Aliment Pharmacol Ther 2003; 17: 1163–1169.
`
`doi: 10.1046/j.0269-2813.2003.01564.x
`
`Gastrointestinal transit and release of 5-aminosalicylic acid from
`153Sm-labelled mesalazine pellets vs. tablets in male healthy
`volunteers
`
`M. BRUNNER*, R. GREINWALD , K . K LETT ERà, H. KVATERNIK §, M. E. COR RADO– ,
`H. G. EICHLER* & M. MU¨ LLER*
`*Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, University of Vienna Medical School, Vienna,
`Austria;  Dr Falk Pharma GmbH, Freiburg, Germany; àDepartment of Nuclear Medicine, University of Vienna Medical
`School, Vienna, Austria; §Austrian Research Centers Seibersdorf, Seibersdorf, Austria; –CROSS S.A., Arzo, Switzerland
`
`Accepted for publication 26 October 2002
`
`SUMMARY
`
`acid)-con-
`(5-aminosalicylic
`Background: Mesalazine
`taining formulations, designed to optimize drug delivery
`to the ileo-caecal region, represent a cornerstone in the
`treatment of inflammatory bowel diseases.
`Aim: To test, by means of pharmaco-scintigraphy,
`whether novel mesalazine-containing pellets release
`5-aminosalicylic acid in the same target region as
`mesalazine tablets (Salofalk).
`Methods: Fourteen healthy male volunteers received a
`single dose of either pellets or tablets containing
`500 mg of mesalazine and 2 mg of 152Sm2O3 with a
`1-week washout period. The gastrointestinal transit of
`153Sm, incorporated into the formulations, was followed
`by gamma-scintigraphy. Mesalazine release was verified
`by assessing 5-aminosalicylic acid plasma pharmacoki-
`netics.
`
`Results: The formulations reached the ileo-caecal tar-
`get region almost at
`the same time (3.3 ± 1 and
`3.8 ± 1 h for pellets and tablets, respectively). Plasma
`5-aminosalicylic acid tmax values were comparable and
`corresponded to the time during which the formula-
`tions were located in the target region. Plasma AUC
`values were significantly lower
`for pellets, which
`might be explained by a more prolonged release of
`5-aminosalicylic acid.
`Conclusions: Novel mesalazine pellets and Salofalk tab-
`lets release active 5-aminosalicylic acid in the same
`target region and pass through the gastrointestinal tract
`under fasting conditions in healthy volunteers in a
`comparable time. From a comparison of
`in vitro
`dissolution and plasma concentration data, a slower
`and more prolonged release of 5-aminosalicylic acid
`from pellets is suggested.
`
`INTRODUCTION
`
`Mesalazine (5-aminosalicylic acid, 5-ASA), the thera-
`peutically active moiety of sulfasalazine,1–3 is routinely
`
`Correspondence to: Dr M. Brunner, Department of Clinical Pharmacology,
`Division of Clinical Pharmacokinetics, University of Vienna Medical School,
`Allgemeines Krankenhaus, Wa¨hringer Gu¨rtel 18–20, A-1090 Vienna,
`Austria.
`E-mail: martin.brunner@univie.ac.at
`
`inflammatory bowel
`employed in the treatment of
`disease, i.e. ulcerative colitis and Crohn’s disease. Orally
`administered mesalazine is rapidly and almost com-
`pletely absorbed from the small intestine.4–6 Hence, only
`a small percentage of the intact drug reaches the lower
`gastrointestinal
`tract,
`the target
`region in which
`mesalazine acts locally after absorption by the colonic
`and ileal mucosa. To provide controlled drug release
`and site-specific delivery to the intestinal target region,
`
`Ó 2003 Blackwell Publishing Ltd
`
`1163
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`Mylan Exhibit 1025
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`

`
`1164 M. BRUNNER et al.
`
`various delivery systems for 5-ASA have been devel-
`oped,
`including tablets coated with an acrylic-based
`resin7, 8 or microgranules (pellets) coated with ethyl-
`cellulose.9, 10
`The in vivo performance of such delivery systems is
`routinely evaluated by the non-invasive technique of
`gamma-scintigraphy.9–13 Gamma-scintigraphy allows
`the gastrointestinal transit of orally ingested dosage
`forms to be followed and the exact time and region of
`disintegration and release to be identified. Consequently,
`it is possible to relate the plasma and urine pharmaco-
`kinetics of the ingested dosage form to the scintigraphic
`pattern within the gastrointestinal tract, thereby allow-
`ing the rate and extent of absorption to be determined in
`a defined region of interest (‘pharmaco-scintigraphy’).
