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RESEARCH ARTICLE

PPrreeppaarraattiioonn aanndd DDiiffffuussiioonnaall EEvvaalluuaattiioonn ooff SSuussttaaiinneedd --RReelleeaassee SSuuppppoossiittoorriieess CCoonnttaaiinniinngg IIbbuupprrooffeennMMiiccrroosspphheerreess

Tamer GÜNER‹*°, Mesut ARICI*, Gökhan ERTAN

Preparation and Diffusional Evaluation of Sustained -Release Suppositories Containing Ibuprofen Microspheres

SummarySustained-release suppositories containing ibuprofenmicrospheres were prepared with hydrophilic polyethyleneglycol (PEG) or lipophilic Witepsol bases. Microspheres wereprepared by solvent evaporation method. The effect of stirringrate on the particle size and drug content of the microsphereswas investigated. Decrease in particle size and drug content ofmicrospheres was observed with an increase in stirring rate. Invitro dissolution studies were performed in phosphate buffersolution (pH 7.2) at 100 rpm. All formulations exhibitednon-Fickian diffusion and first-order or Hixson-Crowell kinetics.Differential scanning calorimetric analyses showed that therewere no crystal forms or decomposition products of drug in thesuppositories.This study suggested that the sustained-release ibuprofensuppositories could be prepared using PEG 400:PEG 4000(5:95) combination with microspheres. These suppositories canbe more useful for clinical use.KKeeyy WWoorrddss :: Ibuprofen, microspheres, sustained-release

suppository.Received : 20.06.2005Revised : 03.10.2005Accepted : 10.10.2005

‹buprofen Mikroküreleri ‹çeren Sürekli-Sal›ml› Supozitu-varlar›n Haz›rlanmas› ve Difüzyonal De¤erlendirilmesi

ÖzetHidrofilik Polietilen Glikol (PEG) veya lipofilik Witepsoltafl›y›c›lar›yla ibuprofen mikroküreleri içeren sürekli-sal›msupozituvarlar haz›rlanm›flt›r. Mikroküreler, çözücübuharlaflt›rma metodu kullan›larak mikrokürelerhaz›rlanm›flt›r. Mikrokürelerin partikül boyutu ve etkin maddeiçeri¤i üzerinde kar›flt›rma h›z›n›n etkisi incelenmifltir.Kar›flt›rma h›z›ndaki art›fl›n, mikrokürelerin partikül boyutu veilaç içeri¤inde azalmaya neden oldu¤u gözlenmifltir. ‹n vitroçözünme çal›flmalar› pH 7.2 fosfat tampon çözeltisinde 100rpm’de gerçeklefltirilmifltir. Tüm formülasyonlar non-Fickiandifüzyon ve birinci-derece ya da Hixson-Crowell kinetik göster-mifllerdir. Diferansiyel taramal› kalorimetrik analizler, supozi-tuvarlarda etkin maddenin kristal flekillerinin ve bozunmaürünlerinin olmad›¤›n› göstermifltir.Bu çal›flma, PEG400-PEG 4000 (5:95) kombinasyonu vemikroküreler kullan›larak sürekli-sal›m sa¤layan ibuprofensupozituvarlar›n›n haz›rlanabilece¤ini göstermektedir.Haz›rlanan supozituvarlar, klinik kullan›mda çok daha faydal›olabilirler.AAnnaahhttaarr KKeelliimmeelleerr :: ibuprofen, mikroküre, sürekli-sal›ml›

supozituvar.

IINNTTRROODDUUCCTTIIOONN

Sustained-release suppositories have been devel-

oped to sustain the effect via rectal route. There are

several reports on the preparation of sustained-

release suppositories using structure-altering

devices and various additive substances. Nishihata

et al.1 have demonstrated that a sustained-release

suppository of sodium diclofenac containing

lecithin as an additive in a glyceride base could be

prepared. Gungor et al.2 prepared sustained release

suppository formulations of tiaprofenic acid with

sucrose fatty acid ester. Ohnishi et al.3 prepared

double-layered suppositories of nifedipine. In this

* Ege University, Faculty of Pharmacy, Department of Pharmaceutical Technology, 35100, Bornova, ‹zmir, TURKEY° Corresponding author e-mail: tamer.guneri@ege.edu.tr

for the preparation of ethylcellulose microspheres.Four different suppository formulations, two ofthem containing pure drug and PEG or Witepsolbase and the other two containing microspheres andthe same bases, were prepared and evaluated basedon the in vitro release testing. The effect of supposi-tory base on the diffusion mechanism was alsoinvestigated.

