【作者】 魏振平；

【导师】 毕殿洲；

【作者基本信息】 沈阳药科大学 ， 药剂学， 2001， 博士

【摘要】 胃内漂浮滞留缓释制剂是根据流体动力学平衡原理（HydrodynamicallyBalanced System HBS）制成的一种特殊缓释剂型，与一般的缓控释剂型不同，这种剂型口服后漂浮在胃内容物之上，在胃内的滞留时间不受胃排空影响。 本研究以阿基米德定律和漂浮制剂的持续浮力决定其胃内滞留时间为理论指导，把漂浮制剂的漂浮性与完整性作为该剂型的两个基本特点，从吸水动力学、膨胀动力学、溶蚀动力学和漂浮动力学四个方面对漂浮制剂的漂浮性和完整性进行了研究。亲水性高分子材料制备的漂浮片，漂浮力的产生和维持受两个方面的影响，吸水膨胀引起密度降低，浮力增大，水渗入导致密度增大，浮力降低。亲水性材料制备漂浮片时，降低压片时的压力可以获得密度小、初始浮力大的漂浮片剂，但是，密度小又会加快水的渗入，使漂浮制剂持浮力降低的速度增大。为了获得足够大的初始浮力和维持稳定的持续浮力，本研究通过加入疏水性材料硬脂酸镁降低水渗入的速度，得到了比较满意的漂浮动力学曲线。溶蚀动力学表明，以高粘度HPMC K100MCR和K15 MCR制备的漂浮片，其漂浮性能要优于低粘度的HPMC如E15-LV，后者的溶蚀符合一级动力学规律，4小时内片面溶蚀达20％，溶蚀速度比前者大22倍，由于速度太快，漂浮制剂的漂浮力因此会迅速降低；高分子材料CMC-Na制备的漂浮片，虽然遇水后迅速膨胀使体积增大，但是，由于水渗入的速度大于体积膨胀的速度，因此不能产生足够的浮力和维持理想的持续浮力，另外，这种材料制备的漂浮片的溶蚀速度太快，4小时内片面溶蚀达30％，漂浮制剂的漂浮力也因此会迅速降低。本研究通过对溶蚀曲线进行相似性检验，发现片面溶蚀主要与材料的性质有关，在一定的压力范围与压力没有显著关系。以水不溶性高分子材料EudragitRS PO制备的漂浮片，其漂浮力主要受到压片时压力的影响。 本文将漂浮缓释制剂的溶蚀对漂浮动力学的影响与缓释制剂的释药机理联系在一起，认为：胃酸中溶解良好的药物，可以制备成单层，也可以制成双层片，靠溶蚀释放的水难溶性药物，应制成双层漂浮片，一层起漂浮作用，另一层起载药和释药作用，否则，靠片面溶蚀达到释药的同时漂浮制剂的漂浮性会降低。 以西沙必利为模型药物，制备了双层胃内漂浮滞留缓释片。为了提高药物的溶解度，本研究以HPMC E15LV为载体，与西沙必利制备了固体分散体，与原形药物相比，固体分散体在水、人工胃液和人工肠液中的溶解度分别提高了3.39，2.32 吨田菏料大学俗士学位快丈？文拘婴 一 和2＊ 倍。用均匀设计法优化了双层片漂浮层和载药层的组成，漂浮片的体外漂 浮动力学表明：在人工胃液中，10 Inn浮力可以达到 100 Due以上，并维持 6 h 以上；在人工胃液中药物以零级速度连续释放8－12 h。由于药物在酸性介质中的溶 解度大于在水和人工肠液中，因此，人工胃液中的释药速度快于人工肠液中。 血浆中的药物常用两步法提取来减少杂质对测定的干扰，首先用有机溶媒提取 血浆中的药物，再用 0．smol＊’的磷酸反提有机溶媒中的药物，最后，吸取水层样 品进行分析。研究发现，反提有机溶媒中的药物时，向有机相加入药物不良溶剂环 己烷可以使反提总回收率由60％提高到80％以上。 采用”“To标记Y闪烁照相技术研究了西沙必利胃漂浮滞留缓释片和非漂浮缓 释片在健康志愿者体内的滞留倩况，结果表明：漂浮片可以漂浮在胃液之上，胃内 滞留达3．5土0．sh，非漂浮缓释片在Zh内便从胃中排入肠道。 分别以家大和健康志愿者为实验对象，研究了西沙必利胃漂浮滞留缓释片的药 物动力学。以家犬为实验对象时，漂浮滞留缓释片、普通缓释片的C＿分别为＊．35 士25．23 ＂g／ml和 111 ＊1士25．85 ＂g／ml都显著低 于速释片 254．49士74．99 ＂g／Inl 中＜0刀5人漂浮缓释片和普通缓释片的Tin。分别为4．0士0．71h和3二士0．45h，和 普通片的1．物士0．55有显著差异中刃刀5人普通缓释片的＊。和Th之间则没有 显著差异中＞0．05人与普通相比，胃漂浮滞留缓释片和普通缓释片的相对生物利 用度分别为 84．90％和74刀2％。以健康志愿者为实验对象进行的药物动力学研究结 果表明：胃漂浮滞留缓释片和普通缓释片的Tinx分别为5．33土1，15 h和2．75士0．50 h，Cm。分别为 42．83士7．24ng／th和 29．70士3．18ng／m，相对于非漂浮缓释片，漂浮 滞留缓释片的生物利用度为 168．81 o／o。由于酸性条件下西沙必利的溶解度增大，胃 内漂浮滞留时间的延长促进了药物的溶解和吸收。 综上，漂浮制剂的漂浮力和持浮力是决定其胃内滞留的前提，为了提高漂浮制更多还原

