【作者】 程光；

【导师】 杜青；

【作者基本信息】 河北医科大学 ， 药剂学， 2008， 硕士

【摘要】 目的:盐酸文拉法辛是一类新的苯乙胺衍生物,是具有独特化学结构和神经药理学作用的新型抗抑郁药。它通过阻滞5-羟色胺(5-HT)和去甲肾上腺素(NE)两种递质的再摄取而发挥抗抑郁作用,文拉法辛适用于各种类型抑郁症、伴有焦虑抑郁症及广泛性焦虑症,对既有精神运动性迟缓又有激越行为特征的抑郁症也有良好疗效。现有普通制剂经常需要一天给药2~3次,血药浓度有起伏较大,副反应显著。因此,迫切需要缓控型的制剂,而渗透泵控释片是缓控释制剂的一个典型代表,将文拉法辛制成渗透泵控释片能够在一定时间范围内以恒定的释药速度释放出一定量的治疗药物,以零级释放动力学为释药特征,减少给要次数,提高病人顺应性,减少副反应,保证用药的安全性和有效性,并且释药速率不受胃肠道的pH、蠕动快慢和胃排空的影响,体内外相关性好。方法:用单冲压片机制备片芯,以醋酸纤维素为包衣材料,PEG400为致孔剂,邻苯二甲酸二乙酯为增塑剂,丙酮为溶剂配制包衣液,锅包衣法制备盐酸文拉法辛渗透泵控释片。在文献和预实验基础上初步确定了包衣过程中的包衣温度、包衣锅转速和喷雾压力。对片芯的硬度、片芯的直径、渗透压促进剂种类、渗透压促进剂的用量、致孔剂的用量和包衣膜重量进行考察,并以相似因子法评价其体外释药曲线的相似性。在上述实验基础上选择渗透压促进剂的用量、致孔剂的用量和包衣膜重量作为3个影响因素,分别选取3个水平,按L9(34)正交实验,采用加权评分法,以2、6、10小时的释放量为3个评分点确定优化处方。按优化处方制备盐酸文拉法辛渗透泵控释片,进行体外释放度实验,得到累积释放的曲线。释放度实验依照《中国人民共和国药典》2005年版二部附录X C溶出度测定法第一法装置,以水900 ml为释放介质,转速75 rpm,介质温度(37.5±0.5)℃,分别在1、2、4、6、8、10、12小时取液5 ml同时补充等体积同温释放介质,过0.8μm微孔滤膜后,续滤液作为供试溶液。另精密取盐酸文拉法辛13 mg置100 ml量瓶中,定容摇匀后精密取25 ml定容于50 ml量瓶中,作为对照溶液。在下述色谱条件下,对对照溶液和供试溶液进行测定,按峰面积计算累积释放度。在文献和预实验基础上,建立了高效液相分析方法测定盐酸文拉法辛。色谱条件:色谱柱为Kromasil C8 (250mm×4.6mm,5μm);流动相为0.1 mol/ml磷酸二氢铵:乙腈(60:40);流速为1.0 ml/min;柱温为25℃;检测波长为230 nm。对盐酸文拉法辛渗透泵控释片进行了初步稳定性考察,影响因素实验包括高温、高湿、强光照射3个影响因素实验,分别在0、5、10天取样对其外观、含量、释放度进行考察。加速实验是在40℃下,相对湿度75%条件下分别在0、6个月取样对其外观、含量、释放度进行考察。体内药代动力学实验:以Beagle犬为实验动物,采用随机分组的方法将Beagle犬分为两组,分别口服给予成都大西南制药股份有限公司生产的博乐欣胶囊和自制盐酸文拉法辛渗透泵控释片,在预定的时间点取血,对血浆处理后进行分析,清洗一周以后进行交叉实验。用高效液相色谱法测定给药后不同时间点的血药浓度,采用非隔室模型方法计算各种药动学参数。结果:通过单因素考察和正交实验,筛选出压片工艺为片芯直径11 mm,硬度8 kg,片重400 mg。包衣工艺为:包衣温度40℃,包衣锅转速60 rpm,喷雾压力2 kg/cm2。最佳处方为:渗透压促进剂为甘露醇和乳糖(1:1),渗透压促进剂与主药比例为4:1,包衣液中PEG400是醋酸纤维素的10%(g/g),包衣膜重量是片芯的3%,醋酸纤维素的浓度为4%(w/v)。用HPLC法对盐酸文拉法辛进行体外含量测定,其保留时间为4.5 min,辅料对测定无干扰,线性范围为5~100μg/ml,线性回归方程为C=21743A+5877.1 (r=0.9999),日间精密度RSD为1.04~1.85%,日内精密度RSD为0.25~0.43%,回收率为98.96~100.12%。影响因素实验中,在92.5%的相对湿度下样品在5天和10天时增重较大,而在75%的相对湿度下样品在5天和10天时不增重,10天后外观、含量和释放不变;在60℃和4500±500 lx强光照射条件下,10天后样品外观、含量和释放都不变。加期实验中,在6个月后样品外观、含量和释放均不变。药物动力学研究,根据所选液相条件进行实验,其主要的药动学参数分别为:渗透泵片和普通胶囊的Tmax(h)分别为6.333±0.816和3.833±0.408;Cmax(μg/ml)分别为0.415±0.106和0.981±0.29;MRT(h)分别为17.09±2.284和7.697±0.738。可见渗透泵片与市售普通胶囊相比,药物达峰浓度的时间和MRT均延长,而峰浓度降低。结论:盐酸文拉法辛渗透泵控释片具有显著控释制剂的释药特征,符合零级释放动力学模型,能够恒速释药12小时,重现性好,而且温度、湿度、光照不影响制剂的质量。同时建立了含量测定、释放度测定的方法,为考察质量提供了可靠方法。体内实验证明药物达峰时间和MRT均比市售胶囊长,且峰浓度降低。更多还原

【Abstract】 Objectives: Venlafaxine Hydrochloride is a new type of phenylethylamine derivative antidepressant drug which has characteristic chemcial constitution and neuropharmacology effect. It educes antidepression effect by prohibiting reuptake of 5-hydroxytryptamine and norepinephrine. It refers to various kinds of depression, depression accompanying anxiety, catholic anxiety disorders and depression both accompanying psychomotor retardation and agitate behavior. But conventional capsule is usually administered two or three times a day, which would lead to large fluctuation in drug plasma concentration and side effect on human body. Controlled release preparation is often desirable. Among these, osmotic pump tablet is a typical example. It