马来酸罗格列酮胃漂浮型缓释片的研究

目的：根据流体动力学平衡控释原理（HBS）研制了马来酸罗列酮胃漂浮型缓释片。方法；以体外释放度和漂浮情况为筛选指标，采用单因素考察和正交试验设计相结合， 对胃漂浮缓释片的处方、制备工艺及体外释放条件进行优化筛选；采用γ闪烁照相技术对优化处方的内漂浮情况进行胃内动态观察。结果：马来酸罗格列酮胃漂浮缓释片在释放介质中迅速起漂，持漂时间超过12h,12h达最大累积释放；初步确定在胃内滞留时间达3h以上。结论：优化处方的释放过程符合Higuchi方程，释放机制为异常扩散；胃漂浮片在胃滞时间明显长于普通片。     

氧化苦参碱胃内滞留缓释片的研制

目的：为延长苦参素的作用时间，降低肠道菌群的降解作用，便于给药，制成苦参素胃内滞留缓释片。方法：以HPMC为骨架材料，十六醇为助漂剂，碱式碳酸镁为产气剂，制备了一天给药两次的胃内滞留型缓释片，并进行体外累积释放度测定。结果：体外释药符合Higuchi方程，r=0．9864，体外释药量与释药时间具有良好的相关性，3个取样点及累积释放百分率分别为：1h20％。45％、2h35％～60％、8h75％以上，且起漂时间不超过5min。结论：该缓释片处方工艺简单，适合工业化生产；缓释效果明显。     

桂枝茯苓透皮贴剂主要成分含量及释放度测定

目的：测定桂枝茯苓透皮贴中芍药苷、肉桂酸、丹皮酚的含量及释放度。方法：建立HPLC法测定贴剂中肉桂酸、芍药苷和丹皮酚含量;按照《中国药典》2015年版四部溶出度与释放度测定法第四法测定贴剂的体外释放性能。结果：建立了同时测定桂枝茯苓贴中3种成分的液相色谱法。芍药苷、肉桂酸和丹皮酚的线性范围分别为16.08~144.72 μg·mL^-1,0.32~2.91 μg·mL^-1和8~72 μg·mL^-1。精密度、重复性、24 h稳定性、加样回收率良好。建立了桂枝茯苓贴剂体外释放度测定方法,贴剂释药曲线符合Higuchi方程。结论：建立的含量和释放度测定方法简便、准确,可用于桂枝茯苓透皮贴剂的质量控制。     

Higuchi equation: derivation, applications, use and misuse

Fifty years ago, the legendary Professor Takeru Higuchi published the derivation of an equation that allowed for the quantification of drug release from thin ointment films, containing finely dispersed drug into a perfect sink. This became the famous Higuchi equation whose fiftieth anniversary we celebrate this year. Despite the complexity of the involved mass transport processes, Higuchi derived a very simple equation, which is easy to use. Based on a pseudo-steady-state approach, a direct proportionality between the cumulative amount of drug released and the square root of time can be demonstrated. In contrast to various other “square root of time” release kinetics, the constant of proportionality in the classical Higuchi equation has a specific, physically realistic meaning. The major benefits of this equation include the possibility to: (i) facilitate device optimization, and (ii) to better understand the underlying drug release mechanisms. The equation can also be applied to other types of drug delivery systems than thin ointment films, e.g., controlled release transdermal patches or films for oral controlled drug delivery. Later, the equation was extended to other geometries and related theories have been proposed. The aim of this review is to highlight the assumptions the derivation of the classical Higuchi equation is based on and to give an overview on the use and potential misuse of this equation as well as of related theories.     

