【作者】 许有威；

【导师】 林原；

【作者基本信息】 大连医科大学 ， 药理学， 2003， 硕士

【摘要】 一．研究目的 天然高分子材料海藻酸钠（Sodium Alginate，简写为NaAlg或ALG）具有温和的溶胶-凝胶性质、良好的生物相容性、便宜的价格，其适于包埋或释放药物、蛋白与细胞。因此ALG微胶囊作为药物缓（控）释放体系日益受到人们的重视。 但目前ALG微胶囊用于药物缓（控）释放体系研究存在如下问题：（1）目前较为成熟的制备方法为喷雾法，但喷雾法制备的微胶囊较大；同时其制备微胶囊的过程是一个接一个的，因而生产规模有限，不能满足药物规模化生产需要。（2）ALG微胶囊为亲水性凝胶，其作为药物载体，包裹水溶性小分子药物，常发生泄漏，造成药物包封率较低，释放时间过短。 因此，针对上述两个问题，本研究拟建立和优化一种新型的具有可规模化生产，同时可制备较小粒径微胶囊的乳化／内部凝胶化方法，并针对ALG微胶囊不适于包裹水溶性小分子药物的缺点，选择脂溶性小分子药物榄香烯作为药物模型，来考察其对脂溶性药物的缓（控）释性能。 二．研究结果 1．乳化／内部凝胶化方法的建立及优化 将混悬有水不溶性钙盐（CaCO₃）的NaALG溶液分散到液体石蜡中形成W／O的乳状液，再通过酸化包埋的钙盐，缓慢放出钙离子，从内部进行凝胶化反应，来制备海藻酸钙凝胶珠。实验结果如下。 （1）表面活性剂Span80浓度主要影响凝胶珠球型度和粒径分布，当浓度为1.5％以上时可以获得球型度好，粒径分布窄的凝胶珠，但是浓度过高会对产量有一定影响。 （2）NaALG浓度对凝胶珠粒径分布和产量有影响，其适宜的浓度为1.5％。 （3）水油相体积比主要影响凝胶珠产量和粒径大小，在水油相体积较小时可以得到较小粒径和较高产量的凝胶珠。适宜的水油相体积比为1：3至1：5。 （4）搅拌速度是影响凝胶珠粒径分布的主要因素。提高速度可减小凝胶珠粒 径，使其集中分布。但速度过高造成产量下降。适宜速度为200⁴00rpm。 （5）在最佳条件下，可制备出粒径分布mode值为223.4林m，sPAN值为0.87， 球形度良好的凝胶珠。 2.制备榄香烯一海藻酸钙凝胶珠 首先将榄香烯分散到NaALG溶液中形成O/W的初乳液，再按照乳化/内部凝胶化方法制备榄香烯一海藻酸钙凝胶珠。结果如下。 （l）一般来说在形成O柳型乳液时需加入表面活性剂，但实验中发现初次乳 化时加入Tween80可显著降低包封率和载药量，所以不应加入Tween8O。 （2）NaA工G浓度对凝胶珠粒径分布、包封率和载药量有一定影响。适宜的海 藻酸钠浓度为1.5%以上。 （3）搅拌速度主要是影响载药凝胶珠粒径分布。在速度较高时对包封率和载药 量影响较大。提高搅拌速度虽有利于形成小粒径凝胶珠，但显著降低包封 率和载药量，适宜的搅拌速度为30Orpm。 （4）水油相体积比对榄香烯一海藻酸钙凝胶珠球粒径有一定的影响，但对包封 率和载药量影响不大。适宜的水油相体积比为1:5。 （5）投药量主要影响包封率和载药量，适宜的投药量为0.19/ml一0.39/ml。 （6）最佳条件下，可制得包封率为“.4%，载药量为13.4mg/ml的榄香烯一海 藻酸钙凝胶珠。 3.榄香烯一海藻酸微胶囊体外模拟释放模型的建立。 通过体外模拟释放试验，研究了榄香烯一海藻酸钙凝胶珠和采用壳聚糖（Chitosan）覆膜后形成的载药微胶囊的体外释放性能。研究结果如下。 （l）榄香烯一海藻酸钙凝胶珠在pH值较高的电解质溶液（模拟肠液和生理盐 水）中，在120min时释放率达到79.6%和72.1%，而在pH值较低的溶液 （模拟胃液）中12Omin释放率只有12.1%。 （2）采用壳聚糖覆膜制成微胶囊后，药物在pH值较高的电解质溶液（生理盐 水）中释放时间明显延长。小分子量（4.8万和7.5万）的壳聚糖成膜制 备的微胶囊释放速率较慢，而采用大分子量（16.8万）的壳聚糖成膜后起 始阶段的暴释现象严重。壳聚糖溶液浓度的提高有利于延缓药物释放，但 浓度过高可引起暴释现象。成膜反应时间延长，微胶囊的释放性能提高。 用分子量为7.5万，浓度为smg/ml的壳聚糖溶液成膜反应smin制备的微 胶囊在生理盐水中需120hr释放率才达到78.2%。 三.结论 本研究（l）初步建立和优化了乳化/内部凝胶化方法，使大规模制备海藻酸微胶囊成为可能。（2）首次采用此方法制备具有一定包封率、载药量的榄香烯一海藻酸微胶囊。（3）体外模拟释放试验证明可以将海藻酸微胶囊作为脂溶性药物的缓释载体，为将其真正作为一种脂溶性药物的缓释剂型应用于临床奠定了基础。更多还原

