Use of coated microtubular halloysite for the sustained release of diltiazem hydrochloride and propr

International Journal of Pharmaceutics 253(2003)

145–157

Use of coated microtubular halloysite for the sustained release of

diltiazem hydrochloride and propranolol hydrochloride

S.R.Levis,P.B.Deasy ?

Department of Pharmaceutics and Pharmaceutical Technology,School of Pharmacy,Trinity College,University of Dublin,Dublin 2,Ireland

Received 11October 2002;received in revised form 9December 2002;accepted 11December 2002

Abstract

Halloysite is a naturally occurring microtubular aluminosilicate mineral.The highly water soluble cationic drug,diltiazem HCl,was shown to bind to the polyanionic surfaces of the material to achieve a slight sustained release effect on dissolution testing due to reversible chemisorption and/or hindered release from the drug loaded lumen.A greater sustained release effect was more apparent when the less water soluble cationic drug,propranolol HCl,was examined.Attempts to further delay drug release by loading diltiazem HCl from a polyvinylpyrrolidone solution into the halloysite had little effect.However,a range of cationic polymers,including chitosan cross-linked with glutaraldehyde,was shown to bind to halloysite and was used to achieve signi?cant delayed drug release.Coating with adequate polyethyleneimine was particularly effective at delaying drug release,being dependent on the architecture of the interaction between the polycation and the mineral.When a range of alkyl-2-cyanoacrylate monomers applied from a non-aqueous solvent by an in situ polymerisation procedure was examined,diltiazem HCl loaded halloysite dispersed in poly-iso -butyl cyanoacrylate was found to be the most effective at reducing the burst effect noted with aqueous coating systems.?2003Elsevier Science B.V .All rights reserved.

Keywords:Halloysite;Microtubular;Sustained release;Diltiazem HCl;Propranolol HCl

1.Introduction

Halloysite is an unusual clay mineral,having a hollow tubular structure in the submicron range,mea-suring typically 3?m long ×0.3?m outer diameter and like most natural materials it varies somewhat in size within and between deposits.It is de?ned as a two-layered aluminosilicate,and is chemically similar to kaolin,which however,has a stacked plate-like structure.The extensive characterisation of this material has been described recently by us (Levis and Deasy,2002),highlighting its potential

?Corresponding author.Tel.:+353-l-608-2784;fax:+353-l-608-2783.

E-mail address:pdeasy@tcd.ie (P.B.Deasy).

for drug loading,particularly of cationic agents by chemisorption onto its polyanionic faces or more extensively by entrapment into its hollow lumen or core.Lipid microtubules or carbon nanotubules have similar morphology with potential for drug loading,but compared to the abundant commercial supplies of halloysite available worldwide at low cost,they are likely to remain prohibitively expensive for most pharmaceutical applications.To-date no studies deal-ing with the use of halloysite for sustained delivery of drugs have been published,though recently work on its use for the extended release of a range of marine biocides has appeared (Price et al.,2001).

Diltiazem HCl was chosen as the main model drug for these studies,because it is a calcium channel blocking agent,frequently administered orally for the

0378-5173/03/$–see front matter ?2003Elsevier Science B.V .All rights reserved.doi:10.1016/S0378-5173(02)00702-0

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treatment of angina and hypertension as a sustained release product to improve clinical ef?cacy.Of par-ticular relevance to this study is that the drug is also cationic facilitating surface binding to the faces of halloysite,and is highly water soluble(>50%,w/v at 25?C as reported by Yang and Fassihi,1997)facilitat-ing easy drug loading into the lumen but posing a very demanding challenge to achieve adequate sustained release property due to the anticipated high diffusion gradient produced.Some comparative studies are re-ported also with another low molecular weight cationic drug frequently formulated as an oral sustained re-lease product,propranolol HCl,which however,is less soluble in water(5%,w/v at25?C;Yang and Fassihi, 1997)and,consequently,should more easily demon-strate prolonged release from this novel microtubular material.

2.Materials and methods

2.1.Materials

A single large batch(25kg)of halloysite,grade G, adequate for all the reported studies,was obtained from New Zealand China Clays Ltd.,Auckland,New Zealand and sieved prior to use through a125-?m mesh.Acetic acid,glutaraldehyde25%,sodium ac-etate(Sigma Chemical Co.,St.Louis,MO),chitosan, medium molecular weight,polyethyleneimine(PEI), 50%,molecular weight25,000(Aldrich),citric acid monohydrate,di-sodium hydrogen phosphate dodec-ahydrate(Riedel de Haen),diltiazem hydrochloride (Profarmaco),eudragit E100(Rohm Pharma),glu-cose(Merck),heptane,tetrahydrofuran(Rathburn), methanol,HPLC grade(Scharlau),nitrogen(Air Products),octyl,n-butyl and iso-butyl cyanoacrylate (Loctite),propranolol hydrochloride(Finechem)and water(glass distilled)were used.All reagents were GPR unless otherwise indicated.

2.2.Determination of halloysite/cation

binding curves

The?rst technique employed to determine the ex-tent of binding between the polyanionic surfaces of halloysite and the cationic polymer chitosan at appro-priate pH involved viscosity measurement.Chitosan solutions0.2%(w/v)were prepared,buffered at pH 2.8or4.5using0.1M acetic acid or0.1M sodium acetate,respectively,and20ml volumes of these so-lutions were mixed with2,4,6,8,10,12,14,16,18 or20ml of an aqueous halloysite suspension0.1%, followed by dilution to40ml with buffer to maintain constant volume.Thus,total chitosan concentration was?xed at0.1%in all samples,but the halloysite content varied.The sample systems were then incu-bated at37?C for48h in a temperature-controlled reciprocating water bath(Precision Scienti?c)set to shake at50rpm.After incubation,the samples were centrifuged(Sanyo Harrier)for20min at3000rpm and the?ow time of the recovered supernatant solu-tions compared to the pure buffer was determined in triplicate at37?C using a suspended level viscometer (Ubbelhode,size1,Technico).The speci?c viscosity was calculated from the mean data.

