have the functions of inhibiting enzymes, promoting penetration and closely contacting with the small intestinal mucosa, and can be used as carriers for oral administration of protein and polypeptide drugs.
第二代超多孔水凝胶SPHC的机械强度虽有所改善，但其在完全溶胀时，因不具有弹性，较脆，在外界各种力的作用下，易碎。Yang等和Kim等合成了第三代超多孔水凝胶-超多孔水凝胶互穿网络聚合物(IPN-SPH)(Semi-interpenetrating polymer networksuperporous hydrogels based on poly(3-sulfopropyl acrylate，potassium salt)and poly(vinylalcohol)：Synthesis and characterization，J.Bioactive Compatible Polymers，2004，19(2)：81-100；Swelling and mechanical properties of superporous hydrogels ofpoly(acrylamide-co-acrylic acid)/polyethylenimine interpenetrating polymer networks，Polylmer，2004，45：189-196)。即将水溶性聚合物溶胀加入到SPH原有的聚丙烯酸-丙烯酰胺骨架中，使其以网络的形式互相贯穿结合。该聚合物具有弹性，可经受拉伸、挤压、扭曲等各种力的作用。上述聚合物中使用的水溶性聚合物为聚乙烯醇和聚乙二胺，因聚乙烯醇和聚乙二胺本身的性质和毒性的限制，使得它们不宜作为蛋白质多肽类药物口服给药的载体。Although the mechanical strength of the second-generation superporous hydrogel SPHC has been improved, when it is fully swollen, it is brittle because it is not elastic, and it is fragile under the action of various external forces. Yang et al. and Kim et al. synthesized the third-generation superporous hydrogel-superporous hydrogel interpenetrating network polymer (IPN-SPH) (Semi-interpenetrating polymer network superporous hydrogels based on poly(3-sulfopropyl acrylate, potassium salt) and poly(vinylalcohol): Synthesis and characterization, J.Bioactive Compatible Polymers, 2004, 19(2): 81-100; Swelling and mechanical properties of superporous hydrogels of poly(acrylamide-co-acrylic acid)/polyethyleneiminepolymerinterpenetrating , 2004, 45:189-196). The water-soluble polymer is swelled and added to the original polyacrylic acid-acrylamide skeleton of SPH to make it interpenetrate and combine in the form of a network. The polymer is elastic and can withstand various forces such as stretching, squeezing, twisting, etc. The water-soluble polymers used in the above polymers are polyvinyl alcohol and polyethylenediamine. Due to the limitations of the properties and toxicity of polyvinyl alcohol and polyethylenediamine, they are not suitable as carriers for oral administration of protein and polypeptide drugs.
发明内容Contents of the invention
本发明的目的在于提供一种机械强度高、弹性好、无毒性限制的互穿网络聚合物超多孔水凝胶及其制备方法，并提供这种互穿网络聚合物超多孔水凝胶的应用，以克服现有技术的不足和缺陷。The purpose of the present invention is to provide a superporous interpenetrating network polymer hydrogel with high mechanical strength, good elasticity and no toxicity limit and its preparation method, and to provide the application of this superporous interpenetrating network polymer hydrogel , to overcome the deficiencies and defects of the prior art.
本发明的构思和原理如下：Design and principle of the present invention are as follows:
壳聚糖(chitosan)是由甲壳质脱乙酰基后得到的一种天然高分子氨基多糖。其吸水溶胀，可作为崩解剂。壳聚糖及其衍生物可黏附于黏膜，从而延长药物在消化道内的滞留时间，延缓药物的释放，提高药物的生物利用度。作为吸收促进剂，N，N，N-三甲基壳聚糖盐酸盐、N-羧甲基壳聚糖等在中性及微碱性条件下可显著提高消化道黏膜通透性，这是由于壳聚糖及其衍生物分子带正电荷，可与细胞膜连接，使得细胞间紧密结合蛋白的结构发生改变，从而打开细胞间的紧密连接，而且此作用是可逆性的，不会对黏膜上皮的紧密结构造成损伤。另外，N-羧甲基壳聚糖上的羧基可以螯合酶的辅助因子和Zn2+，保护蛋白质多肽类药物免于消化道内多种酶的破坏。Chitosan (chitosan) is a natural polymer amino polysaccharide obtained after deacetylation of chitin. It absorbs water and swells and can be used as a disintegrant. Chitosan and its derivatives can adhere to the mucous membrane, thereby prolonging the residence time of the drug in the digestive tract, delaying the release of the drug, and improving the bioavailability of the drug. As absorption enhancers, N, N, N-trimethyl chitosan hydrochloride, N-carboxymethyl chitosan, etc. can significantly improve the permeability of the digestive tract mucosa under neutral and slightly alkaline conditions. It is because chitosan and its derivative molecules are positively charged and can be connected to the cell membrane, which changes the structure of the intercellular tight junction protein, thereby opening the tight junction between cells, and this effect is reversible and will not damage the mucous membrane. Damage to the compact structure of the epithelium. In addition, the carboxyl group on N-carboxymethyl chitosan can chelate cofactors and Zn2+ of enzymes, and protect protein and polypeptide drugs from being destroyed by various enzymes in the digestive tract.
海藻酸钠(sodium alginate)属多糖类的线形聚电解质，是由甘露糖醛酸(M)和古洛糖醛酸(G)1，4连结的嵌段共聚物，包括G和M各自形成的均聚物和GM形成的交替聚合物。海藻酸钠在正常的生理条件下具有较好的溶解性与生物降解性。其分子上糖基具有增强蛋白质稳定性的作用，有利于蛋白质多肽类药物的给药。Sodium alginate (sodium alginate) is a linear polyelectrolyte of polysaccharides, which is a block copolymer connected by mannuronic acid (M) and guluronic acid (G) 1, 4, including G and M respectively The homopolymer of GM and the alternating polymer formed by GM. Sodium alginate has good solubility and biodegradability under normal physiological conditions. The glycosyl on the molecule has the effect of enhancing protein stability, which is beneficial to the administration of protein and polypeptide drugs.
本发明在超多孔水凝胶中加入互穿网络结构，形成一种新型的互穿网络聚合物超多孔水凝胶，使其既具有超多孔水凝胶的快速溶胀的性质，同时因聚合物具有互穿网络结构，机械强度增加，并且具有打开细胞间紧密连接、抑制蛋白酶和保护蛋白质多肽物质的作用，从而使得该互穿网络聚合物水凝胶有利于蛋白质多肽类药物的口服给药。The present invention adds an interpenetrating network structure into the superporous hydrogel to form a novel interpenetrating network polymer superporous hydrogel, which not only has the property of rapid swelling of the superporous hydrogel, but also has With an interpenetrating network structure, the mechanical strength is increased, and it has the functions of opening tight junctions between cells, inhibiting proteases and protecting protein and polypeptide substances, so that the interpenetrating network polymer hydrogel is beneficial to the oral administration of protein and polypeptide drugs.
本发明的技术方案如下：Technical scheme of the present invention is as follows:
本发明提供的互穿网络聚合物超多孔水凝胶，含有两种聚合物，一种是由至少一种不饱和烯单体和多烯交联剂聚合形成的交联聚合物，另一种是线性多糖类聚合物和交联剂聚合形成的交联多糖类聚合物，并具有互穿网络结构和超多孔结构。其中线性多糖类聚合物与交联聚合物的重量比例在0.05∶100到40∶100的范围内。多烯交联剂与不饱和烯单体的重量比例在0.01∶100到10∶100的范围内。用于线性多糖类聚合物聚合的交联剂与线性多糖类聚合物的重量比例在1∶100到100∶100的范围内。The interpenetrating network polymer superporous hydrogel provided by the present invention contains two polymers, one is a cross-linked polymer formed by polymerization of at least one unsaturated ethylenic monomer and a polyene cross-linking agent, and the other It is a cross-linked polysaccharide polymer formed by the polymerization of a linear polysaccharide polymer and a cross-linking agent, and has an interpenetrating network structure and a super-porous structure. Wherein the weight ratio of the linear polysaccharide polymer to the cross-linked polymer is in the range of 0.05:100 to 40:100. The weight ratio of polyene crosslinking agent to unsaturated ethylenic monomer is in the range of 0.01:100 to 10:100. The weight ratio of the cross-linking agent to the linear polysaccharide polymer for the polymerization of the linear polysaccharide polymer is in the range of 1:100 to 100:100.
