双螺杆制粒技术及其在药物制剂领域中的应用

双螺杆制粒(twin screw granulation,TSG)是制药行业新兴的一种连续湿法制粒技术,目前在国内制药行业报道较少。本文系统介绍了双螺杆挤出制粒机的结构及工作原理,制剂的处方特点及工艺参数对所得颗粒的形状、粒径、孔隙率等性质的影响,并综述了目前国内外TSG的发展现状以及面临的机遇和挑战。虽然TSG技术仍存在一些问题,但是其独特的工艺过程在连续制造生产模式中显示出巨大的优势和潜力。TSG技术的这些优势将会吸引更多研究者的关注,伴随着过程分析技术的发展,将来可能成为制药行业的一个研究热点。     

Comparison of Different Dry Binders for Roll Compaction/Dry Granulation

The suitability of different dry binders for roll compaction/ dry granulation was evaluated. Two copovidones and two crospovidones of different particle size beside three celluloses well suited for roll compaction/ dry granulation were included in the study. To classify the binders, they were compared in a binary mixture of binder and dicalciumphosphate and another formulation including a drug. Tensile strength and dissolution properties of tablets compressed from powders or granules were the focus of this study. Tablets containing the small copovidone and the small crospovidone showed the best binder properties in terms of large granule size, low fine particle fraction, and high tensile strength values. Dissolution behavior revealed a significant difference between these two binders. The dissolution of tablets containing small copovidone was significantly slower than the tablets compressed with the small crospovidone. The two copovidones showed comparable dissolution behavior, although tensile strength was higher for the type with small particles. In general, the small crospovidone was most appropriate for uncoated tablets, because it combines superior dry binding properties with fast disintegration and dissolution.     

Effect of Formulation and Processing Variables on the Granulation Kinetics of Hot Melt Granulation (HMG) Process

The objective of the study was to evaluate the effect of formulation factors, such as type of drug and particulate properties of a drug, and processing variables, i.e. jacket temperature, impeller speed, and scale, on granulation kinetics the of hot-melt granulation (HMG) process. Two model active pharmaceutical ingredients (API) Ro-A and indomethacin were selected for this evaluation using poloxamer 188 as a meltable binder. The effect of solid-state properties of API was investigated for Ro-A, whereas the binder properties were maintained constant. General factorial design was used to investigate the effect of independent process variables, impeller speed and jacket temperature using impeller motor power consumption as response variable. Consistent granulation could be developed for Ro-A by optimizing the binder level and impeller speed, however, the addition of third excipient was necessary for indomethacin. The granulation rate was related to the bulk density and the surface area of the drug. The jacket temperature affected overall granulation time but had no significant effect on the granulation kinetics, suggesting that faster heating rate is desirable for optimal productivity. A significant increase in the granulation rate was observed with increase in impeller speed. The effect of impeller speed was further confirmed at 5 L and 25 L scale. From the formulation prospective, the critical factors were the level of binder, inherent binding properties of the API, the solid-state properties of API and binder. From processing perspectives, the impeller speed had a significant effect on the granulation kinetics.     

Optimization of the High-Shear Wet Granulation Wetting Process Using Fuzzy Logic Modeling

A fuzzy model has been developed for the optimization of high-shear wet granulation wetting on a plant scale depending on the characteristics of pharmaceutical active substance particles. The model optimized on the basis of experimental data involves a set of rules obtained from expert knowledge and full-scale process data. The skewness coefficient of particle size distribution and the tapped density of the granulated mixture were chosen as the model input variables. The output of the fuzzy ruled system is the optimal quantity of wetting liquid. In comparison to manufacturing practice, a very strong sensitivity of the optimal quantity of the added wetting liquid to the size and shape of the active substance particles has been identified by fuzzy modeling.     