Differential scanning calorimetry (DSC) analyseswere carried out for the determination of the crys-tallinity and decomposition products of ibuprofenin microspheres and in all suppository formulations.

EEXXPPEERRIIMMEENNTTAALL

MMaatteerriiaallss

Ibuprofen (Atabay, Istanbul, Turkey), methylcellu-lose (Methocel A15-LV, Colorcon Ltd., England),ethylcellulose (Ethocel N-100, Hercules Powder Co.,Wilmington, DE, USA), PEG 400 (Mustafa NevzatPharm. Co., Istanbul, Turkey), PEG 4000 (NovartisPharm. Co., Istanbul, Turkey), and Witepsol H15(Deva Pharm. Co., Istanbul, Turkey) were obtainedfrom the indicated sources. All other chemicals wereof the highest commercial grade and used withoutfurther purification.

PPrreeppaarraattiioonn ooff mmiiccrroosspphheerreess aanndd ddrruugg ccoonntteennttaannaallyyssiiss

Microspheres were prepared according to the sol-vent evaporation method as described below14.Ibuprofen-ethylcellulose ratio was selected as 1:1according to the results of the preliminary studies. 2g of ethylcellulose was dissolved in 20 mL of meth-ylene chloride and 2 g of ibuprofen was added. Thepolymer phase was emulsified in 250 mL of aqueousphase containing 0.25% (w/v) methylcellulose.Stirring rates (Janke and Kungel Stirring Apparatus)were set at three different constant rates, namely500, 750 and 1000 rpm. Stirring was continued atroom temperature until complete evaporation ofmethylene chloride. Microspheres were then collect-ed, washed three times with deionized water, fil-

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solid dispersion system, polyethylene glycol (PEG)4000 was used as a water-soluble carrier and cellu-lose acetate phthalate (CAP) as a poorly soluble car-rier. Although there are several studies available onthe use of microcapsules and micropellets for thepreparation of sustained-release suppositories4-7,only one study has been reported on the use ofmicrospheres8.

More recently, a liquid suppository dosage form ofibuprofen was presented9. It was in liquid form atnormal room temperature but in gel form above30°C. However, such suppositories have some dis-advantages including difficulty in packaging, pro-tection and transport at high temperatures, i.e.above 30°C.

In this study, formulation of sustained-release sup-positories using ibuprofen-ethylcellulose micros-pheres was attempted. Ibuprofen is a nonsteroidalantiinflammatory drug having analgesic andantipyretic effect. Ibuprofen was an appropriatecandidate for sustained-release formulation becauseof its short half-life (1.8-2 h) and undesired gastroin-testinal effects when it is administrated through oralroute, such as peptic ulceration and gastrointestinalbleeding10. In addition, preliminary histologicalexamination showed that it does not exert anyadverse effect on the rectal tissues11. Ibuprofen hasbeen prepared as suppository formulations using itsfree acid and lysinate forms12. Ibrahim et al.13

reported that ibuprofen suppositories were moreefficient than oral solutions and recommended themfor counteracting gastric side effects. Ibuprofen hasbeen prepared in microsphere form using ethylcel-lulose, but only thermal analysis of the matrix struc-ture was performed on the microspheres pre-pared14. Ethlycellulose is an inert material. By usingmicrospheres containing inert material and drug, itmay be possible to prevent undesired interactionsbetween drug and suppository bases and otheradditives during production and storage. In addi-tion, the drugs and additives may also have sideeffects.

In our study, solvent evaporation method was used

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tered and stored overnight in a desiccator.Following the drying, they were sieved by a com-bined sieving system (Retsch Type A.S.T.M.).

