新药研发中药物盐型的筛选策略

在新药研发早期阶段,将候选化合物成盐是一种重要手段,可改善候选化合物的理化性质,如溶解度、结晶度、吸湿性、熔点和固态稳定性等.药物盐型的筛选首先从反离子的选择开始,然后筛选结晶条件制备其相应的盐型,最后根据结晶度、熔点、吸湿性、物理化学稳定性和晶型等因素确定药物的最终盐型.药物盐型的筛选对选择具有适宜药学性质的固态剂型有重要的指导作用.     

成盐药物的研究与开发

成盐是改善药物分子理化性质、提高其成药性的有效手段之一,可改变药物的溶解性,改善其依从性,提高其稳定性,减少其不良反应,而且在药物开发中,还可利用成盐来延长药物的专利保护期或规避其专利保护。在成盐药物的研制过程中,应综合考虑用于成盐的酸或碱的pKa值和安全性以及成盐后的给药途径与剂型、同离子效应等因素,而关键在于选择合适的盐型。综述药物成盐的优点和成盐药物研制的要点。     

有机酸盐药物的临界相对湿度与溶解度关系的初探

目的 用有机酸盐探究药物的临界相对湿度与溶解度之间的关系.方法 用重量法或滴定法测定药物的饱和溶解度.用测定与药物饱和溶液呈平衡的空气相对湿度来测定药物的临界相对湿度.结果 在高湿度范围内,用拉乌尔定律计算的临界相对湿度值与测定值基本符合;在低湿度范围内,用扩展的Wilson模型校正后的临界相对湿度值与测定值基本符合.结论 有机酸盐药物的饱和溶解度与临界相对湿度之间有密切的联系,可将溶解度用于预测药物临界相对湿度.     

药物晶型及其质量控制

介绍药物晶型的基本概念,综述药物的多晶型对药品质量的影响,列举药物晶型的控制方法以及这些方法在药品质量标准中的应用,为制订药品晶型研究指导原则提供参考。     

海洛因及其盐型的红外光谱分析

目的:探讨红外光谱技术在海洛因及其盐型分析中的作用。方法:采用红外光谱技术对海洛因样品进行谱图采集,并对海洛因及其盐型的红外谱图进行谱图解释和分析。结果:应用红外光谱技术,可以很好地鉴别海洛因及其盐型。结论:红外光谱技术可用于海洛因及其盐型的区分。     

替格瑞洛新盐型的制备、表征及溶解性能研究

为改善替格瑞洛溶解性差的问题,采用悬浮液法和加液研磨法制备得到替格瑞洛-3,5-二硝基苯甲酸、替格瑞洛-吡嗪酰胺、替格瑞洛-D-脯氨酸、替格瑞洛-L-脯氨酸4种新盐型物质。利用粉末X-射线衍射法、红外光谱法、差示扫描量热法、核磁共振波谱法和元素分析技术对盐进行表征,分析各分子间盐键等作用力。使用高效液相色谱法测定原料药和盐在pH 1.2和pH 6.8缓冲溶液中的平衡溶解度。替格瑞洛与3,5-二硝基苯甲酸、吡嗪酰胺、D-脯氨酸、L-脯氨酸均以1∶1比例成盐,除替格瑞洛-D-脯氨酸外,其余3种盐型物质在pH 1.2缓冲溶液中平衡溶解度均有所提高,其中,替格瑞洛-3,5-二硝基苯甲酸的溶解度与原料药相比提高了1.7倍。该成盐技术方法简单,能够有效提高替格瑞洛的溶解度。     

抗2型糖尿病药物作用靶点的研究进展

糖尿病发病机制比较复杂，与多种酶和受体有着密切关联。近年来研究的主要作用靶点有：与胰岛素分泌相关的钙通道和ATP敏感性钾通道、与胰岛素增敏相关的过氧化物酶增殖体激活受体(PPAR)、胰岛素信号通路中的关键酶及细胞因子(如STATS)、葡萄糖代谢中的关键酶等。目前，用于临床治疗糖尿病的药物存在多种缺陷，因此通过不断发现和研究糖尿病的相关药物靶点，并以此进行新药开发是探索糖尿病治疗的主要方向。     

多晶型药物的生物利用度研究概况

概述药物的不同多晶型现象，分析归纳多晶型药物在生物利用度方面的异同，同时探讨多晶型药物的不同自由能、溶解度和溶出度对生物利用度的影响。     

pH-敏感型水凝胶在多肽和蛋白质药物给药系统研究中的应用

目的:介绍pH-敏感型水凝胶在多肽和蛋白质药物给药系统研究中的应用.方法:检索分析文献资料,并进行综合、整理与归纳.结果:综述了pH-敏感型水凝胶用作多肽和蛋白质药物给药系统在材料选择、制作方法、具体应用研究等方面的进展.结论:pH-敏感型水凝胶非常适合用作多肽和蛋白质药物给药系统,值得并有待进行广泛和深入的研究.     

