硝苯地平脂质体的制备与体内外评价

发布时间：2018-01-07 11:25

本文关键词：硝苯地平脂质体的制备与体内外评价　出处：《吉林大学》2017年硕士论文　论文类型：学位论文

【摘要】：硝苯地平(Nifedipine,NP)亦称为“心痛定”,化学式为C_(17)H_(18)N_2O_6,是用于预防和治疗冠心病、心绞痛、各种类型高血压的药物之一,具有很广阔的市场前景。但是,硝苯地平溶解度低,直接口服生物利用度差,具有显著的肝脏首过效应,消除半衰期短,常伴随不同程度的毒副作用,因此在临床应用上存在不足。本文制备了一种新型的硝苯地平脂质体,提高了硝苯地平的溶解度、口服生物利用度,并延缓了硝苯地平口服的消除半衰期。主要研究内容包括:1.硝苯地平脂质体体外分析方法学的建立:本实验对NP进行200~400 nm紫外波长扫描,确定硝苯地平的最大吸收波长为235 nm,建立了一种使用高效液相色谱测定硝苯地平含量的方法,并进行了相关的方法学验证,专属性、重现性、回收率、耐用性、稳定性等均符合相关要求,精密度相对标准偏差值小于3%,准确度相对误差值在-1%~2%,为研究新型硝苯地平脂质体的处方优化奠定基础。2.硝苯地平脂质体的制备及处方优化:本实验使用甲醇注入结合喷雾干燥法制备硝苯地平脂质体粉末,采用单因素实验,考察磷脂量、硝苯地平与磷脂的比例、磷脂与胆固醇的比例对重悬所得硝苯地平脂质体包封率、粒径的影响。在单因素实验结果的基础上,以重悬所得硝苯地平脂质体的包封率为主要考察指标,以中心组合设计对硝苯地平脂质体的处方进行优化,最终确定了最优处方的包封率为92.53±0.53%,粒径为114.33±5.88 nm。同时考察重悬所得硝苯地平脂质体与硝苯地平标准品在模拟胃液(pH=1.2)与模拟肠液(pH=6.8)环境中的体外释放度,实验结果证明硝苯地平脂质体在模拟肠胃液环境中,缓释效果明显优于硝苯地平标准品,且在模拟肠液中的释放速度大于在模拟胃液中的释放速度,表明脂质体在胃中稳定,在肠道中可以缓释。3.硝苯地平脂质体体内方法学的建立:本实验建立了一种快速、操作简单、灵敏度高的高效液相色谱法测量血浆样品中硝苯地平的含量。该方法建立的硝苯地平血浆样品浓度在25 ng/m L~3,000 ng/m L范围内线性关系良好,R~2值为0.9978,方法灵敏度高,同时测定硝苯地平血浆样品的日内、日间精密度相对标准偏差值均小于15%。所采用的血浆处理方法可使硝苯地平回收率达到80%以上,内标回收率达到84%以上,相对标准偏差值小于5%,证明此方法的回收率高且稳定。同时从反复冻融稳定性、长期冻存稳定性、室温放置稳定性这三个方面进行了硝苯地平脂质体的稳定性实验,实验结果相对标准偏差值均小于5%,证明该方法稳定性良好。由此可见,本实验建立的高效液相色谱方法可以用于测量血浆中硝苯地平的含量,为硝苯地平脂质体在大鼠体内的药代动力学研究奠定基础。4.硝苯地平脂质体体内药代动力学的研究:本实验考察了自制硝苯地平脂质体与硝苯地平原料药在Wistar大鼠体内的药代动力学,采用口服给药的方式,绘制血浆浓度对时间曲线,进行数据分析,结果显示硝苯地平脂质体组的达峰时间(Time of maximum,T_(max))、血浆浓度对时间曲线下面积(Area under the concentration-time curve,AUC_(0~∞))、平均滞留时间(Mean residence time,MRT_(0~∞))分别是硝苯地平组的2.00倍、10.08倍、2.98倍。表明本实验制备的硝苯地平脂质体可以延缓硝苯地平在血浆中的达峰时间,可以维持较高的血药浓度,减少血药浓度峰谷波动,具有一定的缓释作用,可以提高硝苯地平的口服生物利用度。综上所述:本实验制备的新型硝苯地平脂质体,提供了一种解决硝苯地平溶解度低、口服生物利用度差、消除半衰期短的有效方法,为今后的临床研究奠定理论基础。
[Abstract]:Nifedipine (Nifedipine, NP) also known as "nifepine, chemical formula C_ (17) H_ (18) N_2O_6, is used for the prevention and treatment of coronary heart disease, angina pectoris, one of the various types of drugs for hypertension, and has very broad market prospect. However, the low solubility of nifedipine, directly with poor oral bioavailability significant liver first pass effect, short half-life, often accompanied by different degree of toxicity, therefore in clinical application is insufficient. A new type of nifedipine liposomes were prepared in this paper, to improve the solubility of nifedipine, oral bioavailability, and delayed the half-life ofelim oral nifedipine. The main contents include 1.: the establishment of the liposomes in vitro analysis methodology: the 200~400 nm UV wavelength scanning of NP, determine the maximum absorption wavelength of nifedipine 235 nm, establish a high performance liquid Chromatographic methods for determination of nifedipine content, and has carried on the related method validation, specificity, reproducibility, recovery rate, durability, stability and meet the relevant requirements, the precision of the relative standard deviation is less than 3%, the accuracy of the relative error in -1%~2%, for the study of novel liposomes formulation optimization foundation.2. nifedipine liposome preparation and formulation optimization: the use of methanol injection combined with nifedipine liposomes prepared by spray drying powder, using the single factor experiment, study the content of phospholipids and phospholipid ratio of nifedipine, phospholipids and cholesterol ratio on suspended income nifedipine liposomes, the effects of particle size on the