国内外交联聚维酮在直压工艺中的一致性研究

目的研究国内外不同厂家交联聚维酮(PVPP)在直压工艺中的应用性能,为仿制药一致性评价或新药研发中辅料的选择提供参考。方法选取进口和国产PVPP,对其物理化学性质、粉体学性质和制剂功能性质进行对比研究。结果不同厂家PVPP物理化学性质基本一致,但过氧化物指标略有差异;粉体学性质、制剂功能性质存在差异,尤其是流动性、溶胀性能差异明显,进而导致制备的片剂崩解溶出性能存在差异。结论完善和提高PVPP产品生产工艺是促使其应用性能一致的根本途径。     

来源差异羟丙甲纤维素关键质量属性的表征及对缓释片体外溶出的分析

不同来源药用辅料的质量差异影响粉体的成型结构从而导致最终产品的性能。本文考察了两个生产厂家(A厂家和B厂家)不同规格的羟丙甲纤维素(HPMC)在粒径分布、物理形貌、黏度和粉末物理质量属性差异以及对不同溶解度的模型药物氨茶碱、双氯芬酸钠和盐酸二甲双胍缓释片体外溶出的影响。结果表明, A和B厂家的HPMC在粒径大小、物理形貌、黏度以及粉末堆积性、流动性、可压性存在一定的差异,对后续制得片剂的硬度、脆碎度均有影响。A和B厂家的HPMC理化性质差异对不同载药缓释效果的影响不同,对易溶性的氨茶碱和盐酸二甲双胍释放度无明显影响,对难溶性的双氯酚酸钠释放度影响较大,并且B厂家的HPMC载药缓释效果优于A厂家,本研究的结果将为制剂处方选择合适的辅料提供理论参考。     

几种直压辅料的可压性及其对硬脂酸镁的敏感性

目的比较不同类型的直压辅料,微晶纤维素、预胶化淀粉、山梨醇、乳糖和3种二元混合辅料的可压性以及对硬脂酸镁的敏感性。方法采用压实性和压缩度的测定方法比较辅料的压片性质差异,分别采用不同浓度的硬脂酸镁含量,不同的物料混合时间。不同的辅料粒径大小比较辅料对硬脂酸镁的敏感率。结果含有塑性物料微晶纤维素类的辅料具有较好的可压性,而直压辅料对硬脂酸镁的敏感性强弱为：弹性辅料〉塑性辅料〉脆性辅料。结论不同类型辅料压片性质差异较大,可选择塑性辅料和脆性辅料组合的方式作为填充剂。     

药用辅料可溶性淀粉质量评价与研究

考察药用辅料可溶性淀粉的质量现状及存在问题,分析评价其质量属性。方法：按现行质量标准对5个厂家28批样品进行检验,并开展探索性研究试验,分析评价可溶性淀粉的质量差异。结果：按现行标准检验,2批样品不合格,占总数的7.1%。探索性研究发现,不同植物来源的可溶性淀粉存在差别。真菌毒素多存在于玉米来源的可溶性淀粉,含量较高,应关注其风险;可溶性淀粉的粉体流动性与粒度有关,马铃薯来源的可溶性淀粉颗粒较大,流动性比玉米和木薯来源的要好;动态水分吸附马铃薯来源的较高。结论：可溶性淀粉产品质量评价一般。通过质量评价与研究,为后续制剂研究提供参考,对于中药制剂的发展具有重要意义。     

药用辅料羧甲基纤维素钠物理表征参数研究

目的：对不同来源的羧甲基纤维素钠物理质量属性进行评价。方法：借鉴中药化学指纹图谱的概念,由松密度、振实密度、粒径＜50 μm百分比、粉体粒度分布宽度、粉体粒度分布范围、豪斯纳比、 休止角、颗粒间空隙率、卡尔指数、干燥失重、吸湿性11个指标作为羧甲基纤维素钠的物理表征参数, 并对其进行评价;构建了可压性参数(参数指数、参数轮廓指数和良好可压性指数),预测辅料的压缩特性。结果：不同来源或同一型号不同批次的羧甲基纤维素钠粉体学性质存在明显差异,可压性差异不大。结论：建立的羧甲基纤维素钠物理参数表征方法,可以用于评价不同来源粉体的质量一致性,为药用辅料质量评价和口服固体制剂处方开发及工艺控制提供新的思路。     

