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`DOI:10.1111/j.1365-2125.2005.02517.x
`
`British Journal of Clinical Pharmacology
`
`Gastrointestinal transit, release and plasma
`pharmacokinetics of a new oral budesonide formulation
`
`1
`1
`2
`1
`3
`4
`5
`5
`5
`M. Brunner,
` S. Ziegler,
` A. F. D. Di Stefano,
` P. Dehghanyar,
` K. Kletter,
` M. Tschurlovits,
` R. Villa,
` R. Bozzella,
` G. Celasco,
`
`5
`2
`3
`1
`L. Moro,
` A. Rusca,
` R. Dudczak
` & M. Müller
`1
`3
`Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics,
`Department of Nuclear Medicine, Medical University of
`2
`4
`5
`Vienna, Vienna, Austria;
`Cross Research S.A., Arzo, Switzerland;
`Atomic Institute of the Austrian Universities, Vienna, Austria; and
`Cosmo
`S.p.A., Lainate, Italy
`
`Correspondence
`Martin Brunner, MD,
` Department of
`Clinical Pharmacology, Medical
`University of Vienna, Allgemeines
`Krankenhaus – AKH,
`Waehringer-Guertel 18–20, A-1090
`Vienna, Austria.
`+
`Tel:
`
`43 140400 2981
`+
`Fax:
`
`43 140400 2998
`E-mail:
`
`martin.brunner@meduniwien.ac.at
`
`Keywords
`budesonide, gastrointestinal transit,
`targeted drug delivery, pharmaco-
`scintigraphy, food effect
`
`Received
`28 February 2005
`Accepted
`16 June 2005
`
`Aims
`The aims of the study were to: (1) evaluate the gastrointestinal transit, release and
`absorption of budesonide from tablets with a new multimatrix formulation (M MX®)
`designed to release the drug throughout the whole colon, and (2) assess the
`influence of food on budesonide bioavailability.
`
`Methods
`Two phase I studies, each comprising 12 healthy males, were performed. Gastrointes-
`153
`Sm-labelled tablets containing 9 mg budesonide was evaluated by
`tinal transit of
`means of pharmaco-scintigraphy. The effect of food was tested by comparing plasma
`pharmacokinetics after intake of a high fat and high calorie breakfast with fasting
`controls.
`
`Results
`±
`±
`153
` 6.9 h.
` SD 9.8
`Sm-labelled tablets reached the ascending colon after a mean
`Initial tablet disintegration was observed in the ileum in 42% and the ascending and
`transverse colon in 33% of subjects. Ninety-six per cent of the dose was absorbed
`into the systemic circulation during passage through the whole colon including
`±
`C
` values from 1429
` 1014 to
`the sigmoid. Food significantly decreased
`max
`±
`=
`±
`−
`1
`P
` 601 pg mL
` (
`
` 0.028) and AUC values
`from 14 814
` 11 254
`to
`1040
`±
`=
`−
`−
`1
`1
`P
`t
` 9369 pg h
` mL
` (
`
` 0.008). Mean residence time and
` increased by
`13 486
`max
`12–29%. There was no drug accumulation after 1 week of once daily oral adminis-
`tration of budesomide.
`
`Conclusions
`MMX®-budesonide tablets appear suitable for targeted colonic drug delivery. Transit
`parameters and low systemic bioavailability warrant further studies with the new
`formulation.
`
`Introduction
`The pharmacological treatment of inflammatory bowel
`diseases (IBD) is determined by the location, extent and
`severity of the disease within the gastrointestinal tract.
`The drugs include aminosalicylate formulations, corti-
`costeroids, antibiotics, immunomodulators, and mono-
`
`clonal antibodies [1, 2]. Although corticosteroids are an
`effective option for disease management, dose- and
`duration-dependent side-effects might limit their long-
`term use. Budesonide, a nonhalogenated glucocorticos-
`α
`β
`, 17-butylidendioxy-11
`, 21-dihydroxy-1,4-
`teroid (16
`pregnadien-3,20-dione), is part of a group of new topical
`
`© 2005 Blackwell Publishing Ltd
`
`Br J Clin Pharmacol
`
`61
`
`:1
`
`31–38
`
`31
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`Cosmo Ex 2001-p 1
`Mylan v Cosmo
`IPR2017-01035
`
`

`

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`M. Brunner et al.
