Fabrication of extended-release patient-tailored prednisolone tablets via fused deposition modelling (FDM)3D
printing
Justyna Skowyra a ,b ,Katarzyna Pietrzak a ,c ,Mohamed A.Alhnan a ,?
a
School of Pharmacy and Biomedical Sciences,University of Central Lancashire,Preston,Lancashire,UK
b
Faculty of Pharmacy with the Laboratory Medicine Division,Medical University of Warsaw,Warsaw,Poland c
Faculty of Pharmacy,Medical University of Lodz,Lodz,Poland
a r t i c l e i n f o Article history:
Received 11October 2014
Received in revised form 17November 2014Accepted 18November 2014
Available online 25November 2014Keywords:
Rapid prototyping
Fused ?lament fabrication FFF
Personalized Patient-speci?c 3D printer
a b s t r a c t
Rapid and reliable tailoring of the dose of controlled release tablets to suit an individual patient is a major challenge for personalized medicine.The aim of this work was to investigate the feasibility of using a fused deposition modelling (FDM)based 3D printer to fabricate extended release tablet using predniso-lone loaded poly(vinyl alcohol)(PVA)?laments and to control its dose.Prednisolone was loaded into a PVA-based (1.75mm)?lament at approximately 1.9%w/w via incubation in a saturated methanolic solu-tion of prednisolone.The physical form of the drug was assessed using differential scanning calorimetry (DSC)and X-ray powder diffraction (XRPD).Dose accuracy and in vitro drug release patterns were assessed using HPLC and pH change ?ow-through dissolution test.
Prednisolone loaded PVA ?lament demonstrated an ability to be fabricated into regular ellipse-shaped solid tablets using the FDM-based 3D printer.It was possible to control the mass of printed tablet through manipulating the volume of the design (R 2=0.9983).On printing tablets with target drug contents of 2,3,4,5,7.5and 10mg,a good correlation between target and achieved dose was obtained (R 2=0.9904)with a dose accuracy range of 88.7–107%.Thermal analysis and XRPD indicated that the majority of prednis-olone existed in amorphous form within the tablets.In vitro drug release from 3D printed tablets was extended up to 24h.
FDM based 3D printing is a promising method to produce and control the dose of extended release tablets,providing a highly adjustable,affordable,minimally sized,digitally controlled platform for producing patient-tailored medicines.
ó2015Published by Elsevier B.V.
1.Introduction
Personalized medications focussed on ef?cient diagnostic genetics as well as ?exible drug delivery and targeting (Holmes et al.,2009).A patient-tailored formulation additionally includes ?exible dose manufacturing techniques that allow accurate and dynamic change of dose in response to patient needs.Such an approach may become of signi?cance when a wide range of dose or active pharmaceutical ingredient (API)with narrow therapeutic window is included in the patient’s therapeutic plan.In addition,?nancial pressure on healthcare systems has encouraged trends of reducing the number of inpatients through providing ef?cient outpatient services such as Telehealthcare (McKinstry et al.,2009;McLean et al.,2013).It is therefore of great interest to provide an ef?cient and safe patient-tailored,dose-controlling system for outpatients which can be remotely and digitally controlled by a healthcare provider.
As oral tablets remain the most popular dosage form for patients,there is an increasing demand for a versatile and highly adjustable production method of tablets.Traditional methods of tablet manufacture typically require the use of large batches,mul-tiple production steps,designated and expensive facilities and experienced operators.The high cost of this approach combined with its rigid nature rendered it less suitable a means for preparing personalized medicine (Khaled et al.,2014).Ideally,for a production method to address the new challenges of personalized medicine,it should be (i)highly adjustable,(ii)affordable,(iii)of minimal space requirements,(iv)controllable by network and (v)safe.
Several computer-controlled 3D printing approaches have been developed to produce oral tablets as an alternative to conventional tableting.The design was based on a laying powder bed followed by the deposition of a binder solution from the print-head in a
https://www.doczj.com/doc/5c9054307.html,/10.1016/j.ejps.2014.11.0090928-0987/ó2015Published by Elsevier B.V.
?Corresponding author.
E-mail address:MAlbedAlhnan@https://www.doczj.com/doc/5c9054307.html, (M.A.Alhnan).
multilayer three dimensional fashion(Katstra et al.,2000;Yu et al., 2009;Yu et al.,2007).The proposed technology provided rapid dis-solving(Yu et al.,2007),extended release(Yu et al.,2009)and multi-phase delayed release patterns(Rowe et al.,2000).However, the process required a high level of powder?ow control,moisture content control,and was limited by the choice of binder.Marked improvement could be achieved when considering the accuracy of dosing,aesthetic quality of the tablet and the thickness of layer deposition(Sandler et al.,2014a).More recently,a bench top3D printer was utilized to fabricate a bilayer tablet with immediate and extended release pattern(Khaled et al.,2014).However,the slow solidi?cation and shrinking of the gel model affected the shape of the?nished tablets.
Fused deposition modelling(FDM)is a widely implemented method for3D printing of solid objects(Lim,2010).The expiration of patents of this technology is likely to lead to wide utilization of the3D printing by a large number of consumers at a relatively low cost.The process uses pre-prepared thermoplastic polymeric ?lament(typically with a diameter of1.75mm)as an‘ink’and passes it through a high temperature nozzle where it is heated to a semi-liquid state.The software-controlled nozzle deposits the heated material in layer-by-layer pattern to form a3D structure with a typical thickness of100–300l m.In a rare example, Masood(2007)investigated the in?uence of compactness of a3D printed model tablets and the inter-?lament space on dye penetra-tion through the printed tablets.More recently,Sandler et al. (2014b)demonstrated the fabrication of an anti-bio?lm medical device using a3D printer and antibacterial loaded PVA?laments. Goyanes et al.(2014)investigated the in?uence of changing the degree of in?ll percentage on?uorescein release from cylindrical matrix.However,limited research is available on the use of FDM in the fabrication of dosage forms as well as the accuracy of weight and dosage of this manufacturing technique.
