EMA对药用辅料右旋糖酐新的安全性评价

欧洲药品局（EMA）于2018年11月发布了"人用药品辅料右旋糖酐的包装说明书资料"，该文件引用大量文献全面评价了右旋糖酐的安全性，特别指出含有右旋糖酐辅料的注射和吸入制剂的疫苗与药品，应在说明书中描述有关其过敏反应信息的新要求。介绍该文件的主要内容，期望对我国这类药品说明书的撰写和监管有所帮助。     

益气活血通络方下调TGF-β/ERK信号通路对蛛网膜下腔出血大鼠的神经保护作用

目的探讨益气活血通络方对蛛网膜下腔出血大鼠TGF-β/ERK信号通路的影响及神经保护作用。方法 SD大鼠随机分为假手术组,模型组,益气活血通络方5、10、15 g/kg组和尼莫地平组,除假手术组外,其余各组建立蛛网膜下腔出血模型大鼠,分组处理后,各组大鼠进行神经功能缺损评分;以伊文思蓝染料外渗实验检测大鼠血脑屏障通透性;以TUNEL染色检测大鼠脑皮质神经细胞凋亡情况;以酶联免疫吸附法(ELISA)检测大鼠血清肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)水平;以蛋白免疫印迹法检测大鼠脑皮质组织TGF-β/ERK通路相关蛋白TGF-β1、p-ERK/ERK表达情况。结果与假手术组相比,模型组大鼠神经功能缺损评分、伊文思蓝渗出量、TUNEL阳性细胞比例、血清IL-6、TNF-α水平、TGF-β1表达、p-ERK/ERK明显升高(P0.05)。与模型组相比,益气活血通络方5、10、15 g/kg组和尼莫地平组大鼠神经功能缺损评分、伊文思蓝渗出量、TUNEL阳性细胞比例、血清IL-6、TNF-α水平、TGF-β1表达和p-ERK/ERK水平明显降低(P0.05),且益气活血通络方各组呈剂量相关性,益气活血通络方15 g/kg组与尼莫地平组相比,各指标比较差异无统计学意义。结论益气活血通络方可下调TGF-β/ERK信号,保护蛛网膜下腔出血大鼠神经功能。     

A methodological evaluation and predictive in silico investigation into the multi-functionality of arginine in directly compressed tablets

The acceleration of solid dosage form product development can be facilitated by the inclusion of excipients that exhibit poly-/multi-functionality with reduction of the time invested in multiple excipient optimisations. Because active pharmaceutical ingredients (APIs) and tablet excipients present diverse densification behaviours upon compaction, the involvement of these different powders during compaction makes the compaction process very complicated. The aim of this study was to assess the macrometric characteristics and distribution of surface charges of two powders: indomethacin (IND) and arginine (ARG); and evaluate their impact on the densification properties of the two powders. Response surface modelling (RSM) was employed to predict the effect of two independent variables; Compression pressure (F) and ARG percentage (R) in binary mixtures on the properties of resultant tablets. The study looked at three responses namely; porosity (P), tensile strength (S) and disintegration time (T). Micrometric studies showed that IND had a higher charge density (net charge to mass ratio) when compared to ARG; nonetheless, ARG demonstrated good compaction properties with high plasticity (Y = 28.01 MPa). Therefore, ARG as filler to IND tablets was associated with better mechanical properties of the tablets (tablet tensile strength (σ) increased from 0.2 ± 0.05 N/mm² to 2.85 ± 0.36 N/mm² upon adding ARG at molar ratio of 8:1 to IND). Moreover, tablets’ disintegration time was shortened to reach few seconds in some of the formulations. RSM revealed tablet porosity to be affected by both compression pressure and ARG ratio for IND/ARG physical mixtures (PMs). Conversely, the tensile strength (σ) and disintegration time (T) for the PMs were influenced by the compression pressure, ARG ratio and their interactive term (FR); and a strong correlation was observed between the experimental results and the predicted data for tablet porosity. This work provides clear evidence of the multi-functionality of ARG as filler, binder and disintegrant for directly compressed tablets.     

Some Preformulation Studies of Pyruvic Acid and Other α-Keto Carboxylic Acids in Aqueous Solution: Pharmaceutical Formulation Implications for These Peroxide Scavengers

The purpose of this study is to assess some of the variables determining the aldol-like condensation of pyruvic acid (1), a peroxide scavenger, in aqueous solution to parapyruvic acid and higher oligomers. Its stability is compared to 3 other α-keto carboxylic acids, 2 with sterically hindered methylene groups alpha to the keto functionality (2-3) and phenylglyoxylic acid (4) with no methylene group. High-performance liquid chromatography, nuclear magnetic resonance, and liquid chromatography mass spectroscopy techniques are used in the kinetics and product analyses. 1 condensation is concentration dependent and base catalyzed above pH 7, consistent with the reaction mechanism proceeding through the attack of the fraction of the methylene group, alpha to the keto group, in its anionic form, at the keto group of a second molecule of 1. The major product is confirmed to be parapyruvic acid, but higher-order oligomers are also observed. All 3 of the other α-keto carboxylic acids 2-4 are considerably less reactive, with 4 being completely stable. Stable solutions of 1 can be prepared by the use of relatively dilute solutions maintained at slightly acidic pH values. 1 prevents the oxidation of methionine on addition of hydrogen peroxide.     