所说的不饱和烯单体为丙烯酸、甲基丙烯酸、丙烯酸盐类、甲基丙烯酸盐类、丙烯酸酯类、甲基丙烯酸酯类、丙烯酸酯的盐类或酸类、甲基丙烯酸酯的盐类或酸类、丙烯酸的酰胺类、甲基丙烯酸的酰胺类、丙烯酸的N-烷基酰胺类、甲基丙烯酸的N-烷基酰胺类、丙烯酸的N-烷基酰胺类的盐类和酸类、甲基丙烯酸的N-烷基酰胺类的盐类和酸类、N-乙烯基吡咯烷酮、丙烯酰胺、丙烯酰胺衍生物、甲基丙烯酰胺、甲基丙烯酰胺衍生物中一种或一种以上。Said unsaturated ethylenic monomers are acrylic acid, methacrylic acid, acrylates, methacrylates, acrylates, methacrylates, salts of acrylates or acids, salts of methacrylates Acrylic acid amides, Methacrylic acid amides, Acrylic N-Alkylamides, Methacrylic N-Alkylamides, Acrylic N-Alkylamides salts and acids One or one of the salts and acids of N-alkylamides of methacrylic acid, N-vinylpyrrolidone, acrylamide, acrylamide derivatives, methacrylamide, and methacrylamide derivatives above.
通常所用的不饱和烯单体为丙烯酰胺、N-异丙基丙烯酰胺、2-羟乙基甲基丙烯酸酯、2-羟丙基甲基丙烯酸酯、N-乙烯基吡咯烷酮、丙烯酸、2-丙烯酰胺-2-甲基-1-丙磺酸、3-磺丙基-丙烯酸钾盐中的一种或一种以上。Commonly used ethylenically unsaturated monomers are acrylamide, N-isopropylacrylamide, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, N-vinylpyrrolidone, acrylic acid, 2- One or more of acrylamide-2-methyl-1-propanesulfonic acid, 3-sulfopropyl-acrylic acid potassium salt.
所说的多烯交联剂为N，N-亚甲基-双丙烯酰胺(Bis)、二(甲基)丙烯酸乙二醇酯、哌嗪二丙烯酰胺、戊二醛、表氯醇、含1，2二醇结构的交联剂、含功能肽的交联剂和含蛋白质的交联剂。Said polyene crosslinking agent is N, N-methylene-bisacrylamide (Bis), ethylene glycol di(meth)acrylate, piperazine diacrylamide, glutaraldehyde, epichlorohydrin, containing 1,2-diol structure cross-linking agent, functional peptide-containing cross-linking agent and protein-containing cross-linking agent.
所说的线性多糖类聚合物为海藻酸钠、壳聚糖、壳聚糖盐酸盐、羧甲基壳聚糖、N，N，N-三甲基壳聚糖及其交联产物中的一种。Said linear polysaccharide polymer is sodium alginate, chitosan, chitosan hydrochloride, carboxymethyl chitosan, N, N, N-trimethyl chitosan and cross-linked products thereof kind of.
所说的交联线性多糖类聚合物的交联剂为甲醛、乙醛、戊二醛、京尼平和氯化钙中的一种。优选的京尼平或戊二醛与壳聚糖及其衍生物的比例在1∶10。优选的氯化钙与海藻酸钠的比例在1∶5。The cross-linking agent of the cross-linked linear polysaccharide polymer is one of formaldehyde, acetaldehyde, glutaraldehyde, genipin and calcium chloride. The preferred ratio of genipin or glutaraldehyde to chitosan and its derivatives is 1:10. The preferred ratio of calcium chloride to sodium alginate is 1:5.
本发明的互穿网络聚合物超多孔水凝胶，其平均孔径为50μm至4000μm。优选的平均孔径为100μm至800μm。由于大量孔隙的存在并且它们彼此相互连接，所以该水凝胶溶胀很快并且其达到溶胀平衡的时间也很短。本发明的互穿网络聚合物超多孔水凝胶的溶胀比为5至1000，达到溶胀平衡的时间为1秒至2小时。The interpenetrating network polymer superporous hydrogel of the present invention has an average pore diameter of 50 μm to 4000 μm. A preferred average pore size is 100 μm to 800 μm. Due to the existence of a large number of pores and their interconnection with each other, the hydrogel swells quickly and the time to reach swelling equilibrium is also very short. The swelling ratio of the interpenetrating network polymer superporous hydrogel of the invention is 5 to 1000, and the time to reach swelling equilibrium is 1 second to 2 hours.
本发明的互穿网络聚合物超多孔水凝胶，其制备方法如下：Interpenetrating network polymer superporous hydrogel of the present invention, its preparation method is as follows:
(1)将至少一种不饱和烯单体、一种多烯交联剂、一种线性多糖类聚合物和一种起泡剂混合，室温下形成半互穿网络聚合物超多孔水凝胶；(1) Mix at least one unsaturated ethylenic monomer, a polyene crosslinking agent, a linear polysaccharide polymer and a foaming agent to form a semi-interpenetrating network polymer superporous hydrogel at room temperature glue;
(2)将上述半互穿网络聚合物超多孔水凝胶置于交联剂溶液中，放置0.5～8小时，形成全互穿网络聚合物超多孔水凝胶。(2) Put the above semi-IPN polymer superporous hydrogel in the crosslinking agent solution and let it stand for 0.5-8 hours to form a fully interpenetrating network polymer superporous hydrogel.
其中线性多糖类聚合物与交联聚合物(由至少一种不饱和烯单体和多烯交联剂聚合形成)的比例在0.05∶100到40∶100的范围内。线性多糖类聚合物的用量太大，在聚合过程中不能将其全部包含到聚合物中，有部分线性多糖类聚合物不发生胶凝。所说的不饱和烯单体为丙烯酸、甲基丙烯酸、丙烯酸盐类、甲基丙烯酸盐类、丙烯酸酯类、甲基丙烯酸酯类、丙烯酸酯的盐类或酸类、甲基丙烯酸酯的盐类或酸类、丙烯酸的酰胺类、甲基丙烯酸的酰胺类、丙烯酸的N-烷基酰胺类、甲基丙烯酸的N-烷基酰胺类、丙烯酸的N-烷基酰胺类的盐类和酸类、甲基丙烯酸的N-烷基酰胺类的盐类和酸类、N-乙烯基吡咯烷酮、丙烯酰胺、丙烯酰胺衍生物、甲基丙烯酰胺、甲基丙烯酰胺衍生物中一种或一种以上。Wherein the ratio of linear polysaccharide polymer to cross-linked polymer (formed by polymerization of at least one unsaturated ethylenic monomer and polyene cross-linking agent) is in the range of 0.05:100 to 40:100. The amount of linear polysaccharide polymer used is too large, and it cannot be completely included in the polymer during the polymerization process, and some linear polysaccharide polymers do not gel. Said unsaturated ethylenic monomers are acrylic acid, methacrylic acid, acrylates, methacrylates, acrylates, methacrylates, salts of acrylates or acids, salts of methacrylates Acrylic acid amides, Methacrylic acid amides, Acrylic N-Alkylamides, Methacrylic N-Alkylamides, Acrylic N-Alkylamides salts and acids One or one of the salts and acids of N-alkylamides of methacrylic acid, N-vinylpyrrolidone, acrylamide, acrylamide derivatives, methacrylamide, and methacrylamide derivatives above.
通常所用的不饱和烯单体为丙烯酰胺、N-异丙基丙烯酰胺、2-羟乙基甲基丙烯酸酯、2-羟丙基甲基丙烯酸酯、N-乙烯基吡咯烷酮、丙烯酸、2-丙烯酰胺-2-甲基-1-丙磺酸、3-磺丙基-丙烯酸钾盐中的一种或一种以上。Commonly used ethylenically unsaturated monomers are acrylamide, N-isopropylacrylamide, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, N-vinylpyrrolidone, acrylic acid, 2- One or more of acrylamide-2-methyl-1-propanesulfonic acid, 3-sulfopropyl-acrylic acid potassium salt.
所说的交联剂为N，N-亚甲基-双丙烯酰胺、二(甲基)丙烯酸乙二醇酯、哌嗪二丙烯酰胺、戊二醛、表氯醇、含1，2二醇结构的交联剂、含功能肽的交联剂和含蛋白质的交联剂。其用量为交联剂与单体的比例在0.01∶100到10∶100的范围内。优选的交联剂与单体的比例在1∶100。交联剂浓度太高，引起溶胀的互穿网络聚合物超多孔水凝胶变得易碎，导致溶胀比的降低。反之，交联剂的浓度太低，造成互穿网络聚合物超多孔水凝胶变得更软和易碎。Said cross-linking agent is N, N-methylene-bisacrylamide, ethylene glycol di(meth)acrylate, piperazine diacrylamide, glutaraldehyde, epichlorohydrin, containing 1,2 glycol Structural cross-linking agents, functional peptide-containing cross-linking agents and protein-containing cross-linking agents. The amount used is such that the ratio of crosslinking agent to monomer is in the range of 0.01:100 to 10:100. The preferred ratio of crosslinker to monomer is 1:100. Too high concentration of cross-linking agent caused the swollen interpenetrating network polymer superporous hydrogel to become brittle, resulting in a decrease in swelling ratio. On the contrary, the concentration of cross-linking agent is too low, resulting in softer and brittle interpenetrating network polymer superporous hydrogels.
