应用中药物质组释放动力学理论研究银翘解毒丸的缓释动力学及其同步性

将银翘解毒丸切割成1/4、 1/8、 1/12和1/16的等分块状颗粒，采用桨法装置，在100 r·min^{-1下测定其释放度，以紫外吸收光谱法结合Kalman滤波法对银翘解毒丸物质组进行定量，分别测定整丸及其等剂量按不同切割方式获得的等分块状颗粒的释放度，获得银翘解毒丸的物质组释放动力学特征。实验结果显示银翘解毒丸具有明显的缓释特征，在充分切割时也维持释放达2～4 h；银翘解毒丸的释放速率与切割方式呈现明显的相关性，物质组释放度曲线的Weibull分布参数T_d和T₅₀随着丸剂切割程度的增加而减小，提示大蜜丸的服用方式可能影响其体内药代动力学特征；整丸和等分切割块状颗粒的物质组释放同步性有明显差异，整丸的释放同步性特征明显高于切割后颗粒的释放同步性。本文以物质组释放动力学定量地刻画了传统剂型大蜜丸剂的缓释特征，从释放动力学角度阐释了“丸者缓也”的科学内涵；以取样间隔释放的物质组特征增量等参数为指标，可视化地评价了中药物质组释放同步性特征。中药物质组释放/溶出动力学理论为传统剂型的评价和给药系统设计提供了释放动力学的方法学基础。}     

星点设计法优化盐酸小檗碱树脂复合胃黏附给药系统的研究

本文以离子交换树脂(IER)作为载体吸附盐酸小檗碱，通过包衣将其制成胃黏附微囊，并以胃黏附微囊的载药量，胃滞留时间和体外释药时间作为评价指标，对处方进行优化。考察不同型号载体与不同浓度、温度和pH值的药物溶液对IER载药量的影响；以卡伯姆934与IER的比例(X₁)、丙烯酸树脂(Eudragit)与IER的比例(X₂)、Eudragit RL与Eudragit RS的比例(X₃)为自变量，以制剂累计释放量85%的时间点(Y₁)、制剂在大鼠胃体外黏附滞留百分比(Y₂)为因变量，通过星点设计—效应面法优化胃黏附包衣处方。优化后载药工艺为在37 ℃、pH 5左右条件下，用IRP88离子交换树脂对1.0 mg·mL^-1盐酸小檗碱溶液载药；优化后的包衣液组成为X₁=0.75、 X₂=0.9、 X₃=0.6，所得制剂单位质量载药量高，可在300 min左右达到累计释放总量的85%，同时在所设计条件范围内胃黏附作用最强。     

中药多组分缓释制剂体外释放评价体系的研究进展

目的:为找到更适合中药多组分的评价方法提供思路。方法:以"中药多组分""体外释放""同步释药""多指标""Synchronized""Release in vitro""TCM multicomponent""Multi-index"等为关键词,组合查询2004年1月-2016年6月在PubMed、Elsevier、Springer Link、中国知网、万方、维普等数据库中的相关文献,对中药已知成分作为评价指标、中药指纹图谱在药物体外释放中的应用,以及中药化合物组、吸波面积法、质量权重系数法等方法在中药多组分缓释制剂体外释放中的应用进行综述。结果与结论:共检索到相关文献210篇,其中有效文献42篇。对于成分复杂的中药制剂,溶出度的测定选择其中某种已知的指标成分进行;选择中药组分制剂中的一种或几种药效成分的释放度作为评价指标,可反映中药组分制剂中特定成分的释放特征;以指纹图谱相关峰为指标,可更全面地评价中药多组分缓释制剂的体外释放行为;选择中药多组分制剂中的几种有效成分并结合中药制剂的指纹图谱进行评价中药多组分制剂的释药行为,既可反映多个成分的含量变化,又可反映中药复方整体的含量变化;基于中药化合物组的整体谱特征,采用卡尔曼滤波法,计算获得溶出介质中化合物的含量,能很好地反映中药多组分的释药行为;吸波面积法能考察中药所有成分的释放情况,对复方药物溶出度及体内药动学的研究有指导意义;质量权重法可为中药组分的整体性研究提供参考,但必须明确各成分在整体组分中所占的质量权重系数才能整合反映整体性质。     

