NANO EXPRESS
Preparation and Evaluation of Poly(Ethylene Glycol)–Poly(Lactide)Micelles as Nanocarriers for Oral Delivery of Cyclosporine A
Yanhui Zhang ?Xinru Li ?Yanxia Zhou ?
Xiaoning Wang ?Yating Fan ?Yanqing Huang ?
Yan Liu
Received:5February 2010/Accepted:16March 2010/Published online:27March 2010óThe Author(s)2010.This article is published with open access at https://www.doczj.com/doc/0115785166.html,
Abstract A series of monomethoxy poly(ethylene gly-col)–poly(lactide)(mPEG–PLA)diblock copolymers were designed according to polymer–drug compatibility and synthesized,and mPEG–PLA micelle was fabricated and used as a nanocarrier for solubilization and oral delivery of Cyclosporine A (CyA).CyA was ef?ciently encapsulated into the micelles with nanoscaled diameter ranged from 60to 96nm with a narrow size distribution.The favorable stabilities of CyA-loaded polymeric micelles were observed in simulated gastric and intestinal ?uids.The in vitro drug release investigation demonstrated that drug release was retarded by polymeric micelles.The enhanced intestinal absorption of CyA-loaded polymeric micelles,which was comparable to the commercial formulation of CyA (Sandimmun Neoral ò),was found.These suggested that polymeric micelles might be an effective nanocarrier for solubilization of poorly soluble CyA and further improving oral absorption of the drug.
Keywords Monomethoxy poly(ethylene glycol)–poly(lactide)áPolymeric micelles áCyclosporine A áSolubility parameter áIn vitro release áIntestinal absorption
Introduction
The oral route is the most common route of drug admin-istration in view of its convenience and patient acceptance,even more so in the case of chronic therapies [1].Many existing and new therapeutic entities are characterized by a low degree of water solubility leading to poor and erratic oral bioavailability [2].In order to overcome this hurdle,several strategies such as micronization [3,4],formation of solid solutions [5],microemulsi?cation [6],and novel drug delivery systems,including nanoparticles [7],lipid-based vesicles [8,9],have been proposed.Among these approa-ches,polymeric micelles,constituted of amphiphilic block copolymers,have attracted much attention in the decade [10–12].Generally,block copolymers with concentration above the critical association concentration (CAC)self-assemble into spherical polymeric micelles with a core–shell structure in water:the hydrophobic segments aggre-gate to form an inner core being able to accommodate hydrophobic drugs with improved solubility by hydro-phobic interactions;the hydrophilic shell consists of a brush-like protective corona that stabilizes the micelles in aqueous solution [13–15].Polymeric micelles as novel drug vehicles present numerous advantages,such as reduced side effects of drugs,selective targeting,stable storage,stable toward dilution,and prolonged blood cir-culation time [15,16].Furthermore,polymeric micelles possess a nanoscaled size with a narrow distribution.They can protect drugs against premature degradation in vivo owing to their core–shell architecture [17,18].More importantly,polymeric micelles are fabricated according to the physicochemical properties of drugs and the compati-bility between the core of micelles and drug molecules [15,19].From the pharmaceutical point of view,these amphiphilic carriers can solubilize more poorly
Y.Zhang áX.Li áY.Zhou áX.Wang áY.Fan áY.Liu (&)Department of Pharmaceutics,School of Pharmaceutical
Sciences,Peking University,Xueyuan Road 38,Haidian District,Beijing 100191,People’s Republic of China e-mail:yanliu@https://www.doczj.com/doc/0115785166.html,
Y.Huang
Pharmaceutical Teaching Experiment Center,
School of Pharmaceutical Sciences,Peking University,Beijing 100191,People’s Republic of China
Nanoscale Res Lett (2010)5:917–925DOI 10.1007/s11671-010-9583-4
water-soluble drugs within their hydrophobic core than most surfactant micelles.Since most of polymeric micelles are intended to be administered intravenously[20],the development of polymeric micelles via the oral route has been attracted attention[16,21,22].Francis et al.[9] reported that the polymeric micelles exhibited high sta-bility in gastric and intestinal?uids and no signi?cant cytotoxicity toward Caco-2cells,and the apical-to-basal permeability of Cyclosporine A(CyA)across Caco-2cells increased signi?cantly when loaded in polymeric micelles compared to free CyA.However,the absorption enhance-ment of drug loaded in polymeric micelles by oral delivery to rats has remained elusive.These prompted us to inves-tigate the suitability of polymeric micelles as carriers to enhance the oral absorption of BCS Class II(i.e.,low solubility–high permeability)drugs.
In the present study,CyA which belongs to BCS Class II was selected as a model drug.CyA is a highly lipo-philic cyclic undecapeptide of11amino acids,and a highly effective immunosuppressive agent which is widely used in clinic for prevention of allograft rejection after organ transplantation and treatment of autoimmune disease[23–25].Nevertheless,the oral bioavailability of CyA is low and irregular[26]due to the large molecular weight(1202Da),low solubility in water(23l g/mL at room temperature)[27],very high lipophilicity (log P=2.92)[28],a substrate of P-glycoprotein,and vulnerable to intestinal mucosa and liver P4503A4.The currently available oral formulation of CyA is in the form of a microemulsion containing a high concentration of Cremophor RH40which has been reported to induce undesirable side effects,such as nephrotoxicity and induction of anaphylactic reactions in sensitized patients, although the oral absorption of CyA was remarkably enhanced.Consequently,there has been an urgent requirement to design and develop a novel dosage form of CyA aimed at decreasing the side effects of the current formulation while preserving the bioavailability of the drug.
The purposes of this study were to design and evaluate CyA-loaded polymeric micelles in vitro.Therefore,mono-methoxy poly(ethylene glycol)–poly(lactide)(mPEG–PLA) with molecular weight of2500,5000,10000,and15000Da for PLA block were strategically designed and synthesized by ring-opening polymerization of D,L-dilactide(D,L-LA)in the presence of mPEG with molecular weight of5000Da, respectively.The micelles preparation,CyA solubilization, and micelles properties were investigated by the size mea-surement,drug loading content(LC),encapsulation ef?-ciency(EE),stability in gastrointestinal tract,and in vitro drug release.Intestinal absorption in situ and ex vivo of CyA-loaded polymeric micelles was assessed,respectively.Materials and Methods
Materials
Cyclosporine A(CyA)was kindly donated from Hangzhou Zhongmei Huadong Pharmaceutical Co.Ltd.,China. Monomethoxy poly(ethylene glycol)with molecular weight of5000Da(mPEG)and stannous2-ethylhexanoate were purchased from Sigma.3,6-dimethyl-1,4-dioxane-2,5-dione(D,L-lactide)was obtained from Daigang Bio-logical Technology Co.Ltd.,China.All other reagents were of analytical grade,except those for HPLC assay which were of HPLC grade.
Animals
Sprague-Dawley(SD)rats were obtained from Animals Center of Peking University Health Science Center.All animals were provided with standard food and water ad libitum and were exposed to alternating12-h periods of light and darkness.Temperature and relative humidity were maintained at25°C and50%,respectively.All care and handling of animals were performed with the approval of Institutional Authority for Laboratory Animal Care of Peking University.