The aim of this work is to investigate the feasibility of producing extended-release prednisolone tablets as well as controlling the dose via digital manipulation of the printed volume.Poly(vinyl alcohol) (PVA)is biodegradable and widely used in the pharmaceutical?eld as an extended release matrix for oral delivery(Carstensen et al., 1981),transdermal patches(Wan and Lim,1992)as well as mucoad-hesive and viscosity enhancer for ocular preparations(Davies et al., 1991;Wilson et al.,1983).The availably of PVA as a?lament for 3D printer enabled its use as a model polymer in this study.
2.Materials and methods
2.1.Materials
Prednisolone was purchased from Severn Biotech Ltd (Kidderminster,UK).Polyvinyl alcohol(PVA)?laments (melting point160–170°C,speci?c heat0.4Cal/g°C,density 1.25–1.35g/cm3)were purchased from Reprapcentral(UK). Glycerol,acetonitrile and methanol were supplied by British Drug Houses(BDH,London,UK).Scotch blue painter’s tape(50mm) was supplied by3M(Bracknell,UK).
2.2.Preparation of prednisolone loaded PVA?lament
PVA?laments were loaded with prednisolone via incubation in a saturated solution of prednisolone in methanol at30°C for24h. After which,the?laments were dried in over at40°C and weighed every1h until a stable weight obtained.To assess loading ef?ciency,three representative samples of PVA(100mg)were incubated in100ml of1:1methanol:water mixture under sonica-tion for2h and were assessed using HPLC as detailed in Section2.5.The loading percentage of the?lament was calculated as shown in Eq.(1).
Loading percentageeST?100?
Mass of prednisolone
Total mass of filament
e1T2.3.Tablet design and printing process
Blank and drug loaded PVA tablets were designed in an ellipse shape using Autodeskò3ds MaxòDesign2012software version
14.0(Autodesk,Inc.,USA)and saved in STL format(Fig.1a and
b).The design was imported to the3D printer’s software,Maker-Ware Version2.4.0.17(MakerBot Industries,LLC.,USA)(Fig.1).A series of tablets with increasing volumes were printed by modify-ing the dimensions of the design:length?width?heights(L,H, W)without altering the ratios between these dimensions (W=H=0.4L).The volume of the design(V)was calculated as:
V?p
L W
H?0:04p L3e2TIn order to make a correlation between the volume of the design and the mass of the printed tablet(M),a series of tablets of increased volume was printed and accurately weighed.A linear equation describing this relationship was established:
M?1:0322Vt24:898e3Tsince the target dose D(mg)is calculated as:
D?M:S=100e4Twhere M is the mass of the tablet and S is the percentage of loading ?lament.Therefore,the required dimension(L)to achieve a target dose(D)from?lament with loading percentage(S)can be calculated as:
L?
????????????????????????????????????????
25
100D
S
àá
à24:898
1:0322p
3
s
e5T
A series of tablets were printed according to Eq.(5)to achieve a target dose of2,3,4,5,7.5or10mg.Table1illustrated the details of dimensions,expected and measured mass of these tablets.
2.4.Modi?cation of3D printer
A MakerBot Replicatorò2X Experimental3D Printer(MakerBot Industries,New York,USA)was utilized to print blank PVA tablets. Blank tablets(PVA only)were printed using default settings of the software for PLA?lament as follows:type of printer:Replicator2X; type of?lament:PLA;resolution:standard;temperature of nozzle: 230°C;temperature of building plate:20°C;speed of extruder 90mm/s while extruding and150mm/s while traveling;in?ll: 100%;height of the layer:200l m.No supports or rafts were utilized in the printed model.
In order to be able to print prednisolone loaded PVA tablets,the following modi?cations were implemented:
(i)Kapton tape layer(default)provided poor adhesion of the
designs to the built plate.Scotch Blue painter’s tape was applied to the surface of the printing board to improve adhesion to the surface layer.
(ii)The?lament passed through a plasticizer station containing glycerol before entering the heating nozzle.
(iii)Increasing extruder temperature during printing from 230°C to250°C was essential to maintain constant?ow of prednisolone loaded PVA?lament.
12J.Skowyra et al./European Journal of Pharmaceutical Sciences68(2015)11–17
2.5.Determination of drug content
In order to assess prednisolone content in drug loaded ?laments and the printed tablets,each tablet (or 100mg of ?lament)was accurately weighed and transferred to a 500ml volumetric ?ask.Tablets were incubated for 1h in 150ml of distilled water under sonication followed by completing the volume with methanol to 500ml,and subsequent sonication for an additional 4h at 50°C.After cooling to room temperature,samples were ?ltered through a 0.22l m Millex-GP syringe ?lter (Merck Millipore,USA)and pre-pared for HPLC analysis.
Prednisolone concentration was determined through HPLC analysis method using an Agilent HPLC 1260series (Agilent Technol-ogies,Inc.,Germany)equipped with Kinetex C18column (100?2.1mm,particle size 2.6l m)(Phenomenex,Torrance,USA).The mobile phase (water:acetonitrile)was used in gradient concen-trations:(60:40at time 0,40:60at time 8–12min and 60:40at time 12.01–14min)at a ?ow rate of 0.5ml/min.The injection volume was set at 40l l and the UV detector employed an absorbance wave-length of 250nm.Temperature of the column was maintained at 45°C and stop time for each sample was 14min.2.6.Scanning electron microscopy
The surface morphology of the PVA ?lament,extruded ?lament from the nozzle of the 3D printer as well as the printed tablet was assessed using a Quanta-200SEM microscope at 20kV.Samples were placed on metallic stubs and gold coated under vacuum for 2min using JFC-1200Fine Coater (Jeol,Tokyo,Japan),prior to imaging.
2.7.X-ray powder diffraction
A powder X-ray diffractometer,D2Phaser with Lynxeye (Bruker,Germany)was used to assess the crystallinity of prednis-olone in the drug loaded tablets.Samples were scanned from 2Theta =5°to 50°using a scan type coupled with a two theta/theta scintillation counter over 30min.