色谱指纹图谱指数F和相对指数Fr的研究

目的提出色谱指纹图谱指数(F)和相对指数(F_r)概念，用F和F_r揭示中药色谱指纹图谱信息的丰富程度和分离情况，反映指纹信号强度的大小和均化程度。方法用HPLC和HPCE指纹图谱实验结果进行应用研究。结果评价了射干抗病毒注射液及其各单味药材的指纹图谱结果，并对文献中丹参HPLC指纹图谱进行了评价。当评价中药毛细管电泳指纹图谱时，其F无显著差别，但F_r是HPLC法的1000倍之上。结论F与F_r可客观、全面、简便地用于评价色谱指纹图谱。     

有限采样法估算口服吡格列酮制剂的生物等效性

目的建立有限采样法模型估算盐酸吡格列酮(PGT)制剂的生物等效性。方法以健康志愿者口服PGT参比制剂后的血药浓度数据建模，有限采样法建立多元回归模型估算C_max和AUC_0-t。模型的内部和外部验证分别以Jackknife法和Monte Carlo法生成的模拟数据进行。选择最佳模型进行生物等效性评价。结果给药后1.5 h和2.5 h血药浓度(C_1.5和C_2.5)估算C_max的准确性较好，C_1.5和C₉估算AUC_0-t的准确性较好，平均预测误差<5%、平均绝对误差<9%，参数预测误差超过±20％的样本数<5%。生物等效性评价结果与经典法一致。结论有限采样法估算口服PGT制剂的生物等效性是可行的，为生物等效性研究提供新的思路和方法。     

6α-甲基-17α-羟基-黄体酮和6α-甲基-17α-羟基-11去氧-皮质酮-21-乙酸酯的微生物羟化

6α-甲基-11-去氧-17α-羟基-皮质酮-21-乙酸酯(Ⅱ)经短刺克宁汉霉微生物转化得6β-羟基化合物(Ⅵ_a)及6β,11β-羟基化合物(Ⅶ_a)。6α-甲基-17α-羟基-黄体酮(Ⅰ)经短刺克宁汉霉菌转化亦得6β-羟基化合物(Ⅵ_b)及6β,11β-羟基化合物(Ⅶ_b)。化合物(Ⅱ)如用梨头霉转化则得11α-羟化物(Ⅲ)。Ⅶ_a、Ⅶ_b、Ⅷ_a、Ⅷ_b及Ⅺ_b的结构是通过核磁共振谱和质谱证明的。     

日尺度下的干旱区成龄枣树耗水量敏感因素建模分析--测试文章

以新疆阿克苏地区成龄枣树为研究对象，以日均气温(x₁)、日均相对湿度(x₂)、日均风速(x₃)、日太阳辐射总量(x₄)、日均大气压(x₅)、0～100 cm土壤日均含水率(x₆)及0～20 cm土壤日均温度(x₇)为模型影响因子，采用偏最小二乘回归法建立了枣树耗水量预测模型，在此基础上运用缺省因子法分析了枣树耗水量对各因子的敏感性，并采用灰色关联分析法加以验证。结果表明：偏最小二乘回归模型(PLSR)具有较高的模拟精度（相关系数r=0.9789），不仅能够定量预测枣树耗水量（平均相对误差为6.40%），而且能够从机理上解释各因素对耗水量的影响；枣树耗水量对太阳辐射能量、土壤含水率和温度这3因素最为敏感（敏感性指数分别为3.24、2.18和2.09）；基于缺省因子法的枣树耗水敏感因素排序（x₄＞x₁＞x₆＞x₃＞x₇＞x₂＞x₅）与灰色关联分析计算结果（x₄＞x₁＞x₆＞x₃＞x₇＞x₅＞x₂）基本一致，尤其在主要影响因素的判别上是完全一致的。     