湿法制粒工艺参数对颗粒成型性的影响

目的通过对中药制粒过程中影响因素的考察为中药物料的制粒工艺设计提供参考。方法选取不同类型的中药物料,以颗粒得率和颗粒的粒径分布等为考察指标,对影响制粒结果较为显著的物料的吸湿性、润湿剂、干燥温度、辅料等因素进行试验分析。结果三七粉平衡吸湿量为12.905%,吸湿性最小,在60%的乙醇浓度下颗粒得率和20~60目的颗粒所占的比例较大,干燥温度、辅料等对其影响较小。其他含中药浸膏的粉末平衡吸湿量达到20%以上,黏性大,需要用80%的乙醇、干燥温度>50℃的条件下才能较好地制粒,加入适宜的辅料能显著提高颗粒得率,其中祛白复方浸膏粉加入预胶化淀粉后颗粒得率>80%。结论各类型中药粉末湿法制粒中物料性质、制备条件、辅料等过程参数对颗粒成型性有显著的影响。     

药用辅料对药物转运体影响研究现状

药用辅料是药物制剂中不可缺少的组成成分,其通常作为惰性物质影响药物制剂的崩解、溶出等过程。近年来,随着研究的深入,许多常见药用辅料如表面活性剂,稳定剂,润滑剂等均在体内外表现出一定的生理和药理活性。研究表明药用辅料可通过影响药物转运体和肝药酶,进而影响药物的体内处置过程,导致药动学和药效学行为发生改变,甚至引起临床药物不良反应的发生。药用辅料对常见ATP结合盒转运体,如P-糖蛋白转运体、乳腺癌耐药蛋白和多药耐药相关蛋白,以及溶质载体转运体,如有机阴离子转运肽,有机阴离子转运体,有机阳离子转运体和寡肽转运蛋白等多具有一定的抑制作用,也有少量报道辅料对转运体具有诱导作用,但其抑制和诱导机制尚未完全阐明。本文就目前药用辅料对药物转运体影响的研究及其可能存在的机制展开综述,以期为仿制药及创新药物制剂方面研发提供新思路。     

预混与共处理药用辅料应用进展及其质量控制要点探讨

目的 对预混与共处理药用辅料的生产工艺、应用进展和质量控制要点作最新概述和分析。方法 结合近年来国内外相关文献和药典标准进行介绍、评述和展望。结果 不同工艺制备的预混与共处理辅料性质不同，在药物制剂中的应用不同，从而使其质量控制要点也不尽相同。结论 预混与共处理辅料对于药物制剂的质量与疗效有着重要意义，需根据辅料特性完善能反映产品安全性、功能性与质量均一性的相关质量指标。     

医院中成药口服液、颗粒剂中蔗糖等辅料的相关调查分析

目的：通过调查医院中成药中口服液、颗粒剂两类剂型辅料使用的相关情况,以引起患者和生产厂家重视药品中添加的辅料,便于临床用药。方法：调查分析医院中成药中88种口服液、80种颗粒剂两类剂型辅料的使用情况及药物是否为甜味等的相关情况。结果：部分厂家对此重视,在其外包装和说明书上都进行了标注,但仍有许多厂家没意识到。88种口服液中有48种未标明辅料,占54.55%,含辅料最多的是蔗糖,占27.27%;80种颗粒剂中有48种未标明辅料,占60.00%,含辅料最多的是蔗糖,占25.00%。结论：药剂中添加辅料和在说明书中的填写等有待进一步完善、规范,以便临床用药。     