【Abstract】 For the mild sol-gel character, good biocompatibility and low market value of the natural macromoleculer material Sodium Alginate (NaAlg or ALG), it is fit to release and encapsulate drugs, albumens and cells. Therefore alginate microcapsule as a drug controlled release system is regarding more and more importance.But now the researches on ALG microcapsule as drug controlled system still have some problems to solve: (1) Now the more mature preparation method is spraying method, but the size of microcapsule made by the method is a little big; meanwhile the process of spraying is one-by-one, so the yielding scale is limited and it can not satisfy the demand of large scale production of drugs. (2) ALG microcapsule is a hydrophilic gel, as a drug carrier, it is easily leaked out encapsulated hydrophilic small molecular drugs, and cause a low encapsulate rate and a short releasing time.Therefore aim at the two problems above, this research is planning to set and optimize a novel emulsification/mtemal gelation method which can be used for large scale production and preparation of small diameter microcapsules, and for the reason that the ALG microcapsule is unfit for small molecular hydrophilic drugs, choose the small molecular lipophilic drug elemene as a model drug to examine its control ability to lipophilic drugs.Methods and Results1. Setting up and optimizing of emulsify/internal gelation methodThe NaALG solution containing insoluble calcium salt was dispersed into the paraffine to form a a W / O emulsion. With continuous agitation, the paraffine contain-ning glacial acetic acid was added into the emulsion, liberating divalent calcium for internal gelation of the alginate polyanions, then the bead was produced.(1) Surfactant Span80 concentration effects on sphericity of gel beads anddistributing of diameters. When the concentration is above 1.5%, good sphericity and a narrow diameter distributing could be get, but a high concentration will low down the yielding rate.(2) NaALG concentration effects on the gel beads’ diameter distributing and yielding rate, the best fit rate is 1.5%.(3) Water/oil volume ratio mostly effects on the distributing and diameter of gel beads, when the ratio is bigger, gel bead of a small diameter and high yielding rate will be gained. The best fit water/oil volume ratio is 1:3 to 1:5.(4) The mixing rate is a key factor effecting the diameter distributing of gel beads, enhance the mixing rate could low down the gel beads’ diameter and make them distribute together. However a too high speed could low down the yielding rate also. The best fit mixing rate is 200~400rpm.(5 ) Under the optimized conditions, gel beads of diameter distributing mode of223.4um and SPAN value of 0.87 can be prepared. 2. Preparation of elemene-CaALG gel beadThe elemene was dispersed into NaALG solution to form a O/W origin emulsion and then follow the emulsification/intemal gelation method produce elemene-CaALG gel bead. Results are as follows:(1) Generally when forming O/W emulsion, surfactant is needed, but in experiment it was found that surfactant Tween80 could low down the embedding rate and drug load, so Tween80 should not be added.(2) Concentration of NaALG have effects on the diameter distributing, embedding rate and drug load of gel bead, the fitting concentration of NaALG is over 1.5%.(3) The mixing rate is mainly effects the drug loading gel beads’distrabuting. When at a high mixing rate, small diameter gel beads are easier made but it also low down the embedding rate and drug load remarkably, so fitting mixing rate is 300rpm.(4) Water/oil volume ratio also has effects on the diameter of elemene gel beads, but has little effects on embedding rate and drug load. The fitting water/oil volume ratio is 1:5.(5) Drug adding volume mainly effects embedding rate and drug load, the fitting drug adding volume is 0.1g/ml~0.3g/ml.(6) Under the optimized condition, elemene-CaALG gel beads with a 66.4%embedding rate and 13.4mg/m更多还原