所说的多糖类聚合物为海藻酸钠、壳聚糖、壳聚糖盐酸盐、羧甲基壳聚糖、N，N，N-三甲基壳聚糖及其交联产物中的一种。Said polysaccharide polymer is sodium alginate, chitosan, chitosan hydrochloride, carboxymethyl chitosan, N, N, N-trimethyl chitosan and cross-linked products thereof A sort of.
所说的线性多糖类聚合物的交联剂为甲醛、乙醛、戊二醛、京尼平和氯化钙中的一种。其中甲醛、乙醛、戊二醛和京尼平用于壳聚糖及其衍生物，氯化钙用于海藻酸钠。京尼平或戊二醛与壳聚糖及其衍生物的比例在1∶100到50∶100的范围内。优选的京尼平或戊二醛与壳聚糖及其衍生物的比例在1∶10。京尼平或戊二醛浓度太高，引起溶胀的互穿网络聚合物变得更脆和易碎，导致溶胀比降低，机械强度降低。反之京尼平或戊二醛的浓度太低，互穿网络聚合物超多孔水凝胶变得更软和易碎。氯化钙与海藻酸钠的比例在1∶100到100∶100的范围内。优选的氯化钙与海藻酸钠的比例在1∶5。氯化钙浓度太高，引起溶胀的互穿网络聚合物变得易碎，溶胀比降低，机械强度降低。反之氯化钙的浓度太低，互穿网络聚合物超多孔水凝胶变得更软和易碎。The cross-linking agent of the linear polysaccharide polymer is one of formaldehyde, acetaldehyde, glutaraldehyde, genipin and calcium chloride. Among them, formaldehyde, acetaldehyde, glutaraldehyde and genipin are used for chitosan and its derivatives, and calcium chloride is used for sodium alginate. The ratio of genipin or glutaraldehyde to chitosan and its derivatives is in the range of 1:100 to 50:100. The preferred ratio of genipin or glutaraldehyde to chitosan and its derivatives is 1:10. Too high concentration of genipin or glutaraldehyde caused the swollen IPN polymer to become more brittle and brittle, resulting in lower swelling ratio and lower mechanical strength. On the contrary, when the concentration of genipin or glutaraldehyde was too low, the interpenetrating network polymer superporous hydrogel became softer and brittle. The ratio of calcium chloride to sodium alginate is in the range of 1:100 to 100:100. The preferred ratio of calcium chloride to sodium alginate is 1:5. If the concentration of calcium chloride is too high, the swollen interpenetrating network polymer becomes brittle, the swelling ratio decreases, and the mechanical strength decreases. On the contrary, when the concentration of CaCl was too low, the interpenetrating network polymer superporous hydrogel became softer and brittle.
所说的起泡剂为碳酸氢盐、碳酸盐的一种或一种以上或从外导入气泡。其中常用的为碳酸氢钠、碳酸钠和碳酸钙的一种或一种以上。优选的为碳酸氢钠。Said foaming agent is one or more of bicarbonate and carbonate or introduces bubbles from the outside. One or more of sodium bicarbonate, sodium carbonate and calcium carbonate are commonly used. Preferred is sodium bicarbonate.
上述方法中，在聚合和起泡之前可加入水或泡沫稳定剂。In the above method, water or a foam stabilizer may be added before polymerization and foaming.
上述方法中，在聚合和起泡之前可先加入引发剂和催化剂。In the above method, the initiator and catalyst can be added before the polymerization and foaming.
形成超多孔水凝胶的两个必备的条件为聚合和起泡。为了制备均相互穿网络聚合物超多孔水凝胶，聚合和起泡应当同时发生。因为起泡过程较短并很难稳定气泡长于几分钟，为捕获聚合物网络中的气泡，在气泡稳定时必须发生胶凝。The two necessary conditions for the formation of superporous hydrogels are aggregation and foaming. In order to prepare homogeneous interpenetrating network polymer superporous hydrogels, polymerization and foaming should occur simultaneously. Because the foaming process is short and it is difficult to stabilize the bubbles for longer than a few minutes, in order to trap the bubbles in the polymer network, gelation must occur while the bubbles are stabilizing.
起泡的方法多种多样，包括化学试剂的热分解、机械抖动、低沸点液体的挥发、化学反应、释压时溶解气体的膨胀等化学或机械方法。起泡剂的用量决定气泡孔径的大小和互穿网络聚合物超多孔水凝胶的孔隙率。气泡产生后，为使其在胶凝过程中稳定，需使用泡沫稳定剂，其通过降低膜-气界面张力和增加膜粘度来稳定泡沫。理想的泡沫稳定剂应当把泡沫稳定到胶凝过程的开始。泊洛沙姆(Pluronic F127)是一种较好的泡沫稳定剂，其稳定泡沫的时间较长。但其用量有一定的要求，太少不能提供较好的泡沫稳定效果，而超过一定量同样达不到稳定泡沫的效果。一般来讲，其用量为单体重量的0.1～1.2％(W/W)。优选的用量为单体重量的0.5％(W/W)。There are various methods of foaming, including chemical or mechanical methods such as thermal decomposition of chemical reagents, mechanical shaking, volatilization of low-boiling liquids, chemical reactions, and expansion of dissolved gases when pressure is released. The amount of foaming agent determines the pore size of the bubbles and the porosity of the interpenetrating network polymer superporous hydrogel. After the bubbles are generated, to stabilize them during the gelation process, foam stabilizers are used, which stabilize the foam by reducing the film-air interfacial tension and increasing the film viscosity. An ideal foam stabilizer should stabilize the foam until the onset of the gelling process. Poloxamer (Pluronic F127) is a better foam stabilizer, which stabilizes the foam for a longer time. However, there are certain requirements for its dosage, too little can not provide a good foam stabilization effect, and more than a certain amount can not achieve the same foam stabilization effect. Generally speaking, its dosage is 0.1-1.2% (W/W) of monomer weight. A preferred amount is 0.5% by weight (W/W) of the monomers.
本发明中，在有酸存在时选用碳酸氢钠作为起泡剂来制备互穿网络聚合物超多孔水凝胶，因为碳酸氢钠-酸体系具有其它气体喷吹技术没有的优点。它安全、低廉、容易使用，且允许人为控制形成泡沫的时间和在聚合过程中导入的气体的量。In the present invention, sodium bicarbonate is selected as the foaming agent to prepare interpenetrating network polymer superporous hydrogel in the presence of acid, because the sodium bicarbonate-acid system has advantages that other gas injection technologies do not have. It is safe, inexpensive, easy to use, and allows artificial control of the time of foam formation and the amount of gas introduced during polymerization.
通过控制单体(种类和浓度)、引发剂(种类和浓度)、温度和溶剂可达到快速胶凝。通常水溶性的丙烯酸盐、甲基丙烯酸盐和丙烯酰胺胶凝非常快，因此，优选上述单体制备互穿网络聚合物超多孔水凝胶。Rapid gelation can be achieved by controlling monomer (type and concentration), initiator (type and concentration), temperature and solvent. Generally, water-soluble acrylate, methacrylate and acrylamide gel very quickly, therefore, the above-mentioned monomers are preferred to prepare interpenetrating network polymer superporous hydrogels.
优选使用过硫酸铵作为引发剂，N，N，N′，N′-四甲基乙二胺(TMEDA)作为催化剂，引发剂和催化剂的用量可显著影响聚合的速度。通常，过硫酸铵的浓度和N，N，N′，N′-四甲基乙二胺的浓度分别为单体重量的0.1～5％(W/W)。优选的过硫酸铵的浓度和N，N，N′，N′-四甲基乙二胺的浓度分别为单体重量的2％(W/W)。Ammonium persulfate is preferably used as an initiator, and N,N,N',N'-tetramethylethylenediamine (TMEDA) is used as a catalyst, and the amount of the initiator and catalyst can significantly affect the polymerization rate. Usually, the concentration of ammonium persulfate and the concentration of N,N,N',N'-tetramethylethylenediamine are respectively 0.1-5% (W/W) of monomer weight. The preferred concentrations of ammonium persulfate and N,N,N',N'-tetramethylethylenediamine are 2% (W/W) by weight of the monomers, respectively.