`
`corticosteroids, characterized by potent local anti-
`inflammatory activity, and was initially introduced for
`the treatment of asthma and rhinitis. Due to an extensive
`first-pass elimination its systemic bioavailability is only
`10–15% compared with other corticosteroid formula-
`tions, thus, improved safety and tolerability might be
`anticipated [2].
`For the treatment of IBD, budesonide has been eval-
`uated either as oral controlled-ileal-release formulation
`targeting the distal ileal and right-sided colonic region
`in Crohn’s disease [3], or as enema for the treatment of
`left-sided ulcerative colitis or sigmoiditis [4]. However,
`there are no budesonide formulations available for the
`oral treatment of distally located IBD. To allow the
`homogenous release of budesonide along the whole
`colon at a controlled rate, new gastro-resistant, extended
`release tablets characterized by a multimatrix structure
`(i.e. MMX®-tablets containing 9 mg budesonide), have
`been developed.
` performance of such novel
`To evaluate the
`in vivo
`delivery systems, the noninvasive technique of gamma-
`scintigraphy is routinely employed [5]. This technique
`allows monitoring of the gastrointestinal-transit of
`orally ingested dosage forms, to identify the exact time
`and region of disintegration and to follow the release of
`the active ingredient. Consequently, it is possible to
`relate the plasma and urine pharmacokinetics of the drug
`to the scintigraphic pattern within the gastrointestinal-
`tract and to determine the rate and extent of absorption
`in a defined region of interest (a process termed
`‘pharmaco-scintigraphy’). In the present study, budes-
`onide tablets were labelled by the addition of a non-
`radioactive tracer, which is not absorbed from the
`gastrointestinal-tract, namely
`samarium-152-oxide,
`153
`Sm) by neu-
`which was converted to samarium-153 (
`tron activation before tablet administration [6].
`The present paper describes the results of two inde-
`pendent studies with MMX®-tablets in healthy subjects
`designed to (1) evaluate the gastrointestinal-transit,
`release and absorption of budesonide from MMX®-
`tablets using pharmaco-scintigraphy; (2) assess the
`influence of food on the bioavailability of budesonide;
`(3) characterize the steady-state pharmacokinetics of
`budesonide, and (4) evaluate safety and tolerability of
`the new MMX®-budesonide formulation after a 1-
`week, once daily treatment regimen.
`
`Subjects and methods
`Study design
`Two independent, phase I studies were performed in two
`different study populations. One was a single dose phar-
`maco-scintigraphic pilot study and the other an open,
`
`32
`
`61
`
`:1
`
`Br J Clin Pharmacol
`
`randomized, balanced, single and multiple dose pharma-
`cokinetic study. Both were approved by the local Ethics
`Committees and were performed in accordance with the
`Declaration of Helsinki and the Good Clinical Practice
`Guideline of the European Commission (EC-GCP
`guideline). All subjects received a detailed description
`of the study and written informed consent was obtained.
`
`Study populations
`Twelve male healthy Caucasian subjects took part in
`each study. In the first, the mean age of the subjects was
`±
`±
`32
` 5 years, mean height 178
` 6 cm, mean weight
`±
`±
`−
`2
`. In the
`81.1
` 12.5 kg, and mean BMI 25.5
` 3.1 kg m
`±
`second study the mean age was 22
` 4 years, mean
`±
`±
`height 177
` 8 cm, mean weight 74.1
` 9.2 kg, and BMI
`±
`−
`2
`.
`23.5
` 2.6 kg m
`Before start of each study, subjects were evaluated by
`medical history, physical examination, 12-lead electro-
`cardiogram, measurements of blood pressure and heart
`rate, complete haematology with differential white
`blood cell count, blood chemistry, hepatitis B surface
`antigen, hepatitis C antibody and HIV antibody tests,
`urinalysis and urine drug screening. Subjects were
`excluded if they had taken any prescribed medication or
`over-the-counter drugs within a period of 2 weeks
`before the study. Subjects were excluded from the phar-
`maco-scintography if they had undergone any diagnos-
`tic analysis with radioactive tracers or X-rays during the
`6 months preceding the study.