`Gamma-scintigraphy requires the drug to be labelled
`with a radioactive tracer. Radiolabelling can be
`achieved by either direct incorporation of a radiolabelled
`compound or by neutron activation of a dosage form
`that contains a non-radioactive tracer which is not
`absorbed from the gastrointestinal tract. For the eval-
`uation of complex dosage formulations, such as enteric-
`coated tablets or pellets, labelling is best performed by
`the addition of a non-radioactive tracer which is not
`absorbed from the gastrointestinal
`tract,
`such as
`samarium-152 oxide (152Sm2O3), followed by neutron
`activation of the finished product.12, 14–16
`In the present study, the gastric and intestinal transit
`and absorption of a newly developed mesalazine pellet
`formulation were measured in healthy volunteers by
`pharmaco-scintigraphy, and were compared with phar-
`maco-scintigraphic data for mesalazine tablets. Before
`administration, cold 152Sm was added to both formu-
`lations and was activated to radioactive 153Sm. The
`main objectives of the study were: (i) to demonstrate
`that mesalazine pellets release the active ingredient 5-
`ASA in the same target region (i.e. terminal ileo-caecal
`region) as tablets; and (ii)
`to compare the transit
`behaviour and absorption along the gastrointestinal
`tract of the two radiolabelled formulations.
`
`MATERIALS AND METHODS
`
`The study was approved by the local ethics committee.
`All volunteers were given a detailed description of the
`study and their written consent was obtained. The study
`was performed in accordance with the Declaration of
`Helsinki and the Good Clinical Practice Guideline of the
`European Commission (EC-GCP guideline).
`
`Healthy volunteers
`
`Based on a sample size calculation, 14 healthy male
`volunteers
`(mean age ± s.d., 27 ± 3 years; mean
`weight, 74 ± 4 kg; mean height, 181 ± 6 cm) were
`included in the present study. Each volunteer was
`subjected to a screening examination, including medical
`history, physical examination, 12-lead electrocardio-
`gram, blood pressure, heart rate, complete blood count
`with differential blood analysis, urinalysis, urine drug
`screen, clinical blood chemistry, blood coagulation tests,
`hepatitis B surface antigen and human immunodefi-
`ciency virus antibody test. Subjects were excluded if
`they had taken any prescription medication or over-the-
`counter drugs within a period of 2 weeks prior to the
`study, or if they had undergone any diagnostic analysis
`with radioactive tracers or X-rays during the 6 months
`preceding the study.
`
`Study design and study medication
`
`This phase I study was carried out as a comparative,
`single-centre, randomized, observer-blind, cross-over
`trial. Subjects received either mesalazine pellets or
`mesalazine tablets in a randomized fashion. There was
`a washout period of at least 7 days between treatments.
`The study medication was provided by Dr Falk Pharma
`GmbH, Freiburg, Germany. The test formulation con-
`sisted of pellets containing 500 mg of mesalazine and
`2 mg of 152Sm2O3; the reference formulation consisted
`of tablets containing 500 mg of mesalazine and 2 mg of
`152Sm2O3. Pellets or tablets were taken orally with
`200 mL of water in the morning after an overnight fast.
`Both formulations were coated with Eudragit L, dissol-
`ving at pH ‡ 6.0, with an additional retarding polymer
`in the pellet core providing prolonged release after
`removal of the outer Eudragit L coating.
`
`In vitro tests
`
`In vitro dissolution. The in vitro dissolution profiles of
`the pellets and tablets were examined under conditions
`resembling transit along the gastrointestinal tract. It
`was demonstrated that
`the dissolution rate of
`the
`tablets was significantly higher than that of the pellets,
`with 99.2% of
`the total amount of 5-ASA being
`released after 60 min for
`the tablet
`formulation,
`compared with 30.5% for
`the pellet
`formulation
`(Figure 1).