Continuous Twin Screw Wet Granulation and Drying—Control Strategy for Drug Product Manufacturing

The use of continuous manufacturing has been increasing within the pharmaceutical industry over the last few years. Continuous direct compression has been the focus of publications on the topic to date. The use of wet granulation can improve segregation resistance, uniformity, enhance density, and flow properties for improved tabletability, or improve stability of products that cannot be manufactured by using a direction compression process. This article focuses on development of appropriate control strategies for continuous wet granulation (especially twin screw wet granulation) through equipment design, material properties and manufacturing process along with areas where additional understanding is required. The article also discusses the use of process analytical technologies as part of the control and automation approach to ensure a higher assurance of product quality. Increased understanding of continuous wet granulation should result in increased utilization of the technique, thereby allowing for an increase in diversity of products manufactured by continuous manufacturing and the benefits that comes with a more complex process such as wet granulation compared with direct compression process.     

干法制粒工艺在硫酸氢氯吡格雷片制备中的应用

目的:探讨干法制粒工艺制备硫酸氢氯吡格雷片的最佳工艺参数。方法:以片剂溶出曲线和有关物质含量为评价指标,比较干法制粒工艺与湿法制粒工艺;以颗粒量（16～40目）为指标,采用正交设计优化干法制粒的工艺。结果:干法制粒与湿法制粒两种工艺比较,干法制粒工艺制出片剂的溶出速率较湿法制粒工艺快,但差异无统计学意义,湿法制粒工艺制出片剂的有关物质含量和个数均大于干法制粒工艺;干法制粒最佳工艺条件为轧辊压力为70 bar、轧辊转速为12 r·min^-1、物料的传送速度为60 r·min^-1。结论:干法制粒工艺具有成本低,工艺简单,易于操作,适合大规模生产。     

Use of the Near-Infrared Reflectance Method for Measurement of Moisture Content During Granulation

The purpose of this study was to demonstrate the use of a near-infrared (NIR) method for in-process control of a placebo formulation. An NIR setup with a multichannel detector was applied in the measurement of water during fluidized bed granulation. The effects of two critical granulation parameters were studied using the central composite design. The present NIR setup with three wavelengths proved applicable for in-line moisture measurement. The 1990 nm signal was used for measurement of water and the 1745 and 2145 nm signals were used to correct the change in spectra baseline during granulation. Variations in inlet air conditions proved to be critical factors, explaining differences in the granule size distributions. Differences in granule moistening and drying rates resulting from varying inlet air conditions could be measured with the NIR setup. The moisture content of granules at the end of the spraying phase explained part of the differences in granule size distributions. The moisture content of granules at the end of the drying phase affected the tableting behavior of granules. The results suggested that direct measurement of granule moisture content facilitates the in-process control of the granulation.     

Influence of the Punch Head Design on the Physical Quality of Tablets Produced in a Rotary Press

This study aims to investigate the influence of tablet punch head design on compaction and the resultant tablet mechanical properties. Tablets were prepared using flat-face punches with different head flat and head radius configurations, on a rotary tablet press with compression rolls of different diameters. The results showed that tablets produced using punches with head flats consistently displayed higher tensile strengths and lower capping tendencies. Exclusion of the head flat in the punch head geometry caused the compacts to undergo a state of continual deformation during the compaction cycle, possibly with increasing elasticity without the opportunity for more prolonged stress relaxation. Extension of head flat diameter produced small increments in dwell time and this could bring about significant improvements to the tablet mechanical quality. Changes to the punch head radius were found only to affect the compression profiles marginally, but this only produced insignificant differences in the tablet mechanical properties. A smaller compression roll allowed greater plastic flow during the dwell phase, but this was insufficient to effectively counteract the adverse effects due to increased strain rate during the consolidation phase, leading to deterioration of tablet mechanical quality.     