`
`Study medication
`The study medication for both studies was provided by
`Cosmo S.p.A., Lainate (MI), Italy, and consisted of
`round, film-coated, gastro-resistant, extended-release
`tablets, with multimatrix structure (MMX®) [7], a
`diameter of 10 mm, a weight of 330 mg, and each con-
`taining 9 mg budesonide. Tablets were designed for
`slow and graded budesonide release in the colon, and
`consisted of an inner lipophilic matrix in which the
`active ingredient was dispersed, an outer hydrophilic
`matrix generated by
` hydration of selected poly-
`in situ
`mer chains and a third amphiphilic matrix promoting the
`inert matrix wettability. Tablets were film-coated with
`polymethacrylate to provide gastro-resistance.
`152
`Sm
`O
` (1.67% w/w per
`For scintigraphy, 5 mg of
`2
`3
`152
`tablet) was added to each tablet. Stable
`Sm-oxide was
`γ
`-ray-
`subsequently transformed into the radioactive,
`153
`Sm isotope by neutron activation. Before the
`emitting
`start of the study, preliminary tests were performed on
`152
`Sm
`O
` tablets to determine the most optimal condi-
`2
`3
`tions for activation. Tablets were irradiated for different
`time periods (1–10 min) under different neutron fluxes
`
`Cosmo Ex 2001-p 2
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`−
`−
`−
`11
`13
`2
`1
`) to obtain the intended
` s
` neutrons cm
`10
`(10
`radioactivity level of 0.8 MBq/tablet (i.e. 0.16 MBq/mg
`Sm
`O
`) at the time of drug administration.
` dis-
`In vitro
`2
`3
`solution tests were performed to verify that the release
`profiles of the tablets were not significantly altered by
`the irradiation procedure. After irradiation, the budes-
`onide content of the tablet was determined to verify that
`no degradation of the drug had occurred. Neutron acti-
`vation was found not to alter the pharmaceutical prop-
`erties and the analytical purity of the formulation. The
`±
`mean (
`SD) amount of radioactivity administered was
`±
`1.1
` 0.4 MBq/dose, which is in compliance with the
`Council Directive 96/29 EURATOM, and with the gen-
`eral guidelines of the World Health Organization.
`
`Experimental design
`Subjects attended the Clinical Trial Center in the
`evening before drug administration and remained under
`observation for 24 h postdose. During their stay, sub-
`jects received standardized meals according to normal
`caloric needs for adult healthy males of normal weight
`with slight physical activity. After an overnight fast, the
`study medication was administered orally between
`07.00 and 08.00 h with a defined amount of water.
`Thereafter, subjects underwent scintigraphic scans,
`blood and urine sampling at predetermined intervals up
`to 24 h postdose. To improve scan interpretation, each
`subject had four radioactive point sources taped to their
`skin in the following anatomical sites: the lower end of
`the sternum, the umbilicus, and the left and right iliac
`spine. The transit of budesonide tablets along the gas-
`trointestinal-tract was recorded with the subjects sitting
`γ
`under a large field of view, double-head
`-camera (Axis,
`Picker®) equipped with a low-energy, all-purpose, par-
`allel-hole collimator. Scanning was performed at 3 min
`postdose, and at approximately 20-min intervals up to
`3 h, and then at 30-min intervals up to 10 h. Additional
`scans were taken at 12 and 24 h postdose. In each sub-
`ject, the following regions of interest (ROIs) were iden-
`tified: stomach, small intestine, terminal ileum-caecum,
`ascending colon, transverse colon, descending colon,
`sigmoid colon. Data were stored electronically. The
`location of the labelled formulation in the gastrointesti-
`nal-tract was established by viewing the image on a
`monitor. Quantitative data were obtained by measuring
`the count rates recorded from the ROIs. The geometric
`mean values of the corresponding anterior and posterior
`count rates were calculated and corrected for radioactive
`decay. The appearance or disappearance of the labelled
`formulation to or from the ROIs was evaluated by
`recording the time of the first and last appearance of
`radioactivity in the region.
`
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`Gastrointestinal budesonide transit
`
`Venous blood samples (10 mL) were taken from an
`arm vein at the following times: 0 (predose), 1, 2, 3, 3.5,
`4, 4.5, 5, 6, 7, 8, 10, 12, and 24 h. Plasma samples,
`≤
`−
`°
`obtained by centrifugation were stored at
`
`20
`C until
`analysis.
`
`Single-dose pharmacokinetic and effect of food study
`Subjects attended the Clinical Trial Centre in the
`evening before drug administration and received a stan-
`dardized dinner between 20.00 and 21.00 h Subjects
`were randomized into two groups of six. In the morning,
`one group received a high fat, high caloric breakfast, i.e.