2.8.Differential scanning microscopy
A Mettler Toledo DSC823e DSC (Mettler,Switzerland)was utilized to perform thermal analysis.Samples of approximately 5mg were accurately weighed and placed in a 40l L standard aluminium pan DSC analysis.Analysis was carried on under a nitrogen environment (50mL/min).In order to exclude the effect of humidity,samples were heated to 100°C for 5min then cooled to à20°C at a rate of 10°C/min.This was followed by a heat scan from à20°C to 300°C at a rate of 10°C/min.All measurements were carried out in triplicates.
2.9.In Vitro drug release study via ?ow-through dissolution
A ?ow-through cell (Sotax,Switzerland)dissolution apparatus with an open loop system was utilized to assess drug release pattern from the 3D printed tablets.The dissolution apparatus was connected to piston pumps and a fraction collector (Sotax,Switzerland).Cells of 12mm diameter containing 5mm glass beads were utilized during the study.Filtration was conducted using 25mm glass micro?ber ?lter discs (FG/B)(Whatman,US)which were placed above the cells.The prednisolone loaded tablets were analysed using dissolution media of a pH 1.2(HCl 0.1M)for 2h followed by phosphate buffer (pH 6.8)for additional 22h at 37±0.5°C.The ?ow rate was 8ml/min and samples were collected to Sotax fraction collector at time intervals 0,0.5,1,1.5,2,2.5,3,3.5,4,6,8,10,12,15,18,21and 24h.Samples were further ?ltered through 0.22l m Millex-GP syringe ?lter (Merck Millipore,USA)and analysed by HPLC (section 2.5).Three tablets of each strength were assessed.
3.Results and discussion
Ellipse shaped tablets were printed using an FDM 3D printer loaded with original PVA (drug free)?lament.When a series of PVA tablet with increasing dimensions were printed,a high level of correlation was identi?ed between the theoretical volume of the tablet design and the mass of the printed tablets (R 2=
0.9996).
tablets,(b)rendered image of tablet as viewed in MakerWare,and (c)blank (top)and prednisolone Table 1
The target dose,dimensions,theoretical volume,theoretical and measured mass of prednisolone loaded PVA tablets.Tablet target dose (mg)Dimensions (L ?W ?H )(mm)Tablet theoretical volume (mm 3)Tablet theoretical mass (mg)Tablet measured mass (mg)±SD 28.39?3.36?3.3674.23101.52102±1.73310.11?4.04?4.04129.66158.73168.30±1.43411.29?4.52?4.52180.92211.64216.18±1.01512.34?4.94?4.94236.31268.82283.44±5.037.514.00?5.60?5.60344.71380.71396.67±4.9310
15.50?6.20?6.20
467.66
507.61
498.67±5.69
This indicated the ability of FDM 3D printing method to achieve a suf?cient control of the mass of the printed tablets.Such ability is a key advantage for developing a mini-manufacturing unit that can tailor tablet mass by manipulating the volume of the design through an input on software.
In order to investigate the ability of the printed tablet to contain a given dose of API and control its release,a model drug needed to be incorporated into PVA ?lament before loading it in the nozzle of the 3D printer.Prednisolone was chosen as a model drug due to its high thermal stability and neutral nature.A simple loading process based on incubation in methanolic solution was developed.The yielded prednisolone loaded ?lament showed a drug loading of approximately 1.9%w/w.The choice of methanol as a loading solution was based on its ability to dissolve the drug and swell PVA without dissolving or damaging the physical integrity of the original ?lament.Other solvents such as ethanol and acetone were found to have a degrading effect on the PVA ?lament or a poor loading ef?ciency respectively and were deemed unsuitable for the loading process.
When a similar series of tablets were printed with prednisolone loaded PVA ?lament (Table 1),the correlation between theoretical volume and the mass of the printed tablet was maintained (R 2=0.9983,Eq.(2)).This signi?ed the potential of FDM 3D printer to manufacture a solid tablet with accurate dose,responding to an individual patient’s need when minute increment of dosing is required.The ?nishing quality of prednisolone loaded tablets was observed to be similar to blank tablets (made with PVA ?laments as received)indicating the possibility of adapting a different print setting to suit particular ?lament composition (Fig.1c).
The morphology of the PVA ?lament before and after undergo-ing fused depositing modelling was investigated via SEM imaging.Images of prednisolone loaded PVA ?laments (1.75mm)showed a smooth surface of the ?lament (Fig.2).However,upon extrusion through the 3D printer nozzle at an elevated temperature,the
surface of extruded ?laments (200l m)appeared to be generally rough with irregular pores and voids between layers,this may be due to the rapid evaporation of water content and evaporable additives upon exposure to high temperature.
SEM images of surface of prednisolone loaded PVA indicated an irregular and rough surface with partially fused ?lament (Fig.2).The side of the tablet showed overlaid layers of ?lament with an approximate height of 200l m.When the inner surface of a 50%printed tablet was assessed,the directions of the fused ?lament were distinct between the peripheral and central domains (Fig.3).This might be related to a widely used ?lling pattern of fused ?laments dictated by a software (commonly referred to as slicing engine),where a shell structure is built to outline the outer surface of the design whilst the central space can be either a consistent ?lling or with one or more empty compartments.
To establish the ability of such 3D printing method to control dosage,theoretical doses based on tablet mass and measured dose of prednisolone in the tablet were compared (Fig.4).The range of dose accuracy was between 88.70%±0.79for 10mg tablet and 107.71%±9.96for 3mg tablet (Table 2).The coef?cient of determi-nation between target and achieved dose (R 2=0.9905)showed that it is possible to fabricate tablets with desired dose of prednis-olone through volume modi?cation.The technology holds the potential of digitally controlling a patient’s dose via simple software input.It can also be assumed that degradation of prednis-olone in the nozzle under elevated temperature was minor due to the thermal stability of prednisolone at 250°C (Palanisamy and Khanam,2011)and the relative short exposure time of ?lament in the nozzle (extrusion speed of 90mm/s).