Prediction of Compatibility Between Polymers
and the Drug
Compatibility between polymers and the drug was pre-dicted by interaction parameters calculated from partial solubility parameter[29].The solubility parameter was obtained by Hansen’s approach,where the partial solubility parameters(d d,d h,and d p)for the drug(CyA)and a range of biodegradable polymers(PLA,PLGA,and PCL)were calculated by the group contribution method(GCM)[30] using Eqs.1,2,and3presented below.
d d?
P
F di
V
e1Td p?
????????????
P
F2
pi
q
V
e2Td h?
????????????
P
F hi
p
V
e3Twhere F di,F pi,and F hi refer to the speci?c functional group contributions van der Waals dispersion forces(F di),dipole–dipole interactions(F pi),and hydrogen bonding(F hi), respectively.While the interaction parameter between drug and polymer was calculated according to Eqs.4and5 presented below:
D d ???????????????????????????????????????????????????????????????????????????????????????
d d ;p àd d ;d àá2td p ;p àd p ;d àá2td h ;p àd h ;d àá2q ;e4T
D H M ?/p /d d d ;p àd d ;d àá2td p ;p àd p ;d àá2td h ;p àd h ;d àá2h i
:
e5T
Here,d d,p means the d d of polymer,d d,d the d d of drug (CyA),d p,p the d p of polymer,d p,d the d p of drug (CyA),d h,p the d h of polymer,d h,d the d h of drug (CyA),/p and /d mean the volume fractions of polymer and drug,respectively.
Synthesis and Characterization of mPEG–PLA Copolymers
mPEG–PLA copolymers were synthesized as previously described [20].The synthesized diblock copolymers were referred to as mPEG x –PLA y .x and y represented the number-averaged molecular weight of the mPEG and PLA block in kDa.For example,mPEG5–PLA2.5consisted of a 5-kDa mPEG block connected to a 2.5-kDa PLA block.The critical aggregation concentration (CAC)of mPEG–PLA copolymer was determined by ?uorescence spec-troscopy using pyrene (Fluka,[99%)as a hydrophobic probe as previously reported [20].The ?uorescence spectra of pyrene were measured at varying copolymer concen-trations using a Shimadzu RF-5301PC ?uorescence spectrometer at 25°C.The excitation wavelength was adjusted to 392nm,and the detection of ?uorescence was performed at 333and 335nm.CAC was measured from the onset of a rise in the intensity ratio of peak at 335nm to peak at 333nm in the ?uorescence spectra of pyrene plotted versus the logarithm of polymer concentration.Preparation of mPEG–PLA Polymeric Micelles
mPEG5–PLA2.5and mPEG5–PLA5polymeric micelles were prepared by rotary evaporation method [31].In brief,25mg of mPEG–PLA was dissolved in 10mL of methanol followed by evaporation under vacuum at 60°C to form a homogeneous ?lm.The resulting ?lm was dispersed in 10mL of water at 60°C and then vortexed for 3min.The mixture was ?ltered through a 0.45-l m ?lter (Millex-GV,Millipore,USA)to obtain a clear and homogeneous micellar solution.The CyA-loaded micelles were prepared as described above except 25mg of mPEG–PLA was replaced by a mixture of 5mg of CyA and 25mg of mPEG–PLA.
mPEG5–PLA10and mPEG5–PLA15polymeric micelles were prepared by dialysis method [20].In brief,25mg of mPEG–PLA and 5mg of CyA were dissolved in 3mL of dimethyl sulfoxide (DMSO).The solution was then intro-duced into a dialysis bag (Spectrapor,MWCO =3500)and
dialyzed against 1L of distilled water,which was replaced every 4h in the course over 48h.The micellar solution obtained in the dialysis bag was then ?ltered through a 0.45-l m ?lter (Millex-GV,Millipore,USA)to remove nonencapsulated CyA.CyA-free micelles were produced by the same method without adding CyA at the ?rst stage of the preparation.
Particle Size Measurement
The average particle size and size distribution of polymeric micelles were determined by dynamic light scattering (DLS)(Zetasizer ZEN 3600,Malvern,UK).All DLS measurements were performed with a scattering angle of 90°at 25°C after diluting the micellar solution to an appropriate volume with water.The results were the mean values of three samples.
Determination of Encapsulation Ef?ciency and Drug Loading Content
In order to determine drug loading content (LC,w/w %)and entrapment ef?ciency (EE,w/w %)of micelles,CyA-loaded polymeric micelles solution was freeze-dried and then dissolved in methanol and CyA content in micelles was determined on a Shimadzu series HPLC system (Shi-madzu LC-10AT,Kyoto,Japan)equipped with a UV detector (Shimadzu SPD-10A)and reversed phase column (ODS C18,5l m,4.6mm 9250mm,Dikma,China).The mobile phase consisted of acetonitrile/water (90/10,v/v)and was pumped at a ?ow rate of 1.0mL/min.The detection wavelength was 210nm.The column tempera-ture was set to 70°C.The LC and EE of the micelles were then calculated based on the following formula:LC e%T
?
mass of CyA extracted from freeze-dried micelles total mass of freeze-dried micelle
?100%;
EE e%T
?
mass of CyA extracted from freeze-dried micelles total mass of CyA loaded micelle initially used ?100%:Stability of CyA-Loaded Polymeric Micelles in Simulated Gastric and Intestinal Fluids
The stability of CyA-loaded polymeric micelles in simu-lated gastric ?uid (SGF)and simulated intestinal ?uid (SIF)for a period of 12h was evaluated from the changes of EE
and particle size of micelles with time upon incubation of the micelles samples in SGF or SIF at37°C,respectively. The EE and particle size of micelles were determined as described earlier.
In Vitro Release of CyA from Micelles
One milliliter of micelles solution with known CyA content was placed into a dialysis bag with molecular weight cut-off of50kDa.The dialysis bag was immersed into a?ask containing30mL of release medium(SGF or SIF)con-taining30%(v/v)ethanol(sink condition)which was kept in a constant temperature shaking water bath at37°C and 100rpm.At predetermined time intervals,aliquots(1mL) of the release medium was taken and replaced by fresh medium.The content of CyA in the medium was measured by HPLC method as described above.The cumulative release percentage of CyA was calculated.
Intestinal Absorption
Male SD rats weighing200±20g were used for this research.All animals were housed with free access stan-dard food and tap water,and exposed to alternating12h periods of light and darkness.Temperature and relative humidity were maintained at25°C and50%,respectively. After an acclimatization period of2days,the rats were fasted for12h but allowed free access to water prior to the experiments.Rats were anaesthetized via intraperitoneal injection of15%w/v urethane at a dose of1.5g/kg and a laparotomy was performed.
In situ rat perfusion experiments[32–35]The abdominal cavity was opened,and a segment of the ileum was exposed. The segment was?ushed with50ml of warm Krebs–Ringer buffer solution[KRB,pH7.4,composed of(in mM):NaCl 111.9,KCl 5.0,CaCl2 1.2,MgCl2 1.2,NaH2PO40.4, Na2HPO41.6,NaHCO325.0,NaGlutamate4.9,NaPyruvate 4.9,Na2Fumarate5.4,glucose11.5]to remove the luminal contents and then?ushed with air to minimize the amount of luminal?uid.These rats were placed in a warm table for the absorption studies after surgery.
