聚丙烯瓶装氯化钠注射液中抗氧剂迁移量的测定

目的：采用HPLC法建立聚丙烯输液瓶中抗氧剂1010、抗氧剂1076、抗氧剂168、抗氧剂330的含量测定方法,以及抗氧剂向氯化钠注射液中迁移量的含量测定方法。方法采用DiamonsilTM-C18柱（250mm×4．6mm,5μm）为色谱柱,流动相为甲醇;检测波长为276nm,流速为1．0mL·min-1。结果抗氧剂1010、抗氧剂1076、抗氧剂168、抗氧剂330的质量浓度分别在7．49～299．44,7．78～311．25,8．57～342．61和7．35～294．12μg·mL-1范围内线性关系良好;抗氧剂1010、抗氧剂1076、抗氧剂168、抗氧剂330在聚丙烯输液瓶中及氯化钠注射液中的平均回收率为89．8％～98．8％,RSD为2．4％～4．9％。结论该方法准确、简便、快速,可用于抗氧剂1010、抗氧剂1076、抗氧剂168、抗氧剂330在聚丙烯输液瓶中及氯化钠注射液中迁移量的含量测定。     

聚丙烯输液瓶中抗氧剂含量及迁移量的测定研究

目的研究聚丙烯输液瓶中抗氧剂含量及迁移量的测定。方法采用高效液相色谱法对聚丙烯输液瓶中抗氧剂1010、330、168进行含量测定,以及3种抗氧剂在0.9%氯化钠注射液和5%葡萄糖注射液中的迁移量测定,色谱柱:Agilent ZORBAX-C 18(4.6×150mm×5μm);流动相:乙腈-四氢呋喃-水(63∶30∶7);流速:0.80mL·min^-1;柱温:35℃;检测波长:280nm;进样量:10μL。结果抗氧剂1010、330、168分别在0.016~4.85μg(r=1.0000)、0.014~4.83μg(r=1.0000)、0.0097~4.88μg(r=0.9999)线性良好;含量测定的平均回收率在90.15%~100.24%范围内,RSD均小于4.0%;迁移量测定的平均回收率在91.49%~100.10%,RSD均小于4.0%。结论本方法专属性强,灵敏度高,重现性好,可用于聚丙烯输液瓶质量及相容性评价。     

ICP-MS测定聚丙烯输液瓶中镁、铝元素的含量及提取迁移测定

摘 要 目的：建立聚丙烯输液瓶中镁、铝元素的含量及提取迁移试验中镁、铝含量的ICP-MS测定方法。 方法: 采用炽灼的前处理方法测定材料中镁、铝元素的含量。利用5种不同的提取介质,采用极端提取条件对聚丙烯输液瓶中镁、铝进行提取并测定。采用常用的3种注射液做加速试验,通过ICP MS来测定镁、铝元素迁移量。结果: 镁、铝元素在0.025～1.0 μg·mL^-1范围内呈现良好的线性（r分别为0.999 8,0.999 0）;镁、铝元素在聚丙烯输液瓶及提取迁移试验中平均回收率分别为93.77%105.0%,96.53%～103.89%;RSD分别为0.4%～6.9%,1.0%～7.1%（n=9）。结论:该方法准确、灵敏、操作简便,为聚丙烯输液瓶的安全性提供数据参考。     

HPLC法测定聚丙烯输液瓶中抗氧剂1010、抗氧剂1076、抗氧剂168、抗氧剂330的含量

目的:建立聚丙烯输液瓶中抗氧剂1010、抗氧剂330、抗氧剂1076、抗氧剂168的含量测定方法。方法:采用Venusil MPC18色谱柱(5μm,250 mm×4.6 mm);流动相:甲醇(100%);流速1.0 mL.min-1;柱温25℃;检测波长为274 nm。结果:抗氧剂1010、抗氧剂330、抗氧剂1076、抗氧剂168分别在0.1029～5.145 mg.mL-1、0.1065～5.325 mg.mL-1、0.1034～5.147 mg.mL-1和0.1040～5.200 mg.mL-1范围内线性关系良好,相关系数均为0.999。聚丙烯输液瓶提取方法中的抗氧剂1010、抗氧剂330、抗氧剂1076、抗氧剂168的平均回收率(n=9)分别为101.8%(RSD=1.6%),99.4%(RSD=1.5%)、88.5%(RSD=4.5%)及86.5%(RSD=5.3%)。结论:该方法灵敏快速,操作简便,重复性好,可用于聚丙烯输液瓶中抗氧剂的质量控制。     