N-(4-甲氧羰基-4-邻苯二甲酰亚氨基丁酰基)-N-取代甘氨酸、脯氨酸和焦谷氨酸的合成

报道11个预期有血管紧张素转化酶抑制活性的N-(4-甲氧羰基-4-邻苯二甲酰亚氨基丁酰基)-N-取代甘氨酸(VII_1～9)、脯氨酸(VII₁₀)和焦谷氨酸(VIl₁₁)的合成和鉴定。所有上述化合物以及与VⅡ_1～9相应的叔丁酯(VI_1～9)均未见文献报道。药理初试结果显示，化合物VII₈，VII₉和VI₁₀均有明显降压活性。     

7α和7β-甲基-10β,17β-二乙酰氧基-4-雌甾烯-3-酮的合成

由于7α-甲基或10β-乙酰氧基4(5)烯-3-酮雌(雄)甾化合物具有显著的抗着床或抗蜕膜活性,我们合成了既具有7α-甲基或7β-甲基又具有10β-乙酰氧基的两个新甾族化合物(1_a)和(1_b)。经药理试验表明(1_a)和(1_b)对孕鼠均有抗早孕作用。     

肿瘤的化学治疗——ⅩⅩⅩⅤ.若干植物生长控制剂的衍生物的合成及其抗肿瘤作用

鉴于作者过去曾报道植物生长控制剂与肿瘤细胞的关系及其一些特点,合成了一系列带有强烈生物作用化合物为载体的植物生长控制剂衍生物(Ⅺ_a-d,Ⅻ_a-f,Ⅻ_a-e)和羟基萘乙酸(ⅩⅣ_a-l)羟基萘氧乙酸(ⅩⅤ_a-g)等化合物。药理试验结果Ⅺ_a,Ⅻ_s,b,Ⅻ_a,ⅩⅣ_f,h对肉瘤180或肉瘤37均有明显的抑制作用,其中化合物Ⅺ_a(代号AT-236)已作了初步临床试验,深入工作尚在进行中。     

Multidimensional spatial triangular area as an index for the evaluation of the release-absorption correlation of multiple component traditional Chinese medicines

The paper is aimed to provide a novel index, named as multidimensional spatial triangular area, for the evaluation of the release-absorption correlation of multiple component traditional Chinese medicines (TCMs). The applicability of the method was demonstrated by the example data. The method and standard practice for evaluation of the release-absorption correlation for western medicines with single compound could not be applied to TCMs with multiple components. The release percentage or absorption percentage of the multiple components for TCMs at the sampling time was a point in the multidimensional space. The area of the triangle formed byt the sequential three points represented the changing characteristics of the components' release and absorption kinetics. The side lengths of the triangle could be calculated from the spatial distances between each two of the sequential three points. Then the triangle area could be obtained by the side lengths. The in vitro release-in vivo absorption correlation of the multiple components could be represented by the correlation between the integrating values of the release triangle areas and that of the absorption triangle areas. The results of the examples indicated that the multidimensional spatial triangular area method could treat the multiple components in a holistic way, in line with the holism the hi he TCMs. Therefore, the multidimensional spatial triangular area method provided new methodology for the release-absorption correlation of the TCMs with multiple components.     