The perfusion solution was prepared using1mg/mL of CyA-loaded polymeric micelles(mPEG5-PLA5)or Sand-immun Neoralòin KRB containing3-mg/mL phenol red. Phenol red acted as a nonabsorbable marker in the luminal medium to correct the appreciable in?uence of the secretion or absorption of water on CyA content during the experi-ment.A recirculating system was constructed by connecting a small reservoir containing40mL of stirring perfusion solution kept at37°C with the inlet cannula and by directing the?ow from the outlet cannula back to the res-ervoir.The perfusion pump(BT300-300M,Lange,Co,Ltd.China)was utilized to drive the perfusate at a rate of 2mL/min through the inlet cannula into the intestinal segment.0.5mL of perfusate samples were collected and replaced by fresh KRB containing3-mg/mL phenol red at 0.25,0.5,1,2,3,4,6,8h after perfusion.The CyA con-centration in the perfusate samples was measured by HPLC method as described above,and the phenol red concentra-tion was determined using UV spectrophotometer(Agilent 8453,Agilent Technologies,UK)at558nm.
Ex vivo experiments[29,36]A laparotomy was per-formed and segment of ileum were removed and used for the everted gut sac technique.In brief,the ileum was rinsed twice with saline solution(0.9%NaCl)at room temperature. Then the specimen was put into oxygenated Tyrode solution [pH7.4,composed of(in mM):NaCl115,KCl2.7,CaCl2 1.8,MgCl21.1,NaH2PO40.4,Na2HPO41.6,NaHCO312.7, glucose5.6]immediately at37°C.Then the intestine was gently everted over a glass rod and divided into5-cm sacs which were?lled with fresh oxygenated Tyrode solution using silk suture.The sacs were incubated in gentle shaking oxygenated Tyrode solution containing CyA-loaded poly-meric micelles or Sandimmun Neoralòfor120min. Thereafter,the Tyrode solution with and without sacs was collected.The content of remaining CyA in the medium was measured by HPLC method as described above.The mass of the bound CyA was determined by subtraction of the mass of remaining CyA in the medium from the initial mass of CyA and reported as percent binding:
Binde%T
?1à
mass of CyA remaining in the medium
total mass of CyA loaded micelle initially used
?100%:
The commercial formulation of CyA,Sandimmun Neoralò,was also tested as control.
Statistical Analysis
All data were expressed as mean standard deviation(SD) unless particularly outlined.The statistical signi?cance of differences among more than two groups was determined by one-way ANOVA by the software SPSS13.0.A value of p\0.05was considered to be signi?cant.
Results and Discussion
Compatibility Between Polymers and the Drug
The compatibility between a drug and polymer is known to be one of the key factors in determining the effectiveness
of polymeric delivery systems [30].In general,the better the compatibility between a drug and polymer,the higher the loading content and the slower the drug release as well.Thus,the compatibility between a drug and polymer which was referred to miscibility and interaction has been shown to be of importance in the design of a wide range of delivery systems including polymeric micelles.
Thermodynamic criteria for the mutual miscibility of two substances is based on the Gibbs energy of mixing (D G M )which is de?ned by the following equation:D G M =D H M –T D S M .The two substances are said to be mutually soluble if D G M is negative.Equation 5was used to calculate D H M considering it takes into account all forces:Van der Waals dispersion,dipole–dipole,and
hydrogen bonding.A smaller D H M indicated a stronger interaction between two substances.As shown in Eq.5,the value of D H M mainly depends on that of D ,indicating that the compatibility between a drug and polymer can be evaluated by D or D H M which is referred as interaction parameter.The interaction parameters of CyA with various polymers calculated by GCM were listed in Table 1.The results showed that the interaction parameter of CyA with PLA was lower than those of other drug–polymer pairs,suggesting that PLA was identi?ed to be more compatible to CyA among the three polymers.Based on the results calculated,PLA was therefore selected as the hydrophobic segments of the amphiphilic copolymer for the subsequent studies.
Synthesis and Characterization of mPEG–PLA Copolymers
mPEG–PLA copolymers were synthesized by ring-opening polymerization of D ,L -dilactide by using mPEG as initiator.Various chain lengths of PLA in the copolymers were obtained by modulating the feed ratio of mPEG and
Table 1The interaction parameters for CyA and various polymers Polymer D (J/cm 3)D H M (J)PLA
4.030.78PLGA (LA/GA,50:50)
5.37 2.16PCL
5.68
2.97
Fig.11H-NMR spectrum of mPEG5–PLA2.5copolymer
D,L-dilactide.Figure1showed the1H-NMR spectrum of mPEG5–PLA2.5which was representative for all synthe-sized mPEG–PLAs:the peak at3.6ppm corresponded to methylene protons(–OCH2CH2–)in mPEG blocks,signals at1.5ppm could be attributed to the hydrogen atoms of CH3O-groups for PLA segments,respectively[33].The ratio of number-averaged molecular weight(M n)of the mPEG to PLA blocks of each copolymer was calculated from the1H-NMR data.In brief,the ratio of the number of methylene protons(–OCH2CH2–)in PEG and(–OCH3)in PLA was equally as the ratio of integral value of H in3.6 and1.5ppm.The molecular weight of mPEG was known as5000and the molecular weight of PLA linked to mPEG would be known as listed in Table2.It could be seen that the copolymers could be synthesized reliably.
Micelle formation requires the balance between the attractive interactions of the insoluble PLA moieties and the repulsive interactions of the soluble PEG segments. In effect,PEG moderates the association of PEG–PLA molecules,leading to micelle formation.When the PEG proportion in the copolymer chains is too low,PEG seg-ments cannot moderate the association of the separating PLA–PEG molecules,and macroscopic agglomerates are formed.In line with these observations,Shin et al.reported that micelles could not be formed by a poly(ethylene gly-col)/epsilon-caprolactone copolymer with a too-high cap-rolactone content(70.7%by weight)[37].Moreover,a low CAC is an important feature for the application of these micelles in drug delivery because it assures that micelles will be stable in vivo,where considerable dilution takes place.Polymeric micelles can be formed only when the block copolymer concentration is higher than CAC which characterizes the micelle stability.The micellization behavior of the synthesized mPEG5–PLAy copolymers was therefore investigated.Table2summarized the CAC values of various synthesized mPEG–PLA diblock copolymers ranging from 1.08910-7to 3.07910-7 mol/L.These values appeared much lower than those of low molar mass surfactants,indicating that micelles formed from mPEG–PLA copolymers as drug carriers could pre-serve stability without dissociation after dilution[13,38],which was of major interest for oral administration. Moreover,the hydrophilicity of mPEG–PLA copolymers mainly depending on the mass ratio of mPEG/PLA or mPEG content had much in?uence on the CAC value[39]. As shown in Table2,the CAC values of copolymers appeared to decrease with increasing of PLA block length. mPEG5–PLA15had longer hydrophobic PLA block and, thus,could self-assemble more easily to form micelles, leading to lower CAC value.This was consistent with our previous report[20].
