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粒径均一的用于药物递送的胶体体微囊的制备
Alternative TitlePreparation of uniform-sized colloidosomes suitable for application of drug delivery
南芳芳
Subtype硕士
Thesis Advisor马光辉
2014-05
Degree Grantor中国科学院研究生院
Degree Discipline生物化工
Keyword胶体体微囊   海藻酸   聚合物沉积   快速膜乳化 胰岛素
Abstract胶体体微囊是近几年来被广泛关注的一类具有新型结构的微囊,它的制备模板是一种采用胶体颗粒替代传统表面活性剂为稳定剂的乳液(Pickering乳液)。这种以Pickering乳液为模板制备胶体体微囊的方法体现出多种独特的优势,如不需要表面活性剂,乳液稳定性好,装载效率高等等。此外,可以通过选择合适的胶体颗粒来调节胶体体微囊的生物相容性、渗透性以及机械强度等性能。这些优良特性使胶体体微囊很有希望被用作药物载体。但是,目前关于其在载药领域的研究报道较少,原因有以下几个方面:(1)微囊壁较薄,机械强度差,在采用油水型Pickering乳液为模板制备微囊时,微囊在离心力作用下会发生破裂,导致微囊产率很低;(2)胶体颗粒之间存在较大的孔隙,造成胶体体微囊渗透性高,用作药物载体时,药物释放速度快;(3)目前报道的胶体体微囊使用的胶体颗粒材料大多为不具有生物相容性的无机或合成高分子,导致微囊无法应用于药物递送领域;(4)Pickering乳液的制备大多采用均质、搅拌等传统的乳液分散方法,得到的乳滴分布较宽,导致微囊无法获得均一性良好的胶体体微囊。 针对上述问题本论文旨在通过合适的选材,并结合聚合物沉积法与快速膜乳化法予以解决。利用聚合物沉积法解决微囊机械强度差、产率低以及高渗透性的问题。利用快速膜乳化法制备粒径均一的亚微米级多糖胶体颗粒用于制备胶体体微囊,以获得良好的生物相容性;还将采用快速膜乳化法制备单分散的胶体体微囊。在此基础上,由于胶体体微囊表面胶体颗粒的材料,壳聚糖和海藻酸表现出pH敏感性、粘膜粘附性等适合口服给药的优良特性,将胰岛素包埋到胶体体微囊中,测定胶体体微囊在对胰岛素的包埋与模拟口服体外释放方面体现出的性能。为其作为胰岛素口服给药载体的进一步应用奠定基础。 论文主要分为两个部分,第一部分的目的在于解决Pickering乳液制备过程中的生物相容性问题,并在此基础上,研究乳液稳定性的影响参数,获得稳定的Pickering 乳液。将选取具有生物相容性、pH敏感性等优良性能的海藻酸胶体颗粒作为乳液稳定剂。同时针对海藻酸颗粒的强亲水性以及纳微颗粒的不均一性导致其无法在油水界面上进行有效地自组装这一问题,本论文首先采用快速膜乳化法制备亚微米级的均一的海藻酸颗粒,接着将具有相对较强疏水性的壳聚糖覆层到海藻酸颗粒之上,提高颗粒的疏水性,并制备出稳定的Pickering乳液。此外,还考察了胶体颗粒粒径、水相pH值以及盐浓度对乳液稳定性的影响,并探索了其中潜在的影响机制,明确了乳液稳定的条件范围,为下一步胶体体微囊的制备奠定了基础。 在前一部分的基础上,第二部分结合快速膜乳化法与在油相中加入聚(乳酸-羟基乙酸)的聚合物沉积法制备胶体体微囊。快速膜乳化法可以解决胶体体微囊的均一性问题,而聚合物界面沉积法则可以提高微囊的机械强度和降低其渗透性。考本论文察了压力、胶体颗粒浓度、油水比、膜孔大小等因素对快速膜乳化制备胶体体微囊的影响,最后成功制备了粒径均一可控的胶体体微囊,其粒径分布span值小于0.6。此外,制备的胶体体微囊表现出了产率高,渗透性低的优良特性。鉴于制备的胶体体微囊兼具良好的生物相容性、较窄的粒径分布、高产率、低渗透性等优势,而且微囊表面的壳聚糖覆层的海藻酸胶体颗粒在酸性环境不被溶解,其材料具备粘膜粘附性。因此,本论文将胰岛素包埋到胶体体微囊之中,并测定其包埋率和模拟口服给药时的体外释放曲线,发现相比普通PLGA载药微囊,胶体体微囊表现出高的包埋率,而且,体外释放时可以保护胰岛素在模拟胃液中几乎不释放,而在模拟肠液中较大量释放,为胶体体微囊进一步应用于生物医药领域提供了可能。
Other AbstractColloidosome, as a novel microcapsule, has attracted extensive attentions in recent years. It was usually prepared with a particle-stabilized emulsion (Pickering emulsion) as template. There are various special advantages for the preparation of colloidosomes, such as low toxicity without surfactant, extreme stability, high loading efficiency and so forth. More importantly, much features, such as biocompatibility, permeation and mechanical strength, can be precisely adjusted by choosing proper particles. Such versatility makes colloidosome a favorable candidate for applying in drug delivery though few related reports are available. The reasons are as follows: Firstly, thin shells with low mechanical strength can not survive operation process, resulting in low production rate, worsen for the systems in need of repeated centrifugation to remove the oil phase. Secondly, large micropores exist between particles on the surface, resulting in high permeation and release velocity. Thirdly, most colloidosomes are formed by inorganic and synthetic polymer, resulting in bad biocompatibility. Fourthly, Pickering emulsions are usually prepared with conventional emulsification method, such as