In the second technique employed,halloysite bind-ing curves were constructed for the cationic drug diltiazem HCl and two other possible cationic coating polymers,PEI and eudragit E,using a UV analy-sis technique.One hundred milligram samples of halloysite were mixed with50ml solutions of the aqueous cationic substances(5–160mg diltiazem HCl,2–30mg PEI, 2.5–80mg for eudragit E)in 100ml conical?asks,which were shaken at25?C for 20min at500rpm.Samples of the supernatants were removed,?ltered through0.2?m membrane?lters (Gelman)to remove particulate material and analysed by UV(Shimadzu)at wavelength236nm for dilti-azem HCl,209nm for PEI or229nm for eudragit E. The difference in concentration of the cation solution, based on the mean of triplicate determinations with use of an appropriate calibration curve for each sub-stance,before and after incubation corresponded to the amount bound to the?xed weight of halloysite.

2.3.Loading of halloysite with diltiazem HCl

or propranolol HCl

Samples of halloysite(1.5g)were mixed with 1.5ml of the drug solution(diltiazem HCl,40%, w/v in puri?ed water;propranolol HCl,20%,w/v in methanol).The wetted halloysite was placed in a sealed desiccator vessel and vacuum applied(～30mm Hg)for30s until all the gas was removed.The vac-uum was reapplied twice to ensure that the drug

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solution had fully displaced all the air present be-tween and within the microtubules.The drug loaded samples were then dried in a forced circulation oven (Memmert)for atleast24h at50?C to constant weight.The dried powders were removed from the oven,lightly ground down using a mortar and pestle, and sieved through a125-?m mesh to separate any large agglomerates formed in the loading process. 2.4.Thermogravimetric analysis of dried drug loaded halloysite

Thermogravimetric analysis(TGA)was performed using a Toleda TC15TA controller(Mettler).Analysis was performed over the temperature range30–250?C using a heating rate of10K/min.The sample weights examined were between5and10mg.Nitrogen gas ?owed over the open crucibles containing the sam-ple as the analysis was performed.The percentage weight losses incurred during the heating cycle were estimated using the associated software.

2.5.Coating drug loaded halloysite

The?rst coating procedure examined involved charge neutralisation,whereby appropriate quanti-ties of the dried drug loaded halloysite powder were added to100ml conical?asks and50ml quantities of aqueous solutions of each cationic coating material, buffered as necessary,were added followed by stir-ring at500rpm for2min.Glutaraldehyde(10or20%, w/v)was added as cross-linking agent,if appropriate. The suspensions were then centrifuged at3000×g for10min and the coated halloysite recovered as sed-iment was dried in a forced circulation oven at50?C to constant weight,before being lightly ground to a ?ne powder that was passed through a125-?m mesh. The second coating procedure examined involved in-situ polymerisation using cyanoacrylate monomers. Samples of drug loaded halloysite(3g)were added to20ml volumes of5or10%solutions in heptane of octyl,n-butyl or iso-butyl cyanoacrylate in dry100ml conical?asks.The suspensions were allowed to stir at 500rpm at room temperature for30min,3or8h,dur-ing which surface polymerisation occurred progres-sively,initiated mainly by residual-free water present, which was previously estimated at9.5%(Levis and Deasy,2002).The reaction was quenched by?lter-ing off the encapsulated halloysite,which was dried at50?C to constant weight,ground and sieved as de-scribed above.Samples of the polycyanoacrylate drug loaded halloysite were washed with tetrahydrofuran to remove the coating and the molecular weight of the polymers formed was determined by gel permeation chromatography(Perkin-Elmer).

2.6.Dissolution studies

Various products were subject to dissolution testing at37?C in1l of McIlvaine’s buffer,pH6.8or3.2, using baskets rotated at100rpm and located25mm above the base of the vessel(model DT6,Copley). Finer products were retained in the baskets by seal-ing into coarse membrane?lters.Samples(5ml)were withdrawn periodically with immediate replacement of the dissolution medium,and following?ltration through a0.45-?m?lter(Gelman),were assayed by UV spectroscopy(Shimadzu UV-160)at the appro-priate wavelength.

Similarity factors(f2)for comparing dissolution pro?les were calculated and interpreted as described by Tang and Gan(1998),values below50indicating signi?cant difference.

2.7.Electron microscopy studies

Samples of product were mounted on aluminium stubs,vacuum coated with gold?lm(Polaron SC500) and examined using a scanning electron microscope (Hitachi S-4300?eld emission).

3.Results and discussion

3.1.Ionic binding

The curve for diltiazem HCl binding with the an-ionic sites present on the outer and inner surfaces of halloysite microtubules is shown in Fig.1.The plot is unusual in that as the amount of drug added to hal-loysite increases the amount bound increases initially, then decreases before increasing again to reach a plateau.The pH of all the bulk suspensions remained relatively constant at7.17–7.43and is unlikely to account for the unusual binding pro?le observed.A more likely explanation is change in the pH within

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Fig.1.Binding pro?le showing the effect of increasing amount of diltiazem HCl added to 100mg halloysite in water on the level of drug bound.

the microenvironment of the halloysite surface.When low concentrations of the drug solution are added to the halloysite suspension,the pH of the mineral’s surface would be relatively high (～7.4)and hence the strongly electronegative surface has a high binding af?nity for the cationic drug.As more added drug locates in proximity to the halloysite surface,the accumulation of the acidic drug causes the microen-vironment around the mineral to become increasingly acidic,altering the ionisation of the siloxane groups,thereby reducing the overall negative charge and hence sites available for drug binding.The second binding phase could be due to a build-up of a sec-ond adsorbed layer due to hydrophobic adsorption of unionised drug (approximately 50%as the p K a of the drug is 7.7)to itself or to hydrophobic binding sites on the halloysite surface.Ultimately,a ?nal plateau is reached,indicating complete saturation of all avail-able binding sites by the drug,which was estimated from the plot to be ～2.4mg per 100mg halloysite.3.2.Tubular entrapment