Ibuprofen content of microspheres was determinedspectrophotometrically. 5 mL of phosphate buffersolution (pH 7.2) was added onto 25 mg of micros-pheres and shaken for 23 h. Then, 5 mL of phosphatebuffer solution (pH 7.2) was added and shaken foranother 1 h. After filtration, 100 µL of filtrate wasdiluted to 10 mL with phosphate buffer solution (pH7.2). The absorbance of the solution was measured at223 nm by a spectrophotometer (Shimadzu UV-Visible Recording Spectrophotometer UV-160A)against the blank, and the drug concentration wasdetermined from the calibration curve (n=3).

PPrreeppaarraattiioonn aanndd pphhyyssiiccaall pprrooppeerrttiieess ooff ssuuppppoossiittoorriieess

In order to investigate the release of ibuprofen fromdifferent suppository bases, four different supposi-tory formulations were prepared using lipophilicWitepsol and hydrophilic PEG. Two of these formu-lations were prepared using ibuprofen (Witepsolsuppositories and PEG suppositories) and the otherswere prepared using microspheres (Witepsol-MIsuppositories and PEG-MI suppositories). Theywere prepared by fusion process in a metallic sup-pository mold. The base was fused at 60°C and thenibuprofen or microspheres were added to the melt-ed base and dissolved or dispersed by stirring. Theywere poured into the metallic suppository mold andallowed to solidify at room temperature. Each sup-pository was formulated to contain 300 mg ofibuprofen.

All suppository formulations were evaluated inrespect to content and weight uniformity accordingto BP 1998. Mechanical strength tests were also per-formed (Erweka hardness tester SBT). For contentuniformity analysis of both lipophilic andhydrophilic suppositories, the suppository wasstirred in 150 mL of phosphate buffer solution (pH7.2) at 60°C by a magnetic stirrer. After melting ordissolving process was completed, 100 µL of samplewas adjusted to 10 mL with phosphate buffer solu-

tion (pH 7.2) and drug concentration was deter-mined as described above (n=3).

IInn vviittrroo rreelleeaassee tteessttss

Many research groups have been examining differ-ent techniques and their applicabilities to test fordrug release from rectal dosage systems15. In thepresent study, in vitro release tests were carried outaccording to the method reported by Asikoglu etal.16. Dissolution medium was 150 mL pH 7.2 phos-phate buffer solution at 37°C. Suppository wasplaced in the dissolution medium and stirred with apaddle at 100 rpm. 100 mL aliquots were taken attime intervals after initiation of the test and replacedby 100 mL of pH 7.2 phosphate buffer solution at37°C. Aliquots were diluted to 10 mL with phos-phate buffer solution (pH 7.2) and the drug concen-tration was determined as described above.

Kinetic analyses of dissolution data obtained frommicrospheres and all suppository formulations weredone using zero-order, first-order, Higuchi’s squareroot of time and Hixson-Crowell cube-root models.The release rate constants (k) and determinationcoefficients (r2) were calculated by means of a com-puter program17-18.

CCaallccuullaattiioonn ooff eexxppoonneenntt ‘‘nn’’

Curve fitting was performed using Microsoft Excel2000 version. The dissolution data were fitted toPeppas equation19. Release exponent "n" was calcu-lated.

Mt / M∞ = kptn (1)

where Mt/M∞ is the fraction of drug released at timet, kp is the kinetic constant of the system, and n is theexponent characteristic of the mode transport.

TThheerrmmaall aannaallyyssiiss

Thermal analyses were performed using DifferentialScanning Calorimeter (SETARAM DSC92). DSCanalyses were carried out on the samples of 17.7-

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Güneri, Ar›c›, Ertan

37.7 mg range. All samples were scanned in alu-minium pans from 25°C to 300°C, at a constant rateof 5°C min-1 using nitrogen as effluent gas.

RREESSUULLTTSS AANNDD DDIISSCCUUSSSSIIOONN

It is known that particle size of microspheresdepends on the stirring rate20. Thus, the effects ofthree different stirring rates of 500, 750 and 1000rpm on particle size and drug content were investi-gated (Figures 1 and 2). Microspheres preparedwere sieved through combined sieve system andgrouped based on particle size ranging from <125,125-250, 250-500 and >500 µm. Approximately 87-90% of the microspheres were within the 125-500 µmrange. Therefore, all subsequent studies were per-formed on 125-250 µm and 250-500 µm particles.