`1000 kcal with fat accounting for 50% of the total
`caloric content. One MMX®-budesonide tablet was
`administered within 30 min after the start of breakfast
`with a defined amount of water. The other group
`received one MMX®-budesonide tablet after an over-
`night fast of at least 10 h. All subjects were discharged
`on the third day and returned to the Clinical Trial Centre
`after a 7-day wash-out period for the second phase of
`the cross-over study.
`
`Multiple–dose pharmacokinetic study
`After a 7-day wash-out period the 12 subjects who took
`part in the single dose study attended the trial centre and
`remained confined for 8 consecutive nights. One
`MMX®-budesonide tablet was administered once daily
`in the morning after an overnight fast of 12 h for 7
`consecutive days. Subjects were discharged on day 8.
`Venous blood samples (10 mL) were collected from
`an arm vein at predose on days 2, 4, 6 and 7, and at the
`following time points after the last dose on the 7th
`treatment day: 0 (predose), 2, 3, 4, 5, 6, 7, 8, 10, 12, 16,
`20, 24, 30, 36 and 48 h. Plasma samples, obtained by
`≤
`−
`°
`centrifugation were stored at
`
`20
`C until analysis.
`
`Clinical assessment
`The nature, severity and frequency of adverse events,
`laboratory values outside the normal range and abnor-
`mal ECG measurements were documented.
`
`Budesonide analysis
`All plasma samples were analysed for their budesonide
`content at Pharmakin GmbH, Ulm, Germany using a
`validated GC-MS/NCI method with SIM-detection. Fifty
`µ
`L of 2
`microlitres of triamcinolone acetonide and 50
`M
`NaOH were added to previously thawed and homoge-
`nized 1 mL plasma samples. Budesonide was extracted
`into n-pentane: dichloromethane (70 : 30 v/v). After cen-
`trifugation the organic layer was evaporated to dryness
`°
`C. For derivatization
`under a stream of nitrogen at 40
`µ
`L mixture of 12.5% acetic anhydride/12.5% tri-
`a 100-
`
`Br J Clin Pharmacol
`
`61
`
`:1
`
`33
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`Cosmo Ex 2001-p 3
`Mylan v Cosmo
`IPR2017-01035
`
`

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`M. Brunner et al.
`
`ethylamine in acetonitrile was added to the dry residue.
`After a reaction time of 15 min at room temperature, the
`mixture was dried under nitrogen stream and the residue
`µ
`reconstituted in 30
`L of ethyl acetate. Two microlitres
`of the derivatized extract were subjected to GC-MS anal-
`ysis. The gas chromatograph was equipped with fused
`silica capillary column for the separation of budesonide
`and internal standard triamcinolone acetonide and cou-
`pled to a mass spectrometer. The carrier gas was helium
`−
`1
`. The GC–MS interface
`5.0 at a flow rate of 2.6 mL min
`°
`was at a pressure of 10.1 psi and a temperature of 285
`C.
`The negative chemical ionization mode was used with
`methane 3.5 as ionization gas. The lower limit of quan-
`−
`1
`. Precision
`tification (LLQ) of the assay was 50.0 pg mL
`at the LLQ expressed as a coefficient of variation was
`6% for the samples from both studies.
`
`Data analysis
`In the pharmaco-scintigraphic study the relative percent-
`age of drug absorption in the time during which the
`radioactivity was detectable in the target region (i.e.
`between the ascending and the descending colon), was
`taken as primary outcome parameter and was calculated
`by means of the following equation: Relative percentage
`=
`×
`/AUC
`), where AUC
` is
`absorption
` 100
` (AUC
`target
`24
`target
`the area under the plasma
` time curve in the target
`vs.
` the area under the plasma concentra-
`region and AUC
`24
` time curve for drug up to 24 h postdosing. The
`tion
`vs.
`following variables were described: (1) gastric emptying
`time; (2) small intestinal transit; (3) ileal transit; (4)
`colonic transit; (5) time of initial tablet disintegration.
`Measurement of the distribution of radioactivity was
`achieved by determining the count rates recorded from
`the ROIs. Geometric means of corresponding anterior
`and posterior count rates were calculated and corrected
`for radioactive decay. Whenever plasma samples were
`missing at the start and end times of transit in the rele-
`vant regions, plasma concentrations were obtained by
`linear interpolation of the concentrations available at the
`times immediately preceding and following the time of
`interest.