The physical form of prednisolone within the 3D printed tablets was investigated using thermal and diffractometry methods.Thermal analysis (DSC)showed prednisolone crystals to have a peak at 203°C corresponding to the melting point of prednisolone (Fig.5).The prednisolone loaded tablet showed a glass
transition
view and (b)cross section of PVA ?lament,and PVA after extrusion from nozzle of fused deposition modelling magni?cation.
temperature(Tg)of45°C whereas PVA?lament appeared to have a Tg of35°C.It was expected that the Tg of prednisolone loaded tablet to be lower than PVA?lament due to the plasticizing effect of prednisolone.Such an increase in the Tg could be attributed to loss of plasticizer(s)in the PVA during incubation in methanol for drug loading.The absence of such an endothermic peak of prednisolone in drug loaded tablets
of prednisolone is in amorphous form
On the other hand,XRPD indicated
lone at2Theta=8.7,14.7and18.6
2009).The absence of such peaks in
suggested that the majority of prednisolone
form.Both blank PVA?lament and
showed peaks at2Theta=9.3°,18.7°
be related to the semi-crystalline structure
2011).As the exact PVA?lament composition
by the manufacturer,it was not possible
In vitro release pattern of prednisolone
tablets was studied via a pH-change
system.Fig.7indicated that prednisolone
weights exhibited a similar in vitro
of drug release(>80%)took place after
and over18h for tablets with doses of
imately100%of prednisolone release
tablets with2and3mg drug loading.The faster release of prednis-olone from the smaller size tablets is likely to be related to their larger surface area/mass ratio which promotes both drug diffusion and the erosion of PVA matrix.By the end of the dissolution test (24h),it was visually evident that the tablet had completely eroded within the?ow-through cell.Several studies reported PVA to form a hydrogel system where drug release is governed
images of(a)side surface,(b)top surface and(c)inner side of50%accomplished prednisolone loaded
Fig. 4.Relationship between target and achieved dose of prednisolone loaded
tablets.
by an erosion mechanism(Vaddiraju et al.,2012;Westedt et al., 2006).
In summary we have reported a signi?cant adaptation of a bench top FDM3D printer for pharmaceutical applications.The resultant tablets were solid structures with a regular ellipse shape and adjustable weight/dose through software control of the design’s volume.This fabrication method is applicable to other solid and semisolid dosage forms such as implants and dermal patches.
4.Conclusion
FDM based3D printing was adapted to engineer and control the dose of extended release tablets.Prednisolone loaded PVA?lament demonstrated the ability to be printed into ellipse shaped tablets using3D printer.The mass of a printed tablet was digitally con-trolled by manipulating the design’s volume through computer software.The precision of dose control ranged between88.7%and107%.Thermal analysis and XRPD suggested that the majority of prednisolone exists in amorphous form within the PVA matrix while prednisolone release from a3D printed tablet was extended over24h.In principle,FDM3D printers can be exploited as platform to construct?exible dose tablets from purpose-built drug-containing?laments.
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PAT的五月口语预测 May, 2014 Part 1: (Q's about your personal background ) What’s your favorite subject/course? Do you think people who major in your field can find a job easily when they graduate? What subjects did you study at primary school? What’s your hometown famous for? Is it good for young people? Can you tell me about some recent changes in your hometown? Can you tell me something about the public transport system in your hometown? What's your favorite means of transport? Does your Chinese name have any special meaning? Are there any important traditions about giving children their names in China? (some other general Q’s about yourself and your life) Do you live in a house or a flat? Have you ever considered moving to another place? Which is your favorite room in your house/ flat? Do you prefer to live in a city or in the countryside? Are there any disadvantages to living in the countryside? Do you have a bicycle? Do you think bicycles will become more popular in the future? Have you ever travelled by train? Do people in your country like to travel by train? Do you wear a watch? Why? Why is it important to be punctual? Are you often late for things? Do you have patience? Have you ever lost your patience? Why is it important to be polite? Do you think people in your country are more polite than in the past?
齐头并进堵源治本高校校园网ARP攻击防御解决方案 DIGTIAL CHINA DIGITAL CAMPUS 神州数码网络有限公司 2008-07
前言 自2006年以来，基于病毒的arp攻击愈演愈烈，几乎所有的校园网都有遭遇过。地址转换协议ARP（Address Resolution Protocol）是个链路层协议，它工作在OSI参考模型的第二层即数据链路层，与下层物理层之间通过硬件接口进行联系，同时为上层网络层提供服务。ARP攻击原理虽然简单，易于分析，但是网络攻击往往是越简单越易于散布，造成的危害越大。对于网络协议，可以说只要没有验证机制，那么就可以存在欺骗攻击，可以被非法利用。下面我们介绍几种常见ARP攻击典型的症状： ?上网的时候经常会弹出一些广告，有弹出窗口形式的，也有嵌入网页形式的。下载的软件不是原本要下载的，而是其它非法程序。 ?网关设备ARP表项存在大量虚假信息，上网时断时续；网页打开速度让使用者无法接受。 ?终端不断弹出“本机的XXX段硬件地址与网络中的XXX段地址冲突”的对话框。 对于ARP攻击，可以简单分为两类： 一、ARP欺骗攻击，又分为ARP仿冒网关攻击和ARP仿冒主机攻击。 二、ARP泛洪（Flood）攻击，也可以称为ARP扫描攻击。 对于这两类攻击，攻击程序都是通过构造非法的ARP报文，修改报文中的源IP地址与（或）源MAC地址，不同之处在于前者用自己的MAC地址进行欺骗，后者则大量发送虚假的ARP报文，拥塞网络。 图一 ARP仿冒网关攻击示例
神州数码网络秉承“IT服务随需而动”的理念，对于困扰高教各位老师已久的ARP 攻击问题，结合各个学校网络现状，推出业内最全、适用面最广、最彻底的ARP整体解决方案。 神州数码网络公司从客户端程序、接入交换机、汇聚交换机，最后到网关设备，都研发了ARP攻击防护功能，高校老师可以通过根据自己学校的网络特点，选取相关的网络设备和方案进行实施。
PAT的五月写作预测 1 Good health is a basic human need. Some people think that healthcare services should be provided by the government rather than by private companies. Do you agree or disagree? 2 Some people believe that only the fittest and strongest individuals and teams can succeed in sports. Others think that success in sports depends on mental attitudes. Discuss both these views and give your own opinion. 3 Animal experiments have been used to develop new medicines and to test the safety of many other products. Some people think that these experiments should be banned. To what extent do you agree or disagree? 4 Sending children to boarding schools is becoming increasingly popular. What are the causes of this trend? Do you think it is a positive or negative trend? 5 Today, many young people leave school with a negative attitude towards learning. What are the causes of this? Suggest some solutions. 6 Some people believe that students should study a wide range of subjects. Others, however, argue that students should focus on the subjects they are best at or they find most interesting. Discuss both these views and give your own opinion. 7 Students from rural areas often find it difficult to access university education. Some people think that universities should make it easier for them to access higher education. To what extent do you agree or disagree? 8 Some parents today choose to send their children to private schools. Do the advantages of private schools outweigh the disadvantages? 9 Mobile phones and the Internet are useful tools. However, not many elderly people use them. In what ways can mobile phones and the Internet be useful to elderly people? How can elderly people be encouraged to use them? 10 Early technological developments helped ordinary people and changed their lives more than recent technological developments. Do you agree or disagree? 11 Cheap air travel is increasingly popular in the world today. To what extent do you think the advantages of this trend outweigh the disadvantages?