The potential entrapment volume was estimated previously as ～0.25ml/g (Levis and Deasy,2002)and,consequently,the volume of drug solution used resulting from the use of a 1:1ratio was approxi-mately four times the tubular volume available.It was possible to load this larger drug solution volume into the lesser tubular volume due to the fact that the low pressure created by the vacuum procedure employed tended to cause premature evaporation of the drug solvent,water,thereby effectively reducing the actual volume being loaded.This also had the advantage of concentrating the drug within the tubules to a level greater than the saturation concentration the loading solution,promoting very high https://www.sodocs.net/doc/715534218.html,ing a 40%(w/v)aqueous diltiazem HCl solution at a 1:1ratio,the theoretical entrapment of the drug was calculated to be 28.5%(w/w)of the ?nal product,but was de-termined to be only 25.6%on dissolution testing in water,the discrepancy being due mainly to poorly liberated ionic bound drug (～2.4%,w/w).

The release of drug from the loaded halloysite was examined by dissolution testing in buffer media pH 3.2and 6.8,simulating gastric and small intestinal pH con-ditions,as shown in Fig.2.Release of free drug at both pHs was equally rapid and for clarity is plotted at one pH only.Diltiazem HCl release from halloysite,com-pared to the free drug,was only slightly retarded,with a large burst effect evident at both pH values,indi-cating that for a highly water soluble,low molecular weight drug,simple entrapment in halloysite is un-likely to be effective for producing adequate sustained

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149

Fig.2.Dissolution of diltiazem HCl from drug loaded halloysite at pH 3.2and 6.8for 8h at 37?C,compared to free drug at pH 6.8.

release property.This is not surprising as the diameter of the lumen of tubules was estimated to be 0.1?m previously (Levis and Deasy,2002),enabling the dis-solution medium to readily penetrate the lumen to promoted rapid outward diffusion of the drug.

The Fig.3.Dissolution of diltiazem HCl (P1)and propranolol HCl (P2)from drug loaded halloysite at pH 6.8for 8h at 37?C.

?nal ～8%of drug was released at a much slower rate and probably corresponds to the ～2.4/28.5=～8.4%ionic bound drug discussed above.

Fig.3shows comparative dissolution data for the less soluble cationic drug,propranol HCl,after

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loading from a methanolic solution into halloysite,which causes signi?cant retardation in release rela-tive to the diltiazem HCl.The retardation in release caused by reduction in drug solubility is very appar-ent as only 80–90%of the propranol HCl loading in halloysite was released in 8h,compared to ～100%in 6h for the diltiazem hydrochloride loaded halloysite.The effect should be even more marked with poorly soluble drugs.

In an attempt to further retard the diltazem HCl release from halloysite,the loading solution was thickened by adding 5or 10%PVP,heating to effect solution of the polymer.Only a slight improvement in retarded drug release was observed,which was not deemed signi?cant when similarity factors were calculated.A probable reason for the lack of effect of the added viscosity enhancer was that the loaded hal-loysite was dried to constant weight to recover it as a powder,causing both the drug and PVP to precipitate mainly within the lumen.Upon rehydration during dis-solution testing,the PVP does not dissolve as rapidly as the drug and so the majority of the drug is leached out of the tubule before the increasing viscosity of the solution within it can fully exert its retardant effect.3.3.Halloysite/chitosan binding studies

Initially the binding of cationic chitosan to anionic halloysite was studied to estimate the stoichiometry of the complex formed.Since the magnitude of the charge of both ionic species is highly pH dependent,the effect of two low pH values of the medium was examined,at which chitosan was soluble.Binding pro?les

were Fig.4.Binding pro?les,illustrating the effect of changing ratios of chitosan/halloysite on the speci?c viscosity of the supernatant chitosan solution,in buffer media pH 2.8and 4.5.

obtained by viscosity measurement as used by Takahashi et al.(1990)and the plots are shown in Fig.4.It is apparent for both pH systems that as the ratio of chitosan to halloysite used increases,the spe-ci?c viscosity also increases until a point of in?ection occurs and a maximum speci?c viscosity level is achieved.This level is more evident when the exper-iment was performed at higher pH.The pro?les are best explained by the fact that at high ratio,the amount of chitosan present is signi?cantly greater than the amount of halloysite present.Almost all anionic sites on the halloysite surface are fully saturated or bound and the viscosity of the supernatant chitosan solution is very close to that of the original stock solution.As the ratio decreases,an in?ection point is reached below which the amount of unbound anionic sites on the hal-loysite mineral increases dramatically,and so a greater proportion of the chitosan present is bound to the halloysite.This causes a pronounced decrease in the speci?c viscosity of the supernatant solution.Hence the point of in?ection re?ects the ratio of chitosan to halloysite that nearly saturates all available anionic binding sites on the mineral’s surface.Ratios below this critical point represent only partial saturation,whereas those above represent near fully saturation.The near complete saturation ratios,as indicated by points of in?ection in Fig.4,were similar at ～0.1for both pH systems.Hence binding ratios were con-stant despite the change in pH value,similar to the ?nding of Takahashi et al.(1990)for the binding between chitosan and sodium alginate.The degree of ionisation of halloysite decreases with decreasing pH (Levis and Deasy,2002),whereas the ionisation

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151

Fig.5.Dissolution of diltiazem HCl from drug loaded halloysite,coated with chitosan(three levels,indicating the actual chitosan/halloysite ratio)or uncoated,at pH6.8for8h at37?C.

of chitosan increases.Hence it would be expected that the unit molecular binding ratio would alter with changing pH.As this was not observed at37?C,it may be due to the rigidity of the halloysite mineral, which Takahashi et al.(1990)observed to have an important role in polyion complex formation.How-ever,the overall speci?c viscosity was higher in the aqueous solution of lower pH,due to greater protona-tion of available amino groups in chitosan,resulting in greater electrostatic repulsion between the solubilised chitosan molecules.

