【作者】 纪立伟；

【导师】 陈桂兰；

【作者基本信息】 河北医科大学 ， 药剂学， 2002， 硕士

【摘要】 目的：盐酸地尔硫卓是一种高效的钙通道拮抗剂，是治疗心绞痛、高血压、心血管疾病的一线药物之一，应用前景广阔。目前国内生产了盐酸地尔硫卓普通片、缓释片、控释片以及针剂。本研究根据盐酸地尔硫卓具有时辰药理节律的特点拟将其制成盐酸地尔硫卓控时释放片，为临床用药提供一种新剂型。研究拟采用德国RHM药厂生产的产品Eudragit L100、S100两种丙烯酸树酯共聚物，与乙基纤维素以一定比例混合作为阻滞层，外面再包以起保护和隔离作用的衣膜，通过多层薄膜包衣技术，达到控时释放的目的 方法：在预试验的基础上以湿法制粒压片法制备速释片芯。然后通过四因素三水平正交实验对阻滞包衣层进行筛选，通过人体实验验证具有一定时滞后，再进行盐酸地尔硫卓控时释放片质量检查和稳定性实验。 包衣片的制备：通过预试验筛选出具有良好崩解性能的速释片芯处方。将处方量的主药（60mg）、预胶化淀粉、崩解剂X按等量递加法混和，过筛混匀后，以湿法制粒法压片制得片芯。选取合格片芯，以不同条件制备包衣片，进行影响药物时滞的单因素考察。在此基础上，通过正交实验L₉（3⁴），以pH6.8磷酸盐缓冲液中薄膜 中文摘要衣片的溶出则－滞等因素为指标对阻滞包衣层处方及制折工艺进行筛选、评分，并对评分结果进行极差分析和方差分析，以啪定包衣料处方及制备上艺。 形态观察：通过扫描电镜观察盐酸地尔硫卓控时释放片的表面、断层形态。依据2000版仁中国药典》溶出实验转蓝法要求将盐酸地尔硫卓控时释放)－t“浸在0．lino＊盐酸进行2刁时，冉在叫6．8磷酸盐缓冲液进行4刁时，最后于州7．2磷酸盐缓冲液中释放时分别留样，利川扫描电镜观察薄腆衣)｝的人m变化。 含量测定力“法：采川简便、快速、灭敏的高效液札色谱法测定盐酸地尔硫卓控；v释放片含量及血浆中药物浓厦。盐酸地尔硫卓控时释放片含量测定选择外标法。外标为盐酸地尔硫卓对IKt品。色谱条件和系统适用性实验条件为：色谱柱0！KMA“C旧 柱（4．61。IX乃omm，sum），流动柏：＊醇一水门5：25)，流速：1刀。＊1／mh，检测波长：240 urn，温度：车洲／ ／小、而三个浓以…g加l)口 11训父率分别为 101．62o、100．60O、100．99％。RSD分别为l．940、l．86o、l．67％。人体血浆中盐酸地尔硫卓的浓度测定选抒内标沾，内标为地的伴。色谱条件和系统适用。叮实验条件为：色谱柱 DIKMA“CIS柱N．6mm＼250一，5um)；流动相：乙＊－r醇一水（5：2：3）；流速：l刀ml／min检测波长：240 urn；温度：室温。论文所建立的血浆处现方法于扰少，线形关系强（r＝0．9990X低。中、高三个浓度＊g／ml）的回收率分别为 98．98％09．56％、101＊0％，RSD分别为 1＊2％、0、92％、3＊6％。通过检 2 中文摘要 测药物浓度确定药物在体内的时滞和达峰时间。 释放度考察：依据人体胃肠道pH特点及2000版《中 国药典》溶出实验转蓝法要求将盐酸地尔硫卓控时释放 片先放在 0刁 mol／l盐酸中进厅 2小时，取出再在 pH6．8 磷酸盐缓冲液进行4小时，最后取出置于pH7．2磷酸盐 缓冲液中。按规定时间取样，于240nm处测定吸收度， 根据标准曲线计算药物浓度，求得盐酸地尔硫卓控时释 放片累积释放百分比。 人体验证实验：选择四名男性健康志愿者进行盐酸 地尔硫卓控时释放片体内时滞验证。采取随机交叉分组 的方法，四名受试者单剂量口服盐酸地尔硫卓控时释放 片“0mg)和市售合心爽对照片 (30m在片人血药浓 度数据用3P87程序处理。在服药后不同时间于前臂静脉 取血。以高效液相色谱法测定血浆中盐酸地尔硫卓浓度。 稳定性考察：进行盐酸地尔硫卓控时释放片优选处 方的稳定性影响因素实验（强光照射实验、高温实验、 高湿实验），加速实验及长期实验。根据2000版《中国 药典》片剂稳定性重点考察项目进行实验。 结果：包衣片制备，通过预实验确定的速释片芯， 崩解并全部通过筛网的平均时间为32土0．12秒，其外观 好，表面光洁圆整，硬度在4kg左右。依据正交结果的 极差分析和方差分祈得知，片剂时滞的最主要影响因素 是包衣材料的配比、增塑剂用量，其次为包衣厚度，影 响最小的因素是包衣片的后处理方法。按照筛选出的处 万将 Eudragit“LI 00、SI 00与乙基纤维素以一定比例溶 3 中文摘要于丙酮与异内酮混合溶液L！＼ 冉加入增塑剂，通过锅包衣法制爷了盐酸地尔硫卓控时释放?更多还原