FFiigguurree 11.. Fraction percentage of microspheres prepared at differ-

ent stirring rates (n=3).

FFiigguurree 22.. Ibuprofen content of microspheres prepared at different

stirring rates (n=3).

The amounts of 125-250 µm microspheres prepared

at 500, 750 and 1000 rpm were determined to be14%, 40% and 43%, respectively. On the other hand,the amounts of 250-500 µm microspheres preparedat the same stirring rates were determined to be70%, 50% and 44%, respectively. It was found thatthe amount of <250 µm microspheres increasedwhile the amount of >250 µm microspheresdecreased with an increase in stirring rate (Figure 1).

The drug contents of 125-250 µm microspheres pre-pared at 500, 750 and 1000 rpm were 47%, 45% and37%, respectively. The drug contents of 250-500 µmmicrospheres prepared at the same stirring rateswere 50%, 47.5% and 40%, respectively. When thestirring rate was increased, drug content of themicrospheres decreased slightly (Figure 2). Based onthese present results, 250-500 µm particles preparedat 500 rpm were used in the preparation of supposi-tory formulations since they were obtained at highyield (73%) with high drug content (50%).

The suppositories prepared were found to be inaccordance with BP 1998 requirements for weightuniformity. Drug contents were homogeneous forall suppositories according to content uniformitytests. The hardness of lipophilic suppositories wasalmost 2 kg, but suppositories prepared using PEG4000 were very hard (>5 kg). Therefore, combinationstudies were performed to decrease the hardness.As a result of these studies, PEG 400:PEG 4000 (5:95)combination was selected after preliminary studiesand used in all hydrophilic suppositories. Theresults related to suppository properties are given inTable 1.

TTaabbllee 11.. Weight variation, content uniformity andhardness of suppositories

Formulation Weight variation (g) Content uniformity (mg) Hardness (kg)–X ±SDa –X ±SDb –X ±SDa

PEG Supp. 1.94 0.018 301.90 1.516 3.92 0.075Witepsol Supp. 1.66 0.037 301.01 1.722 2.02 0.132PEG-MI Supp. 1.74 0.107 299.54 2.118 3.42 0.116Witepsol-MI Supp. 1.65 0.040 301.10 2.514 1.72 0.147a n=20, b n=3

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In vitro release tests were conducted on bothmicrospheres and four suppository formulations asshown in Figure 3. The complete dissolution of bothpure ibuprofen and PEG suppositories lasted 2 h.While 80% of pure ibuprofen was dissolved within30 min, this value was only 40% for PEG supposito-ries because of the slow melting of the suppositoriesin the dissolution medium. However, it wasobserved that PEG base did not have any effect onthe drug release. Ibuprofen was completely releasedfrom Witepsol suppositories in approximately 5 h.This time period was longer than that of PEG sup-positories because of the lipophilicity and phaseseparation from the dissolution medium of Witepsolbase. In this phenomenon, ibuprofen stayed in asolid form in the melted base and then separatedvery slowly from the base with the agitation of thedissolution medium. These results are consistentwith the findings of Gjellan and Graffner21.

The dissolution of the drug from Witepsol-MI sup-positories was about 80% after 8 h. In pure micros-phere tests, 94% of the drug was released in 8 h. Thedecrease in release of ibuprofen from Witepsol-MIsuppositories may be due to the lipophilicity of theWitepsol base. From PEG-MI suppositories, 90% ofibuprofen was released in 8 h. It is clearly seen inFigure 3 that the PEG base did not show any signif-icant effect on the dissolution and thus the releasewas almost the same as with the microspheres.Therefore, PEG combination seems to be suitable forsustained-release ibuprofen suppositories.Similarly, Ermifl and Tar›mc›22 reported that PEGmixtures as a hydrophilic base were suitable forketoprofen sustained-release suppositories contain-ing hydroxypropylmethylcellulose phthalate as theinert matrix material. 100% dissolution from PEGformulation prepared with microspheres was notobserved due to the low incorporation of drug in themicrospheres. Nakajima et al.6 performedindomethacin release test carried out withindomethacin-ethylcellulose microcapsules to deter-mine the effect of suppository bases. They foundthat the release was almost the same for PEG andWitepsol suppositories containing microcapsules. Inour study, it was found that only lipophilic Witepsol

base slightly affected the dissolution, most probablydue to the fact that ibuprofen is more soluble thanindomethacin. Moreover, in the study of Arra et al.7,the dissolutions of both pure micropellets and con-ventional suppositories of the terbutaline sulfatewere higher than of PEG suppositories preparedwith micropellets. Therefore, it can be concludedthat dissolution from sustained-release supposito-ries containing microparticulate dosage formsdepends on the solubility of the drug and lipophilic-ity or hydrophilicity of the base used.