吲达帕胺片在2种介质中的溶出度考察

目的比较国内3厂家的吲达帕胺片在2种介质中的体外溶出度。方法采用紫外分光光度法测定3厂家吲达帕胺片的含量和在2种不同介质中的溶出度,利用f2因子法比较溶出曲线。结果在2种介质中两厂家的吲达帕胺片的溶出曲线差异较大,有1厂家的吲达帕胺片的溶出曲线具有相似性;在相同的溶出介质中不同厂家的吲达帕胺片的溶出曲线差异较大。结论不同厂家的辅料、生产工艺和生产规模导致了吲达帕胺片溶出度的差异。     

Evaluation of selected micronized poloxamers as tablet lubricants

The primary objective of this study was to compare the lubrication properties of micronized poloxamer 188 (Lμ trol micro 68^®) and micronized poloxamer 407 (Lμ trol micro 127^®) with certain conventional lubricants such as magnesium stearate and stearic acid. The secondary objective was to use these micronized poloxamers as water-soluble tablet lubricants in preparation of effervecsent tablets. The results showed that these micronized poloxamers have superior lubrication properties compared with stearic acid, with no negative effect on tablet hardness, friability, disintegration, or dissolution. Moreover, lubricant mixing time had no significant effect on tablet properties when poloxamers were used as lubricants. Effervescent tablets also were produced successfully using micronized poloxamers as lubricants. The micronized poloxamers had a better lubrication effect in compariason with that of water-soluble lubricant l-leucine.     

Evaluation of Selected Micronized Poloxamers as Tablet Lubricants

The primary objective of this study was to compare the lubrication properties of micronized poloxamer 188 (Lμ trol micro 68®) and micronized poloxamer 407 (Lμ trol micro 127®) with certain conventional lubricants such as magnesium stearate and stearic acid. The secondary objective was to use these micronized poloxamers as water-soluble tablet lubricants in preparation of effervecsent tablets. The results showed that these micronized poloxamers have superior lubrication properties compared with stearic acid, with no negative effect on tablet hardness, friability, disintegration, or dissolution. Moreover, lubricant mixing time had no significant effect on tablet properties when poloxamers were used as lubricants. Effervescent tablets also were produced successfully using micronized poloxamers as lubricants. The micronized poloxamers had a better lubrication effect in compariason with that of water-soluble lubricant l-leucine.     

Impact of solid-state properties on lubrication efficacy of magnesium stearate

The advent of high-speed tableting and slug capsule-filling machines has ushered in an increasingly important role for the lubricants to enact during manufacturing of dosage forms. Although lubricants help in processing, they can also adversely affect the flow properties and dissolution profile of the drug. It is thus critical to maintain a balance between these two behaviors, by understanding the underlying mechanisms and using their optimum concentration in the formulation. The source and manufacturing process inculcate different solid-state properties to magnesium stearate, the most commonly used lubricant, leading to variations in its lubrication efficacy. However, there has been no complete study relating the lubrication efficacy of magnesium stearate to various levels of solid state. Hence, this study was aimed at comprehensively scrutinizing the role of molecular, particle, and bulk level properties of solid state on the lubrication efficacy of magnesium stearate. A method based on net work done during compression using texture analyzer, was developed and validated to analyze its performance. Particle and bulk-level properties were studied using microscopy, particle size analysis, and particle surface area determination, and molecular level was characterized using thermal, spectroscopic, and crystallographic methods. Interplay of solid-state characteristics such as particle size, degree of agglomeration, and crystal habit were found to markedly influence the lubrication potential of magnesium stearate.     