Characterization of mPEG–PLA Polymeric Micelles
The polymeric micelles were evaluated by particle size, encapsulation ef?ciency,and drug loading content.The mean particle size and size distribution of CyA-loaded polymeric micelles were determined by DLS.The mean diameter ranged from60to96nm for CyA-loaded micelles with narrow distributions(Table2).It appeared that the micelle size gradually increased with increasing of the length of PLA chains,which was consistent with our previous report[20].This result was also in agreement with the characteristic of amphiphilic copolymeric micelles,i.e., the shorter the hydrophobic block length,the smaller the micelles.It might be attributed to the fact that it is dif?cult to form compact polymeric micelles for amphiphilic copolymers with longer hydrophobic chain length.
The encapsulation ef?ciency(EE)and loading content (LC)of micelles were presented in Table2.It could be found that the LC and EE of CyA-loaded mPEG5–PLA5 polymeric micelles were signi?cantly higher than those of others(p\0.05for LC and p\0.01for EE,respectively). Notably,the results were not the general trend that LC and EE of polymeric micelles increased with increasing hydrophobic chain length.This?nding may be assigned to the factors contributing to LC and EE.In general,LC and EE depend on the composition of the copolymers[38,40, 41],the length of hydrophobic block[42],initial diblock copolymeric concentration or the feed weight ratio of the drug to the copolymer,the solvent used in formulation process[41,43]and micelle preparation method[44,45],
Table2Characterization of mPEG5–PLAy copolymers and polymeric micelles
Copolymers M n(PLA)CAC(10-7mol/L)CyA loaded LC(%)EE(%)
d(nm)PDI
mPEG5–PLA2.52249 3.0760.1±8.20.2312.1±0.844.0±3.0 mPEG5–PLA54802 1.9971.9±0.40.1915.2±1.177.9±4.1 mPEG5–PLA109247 1.5789.0±0.50.2010.7±1.533.1±2.1 mPEG5–PLA1515825 1.0895.2±1.20.239.7±0.210.9±0.2
d and PDI represent th
e average diameter and the polydispersity index(PDI)o
f micelles in aqueous solution,respectively
and so on.In the case of our experiment,mPEG5–PLA2.5 and mPEG5–PLA5polymeric micelles were prepared by rotary evaporation method,whereas mPEG5–PLA10and mPEG5–PLA15polymeric micelles were prepared by dialysis method.In general,the LC and EE of polymeric micelles prepared by rotary evaporation method are higher than those of polymeric micelles prepared by dialysis method[45–47].The results in current study were in agreement with this trend.Moreover,for mPEG5–PLA2.5 and mPEG5–PLA5polymeric micelles,the LC and EE were the general trend,i.e.,increased with increasing hydrophobic chain length,however,the results were opposite for mPEG5–PLA10and mPEG5–-PLA15poly-meric micelles,as reported that LC and EE decreased with increasing hydrophobic chain length when polymeric micelles were prepared by dialysis method due to enhanced water-insolubility of copolymers[48].
Stability Studies of CyA-Loaded Polymeric Micelles
in Simulated Gastric and Intestinal Fluid
The particle size and entrapment ef?ciency of micelles incubated in SGF and SIF at37°C were determined at predetermined time intervals.As shown in Fig.2,there was no signi?cant change in either EE or particle size of micelles with time from0h until12h,indicating that the CyA-loaded polymeric micelles were stable in SGF and SIF at37°C for a long enough time.Further,the micelles appeared equally stable in these two media for the time period studied.
In addition,in the case of release experiment,it was found that no CyA was detected in SGF or SIF at the end of 24h,which might be due to the fact that the amount of released drug was probably below the detection limit of HPLC method.This might be advantageous in micelle stability aspect[49].Since micelles retained almost all the incorporated CyA,the formulations had high stability,and drug in micelle core would be protected from biological degradation in GI before reaching absorption site.Thus, from a stability perspective,these micelles appear to be suitable candidates as an oral dosage form of CyA.
In Vitro Release of CyA from Micelles
When developing oral colloidal delivery systems for highly hydrophobic drugs such as CyA,it is important to ade-quately control the release rate to avoid precipitation upon dilution in the stomach and maximize the absorption in the small bowel.Therefore,the in vitro release of CyA from polymeric micelles at different release medium was eval-uated.Prior to conducting these release assays,it was veri?ed that CyA could freely diffuse through the dialysis membrane(Fig.3),and that sink condition was respected by addition of30%(v/v)ethanol in the release medium while preserving the stability of polymeric micelles(data not shown).In addition,the release property of CyA from polymeric micelles in SGF did not differ from that in SIF (data not shown),indicating that the release media had no effect on the release of CyA from micelles.Consequently, SIF was chosen as the release medium for the subsequent release studies.
As shown in Fig.3,85%of CyA was released from polymeric micelles within24h.The comparison of the pro?les of CyA release from the micelles and the solution showed that the entrapment of CyA in the mPLA–PEG micelles could signi?cantly retard its in vitro release [16,50].Assuming that similar sustained release also occurs in vivo,this would provide the micelles the necessary time required to exert their in?uence on drug bioavailability.In addition,the release rate of CyA from mPEG5–PLA10 micelles was comparable to that from mPEG5–PLA15 micelles and faster than that from mPEG5–PLA2.5
and
mPEG5–PLA5micelles,and remarkable burst release was observed in the release pro?les of the former.These might be attributed to the fact that it is dif?cult to form compact polymeric micelles for amphiphilic copolymers with longer hydrophobic chain length.Furthermore,polymeric micelles prepared by dialysis method were looser than those pre-pared by other methods.In addition,as compared to the CyA-loaded mPEG5–PLA2.5micelles,mPEG5–PLA5 micelles released markedly slower,which was consistent with previous report[51].This might be assigned to the relatively bigger size of mPEG5–PLA2.5micelles[52]and stronger interaction between CyA and longer hydrophobic chain of PLA.As reported earlier,the release of a drug from polymeric micelles could be affected by the level of drug encapsulation,its physical state,the nature of the polymer and the level of polymer-drug compatibility[30,53,54].
Based on the results of CyA-loading and CyA-release experiments,mPEG5–PLA5polymeric micelles were therefore selected for the subsequent studies.
Intestinal Absorption
The absorption pro?les of CyA-loaded mPEG5–PLA5 polymeric micelles and commercial formulation(iSan-dimmun Neoralò)were evaluated,respectively.As shown in Fig.4,the cumulative absorption percentage of CyA-loaded polymeric micelles was higher than that of Sand-immun Neoralòat each determined time point.For example,the cumulative absorption percentage of CyA-loaded polymeric micelles was higher than65%within the ?rst2h while it was lower than60%for Sandimmun Neoralò.This absorption enhancement of CyA-loaded polymeric micelles compared with Sandimmun Neoralòwas further con?rmed by the everted sac experiment which showed that the binding percentage(59.93±2.17%)of CyA-loaded polymeric micelles was signi?cantly higher than that of Sandimmun Neoralò(51.24±5.79) (p\0.05).The absorption enhancement of CyA by poly-meric micelles could be attributed to the fact that the sol-ubility of CyA which belongs to BCS class II drug(i.e., low solubility–high permeability)according to BCS was enhanced and the nanoscaled size of micelles would make the micelles adhere to the intestinal mucosal epithelial to get a longer absorbed time.