Note on the Use of Diametrical Compression to Determine Tablet Tensile Strength

The diametrical compression (DC) test, as defined in United States Pharmacopeia <1217> and in American Society for Testing and Materials testing standard D 3967, has been used extensively to derive the tensile strength (TS) of pharmaceutical tablets from the measured breaking force. DC-derived TSs provide a good approach to measuring the consistency of tablet mechanical properties from one batch to the next. For these quality control type applications, method precision is required, but accuracy is not. In addition, DC has been used to calibrate parameters of the Druker Prager Cap model, a yield criterion expressing the failure of a powder compact under arbitrary 3D loading conditions. For this application, the DC method must not only provide suitable precision but also provide accuracy. In this work, we explore the accuracy of the DC method by comparing TS results to those of the 3-point bend test method (also defined in United States Pharmacopeia <1217>). We conclude that the true TS of a powder compact is approximately double the DC-derived value. Although historical literature assumes that tablets fracture under tension along the centerline of the tablet, analysis of the stress state suggests that tablets are likely to fracture under shear. The impact of this ～50% error should be considered when accuracy of the TS result is required.     

Application of In-line Focused Beam Reflectance Measurement to Brivanib Alaninate Wet Granulation Process to Enable Scale-up and Attribute-based Monitoring and Control Strategies

Application of in-line real-time process monitoring using a process analytical technology for granule size distribution can enable quality-by-design development of a drug product and enable attribute-based monitoring and control strategies. In this study, an in-line laser focused beam reflectance measurement (FBRM) C35 probe was used to investigate the effect of formulation and process parameters on the granule growth profile over time during the high shear wet granulation of a high drug load formulation of brivanib alaninate. The probe quantitatively captured changes in the granule chord length distribution (CLD) with the progress of granulation and delineated the impact of water concentration used during granulation. The results correlated well with offline particle size distribution measured by nested sieve analyses. An end point indication algorithm was developed that was able to successfully track the process time needed to reach the target CLD. Testing of the brivanib alaninate granulation through 25-fold scale-up of the batch process indicated that the FBRM CLD profile can provide a scale-independent granule attribute-based process fingerprint. These studies highlight the ability of FBRM to quantitate a granule attribute of interest during wet granulation that can be used as an attribute-based scale-up and process monitoring and control parameter.     

Assessment of Intragranular and Extragranular Fracture in the Development of Tablet Tensile Strength

When a tablet is compacted from deformable granules and then broken, the fracture plane may cleave granules in 2 (intragranular fracture) or separate neighboring granules (extragranular fracture). In this study, a novel method was developed to quantify the extent of intragranular versus extragranular fracture by compacting tablets from multicolored ideal granules and evaluating fracture surfaces. The proportions of intragranular and extragranular fracture were quantified and modeled in light of a new metric; the deformation potential, Δ, reflecting the solid fraction increase as an initial granule bed is compressed into a final tablet. Results show that a measurable tablet strength is achieved at Δ > 0.18, but intragranular fracture is not observed until Δ > 0.21. At very large Δ, tablets experience almost exclusively intragranular fracture, yet the tablet tensile strength is considerably lower than that of a tablet compacted from raw powders versus precompacted granules. Thus, secondary compaction of granules appears to weaken the granule matrix, leading to reduced tablet tensile strength even in the presence of strong extragranular bonding.     

PDCA循环在提高癌痛患者阿片类用药合理性中的作用

目的 观察PDCA循环在提高癌痛患者阿片类药物合理使用性中的作用。方法 收集PDCA循环前后的患者资料,评估PDCA循环对阿片类药物合理使用率的影响。结果 PDCA循环后阿片类药物的合理使用率从20.24%升高至87.59%,其中,强阿片类药物合理使用率从34.19%升高至91.20%,弱阿片类药物合理使用率从3.45%升高至66.67%,阿片类复方制剂合理使用率从6.12%升高至62.50%。结论 PDCA循环管控模式有效提高了阿片类药物的合理使用率。     

TIMERx®: novel polysaccharide composites for controlled/programmed release of drugs in the gastrointestinal tract