3.4.Cationic coated drug loaded halloysite

Three chitosan/halloysite ratios were examined at the higher pH of4.5for coating diltiazem HCl loaded mineral,two being below the point of in?ection and representing incomplete neutralisation and?lm for-mation(0.02and0.05)and one above representing complete saturation and?lm formation(0.40).Disso-lution studies were performed at two pH values,3.2 and6.8,and the results at pH6.8only are shown in Fig.5.The results at pH3.2were qualitatively similar,though release rates for coated products were a little faster,as Singh and Ray(1999)have indi-cated that greater protonation of free amino groups at low pH causes chitosan molecules in?lms to un-coil,elongate and become more permeable.If data as-sociated with the large burst effect occurring in the ?rst15min was omitted,the remaining data gave sig-ni?cant correlation coef?cients of greater than0.97 (P=0.05)for pseudo-zero-order drug delivery at all coating levels and pHs examined,suggestive of membrane-controlled release systems.Work by Singh and Ray(1999)demonstrated also that controlled re-lease of glucose through chitosan membranes followed pseudo-zero-order release.

It is evident from Fig.5that as the ratio of chitosan to halloysite used to coat the loaded halloysite by com-petitive displacement of drug from surface binding sites,there was a progressive retardation effect on drug release,with the expected maximum effect apparent at the highest ratio used where maximum coating conti-nuity should have been achieved.A pronounced burst effect was observed for all coated products(24–47% dissolved at15min for both pHs examined),probably due to the chitosan coating being applied in the form of an aqueous solution,which was capable of dissolv-ing some of the entrapped drug causing it to become entrapped in the coating on subsequent drying before dissolution testing.This suggestion was con?rmed by a large decrease in the drug encapsulation yield for

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Fig.6.Dissolution of diltiazem HCl from non cross-linked and cross-linked (10and 20%,w/w glutaraldehyde)chitosan coated (0.05)drug loaded halloyisite at pH 6.8for 8h at 37?C.

the uncoated halloysite (25.6%,w/w)to 7.8,5.6and 5.3%(w/w)for the 0.02,0.05and 0.40ratios exam-ined,respectively.As the chitosan/halloysite ratio in-creased,the encapsulation yield decreased,probably due to the thicker ?lm formed around the halloysite particles,thus,increasing their overall weight and ef-fective %drug loading.Increasing coating deposition tended to progressively reduce the burst effect.Similar burst effects have been observed with 5-?uorouracil loaded microspheres (Denkbas et al.,1999),

where Fig.7.Binding pro?le,illustrating the effect of changing amount of eudragit E (mg)added to halloysite (100mg)on the amount of polymer bound.

almost 50%of the drug loading was released within the ?rst hour.

In an attempt to further delay drug release from the chitosan/halloysite 0.05ratio coated drug loaded system,glutaraldehyde was incorporated as a cross-linking agent at 10and 20%of the chitosan content into the coating solution immediately prior to appli-cation.The results for the dissolution pro?le obtained at pH 6.8are shown in Fig.6indicating that the cross-linking treatment produced some additional

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153

Fig.8.Dissolution of diltiazem HCl from drug loaded halloysite,coated with PEI(three levels)or uncoated,at pH6.8for8h at37?C.

delayed release,as was also observed at pH3.2.Ex-cessive use of the cross-linking agent(20%)was less effective than the lower level examined,presumably by making the coating brittle and prone to crack pre-maturely,facilitating dose dumping.A similar effect was reported by Ganza-Gonzalez et al.(1999),who ascribed the effect partially to increasing formation of polyglutaraldehyde/chitosan copolymer with increas-ing glutaraldehyde addition,the resultant copolymer having more permeable hydrophilic domains.Thus, an optimum level of the cross-linker was required to maximise delayed drug delivery from chitosan coated halloysite,which level was not established in this study.

Two other cationic polymeric coatings were exam-ined as alternatives to chitosan,namely eudragit E and PEI.Eudragit E is a polmethacrylate which is used frequently as a?lm former for taste and odour mask-ing that becomes water soluble by forming salts with acids at low pH2–5.A halloysite/eudragit E binding curve was constructed initially to study the polyion complexation,dissolving the polymer in0.1M acetic acid to effect solution and using UV analysis to de-termine the extent of binding as shown in Fig.7.The pro?le was similar to that obtained with chitosan and based on this study three ratio levels were chosen for the coating of diltiazem HCl loaded halloysite,namely 0.025,0.30and0.70,equating to below,approximately at,and above the in?ection point.Dissolution studies were performed on the products at pH3.2and6.8and gave results generally similar to those obtained with chitosan.