`
`Ó 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 17, 1163–1169
`
`

`
`GASTROINTESTINAL TRANSIT OF MESALAZINE
`
`1165
`
`observation for 24 h post-dose. During hospitalization,
`volunteers received standardized meals according to a
`fixed time-table based on the normal caloric need of a
`healthy male adult with normal weight and slight
`physical activity. After an overnight
`fast,
`the trial
`medication was administered to the subjects between
`07.30 and 09.00 h with 200 mL of water. Thereafter,
`volunteers underwent scintigraphic scans, blood and
`urine sampling at predetermined intervals up to 24 h
`post-dose. On the following day, subjects underwent
`24-h plasma sample collection, collection of overnight
`urine and a last scintigraphic scan.
`The transit of mesalazine pellets and tablets along the
`gastrointestinal
`tract was recorded scintigraphically
`using a ‘large field of view’ gamma camera (Toshiba
`GCA-901A), equipped with a low-energy, all-purpose,
`parallel-hole collimator. Scanning was performed at
`approximately 20-min intervals up to 6 h, and there-
`after at approximately 30-min intervals up to 10 h.
`Additional scans were taken at 12 and 24 h post-dose.
`In each subject, the following regions of interest were
`identified on the basis of anatomic subdivisions:
`stomach,
`small
`intestine,
`terminal
`ileum-caecum,
`ascending colon, transverse colon, descending colon
`and sigmoid colon. The location of the labelled dosage
`formulation in the gastrointestinal tract was deter-
`mined by viewing the images on a monitor. The
`number of counts for each region was recorded at each
`time interval. Afterwards, the geometric means of the
`corresponding anterior and posterior count rates were
`calculated, corrected for radioactive decay and finally
`expressed as percentages of the total radioactivity in
`the abdomen.
`In order to determine the appearance or disappearance
`of the labelled formulation to or from the target region,
`the relative amount of radioactivity was defined as 15%
`(for appearance) or 85% (for disappearance) of the total
`radioactivity in the region.
`
`Sampling of venous plasma
`
`Venous blood samples (8 mL) were taken from an arm
`vein using an indwelling catheter with a switch valve at
`the following times: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 5,
`6, 8, 10, 12, 16 and 24 h. Blood samples were
`immediately centrifuged at about 2500 · g for 5 min.
`The plasma samples (3–4 mL) obtained were equally
`divided into two tubes and frozen at ) 80 °C until
`analysis.
`
`Figure 1. In vitro dissolution profiles for pellets and tablets,
`depicting the percentage of 5-aminosalicylic acid (5-ASA) released
`from non-irradiated pellets (n ¼ 1, n), irradiated pellets (n ¼ 3, n),
`non-irradiated tablets (n ¼ 1, d) and irradiated tablets (n ¼ 3, ,).
`Results are depicted as the mean ± standard deviation.
`
`Activation procedures. Before the clinical part of the
`study was started, a series of activation tests was
`performed on 152Sm2O3-containing tablets to identify
`the optimal activating conditions. In several experi-
`ments, tablets were irradiated for a time varying from 1
`to 40 min under different neutron fluxes to transform
`stable 152Sm into the radioactive 153Sm isotope. The
`optimal activating condition was 1 MW with a neutron
`flux of 9 · 1012 cm2/s for 1.3 min for pellets and
`7.5 min for tablets.
`
`Stability. Further in vitro dissolution tests were per-
`formed to demonstrate an equal mesalazine content for
`irradiated and non-irradiated pellets and tablets, and to
`verify that the irradiation process did not alter the
`release profiles. Dissolution was examined by a standard
`paddle apparatus system which automatically changed
`the pH at predetermined times. The dissolution tests
`were carried out in buffer at pH 1.2 for 2 h, and then at
`pH 6.8 for 1 h (tablets) or 5 h (pellets). The appearance
`of mesalazine in the buffer was measured spectropho-
`tometrically. The dissolution profiles of the irradiated
`and non-irradiated formulations were comparable,
`indicating that the irradiation process did not alter the
`performance of either pellets or tablets (Figure 1).
`
`Experimental design
`
`Volunteers attended the Clinical Trial Centre the
`evening before drug administration and remained under
`
`Ó 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 17, 1163–1169
`
`

`
`1166 M. BRUNNER et al.
