中药制剂单用确定性与合用调配性的关键理论技术问题研究

目的:通过分析中药制剂研究特点,明确该学科的长期发展方向,并提出本学科亟待解决的关键问题及对策。方法:根据中药制剂研究的发展轨迹,结合中医药基础理论、现代新药研究技术与本人从事中医药现代化研究经验,从中药制剂发展方向、特点、亟需解决的关键问题与对策等方面进行探讨。结果:建立以结构与作用明确的多成分群为原料,按中医药基础理论或现代网络医药为指导,以来源方便的动、植、矿物为原料,单用确定性(有效、稳定、可控),合用可调性(可预、最优效、最低毒)整体相统一的单个、群体与中药复方制剂体系。在实现上述目标时,需解决成分有效性归属、遗传稳态性与一次投料量、成分间理化性质迁移规律、提取过程动态性与稳态性规律、制备时整体模型受控与紊湍受控规律、体内外的评价规律、微观质量与宏观质量、单用的确定性与合用的调配性等关键技术问题。结论:中药制剂是体现单用确定性与合用调配性高度统一的整体有效成分群制剂。     

Recent advances in cyclodextrin delivery techniques

Introduction: Active pharmaceutical ingredients (APIs) are evolving from low-molecular-weight drugs to peptide-, protein-, gene-, oligonucleotide- and cell-based drugs. Therefore, advanced pharmaceutical technologies are required to achieve manifestation of the drug efficacy, side effect reduction and the adequate dosage form design.

Areas covered: In this review, the authors highlight the recent advances in drug delivery techniques utilizing cyclodextrins (CyDs), and cyclic oligosaccharides consisting of α-1,4-linked α-D-glucopyranose units, for various drugs described above. Especially, drug delivery system consisting of combination systems of CyDs and functional materials such as dendrimer, liposome and PEG are introduced. Furthermore, the utilities of CyDs as APIs have been also described.

Expert opinion: To achieve the controlled release and/or targeting of low-molecular-weight drugs in systemic administration, the construction of novel CyDs and CyD the supramolecular system should be a useful approach because of the stable complexation of drugs with CyDs. In addition, the combination systems of CyDs and various carriers have the potential as advanced drug delivery systems for proteins and nucleic acids. Furthermore, CyDs have great potential as APIs for various diseases with few side effects, although the detailed mechanism, especially cellular uptake of CyDs, should be clarified.     

DPE对正丁基锂及聚苯乙烯活性种缔合体的影响

以具有较大空间位阻的1,1-二苯基乙烯（DPE）作为盖帽剂,使用核磁锂谱研究了正丁基锂（n-BuLi）经其盖帽以后缔合态的变化。结果表明:DPE的加入使n- BuLi中的超大缔合体解缔合成六元缔合体,但是不会影响原有的六元缔合体。由1,1-二苯基己基锂引发的苯乙烯本体聚合实验中存在转化率突变点。在突变点前的聚合产物中存在超分子结构,并随着聚合反应的进行逐渐解缔合;突变点过后超分子结构解缔合完全,反应加速进行。     

补阳还五汤的研究现状及其新药创制关键技术

补阳还五汤是目前治疗缺血性脑卒中疗效公认的著名方剂,该方每年有500余篇文献报道,包括药材资源、物质基础、药物制剂、药理作用、临床配伍应用及剂型改革等各方面,研究范围宽广而精深。但该方成分复杂,目前的网络药理拓扑学方法也很难阐明该方的物质基础及药理学作用机制。系统梳理补阳还五汤近10年相关研究工作,归纳总结药学、药理毒理学的研究概况,提出目前研究存在的问题及作为组分中药或天然复方药物创制研究亟待解决的关键问题;同时结合中药超分子"印迹模板"自主作用规律和化学定量网络谱学的研究,与目前主要治疗缺血性脑卒中药物的结构进行比较,拟对其物质基础、效应成分与作用靶点关联等关键技术进行探讨,为进一步开发出新组分中药或天然复方药物奠定基础。     

分枝型聚乙烯亚胺/寡核苷酸组装体的制备及细胞摄取研究

 目的制备分枝型聚乙烯亚胺(B-PEI)/反义寡核苷酸(ASON)超分子组装体(assembly)。方法分析(Zetasizer)组装体的粒径分布及Zeta电位,观察组装体的形态,单因素实验优化制备工艺条件。琼脂糖凝胶电泳分析组装体中ASON的包封率及组装体中ASON抗DnaseⅠ降解的能力。激光扫描共聚焦显微镜观察细胞的摄入情况。结果N/P(B-PEI含有氮原子的摩尔数/ASON含有磷原子的摩尔数)为4.0时制得粒径较小,Zeta电位较高的B-PEI/ASON超分子组装体,组装体呈球状,形态规则。N/P高于3.5时ASON的包封率接近100%,B-PEI/ASON超分子组装体荷载的有较强的抗酶解能力。共聚焦显微镜观察结果表明,组装体明显提高细胞对ASON的摄入率。结论B-PEI是一种组装能力强的多聚阳离子,B-PEI/ASON超分子组装体具有较好的物理化学性质,并能够显著增加细胞摄入率。     