更昔洛韦氯化钠注射液与聚丙烯输液瓶的相容性评价

目的 探讨聚丙烯输液瓶的安全性及其与更昔洛韦氯化钠注射液的相容性。方法 建立抗氧剂、抗酸剂的检测方法,通过提取试验、迁移试验和吸附试验研究注射液与包装材料的相互作用,根据添加剂的毒理学研究资料评价其相容性。结果 抗氧剂及其氧化物和降解物采用HPLC测定,报告限为0.098~0.98 μg·mL^-1;抗酸剂中的镁、铝元素采用AAS测定,报告限为0.025~0.1 μg·mL^-1。各添加剂的分析评价阈值为0.83~117 μg·mL^-1,均高于各自报告限。提取和迁移试验中注射液中未检出添加剂成分,也未见API被明显吸附。结论 聚丙烯输液瓶浸出物含量低于每日允许最大暴露量,对更昔洛韦氯化钠注射液没有吸附作用,相容性好。     

HPLC考察妥布霉素滴眼液中11种抗氧剂

目的 建立妥布霉素滴眼液中11种抗氧剂含量的测定方法,考察包材中抗氧剂向药液的迁移。方法 采用以聚合物基质吸附剂为填料的固相萃取小柱,对样品中的抗氧剂进行富集。利用液相色谱建立妥布霉素滴眼液包材中抗氧剂BHA、抗氧剂XH-245、抗氧剂BHT、抗氧剂1790、抗氧剂LK-1081、抗氧剂702、抗氧剂3114、抗氧剂1010、抗氧剂330、抗氧剂1076、抗氧剂168含量的方法,进行方法学验证。50℃放置5天和10天考察抗氧剂在滴眼液中的迁移情况。结果 各抗氧剂峰均分离良好,空白辅料无干扰,线性范围、准确度、精密度、耐用性均符合要求。50℃放置5天和10天后,药液中抗氧剂含量有不同程度的提高。结论 所建立的方法灵敏、快速、准确、重复性好,经验证,可用于包材中11种抗氧剂向妥布霉素滴眼液中迁移量的监测。包材中的抗氧剂会向药液中迁移。     

聚丙烯输液瓶高压蒸气灭菌法

本文介绍了聚丙烯 J-300作为输液容器采用高压蒸汽灭菌法,使之达到药品的消毒灭菌,而不影响药液质量的要求又解决了输液瓶的变形和爆破等问题。     

国产粒料制与进口粒料制聚丙烯输液瓶的质量对比评估初探

对国家评价性抽检的16批聚丙烯输液瓶进行细胞毒性、不溶性微粒、易氧化物、正己烷不挥发物、透光率、雾度以及提取和溶出的有关物质进行检测，以评估国产粒料和进口粒料制聚丙烯输液瓶的质量差异。结果表明，国产粒料和进口粒料制瓶的易氧化物和不溶性微粒均无显著性差异，正己烷不挥发物含量分别为(118.0±30.7)和(137.1±48.2)mg。在抗氧剂和除酸剂的添加量上，国产粒料和进口粒料制聚丙烯输液瓶控制在了相同级别，分别约为0.05%和0.25%。从小分子挥发物测定结果推测国产粒料和进口粒料使用了相同的聚丙烯聚合催化剂。以现有项目分析，国产粒料制和进口粒料制聚丙烯输液瓶的质量控制在了相同水平，但后续仍需进一步拓展评价项目以进行更全面的质量对比。     

外用液体药用聚氯乙烯瓶中添加剂的含量和迁移量研究

目的 研究外用液体药用聚氯乙烯瓶中添加剂在复方黄松洗液中的迁移量,及对药品质量的影响。方法 分别采用HPLC、GF-AAS、HS-GC/MS测定外用液体药用聚氯乙烯瓶中增塑剂邻苯二甲酸二辛酯(DOP)、热稳定剂硫醇甲基锡、增强剂甲基丙烯酸甲酯-丁二烯-苯乙烯共聚物(MBS)中苯乙烯单体的含量和在复方黄松洗液中的迁移量。结果 建立外用液体药用聚氯乙烯瓶中多种添加剂在复方黄松洗液中迁移量的测定方法。结论 所检测的添加剂在复方黄松洗液中的迁移量均远低于相关标准的限度。     

