【作者】 金朝辉；

【导师】 蒋学华；

【作者基本信息】 四川大学 ， 药剂学， 2004， 硕士

【摘要】 HT系从防己科植物黄藤的茎部提取得到的生物碱,有清热解毒作用。临床用于妇科炎症、菌痢、肠炎、呼吸道及泌尿道感染、外科感染等。 本课题以HT为模型药物探讨在药剂学理论指导下进行缓释片研制的思路和方法。课题选用HPMC为基本骨架材料,PVP(8%的乙醇溶液)为黏合剂,硬脂酸镁为润滑剂制备了持续释放12h的HT缓释片。在处方筛选中,以不改变HT的生物活性为前提,以片剂的基本药剂学要求为指标,初步考察并确定了HT缓释片的基本处方和制备工艺。在处方筛选中,以释放度主要指标,建立了HT缓释片释放度测定的方法,考察了影响HT缓释片释放的各种因素,在单因素考察的基础上采用正交实验优化处方。以优化处方制备的HT缓释片在既定的释放度测定条件下,主药在2h、6h、10h的累计释放度分别为15～35%、40～65%和75%以上,符合相关规定。f2相似因子分析表明,优化后的HT缓释片释放重现性好,工艺稳定。 在HT缓释片的质量评价研究中,建立了HT缓释片的鉴别方法;确定了缓释片中HT的HPLC含量测定方法,建立了HT缓释片释放度与有关物质的检查方法。通过质量研究,建立了初步的质量标准。对各种方法的评价研究结果表明,HT缓释片质量评价方法科学合理。按拟定的质量标准对HT缓释片质量进行检查,结果表明,HT缓释片质量可控。对HT缓释片的释放规律的研究结果表更多还原

【Abstract】 The paper discussed the thinking and the pathway of the manufacture of sustained-release form based on HT as model drug by using the principles of pharmaceutics. The thesis adopted HPMC as the basic matrix material, PVP (8% alcohol solution) as compression aids, magnesium stearate as lubricant. The HT sustained-release tablet was prepared which could release twelve hours continuously in vitro. The basic prescription and preparation technology was initially defined by the study about formulation screening and technology optimizing ,based on the pharmacy rule as indicator and the stability maintaining of HT. Dissolution rate is an important factor of influencing internal quality of tablet. The determination method was initially set up for the dissolution rate of the HT sustained-release tablet. And the various factors were studied, which influence the HT release of HT sustained-release tablet. Orthogonal project was employed to screen the prescriptions which based on the study of mono-factor experiment Verification experiments about the dissolution rate of optimized prescription were done . The results showed that the dissolution rate of HT among the HT sustained-release tablets at 2h,6h,10h was 15~35%,40~60%,>75% respectively. The f2 similar factor analysis explained that the recur capability of HT sustained-release tablets releasing was good and the craft was stable.The quality study of the HT sustained-release tablet was done. The maincomponents included that the identification methods were set up, and the palmetine sustained-release tablet examining method of the correlated material was founded. The studying results according to items of the quality evaluating showed that evaluating method was reasonable and Ihe quality of the HT sustained-release tablet was under the control. The study on the releasing mechanism of HT sustained-release tablet was performed. Higuchi model was selected as the description of the HT sustained-release tablet’s releasing mechanism, and the n, the releasing parameter, equaling to 0.72(0.45 <n<0.89) meant that HT sustained-release tablet is non-Fick diffusion that drug diffusion and matrix corrosion is synergetic.The initial stability study showed that high temperature and light have not obvious effects on the HT sustained-release tablet but the humidity was of influence. The result gave a clue that the HT sustained-release tablet should be packed in moisture-proof material and preserved under dry environment.The pharmacokinetics and bioavailability study of the palmetine sustained-release tablet in dogs was made. The HPLC method which determinates the palmetine concentration in the dog plasma was established. The results of the method evaluation and pharmacokinetics experiment showed that the method could satisfy the needs of experiment and study. As the palmetine ordinary tablet being the reference preparation, experiments of single and multiple dosage regimens were done by self-comparison crossing trial design. The result indicated that the palmetine fits the one-compartment. After administering single dosage of the sample and the reference preparation to dogs respectively, AUQ>*, is 212.0± 62.9nghml"1 and 215.8 ± 62.0 nghml’respectively; W is 2.9± 0.4 h and 0.71± 0.19 h respectively; Cn^ is 81.6 ±40.1 ng-ml’1 and 143.48± 93.2 ngml’respectively. After administering multiple dosage to dogs, AUQ>*risl519.6±761.4nghml’1 and 1523.1 ±737.4nghml1 respectively; T?is4.4±0.2h and 1.7 ± 0.3h respectively; Q? is 320.5 ± 175.6 ngml"1 and 317.3 ± lOSJngml"1 respectively, Cav is 21.3544 ± 10.3448ng/ml and 20.9046± 10.4683ng/ml respectively, DF is 152.7508%±129.5072% and 261.7121%t299.8839% respectively, C*? is 42.53 ± 16.5ng/ml and 8.42 ± 3.16ng/ml respectively, relative bioavailability of singleand multiple dosage regimens is 108.0%±9.1% and 103.2%±3.(^respectively. The evaluation result of bioequivalence showed that AUC is bioequivalent but C^ax and W are beyond the confine. The Cn?x and the DF are smaller by contrast with the ordinary tablet, but the T^x is prolonged. The palmetine sustained-release tablet has the characteristic of sustained-release and the result comes to the purpose of the paper design.In vivo-in vitro correlation evaluation of the palmetine sustained-release tablet was studied by Wanger-Nelson method .The result proved that in vivo-in vitro correlation is significant. The release determination method is scientific and reasonable, which could guarantee the internal quality under the control.It have few reports about palmetine sustained-release form inside and outside China. Little data can be used for reference. So it is a pilot study. The results studied will be a good foundation of comprehensive development for diverse forms.更多还原