homogenization and mixing, leading to broad size distribution of colloidosomes. In this paper, combining polymer deposition and premix membrane emulsification method, we aimed at resolving the above-mentioned problems. The former was employed to overcome the weak mechanical strength and high permeation, and the latter was chosen to controllably prepare submicron polysaccharide particles with narrow size distribution used to form biocompatible colloidosomes. Then premix membrane emulsification was further used to prepare monodisperse colloidosomes. Due to much excellent properties for oral administration of alginate and chitosan, such as pH sensitivity and mucoadhesive, insulin was encapsulated into colloidosomes, and their performance in embedding and in vitro release as an oral drug carrier was determined, laying further foundation for their application as drug encapsulation vehicles. The paper contains two parts. The first part focuses on preparing stable Pickering emulsions after overcome their biocompatibility. Alginate particles with excellent properties, such as biocompatibility and pH sensitivity, were chosen as emulsifier. However, the particle can not effectively self-assembly at the interface due to its high hydrophilicity and difficulty in fabrication of submicron particles with narrow size distribution. We developed two strategies to circumvent above shortcomings. Uniform alginate particles with submicron were successfully prepared by premix membrane emulsification. In addition, the uniform particles were coated with relatively hydrophobic chitosan to overcome the high hydrophilicity of alginate particles. These uniform coated particles effectively stabilized the oil-in-water Pickering emulsion. To provide extended control of emulsion stability, the effect of particle size, pH of aqueous phase and salt concentration were investigated and the underlying mechanism was discussed in detail. The condition of emulsion stability was determined, laying bases for fabricating colloidosomes. Based on the first part, the second was about the combination of premix membrane emulsification and polymer deposition to prepare colloidosomes. Premix membrane emulsification was used to overcome the broad size distribution of the colloidosome, and employing polymer deposition with dissolving poly lactic acid-co-glycolic acid, to enhance the mechanical strength and reduce permeation of colloidosomes. The impacts of transmembrane pressure, particle concentration, volume ratio of oil to water and pore size of membrane on preparation of colloidosomes were investigated. As a consequence, uniform-sized colloidosomes were controllably prepared with span value lower than 0.6. The new prepared colloidosomes possess biocompatibility, narrow size distribution, high yield
Language中文
Document Type学位论文
Identifierhttp://ir.ipe.ac.cn/handle/122111/15567
Collection研究所(批量导入)
Recommended Citation
GB/T 7714
南芳芳. 粒径均一的用于药物递送的胶体体微囊的制备[D]. 中国科学院研究生院,2014.
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