A halloysite/PEI binding curve was constructed also to study the stoichiometry of the complexation by UV analysis,where the PEI was added as an aqueous solution to produce a pro?le similar to that obtained with chitosan.Three PEI/halloysite ratio levels were chosen for coating drug loaded halloysite,being0.03, 0.14and0.28corresponding to below,approximately at,and above the in?ection point.The dissolution pro?les at pH6.8of the products obtained are shown in Fig.8.Whereas all the coated products had delayed release relative to the uncoated product,surprisingly the lowest coating ratio examined produced the max-imum retardation of drug release with relatively little burst effect.A possible reason for this unexpected observation is that the architecture of the interaction between the clay mineral and the polycation was re-sponsible as suggested by Lvov et al.(1996).When low concentrations of PEI are used(0.03),the indi-vidual molecules have more space for undisturbed movement.This allows the polycation to align with the

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Fig.9.Schematic representation of proposed binding patterns of the cationic linear PEI polymer to halloysite when (i)dilute and (ii)more concentrated aqueous solutions are used.

halloysite tubules as shown diagrammatically in Fig.9to create a thin but well organised dense ?lm with good retardant properties.At higher levels (0.14and 0.28),however,the polymer molecules are more con-strained due to stearic dif?culties created by reduced space.As a result,the polymer binds to the halloysite in a more random arrangement,and even though the ?lm formed appears thicker,it is loose,less dense and more permeable.Whereas the optimum level of PEI to effect maximum retardation in drug release was not determined,PEI was not investigated further as it does not have regulatory approval for use in pharmaceuti-cals.However,in applications not subject to such con-straints like agrichemical loaded halloysite,PEI should be a very useful coating material easily applied from dilute aqueous solution to produce prolonged release products.

3.5.Coating drug loaded halloysite using cyanoacrylate polymers

An alternative to the use of aqueous solutions of cationic coating polymers,should be the treat-ment of drug loaded halloysite with various alkyl-2-cyanoacrylate monomers dissolved in a water insoluble solvent like hexane,where gradual diffu-sion of monomer to the interface should lead to the progressive formation of a polymerised coating on the halloysite particles.The residual moisture con-tent in the dried drug loaded particles before coating was estimated by TGA to be ～1.97%,which water should act as an initiator for the in situ polymerisa-tion reaction.This coating technique should have the advantage over the aqueous charge neutralisation pro-cedures examined,particularly for very water soluble

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155

Fig.10.Dissolution at pH6.8for8h at37?C of diltiazem HCl from drug loaded halloysite,coated with poly-n-butyl cyanoacrylate polymerised for30min,3or8h.

compounds like diltiazem HCl which is hexane insol-uble,in not stripping the drug from the halloysite dur-ing the coating operation and,thus,preserving high loading.These biodegradable polymers are currently used as tissue adhesives and have been investigated extensively for drug delivery applications(Couvreur and Vauthier,1991).

Fig.10shows the effect of polymerisation reaction time for5%n-butyl cyanoacrylate applied on drug release from the coated diltiazem HCl loaded hal-loysite.The coated preparations all showed retarded drug release compared to free drug and drug loaded halloysite,longer polymerisation time tending to in-crease the effect presumably by forming thicker coat-ings as indicated by the%drug loading dropping from18.51to18.0to17.83%for products coated for0.5,3and8h,respectively.Longer polymerisa-tion times also favoured the formation of polymers with higher average molecular weights,been deter-mined as～215,000,～250,000and～550,000,respec-tively,larger molecular weight polymers been less biodegradable and less permeable during dissolution studies.

Fig.11shows the in?uence on drug release of us-ing three different alkylcyanoacrylate monomers at 5%for coating,all with a polymerisation time of8h.The greatest retarded release was observed using the iso-butyl derivative,the other two monomers resulting in coatings with similar release pro?les.If the burst ef-fect associated with the initial15min was subtracted, the remaining dissolution data for the latter two prod-ucts was best?tted to a pseudo-zero-order model, indicative of release from a coated reservoir device, whereas the poly-iso-butyl cyanoacrylate product was best?tted a square-root of time dependence,indica-tive of release from an inert matrix.This matrix was observed directly in transmission electron microscopy (TEM)studies for the poly-iso-butyl cyanoacrylate product only as shown in Fig.12,where the drug loaded halloysite was shown to be dispersed in the polymer matrix,with individual tubules evident at the edge of the irregular particles recovered.GPC data con?rmed also that the poly-iso-butyl coating had the highest average molecular weight(～720,000),com-pared～550,000and～570,000for the corresponding poly-n-butyl and poly-octyl coatings,thus,explaining its greater retardant effect.

The encapsulation yields for the poly-n-butyl, poly-iso-butyl and poly-octyl cyanoacrylate coatings, after polymerisation for8h from5%monomer so-lutions,were17.83,18.75and21.46%,respectively, compared to25.6%for the uncoated drug loaded

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Fig.11.Dissolution at pH6.8for8h at37?C of diltiazem HCl from drug loaded halloysite,coated with poly-n-butyl,poly-iso-butyl or poly-octyl cyanoacrylate polymerised for8h.

Fig.12.TEM of poly-iso-butyl cyanoacrylate coated,drug loaded halloysite particles(70,000×).Individual halloysite microtubules are indicated(A).

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halloysite.This indicated that the least polymer gain per unit mass of drug load halloysite occurred with the poly-octyl cyanoacrylate product as its encapsulation ef?ciency is closest to that of the uncoated halloysite powder.The speci?c polymer weight gains for the poly-n-butyl and poly-iso-butyl coated products are similar,suggesting that a major factor responsible for the delayed drug release of the latter is its higher average polymer molecular weight rather than overall coating gain.

4.Conclusions

The surface charge of the halloysite particles should have become reversed as a consequence of the polycation polymer coat binding,since polyelec-trolyte concentrations used were suf?cient to form a saturated layer.As a result,there should be potential to further delay drug release from these systems by subsequent application of alternating polyanionic and polycationic polymeric layers,thereby increasing the coating thickness and barrier property,as demon-strated in the research of Lvov et al.(1996)and Sukhorukov et al.(1998).Also other approaches to improving handling and modifying release from drug loaded coated halloysite could involve incorporation into solid lipid microparticles or pellet formation by extrusion/spheronisation.The results of these studies for a range of pharmaceutical and other applications will be published.

Acknowledgements

The halloysite used was supplied free by New Zealand China Clays,Auckland,New Zealand. Cyanoacrylate monomers where generously provided by Loctite(Ireland)Ltd,Dublin,who also determined the molecular weight of the extracted polycyanoacry-late coatings formed.