本发明的互穿网络聚合物超多孔水凝胶的溶胀比和密度的测定方法如下：The measuring method of the swelling ratio and the density of interpenetrating network polymer superporous hydrogel of the present invention is as follows:
溶胀比的测定：溶胀比的定义为Q＝(Ws-Wd)/Wd，其中Ws是溶胀后的互穿网络聚合物超多孔水凝胶的重量，Wd是干的互穿网络聚合物超多孔水凝胶的重量。首先称重干互穿网络聚合物超多孔水凝胶，得到Wd，把样品置于过量的双蒸水中，用带筛网的容器定时取出，去掉筛网中剩余的水，然后称重，得到Ws，即可求得溶胀比Q。The mensuration of swelling ratio: the definition of swelling ratio is Q=(Ws-Wd)/Wd, wherein Ws is the weight of the interpenetrating network polymer superporous hydrogel after swelling, and Wd is the dry interpenetrating network polymer superporous hydrogel hydrogel weight. First weigh the dry interpenetrating network polymer superporous hydrogel to obtain Wd, place the sample in excess double-distilled water, take it out regularly with a container with a screen, remove the remaining water in the screen, and then weigh it to obtain Ws, the swelling ratio Q can be obtained.
密度的测定：密度为d＝Wd/Vd，其中Wd是干互穿网络聚合物超多孔水凝胶的重量，Vd是互穿网络聚合物超多孔水凝胶的体积。其中Vd是利用溶剂替换法测得，即将互穿网络聚合物超多孔水凝胶置于已测得直径和高度的、装有正己烷的圆柱形试管中，通过高度的变化得知Vd，从而求得密度。Determination of density: the density is d=Wd/Vd, wherein Wd is the weight of the dry interpenetrating network polymer superporous hydrogel, and Vd is the volume of the interpenetrating network polymer superporous hydrogel. Among them, Vd is measured by the solvent replacement method, that is, the interpenetrating network polymer superporous hydrogel is placed in a cylindrical test tube that has measured diameter and height, and n-hexane is housed, and Vd is known through the change of height, so that Find the density.
体外抑酶试验：分别制得1.2mg·ml-1的胰蛋白酶溶液和1.6mg·ml-1的α-糜蛋白酶PBS溶液。在加有10ml PBS的三角烧瓶中分别加入100μl胰蛋白酶溶液或100μl α-糜蛋白酶溶液，然后加入200mg含壳聚糖及其衍生物或海藻酸钠的IPN-SPH，使之充分溶胀并吸收蛋白酶溶液，30min后在上述溶液中加入10ml 100μg·ml-1的胰岛素溶液，制得样品溶液。加入蛋白水解酶但不加入IPN-SPH为胰岛素溶液阳性对照，不加入蛋白水解酶和IPN-SPH的胰岛素溶液为阴性对照。37℃、150rpm振荡上述样品溶液和对照品溶液，60min时取样100μl，样品中加入150μl三氟乙酸溶液(pH1.8)终止酶解反应。经12,000rpm离心10min，取上清液注入液相色谱仪，测定胰岛素含量。In vitro enzyme inhibition test: 1.2 mg·ml-1 trypsin solution and 1.6 mg·ml-1 α-chymotrypsin PBS solution were prepared respectively. Add 100 μl trypsin solution or 100 μl α-chymotrypsin solution to the conical flask with 10ml PBS, then add 200mg IPN-SPH containing chitosan and its derivatives or sodium alginate to fully swell and absorb protease After 30 minutes, 10 ml of 100 μg·ml-1 insulin solution was added to the above solution to prepare a sample solution. Adding proteolytic enzymes but not adding IPN-SPH was used as a positive control for insulin solution, and the insulin solution without adding proteolytic enzymes and IPN-SPH was used as a negative control. The above sample solution and reference solution were shaken at 37°C and 150 rpm, 100 μl of sample was taken at 60 min, and 150 μl of trifluoroacetic acid solution (pH 1.8) was added to the sample to terminate the enzymatic hydrolysis reaction. After centrifugation at 12,000 rpm for 10 min, the supernatant was injected into a liquid chromatograph to measure the insulin content.
表1 IPN-SPH的密度、溶胀比、溶胀时间(n＝3)
表2 IPN-SPH的抑酶作用
本发明的优点在于：The advantages of the present invention are:
(1)所加入的壳聚糖及其衍生物具有快速溶胀的特点，其与超多孔水凝胶形成的互穿网络聚合物仍具有快速溶胀的特性；(1) The added chitosan and its derivatives have the characteristics of rapid swelling, and the interpenetrating network polymer formed with the superporous hydrogel still has the characteristics of rapid swelling;
(2)壳聚糖及其衍生物和海藻酸钠互穿网络的引入，使得该互穿网络聚合物的机械强度得到改善，有利于载药量的提高；(2) The introduction of chitosan and its derivatives and sodium alginate interpenetrating network improves the mechanical strength of the interpenetrating network polymer, which is conducive to the improvement of drug loading;
(3)壳聚糖及其衍生物和海藻酸钠互穿网络的引入，使得该互穿网络聚合物的机械强度得到改善，有利于提高给药部位药物的浓度梯度，增加药物的扩散量；(3) The introduction of chitosan and its derivatives and sodium alginate interpenetrating network improves the mechanical strength of the interpenetrating network polymer, which is conducive to improving the concentration gradient of the drug at the administration site and increasing the diffusion amount of the drug;
(4)壳聚糖及其衍生物和海藻酸钠的加入，使得该互穿网络聚合物超多孔水凝胶具有打开上皮细胞紧密连接作用和蛋白酶抑制作用，有利于蛋白质多肽药物的口服给药。(4) The addition of chitosan and its derivatives and sodium alginate makes the interpenetrating network polymer superporous hydrogel have the effect of opening tight junctions of epithelial cells and protease inhibition, which is conducive to the oral administration of protein polypeptide drugs .
附图说明Description of drawings
附图1大鼠口服载有胰岛素的IPN-SPH肠溶胶囊后的降血糖效果图Accompanying drawing 1 is the hypoglycemic effect diagram after oral administration of IPN-SPH enteric-coated capsules loaded with insulin in rats
具体实施方式Detailed ways
实施例1含壳聚糖的聚(丙烯酸-丙烯酰胺)IPN-SPHEmbodiment 1 poly(acrylic acid-acrylamide) IPN-SPH containing chitosan
在高型称量瓶(40mm×25mm)中依次加入下列成分：300μl 50％的AM(丙烯酰胺)；200μl 50％的AA(丙烯酸)；100μl 2.5％的BIS(N，N′-亚甲基-双丙烯酰胺)；300μl DDW(双蒸水)；30μl 10％的PluronicF127(PF127，泊洛沙姆)；25μl 20％的APS(过硫酸铵)；25μl 20％的TEMED(N，N，N′，N′-四甲基乙二胺)；300μl 4％的壳聚糖(用2％乙酸溶解)。在加入每种成分之后，震荡混合溶液。在发生胶凝前2分钟加入120mg碳酸氢钠，涡旋振荡。将上述含壳聚糖的超多孔水凝胶聚合物在含1％戊二醛的HCl/无水乙醇(3∶7，v/v)中放置2h，即可得到含壳聚糖的聚(丙烯酸-丙烯酰胺)IPN-SPH。In a tall weighing bottle (40mm×25mm), add the following components in sequence: 300μl 50% AM (acrylamide); 200μl 50% AA (acrylic acid); 100μl 2.5% BIS (N, N'-methylene - bisacrylamide); 300 μl DDW (double distilled water); 30 μl 10% Pluronic® F127 (PF127, poloxamer); 25 μl 20% APS (ammonium persulfate); 25 μl 20% TEMED (N, N , N', N'-tetramethylethylenediamine); 300 μl of 4% chitosan (dissolved with 2% acetic acid). After each ingredient is added, the solution is vortexed to mix. Add 120 mg of sodium bicarbonate 2 minutes before gelation occurs and vortex. Place the above-mentioned ultraporous hydrogel polymer containing chitosan in HCl/absolute ethanol (3:7, v/v) containing 1% glutaraldehyde for 2h to obtain the poly( Acrylic acid-acrylamide) IPN-SPH.