`
`Urine collection
`
`Immediately before drug administration, subjects were
`asked to empty their bladder (pre-dose urine). After
`administration of the study drugs, urine was collected
`over three periods: 0–6, 6–12 and 12–24 h. The total
`volume of each fraction and the total 24-h urine volume
`were calculated. At all collection times,
`two 5-mL
`aliquots were frozen at ) 80 °C for analytical investiga-
`tion.
`
`Sample analysis
`
`Orally administered 5-ASA is absorbed by the colonic
`and ileal mucosa and is primarily acetylated to its major
`metabolite N-acetyl-5-ASA (Ac-5-ASA) in the gut wall
`and in the liver. Blood and urine samples were analysed
`for
`their 5-ASA and Ac-5-ASA content by high
`performance liquid chromatography according to the
`literature.17, 18
`
`Data analysis
`
`From scintigraphy, the following variables could be
`described: (i) gastric emptying time (h); (ii) location in
`the small intestine (h); (iii) small intestinal transit time
`(h); (iv) time of disappearance from the small intestine
`(h); (v) colonic arrival (h); (vi) time of complete tablet
`disintegration (h); (vii) colonic transit time (h).
`The percentage of 5-ASA absorption in the ileo-caecal
`target region and the ascending colon was calculated
`for the test and reference formulations from the ratio
`between the extent of absorption in the target region
`(AUCtr) and the overall extent of absorption up to the
`time of the last detectable concentration of 5-ASA
`(AUCt), according to the following equation:
`Relative absorptionð%Þ ¼ 100  ðAUCtr=AUCtÞ
`In two subjects, the target region could not be iden-
`tified exactly. Therefore, these subjects were excluded
`from the analysis. Due to practical difficulties, the time
`of blood collection did not always correspond exactly to
`the time at which the scintigraphic images were taken.
`When plasma samples were missing at the start and end
`of transit in the relevant region, plasma levels were
`obtained by linear interpolation of the concentrations
`available at
`the times immediately preceding and
`following the time of interest. Pharmacokinetic param-
`eters were calculated by KineticaTM software, Version
`
`2.00.200 (Innaphase, France) for both 5-ASA and Ac-
`5-ASA.
`
`Statistical analysis
`
`Data collected during the study were analysed by des-
`criptive statistics (mean, standard deviation) using SAS
`6.12 software. The analysis of relative absorption was
`carried out using the chi-squared test for independent
`samples. Scintigraphic variables were analysed by
`analysis of variance (anova) for a cross-over design.
`The pharmacokinetic parameters obtained after the
`administration of mesalazine pellets (test drug) and
`mesalazine tablets (reference drug) were compared by
`complete anova, with period, subject, formulation and
`sequence as factors, after logarithmic transformation.
`tmax values were compared non-parametrically using
`the Friedman test without transformation. AUCt values
`calculated after the administration of mesalazine pellets
`and tablets were compared by anova. Statistical tests
`were performed using KineticaTM software. P < 0.05
`was considered to be statistically significant.
`
`RESULTS
`
`The gastrointestinal distribution of 153Sm radioactivity
`incorporated into both mesalazine formulations was
`measured by means of scintigraphic imaging. Transit
`parameters are shown in Table 1. By definition, the
`study drug entered a gastrointestinal region when the
`relative amount of radioactivity was ‡ 15% and left it
`when ‡ 85% had disappeared. For both formulations,
`gastrointestinal transit was comparable, and the test
`
`Table 1. Transit parameters (h) for mesalazine pellets and tablets
`(mean ± standard deviation)
`
`Transit
`
`Pellets
`
`Tablets
`
`Gastric emptying
`Location in small intestine
`Transit time in small intestine
`Disappearance from
`small intestine
`Ileo-caecal region
`(target region)
`Ascending colon region
`
`Overall transit time in colon
`
`0.94 ± 0.70
`0.65 ± 0.40
`3.07 ± 0.88
`3.71 ± 1.08
`
`0.56 ± 0.71
`0.79 ± 0.71
`3.00 ± 0.84
`3.79 ± 1.17
`
`3.83 ± 0.89*
`3.31 ± 1.03*
`5.56 ± 1.57 
`6.15 ± 2.48 
`4.74 ± 1.15*
`4.08 ± 1.39*
`13.57 ± 4.45  10.88 ± 1.48 
`19.92 ± 1.39
`17.37 ± 4.80
`
`* Entrance.