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The use of force

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曹操《短歌行》其二翻译及赏析

曹操《短歌行》其二翻译及赏析 引导语：曹操(155—220)，字孟德，小名阿瞒，《短歌行 二首》 是曹操以乐府古题创作的两首诗， 第一首诗表达了作者求贤若渴的心 态，第二首诗主要是曹操向内外臣僚及天下表明心迹。 短歌行 其二 曹操 周西伯昌，怀此圣德。 三分天下，而有其二。 修奉贡献，臣节不隆。 崇侯谗之，是以拘系。 后见赦原，赐之斧钺，得使征伐。 为仲尼所称，达及德行， 犹奉事殷，论叙其美。 齐桓之功，为霸之首。 九合诸侯，一匡天下。 一匡天下，不以兵车。 正而不谲，其德传称。 孔子所叹，并称夷吾，民受其恩。 赐与庙胙，命无下拜。 小白不敢尔，天威在颜咫尺。 晋文亦霸，躬奉天王。 受赐圭瓒，钜鬯彤弓， 卢弓矢千，虎贲三百人。 威服诸侯，师之所尊。 八方闻之，名亚齐桓。 翻译 姬昌受封为西伯，具有神智和美德。殷朝土地为三份，他有其中两分。 整治贡品来进奉，不失臣子的职责。只因为崇侯进谗言，而受冤拘禁。 后因为送礼而赦免， 受赐斧钺征伐的权利。 他被孔丘称赞， 品德高尚地位显。 始终臣服殷朝帝王，美名后世流传遍。齐桓公拥周建立功业，存亡继绝为霸 首。

聚合诸侯捍卫中原，匡正天下功业千秋。号令诸侯以匡周室，主要靠的不是 武力。 行为磊落不欺诈，美德流传于身后。孔子赞美齐桓公，也称赞管仲。 百姓深受恩惠，天子赐肉与桓公，命其无拜来接受。桓公称小白不敢，天子 威严就在咫尺前。 晋文公继承来称霸，亲身尊奉周天王。周天子赏赐丰厚，仪式隆重。 接受玉器和美酒，弓矢武士三百名。晋文公声望镇诸侯，从其风者受尊重。 威名八方全传遍，名声仅次于齐桓公。佯称周王巡狩，招其天子到河阳，因 此大众议论纷纷。 赏析 《短歌行》 (“周西伯昌”)主要是曹操向内外臣僚及天下表明心 迹，当他翦灭群凶之际，功高震主之时，正所谓“君子终日乾乾，夕惕若 厉”者，但东吴孙权却瞅准时机竟上表大说天命而称臣，意在促曹操代汉 而使其失去“挟天子以令诸侯”之号召， 故曹操机敏地认识到“ 是儿欲据吾著炉上郁!”故曹操运筹谋略而赋此《短歌行 ·周西伯 昌》。 西伯姬昌在纣朝三分天下有其二的大好形势下， 犹能奉事殷纣， 故孔子盛称 “周之德， 其可谓至德也已矣。 ”但纣王亲信崇侯虎仍不免在纣王前 还要谗毁文王，并拘系于羑里。曹操举此史实，意在表明自己正在克心效法先圣 西伯姬昌，并肯定他的所作所为，谨慎惕惧，向来无愧于献帝之所赏。 并大谈西伯姬昌、齐桓公、晋文公皆曾受命“专使征伐”。而当 今天下时势与当年的西伯、齐桓、晋文之际颇相类似，天子如命他“专使 征伐”以讨不臣，乃英明之举。但他亦效西伯之德，重齐桓之功，戒晋文 之诈。然故作谦恭之辞耳，又谁知岂无更讨封赏之意乎 ?不然建安十八年(公元 213 年)五月献帝下诏曰《册魏公九锡文》，其文曰“朕闻先王并建明德， 胙之以土，分之以民，崇其宠章，备其礼物，所以藩卫王室、左右厥世也。其在 周成，管、蔡不静，惩难念功，乃使邵康公赐齐太公履，东至于海，西至于河， 南至于穆陵，北至于无棣，五侯九伯，实得征之。 世祚太师，以表东海。爰及襄王，亦有楚人不供王职，又命晋文登为侯伯， 锡以二辂、虎贲、斧钺、禾巨 鬯、弓矢，大启南阳，世作盟主。故周室之不坏， 系二国是赖。”又“今以冀州之河东、河内、魏郡、赵国、中山、常 山，巨鹿、安平、甘陵、平原凡十郡，封君为魏公。锡君玄土，苴以白茅，爰契 尔龟。”又“加君九锡，其敬听朕命。” 观汉献帝下诏《册魏公九锡文》全篇，尽叙其功，以为其功高于伊、周，而 其奖却低于齐、晋，故赐爵赐土，又加九锡，奖励空前。但曹操被奖愈高，心内 愈忧。故曹操在曾早在五十六岁写的《让县自明本志令》中谓“或者人见 孤强盛， 又性不信天命之事， 恐私心相评， 言有不逊之志， 妄相忖度， 每用耿耿。