10月慎小嶷雅思大作文预测 1 Some people argue that air transport can bring us more choices while others claim it makes industrial and agricultural products cost more. Discuss both views and give your own opinion. 1有些人认为，航空运输能够给我们带来更多的选择，而有些人则认为它增加了工业品和农产品的花费成本。讨论这两种意见，并给自己的观点。 2 The government should not put money in building theaters and sports stadiums. Instead, it should spend money on medical care and education. Do you agree or disagree? 2，政府不应该把钱花在在建设剧院和体育场馆上。相反，它应该花在医疗保健和教育上。你是否同意或不同意？ 3 Some people believe rich countries and international organisations should give other types of help to poor countries rather than financial aid. To what extent do you agree or disagree? 3，有些人认为富裕国家和国际组织应给予贫困国家其它类型的帮助而不是财政援助。你同意哪种观点？ 4 Many people use distance-learning programmes to study at home while other people think that these programmes cannot bring as much benefit as attending college or university. What is your opinion? 4，很多人使用远程学习方法在家里学习，而其他人认为，这些方案不能带来像去大学或学院一样多的好处。你的意见是什么？ 5 Some people think that intelligent children should be taught separately and given special treatment. Others think that students of different abilities should be taught together. Discuss both views and give your own opinion. 5有人认为，聪明的孩子应该单独授课和特殊的待遇。另一些人则认为，不同能力的学生也应被共同讲授。讨论这两种意见，并给自己的观点。
前言 ?出于对剑桥雅思的爱恨交加，出于对那些需要完成留学梦移民梦的人的感同身受，出于对那些在烤鸭路上屡战屡败屡败屡战的人的精神支持，出于对那些仍在迷茫、仍在盲目背单词、仍在疯狂买参考书、仍在迷恋机经的人的劝勉与鼓励，出于对网络上面所谓出售雅思写作7分资料的虚假广告的无比痛恨，出于对某些所谓名师名校培训机构的不齿不屑，出于那些迷恋习惯背诵范文依赖别人的鸭子们的真诚忠告，出于对那些急需在7月1日之前考到雅思4个7（澳洲会计毕业生，你懂的）的人的理解和帮助，出于上天对我的眷顾和怜悯，出于·········出于因为我曾经也是这么一种人，也是有这么一种经历，我决定，无偿地，毫无保留地，完整地分享我在过去三月自己总结的雅思复习计划和资料（本人曾经的弱项是写作和口语（对，是曾经，哈哈！），所以，我的资料绝大多数都是写作和口语）~~~ ?争取写一篇最全最好的雅思写作经验分享，和更多的鸭友们远离全聚德烤鸭店的火海！ 从4年前为了完成踏进悉尼大学的留学梦，到现在努力实现的澳大利亚梦，雅思成为了一个绕不开的情意结。其中走了特别多的弯路，摔了特别多的跤，失去了很多，也收获了很多。从当初的总分6.5而单科不低于6分的大学门槛到现在的A类4个7的独木桥，对于这个来自英国的―老熟人‖，可谓百般滋味在心头。雅思的备考也是一种―被烤‖，在烤鸭过程中，一不小心，有可能首先被这只鸭给烤焦了。焦虑，迷茫，急躁，失落，绝望，期待，紧张，亢奋，XX失调等所有更年期综合症状都会在备考的过程中轮番上映。 从2010年12月到2011年2月底，我一共参加了4次雅思考试(12月11日，1月22日，2月12日和2月26日)，成绩为： 12月11日：听力：7.0，阅读：6.5，写作：6.0，口语：6.0 01月22日：听力：6.5，阅读：7.0，写作：6.0，口语：7.0 02月12日：听力：7.0，阅读：7.5，写作：6.5，口语：8.5 02月26日：听力：7.0，阅读：7.5，写作：7.5，口语：7.0 03月05日：听力：7.0，阅读：7.5，写作：7.0，口语：8.0 可以说，在过去的三个月里面，我感受过裸考过后无言以对的惶恐，体味过努力过后略有进步的喜悦，忍受着就差0.5、与目标无比接近却未能接近的失落，最后，苦尽甘来。因为这次考试，至少再一次让我确信‖天道酬勤―。NO SWEAT, NO SWEET; NO PAIN, NO GAIN。
1．下列应用使用TCP连接的有（本题3项正确） A.Telnet B.BGP C.FTP D.TFTP 2．TCP和UDP协议的相似之处是 A.传输层协议 B.面向连接的协议 C.面向非连接的协议 D.其它三项均不对 3．下列应用使用UDP连接的有（本题3项正确） A.TFTP B.Syslog C.SNMP D.HTTP 4．第一个八位组以二进1110开头的IP地址是（）地址 A.Class A B.Class B C.Class C D.Class D 5．下面哪些不是ICMP提供的信息 A.目的地不可达 B.目标重定向 C.回声应答 D.源逆制 6．C类地址最大可能子网位数是 A.6 B.8 C.12 D.14 7．（）协议是一种基于广播的协议，主机通过它可以动态的发现对应于一个IP地址的MAC地址 A.ARP B.DNS C.ICMP D.RARP 8．IP地址为子网掩码为的地址，可以划分多少个子网位，多少个主机位 A.2，32 B.4，30 C.254，254 D.2，30 9．关于IPX的描述正确的是（本题3项正确） A.IPX地址总长度为80位，其中网络地址占48位，节点地址占32位 B.IPX地址总长度为80位，其中网络地址占32位，节点地址占48位
C.IPX是一个对应于OSI参考模型的第三层的可路由的协议 D.NCP属于应用层的协议，主要在工作站和服务器间建立连接，并在服务器和客户 机间传送请求和响应 10．在无盘工作站向服务器申请IP地址时，使用的是（）协议 A.ARP B.RARP C.BOOTP D.ICMP 11．以太网交换机的数据转发方式可以被设置为（本题2项正确） A.自动协商方式 B.存储转发方式 C.迂回方式 D.直通方式 12．当交换机检测到一个数据包携带的目的地址与源地址属于同一个端口时，交换机会怎样处理？ A.把数据转发到网络上的其他端口 B.不再把数据转发到其他端口 C.在两个端口间传送数据 D.在工作在不同协议的网络间传送数据 13．下面哪个标准描述了生成树协议 A. B. C. D. 14．下列有关端口隔离的描述正确的是：(本题2项正确) A.DCS-3726B出厂时即是端口隔离状态，所有端口都可以与第一个端口通信，但之 间不可以互通 B.DCS-3726S可以通过配置实现与3726B一样的端口隔离功能，但出厂默认不时隔 离状态 C.可以通过配置私有VLAN功能实现端口隔离 D.可以通过配置公用端口实现端口隔离 15．下列关于静态配置链路聚合和动态配置链路聚合的理解正确的是: A.静态配置链路聚合需要在聚合组的每个聚合端口中进行配置 B.动态配置链路聚合只需要在主端口中配置一次，在全局模式中配置启用lacp协 议即可 C.静态配置链路聚合不能进行负载均衡 D.动态配置链路聚合不需要配置聚合组号，交换机会根据目前聚合组的情况自动 指定 16．网络接口卡(NIC)可以做什么？ A.建立、管理、终止应用之间的会话，管理表示层实体之间的数据交换 B.在计算机之间建立网络通信机制 C.为应用进程提供服务 D.提供建立、维护、终止应用之间的会话，管理表示层实体之间的数据交换17．以下关于以太网交换机的说法哪些是正确的?