HPLC法测定硫酸庆大霉素滴眼液中8种抗氧剂

摘要：目的 建立硫酸庆大霉素滴眼液中8种抗氧剂含量的HPLC测定方法,考察包材中抗氧剂向药液的迁移情况。方 法 采用Inertsil ODS-3色谱柱(4.6 mm×100 mm,3 μm);检测波长：200 nm;流速：1.0 mL/min;柱温：35℃;进样量：10 μL;流 动相为水-乙腈,梯度洗脱。采用正己烷对样品中的抗氧剂进行提取,建立硫酸庆大霉素滴眼液中抗氧剂BHA、抗氧剂XH-245、 抗氧剂BHT、抗氧剂3114、抗氧剂1010、抗氧剂330、抗氧剂1076和抗氧剂168含量的测定方法,并进行方法学验证,同时测定 了企业提供的原辅料和包材中8种抗氧剂的含量,并对制剂进行了影响因素考察试验。结果 8种抗氧剂之间的分离度良好,均 在0.3~30 μg/mL 浓度范围内线性关系良好(r≥0.9994)。方法精密度、重复性、回收率、稳定性均符合有关规定。硫酸庆大霉素 滴眼液、原辅料中均未检出8种抗氧剂,包材中仅检出抗氧剂BHT,影响因素试验表明样品中8种抗氧剂的迁移不受高温、高湿 和强光照射的影响,表明本品由包材中抗氧剂迁移带来的安全风险较低。结论 所建立的方法灵敏、快速、准确、重复性好, 提取方法简单,可用于硫酸庆大霉素滴眼液中8种抗氧剂迁移情况的监测和溯源。     

4-Hydroxynonenal – A Toxic Leachable from Clinically Used Administration Materials

Introduction: The migration of chemicals from processing materials into biopharmaceuticals can lead to various problems. Leachables from administration materials, with no possibility of further clearance, are of particular concern. Released chemicals can be toxic or react with formulation components, thereby impacting product safety. Therapeutic proteins, which are susceptible to chemical modifications, have highest risk to be affected.Aim: The aim of this study was to identify a previously unknown leachable compound from clinical administration sets, which was present above the applied generic safety threshold.Methods: Extracts of commonly used clinical administration sets were analyzed using a recently established specific assay allowing the identification and quantification of the α,β-unsaturated aldehyde 4-hydroxynonenal (HNE) in a drug product surrogate solution. HNE was quantified after derivatization with 2,4-dinitrophenylhydrazine (DNPH) and liquid extraction of the formed hydrazone by LC-MRM analysis.Results: Potentially genotoxic HNE was a leachable compound from all tested administration sets, in parts exceeding safety thresholds for genotoxicants. The HNE-releasing polymer was identified as PVC.Conclusion: Clinical administration sets should be, like manufacturing materials and container closure systems, in the focus of routine leachables studies. Manufacturers of clinical administration sets should show responsibility to avoid the presence of safety concerning chemicals, like HNE.     

水溶性添加剂对聚乳酸-聚乙烯醇酸共聚物基质释药动力学的影响

目的选择不同亲水性及空间构型的添加剂，研究其对聚乳酸-聚乙烯醇酸共聚物(poly lactic-co-glycolic acid, PLGA)药物释放动力学的影响，为心血管药物局部用药控释制剂的研究提供理论依据。方法用抗细胞增生药物2-氨基色酮(U-86)作为代表性药物，用溶剂浇铸和压膜结合的方法制备药物/PLGA/添加剂双层膜，在37 ℃磷酸缓冲液中测定体外药物释放并用扫描电镜观察表面形态。结果水溶性添加剂明显地提高了U-86的释放率，并转变为近似的单阶段模式。药物释放速率与基质的失重速率非常吻合。水溶性添加剂的基质在水中形成高度多孔的结构。结论添加剂的水溶性、分子量大小及空间构型等对于聚合物基质的孔隙结构具有决定性作用，而这些孔隙结构的特征又影响着药物释放机制以及释放动力学模式。     

Identification of an Adduct Impurity of an Active Pharmaceutical Ingredient and a Leachable in an Ophthalmic Drug Product Using LC-QTOF

Impurity investigations are important in pharmaceutical development to ensure drug purity and safety for the patient. The impurities typically found in drug products are degradants or reaction products of the active pharmaceutical ingredient (API) or leachable compounds from the container closure system. However, secondary reactions may also occur between API degradants, excipient impurities, residual solvents, and leachables to form adduct impurities. We hereby report an adduct-forming interaction of API (moxifloxacin) with a leachable compound (ethylene glycol monoformate) in moxifloxacin ophthalmic solution. The leachable compound originated from a low-density polyethylene bottle used in the packaging of drug products. The adduct impurity was tentatively identified as 1-cyclopropyl-6-fluoro-7-(1-(2-(formyloxy)ethyl) octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (C₂₄H₂₈FN₃O₆, MW = 473.19621) using accurate mass LC-QTOF analysis. The mass accuracy error between the theoretical mass and the experimental mass of an impurity was found to be 0.2 ppm. An MS/MS analysis was utilized to provide mass spectrometry fragments to support verification of the proposed structure.     