The dissolution data obtained were subsequentlyanalyzed according to Eq. (1). The value of n indi-cates the drug release mechanism from the non-swellable and swellable spherical devices and thevalue of n= 0.43 indicates Fickian diffusion. Valuesof 0.43< n <1.0 indicate anomalous non-Fickiantransport, whereas the value of n= 1.0 indicates case-II or zero-order release23. It is clear from the n valuesshown in Table 2 that microspheres and supposito-ries exhibited a non-Fickian diffusion mechanism. nvalue was 0.273 for the ethylcellulose microspheresprepared, which is far below 0.43. Grattard et al.24

found that the n values for the lactase, Tempol andTempo (small paramagnetic probes) microspheresprepared with ethylcellulose were approximately0.26. This data fit our findings very well. Ritger andPeppas 23 explained that the size distribution ofmicrospheres could influence the value of n. Size ofour microspheres was 250-500 µm; Grattard et al.prepared 30.2 µm microspheres. There seems to be agreat difference among the prepared microspheres.Therefore, there might be another reason for the lown value. The n value of PEG-MI suppositories was0.290, which indicates that the hydrophilic base hasno effect on the dissolution from microspheres.Moreover, dissolution profiles from these micros-pheres and suppositories were very similar (Figure3). The n value of only PEG suppositories was 0.767,showing the non-Fickian drug release. This type ofdiffusion contains Fickian and relaxation or gelationproperties together, but PEG does not have theseproperties. The reason for the high n value could bethe rapid melting of the suppository in the dissolu-tion medium (2 h) and the linearity of the first 80%of the dissolution profile. It is known that n value

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Güneri, Ar›c›, Ertan

approaches 1.0 with the linearity of the dissolutionprofile. For correction based on this knowledge, asimulation study was done on the 80% of the disso-lution profile of the PEG suppository and it wasobserved that the n value increased to 0.893 from0.767 and r2 increased to 0.994 from 0.895 for zero-order drug release.

The Witepsol suppositories surprisingly showed a lown value (n=0.305) like microspheres. It can be explainedby the slow drug diffusion from the separated Witepsolphase in the aqueous dissolution medium. Anotherunexpected finding for the Witepsol-MI suppositorywas a rise in n value to nearly 0.5. This could be non-Fickian drug diffusion, but this phenomenon is stillunknown. It is thought that the restriction of the contactof microspheres with the dissolution medium byWitepsol causes a slow release at the beginning of thedrug dissolution and the release profile somehowapproaches linearity (Figure 3).

FFiigguurree 33.. Dissolution profiles of ibuprofen – ( ) pure ibuprofen;

( ) PEG suppositories; ( ) Witepsol suppositories; ( )

microspheres; ( ) PEG-MI suppositories; ( ) Witepsol-

MI suppositories (mean values ±SD, n=3).

It is well known that Higuchi’s square root of timerelationship indicates a pure Fickian diffusion con-trolled mechanism25. None of the formulationsshowed Higuchi kinetics as shown in Table 2. This isa good evidence for the non-Fickian diffusion mech-anism explained above. The best kinetics wereobserved by Hixson-Crowell model for bothWitepsol and PEG suppositories (represented by aninitial burst followed by a gradual increase in drugrelease) and by first-order model for other micros-pheres and suppositories prepared with micros-pheres (showing both the non-Fickian diffusion andproportional drug release with the reservoir).Results concerning dissolution kinetics are shown inTable 2.

