【作者】 朱旻鹏；

【导师】 李新华；

【作者基本信息】 沈阳农业大学 ， 食品科学与工程， 2009， 博士

【摘要】 淀粉微球是天然淀粉的一种人造衍生物,已经作为制剂的药物载体在鼻腔给药系统、动脉栓塞、放射性治疗、免疫分析等领域得到了应用,是一类极具开发潜力的新型药物载体。但由于淀粉微球制备的过程的复杂性和试验参数的多样性,制备直径小,分布范围窄的微球一直是淀粉微球制备的难点之一;另外,目前的淀粉微球普遍存在着载药率低,控释效果不好的缺点;淀粉微球多为一步交联变性而成,化学性质单一,所能够担载的药物种类、类型有限。针对上述问题,本论文对含固相淀粉反相乳液稳定性进行了研究,以此为基础,采用反相乳液法,以可溶性淀粉为原料,环氧氯丙烷和N,N’-亚甲基双丙烯酰胺(MBAA)为交联剂制备交联淀粉微球,并优化了淀粉微球制备工艺,以中性淀粉微球为基础,制备了离子化淀粉微球,对淀粉微球的微观颗粒形貌,理化性质进行了表征,制备了姜黄素淀粉微球和精氨酸淀粉微球,对微球的载药和释药性能进行了研究。具体研究内容如下:1.采用单因素试验的方法对含固相淀粉反相乳液的稳定性进行了研究,得出以淀粉水溶液为分散相,液体石蜡为连续相,span60为乳化剂,制备稳定性良好的反相乳液条件为:乳化剂的HLB值4.7、淀粉浓度为16%、油相水相体积比为3:1、乳化强度17500r/min搅拌时间30s、乳化剂用量为0.6%。2.采用正交试验的方法,对制备环氧氯丙烷交联淀粉微球(EMS)工艺进行了优化,以ESM平均粒径最小为指标,最佳工艺参数为:油相水相体积比为4:1、交联剂用量为3ml、反应温度为45℃、乳化剂用量为0.3%;以ESM沉降积最小为指标,最佳工艺参数为:油相水相体积比为4:1、交联剂用量为4ml、反应温度为50℃、乳化剂用量为0.4%;对两指标取最小值综合考虑,较优工艺参数为:油相水相体积比为4:1、交联剂用量为3ml、反应温度为50℃、乳化剂用量为0.4%;此条件下制备的ESM平均粒径为40um,沉降积为1.1ml。3.采用均匀试验设计的方法,优化N,N’-亚甲基双丙烯酰胺交联淀粉微球(MSM)的制备工艺,得出以MSM平均粒径最小为指标,最佳工艺参数为:引发剂浓度18mmol/L、乳化剂浓度0.23%油相、交联剂浓度0.025mol/L、反应时间2.1h、反应温度40.4℃、油相水相体积比为2:1、搅拌速度400r/min;以MSM交联度最大为指标,最佳工艺参数为:引发剂浓度17mmol/L、乳化剂浓度0.6%、交联剂浓度0.025mol/L、反应时间4.4h、反应温度51.2℃、油相水相体积比2.1、搅拌速度400r/min。4.SEM、IR和DSC分析表明,EMS近似球状,球体表面粗糙,粒径分布均匀,结构呈多孔立体网络结构,淀粉的部分羟基发生了交联反应;MSM球形圆整,粒径分布较窄,未出现双宽峰分布;淀粉与MBAA有明显的交联;MSM交联过程中,MBAA发生均聚物,交联使ESM、MSM热稳定性增加。5.利用人工胃液、人工小肠液和人工血液对ESM、MSM的降解性能进行了体外模拟,结果表明,ESM和MSM在人工体液中均表现出了一定的抗降解的能力,降解速度与微球粒径和交联度呈反比,ESM和MSM满足结肠靶向给药,栓塞治疗和药物缓释载体对降解性的要求。6.对姜黄素稳定性进行了研究,结果表明,姜黄素在pH值为2～7条件下稳定性较好,降低温度利于其稳定性的提高;姜黄素易溶于有机溶剂,在20%的乙醇溶液中稳定性较好。7.以MSM为载体,采用吸附法制备了姜黄素淀粉微球,对其载药和释药性能进行了研究,结果表明,MSM的载药量与直径的呈反比,与交联度呈正比;MSM与姜黄素质量比为5:1时,吸附2h达到最大载药量134.24mg/g,载药率为83.9%;MSM姜黄素载药微球在含0.8%十二烷基硫酸钠的20%乙醇溶液中,25h时累积释药率达到80.53%。对姜黄素淀粉微球进行了DSC分析,结果表明,在微球中,姜黄素已失去晶体结构,与MSM形成复合物的形式存在。8.以ESM为载体,采用吸附法制备了精氨酸淀粉微球,对其载药和释药性能进行了研究,结果表明,ESM的载药量与直径的呈反比,与交联度呈正比;ESM与精氨酸质量比为2:1,吸附1.5h达到最大载药量31mg/g,载药率为6.22%:ESM精氨酸载药微球在水溶液中,6h时累积释药率达到85.53%。9.以ESM为原料,STP为离子化剂制备阴离子淀粉微球,IR和DSC分析表明,STP与淀粉酯化成功,STP与淀粉的二次交联增加了阴离子点微球的热稳定性;对阴离子淀粉微球的载药和释药性能进行了研究,结果表明,阴离子淀粉微球对精氨酸的载药量高于ESM,载药量随取代度增加而提高,在微球与精氨酸质量比为250:1时,DS为0.02的阴离子微球载药量为4.54mg/g,阴离子淀粉微球对精氨酸的释放也存在突释现象,但缓释效果更突出。10.以MSM为原料,GTA为离子化剂制备阳离子淀粉微球,IR和DSC分析表明,GTA与淀粉反应成功,微球阳离子化后分解放热温度范围较宽;阳离子微球的载药和释药性能进行了研究,结果表明,阳离子微球对姜黄素的载药量高于MSM,随着取代度提高,载药量随取代度增加而提高,当微球与姜黄素质量比为250:1时,DS为0.024时微球载药量达到最大值9.26mg/g,载药阳离子微球仍有突释现象,但缓释效果更加突出。更多还原

【Abstract】 Starch microsphere(SM) is a kind of artificial derivant from natural starch. As drug delivery carrier, it has been used in the fields such as intranasal administration, arterial embolization, radiation therapy, immunoassay and so on. SM is one of the great potential new type drug delivery carrier. However, due to the complexity of the SM process and the diversity of the process parameters, one of the challenges in process is the preparation of the SM with narrow diameter distribution. SM also has shortcomings on the drug loading efficiency and drug control release. Moreover, SM is prepared by one-step cross-linked methods mostly and has single chemical properties, so it has single drug loading properties. In order to solve the above problems, this thesis studies the stabilitiy of inverse emulsion including starch granule. Based on these research, using soluble starch as raw material, epichlorohydrin (ECU) and N,N’-methylenebisacrylamide(MBAA) as crosslinker, this thesis studies the preparation of crosslingked starch microspheres(CSM) by the inverse emulsion method and the optimal conditions for preparation are studied. Using CSM as the raw material, the ionized starch