实施例2含壳聚糖盐酸盐的聚(丙烯酸-丙烯酰胺)IPN-SPHEmbodiment 2 contains poly(acrylic acid-acrylamide) IPN-SPH of chitosan hydrochloride
在高型称量瓶(40mm×25mm)中依次加入下列成分：300μl 50％的AM(丙烯酰胺)：200μl 50％的AA(丙烯酸)；100μl 2.5％的BIS(N，N′-亚甲基-双丙烯酰胺)；300μl DDW(双蒸水)；30μl 10％的PluronicF127(PF127，泊洛沙姆)；25μl 20％的APS(过硫酸铵)；25μl 20％的TEMED(N，N，N′，N′-四甲基乙二胺)；300μl 4％的壳聚糖盐酸盐。在加入每种成分之后，涡旋混合溶液。在发生胶凝前2分钟加入120mg碳酸氢钠，涡旋振荡。将上述含壳聚糖盐酸盐的超多孔水凝胶聚合物在含1％戊二醛的HCl/无水乙醇(3∶7，v/v)中放置2h，即可得到含壳聚糖盐酸盐的聚(丙烯酸-丙烯酰胺)IPN-SPH。In a tall weighing bottle (40mm × 25mm), add the following ingredients in turn: 300μl 50% AM (acrylamide): 200μl 50% AA (acrylic acid); 100μl 2.5% BIS (N, N'-methylene - bisacrylamide); 300 μl DDW (double distilled water); 30 μl 10% Pluronic® F127 (PF127, poloxamer); 25 μl 20% APS (ammonium persulfate); 25 μl 20% TEMED (N, N , N', N'-tetramethylethylenediamine); 300 μl of 4% chitosan hydrochloride. After adding each ingredient, the solution was vortexed to mix. Add 120 mg of sodium bicarbonate 2 minutes before gelation occurs and vortex. Place the above-mentioned ultraporous hydrogel polymer containing chitosan hydrochloride in HCl/absolute ethanol (3:7, v/v) containing 1% glutaraldehyde for 2h to obtain chitosan-containing Poly(acrylic acid-acrylamide) IPN-SPH hydrochloride.
实施例3含壳聚糖三甲基季铵盐(TMC)的聚(丙烯酸-丙烯酰胺)IPN-SPHEmbodiment 3 contains the poly(acrylic acid-acrylamide) IPN-SPH of chitosan trimethyl quaternary ammonium salt (TMC)
在高型称量瓶(40mm×25mm)中依次加入下列成分：300μl 50％的AM(丙烯酰胺)；200μl 50％的AA(丙烯酸)；100μl 2.5％的BIS(N，N′-亚甲基-双丙烯酰胺)；300μl DDW(双蒸水)；30μl 10％的PluronicF127(PF127，泊洛沙姆)；25μl 20％的APS(过硫酸铵)；25μl 20％的TEMED(N，N，N′，N′-四甲基乙二胺)；300μl 8％的TMC。在加入每种成分之后，涡旋混合溶液。在发生胶凝前2分钟加入120mg碳酸氢钠，涡旋振荡。将上述含TMC的超多孔水凝胶聚合物在含1％戊二醛的HCl/无水乙醇(3∶7，v/v)中放置4h，即可得到含壳聚糖三甲基季铵盐(TMC)的聚(丙烯酸-丙烯酰胺)IPN-SPH。In a tall weighing bottle (40mm×25mm), add the following components in sequence: 300μl 50% AM (acrylamide); 200μl 50% AA (acrylic acid); 100μl 2.5% BIS (N, N'-methylene - bisacrylamide); 300 μl DDW (double distilled water); 30 μl 10% Pluronic® F127 (PF127, poloxamer); 25 μl 20% APS (ammonium persulfate); 25 μl 20% TEMED (N, N , N',N'-tetramethylethylenediamine); 300 μl of 8% TMC. After adding each ingredient, the solution was vortexed to mix. Add 120 mg of sodium bicarbonate 2 minutes before gelation occurs and vortex. The above-mentioned superporous hydrogel polymer containing TMC is placed in HCl/dehydrated alcohol (3:7, v/v) containing 1% glutaraldehyde for 4h, and then trimethyl quaternary ammonium containing chitosan can be obtained. Poly(acrylic acid-acrylamide) IPN-SPH of salt (TMC).
实施例4含壳聚糖三甲基季铵盐(TMC)的聚(丙烯酸-丙烯酰胺)IPN-SPHEmbodiment 4 contains the poly(acrylic acid-acrylamide) IPN-SPH of chitosan trimethyl quaternary ammonium salt (TMC)
在高型称量瓶(40mm×25mm)中依次加入下列成分：300μl 50％的AM(丙烯酰胺)；200μl 50％的AA(丙烯酸)；100μl 2.5％的BIS(N，N′-亚甲基-双丙烯酰胺)；300μl DDW(双蒸水)；30μl 10％的PluronicF127(PF127，泊洛沙姆)；25μl 20％的APS(过硫酸铵)；25μl 20％的TEMED(N，N，N′，N′-四甲基乙二胺)；300μl 16％的TMC。在加入每种成分之后，涡旋混合溶液。在发生胶凝前2分钟加入120mg碳酸氢钠，涡旋振荡。将上述含TMC的超多孔水凝胶聚合物在含1％戊二醛的HCl/无水乙醇(3∶7，v/v)中放置8h，即可得到含壳聚糖三甲基季铵盐(TMC)的聚(丙烯酸-丙烯酰胺)IPN-SPH。In a tall weighing bottle (40mm×25mm), add the following components in sequence: 300μl 50% AM (acrylamide); 200μl 50% AA (acrylic acid); 100μl 2.5% BIS (N, N'-methylene - bisacrylamide); 300 μl DDW (double distilled water); 30 μl 10% Pluronic® F127 (PF127, poloxamer); 25 μl 20% APS (ammonium persulfate); 25 μl 20% TEMED (N, N , N',N'-tetramethylethylenediamine); 300 μl of 16% TMC. After adding each ingredient, the solution was vortexed to mix. Add 120 mg of sodium bicarbonate 2 minutes before gelation occurs and vortex. The above-mentioned superporous hydrogel polymer containing TMC is placed in HCl/dehydrated alcohol (3:7, v/v) containing 1% glutaraldehyde for 8h, and then trimethyl quaternary ammonium containing chitosan can be obtained. Poly(acrylic acid-acrylamide) IPN-SPH of salt (TMC).
实施例5含羧甲基壳聚糖(CMC)的聚(丙烯酸-丙烯酰胺)IPN-SPHEmbodiment 5 poly(acrylic acid-acrylamide) IPN-SPH containing carboxymethyl chitosan (CMC)
在高型称量瓶(40mm×25mm)中依次加入下列成分：300μl 50％的AM(丙烯酰胺)；200μl 50％的AA(丙烯酸)；100μl 2.5％的BIS(N，N′-亚甲基-双丙烯酰胺)；300μl DDW(双蒸水)；30μl 10％的PluronicF127(PF127，泊洛沙姆)；25μl 20％的APS(过硫酸铵)；25μl 20％的TEMED(N，N，N′，N′-四甲基乙二胺)；600μl 4％的CMC。在加入每种成分之后，涡旋混合溶液。在发生胶凝前2分钟加入120mg碳酸氢钠，涡旋振荡。将上述含CMC的超多孔水凝胶聚合物在含1％戊二醛的HCl/无水乙醇(3∶7，v/v)中放置2h，即可得到含羧甲基壳聚糖(CMC)的聚(丙烯酸-丙烯酰胺)IPN-SPH。In a tall weighing bottle (40mm×25mm), add the following components in sequence: 300μl 50% AM (acrylamide); 200μl 50% AA (acrylic acid); 100μl 2.5% BIS (N, N'-methylene - bisacrylamide); 300 μl DDW (double distilled water); 30 μl 10% Pluronic® F127 (PF127, poloxamer); 25 μl 20% APS (ammonium persulfate); 25 μl 20% TEMED (N, N , N',N'-tetramethylethylenediamine); 600 μl of 4% CMC. After adding each ingredient, the solution was vortexed to mix. Add 120 mg of sodium bicarbonate 2 minutes before gelation occurs and vortex. The above-mentioned superporous hydrogel polymer containing CMC was placed in HCl/dehydrated alcohol (3:7, v/v) containing 1% glutaraldehyde for 2h to obtain carboxymethyl chitosan (CMC ) of poly(acrylic acid-acrylamide) IPN-SPH.