`For both studies the pharmacokinetic parameters for
`budesonide were calculated using Kinetica Software,
`Version 2000 (Innaphase Corporation, Philadelphia, PA,
`USA).
`
`Statistical analysis
`±
`Mean
`SD data were calculated using SAS® software
`version 8.2 for Windows® (SAS Institute Inc., USA).
`Statistical comparisons of pharmacokinetic data were
`performed using Kinetica Software. A P-value <0.05
`was considered to be statistically significant.
`
`34
`
`61
`
`:1
`
`Br J Clin Pharmacol
`
`Cmax values were compared using the analysis of vari-
`ance (ANOVA) at the level of significance of P < 0.05
`with study treatment (single dose vs. multiple dose) as
`covariate and the 90% CI for log-transformed data. The
`coefficient of accumulation after repeated administra-
`tion was calculated as the repeated/single dose ratios for
`Cmax and AUC.
`According to the latest version of an FDA guideline
`on Food-Effect Bioavailability and Fed Bioequivalence
`Studies [8], ‘an absence of food effect on BA is not
`established if the 90% CI for the ratio of population
`geometric means between fed and fasted treatments,
`based on log-transformed data, is not contained in the
`equivalence limits of 80–125% of either AUC∞ (AUC48
`when appropriate) or Cmax’. Thus, AUC and Cmax calcu-
`lated for the two diet regimens (fed and fasted) after
`administration were compared by analysis of variance
`(ANOVA) for a cross-over design (log-transformed data)
`at the level of significance P < 0.05. The 90% CI for the
`ratio of population geometric means between fed and
`fasted condition was calculated. tmax after administration
`of drug under fed or fasted conditions was compared
`using the nonparametric Friedman test (nontransformed
`data).
`
`Results
`MMX®-budesonide tablets were detected by scinto-
`graphic imaging in the ascending colon between 4 and
`>24 h after dosing (Figure 1). The drug left the descend-
`ing colon at 12 to >24 h postdosing. To estimate the
`relative percentage of budesonide absorbed from the
`target region (i.e. that between the ascending and
`the descending–sigmoid colon) the AUCtarget/AUC24
`ratio was calculated from the plasma AUC over the time
`during which radioactivity was detectable in the target
`region (mean ± SD AUCtarget: 15 114 ± 14 402 pg
`h−1 mL−1) and plasma AUC values during the 24 h obser-
`vation period (mean AUC24: 15 607 ± 14 549 pg h−
`1 mL−1). The mean relative absorption was 95.9 ± 4.2%
`indicating that during the study period absorption of
`budesonide occurred throughout the whole colon
`including the sigmoid.
`Initial tablet disintegration/erosion (ITD) started at
`9.48 ± 5.11 h after administration either in the small
`intestine (n = 2), the ileum (n = 5), the ascending
`(n = 2), transverse (n = 2) or sigmoid colon (n = 1). Indi-
`vidual times and location are given in Table 1. The times
`of tablet residence in different ROIs were 17–117 min
`(stomach), 37 min to 9.95 h (small intestine), 0.5–12 h
`(ileum), 1.5 to >15.5 h (ascending colon), 2 to >17 h
`(transverse colon), and 12 to >17 h (descending colon).