2008年浙师大《外国文学名著鉴赏》期末考试答案

（一）文学常识 一、古希腊罗马 1．（1）宙斯(罗马神话称为朱庇特)，希腊神话中最高的天神，掌管雷电云雨，是人和神的主宰。 （2）阿波罗，希腊神话中宙斯的儿子，主管光明、青春、音乐、诗歌等，常以手持弓箭的少年形象出现。 （3）雅典那，希腊神话中的智慧女神，雅典城邦的保护神。 （4）潘多拉，希腊神话中的第一个女人，貌美性诈。私自打开了宙斯送她的一只盒子，里面装的疾病、疯狂、罪恶、嫉妒等祸患，一齐飞出，只有希望留在盒底，人间因此充满灾难。“潘多拉的盒子”成为“祸灾的来源”的同义语。 （5）普罗米修斯，希腊神话中造福人间的神。盗取天火带到人间，并传授给人类多种手艺，触怒宙斯，被锁在高加索山崖，受神鹰啄食，是一个反抗强暴、不惜为人类牺牲一切的英雄。 （6）斯芬克司，希腊神话中的狮身女怪。常叫过路行人猜谜，猜不出即将行人杀害；后因谜底被俄底浦斯道破，即自杀。后常喻“谜”一样的人物。与埃及狮身人面像同名。 2．荷马，古希腊盲诗人。主要作品有《伊利亚特》和《奥德赛》，被称为荷马史诗。《伊利亚特》叙述十年特洛伊战争。《奥德赛》写特洛伊战争结束后，希腊英雄奥德赛历险回乡的故事。马克思称赞它“显示出永久的魅力”。 3．埃斯库罗斯，古希腊悲剧之父，代表作《被缚的普罗米修斯》。6．阿里斯托芬，古希腊“喜剧之父”代表作《阿卡奈人》。 4．索福克勒斯，古希腊重要悲剧作家，代表作《俄狄浦斯王》。5．欧里庇得斯，古希腊重要悲剧作家，代表作《美狄亚》。 二、中世纪文学 但丁，意大利人，伟大诗人，文艺复兴的先驱。恩格斯称他是“中世纪的最后一位诗人，同时又是新时代的最初一位诗人”。主要作品有叙事长诗《神曲》，由地狱、炼狱、天堂三部分组成。《神曲》以幻想形式，写但丁迷路，被人导引神游三界。在地狱中见到贪官污吏等受着惩罚，在净界中见到贪色贪财等较轻罪人，在天堂里见到殉道者等高贵的灵魂。 三、文艺复兴时期 1．薄迦丘意大利人短篇小说家，著有《十日谈》拉伯雷，法国人，著《巨人传》塞万提斯，西班牙人,著《堂?吉诃德》。 2．莎士比亚，16-17世纪文艺复兴时期英国伟大的剧作家和诗人，主要作品有四大悲剧——《哈姆雷特》、《奥赛罗》《麦克白》、《李尔王》，另有悲剧《罗密欧与朱丽叶》等，喜剧有《威尼斯商人》《第十二夜》《皆大欢喜》等，历史剧有《理查二世》、《亨利四世》等。马克思称之为“人类最伟大的戏剧天才”。 四、17世纪古典主义 9．笛福，17-18世纪英国著名小说家，被誉为“英国和欧洲小说之父”，主要作品《鲁滨逊漂流记》，是英国第一部现实主义长篇小说。10．弥尔顿，17世纪英国诗人，代表作：长诗《失乐园》，《失乐园》，表现了资产阶级清教徒的革命理想和英雄气概。 25．拉伯雷，16世纪法国作家，代表作：长篇小说《巨人传》。 26．莫里哀，法国17世纪古典主义文学最重要的作家，法国古典主义喜剧的创建者，主要作品为《伪君子》《悭吝人》（主人公叫阿巴公）等喜剧。 五、18世纪启蒙运动 1）歌德，德国文学最高成就的代表者。主要作品有书信体小说《少年维特之烦恼》，诗剧《浮士德》。 11．斯威夫特，18世纪英国作家，代表作：《格列佛游记》，以荒诞的情节讽刺了英国现实。 12．亨利·菲尔丁，18世纪英国作家，代表作：《汤姆·琼斯》。 六、19世纪浪漫主义 （1拜伦， 19世纪初期英国伟大的浪漫主义诗人，代表作为诗体小说《唐璜》通过青年贵族唐璜的种种经历，抨击欧洲反动的封建势力。《恰尔德。哈洛尔游记》 （2雨果，伟大作家，欧洲19世纪浪漫主义文学最卓越的代表。主要作品有长篇小说《巴黎圣母院》、《悲惨世界》、《笑面人》、《九三年》等。《悲惨世界》写的是失业短工冉阿让因偷吃一片面包被抓进监狱，后改名换姓，当上企业主和市长，但终不能摆脱迫害的故事。《巴黎圣母院》 弃儿伽西莫多，在一个偶然的场合被副主教克洛德.孚罗洛收养为义子，长大后有让他当上了巴黎圣母院的敲钟人。他虽然十分丑陋而且有多种残疾，心灵却异常高尚纯洁。 长年流浪街头的波希米亚姑娘拉.爱斯梅拉达，能歌善舞，天真貌美而心地淳厚。青年贫诗人尔比埃尔.甘果瓦偶然同她相遇，并在一个更偶然的场合成了她名义上的丈夫。很有名望的副教主本来一向专心于"圣职"，忽然有一天欣赏到波希米亚姑娘的歌舞，忧千方百计要把她据为己有，对她进行了种种威胁甚至陷害，同时还为此不惜玩弄卑鄙手段，去欺骗利用他的义子伽西莫多和学生甘果瓦。眼看无论如何也实现不了占有爱斯梅拉达的罪恶企图，最后竟亲手把那可爱的少女送上了绞刑架。 另一方面，伽西莫多私下也爱慕着波希米亚姑娘。她遭到陷害，被伽西莫多巧计救出，在圣母院一间密室里避难，敲钟人用十分纯朴和真诚的感情去安慰她，保护她。当她再次处于危急中时，敲钟人为了援助她，表现出非凡的英勇和机智。而当他无意中发现自己的"义父"和"恩人"远望着高挂在绞刑架上的波希米亚姑娘而发出恶魔般的狞笑时，伽西莫多立即对那个伪善者下了最后的判决，亲手把克洛德.孚罗洛从高耸入云的钟塔上推下，使他摔的粉身碎骨。 （3司汤达，批判现实主义作家。代表作《红与黑》，写的是不满封建制度的平民青年于连，千方百计向上爬，最终被送上断头台的故事。“红”是将军服色，指“入军界”的道路；“黑”是主教服色，指当神父、主教的道路。 14．雪莱，19世纪积极浪漫主义诗人，欧洲文学史上最早歌颂空想社会主义的诗人之一，主要作品为诗剧《解放了的普罗米修斯》，抒情诗《西风颂》等。 15．托马斯·哈代，19世纪英国作家，代表作：长篇小说《德伯家的苔丝》。 16．萨克雷，19世纪英国作家，代表作：《名利场》 17．盖斯凯尔夫人，19世纪英国作家，代表作：《玛丽·巴顿》。 18．夏洛蒂?勃朗特，19世纪英国女作家，代表作：长篇小说《简?爱》19艾米丽?勃朗特，19世纪英国女作家，夏洛蒂?勃朗特之妹，代表作：长篇小说《呼啸山庄》。 20．狄更斯，19世纪英国批判现实主义文学的重要代表，主要作品为长篇小说《大卫?科波菲尔》、《艰难时世》《双城记》《雾都孤儿》。21．柯南道尔，19世纪英国著名侦探小说家，代表作品侦探小说集《福尔摩斯探案》是世界上最著名的侦探小说。 七、19世纪现实主义 1、巴尔扎克，19世纪上半叶法国和欧洲批判现实主义文学的杰出代表。主要作品有《人间喜剧》，包括《高老头》、《欧也妮·葛朗台》、《贝姨》、《邦斯舅舅》等。《人间喜剧》是世界文学中规模最宏伟的创作之一，也是人类思维劳动最辉煌的成果之一。马克思称其“提供了一部法国社会特别是巴黎上流社会的卓越的现实主义历史”。