实施例6含羧甲基壳聚糖(CMC)的聚(丙烯酸-丙烯酰胺)IPN-SPHEmbodiment 6 contains the poly(acrylic acid-acrylamide) IPN-SPH of carboxymethyl chitosan (CMC)
在高型称量瓶(40mm×25mm)中依次加入下列成分：300μl 50％的AM(丙烯酰胺)；200μl 50％的AA(丙烯酸)；100μl 2.5％的BIS(N，N′-亚甲基-双丙烯酰胺)；300μl DDW(双蒸水)；30μl 10％的PluronicF127(PF127，泊洛沙姆)；25μl 20％的APS(过硫酸铵)；25μl 20％的TEMED(N，N，N′，N′-四甲基乙二胺)；600μl 8％的CMC。在加入每种成分之后，涡旋混合溶液。在发生胶凝前2分钟加入120mg碳酸氢钠，涡旋振荡。将上述含CMC的超多孔水凝胶聚合物在含1％戊二醛的HCl/无水乙醇(3∶7，v/v)中放置4h，即可得到含羧甲基壳聚糖(CMC)的聚(丙烯酸-丙烯酰胺)IPN-SPH。In a tall weighing bottle (40mm×25mm), add the following components in sequence: 300μl 50% AM (acrylamide); 200μl 50% AA (acrylic acid); 100μl 2.5% BIS (N, N'-methylene - bisacrylamide); 300 μl DDW (double distilled water); 30 μl 10% Pluronic® F127 (PF127, poloxamer); 25 μl 20% APS (ammonium persulfate); 25 μl 20% TEMED (N, N , N',N'-tetramethylethylenediamine); 600 μl of 8% CMC. After adding each ingredient, the solution was vortexed to mix. Add 120 mg of sodium bicarbonate 2 minutes before gelation occurs and vortex. The above-mentioned superporous hydrogel polymer containing CMC was placed in HCl/dehydrated alcohol (3:7, v/v) containing 1% glutaraldehyde for 4h to obtain carboxymethyl chitosan (CMC ) of poly(acrylic acid-acrylamide) IPN-SPH.
实施例7含海藻酸钠(SA)的聚(丙烯酸-丙烯酰胺)IPN-SPHExample 7 Poly(acrylic acid-acrylamide) IPN-SPH containing sodium alginate (SA)
在高型称量瓶(40mm×25mm)中依次加入下列成分：300μl 50％的AM(丙烯酰胺)；200μl 50％的AA(丙烯酸)；100μl 2.5％的BIS(N，N′-亚甲基-双丙烯酰胺)；300μl DDW(双蒸水)；30μl 10％的PluronicF127(PF127，泊洛沙姆)；25μl 20％的APS(过硫酸铵)；25μl 20％的TEMED(N，N，N′，N′-四甲基乙二胺)；300μl 4％的SA。在加入每种成分之后，涡旋混合溶液。在发生胶凝前2分钟加入120mg碳酸氢钠，涡旋振荡。将上述含SA的超多孔水凝胶聚合物在含1％ CaCl2的HCl/无水乙醇(3∶7，v/v)中放置0.5h，即可得到含海藻酸钠(SA)的聚(丙烯酸-丙烯酰胺)IPN-SPH。In a tall weighing bottle (40mm×25mm), add the following components in sequence: 300μl 50% AM (acrylamide); 200μl 50% AA (acrylic acid); 100μl 2.5% BIS (N, N'-methylene - bisacrylamide); 300 μl DDW (double distilled water); 30 μl 10% Pluronic® F127 (PF127, poloxamer); 25 μl 20% APS (ammonium persulfate); 25 μl 20% TEMED (N, N , N',N'-tetramethylethylenediamine); 300 μl 4% SA. After adding each ingredient, the solution was vortexed to mix. Add 120 mg of sodium bicarbonate 2 minutes before gelation occurs and vortex. The above superporous hydrogel polymer containing SA was placed in HCl/absolute ethanol (3:7, v/v) containing 1% CaCl2 for 0.5h, and the polymer containing sodium alginate (SA) could be obtained. (acrylic acid-acrylamide) IPN-SPH.
实施例8含海藻酸钠(SA)的聚(丙烯酸-丙烯酰胺)IPN-SPHExample 8 Poly(acrylic acid-acrylamide) IPN-SPH containing sodium alginate (SA)
在高型称量瓶(40mm×25mm)中依次加入下列成分：300μl 50％的AM(丙烯酰胺)；200μl 50％的AA(丙烯酸)；100μl 2.5％的BIS(N，N′-亚甲基-双丙烯酰胺)；300μl DDW(双蒸水)；30μl 10％的PluronicF127(PF127，泊洛沙姆)；25μl 20％的APS(过硫酸铵)；25μl 20％的TEMED(N，N，N′，N′-四甲基乙二胺)；300μl 8％的SA。在加入每种成分之后，涡旋混合溶液。在发生胶凝前2分钟加入120mg碳酸氢钠，涡旋振荡。将上述含SA的超多孔水凝胶聚合物在含1％ CaCl2的HCl/无水乙醇(3∶7，v/v)中放置2h，即可得到含海藻酸钠(SA)的聚(丙烯酸-丙烯酰胺)IPN-SPH。In a tall weighing bottle (40mm×25mm), add the following components in sequence: 300μl 50% AM (acrylamide); 200μl 50% AA (acrylic acid); 100μl 2.5% BIS (N, N'-methylene - bisacrylamide); 300 μl DDW (double distilled water); 30 μl 10% Pluronic® F127 (PF127, poloxamer); 25 μl 20% APS (ammonium persulfate); 25 μl 20% TEMED (N, N , N',N'-tetramethylethylenediamine); 300 μl 8% SA. After adding each ingredient, the solution was vortexed to mix. Add 120 mg of sodium bicarbonate 2 minutes before gelation occurs and vortex. The above-mentioned SA-containing superporous hydrogel polymer was placed in HCl/absolute ethanol (3:7, v/v) containing 1% CaCl for 2h to obtain poly( Acrylic acid-acrylamide) IPN-SPH.
实施例9含海藻酸钠(SA)的聚(丙烯酸-丙烯酰胺)IPN-SPHExample 9 Poly(acrylic acid-acrylamide) IPN-SPH containing sodium alginate (SA)
在高型称量瓶(40mm×25mm)中依次加入下列成分：300μl 50％的AM(丙烯酰胺)；200μl 50％的AA(丙烯酸)；100μl 2.5％的BIS(N，N′-亚甲基-双丙烯酰胺)；300μl DDW(双蒸水)；30μl 10％的PluronicF127(PF127，泊洛沙姆)；25μl 20％的APS(过硫酸铵)；25μl 20％的TEMED(N，N，N′，N′-四甲基乙二胺)；450μl 8％的SA。在加入每种成分之后，涡旋混合溶液。在发生胶凝前2分钟加入120mg碳酸氢钠，涡旋振荡。将上述含SA的超多孔水凝胶聚合物在含1％ CaCl2的HCl/无水乙醇(3∶7，v/v)中放置4h，即可得到含海藻酸钠(SA)的聚(丙烯酸-丙烯酰胺)IPN-SPH。In a tall weighing bottle (40mm×25mm), add the following components in sequence: 300μl 50% AM (acrylamide); 200μl 50% AA (acrylic acid); 100μl 2.5% BIS (N, N'-methylene - bisacrylamide); 300 μl DDW (double distilled water); 30 μl 10% Pluronic® F127 (PF127, poloxamer); 25 μl 20% APS (ammonium persulfate); 25 μl 20% TEMED (N, N , N',N'-tetramethylethylenediamine); 450 μl 8% SA. After adding each ingredient, the solution was vortexed to mix. Add 120 mg of sodium bicarbonate 2 minutes before gelation occurs and vortex. The above-mentioned SA-containing superporous hydrogel polymer was placed in HCl/absolute ethanol (3:7, v/v) containing 1% CaCl for 4h to obtain poly(SA)-containing poly( Acrylic acid-acrylamide) IPN-SPH.