药物多晶型与固体制剂的关系研究进展

目的：介绍药物多晶型与固体制剂的关系研究的进展情况,方法：通过参考90年代国内外有关文献,综述药物多晶对固体制剂的稳定性,溶出度,生物利用度等性质的影响,固体制剂的工艺过程,如干燥,粉碎,研磨,压片等亦会影响药物多晶型的特性,结果：药物多晶型与固体制剂相互影响,结论：药物多晶型研究与固体制剂的研究意义深远。     

Conformational changes of bovine plasma albumin prior to the salting-out of the protein in concentrated salt solution

By working at very low protein concentration (ca. 0.003%), it is possible to measure tryptophyl fluorescence intensity at 350nm (F₃₅₀) of bovine plasma albumin (BPA) as a function of pH under precipitating conditions (acidic concentrated salt solutions). Under such conditions, distinct changes in F₃₅₀ were seen before the starting of precipitation of BPA and no further changes in F₃₅₀ over the precipitating pH range. Comparison of pH-profiles monitored by F₃₅₀ with those by solubility in the presence of various salts at various concentrations indicated that the change of solubility is observed after definite changes in conformation of the protein.     

Crystalline Form Information from Multiwell Plate Salt Screening by Use of Raman Microscopy

Purpose The purpose of this study was to establish a useful methodology, possibly providing information on the stoichiometry of pharmaceutical drug salts obtained from salt screening by using a multiwell plate and a Raman microscope. Methods Tamoxifen salt screening was conducted with monobasic and polybasic acids on 96-well quartz plates with a Raman microscope. Appearance and crystalline forms of salts prepared on 96-well plates were observed by polarizing light microscope and Raman microscope, respectively. Based on the results of the salt screening, tamoxifen citrate and fumarate salts were prepared on a large scale. The salts prepared were characterized by powder X-ray diffractometry (PXRD) and ion chromatography. Results The results of the multiwell salt screening indicated that tamoxifen has a tendency toward the formation of mono salt as opposed to hemi salt with polybasic acid, and that most of tamoxifen salts gave several potential polymorphic forms. PXRD patterns of scaled-up tamoxifen citrate and fumarate salts suggested that the same crystalline form was obtained from the binary mixture regardless of molar ratios of 2:1 or 1:1 (tamoxifen/acid). The crystalline forms obtained were tamoxifen monocitrate and monofumarate salts as measured by ion chromatography. Conclusions Salt screening on multiwell plates with a Raman microscope provided novel insight into the characteristics prediction of the stoichiometrical salts in addition to potential polymorph information. Based on the stoichiometrical information of salts, the amount of compound and time required for crystalline form selection of drug candidates would be significantly reduced.     

Predictive Screening Tools Used in High-Concentration Protein Formulation Development

This review examines the use of predictive screening approaches in high-concentration protein formulation development. In addition to the normal challenges associated with protein formulation development, for high-concentration formulations, solubility, viscosity, and physical protein degradation play major roles. To overcome these challenges, multiple formulation conditions need to be evaluated such that it is desirable to have predictive but also low-volume and high-throughput methods in order to identify optimal formulation conditions very early in development without time- and material-consuming setups. Many screening techniques have been reported for use in high-concentration formulation development, but not all fulfill the requirements mentioned previously. This review summarizes the advantages and disadvantages of different screening approaches currently used in formulation development and the correlation of predictive data to protein solubility, viscosity, and stability at high protein concentrations.     

Optimization of Primary Drying in Lyophilization During Early-Phase Drug Development Using a Definitive Screening Design With Formulation and Process Factors

Development of optimal drug product (DP) lyophilization cycles is typically accomplished via multiple engineering runs to determine appropriate process parameters. These runs require significant time and product investments, which are especially costly during early phase development when the DP formulation and lyophilization process are often defined simultaneously. Even small changes in the formulation may require a new set of engineering runs to define lyophilization process parameters. To overcome these development difficulties, an 8 factor definitive screening design, including both formulation and process parameters, was executed on a fully human monoclonal antibody DP. The definitive screening design enables evaluation of several interdependent factors to define critical parameters that affect primary drying time and product temperature. From these parameters, a lyophilization development model is defined where near optimal process parameters can be derived for many different DP formulations. This concept is demonstrated on a monoclonal antibody DP where statistically predicted cycle responses agree well with those measured experimentally. This design of experiments approach for early phase lyophilization cycle development offers a workflow that significantly decreases the development time of clinically and potentially commercially viable lyophilization cycles for a platform formulation that still has variable range of compositions.     

基于细胞模型的高通量筛选技术在药物研发中的应用进展

发现一种具有临床疗效的新药,通常需要对成千上万种化合物进行逐一筛选,获得目标化合物后,再对其进一步深入验证,这个过程工作量大且周期长.高通量高内涵筛选技术的出现缩短发现目标化合物的时间,选用适当的生物模型提高了目标化合物的验证结果的准确性.本文主要对干细胞生物模型、CRISPR/Cas9基因编辑细胞模型及3D细胞培养模...     