Tablet lubricants I. Theory and modes of action

Tablet lubricants are essential components of all tablet formulations, since they prevent sticking of the tablets in the dies. Without tablet lubricants, tablets cannot be produced. A lubricant may be defined as a suitable material, a small amount of which interposed between two rubbing surfaces will reduce friction arising at the interface (Strickland et al., 1960; Komarek, 1967).A lubricant should also be capable of reducing wear on the rubbing surfaces (Silversher, 1969). To perform this function the lubricant must provide a film that will prevent solid-to-solid contact, and is easily sheared (Jentgen, 1971). Lubricants are added to tablet formulations primarily to reduce friction between the die wall and granules as the tablet is formed and ejected (Sprowl, 1974; Lachman et al., 1970). The other main activities attributed to a lubricant are: (a) prevention of sticking of granules to the tooling—anti-adherent; and (b) improvement of granule flow properties—glidant (Lachman et al., 1970). A given lubricant may provide one or more of these actions to varying degrees but no one material is highly efficient in all categories (Sperandeo and De Machi, 1976; Strickland, 1959; Sprowl, 1974). Accordingly combinations of lubricants are often selected to provide the necessary total lubricant effect (Maly, 1963; Munzel and Kogi, 1954). Careful selection is necessary since some lubricants may interact adversely when in combinations; for example, magnesium stearate and talc (De Blaey, 1972), although some authors have found that these two lubricants are compatible (Rubio, 1957; Esnaud et al., 1973). Although tablet lubricants have been used in practice for many decades it is only in the last 15 years that the lubrication process has been studied fundamentally.     

Hexagonal boron nitride as a tablet lubricant and a comparison with conventional lubricants

The objective of this study was to investigate the lubrication properties of hexagonal boron nitride (HBN) as a new tablet lubricant and compare it with conventional lubricants such as magnesium stearate (MGST), stearic acid (STAC), and glyceryl behenate (COMP). Tablets were manufactured on an instrumented single-station tablet press to monitor lower punch ejection force (LPEF) containing varied lubricants in different ratio (0.5, 1, 2%). Tablet crushing strength, disintegration time and thickness were measured. Tensile strength of compacted tablets were measured by applying a diametrical load across the edge of tablets to determine mechanical strength. The deformation mechanism of tablets was studied during compression from the Heckel plots with or without lubricants. MGST was found to be the most effective lubricant based on LPEF-lubrication concentration profile and LPEF of HBN was found very close to that of MGST. HBN was better than both STAC and COMP. A good lubrication was obtained at 0.5% for MGST and HBN (189 and 195N, respectively). Where COMP and STAC showed 20 and 35% more LPEF compare to that of MGST (239 and 288N, respectively). Even at the concentration of 2% COMP and STAC did not decrease LPEF as much as 0.5% of MGST and HBN. Like all conventional lubricants the higher the concentration of HBN the lower the mechanical properties of tablets because of its hydrophobic character. However, this deterioration was not as pronounced as MGST. HBN had no significant effect on tablet properties. Based on the Heckel plots, it was observed that after the addition of 1% lubricant granules showed less plastic deformation.     

市售3厂家甲硝唑注射剂的质量评价

目的:对市售3个厂家生产的9批甲硝唑注射剂进行质量比较,为临床选药提供参考。方法:参考《美国药典》、《英国药典》、《中国药典》、卫生部部颁标准和企业内控标准,选择临床有意义的指标进行比较,包括澄明度、pH值、不溶性微粒、渗透压、无菌、细菌内毒素、含量、有关物质等项目。对于药典未收载的注射用无菌粉末建立了以高效液相色谱法测定含量和有关物质的方法,经过验证能满足检测需要。结果:除注射用无菌粉末的渗透压、不溶性微粒较高外,所测各厂产品均符合《中国药典》的要求。结论:不同厂家的产品存在一定的质量差异,建议对甲硝唑注射用无菌粉末的质量项目加以注意并控制。     

Measuring the distribution of density and tabletting force in pharmaceutical tablets by chemical imaging