Over the last 100 years tablets have grown from first invention to becoming the world's leading medicinal form, by any measure. This article considers some of the reasons for the pre-eminence of pharmaceutical tablets. Particular attention has been given to the role of controlled-release tablets and to a very versatile hydrogel-based controlled-release technology, called TIMERx^®. The unique nature of TIMERx intermolecular physical chemistry is described in relation to the technology's potential to provide any one of a number of different release profiles, ranging from zero order to chronotherapeutic release. The unusual nature of TIMERx technology lies in its ability to provide different release kinetics by the manipulation of molecular interactions. This 'molecular engine' replaces the need for complex processing or novel excipients and allows desired drug release profiles to be 'factory set' following a simple formulation development process. The article describes the physico-chemical interactions of TIMERx technology at a molecular level and how they can be manipulated by formulation considerations. The article describes how TIMERx technology has been developed to the point where today it underpins a number of marketed pharmaceutical CR products as well as products under development by Penwest Pharmaceuticals.     

On the Use of Infrared Thermography for Monitoring a Vial Freeze-Drying Process

Monitoring a vial freeze-drying process without interfering with product dynamics is a challenging issue. This article presents a novel device constituted by an infrared camera designed to be placed inside the drying chamber, able to monitor the temperature of the vials, very close to that of the product inside. By this way it is possible to estimate the ending point of the primary drying, the heat transfer coefficient to the product (K_v), and the resistance of the dried product to vapor flux (R_p). Experiments were carried out in a pilot-scale freeze-dryer, processing 5% and 10% sucrose solutions at different values of shelf temperature and chamber pressure, using both thermocouples and the IR camera to track product dynamics. Results evidence that the measurements (of temperature) and the estimates (of the ending point of the main drying and of K_v and R_p) obtained using the 2 systems are very close, thus validating the IR camera as an effective process analytical technologies for the freeze-drying process. Besides, it was shown that the presence of the IR camera in the chamber is not responsible for any additional heating to the product and that monitored vials are representative of the majority of the vials of the batch.     

应用PDCA循环管理法提高门诊药房的药品调剂质量

目的适应医院的信息系统,减少门诊药房发药差错,提高门诊药房调剂工作质量。方法采用PDCA循环管理法对门诊药房的药品调剂工作进行管理,目标将药品调剂差错率控制在1％。以下。管理措施主要包括：解决计算机网络系统运行中存在的问题;提高药品调剂工作效率;减少药品调剂差错。每月检查药学人员执行PDCA管理措施的情况,计算药品调剂差错率,并进行分析和评定,检查整改的效果,提出新的计划和措施。结果运用PDCA循环管理后,门诊药房的药品调剂工作效率显著提高,药品调剂差错率降至0．89％。（223／251238）,达到本轮PDCA循环的目标。结论采用PDCA循环管理法可有效减少门诊药房药品调剂差错,提高门诊调剂工作质量。     

Part IV. EpilogueChapter 14. Discussion About Narrative Methods as a Strategy for Investigating and Understanding the Use and Misuse of Alcohol and Drugs

Preliminary and tentative conclusions concerning theoretical and methodological issues about narrative methods and their use as a research strategy for investigating and understanding the use and misuse of alcohol and drugs are presented. The treatment methods that are influenced by narrative strategies as well as this tool's limitations are noted. The article focuses particularly on approaches based on, and influenced by, psychology, sociology and social work when conducting narrative research.     