`Due to the absence of scans between 12 and 24 h after
`
`Cosmo Ex 2001-p 4
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`IPR2017-01035
`
`

`

`Table 1
`Individual times and locations of initial tablet disintegration
`(ITD) within the gastrointestinal tract of 153Sm-labelled
`MMX®-budesonide tablets
`
`Subject
`
`ITD (h)
`
`Location in the gastrointestinal tract
`
`01
`02
`03
`04
`05
`06
`07
`08
`09
`10
`11
`12
`
`>24
`8.5–9
`12–24
`10–12
`4–4.5
`10–12
`5.5–6
`7–7.5
`6–6.5
`8–8.5
`9.5–10
`6.5–7
`
`Sigmoid colon
`Ascending colon
`Ileum/ascending colon
`Small intestine/ileum
`Ileum/ascending colon
`Ileum
`Transverse colon
`Small intestine/ileum
`Ileum
`Ileum/ascending colon
`Transverse/descending colon
`Ascending/transverse colon
`
`Gastrointestinal budesonide transit
`
`high
`
`low
`
`Figure 1
`A representative scintigraphic image, depicting the dispersion of 153Sm-
`labelled MMX®-budesonide tablets in the colon. The image shown was
`acquired approximately 7 h after drug administration
`
`3000
`
`STOMACH
`
`SMALL INTESTINE
`
`ILEUM
`
`ASCENDING COLON
`TRANSVERSE COLON
`DESCENDING COLON
`SIGMOID COLON
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`0
`
`0
`
`Budesonide plasma concentration (pg/mL)
`
`Figure 2
`The mean ±SD plasma concentration vs. time
`profile of budesonide after single-dose
`administration of 153Sm-labelled MMX®-tablets
`to 12 healthy males. Lines depict periods
`between minimal time to arrive and maximal
`time to leave different gastrointestinal regions
`
`3
`
`6
`
`9
`
`15
`12
`Time (hrs)
`
`18
`
`21
`
`24
`
`drug administration, transit times in the transverse,
`descending and sigmoid colon and the percentage of
`drug absorption in the target ROI were approximated or
`not available.
`Budesonide was first detected in plasma 6.8 ± 3.2 h
`post administration (tlag) (Figure 2). The mean time to
`reach Cmax (tmax) was 14.0 ± 7.7 h and the mean Cmax of
`1768.7 ± 1499.8 pg mL−1. The difference between tmax
`and tlag was 7.2 ± 5.5 h. This period may be regarded as
`
`the time during which most of the drug is released and
`absorption dominates over elimination.
`Following oral single dose administration, budes-
`onide was detectable in plasma between 3 and 16 h
`under fasting conditions and between 5 and 16 h after a
`meal. The corresponding peak concentrations occurred
`between 12 and 24 h and between 10 and 36 h. Mean
`budesonide plasma concentration vs. time profiles after
`single dose administration under fasting and fed condi-
`
`Br J Clin Pharmacol
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`61:1
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`

`M. Brunner et al.
`
`Table 2
`The plasma pharmacokinetics of budesonide after a single
`oral dose of MMX®-budesonide tablets containing 9 mg
`of the drug to fasting and fed subjects. Results are
`presented as means ±SD, n = 12
`
`Table 3
`The plasma pharmacokinetics of budesonide at steady-
`state following once daily administration of MMX®-
`budesonide tablets containing 9 mg of the drug for 7 days.
`Results are presented as means ±SD, n = 12
`
`Fasting
`
`Fed
`
`Mean ±SD
`
`Max
`
`Min
`
`CV%
`
`Cmax (pg mL−1)
`tlag (h)
`tmax (h)
`AUC48 (pg h −1 mL−1)
`AUC∞ (pg h −1 mL−1)
`thalf (h)
`MRT (h)
`
`1428.7 ± 1013.5
`7.4 ± 4.2
`16.0 ± 3.4
`14 814 ± 11254
`15 503 ± 11340
`5.4 ± 2.0
`19.9 ± 4.6
`
`1039.9 ± 601.4
`9.8 ± 3.6
`20.7 ± 8.7
`13 486 ± 9369
`12 512 ± 7569*
`5.6 ± 2.9*
`22.3 ± 6.0*
`
`*Mean and SD of 10 subjects; Cmax, maximum plasma
`concentration; tlag, time to detect drug concentration in
`plasma; tmax, time to achieve Cmax; AUC48, area under
`the concentration curve from administration to last
`observed; concentration time t (48 h).; AUC∞, area under
`the concentration/time curve extrapolated to infinity; thalf,
`elimination half-life; MRT, mean residence time.
`
`Cssmin
`Cssmax
`tssmax
`Caverage
`AUCss
`%PTF
`
`109.9 ± 75.3
`891.3 ± 294.1
`11 ± 4.9
`387.3 ± 153.9
`9295.2 ± 3694.2
`205.9 ± 83.9
`
`269.4
`1433.5
`16
`607.8
`14588
`412.5
`
`0
`158
`0
`82.4
`1978.5
`128.5
`
`68.5
`44.2
`44.9
`39.7
`39.7
`40.7
`
`Cssmin, minimum plasma concentration at steady state;
`Cssmax , maximum plasma concentration at steady state;
`tssmax, time at which Cssmax is achieved; Caverage, mean or
`average steady state drug concentration; AUCss, area
`under the concentration/time curve during the selected
`dosing; interval at steady state calculated with trapezoidal
`method; %PTF, peak-through- fluctuation percentage.