阿司匹林壳聚糖缓释片的体外释放度研究

目的:研究阿司匹林壳聚糖缓释片的体外释放度。方法:以壳聚糖作为骨架材料制备阿司匹林缓释片并进行体外释放度实验。结果:自制阿司匹林壳聚糖缓释片在1h、2h、4h、6h、8h、10h的体外释放度为(18.60±0.88)%、(35.58±2.15)%、(60.22±1.07)%、(80.66±1.64)%、(98.53±1.15)%、(98.55±1.76)%。结论:药物的体外释放模型符合Higuchi方程。     

氯氮平胃内漂浮片的研制

采用羟丙甲纤维素、十六醇等材料,湿法制颗粒压片,制备了氯氮平胃内漂浮片进行了体外漂浮性与体外释放度的研究。与普通氯氮平片比较,本品体外漂浮性良好,具有很好的缓释效果,其体外释放行为符合Higuchi方程。     

An automated process for building reliable and optimal in vitro/in vivo correlation models based on Monte Carlo simulations

Many mathematical models have been proposed for establishing an in vitro/in vivo correlation (IVIVC). The traditional IVIVC model building process consists of 5 steps: deconvolution, model fitting, convolution, prediction error evaluation, and cross-validation. This is a time-consuming process and typically a few models at most are tested for any given data set. The objectives of this work were to (1) propose a statistical tool to screen models for further development of an IVIVC, (2) evaluate the performance of each model under different circumstances, and (3) investigate the effectiveness of common statistical model selection criteria for choosing IVIVC models. A computer program was developed to explore which model(s) would be most likely to work well with a random variation from the original formulation. The process used Monte Carlo simulation techniques to build IVIVC models. Data-based model selection criteria (Akaike Information Criteria [AIC], R2) and the probability of passing the Food and Drug Administration "prediction error" requirement was calculated. To illustrate this approach, several real data sets representing a broad range of release profiles are used to illustrate the process and to demonstrate the advantages of this automated process over the traditional approach. The Hixson-Crowell and Weibull models were often preferred over the linear. When evaluating whether a Level A IVIVC model was possible, the model selection criteria AIC generally selected the best model. We believe that the approach we proposed may be a rapid tool to determine which IVIVC model (if any) is the most applicable.     

释放分割法体外评价释放特征符合Higuchi方程的缓释制剂药物动力学

提出一种Higuchi释放缓释制剂药物动力学体外评价方法 ,将Higuchi释放以高斯 牛顿法分割成零级释放、一级释放和速释部分 ,每部分释放对体内药物动力学的贡献值则通过经典的药物动力学计算获得。方法学研究证明了释放分割法与基于零级释放药物动力学的剂量分割法效果相当 ,释放分割法计算得到的血药浓度 (CRD)与剂量分割法计算得到的血药浓度 (CDD)间的相关方程为CDD=-0 2 5 88+1 0 1 4CRD(r=0 993 6)。由于任意Higuchi释放曲线可以通过归一化的Higuchi释放曲线线性化表达 ,所以归一化Higuchi释放曲线的分割系数可作为非归一化的Higuchi释放的体外评价的模数。释放分割法可以对制剂的体外释放行为进行经济的评价 ,适用于缓释制剂的处方筛选、体内外相关性研究等     

日朝医学交流史的生动写照——《韩客治验》

日本京都大学附图书馆富士川文库藏有1749年刊印的橱口道与所著《韩客治验》一书。此书详细记载了1748年夏橱口道与受官府之命为朝鲜通信使治病的经过，对14名患者的姓名、年龄、症状、诊断以及用药等都有详细记述。由其记载可知，朝鲜通信使患病种类多样，而日本汉医橱口氏诊断明确，理论知识扎实，用药经验丰富，且治疗方法灵活。《韩客治验》比较翔实地反映了日本与朝鲜之间的医学交流活动，是日朝医学交流史的生动写照。     

T wave polarity related to the repolarization process of epicardial and endocardial ventricular surfaces

The reason for normal upright and negative T waves was examined by studies on the difference in durations of the action potentials (transmural gradient) in the epicardial (APDepi) and endocardial (APDend) surfaces. A unipolar epicardial electrogram (ECGepi) was recorded simultaneously with monophasic action potentials from both the epicardial and endocardial surfaces with suction electrodes in seven dogs. The duration of the action potential was altered by warming or cooling the epicardial surface of the heart. The T waves in the ECGepi were negative at room temperature in all experiments. When the epicardial surface was warmed, the T waves became less negative and finally became upright. Isoelectric T waves were obtained when APDend was 20 to 40 msec longer than APDepi. The amplitude of the T wave increased with increase in the transmural gradient (r value = 0.82 to 0.98). These results suggest that an APD of 40 to 60 msec is required for an upright T wave.