网络在线审批流程实施前后我院特殊使用级抗菌药物使用情况及细菌耐药分析

摘 要 目的：分析网络在线审批流程实施前后我院特殊使用级抗菌药物使用指标和耐药率,为改进特殊使用级抗菌药物管理方法,促进其合理使用提供参考。方法: 采用回顾性调查方法,调查我院 2012～2015年抗菌药物和特殊使用级抗菌药物用量、销售金额、使用率、使用强度、微生物标本送检率及主要致病菌对特殊使用级抗菌药物的耐药率等。结果: 我院特殊使用级抗菌药物审批会诊流程由手工申请单递送会诊发展为网络在线审批会诊;从2012～2015年我院抗菌药物使用指标略呈上升,住院患者抗菌药物人均费用由1 602.85元上升至1 888.63元,住院患者抗菌药物使用强度由54.50 DDDs/(100人·天)上升至65.47 DDDs/(100人×天);特殊使用级抗菌药物使用金额占比2013年最低为13.90%,2015年最高为17.34%;特殊使用级抗菌药物使用强度由4.85 DDDs/（100人×天）上升至6.37 DDDs/（100人×天）;特殊使用级抗菌药物治疗前微生物送检率由85.5％上升至90.0％;主要病原菌为金黄色葡萄球菌、大肠埃希菌、肺炎克雷伯菌、铜绿假单胞菌、鲍曼不动杆菌,主要致病菌构成比例均有微弱变化;除了金黄色葡萄球菌,其他四种病原菌对特殊使用级抗菌药物的耐药率呈上升趋势,鲍曼不动杆菌对头孢吡肟和碳青霉烯类的耐药率超过了50%。结论:我院还需对特殊使用级抗菌药物在线审核流程进行加强和管理,真正做到严控特殊级抗菌药物不合理滥用现象。     

处方点评对促进某院合理用药的探讨

目的探讨处方点评对合理用药的促进作用。方法每月对我院上月门诊处方抽取一次,每次抽取200份,组织医学及药学专家逐一进行点评,并将点评结果汇总整理后进行公示,通报不合理处方及处方存在的问题,并根据处方中出现的问题提出改进的建议及措施。结果 1月份所出具的处方中合理处方为101份,占50.5%;2011年12份所出具的处方中合理处方为193份,占96.5%。两组相比较2011年12月份处方的合格率显著提高,χ2=108.6382,P<0.01,差异有统计学意义。结论定期进行处方点评促使医务人员主动地加强知识更新,增强了责任意识,显著的提高处方的适当性,使临床不合理用药现象得到抑制。     

Improving Confidence in the Determination of Free Fraction for Highly Bound Drugs Using Bidirectional Equilibrium Dialysis

Equilibrium dialysis has been widely used for the measurement of the fraction of unbound drug (f_u) in plasma, but it suffers from the accuracy and reliability for low f_u values. To address this concern, an orthogonal approach, called the bidirectional equilibrium dialysis, is described to simultaneously measure a pair of f_u values for each drug based on equilibration in 2 opposite dialysis directions: from plasma to buffer (f_u,p/b) and from buffer to plasma (f_u,b/p). Hypothetically, if true equilibrium is attained in both dialysis directions, the measured f_u,b/p and f_u,p/b values for a given drug should converge, and thus, the ratio of f_u,b/p to f_u,p/b becomes unity (1.0). Thus, the ratio can be used as a tangible readout for data reliability. This methodology has been extensively tested in the present study using various drugs with distinct plasma binding characteristics. Our results clearly showed that low f_u values (<0.01) could be reliably determined and verified using either the standard or dilution bidirectional equilibrium dialysis method for some known highly bound drugs; for extensively bound drugs with high logD_7.4, such as montelukast, bedaquiline, and venetoclax, only a range of f_u can be reported with confidence because of uncertainty in the true equilibrium.     

医疗用毒性药品管理现状的分析及建议

目的:强化医疗用毒性药品(以下简称毒性药品)管理。方法:查阅毒性药品管理的相关文件,结合我院毒性药品管理的现状加以分析。结果:毒性药品的管理存在一些问题,如法规滞后,不利执行,品种的认定缺乏科学依据,医务人员重视不足,管理上存在安全隐患等。结论:建议有关部门尽快修订毒性药品相关法规,强化毒性药品管理。