In pharmaceutical processing, the lubricant magnesium stearate (MgS) can affect compaction efficiency based on blend time and amount of MgS used. Insufficient lubrication produces intra-tablet variations in density. Consistent tablet density profiles and uniform compaction force, as managed by proper lubrication, are important for predictable performance. The current work demonstrates the utility of near-infrared (NIR) chemical imaging in measuring density variations within compacts, and relates these variations to tabletting forces as controlled by frictional properties and quantity of MgS. Lactose monohydrate was blended with 0%, 0.25%, or 1.0% MgS for 30s or 30min. Compacts were prepared of each blend, with compaction forces monitored by load cells. Frictional properties were measured by automated shear cell. NIR chemical images were collected for each tablet, and the density at each image pixel was calculated. Density distribution within compacts was well perceived within the NIR images. Uniformity of intra-tablet density was strongly dependent upon friction between powder and die walls: tablets with no MgS or 0.25% MgS were less uniform than tablets with 1.0% MgS. In addition, absorbance variations along tablet edges, reflective of corresponding density variation, agreed with force transmission within the tablet and final tablet ejection force. Chemical imaging techniques can be used to non-destructively assess density profiles of tablets, and confirm prediction of friction alleviation and improvement in force distribution during tabletting. The density profiles were both qualitative, showing differences in density profiles between tablets of different blends, and quantitative, providing actual density and tabletting force information within a single tablet. This work demonstrates that near-infrared chemical imaging can be an effective tool in monitoring not only the physical quality of pharmaceutical tablets, but the corresponding die forces controlling tabletting and final ejection.     

不同厂家复方丹参片物质组溶出度研究

目的 建立测定复方丹参片三组物质组（多指标物质组、指纹物质组、有效部位物质组）溶出度检测方法,并考察不同厂家复方丹参片物质组溶出度的情况。方法 按照《中国药典》2010年版二部附录XC溶出度测定第三法,以200 mL水为溶出介质进行溶出实验,并采用高效液相及紫外分别检测三组物质组的体外溶出度,绘制累积溶出曲线,且对各曲线进行相似因子的比较。结果 测定结果显示在60 min内除物质组一中丹参酮Ⅱ_A的溶出仅为23.41%外,其他物质组均能溶出95%以上,且不同厂家复方丹参片物质组溶出曲线相似因子f₂值大多小于50。结论 复方丹参片三组物质组的溶出度总体呈良好的相关性,故可作为质量检测的标准之一。不同厂家复方丹参片物质组的溶出度存在显著性差异,这可能是由于各厂家生产工艺不尽相同所致,因此建议中成药的质量控制应增加主成分或适宜物质组的溶出度检测。     

Coating and Density Distribution Analysis of Commercial Ciprofloxacin Hydrochloride Monohydrate Tablets by Terahertz Pulsed Spectroscopy and Imaging

Terahertz pulsed spectroscopy was used to qualitatively detect ciprofloxacin hydrochloride monohydrate (CPFX·HCl·H₂O) in tablets, and terahertz pulsed imaging (TPI) was used to scrutinize not only the coating state but also the density distribution of tablets produced by several manufacturers. TPI was also used to evaluate distinguishability among these tablets. The same waveform, which is a unique terahertz absorption spectrum derived from pure CPFX·HCl·H₂O, was observed in all of the crushed tablets and in pure CPFX·HCl·H₂O. TPI can provide information about the physical states of coated tablets. Information about the uniformity of parameters such as a coating thickness and density can be obtained. In this study, the authors investigated the coating thickness distributions of film-coated CPFX·HCl·H₂O from four different manufacturers. Unique terahertz images of the density distributions in these commercial tablets were obtained. Moreover, B-scan (depth) images show the status of the coating layer in each tablet and the density map inside the tablets. These features would reflect differences resulting from different tablet-manufacturing processes.     

过程分析考察不同厂家盐酸维拉帕米片的溶出度

目的：利用光纤溶出度过程分析方法,监测盐酸维拉帕米片的溶出度,反映不同厂家及同一厂家不同批号盐酸维拉帕米片间的质量差异.方法：采用《中国药典》盐酸维拉帕米片溶出度检测方法中的条件,利用光纤传感溶出度实时过程分析方法考察4个不同厂家及同一厂家5个不同批号盐酸维拉帕米片的溶出度.结果：过程溶出曲线反映每一药片溶出过程全部信息.4个不同厂家盐酸维拉帕米片的溶出度均符合《中国药典》2010年版规定,但溶出速度和曲线存在差异.结论：光纤溶出度过程分析原位实时反映了药物体外溶出特性,并真实地反映了同一药物的药片存在明显的差异.对考察体内外相关性、评价药品品质和评价生物等效性提供了有效途径.