microspheres are prepared.The morphologies and physical and chemical properties of the SM are characterized. The curcumin-loading CSM and arginine-loading CSM are prepared and their drug loading and drug release properies are observed separately. The main results are listed as follows:1. The stabilities of inverse emulsion including starch are investigated by the single factor test. The results show that when the value of HLB of emulsifier is 4.7, the concentration of the starch solution is 16%, volume ratio between oil phase and aqueous phase is 3:1, the agitation strength is 17500r/min mixing 30s, the amount of the emulsifier is 0.6%, inverse emulsion has the best stability.2.The optimum conditions of the starch microspheres crosslinked with ECH (ESM) preparation are determined by orthogonal experiments. The results show when the volume ratio between oil phase and aqueous phase is 4:1, the amount of crosslinker is 3 ml, the temperature is 45℃, the amount of emulsifier is 0.3%, the average diameter of ESM are smallest and when the volume ratio between oil phase and aqueous phase is 4:1, the amount of crosslinker is 4 ml, the temperature is 50℃, the amount of emulsifier is 0.4%, the deposition volume of ESM are smallest. Considered the two index, the optimum conditions of ESM preparation are decided as the volume ratio between oil phase and aqueous phase is 4:1, the amount of crosslinker is 3 ml, the temperature is 50℃, the amount of emulsifier is 0.4%. The average diameter of the ESM prepared under the condition is 39.5um, deposition volume is 1.1ml.3. The optimum conditions of the starch microspheres crosslinked with MBAA (ESM) preparation are determined by Uniform desgin experiments. The results show when the concentration of the initiator is 18mmol/L, the amount of the emulsifier is 0.23%, the concentration of the crosslinker is 0.025mol/L, the reaction time is 2.1h, the reaction temperature is 40.4℃, the volume ratio between oil phase and aqueous phase is 2:1, the speed of agitation is 400r/min, the average diameter of MSM is smallest and when the concentration of the initiator is 17mmol/L, the amount of the emulsifier is 0.23%, the concentration of the crosslinker is 0.025mol/L, the reaction time is 4.4h, the reaction temperature is 51.2℃, the volume ratio between oil phase and aqueous phase is 2.1, the speed of agitation is 400r/min, the deposition volume of MSM is smallest.4.The analysis results of SEM, IR and DSC prove that EMS is almost spherical, even distributing particulates with rough surface and has tri-dimensional structure, crosslink reaction occurs between some hydroxyl groups of starch. The analysis results of SEM, IR and DSC proved that MSM is spherical, diameter distribution of MSM is narrow, crosslink reaction between starch and MBAA is success, MBAA occurs polymerization during crosslink reaction. After crosslinked, the thermal stabilities of ESM and MSM are improved.5.With In-Vitro degradability model, the degradabilities of ESM and MSM are tested in simulated gastric fluid, simulated intestinal fluid and simulated blood. The results indicate that ESM and MSM have some degree anti-degradation ability in the artificial body fluids and the rate of the degradation is decreased with the diameter and the crosslinking degree increased. ESM and MSM have prospects on the application to colonic targeted drug delivery, arterial embolization and drug control release. 