Differential scanning calorimetry (DSC) is one of thethermal methods used in pharmaceutical systemsfor studying the physical nature of pure com-pounds26. It has also been used to detect the pres-ence of decomposition products formed in amino-phylline suppositories prepared at high tempera-tures 27. Figures 4-6 show the thermograms of pureibuprofen, ethylcellulose, microspheres, supposito-ry bases and suppositories.

As shown in Figure 4, ibuprofen has a well-definedpeak at approximately 78°C and ethylcelluloseshows no peak at a temperature range of 25°C to300°C. Microspheres, however, exhibit a small peakat approximately 75°C, demonstrating that they con-tain ibuprofen in crystalline form.

In Figure 5, Witepsol base shows a peak around45°C and suppositories show no transition peak attemperatures between 75-78°C, which indicates the

TTaabbllee 22.. Results of the exponent "n" and dissolution kinetics of microspheres and suppository formulationsFFoorrmmuullaattiioonn PPeeppppaass eeqquuaattiioonn HHiigguucchhii FFiirrsstt--oorrddeerr HHiixxssoonn--CCrroowweellll ZZeerroo--oorrddeerr

kkpp nn rr22 kkHH rr22 kk11 rr22 kkHHCC rr22 kkoo rr22

((mmiinn––11//22)) ((mmiinn––11)) ((mmiinn––11)) ((mmiinn––11))PEG Supp. 2.996 0.767 0.967 -20.266 0.956 5.531 0.942 -0.215 0.995 20.146 0.895Witepsol Supp. 17.587 0.305 0.997 28.778 0.987 4.551 0.959 0.657 0.998 51.182 0.935Microspheres 18.578 0.273 0.961 35.988 0.917 3.960 0.958 1.000 0.920 55.032 0.810PEG-MI Supp. 16.062 0.290 0.949 32.341 0.901 3.965 0.925 0.941 0.886 51.236 0.789Witepsol-MI Supp. 4.269 0.495 0.963 6.281 0.949 4.328 0.956 0.462 0.929 30.060 0.861r2: Determination coefficient. k: Release rate constant for respective models. MI: Microspheres.

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absence of ibuprofen in crystalline form.

FFiigguurree 44.. Differential scanning thermograms of (A) pure ibupro-

fen, (B) ethylcellulose and (C) microspheres.

FFiigguurree 55.. Differential scanning thermograms of (A) pure ibupro-

fen, (B) Witepsol H15, (C) Witepsol suppository and (D)

Witepsol-MI suppository.

As shown in Figure 6, PEG 4000 or its combination

shows a peak at temperatures between 67-69°C and

there is no transition peak for suppositories at tem-

peratures between 75-78°C. This indicates that

ibuprofen is not present in crystalline form in sup-

positories and also that there is no decomposition

product of the drug in all suppository formulations.

On the other hand, although ibuprofen is known as

thermally stable even at high temperatures28, a

metastable molecular dispersion could exist in the

ethylcellulose microsphere and these molecules will

tend to recrystallize under storage, leading to a

modification of the release profiles of the supposito-

ries14.

FFiigguurree 66.. Differential scanning thermograms of (A) pure ibupro-fen, (B) PEG 4000, (C) PEG 400:PEG 4000 (5:95) drug-free combination, (D) PEG suppository and (E) PEG-MIsuppository.

CCOONNCCLLUUSSIIOONN

In this study, sustained-release ibuprofen supposi-tories containing microspheres were prepared andinvestigated in terms of kinetics, diffusional behav-ior and DSC analysis. To our knowledge, this is thefirst time that microspheres have been used in sus-tained-release suppository formulations. Accordingto the results of this study, type of salt and basicform of drug, suppository base and particle size ofthe microparticulate system must be selected care-fully to prepare the sustained-release suppositorydosage forms. With this kind of formulation, theundesired gastrointestinal and first-pass effects ofthe drug can be eliminated, and a sustained effectcan be obtained. Therefore, ibuprofen suppositoriesprepared in this study are promising as being moreuseful than conventional formulations in therapy.

AAcckknnoowwlleeddggeemmeenntt

The authors would like to thank Prof. Dr. DevrimBALKÖSE of ‹zmir Institute of Technology, Facultyof Engineering Department, for thermal analyses.This work was supported by Ege UniversityResearch Fund.

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