Recommendation of Single Time Point Leachables Testing for Lyophilized Biotechnology Products Stored in Rubber Stoppered Glass Vial Systems

As a popular format of primary container closure systems, rubber stoppered glass vials are often used in storing and delivering lyophilized and liquid formulated therapeutic protein products. Assessing extractables and leachables from rubber stoppered glass vial systems is required to ensure drug product quality and patient safety. Lyophilized biopharmaceutical drug products are generally considered as less impacted by leachables during storage and transportation than the liquid formulated drug products. Single time point leachables testing for lyophilized biopharmaceutic drug products is recommended. The recommendation is based on our published comprehensive leachable data collected at multiple time points for five lyophilized drug products stored in different rubber stoppered glass vial systems with additional supporting comprehensive leachable data collected for nineteen liquid formulated drug products stored in different syringe and vial systems, which is statistically and scientifically sound. The leachable data evaluated herein were generated based on a holistic approach which ensured successful qualification of different vial systems as primary containers and delivery systems for various biotherapeutic products. The organic and elemental impurities of the leachable profiles of all the twenty-four drug product samples were below the limit of detection at all the time points. For lyophilized drug products, product surface interaction during storage time and shipping is unlikely. Timing of single time point leachables testing can be flexible. Performing leachables testing at one-year time point is recommended as it allows for enough time for chemicals to leach out from product contact surfaces into drug products and thus provides the earliest opportunity for mitigation of unpredicted leachables of concern, if any. However, testing at other stability time points can also be considered depending on the development strategy of the sponsor. Therefore, recommendation of single time point leachables testing for lyophilized drug products stored in rubber stopped glass vials at an appropriate time point is a scientifically sound approach.     

可提取物与浸出物的毒理学风险评价策略

生产用一次性组件与容器密闭系统中的可提取物和浸出物（extractable&leachable，E&L）安全性评估是药品上市申报的重要环节之一。E&L的毒理学评价是其安全性评估的重点内容，目前尚未有E&L毒理学评价的系统性指导法规，特别是多个毒理数据来源的合理选择，以及毒理数据缺乏的问题，是E&L安全性评估的难点。基于E&L安全性评估，重点介绍了安全阈值的确定策略，包括每日允许最大暴露量和日摄入量计算、多层次毒理学关注阈值的选择；相关毒理数据的选择和评价，包括毒理学观测指标和试验选择，以及关键毒性效应的选择。并结合实际事例，为解决E&L研究中安全性评估问题提供新思路，为药品研发及生产企业提供借鉴。     

尼索地平缓释胶囊工艺处方的调整

目的:调整尼索地平缓释胶囊处方,确保药物稳定释放。方法:加入硬脂酸镁协同羟丙甲纤维素(HPMC)对药物释放进行调控。结果:处方量0.5%的硬脂酸镁可达到理想效果。结论:尼索地平缓释胶囊释药稳定,工艺重现性良好。     

Safety assessment of butylated hydroxyanisole and butylated hydroxytoluene as antioxidant food additives.

Butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are widely used antioxidant food additives. They have been extensively studied for potential toxicities. This review details experimental studies of genotoxicity and carcinogenicity which bear on cancer hazard assessment of exposure to humans. We conclude that BHA and BHT pose no cancer hazard and, to the contrary, may be anticarcinogenic at current levels of food additive use.     

Linking extractables and leachables in container/closure applications

Establishing a link between extractables and leachables may be necessary to understand, interpret, assess, quantify, or control the interaction between a drug product and its container/closure system. This paper considers the various factors that affect the rigor with which such a linkage is established and justified. Such an assessment considers the origin and/or genesis of the leachable or extractable, enumerates situations in which extractables/leachables linkages are useful, ties such situations to the drug product's lifecycle, defines a hierarchy of linkages based on the rigor with which the linkages are established and justified, and establishes guidelines for how to determine what kind of linkage is appropriate for certain circumstances and situations. Additionally, this paper gives several examples of linkages relevant to flexible plastic drug product containers.     

Antioxidant treatment for lung diseases

The lung is constantly exposed to endogenous (i.e., recruitment of inflammatory cells) as well exogenous sources of oxidative stress (i.e., oxygen, air pollution and tobacco smoke and particulate matter) and, therefore, is well-equipped with multiple antioxidant mechanisms. Increased pulmonary exposure to oxidative sources and/or reduced antioxidant defences may lead to an imbalance known as oxidative stress. The pulmonary effects of this oxidant–antioxidant imbalance can vary from progressive airway remodelling to overwhelming lung injury, depending on its severity and chronicity. This review will discuss the main sources for oxidation in the lung and how they relate to pulmonary antioxidant mechanisms, together with the mechanisms by which oxidative stress leads to an amplification of the inflammatory cascade, as well as the development of antioxidant mechanisms. This section will be followed by an in-depth discussion of each class of antioxidants, including current therapeutic uses and potential clinical applications related to lung diseases. Antioxidant treatment has had limited therapeutic success even for lung disorders, in which oxidative stress is known to play an important role. Potential reasons to explain antioxidant limitations will be discussed in the Expert opinion section of this review.