6. The stability of curcumin is studied and the result shows that it has good stability when pH value is 2-7. Lower temperature could improve the cucumin stability. The curcumin is soluble in the organic solvents and it has better stability in the 20% ethanol solution.7.Using the MSM as drug carrier, the curcumin-loading starch microspheres is prepared by adsorption method. The drug loading properties and drug release properties of curcumin-loading starch microspheres are studied. The results show the curcumin loading amount of MSM is increased with diameter decreased and with crosslinking degree increased. When the quantity ratio between MSM and curcumin is 5:1, the curcumin loading is 134.24mg/g, the rate of drug-loading is 83.9% after absorpting for 2h. The curcumin release ratio of the curcumin-loading MSM is 80.53% in the 20% ethanol solution including 0.8% sodium dodecyl sulfate after 25h. The analysis results of DSC prove that curcumin lose its crystal structure and exist as the complex with the MSM in curcumin-loading starch microspheres.8.Using the ESM as drug carrier, the arginine-loading starch microspheres is prepared by adsorption method. The drug loading properties and drug release properties of arginine-loading starch microspheres are studied. The results show the arginine loading amount of ESM is increased with diameter decreased and with crosslinking degree increased. When the quantity ratio between ESM and arginine is 2:1, the arginine loading is 31mg/g, the rate of drug-loading is 6.22% after absorpting for 1.5h. The arginine release ratio of the arginine-loading ESM is 85.53% in the water after 6h.9.Using the ESM as raw material and STP as ionize agent, the anionic starch microspheres is prepared. The analysis results of IR and DSC show that the crosslink reaction between STP and ESM is success and thermal stability of anionic starch microspheres increases. The drug loading properties and drug release properties of anionic starch microspheres are studied. The results show the arginine loading amount of anionic starch microspheres is higher than ESM, the arginine loading amount of anionic starch microspheres is increased with DS increased. When the quantity ratio between anionic starch microspheres and arginine is 250:1, the arginine loading of anionic starch microspheres with DS 0.02 is 4.54mg/g. The release of arginine from anionic starch microspheres has the phenomenon of drug burst release, but the anionic starch microspheres has better drug control release properties than ESM. 10.Using the MSM as raw material and GTA as ionize agent, the cationic starch microspheres is prepared. The analysis results of IR and DSC show that the reaction between GTA and MSM is success and cationic starch microspheres decomposes in a wider temperature range than MSM. The drug loading properties and drug release properties of cationic starch microspheres are studied. The results show the curcumin loading amount of cationic starch microspheres is higher than MSM, the curcumin loading amount of cationic starch microspheres is increased with DS increased. When the quantity ratio between cationic starch microspheres and curcumin is 250:1, the curcumin loading of anionic starch microspheres with DS 0.024 is 9.26mg/g. The release of curcumin from cationic starch microspheres has the phenomenon of drug burst release, but the cationic starch microspheres has better drug control release properties than MSM.更多还原