实施例10含海藻酸钠(SA)的聚(丙烯酰胺-丙烯酸3-磺丙酯钾盐)IPN-SPHExample 10 Poly(acrylamide-acrylic acid 3-sulfopropyl potassium salt) IPN-SPH containing sodium alginate (SA)
在高型称量瓶(40mm×25mm)中依次加入下列成分：300μl 50％的AM(丙烯酰胺)；200μl 50％的SPAK(丙烯酸3-磺丙酯钾盐)；100μl 2.5％的BIS(N，N′-亚甲基-双丙烯酰胺)；30μl 10％的PluronicF127(PF127，泊洛沙姆)；25μl 20％的APS(过硫酸铵)；25μl 20％的TEMED(N，N，N′，N′-四甲基乙二胺)；450μl 8％的SA。在加入每种成分之后，涡旋混合溶液。在发生胶凝前2分钟加入120mg碳酸氢钠，涡旋振荡。将上述含SA的超多孔水凝胶聚合物在含1％ CaCl2的HCl/无水乙醇(3∶7，v/v)中放置4h，即可得到含海藻酸钠(SA)的聚(丙烯酰胺-丙烯酸3-磺丙酯钾盐)IPN-SPH。In a tall weighing bottle (40mm×25mm), add the following ingredients in turn: 300μl 50% AM (acrylamide); 200μl 50% SPAK (3-sulfopropyl acrylate potassium salt); 100μl 2.5% BIS (N , N'-methylene-bisacrylamide); 30 μl 10% Pluronic® F127 (PF127, poloxamer); 25 μl 20% APS (ammonium persulfate); 25 μl 20% TEMED (N, N, N',N'-tetramethylethylenediamine); 450 μl 8% SA. After adding each ingredient, the solution was vortexed to mix. Add 120 mg of sodium bicarbonate 2 minutes before gelation occurs and vortex. The above-mentioned SA-containing superporous hydrogel polymer was placed in HCl/absolute ethanol (3:7, v/v) containing 1% CaCl for 4h to obtain poly(SA)-containing poly( Acrylamide-acrylic acid 3-sulfopropyl potassium salt) IPN-SPH.
实施例11含羧甲基壳聚糖(CMC)的聚(丙烯酰胺-丙烯酸3-磺丙酯钾盐)IPN-SPHExample 11 Poly(acrylamide-acrylic acid 3-sulfopropyl potassium salt) IPN-SPH containing carboxymethyl chitosan (CMC)
在高型称量瓶(40mm×25mm)中依次加入下列成分：300μl 50％的AM(丙烯酰胺)；200μl 50％的SPAK(丙烯酸3-磺丙酯钾盐)；100μl 2.5％的BIS(N，N′-亚甲基-双丙烯酰胺)；30μl 10％的PluronicF127(PF127，泊洛沙姆)；25μl 20％的APS(过硫酸铵)；25μl 20％的TEMED(N，N，N′，N′-四甲基乙二胺)；600μl 8％的CMC。在加入每种成分之后，涡旋混合溶液。在发生胶凝前2分钟加入120mg碳酸氢钠，涡旋振荡。将上述含CMC的超多孔水凝胶聚合物在含1％戊二醛的HCl/无水乙醇(3∶7，v/v)中放置4h，即可得到含羧甲基壳聚糖(CMC)的聚(丙烯酰胺-丙烯酸3-磺丙酯钾盐)IPN-SPH。In a tall weighing bottle (40mm×25mm), add the following ingredients in turn: 300μl 50% AM (acrylamide); 200μl 50% SPAK (3-sulfopropyl acrylate potassium salt); 100μl 2.5% BIS (N , N'-methylene-bisacrylamide); 30 μl 10% Pluronic® F127 (PF127, poloxamer); 25 μl 20% APS (ammonium persulfate); 25 μl 20% TEMED (N, N, N',N'-tetramethylethylenediamine); 600 μl of 8% CMC. After adding each ingredient, the solution was vortexed to mix. Add 120 mg of sodium bicarbonate 2 minutes before gelation occurs and vortex. The above-mentioned superporous hydrogel polymer containing CMC was placed in HCl/dehydrated alcohol (3:7, v/v) containing 1% glutaraldehyde for 4h to obtain carboxymethyl chitosan (CMC ) of poly(acrylamide-acrylic acid 3-sulfopropyl potassium salt) IPN-SPH.
实施例12含壳聚糖三甲基季铵盐(TMC)的(丙烯酰胺-丙烯酸3-磺丙酯钾盐)IPN-SPHExample 12 (acrylamide-acrylic acid 3-sulfopropyl potassium salt) IPN-SPH containing chitosan trimethyl quaternary ammonium salt (TMC)
在高型称量瓶(40mm×25mm)中依次加入下列成分：300μl 50％的AM(丙烯酰胺)；200μl 50％的AA(丙烯酸)；100μl 2.5％的BIS(N，N′-亚甲基-双丙烯酰胺)；300μl DDW(双蒸水)；30μl 10％的PluronicF127(PF127，泊洛沙姆)；25μl 20％的APS(过硫酸铵)；25μl 20％的TEMED(N，N，N′，N′-四甲基乙二胺)；300μl 16％的TMC。在加入每种成分之后，涡旋混合溶液。在发生胶凝前2分钟加入120mg碳酸氢钠，涡旋振荡。将上述含TMC的超多孔水凝胶聚合物在含1％戊二醛的HCl/无水乙醇(3∶7，v/v)中放置8h，即可得到含壳聚糖三甲基季铵盐(TMC)的(丙烯酰胺-丙烯酸3-磺丙酯钾盐)IPN-SPH。In a tall weighing bottle (40mm×25mm), add the following components in sequence: 300μl 50% AM (acrylamide); 200μl 50% AA (acrylic acid); 100μl 2.5% BIS (N, N'-methylene - bisacrylamide); 300 μl DDW (double distilled water); 30 μl 10% Pluronic® F127 (PF127, poloxamer); 25 μl 20% APS (ammonium persulfate); 25 μl 20% TEMED (N, N , N',N'-tetramethylethylenediamine); 300 μl of 16% TMC. After adding each ingredient, the solution was vortexed to mix. Add 120 mg of sodium bicarbonate 2 minutes before gelation occurs and vortex. The above-mentioned superporous hydrogel polymer containing TMC is placed in HCl/dehydrated alcohol (3:7, v/v) containing 1% glutaraldehyde for 8h, and then trimethyl quaternary ammonium containing chitosan can be obtained. Salt (TMC) (acrylamide-acrylic acid 3-sulfopropyl potassium salt) IPN-SPH.
实施例13含海藻酸钠(SA)的聚(N-异丙基丙烯酰胺-甲基丙烯酸)IPN-SPHExample 13 Poly(N-isopropylacrylamide-methacrylic acid) IPN-SPH containing sodium alginate (SA)
在高型称量瓶(40mm×25mm)中依次加入下列成分：300μl 50％的NIPAM(异丙基丙烯酰胺)；200μl 50％的MAA(甲基丙烯酸)；100μl 2.5％的BIS(N，N′-亚甲基-双丙烯酰胺)；30μl 10％的PluronicF127(PF127，泊洛沙姆)；25μl 20％的APS(过硫酸铵)；25μl20％的TEMED(N，N，N′，N′-四甲基乙二胺)；450μl 8％的SA。在加入每种成分之后，涡旋混合溶液。在发生胶凝前2分钟加入120mg碳酸氢钠，涡旋振荡。将上述含SA的超多孔水凝胶聚合物在含1％ CaCl2的HCl/无水乙醇(3∶7，v/v)中放置4h，即可得到含海藻酸钠(SA)的聚(N-异丙基丙烯酰胺-甲基丙烯酸)IPN-SPH。Add the following ingredients in a tall weighing bottle (40mm×25mm): 300 μl 50% NIPAM (isopropylacrylamide); 200 μl 50% MAA (methacrylic acid); 100 μl 2.5% BIS (N, N '-methylene-bisacrylamide); 30 μl of 10% Pluronic(R) F127 (PF127, poloxamer); 25 μl of 20% APS (ammonium persulfate); 25 μl of 20% TEMED (N, N, N', N'-tetramethylethylenediamine); 450 μl 8% SA. After adding each ingredient, the solution was vortexed to mix. Add 120 mg of sodium bicarbonate 2 minutes before gelation occurs and vortex. The above-mentioned SA-containing superporous hydrogel polymer was placed in HCl/absolute ethanol (3:7, v/v) containing 1% CaCl for 4h to obtain poly(SA)-containing poly( N-isopropylacrylamide-methacrylic acid) IPN-SPH.