offers several advantages, such as releasing drug at the rate of approximate zero-order, reducing risk of adverse reactions, independing on pH and peristalsis of gastro-intestinal tract and gastric emptying, improving compliance of patients and exhibiting comparable in vitro/in vivo drug release.Methods: A method for preparation of venlafaxine hydrochloride osmotic pump release tablets was obtained by coating core tablet compressed by single punch tablet machine. Cellulose acetate, PEG 400, diethyl phthalate and acetone were respectively used as coating material, channeling agent, plasticizer and solvent. On the basis of pretesting and scientific literatures, the temperature of coating, rotary speed of coating pot and pressure of spraying were determined. The hardness and diameter of tablet, type and amount of osmotic agent, thickness of coating membrane were investigated and evaluated by similarity factor(?2). The orthogonal experiment was designed to optimize formula in which the amount of osmotic agent, PEG 400 and thickness of coating membrane were taken as three influential factors and three different levels were selected to part, each of them was selected refer to the L9(34) orthogonal design table. According to accumulative release percentage at 2h,6h,10h to select optimal formula with the colligation evaluation. The osmotic pump tablet with the optimal formula was prepared and its in vitro cumulative release profile was obtained.In vitro release test was performed in a dissolution apparatus using the first method according to CHP. The stirring rates in water was 75rpm. The temperature was maintained at (37±0.5)℃. At the predetermined intervals (1, 2, 4, 6, 8, 10, 12h), 5ml samples were withdrawn from each vessel, filtered with a 0.8μm membrane, and analyzed with HPLC method for venlafaxine hydrochloride. The same volume of fresh medium was replaced after sampling.Concentration of venlafaxine hydrochloride was determined using a HPLC system. Separation was achieved by using a Kromasil column(C8, 4.6mm×250mm, 5μm). The mobile phase consisted of acetonitrile and 0.1mol/ml ammonium dihydrogen phosphate aqueous solution at a ratio of 40:60(v/v). The flow rate was 1.0ml/min, and the injection volume was 20μl. All chromatographic separations were performed at 25℃. The wavelength of detectionwas set at 230nm.The chemical and physical stability of optimal formula was investigated under following circumstances: high humidity, high temperature, strong illumination and accelerated condition (40℃/75% RH for 6 months). At the end of the study period, the formula was observed for change in physical appearance, drug content and drug release characteristics.Pharmacokinetics study in vivo: we selected the Beagle dogs as laboratory animal, which were divided into two groups in random. One group was given osmotic pump release tablets and the other was given market conventional capsules. Plasma samples were obtained