(完整版)the的用法

定冠词the的用法： 定冠词the与指示代词this ,that同源,有“那(这)个”的意思,但较弱,可以和一个名词连用,来表示某个或某些特定的人或东西. (1)特指双方都明白的人或物 Take the medicine.把药吃了. (2)上文提到过的人或事 He bought a house.他买了幢房子. I've been to the house.我去过那幢房子. (3)指世界上独一无二的事物 the sun ,the sky ,the moon, the earth (4)单数名词连用表示一类事物 the dollar 美元 the fox 狐狸 或与形容词或分词连用,表示一类人 the rich 富人 the living 生者 (5)用在序数词和形容词最高级,及形容词等前面 Where do you live?你住在哪? I live on the second floor.我住在二楼. That's the very thing I've been looking for.那正是我要找的东西. (6)与复数名词连用,指整个群体 They are the teachers of this school.(指全体教师) They are teachers of this school.(指部分教师) (7)表示所有,相当于物主代词,用在表示身体部位的名词前 She caught me by the arm.她抓住了我的手臂. (8)用在某些有普通名词构成的国家名称,机关团体,阶级等专有名词前 the People's Republic of China 中华人民共和国 the United States 美国 (9)用在表示乐器的名词前 She plays the piano.她会弹钢琴. (10)用在姓氏的复数名词之前,表示一家人 the Greens 格林一家人(或格林夫妇) (11)用在惯用语中 in the day, in the morning... the day before yesterday, the next morning... in the sky... in the dark... in the end... on the whole, by the way...

The use of force

The use of force 大意: Mathilda had been ill for three days. Her mother had given her some medicine, but it didn’t do any good. So they had to ask the doctor to come. There had been a number of cases of diphtheria in Mathilda School and two of them had been dead. When the doctor arrived at Olson’s home, he wanted to examine Mathilda throat first. But no matter how he coaxed, She wouldn’t open her mouth. So the doctor had to get the tongue depressor into her mouth. But Mathilda reduced it to splinters. In orde r to protect Mathilda herself and other children, the doctor had to make sure whether she had diphtheria or not, so that he could treat her in time. Letting Mathilda‘s father hold her wrists he tried his best to open her mouth and found she really had diphtheria. This story made us can think such a question that something in life can’t only depend on self-willingness. Under some circumstances, certain force seems necessary. 对医生的评价:After the doctor arrived at the girl’s home, he wanted to see her throat. As there had been a number of cases of diphtheria in the school to which the girl went during that month, the doctor also thought that of the girl. So he smiled to the girl and asked her to open her mouth and let him have a look at her throat. No matter how the doctor coaxed, the girl shut her mouth firmly. Thinking that the girl might have diphtheria and possibly die of it, the doctor decided to use force to open her mouth. He had seen at least two children lying dead in bed of neglect in such cases. He felt that he must get a diagnosis now. So he grasped the girl’s head with his left hand and tried to get the wooden tongue depressor between her teeth. But when the doctor got the wooden spatula behind her last teeth. She gripped the blade between her molars and reduced it to splinters. In the final unreasoning assault the doctor outer powered the girl. He forced the heavy silver spoon back of her teeth and down her throat till she gagged. Her both tonsils were covered with membrane. From that the doctor had done, I thought he was a responsible person. In order to save the lives of the patients, especially those children who did not know how to co-operate with the doctor, he had to take some measure. Otherwise a good or suitable time of treatment would be missed. The doctor appears to be compassionate and keen to human behavior, characteristic of a good doctor, though he is also undeniably blunt and slightly prejudiced. 思想: Though there are reasons often justifiable, what compels the use of force against others isn't simply altruism alone. The overall theme of the story revolves around power and submission and the doctor's unnerved feeling following the forceful encounter. 作者如何写的: The story is narrated in first person by a doctor, who is answering a house visit to see a sick girl. Williams uses interior monologue as a "stream-of-consciousness" tool reflects the narrator's experience of dialogue and gives insight into the character and his appraisal of the situations he encounters. The story is written without the use of quotation marks, and the dialogue is not distinguished from the narrator's comments. The story is rendered from the subjective point of view of the doctor, and explores his subdued enjoyment of forcefully subduing the stubborn child in an attempt to acquire the throat sample.

外国名著赏析论文

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