Cadmium‐coordinated supramolecule suppresses tumor growth of T‐cell leukemia in mice

Cadmium is a toxic pollutant with occupational and environmental significance, due to its diverse toxic effects. Supramolecules that conjugate and decontaminate toxic metals have potential for use in treatment of cadmium intoxication. In addition, metal‐coordinating ability has been postulated to contribute to the cytotoxic effects of anti‐tumor agents such as cisplatin or bleomycin. Thiacalixarenes, cyclic oligomers of p‐alkylphenol bridged by sulfur atoms, are supramolecules known to have potent coordinating ability to metal ions. In this study, we show that cadmium‐coordinated thiacalix[4]arene tetrasulfate (TC4ATS‐Cd) exhibits an anti‐proliferative effect against T‐cell leukemia cells. Cadmium exhibited cytotoxicity with IC₅₀ values ranging from 36 to 129 μM against epithelia‐derived cancer cell lines, while TC4ATS‐Cd elicited no significant cytotoxicity (IC₅₀ > 947 μM). However, a number of T‐cell leukemia cell lines exhibited marked sensitivity to TC4ATS‐Cd. In Jurkat cells, toxicity of TC4ATS‐Cd occurred with an IC₅₀ of 6.9 μM, which is comparable to that of 6.5 μM observed for cadmium alone. TC4ATS‐Cd induced apoptotic cell death through activation of caspase‐3 in Jurkat cells. In a xenograft model, TC4ATS‐Cd (13 mg/kg) treatment significantly suppressed the tumor growth of Jurkat cells in mice. In addition, TC4ATS‐Cd‐treated mice exhibited significantly less cadmium accumulation in liver and kidney compared to equimolar cadmium‐treated mice. These results suggest that cadmium‐coordinated supramolecules may have therapeutic potential for treatment of T‐cell leukemia.     

美拉德反应研究现状及对中药炮制和制剂工艺研究方法的影响

美拉德反应主要是羰基和氨基化合物之间发生的非酶促反应,也称为羰氨反应,广泛存在于食品加工中。“药食同源”的中药在加工炮制与制剂过程中,存在比食品加工更复杂的美拉德反应,攸关中药炮制与制剂产品的质量,会改变中药炮制及制剂成品的色泽、药味,会产生具有药理活性的新成分,是中药制剂呈“黑精”的重要原因,将对中药炮制与制剂质量产生重要影响,应对目前中药炮制与制剂的研究方法进行补充完善。从美拉德反应机制、历程、影响因素与生理作用等方面进行综述,根据“药食同源”论探讨中药炮制与制剂过程的美拉德反应及工艺研究方法。     

当归补血汤煎煮过程发生美拉德反应的物质基础研究

中药的"黑"长期为人诟病,能影响产品色泽和气味的美拉德反应广泛存在于食品加工过程中,"与食同源"的中药加工过程中亦存在有其发生的合适条件,该反应的发生对中药复方物质基础研究具有重大影响,应展开中药加工过程中美拉德反应及其产物的研究。以当归补血汤为例,利用西北农林科技大学生命科学学院所创的中药系统药理学数据库查阅方中药材所含化学成分,并进行归类,分析加工过程中美拉德反应发生的可能性,探讨中药复方物质基础研究的新思路。     

基于超分子释药“物质单元”特征的中药缓控释制剂研究策略

中药缓控释制剂发展历史悠久,但现代中药缓控释制剂因中药化学成分复杂、物质基础不明确和质量评价体系不健全等限制了其发展。中药缓控释制剂设计与评价成为中药制剂领域亟需攻克的科学问题。中药制剂不能像化学药物仅依靠药物动力学与释药动力学方法建立剂型设计与评价研究方法。中药缓控释制剂可结合以超分子“印迹模板”整合成分群为释药“物质单元”来进行重构,关联谱动学与谱效动力学进行生物药剂学评价。因此,提出以谱动学与谱效动力学关联构建具超分子释药“物质单元”特征的中药缓控释制剂设计与评价生物药剂学研究方法,符合中药多成分整体受控、同步释放制剂制备指导原则。超分子释药的“物质单元”结合中药谱动学与谱效动力学建立中药缓控释制剂处方设计和多成分缓控释制剂评价标准体系,旨在为建立符合中药制剂特征的生物药剂学研究方法提供参考。