at different times. Crossover experiment was taken after two weeks. HPLC with Ultraviolet detector was adopted in examining concentration of plasma. Then pharmacokinetics parameters were caculated by non-compartmental model analysis method.Results: The optimal technology and formula were defined through simple factor test and orthogonal experiments. The core tablet conditions were as follows: hardness of tablet, 8kg; diameter of tablet, 11mm; weight of tablet, 400mg. The coating conditions were as follows: coating temperature, 40℃; rotation rate of pot, 60rpm; spray pressure, 2kg/cm2. The optimal formula were as follows: the type of osmotic agent, mannitol and lactose a ratio of 1:1(g/g); osmotic agent in the drug of core tablet, 25%(g/g); PEG 400 in the cellulose acetate, 10%(g/g); coating membrane in core tablet, 3%(g/g). Total coating materials in the coating solution: 4.0%(w/v).The results of the system serve experiment of the HPLC method to determine the content of venlafaxine hydrochloride: the reserve time of venlafaxine hydrochloride were about 4.5min, the recoveries were 98.96~100.12%, the within-day precision was 0.25~0.43%, the between-day precision was 1.04~1.85%. Regression equation was C=21743A+ 5877.1(r=0.9999). The linearity range of venlafaxine hydrochloride was 5μg/ml~100μg/ml. Excipients had no interference with the results.Stability experiment: the result of high humidity test showed that 10 days after osmotic pump release tablets being placed in humidity(RH 92.5%), the weight highly increased. But in humidity(RH 75%), the weight hardly increased. There was no change in physical appearance, drug content and drug release characteristics after being stored at high humidity(RH 75%), high temperature(40℃) and strong illumination (4500±500 lx) for 10 days. The result of accelerated experiment showed that the data were not significantly different from before. Pharmacokinetic study: we took the experiment according to defined HPLC condition. The main pharmacokinetics parameters were respectively as following: Tmax(h), Cmax(μg/ml) and MRT of osmotic pump tablet were 6.333±0.816, 0.415±0.106 and 17.09±2.284 respectively. Tmax(h), Cmax(μg/ml) and MRT of conventional capsule were 3.833±0.408, 0.981±0.29 and 7.697±0.738 respectively.Compared with market conventional capsule, both peak time and MRT of osmotic pump tablet was extended and concentration of osmotic pump tablet was decreased.Conclusions: Venlafaxine hydrochloride osmotic pump tablets had good effect of controlled release property and repetition in vitro. The quality is independent on temperature, humidity and illumination. The methods of assay and dissolution for venlafaxine hydrochloride osmotic pump tablets were established, which provided a guideline with quality control. The experiment in vivo showed that both peak time and MRT of osmotic pump tablet was extended and plasma concentration of osmotic pump tablet was decreased.更多还原