`  Exit.
`
`Ó 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 17, 1163–1169
`
`

`
`GASTROINTESTINAL TRANSIT OF MESALAZINE
`
`1167
`
`Figure 2. Scintigraphic images for one
`volunteer, depicting the gastrointestinal
`transit of 153Sm-labelled mesalazine tablets.
`The scintigrams shown were acquired at
`the start (3 min) and 4 h 20 min, 9 h
`30 min and 24 h after tablet administra-
`tion. The predominant activity at 4 h
`20 min is in the target region. At 24 h, the
`image is faint, indicating that most of the
`activity has been excreted. The inset depicts
`the respective plasma concentration vs.
`time profile for 5-aminosalicylic acid
`(5-ASA) (n) and N-acetyl-5-ASA
`(Ac-5-ASA) (.). The black horizontal bars
`indicate the time during which the formu-
`lation was located in the small intestine
`(SI), the target region (TR) and the
`ascending colon (AC).
`
`and reference formulations reached the ileo-caecal
`region almost at
`the
`same
`time
`(3.3 ± 1 and
`respectively, P ¼ 0.08). The differences
`3.8 ± 1 h,
`observed between subjects are due to individual vari-
`ability and the difficulty in defining the gastrointestinal
`regions exactly.
`Figure 2 shows the mean plasma concentration vs.
`time course for 5-ASA and Ac-5-ASA. The mean tmax
`values were
`comparable
`for pellets and tablets
`(4.1 ± 1.0 and 5.1 ± 1.2 h, respectively) and corres-
`ponded to the time during which the formulations were
`located in the target region. The Cmax values for 5-ASA
`after administration of the pellets were lower than after
`administration of the tablets, but the difference was not
`statistically
`significant
`(429 ± 262 and 1241 ±
`1305 ng/mL, respectively, P ¼ 0.12). The mean relat-
`ive percentage absorption values of 5-ASA during
`location in the ileo-caecal
`target
`region and the
`ascending
`colon
`were
`52.42 ± 25.48
`and
`45.85 ± 30.32 for pellets and 39.91 ± 29.41 and
`54.29 ± 30.33 for tablets, respectively. The differences
`were not significantly different (P ¼ 0.27 for the ileo-
`caecal region and P ¼ 0.22 for the ascending colon).
`However, the AUCt values for 5-ASA were significantly
`lower (P ¼ 0.02) for pellets (968 ± 629 ng.h/mL) than
`for tablets (2206 ± 1767 ng.h/mL).
`After the oral administration of pellets and tablets, the
`cumulative amounts of 5-ASA and Ac-5-ASA excreted
`in the urine were 14.53 ± 2.92% and 20.71 ± 11.97%
`of the total administered dose, respectively.
`
`DISCUSSION
`
`In the treatment of ulcerative colitis and Crohn’s
`disease, oral slow-release 5-ASA preparations have
`been developed to deliver
`sufficient quantities of
`5-ASA to the lower small intestine and colon. The fate
`of a slow-release preparation in the small
`intestinal
`lumen is determined by gastric emptying, small intes-
`tinal
`transit,
`the intraluminal pH and the specific
`coating. In the present study, the reference formulation
`(Salofalk) was coated with an acid-resistant, acrylic-
`based resin (Eudragit L) and contained 5-ASA in a
`sodium carbonate–glycine buffering mixture; this disin-
`tegrates and releases 5-ASA at and above pH 6.0, the
`prevailing pH in the mid and lower small intestine and
`colon. Pellets with the same Eudragit L coating, but
`with a matrix polymer in the pellet core to provide
`prolonged release, could show some advantages com-
`pared with tablets,
`such as passage through the
`stomach independent of concomitant food intake or
`facilitated passage through strictures in the upper
`gastrointestinal tract. Furthermore, microgranules offer
`the possibility to administer larger quantities of mesal-
`azine in a more convenient manner than with tablets;
`this is desirable as clinical trials have demonstrated the
`greater efficacy of higher mesalazine dosages (up to 4 g
`daily) in both ulcerative colitis and Crohn’s disease.19
`Finally, the intake of 5-ASA in the form of pellets offers
`better palatability, and is therefore more acceptable and
`preferable to the intake of 5-ASA-containing tablets, as
`
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`

`
`1168 M. BRUNNER et al.