Investigation of Solid Dosage Form Components Interaction Using Orthogonal Techniques- Discovery of New Forms of Sodium Stearyl Fumarate

Physical or chemical interactions between drug product (DP) components can occur during manufacturing and/or upon storage; and may alter DP shelf life and performance. In this work a new Powder X-ray Diffraction (PXRD) peak was observed in DP under accelerated storage conditions. Due to the complex drug product matrix (including API, polymer, fillers, super disintegrant and lubricant), it was challenging to pinpoint the component(s) responsible for the new peak. In addition to PXRD, other orthogonal techniques including Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), Solid State Nuclear Magnetic Resonance (SSNMR) and Infrared (IR) spectroscopy were employed in this investigation to understand the root cause mechanistically. Specifically, multi nuclei SSNMR (¹H, ²³Na, ¹³C) was instrumental in delineating the components of the matrix. We identified the root cause to be an acid base reaction occurring in the DP, whereby sodium ion in sodium stearyl fumarate (SSF) is replaced by proton leading to SSF form conversion. We also identified commercially available SSF to be a hydrate that can dehydrate to an anhydrous form upon heating. In general, the same techniques can be used to investigate interactions of any multi component solid dosage forms.     

十二烷基硫酸钠中脂肪醇组成及含量的测定

目的：研究十二烷基硫酸钠中脂肪醇组成的测定方法。方法：采用加酸回流的前处理方法将烷基硫酸钠转化为脂肪醇;采用气相色谱直接进样,HP-5（30m×320μm,0.25μm）、RTX-5（30m×320μm,0.25μm）毛细管色谱柱;进样口温度为270℃,FID检测器温度为300℃;分流比为10：1;升温程序：80℃保持5min,以10℃?min-1的速率升至180℃,保持6min,以10℃?min-1的速率升至280℃,保持5min。采用面积归一化法计算各脂肪醇组成。结果：在选定的色谱条件下,辛醇、癸醇、十二烷醇、十四醇和十六醇5个组分可达到有效分离;精密度和稳定性的RDS均不大于2.0%,各脂肪醇的检出限均为2μg?mL-1。测定供试品15批,国产和进口十二烷基硫酸钠辅料样品其脂肪醇组成差别显著;分析纯和色谱纯十二烷基硫酸钠试剂其脂肪醇组成差别显著。结论：本方法适用于十二烷基硫酸钠中脂肪醇组成的测定,为十二烷基硫酸钠品种的标准完善、产品的控制和分型提供技术支撑。     

Applications of Polymers as Pharmaceutical Excipients in Solid Oral Dosage Forms

Over the last few decades, polymers have been extensively used as pharmaceutical excipients in drug delivery systems. Pharmaceutical polymers evolved from being simply used as gelatin shells comprising capsule to offering great formulation advantages including enabling controlled/slow release and specific targeting of drugs to the site(s) of action (the “magic bullets” concept), hence hold a significant clinical promise. Oral administration of solid dosage forms (e.g., tablets and capsules) is the most common and convenient route of drug administration. When formulating challenging molecules into solid oral dosage forms, polymeric pharmaceutical excipients permit masking undesired physicochemical properties of drugs and consequently, altering their pharmacokinetic profiles to improve the therapeutic effect. As a result, the number of synthetic and natural polymers available commercially as pharmaceutical excipients has increased dramatically, offering potential solutions to various difficulties. For instance, the different polymers may allow increased solubility, swellability, viscosity, biodegradability, advanced coatings, pH dependency, mucodhesion, and inhibition of crystallization. The aim of this article is to provide a wide angle prospect of the different uses of pharmaceutical polymers in solid oral dosage forms. The various types of polymeric excipients are presented, and their distinctive role in oral drug delivery is emphasized. The comprehensive know‐how provided in this article may allow scientists to use these polymeric excipients rationally, to fully exploit their different features and potential influence on drug delivery, with the overall aim of making better drug products.     

药物与辅料相互作用差异与结构特征的相关性研究

目的:探索药物的结构特征参数在预测药物与辅料相互作用中的规律。方法:采用两室渗透模型测定不同性质的21种药物的透膜速度，考察辅料对药物渗透的阻滞作用。通过计算药物的分子大小、电荷和形状相关的特征参数，考察药物特征参数与辅料相互作用的相关性。结果:根据12 h时9种辅料对21个药物渗透速度的影响，得到辅料对药物的阻滞率，将药物分为5类。第1类药物的阻滞率小于-25%，辅料表现出加速渗透作用；第2类药物对辅料不敏感，此类药物除非极性可及表面积（ASA_P）与偶极矩（dipole）参数外都与其他药物存在显著差异（Z=-0.704、-0.503，P=0.534、0.669）；第3类药物对表面活性剂敏感，此类药物的重原子数量（a_heavy）、分子范德华体积（vol）、正电荷可及表面积（ASA+）参数的差异显著（Z=-1.965、-2.211、 -2.111，P=0.047、0.024、0.035）；第4类对表面活性剂和崩解剂敏感，此类药物参数的差异不显著；第5类药物对多类辅料敏感，此类药物的负电荷可及表面积（ASA-）、ASA_P 、dipole 等参数的差异显著（Z=-2.836、-2.611、-2.462，P=0.003、0.007、0.012）。结论:分子大小、极性、形状指标能够较好预测药物与辅料相互作用关系。