Characterization and mapping of the multi-component release kinetics of a Traditional Chinese Medicine dosage form using a modified LC/MS/MS method and chemomic release kinetic theory

It is essential to develop effective methods for the quality control of the traditional medicine with multiple components. However, few researches on the quality control have been conducted to interpret the holistic characteristics of the traditional medicine in terms of dissolution/release. In this study, the multi-component release kinetics of Traditional Chinese Medicine (TCM) dosage forms was characterized and mapped by multivariate analysis techniques in the field of “-omics”. The Liuweidihuang pill was used as a model formulation. The multi-component release kinetics of the concentrated and water-honeyed Liuweidihuang pills at rotation speeds of 50 and 100 rpm were analyzed by chemomic release kinetic theory and modified LC/MS/MS method. Mass features of 103 (concentrated pills) and 101 (water-honeyed pills) were selected with a linear correlation coefficient ≥0.99 between mass responses and concentrations. To compose the chemomic standard spectrum, the relative abundance of both mass features was no less than 1% as compared with an internal standard. The correlation coefficients between six samples of various solutions were in line with analytical requirements of precision (r≥0.985). The score plots of principal component analysis showed that the concentrated Liuweidihuang pills presented better chemomic release reproducibility than the water-honeyed pills. Conversely, the impact of rotation speed on the chemomic release was less obvious. The heat maps of hierarchical clustering analysis did not show significant changes in individual clusters of mass features along different time intervals, reflecting the release integrity of the mass features. Therefore, both multivariate analysis methods, the principal component analysis and the hierarchical clustering analysis, seemed to be effective techniques to demonstrate the multiple component release performance of TCM. The research provided the basis of a new strategy for the quality control procedures of the dissolution/release for the traditional medicine and multi-component natural products to address increasing regulatory requirements and scrutiny across the world.     

Influence of the type of vegetable oil on the drug release profile from lipid-core nanocapsules and in vivo genotoxicity study

Abstract

The use of rice bran (RB), soybean (SB) or sunflower seed (SF) oils to prepare lipid-core nanocapsules (LNCs) as controlled drug delivery systems was investigated. LNCs were prepared by interfacial deposition using the preformed polymer method. All formulations showed negative zeta potential and adequate nanotechnological characteristics (particle size 220–230?nm, polydispersity index < 0.20). The environmental safety was evaluated through an in vivo protocol (Allium cepa test) and LNCs containing RB, SB or SF oils did not present genotoxic potential. Clobetasol propionate (CP) was selected as a model drug to evaluate the influence of the type of vegetable oil on the control of the drug release from LNCs. Biphasic drug release profiles were observed for all formulations. After 168?h, the concentration of drug released from the formulation containing SF oil was lower (0.36?mg/mL) than from formulations containing SB (0.40?mg/mL) or RB oil (0.45?mg/mL). Good correlations between the consistency indices for the LNC cores and the burst and sustained drug release rate constants were obtained. Therefore, the type of the vegetal oil was shown as an important factor governing the control of drug release from LNCs.     

细胞膜色谱法及其在中药活性成分分析中的应用(英文)

中药经过了长期的临床试验,具有可靠的治疗效果,并为新药开发提供极好的活性化合物库,已逐渐得到全球范围内的广泛关注。中药中通常含有成百上千的化学物质,但其中只有少数的化合物具有药理作用,而其余大多数成分的存在使得分析和筛选中药的活性成分非常困难。因此,探寻用于分析和筛选中药活性成分的策略是中药研究中长期关注的问题,细胞膜色谱法已成为研究中药活性成分的有效方法。本文将概述细胞膜色谱法的原理、特点、应用前景及其在中药研究中可能面临的问题,细胞膜色谱法在中药活性成分分析和筛选中的作用将日益突出。     

f2法评价通脉浓缩丸与原制剂体外释放曲线相似性

目的：引入f₂相似因子法对通脉浓缩丸与原制剂通脉丸中两指标成分竹节香附素A（RDA）及苯甲酰新乌头原碱（BZC）的释放曲线进行分析,以对比评价其体外释放。方法：运用高效液相色谱法（HPLC）测定通脉浓缩丸与原制剂中指标成分RDA和BZC的体外释放率,并进行f₂相似因子计算。结果：通脉浓缩丸与原制剂中两指标成分的f₂均大于50,说明工艺改变前后两指标成分的体外释放曲线具有较好的相关性。结论：f₂相似因子法可运用于制剂工艺改变前后指标成分的体外释放评价。     