`
`(a)
`
`(b)
`
`Figure 3. Mean plasma concentration vs.
`time profiles for 5-aminosalicylic acid (5-
`ASA) (n) and N-acetyl-5-ASA (Ac-5-ASA)
`(.) after the administration of pellets (a) or
`tablets (b) containing 500 mg mesalazine
`and 2 mg 152Sm2O3 (n ¼ 14). Results are
`
`depicted as the mean ± standard deviation.
`
`reported previously.20, 21 The present
`study was
`designed to evaluate whether Salofalk tablets and
`recently developed pellets release 5-ASA in the same
`gastrointestinal target region,
`i.e. the terminal
`ileo-
`caecal region. Gamma-scintigraphy was employed to
`follow the transit of 153Sm,
`incorporated into both
`formulations, along the gastrointestinal
`tract. The
`release of mesalazine was verified by assessing the
`plasma pharmacokinetics of 5-ASA and Ac-5-ASA.
`For tablets and pellets, peak 5-ASA plasma concentra-
`tions were attained when 153Sm radioactivity was
`localized in the target region (Figure 2), indicating that
`the major release and absorption of the active moiety
`occur in the designated part of the gastrointestinal tract.
`Plasma AUCt values were significantly lower for the
`pellet formulation. One explanation for this finding
`involves the lower in vitro dissolution rate of the pellets
`(Figure 1). Assuming that the dissolution rate remains
`constant in vivo, the observed lower systemic availability
`of the pellets might be explained on this basis. Looking
`at the intestinal metabolism and elimination of 5-ASA,
`there is another possible explanation for the lower AUC
`values. Once 5-ASA has been delivered to the intestinal
`target region, carrier-mediated, saturable, transepithel-
`ial 5-ASA transport occurs into the mucosal cells.22
`Intracellularly, 5-ASA is metabolized to Ac-5-ASA,
`which is predominantly secreted into the intestinal
`lumen. When drug absorption is saturated, 5-ASA is
`systemically absorbed via the paracellular pathways
`and is mainly metabolized by the liver. Thus, it can be
`speculated that, due to the slower release of 5-ASA from
`the pellets in the present study, the transport process is
`
`leading to a more prolonged rate of
`not saturated,
`absorption. In addition, this could explain the longer
`terminal elimination half-life of 5-ASA from the pellets,
`which can be extrapolated from the mean concentration
`vs.
`time profile in Figure 3, although it was not
`calculated in the present study due to the low number
`of time points.
`It should be noted that the present pharmaco-scinti-
`graphic data were collected in fasting healthy volun-
`teers and might not reflect the delivery patterns in
`patients, although, as yet, there has been no evidence to
`indicate that
`inflammatory bowel diseases have a
`significant
`impact on the delivery and release of
`mesalazine-containing formulations.23–25 In healthy
`volunteers,
`direct
`intraluminal measurements
`of
`5-ASA from tablets and pellets have demonstrated that
`the major portion of oral 5-ASA is delivered to the
`colon,26, 27 whereas considerable intraluminal concen-
`trations are present throughout the small intestine for
`several hours, thereby providing an explanation for the
`effectiveness of oral controlled-release 5-ASA prepara-
`tions in small intestinal Crohn’s disease.19, 28, 29 Based
`on these findings and the results of the present study, it
`can be speculated that the new pellet formulation could
`be employed not only in ulcerative colitis or Crohn’s
`colitis, but also in Crohn’s disease of the small intestine,
`although further studies are needed to confirm this
`hypothesis.
`Gamma-scintigraphy has shown that the novel mesal-
`azine pellet formulation and Salofalk tablets release the
`active ingredient, 5-ASA, in the same gastrointestinal
`target region, and pass through the gastrointestinal
`
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`
`

`
`GASTROINTESTINAL TRANSIT OF MESALAZINE
`
`1169
`
`tract under fasting conditions in healthy volunteers in a
`comparable time. Furthermore,
`the comparison be-
`tween in vitro dissolution and plasma concentration
`data suggests a slower and more prolonged release of 5-
`ASA from the pellets.
`
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`Ó 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 17, 1163–1169