Part 1: (Q's about your personal background) What’s your favorite subject/course? Do you think people who major in your field can find a job easily when they graduate? What subjects did you study at primary school? What’s your hometown famous for? Is it good for young people? Can you tell me about some recent changes in your hometown? Can you tell me something about the public transport system in your hometown? What's your favorite means of transport? Does your Chinese name have any special meaning? Are there any important traditions about giving children their names in China? (some other general Q’s about yourself and your life) Do you live in a house or a flat? Have you ever considered moving to another place? Which is your favorite room in your house/ flat? Do you prefer to live in a city or in the countryside? Have you ever been to the countryside? Are there any disadvantages to living in the countryside? Do you have a bicycle? Do you think bicycles will become more popular in the future? Have you ever travelled by train? Do people in your country like to travel by train? Do you wear a watch? Why? Do you often use dictionaries? Do you use paper dictionaries or electronic dictionaries? Why? How many languages can you speak? Do you want to learn another language? How are you going to learn it? Do you like pets? Why do people keep pets? Do you like wild animals? Do you think zoos are still important today? Do you like plants? Do you have any plants in your house / flat? How do you take care of the plants? Do you think trees and forests are important to us? Do you wish to live in a place with many trees? Do you think places with lots of trees can attract many visitors? Why are gardens and parks important to us? Do you like to walk in cities? How can large cities become more pedestrian-friendly and walkable? Do you like rainy days? Why? Do you like to go out on sunny days? What do you usually do on sunny days? Is there anything that you don’t like to do on sun ny days? Why? Do you think sunshine can make people happy and friendly? What’s your favorite kind of weather? Do you have patience? Have you ever lost your patience? Why is it important to be polite? Do you think people in your country are more polite than in the past? Why is it important to be punctual? Are you often late for things? Do you prefer to write letters or emails? Or would you prefer to use a mobile phone? How often do you send an email? Do you like writing? Do you think you're good at it? What did you write about in high school? How do you get news? How often do you read newspapers? Are you more interested in international news or news about your own country? Do you want to become a journalist? When do you do your housework? Do you think children should help their parents with housework? What do you think is the most difficult housework task? Who cooks in your family? Can you cook? How did you learn to cook? Do you want to take cooking classes? Are cooking shows popular in China? Do you think children should learn how to cook? What’s y our favorite activity after school (or after work)? Do you often buy things online? Why are things so expensive today? Where do you usually buy clothing? What is your favorite kind of clothing? Do you think clothing is less expensive in China than in other countries? Do you often help your friends shop for clothing? Do you like going to parties? Why? Do you prefer to go to parties with your family or with your friends? What do you dislike