符合中药特点的致癌风险评价方法

如何对中药的致癌性风险作出科学而合理的评价是毒理学研究的难点之一。因中药成分和配伍的复杂性,现有的常规遗传毒性评价方法在评价中药方面有所局限。在原有试验原理基础上开发高通量筛选方法,以及利用新型生物标志物和基于新原理的试验技术已在中药毒性预测和评价领域显露一定的应用价值。本文聚焦适合大量成分毒性筛选及靶器官毒性评价的试验方法,包括改良的传统试验方法、自动化检测手段、生物标志物、三维组织培养技术和计算机毒理学的引入等,为中药致癌性评价提供借鉴思路。     

A comprehensive review of recent studies on pharmacokinetics of traditional Chinese medicines (2014–2017) and perspectives

Traditional Chinese medicines (TCMs) have a long history for safely treating human diseases. Unlike western medicine, TCMs usually contain multiple components synergistically and holistically acting on the diseases. It remains a big challenge to represent rationally the in vivo process of multiple components of TCMs for understanding the relationship between administration and therapeutic effects. For years, efforts were always made to face the challenge, and the achievements were obvious. Here, we give an comprehensive overview of the recent investigation progress (from 2015 to 2017, except the part of ‘integrated pharmacokinetics of TCMs’ from 2014 to 2017 and the part of ‘reverse pharmacokinetics in drug discovery from natural medicines’ in 2014) on pharmacokinetics of TCMs, mainly referring to the following six aspects: (1) classical pharmacokinetic studies on TCMs; (2) absorbed components and metabolites identification of TCMs; (3) pharmacokinetic herb–drug interactions and herb–herb interactions with TCMs; (4) integrated pharmacokinetics of TCMs; (5) pharmacokinetic and pharmacodynamic combination studies to dissect the action mechanisms of TCMs; and (6) reverse pharmacokinetics in drug discovery from natural medicines. Finally, based on the insights from the recent progress and our latest efforts, we propose new perspectives on the integrated pharmacokinetics of TCMs.     

Screening of permeable compounds in Flos Lonicerae Japonicae with liposome using ultrafiltration and HPLC

A new method for the screening of membrane-permeable compounds in traditional Chinese medicines (TCMs), using ultrafiltration and HPLC analysis, has been proposed. We hypothesized that exposure of a TCM extract to a liposome membrane, the concentration of membrane-permeable compounds in the solution should decrease. Using this approach, the permeability of compounds in Flos Lonicerae Japonicae (Japanese honeysuckle) was investigated. By comparing chromatograms of samples prepared before and after interaction with a liposome membrane, eight permeable compounds of Flos Lonicerae Japonicae were identified, and all of them were proven to be biologically active. Based on the significance of these results, this method could be a novel approach for identifying potentially bioactive components in other TCMs.     

数理模型在中药药性及配伍规律研究中的应用概况

基于中医药理论和数学理论,构建并应用合理的数理模型是中药药性理论和复方配伍研究的新模式,亦是践行中医药传承与创新的重要举措之一。近年来网络理论、数据挖掘、路径模型等方法已被广泛用于中药药性理论和配伍研究。通过归纳、总结近年来基于数理模型的中药药性理论和复方配伍研究,以期为用现代科学语言解释深奥的中药药性理论和复方配伍,为深入阐释其科学内涵,并为中医药国际化和现代化提供研究思路。     

中药干预细胞能量代谢治疗心脑血管疾病的研究进展

目的总结近年来中药干预细胞能量代谢治疗心血管疾病的研究进展。方法对文献进行归纳总结。结果细胞能量代谢障碍是心脑血管疾病发生、发展的重要因素,中药能改善能量代谢,进而治疗和预防心脑血管疾病。结论中药干预细胞能量代谢治疗心血管疾病疗效显著,为防治心脑血管疾病药物的开发提供了新的策略。