Earlier investigation demonstrated that polymeric micelles transported Caco-2cell monolayers neither by the paracellular route nor by M-cells.One possible mechanism was that polymeric micelles might undergo an active transport that probably involved endocytosis,which was con?rmed by using FAE cell model which mimics M-cells and are specialized in the uptake of macromolecules and particles via transcytosis[55].Further experiments should be conducted using Caco-2cell model due to the fact Caco-2cells were considered to be a representative model for assessing intestinal uptake of drugs,which are in progress by our group.
Conclusions
mPEG–PLA micelles were designed and prepared to encapsulate CyA,a highly lipophilic drug.The results of the present study demonstrated that polymeric micelles sustained the drug release,and the CyA-loaded mPEG–PLA micelles were stable in gastrointestinal tract.As anticipated,the intestinal absorption of CyA was signi?-cantly improved by polymeric micelles and comparable to that of Sandimmun Neoralò.These?ndings indicated that polymeric micelles would be a promising nanocarrier for improving the oral absorption of poorly absorbable drugs although the mechanism of polymeric micelles to cross intestinal barrier is still uncertain.
Acknowledgments We would like to acknowledge the support of this work by the National Development of Signi?cant New Drugs (New Preparation and New Technology,2009zx09310-001)and the National Basic Research Program of China(973program, 2009CB930300).
Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which per-mits any noncommercial use,distribution,and reproduction in any medium,provided the original author(s)and source are credited. References
https://www.doczj.com/doc/0115785166.html,velle,N.W.Thomas,J.Holland,S.S.Davis,Adv.
Drug Deliv.Rev.18,5
(1995)
2.C.A.Lipinski,F.Lombardo,B.W.Dominy,P.J.Feeney,Adv.
Drug Deliv.Rev.46,3(2001)
3.D.R.Guay,Ann.Pharmacother.33,1083(1999)
4.R.G.Strickley,Pharm.Res.21,201(2004)
5.A.T.Serajuddin,J.Pharm.Sci.88,1058(1999)
6.K.Kawakami,T.Yoshikawa,T.Hayashi,Y.Nishihara,
K.Masuda,J.Control.Release81,75(2002)
7.R.H.Muller,K.Mader,S.Gohla,Eur.J.Pharm.Biopharm.50,
161(2000)
8.C.J.Porter,W.N.Charman,Adv.Drug Deliv.Rev.50(Suppl.1),
S127(2001)
9.M.F.Francis,M.Cristea,Y.Yang,F.M.Winnik,Pharm.Res.22,
209(2005)
10.V.P.Torchilin,Adv.Drug Deliv.Rev.54,235(2002)
11.A.Rosler,G.W.Vandermeulen,H.A.Klok,Adv.Drug Deliv.
Rev.53,95(2001)
12.M.Jones,J.Leroux,Eur.J.Pharm.Biopharm.48,101(1999)
13.X.Shuai,T.Merdan,A.K.Schaper,F.Xi,T.Kissel,Bioconjug.
Chem.15,441(2004)
14.T.Riley,C.R.Heald,S.Stolnik,M.C.Garnett,L.Illum,S.S.
Davis,Langmuir19,8428(2003)
15.L.Liu,C.Li,X.Li,Z.Yuan,Y.An,B.He,J.Appl.Polym.Sci.
80,1976(2001)
16.E.Pierri,K.Avgoustakis,J.Biomed.Mater.Res.75,639(2005)
17.M.Wilhelm,C.L.Zhao,Y.C.Wang,R.L.Xu,M.A.Winnik,J.L.
Mura,G.Riess,M.D.Croucher,Macromolecules24,1033(1991) 18.R.Barreiro-Iglesias,L.Bromberg,M.Temchenko,T.A.Hatton,A.
Concheiro,C.Alvarez-Lorenzo,J.Control.Release97,537(2004) 19.P.Z.Li,X.R.Li,H.X.Zhou,Y.H.Zhang,F.Wang,Y.Liu,Chin.
J.New Drug18,262(2009)
20.Z.L.Yang,X.R.Li,K.W.Yang,Y.X.Zhou,X.W.Chen,Y.H.
Zhang,F.Wang,L.J.Ren,Nanoscale Res.Lett.4,1502(2009) 21.M.Tobio,A.Sanchez,A.Vila,I.I.Soriano,C.Evora,J.L.Vila-
Jato,M.J.Alonso,Colloids Surf.B18,315(2000)
22.H.Yin,Y.H.Bae,Eur.J.Pharm.Biopharm.71,223(2009)
23.S.Noble,A.Markham,Drugs50,924(1995)
24.C.Richardson,P.Emery,Drugs50(Suppl.1),26(1995)
25.J.Dai,T.Nagai,X.Wang,T.Zhang,M.Meng,Q.Zhang,Int.J.
Pharm.280,229(2004)
26.A.Lindholm,S.Henricsson,M.Lind,R.Dahlqvist,Eur.J.Clin.
Pharmacol.34,461(1988)
27.K.Miyake,F.Hirayama,K.Uekama,J.Pharm.Sci.88,39(1999)
28.J.S.Woo,M.G.Piao,D.X.Li,D.S.Ryu,J.Y.Choi,J.A.Kim,J.H.
Kim,S.G.Jin,D.D.Kim,W.S.Lyoo,C.S.Yong,H.G.Choi,Int.
J.Pharm.345,134(2007)
29.L.Barthe,J.Woodley,G.Houin,Fundam.Clin.Pharmacol.13,
154(1999)
30.J.Liu,Y.Xiao,C.Allen,J.Pharm.Sci.93,132(2004)31.X.Zhang,J.K.Jackson,H.M.Burt,Int.J.Pharm.132,195(1996)
32.S.M.Chen,J.F.Liao,C.D.Kuo,L.T.Ho,Nephron.Physiol.96,
113(2004)
33.S.Deferme,R.Mols,W.Van Driessche,P.Augustijns,J.Pharm.
Sci.91,2539(2002)
34.J.Van Gelder,S.Deferme,P.Annaert,L.Naesens,E.De Clercq,
G.Van den Mooter,R.Kinget,P.Augustijns,Drug Metab.
Dispos.28,1394(2000)
35.P.Annaert,J.J.Tukker,J.van Gelder,L.Naesens,E.de Clercq,
G.Van den Mooter,R.Kinget,P.Augustijns,J.Pharm.Sci.89,
1054(2000)
36.C.A.Santos,J.S.Jacob,B.A.Hertzog,B.D.Freedman,D.L.
Press,P.Harnpicharnchai,E.Mathiowitz,J.Control.Release61, 113(1999)
37.I.G.Shin,S.Y.Kim,Y.M.Lee,C.S.Cho,Y.K.Sung,J.Control.
Release51,1(1998)
38.S.Y.Kim,I.G.Shin,Y.M.Lee,C.S.Cho,Y.K.Sung,J.Control.