选择题（每题2分）共40题 1. 如下图所示,某学校在市中心有三栋楼，楼之间的距离都是200米，要求楼宇之间使用千兆互连，综合楼中网管工作室有三台服务器,要求全部使用千兆连接,则综合楼里的核心交换机上应该安装多少个千兆端口: A、 4个 B、 5个 C、 6个 D、 7个 2. 下面的说法正确的是： A、企业级服务器应该放置在核心层 B、企业级服务器应该放置在汇聚层 C、工作组级服务器应该放置在汇聚层 D、工作组级服务器应该放置在接入层 3. 集线器目前一般处于分层的局域网的哪个层次 A、接入层 B、核心层 C、传输层 D、汇聚层 4. 三层架构中，核心层的中心任务是： A、提供足够的端口密度 B、高速数据交换 C、提供全面的路由策略 D、远程站点的接入 5. 以下几种网络的拓扑结构中，可靠性最高的结构是： A、星型网络 B、环形网络 C、网状网络 D、树型网络 6. 可扩展交换局域网络（2-2-3）的缺点是： A、投资最大
B、会聚层有较大的延迟 C、如果不划分VLAN，网络只有有限的广播域 D、低成本，易安装，可划分VLAN 7. 下面哪一个协议不使用广播进行通信： A、 RIP B、 IGRP C、 DHCP D、 OSPF 8. 下面哪些设备可以有效的隔离广播域 A、二层交换机 B、网桥 C、路由器 D、中继器 E、集线器 9. 如下图所示, 某学校在市中心有三栋楼，楼之间的距离都是200米，要求楼宇之间使用千兆互连，如果服务器可以采用百兆的连接，那么综合楼以下的设计中，哪一个是最佳方案： A、使用一台DCS-3950S，最多可以提供2个GBIC接口，同时提供52个百兆端口 B、使用一台DCS-3950S和一台DCS-3926S，可以提供2个GBIC接口，同时提供72个百兆端口 C、使用一台DCS-3950S和一台DCS-3926S，可以提供2个GBIC接口，同时提供78个百兆端口 D、使用一台DCS-3950S和一台DCS-3926S，可以提供2个GBIC接口，同时提供74个百兆端口 10. 目前端口扩展的主要技术有： A、堆叠 B、聚合 C、生成树 D、级联 E、冗余
神州数码大型企业网络防火墙解决方案 神州数码大型企业网络防火墙整体解决方案，在大型企业网络中心采用神州数码DCFW-1800E防火墙以满足网络中心对防火墙高性能、高流量、高安全性的需求，在各分支机构和分公司采用神州数码DCFW-1800S 防火墙在满足需要的基础上为用户节约投资成本。另一方面，神州数码DCFW-1800系列防火墙还内置了VPN 功能，可以实现利用Internet构建企业的虚拟专用网络。 返回页首 防火墙VPN解决方案 作为增值模块，神州数码DCFW-1800防火墙内置了VPN模块支持，既可以利用因特网（Internet）IPSEC 通道为用户提供具有保密性，安全性，低成本，配置简单等特性的虚拟专网服务，也可以为移动的用户提供一个安全访问公司内部资源的途径，通过对PPTP协议的支持，用户可以从外部虚拟拨号，从而进入公司内部网络。神州数码DCFW-1800系列防火墙的虚拟专网具备以下特性： - 标准的IPSEC,IKE与PPTP协议 - 支持Gateway-to-Gateway网关至网关模式虚拟专网 - 支持VPN的星形（star）连接方式
- VPN隧道的NAT穿越 - 支持IP与非IP协议通过VPN - 支持手工密钥，预共享密钥与X.509 V3数字证书,PKI体系支持 - IPSEC安全策略的灵活启用：管理员可以根据自己的实际需要，手工禁止和启用单条IPSEC安全策略，也为用户提供了更大的方便。 - 支持密钥生存周期可定制 - 支持完美前项保密 - 支持多种加密与认证算法： - 加密算法：DES, 3DES,AES,CAST,BLF，PAP，CHAP - 认证算法：SHA, MD5, Rmd160 - 支持Client-to-Gateway移动用户模式虚拟专网 - 支持PPTP定制：管理员可以根据自己的实际需要，手工禁止和启用PPTP。 返回页首
1. 基本配置： 开启SSH服务：debug ssh-server 设置特权模式密码：enable password [8]
法国1867年巴黎世界博览会 [编辑本段] 法国1867年巴黎世界博览会简介 地点：法国巴黎 会期：1867年4月1日至1867年11月3日 主题：劳动的历史 本届世博会在1855巴黎世博会的基础上，有了新的调整和突破。毫不夸张地说，它已经具备了现代世博会的雏形。 首先，法国人希望扭转1855年巴黎世博会亏损的局面，政府通过政策和人员的设置达到了目标； 第二，此届世博会降低了艺术品展的规模，没有设置艺术品专用展馆。原因是因为1855年巴黎世博会对艺术作品进行了世界范围的回溯性精品展示，若仅十多年后再次大规模组展，则很难突破提高。这届世博会主展馆中只有一个最小的厅布置艺术品展，而比利时、荷兰、瑞士等国只能在各自的国家馆中布置艺术品展； 第三，在世博会布展思想上，第一次使用了成体系的分类法； 第四，在世博会展示形式上，第一次出现了参展国的国家馆，在主展馆周围的公园内，参展国建造了具有本国风情的国家馆及休闲设施，如奥地利酒吧，英国小酒馆、突尼斯咖啡屋、晚间音乐会等，煤气灯长亮，直到晚上11点； 第五，在世博会理念上，第一次有了展示主题——劳动的历史； 第六，第一次将世博会展览从展馆延伸到园区，展馆周围5万平方米的公园，布置有草坪、林荫道、溪流、瀑布和假山。花房里是来自地球上不同气候地区的植物，巨大的鸟园里有来自世界各地的珍奇鸟类。两个水族箱分别装有淡水鱼和海水鱼及其他水下生物，充满异国情调的观赏藻类在水底摇曳。 世博会，展示人类文明与发展的盛宴 法国在这届世博会的布局上，施行了工程师弗雷德里克·勒·普雷(F.Le Play)为展品设计的分类体系。这套意义深远的分类体系涵盖了人类的全部行业与产品，反映了人类的生活习惯，以及人与人之间、人与社会之间乃至人与进步文明之间的关系，是一种有一定从属关系的不同等级的系统的逻辑方法。沿循本届世博会展品分类的视角，我们第一次全面领略了世博会这场展示人类文明与发展的盛宴：第一类为艺术品。包括油画和其他画作、雕塑、雕刻和建筑设计(模型)。 第二类为学术用具及应用。包括出版印刷、文具、书籍装帧、绘画用材料、工业设计塑模、摄影器材、乐器和医学影像设备。 第三类为家具和其他住宅用品。包括家具、室内饰品、水晶或玻璃制品、陶瓷、地毯或挂毯、壁纸、日用刀具、钟表、室内装饰金器或青铜器、采暖设备、香熏、玩具和箱篮器皿。