实施例14含壳聚糖三甲基季铵盐(TMC)的聚(N-异丙基丙烯酰胺-甲基丙烯酸)IPN-SPHExample 14 Poly(N-isopropylacrylamide-methacrylic acid) IPN-SPH containing chitosan trimethyl quaternary ammonium salt (TMC)
在高型称量瓶(40mm×25mm)中依次加入下列成分：300μl 50％的NIPAM(异丙基丙烯酰胺)；200μl 50％的MAA(甲基丙烯酸)；100μl 2.5％的BIS(N，N′-亚甲基-双丙烯酰胺)；300μl DDW(双蒸水)；30μl 10％的PluronicF127(PF127，泊洛沙姆)；25μl 20％的APS(过硫酸铵)；25μl 20％的TEMED(N，N，N′，N′-四甲基乙二胺)；300μl 16％的TMC。在加入每种成分之后，涡旋混合溶液。在发生胶凝前2分钟加入120mg碳酸氢钠，涡旋振荡。将上述含TMC的超多孔水凝胶聚合物在含1％戊二醛的HCl/无水乙醇(3∶7，v/v)中放置8h，即可得到含壳聚糖三甲基季铵盐(TMC)的聚(N-异丙基丙烯酰胺-甲基丙烯酸)IPN-SPH。Add the following ingredients in a tall weighing bottle (40mm×25mm): 300 μl 50% NIPAM (isopropylacrylamide); 200 μl 50% MAA (methacrylic acid); 100 μl 2.5% BIS (N, N '-methylene-bisacrylamide); 300 μl DDW (double distilled water); 30 μl 10% Pluronic® F127 (PF127, poloxamer); 25 μl 20% APS (ammonium persulfate); 25 μl 20% TEMED (N,N,N',N'-tetramethylethylenediamine); 300 μl of 16% TMC. After adding each ingredient, the solution was vortexed to mix. Add 120 mg of sodium bicarbonate 2 minutes before gelation occurs and vortex. The above-mentioned superporous hydrogel polymer containing TMC is placed in HCl/dehydrated alcohol (3:7, v/v) containing 1% glutaraldehyde for 8h, and then trimethyl quaternary ammonium containing chitosan can be obtained. Poly(N-isopropylacrylamide-methacrylic acid) IPN-SPH of salt (TMC).
实施例15含羧甲基壳聚糖(CMC)的聚(N-异丙基丙烯酰胺-甲基丙烯酸)IPN-SPHExample 15 Poly(N-isopropylacrylamide-methacrylic acid) IPN-SPH containing carboxymethyl chitosan (CMC)
在高型称量瓶(40mm×25mm)中依次加入下列成分：300μl 50％的NIPAM(异丙基丙烯酰胺)；200μl 50％的MAA(甲基丙烯酸)；100μl 2.5％的BIS(N，N′-亚甲基-双丙烯酰胺)；300μl DDW(双蒸水)；30μl 10％的PluronicF127(PF127，泊洛沙姆)；25μl 20％的APS(过硫酸铵)；25μl 20％的TEMED(N，N，N′，N′-四甲基乙二胺)；600μl 8％的CMC。在加入每种成分之后，涡旋混合溶液。在发生胶凝前2分钟加入120mg碳酸氢钠，涡旋振荡。将上述含CMC的超多孔水凝胶聚合物在含1％戊二醛的HCl/无水乙醇(3∶7，v/v)中放置4h，即可得到含羧甲基壳聚糖(CMC)的聚(N-异丙基丙烯酰胺-甲基丙烯酸)IPN-SPH。Add the following ingredients in a tall weighing bottle (40mm×25mm): 300 μl 50% NIPAM (isopropylacrylamide); 200 μl 50% MAA (methacrylic acid); 100 μl 2.5% BIS (N, N '-methylene-bisacrylamide); 300 μl DDW (double distilled water); 30 μl 10% Pluronic® F127 (PF127, poloxamer); 25 μl 20% APS (ammonium persulfate); 25 μl 20% TEMED (N,N,N',N'-tetramethylethylenediamine); 600 μl of 8% CMC. After adding each ingredient, the solution was vortexed to mix. Add 120 mg of sodium bicarbonate 2 minutes before gelation occurs and vortex. The above-mentioned superporous hydrogel polymer containing CMC was placed in HCl/dehydrated alcohol (3:7, v/v) containing 1% glutaraldehyde for 4h to obtain carboxymethyl chitosan (CMC ) of poly(N-isopropylacrylamide-methacrylic acid) IPN-SPH.
实施例16含海藻酸钠(SA)的2-羟乙基甲基丙烯酸酯IPN-SPHExample 16 2-hydroxyethyl methacrylate IPN-SPH containing sodium alginate (SA)
在高型称量瓶(40mm×25mm)中依次加入下列成分：300μl 2-羟乙基甲基丙烯酸酯；60μl 2.5％Bis；60μl 10％Pluronic F127；涡旋混合；60℃保温，加入20μl 20％的过硫酸铵；450μl 8％的SA；20μl 15％TEMED。在加入每种成分之后，涡旋混合溶液，在发生胶凝前2分钟加入50mg碳酸氢钠，涡旋振荡。将上述含SA的超多孔水凝胶聚合物在含1％CaCl2的HCl/无水乙醇(3∶7，v/v)中放置4h，即可得到含海藻酸钠(SA)的2-羟乙基甲基丙烯酸酯IPN-SPH。Add the following ingredients in sequence to a tall weighing bottle (40mm×25mm): 300μl 2-hydroxyethyl methacrylate; 60μl 2.5% Bis; 60μl 10% Pluronic F127; vortex mixing; keep warm at 60°C, add 20μl 20 % ammonium persulfate; 450 μl 8% SA; 20 μl 15% TEMED. After the addition of each component, the solution was vortex mixed, 50 mg of sodium bicarbonate was added 2 minutes before gelling, and vortexed. The above-mentioned SA-containing superporous hydrogel polymer was placed in HCl/absolute ethanol (3:7, v/v) containing 1% CaCl2 for 4h to obtain 2- Hydroxyethyl methacrylate IPN-SPH.
实施例17含海藻酸钠(SA)的聚N-乙烯基吡咯烷酮IPN-SPHExample 17 Poly N-vinylpyrrolidone IPN-SPH containing sodium alginate (SA)
在高型称量瓶(40mm×25mm)中依次加入下列成分：500μl N-乙烯基吡咯烷酮；200μl 2.5％Bis；100μl DDW(双蒸水)；50μl 10％Pluronic F127；20μlAA；20μl 20％的APS；450μl 8％的SA；20μl 15％TEMED。在加入每种成分之后，涡旋混合溶液。85℃水浴2分钟后加入50μl 10％V545。在发生胶凝前2分钟加入50mg碳酸氢钠，涡旋振荡。85℃反应5分钟。将上述含SA的超多孔水凝胶聚合物在含1％ CaCl2的HCl/无水乙醇(3∶7，v/v)中放置4h，即可得到含海藻酸钠(SA)的聚N-乙烯基吡咯烷酮IPN-SPH。Add the following ingredients in a tall weighing bottle (40mm×25mm): 500 μl N-vinylpyrrolidone; 200 μl 2.5% Bis; 100 μl DDW (double distilled water); 50 μl 10% Pluronic F127; 20 μl AA; 20 μl 20% APS ; 450 μl 8% SA; 20 μl 15% TEMED. After adding each ingredient, the solution was vortexed to mix. 50 μl of 10% V545 was added after 2 minutes of water bathing at 85°C. Add 50 mg of sodium bicarbonate 2 minutes before gelling, and vortex. React at 85°C for 5 minutes. The above superporous hydrogel polymer containing SA was placed in HCl/absolute ethanol (3:7, v/v) containing 1%CaCl2 for 4h, and the polyN containing sodium alginate (SA) could be obtained. - Vinylpyrrolidone IPN-SPH.
实施例18胰岛素口服给药系统Embodiment 18 Insulin Oral Delivery System
胰岛素首先用0.1N的HCl溶解，加水制得2mg/ml的溶液；取出15ml，将实施例4所得样品加入其中；待其将胰岛素溶液完全吸收后，室温下干燥2天，装入供大鼠肠溶胶囊即得。Insulin was first dissolved with 0.1N HCl, and water was added to obtain a 2mg/ml solution; 15ml was taken out, and the sample obtained in Example 4 was added to it; after it completely absorbed the insulin solution, it was dried at room temperature for 2 days, and packed into a Enteric-coated capsules are available.
正常的SD大鼠灌胃给予胰岛素溶液和载有胰岛素的IPN-SPH(实施例4)肠溶胶囊，给药量为100U/kg，分别于0.5、1、1.5、2、3、4、5、6、8小时尾静脉取血0.2ml，待血液凝固后，12,000rpm离心4分钟，取血清20ul，葡萄糖氧化酶法测定血糖值。结果见附图1。由图可知大鼠灌胃给予载有胰岛素的IPN-SPH肠溶胶囊后，产生降血糖作用。Normal SD rats were administered intragastrically insulin solution and IPN-SPH (embodiment 4) enteric-coated capsules loaded with insulin, and the dosage was 100U/kg, respectively at 0.5, 1, 1.5, 2, 3, 4, 5 6. Take 0.2ml of blood from the tail vein at 6 and 8 hours. After the blood coagulates, centrifuge at 12,000rpm for 4 minutes, take 20ul of serum, and measure the blood sugar level by the glucose oxidase method. The results are shown in Figure 1. It can be seen from the figure that after intragastric administration of IPN-SPH enteric-coated capsules loaded with insulin in rats, hypoglycemic effect occurs.
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