base of the single. The factors on the experimental results, the encapsulation efficiency of the liposome suspension of nifedipine was the main index, with the central composite design to optimize the prescription of nifedipine liposomes Finally, to determine the entrapment efficiency of the optimal prescription was 92.53 + 0.53%, 114.33 + 5.88 nm. particle size was also investigated the heavy suspension of nifedipine liposomes and nifedipine standard in simulated gastric fluid (pH=1.2) and simulated intestinal fluid (pH=6.8) in the in vitro release rate, experimental results show that the liposomes in simulated gastrointestinal fluid in the environment, better than nifedipine sustained-release standard, and the release rate in simulated intestinal fluid is greater than the release rate in simulated gastric fluid, show that the stability of liposomes in the stomach, in the intestine can establish.3. liposome sustained-release nifedipine methodology: this experiment established a rapid and simple operation, the content of nifedipine measurement of plasma samples by high performance liquid chromatography. The high sensitivity of nifedipine plasma samples concentration the method to establish a good relationship in the 25 ng/m L~3000 ng/m L range of R~2. A value of 0.9978. The method is of high sensitivity, simultaneous determination of nifedipine plasma samples within day precision RSD values were less than the plasma processing method used by 15%. can make the nifedipine recovery rate of more than 80%, in the recovery rate of more than 84%, relative standard deviation is less than 5%, the recovery rate of this method is that high and stable. At the same time from repeated freeze-thaw stability, long-term freezing stability, room temperature stability in the three aspects of the stability of liposomes, the experimental results of the relative standard deviation was less than 5%, which proves that the method has good stability. Therefore, the establishment of experimental high-performance liquid chromatography method can be used for measuring content of nifedipine in the plasma, for the study of nifedipine liposomes in pharmacokinetics of foundation.4. liposomes in vivo pharmacokinetics: The effects of nifedipine and nifedipine self-made liposome APIs in Wistar rats in vivo pharmacokinetics, by oral administration, drawing on plasma concentration time curve, data analysis, results showed that the liposomes group the peak time (Time of maximum T_ (max)), the plasma concentration area the time under the curve (Area under the concentration-time curve, AUC_ (0~ 2)), mean residence time (Mean residence time, MRT_ (0~ 2)) were 2 times, 10.08 times of the nifedipine group, 2.98 times. The results indicated that the liposomes prepared by this experiment can delay the peak of nifedipine in plasma time can maintain higher blood drug concentration, reduce the blood drug concentration peaks and valleys, has a certain sustained-release effect, can improve the oral bioavailability of nifedipine utilization. To sum up: the new experimental preparation of nifedipine Liposomes provide an effective way to solve the nifedipine low solubility, poor oral bioavailability and eliminate half life. It will lay a theoretical foundation for future clinical research.

【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943

【相似文献】