确定性筛选设计优化奥氮平片的处方和工艺

目的 研究奥氮平片处方和制备工艺。方法 用HPLC测定奥氮平片的奥氮平和有关物质含量,用光纤药物溶出度实时测定仪测定溶出曲线,用确定性筛选设计优化奥氮平片的处方和工艺。结果 微晶纤维素加入方式（内加或外加）和羟丙基纤维素用量对颗粒大小分布有显著影响,羟丙基纤维素用量和制粒搅拌速率对溶出曲线相似因子f₂有显著影响。经过优化得到的奥氮平片处方为奥氮平2.5%、乳糖78%、微晶纤维素10%（内加）、羟丙基纤维素4%、交联聚维酮5%、硬脂酸镁0.5%;制粒工艺参数：切割速度30 rps、搅拌速度3 rps、制粒时间5 min。结论 确定性筛选设计适用于奥氮平片处方和制备工艺的筛选和优化,根据确定性筛选设计确定的处方和制备工艺所制的奥氮平片,其溶出曲线与参比制剂相似,其含量均匀度和有关物质均符合中国药典2015年版标准。     

Experimental and Computational Screening Models for Prediction of Aqueous Drug Solubility

Purpose. To devise experimental and computational models to predict aqueous drug solubility. Methods. A simple and reliable modification of the shake flask method to a small-scale format was devised, and the intrinsic solubilities of 17 structurally diverse drugs were determined. The experimental solubility data were used to investigate the accuracy of commonly used theoretical and semiexperimental models for prediction of aqueous drug solubility. Computational models for prediction of intrinsic solubility, based on lipophilicity and molecular surface areas, were developed. Results. The intrinsic solubilities ranged from 0.7 ng/mL to 6.0 mg/mL, covering a range of almost seven log₁₀ units, and the values determined with the new small-scale shake flask method agreed well with published solubility data. Solubility data computed with established theoretical models agreed poorly with the experimentally determined solubilities, but the correlations improved when experimentally determined melting points were included in the models. A new, fast computational model based on lipophilicity and partitioned molecular surface areas, which predicted intrinsic drug solubility with a good accuracy (R ²of 0.91 and RMSE_tr of 0.61) was devised. Conclusions. A small-scale shake flask method for determination of intrinsic drug solubility was developed, and a promising alternative computational model for the theoretical prediction of aqueous drug solubility was proposed.     

Fluorescence-Based High-Throughput Salt Screening

The present study reports a high-throughput screening method for the salt formation of amine-containing active pharmaceutical ingredients (APIs) based on fluorescence measurements. A free form amine API was alkynylated by a solid–vapor reaction using propargyl bromide, and a fluorescent compound was produced by a subsequent reaction using 9-azidomethylanthracene. In contrast, salts were inert to propargyl bromide; thus, no fluorescence was observed. Samples for salt screening were prepared by grinding haloperidol with various counter acids, and these mixtures were derivatized in a 96-well microplate to determine whether the salt formation had occurred between haloperidol and the counter acids. Samples that turned into fluorescent and nonfluorescent were confirmed to be free form and salt form, respectively, using powder X-ray diffraction and Raman spectroscopy. In conclusion, our method adequately functions as an indicator of the salt formation of amine APIs. Further, this method allows for the rapid evaluation of the salt formation of APIs using 96-well microplates without the need for special reagents or techniques; thus, it is valuable for the discovery of an optimal salt form of newly developed amine APIs in the pharmaceutical industry.     

铋盐类药物的研发及在Hp根除治疗中的应用

目的 使广大医务人员对铋盐类化合物药物的作用机制、临床应用、发展前景有一个深刻的理解和认识,使该类药物在胃肠疾病的治疗中发挥更大的作用.方法 在查阅大量国内外文献的基础上,对胃肠疾病的发病机制、临床常用药物及治疗方案、铋盐类化合物及联合用药方案,以及新的铋盐类药物的研发和在Hp根除治疗中的应用进行陈述.结果与结论 随着对胃肠疾病发病机制研究的深入,根除Hp的药物及治疗方案层出不穷,但由于Hp对抗生素的耐药菌株不断出现,导致抗生素三联、四联治疗的失败.铋盐类化合物是杀灭Hp的安全有效药物,新的铋盐类化合物及制剂不断研发并在临床上推广应用,在胃肠疾病的治疗中发挥了重要作用.     

人参皂苷类化合物水溶性提升方法的研究进展

水溶性是人参皂苷类化合物关键的物理化学性质,也是其药物研发过程中极为重要的问题之一。人参皂苷类药物具有良好的水溶性会有助于药效的发挥和药动学性质的改善,所以其水溶性提升方法的研究引起了人们的关注。通过查阅整理近十年的国内外文献,对人参皂苷类化合物水溶性提升的方法进行了综述,包括成盐、引入极性基团、降低不饱和度、氨基酸酯化、糖基化、二元酸酯化等化学方法,以及制成微球以及自微乳释药系统等物理化学方法,为该类化合物的进一步研发利用提供参考。