<备考经验>三战雅思终上四项全7，换来IC和LSE的unconditional offer 先说下本人基本情况，从小英语一直不好，四级63分，六级考了三次，前两次50多，最后一次采用新的积分制458，当时对英语都没啥信心了，工作几年之后想出国，无奈只能边工作边硬着头皮准备雅思。 $ H" V: r+ b* g 我三次用于雅思准备上的时间分别是三个月、两个月和一个月，三次成绩如下： 一战：2010年8月14日 overall 6.5 L 7 R 7.5 W 5.5 S 5.5 h$ F9 l0 c1 N" J; C1 `" i% \ 二战：2010年12月18日overall 6.5 L 6 R7.5 W 6 S 6.5 三战：2011年3月19日 overall 7 L 6.5 R7.5 W 7 S 6 拿到成绩有些意外，因为从三次考雅思的感觉来说，第一次感觉最好，最后一次感觉最差，但成绩却截然相反，特别是写作，经过我一番思考，总结了一些体会和大家分享，希望对在写作上想突破的同学们有些帮助。 / |- s1 Q$ j0 C- h1 W5 k" G _ 第一次感觉最好是因为大作文之前看过类似的一篇，记得那一次的题目是有关人们住在大城市的问题和解决建议，这篇文章我正好在由亚历山大撰写的英语辩论手册上看到过类似的一篇，当时很兴奋，奋笔疾书，用到了那篇文章里一些华丽的句子和词汇，其中还用到了一个排比句，自我感觉很好，但成绩下来却5.5，怎么回事儿呢？总结一下，雅思的大作文是议论文，对逻辑结构和框架有要求，而我的写法比较松散，有点像散文了，所以失败。 ' A7 r2 b/ m" A# n 2 b* Y. ?! l; y/ J 二战我准备得非常认真，期间仔细研读了慎小嶷的《十天突破雅思写作》，觉得很受启发，写了不下20篇的作文，并自己逐一修改，尽量用上《十天》里的词汇和句型，这次写作从5.5提升到6。经验：注重了议论文逻辑结构的控制；不足：文章比较模板化，太刻意使用书中的大词和句式，给人的感觉过于死板。 7 s3 R, i' O# I+ }1 k4 e( { ; D! }2 b! H0 [! j( E* z+ k7 B 三战准备的时候我又认真研读了《十天》的续集，6-9分范文全解，发现高分作文大都有自己的逻辑框架和结构，套用模板的痕迹不多，于是我又写了20篇预测作文，这次尽量使用自己的套路，能避免模板的地方都避免，刚开始很痛苦，慢慢地就写出感觉了，有时候还能有创作的快感^_^ % v3 T. s$ ?. m
Where can you discover the charm of Paris for yourself? Is it in the legacy of all the F rench rulers who worked to beautify their beloved city? Is it in the famous castles, pal aces, statues and monuments, such as the Eiffel Tower? Can you find it in the world-cl ass museums, such as the Louvre? Perhaps Paris’ allure lies in the zest and style of the Parisians. 你在哪里可以找到巴黎对你自己的吸引力呢？是否是在历任的法国统治者们在美化他所钟爱的城市所留下?淼囊挪?里？还是在那些有名的城堡、皇宫雕像和纪念碑。例如艾菲尔铁塔之中？你能否在世界一流的博物馆，例如卢浮宫中找着呢？或许巴黎的诱惑力在于巴黎人的特殊品味和风格。 Take a stroll along the Seine River. Browse through the art vendors, colorful paintings . Peek through delicate iron gates at the well-kept gardens. Watch closely for the Fren ch attention to detail that has made France synonymous with good taste. You will see i t in the design of a doorway or arch and in the little fountains and quaint balconies. N o matter where you look, you will find everyday objects transformed into works by art. 沿著塞纳河漫步。浏览艺术家们丰富色彩的绘画，透过那些精致的铁门，向?韧蹈Q那些精心照看的花园。仔细留心法国人对于细节的留心。这使得法国成为“好品味”同义字。你可以在门廊或拱门以及小喷泉和古怪有趣的走廊的设计上看见。不管你往哪里看，你都可以发现日常物品已经变成了艺术品。 As evening comes to Paris, enchantment rises with the mist over the riverfront. You m ay hear music from an outdoor concert nearby: classical, jazz, opera or chansons, thos e French folk songs. Parisians love their music. The starry sky is their auditorium. You can also hear concerts in the chateaux and cathedrals. In Paris the Music never ends. 巴黎到了傍晚时分，随着码头上的雾气升起，巴黎的诱惑力也随之而起。你也会听到附近室外音乐会所演奏的乐曲。古典、爵士、歌剧或是香颂即法国的民歌。巴黎人热爱自己的音乐，繁星点缀的天空，就是他们演奏的大礼堂。你也可以在皇宫或教堂里聆听音乐会。在巴黎，音乐是不会停止的。 Don’t miss the highlight of Paris evening: eating out. Parisians are proud of their cuisi ne. And rightly so; it’s world famous. Gourmet dining is one of the indispensable joys of living. You need a special guidebook to help you choose one of the hundreds of exc ellent restaurants. The capital of France boasts every regional specialty, cheese and wi ne the country has to offer. If you don’t know what to order, ask for the suggested me nu. The chef likes to showcase his best dishes there. Remember, you haven’t tasted th e true flavor of France until you’ve dined at a French restaurant in Paris. 错过了巴黎夜晚的高潮：下馆子。巴黎人对其烹饪非常骄傲。理当如此，因为它世界驰名。美食本来就是与生活享乐不可分割的。为了帮你从几百家绝佳的餐厅中作选择，你需要一本特?e的指南。法国的首都以各地的特色风味、乳酪和酒著称于世，如果你不知道要叫什么，可以要“推荐菜单”来看。大厨喜欢在此将他最拿手的菜作一番橱窗展示。请记住，在你尚未在巴黎的法国餐厅里吃过饭之前，都不算尝过法国真正的风味 Paris has long inspired opinionated outbursts, from delusional to denouncing, but on one matter travelers remain in agreement: it's among the most stimulating cities in the world. Paris assaults all the senses, demanding to be seen, heard, touched, tasted and smelt. From luminescent landmarks to fresh poodle droppings on the pavement, the city is everything it should be - the very essence of all French things. If you come here expecting all you've heard to be true, you won't leave disappointed.