【Abstract】 Objective: Diltiazem hydrochloride(DIL) is a benzothiazepine derivative with calcium-channel activity, which can prevent circadian angina pectoris. The main products in China are ordinary tablets, sustained-release tablets and injections. According to chronopharmacokinetics and the gastrointestinal pH in normal human subjects, the tablets in this paper were designed to time controlled release with a predetermined lag time by the method of multiply film-coated.Method: The systems consisted of a protected layer, a less water permeable layer and a fast disintegrate core tablet. Through the pre-experiment, the core of time-controlled release tablets of diltiazem hydrochloride (TCT-DIL) was designed. Based on the analysis of the factors which were relative to the lag time of TCT-DIL dissolved in phosphate buffer pH 6.8, the orthogonal experiment design L9(34)was used to select the less water permeable layer of TCT-DIL, which consisted of ethylcellulose, Eurdragit L100 S100, et al.The scanning electron photomicrographs of surfaces ofTCT-DIL were taken before and after dissolution.The content of diltiazem in TCT-DIL was determined by High-performance Liquid Chromatograph (HPLC) with Ultraviolet detector. Diltiazem hydrochloride was reference. The liquid chromatograph is equipped with a 240nm detector and a DIKMA C18 ( 4.6mm X 250mm,5um ) column. Mobile phase is a suitable filtered mixture of methyl alcohol-water(75:25). The flow rate is about 1.0ml per minute. The correlation of the linear range was good between 20 and 220 u g/ml, C =2.284677 X 10-5A-3.181635(n=5), r =0.9980.The column efficiency is not less than 3000 theoretical plates. The recoveries of external standard were 101.62%, 100.60%, 100.99%, respectively. RSD: 1.94%, 1.86%, 1.67%, respectively.Cylindrical basket method was employed in the experiment of dissolution test.The concentration of diltiazem in dissolution of TCT-DIL was determined at 240nm by Ultraviolet spectrophotometer. The best formulation and technology were obtained by terms of the speed of dissolution of TCT-DIL in phosphate buffer pH6.8.The optimal formation of TCT-DIL(60mg) and reference tablets(60mg) were given in a single dose to four healthy volunteers in a cross-over way. The diltiazem concentrations in plasma were determined by HPLC with Ultraviolet detector. The parameters were fitted and calculated by 3P87program. Diazepam was reference. Chromatograph system-trie liquid chromatograph is equipped with a 240nm detector and a DIKMA CIS ( 4.6mm X 250mm,5um ) column. Mobile phase is a suitable filtered mixture of acetonitrile-methyl alcohol-ammonium acetate solution(5:2:3).The flow rate is about 1.0ml per minute. The correlation of the linear range was good between 5 and 95ng/ml, C = 164.093613 As/Ai-8.903321,r=0.9990.The recoveries of reference solution were 98.98%, 99.56% and 101.00%, respectively.RSD:1.62%, 0.92% , 3.66%,respectively.The chemical and physical stability of the optimal formation of TCT-DIL was investigated, including stress testing (high humidity testing, optical testing, high temperature testing), accelerated testing and long-term testing.Results: The results of orthogonal experiment design were found. The lag time of TCT-DIL was mainly determined by composition of the less water permeable layer, that is the proportion of ethylcellulose and Eurdragit L100/S100. The amount of plastizer was important than the thickness of the less water permeable layer.The surface of TCT-DIL was no significant change when it was put into 0.1M HCL and into phosphate buffer pH 6.8. Some small cracks were found in the surface of TCT-DIL when it was put into phosphate buffer pH 7.2.The cumulative release percentage of diltiazem of TCT-DIL(60mg) in 0.1M HCL after 2 hours is less then 10% and in phosphate buffer pH6.8 after 4 hours is less then 10% .The cumulative release percentage in phosphate buffer pH7.2 after 6 hours is more then 75%.The parameter of TMAX and the lag time was significantly different (p<0.01) then control HEXINSHUANG, other更多还原