【Abstract】 Sustained release floating dosage forms for gastric retention are designed according to the principle of Hydrodynamically Balanced System. Unlike the conventional sustained release dosage forms, this kind of special sustained release dosage will float on the surface of gastric content when taken orally and its gastric retention is rarely influenced. Under the guidance of the law of Archimede and the discovery that buoyancy duration is the key factor determining the gastric retention of the floating dosage, the experiment was carried by studying the floatage and integrity梩he preconditions for floating dosage for gastric retention from following four aspects, that is water uptake kinetics, swelling kinetics, eroding kinetics and floating kinetics. For the floating tablet made of hydrophilic macromolecular materials, buoyancy generation and duration is controlled by the water uptake and swelling of the floating tablet. Lowing the manufacturing pressure can make tablets with low density and greater initial buoyancy. However, for the tablet of lower density, the accelerated water uptake will then increase the tablet density and decrease the buoyancy duration. That is why some hydrophobic ingredients should be added in order to made floating tablet with ideal floating duration other than decreasing the tableting pressure alone. According to the eroding kinetics, the floating tablet made of HPMC with greater viscosity as Kl00 MCR and K15 MCR is better than that made of HPMC E 15 LV. The erosion of the tablet made of HPMC E 15 LV followed the first order kinetics. 20 % of the tablet eroded with 4 hours which is 22 times that of the tablet made of HPMC K 100 MCR. The fast erosion of the tablet made of HPMC E 15 LV led to quick buoyancy decrease. The quick swelling of floating tablet made of CMC-Na led to quicker water uptake. Moreover, its quick erosion at a speed of 30% within 4 hours of its original weight led to buoyancy decrease. Evaluation by similarity showed that the type of materials other than pressure determine the tablet erosion. The buoyancy of tablet made of water insoluble Eudragit RS P0 generally comes from its density. Because of the influence from tablet erosion on the buoyancy, single or two-layer tablet can be made if the drug dissolves well in gastric content. For drugs that dissolute by means of tablet erosion, two-layer tablet should be made. One layer is for buoyancy and the other for drug release. Otherwise, tablet erosion will lead to simultaneous buoyancy decrease. A two條ayer floating tablet for gastric retention was made using cisapride as a model 3 drug. In order to improve the solubility of the model drug, solid dispersion was made using HPMC E 15 LV as carrier at a ratio of 1:4 ( drug:carrier). The solubility of cisapride was increased by3.39, 2.32 and 2.18 times in water SGF and SW separately. As to the in vitro buoyancy test, the tablet went up to medium surface in less than 10 mm. A floating ability as great as 100 Dyne was maintained for more than 6 h. A zero order in vitro drug release as long as 8-12 h was achieved when simulated gastric fluid was used as dissolution medium. The in vitro dissolution in simulated gastric fluid (SGF) is faster than in simulated intestinal fluid (SiT) because the drug has a greater solubility in SGF than in SIT. Tablet erosion and drug dissolution does not go simultaneously if SW is used. Counter extraction was used for processing the bl更多还原