Release51,13(1998)
39.S.Li,M.Vert,Macromolecules36,8008(2003)
40.Y.Hu,X.Jiang,Y.Ding,L.Zhang,C.Yang,J.Zhang,J.Chen,
Y.Yang,Biomaterials24,2395(2003)
41.V.Pade,S.Stavchansky,Pharm.Res.14,1210(1997)
42.S.Cheon Lee,C.Kim,I.Chan Kwon,H.Chung,S.Young Jeong,
J.Control.Release89,437(2003)
43.Y.Dong,S.S.Feng,Biomaterials26,6068(2005)
44.V.P.Sant,D.Smith,J.C.Leroux,J.Control.Release97,301
(2004)
45.G.Gaucher,M.H.Dufresne,V.P.Sant,N.Kang,D.Maysinger,
J.C.Leroux,J.Control.Release109,169(2005)
46.F.Kohori,M.Yokoyama,K.Sakai,T.Okano,J.Control.Release
78,155(2002)
https://www.doczj.com/doc/0115785166.html,vasanifar,J.Samuel,G.S.Kwon,J.Control.Release77,
155(2001)
48.H.Ge,Y.Hu,X.Jiang,D.Cheng,Y.Yuan,H.Bi,C.Yang,
J.Pharm.Sci.91,1463(2002)
49.Z.Gao,A.N.Lukyanov,A.Singhal,V.P.Torchilin,Nano Lett.2,
979(2001)
50.Z.L.Yang,X.R.Li,K.W.Yang,Y.Liu,J.Biomed.Mater.Res.
85,539(2008)
51.Y.Zhang,T.Jin,R.X.Zhuo,Colloids Surf.B44,104(2005)
52.K.W.Yang,X.R.Li,Z.L.Yang,P.Z.Li,F.Wang,Y.Liu,
J.Biomed.Mater.Res.88,140(2009)
53.Y.I.Jeong,J.B.Cheon,S.H.Kim,J.W.Nah,Y.M.Lee,Y.K.
Sung,T.Akaike,C.S.Cho,J.Control.Release51,169(1998)
54.J.Lee,E.C.Cho,K.Cho,J.Control.Release94,323(2004)
55.F.Mathot,A.des Rieux,A.Arien,Y.J.Schneider,M.Brewster,
V.Preat,J.Control.Release124,134(2007)
雅思口语素材汇总之端午节 雅思口语素材:Dragon Boat Festival(端午节) Qu Yuan The Dragon Boat Festival, also called the Duanwu Festival, is celebrated on the fifth day of the fifth month according to the Chinese calendar. For thousands of years, the festival has been marked by eating zong zi (glutinous rice(糯米)wrapped to form a pyramid using bamboo or reed leaves) and racing dragon boats. The festival is best known for its dragon-boat races, especially in the southern provinces where there are many rivers and lakes. This regatta(赛舟会)commemorates the death of Qu Yuan , an honest minister who is said to have committed suicide by drowning himself in a river. Qu was a minister of the State of Chu situated in present-day Hunan and Hubei provinces, during the Warring States Period (475-221BC)(战国时期). He was upright, loyal and highly esteemed for his wise counsel that brought peace and prosperity to the state. However, when a dishonest and corrupt prince vilified Qu, he was disgraced and dismissed from office. Realizing that the country was now in the hands of evil and corrupt officials, Qu grabbed a large stone and leapt into the Miluo River on the fifth day of the fifth month. Nearby fishermen rushed over to try and save him but were unable to even recover his body. Thereafter, the state declined and was eventually conquered by the State of Qin. The people of Chu who mourned the death of Qu threw rice into the river to feed his ghost every year on the fifth day of the fifth month. But one year, the spirit of Qu appeared and told the mourners that a huge reptile(爬行动物)in the river had stolen the rice. The spirit then advised them to wrap the rice in silk and bind it with five different-colored threads before tossing it into the river. During the Duanwu Festival, a glutinous rice pudding called zong zi is eaten to symbolize the rice offerings to Qu. Ingredients such as beans, lotus seeds(莲子), chestnuts(栗子), pork fat and the golden yolk of a salted duck egg are often
口语常用背诵素材 一，喜好和厌恶： 1.（释放压力）I guess most young people enjoy listening to music. It’s a perfect way to reduce stress/relieve stress. (*It’s a perfect stress-buster.) 2.（休闲）I think the best way to relax and kill time (kick back and relax) is to be with friends. Chatting with them helps me unwind/wind down (* Chatting with them is very therapeutic). 3.（放松）I found it pretty relaxing to flick through a magazine before going to bed (*before hitting the sack/hitting the hay). 4.（运动）Jogging on sunny days and simply basking in the sun(bathing in the sun) is super enjoyable(pleasurable). /Jogging is my favorite workout. It can always cheer me up after I’ve been down and depressed. And it can help me shed some unwanted weight. 5.（喜欢，提升心情）I’m quite into watching sitcom (I’m fascinated by, I’m crazy about, I adore, I’m very fond of...). Spending 20 minutes in front of the screen and having a good laugh after dinner really puts me in a better mood/ switch my mood/ lift my spirits. 6.（天气）I fancy spring most compared to the other three. Summer is simply too hot and stuffy (*muggy), and you can’t stay out for two minutes without getting sweaty and smelly. Autumn is too dry and winter too freezing cold. 7.（电影）I’m a movie buff (Movies are my biggest pastime), and I would either catch one on my couch or go to the movie theatre when they have the one I like on the big screen./ It's a great form of relaxation for me to while away the hours of a long flight, to keep my family together on the sofa, and to give me a bit of a thrill. 8.（无聊困难）I’m terrible at what I study now./(History is never my forte/ my strong suit). The classes are kind of a drag (It’s super dull/ *It’s mind-numbing), and there’s always loads of (tons of) homework to do. Memorizing those facts and years is a lot of effort (is tricky; is no picnic; is challenging for me). 9.（不能忍）I can’t stand (I hate, I totally dislike) the busy traffic in my city. I’m sick and tired of always getting stuck in traffic for a long time during rush hours. It really bothers me (It drives me crazy, *It drives me up the wall). 10. （受欢迎）Hip-hop is really trendy (is catching on, is all the rage) among young people these days. 二，时间和地点 11. （优点）What’s great about my home town is that there are plenty of shopping malls, coz I’m a shopaholic and I can shop for hours. 12. （远）The stadium is quite far away from where I live, and every time I want to do there, it takes me roughly 40 minutes by bus to arrive. (It’s one-hour drive from the city center.) 13. （方便）My apartment is in the center/heart of the city, a handy location where I can find supermarkets and clubs right on my doorstep. It’s a bit noisy though. 14. （近）I’m a movie-goer and and there’s a movie theater pretty close to my home, so I go there quite often (frequently). (close to my home= *within walking distance of my home , *in close proximity to my home) 15. （经常）I have a heavy workload at school, so I have to go to the library to study pretty much
雅思口语素材 Document serial number【LGGKGB-LGG98YT-LGGT8CB-LGUT-
Useful Expressions: Words and phrases Friends and communication: solidify/ strengthen/ enhance/ promote communication / connection with mutual understanding relationship network/circle of f r i e n d s cultivate/develop friendship with s b . keep steady relationship with sb. establish interpersonal networksac build up the social circle spur message transmission Knowledge and experience widen one’s outlook broaden one’s vision/horizon acquire knowledge and skills comprehensive/overall quality
expand/enlarge one’s scope of knowledge knowledge reserve/base/storage theoretical knowledge practical skills social experience broaden one’s knowledge base promote one’s overall/ comprehensive competence accumulate experiences learn lessons from past experiences Work and experience the scarcity of employment o p p o r t u n i t i lay the foundations for career p r o s p e r i t y
U s e f u l E x p r e s s i o n s: Words and phrases Friends and communication: mutual understanding solidify/ strengthen/ enhance/ promote communication / connection with relationship network/circle of friends cultivate/develop friendship with sb. keep steady relationship with sb. establish interpersonal networksac build up the social circle spur message transmission Knowledge and experience widen one’s outlook broaden one’s vision/horizon acquire knowledge and skills comprehensive/overall quality expand/enlarge one’s scope of knowledge knowledge reserve/base/storage theoretical knowledge practical skills social experience broaden one’s knowledge base promote one’s overall/ comprehensive accumulate experiences competence learn lessons from past experiences Work and experience the scarcity of employment opportunities lay the foundations for career prosperity immerse oneself in endless job tasks boost/augment/enhance efficiency be adept in boost one’s c ompetitiveness Health and pressure diminish individuals' leisure time drive away lassitude lighten one’s burden homework/workforce overload
近期雅思口语卡片新题素材汇总 人物Describe a classmate of yours Describe a good friend Describe a happy person Describe a colleague Describe a neighbor Describe your own personality Describe a family member Describe a child you know Describe an old person Describe an old person who has influenced you the most Describe a successful person Describe a singer Describe a sportsman Describe a movie star Describe a character in TV or movie Describe a teacher of yours Describe a famous person that you want to spend a day with.地点Describe a building at schools Describe a historical place
Describe a monument Describe an interesting building Describe a lake, river or sea. Describe a peaceful place Describe a leisure place Describe a park Describe a place of interest Describe a natural beauty Describe a city you want to live in Describe a place you have visited Describe a place you always go for shopping
一.雅思P2相关话题 一日假期 和外国朋友一起吃饺子的建议 1.The best way to eat a dumpling is in one bite. “Dumplings are designed to be consumed in one mouthful, as it’s the best way to enjoy the combination of the meat filling and the very thin and springy flour wrapper,” If you can’t use chopsticks, eat your dumplings with your fingers. Avoid using a fork at all costs, as piercing the dumpling will compromise the flavour. 3.Mix two parts vinegar with one part soy sauce for the perfect dumpling sauce. Add young ginger slices too， Chili oil is also a great addition when available. 4.Dumplings are just one element of dim sum. “Dim sum doesn’t just include dumplings. It’s also braised dishes like pork ribs, chicken feet, and beef balls. It’s actually small tapas-style dishes that are eaten in Cantonese restaurants at lunchtime,” 5.Xiao long bao dumplings are different from others as they contain broth. They originated in the Jiangnan region of China and are prepared in bamboo steaming baskets called xiao long, hence the name. 6.When eating xiao long bao or a dumpling with a ~soupy~ interior, opt for chopsticks and a spoon. “As soon as the dumplings arrive at your table, lift one from the steamer basket onto a soup spoon. Next, tear the skin of the dumpling by pressing the chopsticks from the side of the dumpling onto the spoon. The broth will ooze out onto the spoon. Sip the soup then enjoy the dumpling in one mouthful.” 7.You can tell whether your dumpling was cooked fresh or frozen by looking at the skin. “The skin of a freshly made dumpling is springy and light. “Frozen ones tend to be soggy.” 8.When makingdumplingsat home, try to keep your packages small.
雅思口语素材训练 by Tina Li Do you like music??A—肯定:Definitely yes, everyone enjoys music, and I am no exception! I love... 否定 :Well, honestly speaking, music is really not my cup of tea, simply because... ( 给出直接原因) What—pop, techno ( 电音音乐), hip-hop, rock, meditation ( 冥想乐) and especially light music.( 罗列名词) Where—Normally speaking, I would like to listen to music with my earphones when I take a ride on public transportation. ( 给出一个具体的场景) When—As long as I couldn’t go to sleep, I’d like to listen to some light music to calm myself down. ( 给出一个条件 :As long as I..., I would...)
Who—My most favourite singers include Adele, James Blunt, Avril Lavigne, and so forth. ( 喜欢的歌手) Why—I am fond of music mainly because it can cheer me up greatly when I feel down/low/ blue/bored/tired/depressed. ( 心情不好的时候让我高兴起来)?Besides, I also believe that music is an indispensable part of culture and tradition, through which I could have a better understanding of different cultures around the world, including cowboy culture, African-American street culture, the three main reli- gions and so on. ( 有助于理解不同的文化) Do you like watching movies?? A—Speaking of movies, yes, I am a big fan of all types of movies, such as...?What—comedy, action, romance, sci-fi, manga, vampire, zombie, animation...
做有偿工作的人 Describe a person you know who is doing a paid job. You should say: Who this person is What job it is; How long the job lasted; And explain why you or this person chose to do this job. 让你笑的小孩 Describe a time that a child did something that made you laugh. You should say: When this happened Who the child was What the child did And explain why it was funny 特殊的旅行 Describe an educational trip you went on when you were in school. You should say: When and where you went; Who you went with; What you did; And explain what you learned on this trip.
Describe an electronic machine you want to buy. You should say: What it is When you know this machine What specific And explain why you want this machine 难忘的广告 Describe an unforgettable advertisement (that you saw or heard liked) You should say: Where you saw or heard it What kind of advertisement it was What the contents of the advertisement were (or, what product or service was advertised) And explain how you felt when you saw or heard this advertisement/why you like it
【2019-2020】雅思口语话题素材-精选word文档 本文部分内容来自网络整理，本司不为其真实性负责，如有异议或侵权请及时联系，本司将立即删除！ == 本文为word格式，下载后可方便编辑和修改！ == 雅思口语话题素材 雅思口语素材总结雅思口语要求学生平时多多的积累素材，在口语方面要不断的加强练习。烤鸭们要多模拟不同的场景，多用丰富的口语短语，这 样你的雅思口语水平才能越来越高。下面是常用的一些口语短语，供大家参考！ 1、 a change of pace 改变步调;换口味 You cant do these chemistry experiments all day long . You certainly need a change of pace . 2、 a far cry from 相距甚远 The published book is a far cry from the early manuscript . 3、 and how 的确 A ： Shes a good dancer . B ： And how . 4、 a matter of time 时间问题 It is only a matter of time . 5、 a phone call away 一个电话之远，即愿意过来帮忙 If you need my help , do let me know . Just remember I am a phone call away . 6、 a while back 不久以前 Well , I listened to that CD you lent me a while back . 7、 all along 一直 I knew it all along . 8、 anything but 绝对不 I was anything but happy about going . 9、 account for 解释 How do you account for it ? 10、 after all 毕竟;终究 A ： Ive just seen the X - rays and your teeth look just fine . B ： I see . Then there is nothing to worry about after all . 11、allergic to 对过敏 Oh man ! Something in this room is making my eyes itch . I must be allergic to something . 12、 at sbs service 愿为某人服务 I am at your service at any time . 13、 around the clock 24小时不停 Martha studied around the clock for management exam . 14、 as far as I know 就我所知 But as far as I know , he once won the world champion at the Olympic Games . 15、 at home with 对很熟悉 She is at home with problems like this . 16、 back out 退出 A ： Wasnt Bert supposed to sing tonight ? B ： Yes , but he backed out at last minute . 17、be cut out for 适合于，有做某事物的天赋 She is cut out for a dancer . 18、 be absorbed in 全神贯注于某事物 She has been absorbed in a horrorfiction . I cant tear her away . 19、 be addicted to 对某事物上瘾 She has been addicted to drugs for years . 20、 be attached to 对某事物有感情 A ： Im amazed that you are still driving that old car of yours . I thought you would have gotten rid of it years ago . B ： It runs well and Ive actually been quite attached to it .
雅思口语雅思托福技巧雅思口语-美联国际教育雅思口语话题素材积累：Hometown 2014-02-18 17:00 类别：雅思口语来源：enguo 责编：meten 考生们在练习备考雅思口语过程中，可以多从身边的生活中取材，锻炼自己的口语表达能力。下面小编就为大家整理了雅思口语话题素材：Hometown，希望对大家备考有所帮助。 1、Where do you come from? 2、What tourist attractions are there in your hometown? Would a foreign visitor enjoy them? 3、Did you learn much about the history of your hometown in school? 4、What do you think needs to change in your hometown? 5、What place(s) in your hometown do you go to in your spare time? 6、Why did you choose to live here/there? 7、What do you like about your hometown? 8、What do you think needs to be done to make your hometown a better place to live in? 9、For you, what benefits are there to living in a big city? 10、What facilities does your hometown have? 11、What sorts of buildings are there in your hometown? 12、What's the most attractive part of your hometown? 13、What forms of transport do visitors use to come to your hometown? 14、How could your hometown attract more visitors? 15、Has the weather in your hometown changed much in recent years? Important: At the moment (2012) in China, there are about 30 different topics being used in Part 1. These topics and questions are in the examiner's question book(topic pool), the examiner is not allowed to make his or her own questions in Part 1 test. 众所周知，雅思口语考试是非常重视临场发挥的，虽然这些雅思口语考试试题看上去都很平常，但是还是要求大家在自己熟悉的题目和熟悉的事物中发挥自己的真实水平，所以大家一定不能掉以轻心，平时就要多加训练，在考场上正常甚至超常发挥出来。
雅思口语高分模板汇总 多看一些雅思口语高分模板，有助于提升英语说话的逻辑，还能增强我们遣词造句的能力。下面就和大家分享，来欣赏一下吧。 雅思口语高分模板：描述兴趣爱好的话题 雅思口语高分模板一： From a middle class family, I was born in Hsin Ying, Tainan on October 10th, 1965. My father is a civil official at Tainan City Government. My mother is a house wife good at . Although I am the only child of my parents, I am by no mans a spoiled one. On the contrary, I have been expected to be . I study hard at school. Besides texts knowledge, journalism is my favorite; whenever reading, my heart is filled with great joy and interesting. 从中产阶级家庭，我出生在Hsin Ying，台南1965年10月10日。我父亲是台南市政府的一名公务员。我母亲是一位善于烹饪的家庭主妇。虽然我是我父母的独生子女，但我决不是一个被宠坏的孩子。相反，我被认为是一个成功的受过高等教育的人。我在学校努力学习。除了文字知识，新闻是我的最爱;每当阅读，我心中充满了极大的乐趣和乐趣。
雅思口语试题参考素材 1.被污染的地方 Last vacation, I went to Hainan with my family.Hainan is such a wonderful place that I will never forget it. It's really a good place where gave me a rather good impression. I feel so wonderful during the journey, as I have experienced a lot of things for the first time. The sky is also brighter and clearer than that I had ever seen. It was my first time to experience the sea and the beach in the sunshine. When sitting on the cruise, I could clearly see the ocean waves pushing the windows of the cruise. But last week, I went to Hainan again. I went to the beach the second time, but this trip changed my idea about its scenery. There were a lot of rubbish. The water was full of flotsam and refuse.When I walked along the sea, terrible smell went into my nose.The beach had been affected by pollution.Due to poor management, people who visited there damaged the environment. It is to be regretted that a beautiful place has gone.
描述一个未来你想安家的地方。 This place is a coastal mountain in Hong Kong, I have been there followed a tour group last winter vacation.The mountain is not high, but it is arborous.And when you walk in the mountain,you will find the air is particularly fresh. The sky way stretching from the foot of the mountain to the peak , and there are many apartment buildings and villas in there. Down from the mountain is the ocean, it has soft beach as well as clear seawater,sea birds flying overhead time to time. The inhabitants of the mountain exercise along the highway by running or cycling every morning. I am aspire to live in that place because it isvery comfortable. In addition to the good environment , another reason I choose to make a home there is that, Hong Kong is an international metropolis, and there are a lot of employment opportunities, I think I can find a nice job there. And Hong Kong are referred to as the shopping paradise, the stuff is superior in quality and the price is relatively cheap. But in Hong Kong, people have a rapid pace of life, I think I can’t adapt to the fast pace of life. So living in the mountain far away from the downtown is a good choice for me because I can go to work in downtown during the day, and go back to the mountain to release the pressure of a day at night. In addition,the traffic is very developed in Hong Kong, so there is no need to worry about the traffic, I can arrive quickly at the downtown if i want. 我喜欢的一个喜剧演员是马特·勒布朗，他在情景喜剧《老友记》中饰演乔伊·崔比安尼。剧中乔伊与钱德勒为共租公寓的室友，是一位没什么天分但很执着的龙套演员，他从没有拍过什么很重要的角色，但是对于每一个上镜机会他都非常珍惜，非常认真。在拍戏方面的每一点进步都会让他非常兴奋。我觉得他是《六人行》里最单纯最可爱的一个人，他四肢发达、头脑简单，他的很多台词都非常搞笑，动作也很滑稽。另外乔伊是一个非常善良，富有爱心的人，他非常关心他的五个朋友，总能给人带去温暖。马特真的把这个演员演活了。从乔伊身上我们能看到自己的影子，虽然我们都是平凡的普通人，但是为了自己的梦想一直在努力，就算遇到很多挫折依然很乐观。我觉得这是马特塑造的这个角色最成功的地方，它能给人带去希望。 One of my favorite comedian is Matt Leblanc, he played in the situation come dy Friends,which i watched a couple years ago,he played in friends as the cha racter,Joey Tribbiani . In Friends ,joey is an actor, an utility man.Although he had never took a chance to play a big role,he cherish every chance he got.An d with one hundred percent of the effort.Every bit of progress in performance would make him very excited. I think he is a simple person as well as the most lovely one in Friends.he is limbs developed but simple-minded, and many of his lines are very funny, actionsare also very funny, Matt just make the ch