`
`68–134% for Cmax and 67–131% for AUC48. Mean resi-
`dence time (MRT) and tmax were increased by 12–29%
`after a meal (Table 2), compared with fasting, but the
`difference was not statistically significant (Friedman
`P = 0.248).
`Twenty-four hours after the first dose of the dose
`regimen, plasma concentrations ranged from 105 to
`1163 pg mL−1 Pre-dose concentrations on days 4 and
`6 were 409 ± 379 pg mL−1 and 336 ± 259 pg mL−1,
`respectively. After the final dose in the morning of day
`7 budesonide concentrations reached peak concentra-
`tions after 11 ± 4.9 h. Forty-eight hours after the last
`dose, all plasma budesonide concentrations were below
`the limit of detection. Table 3 summarizes the pharma-
`cokinetic parameters at steady state. The AUCss/AUC∞
`and Cssmax/Cmax ratios were 0.82 ± 0.47 (90% CI: 47.88–
`103.44%) and 0.87 ± 0.51 (90% CI: 46.58–97.71%),
`indicating a lack of drug accumulation after the 1-week
`treatment period.
`During both studies no serious adverse events were
`reported. The study medication was well tolerated by all
`subjects.
`
`Discussion
`In the treatment of patients with moderately severe
`ulcerative colitis or Crohn’s disease, oral corticosteroids
`such as prednisolone are commonly administered when
`5-aminosalicylate-based compounds are not effective.
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`0
`
`0
`
`6
`
`12
`
`30
`24
`18
`Time (hrs)
`
`36
`
`42
`
`48
`
`Budesonide plasma concentration (pg/mL)
`
`Figure 3
`The mean ±SD plasma concentration vs. time profiles of budesonide after
`single-dose administration of 9 mg MMX®-tablets to 12 males under
`fasting (䉭) and fed conditions (䉮)
`
`tions are depicted in Figure 3, and the pharmacokinetic
`data are summarized in Table 3.
`Food significantly decreased Cmax and AUC48
`(P = 0.028 and P = 0.008, respectively). The 90% CI
`values for the percentage ratio of population geometric
`mean values between fed and fasted conditions were
`
`36
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`61:1
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`
`Cosmo Ex 2001-p 6
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`However, the potent anti-inflammatory activity of corti-
`costeroids must be balanced against potential, some-
`times serious side-effects [1].
`Owing to its extensive hepatic first pass metabolism
`budesonide is likely to cause less steroid related side-
`effects [9]. Currently, oral budesonide is available as
`controlled ileal release formulation for targeted drug
`delivery to inflamed intestinal regions. This time- and
`pH-dependent delivery system consists of enteric coated
`(Eudragit L) pellets with a rate-limiting polymer con-
`taining the active drug. This formulation releases 70%
`of budesonide in the distal ileum and right sided colon
`[3], the main location of Crohn’s disease lesions. In the
`present study, the release, absorption and plasma phar-
`macokinetics of budesonide were evaluated after admin-
`istration of newly patented MMX®-tablets to healthy
`subjects. The MMX® matrix has a polymeric structure
`and was designed to slowly and homogenously release
`the active drug at a controlled rate throughout the whole
`colon for the oral treatment of IBD with a more distal
`location than the ileo-caecal region. This formulation
`has been successfully employed for the delivery of ami-
`nosalicylate [7].
`Gastrointestinal-transit was studied by means of
`pharmaco-scintigraphy. Evaluation of the scintigraphic
`images showed that 153Sm-labelled MMX®-budesonide
`tablets reached the colonic region after a mean of 9.8 h.
`Initial tablet disintegration was observed in the ileum in
`42% of subjects, whereas in 33% the main site of dis-
`integration was either the ascending or transverse colon.
`Budesonide plasma concentrations were first detected
`after 6.8 ± 3.2 h, whereas maximum plasma concentra-
`tions were reached approximately 7 h
`later,
`i.e.
`14.0 ± 7.7 h after drug administration. These findings
`suggest that drug release began before break-down of
`the tablet matrix. The lag-time between the initial detec-
`tion of budesonide in plasma and tmax indicates sustained
`drug release from MMX®-tablets. Furthermore, about
`96% of budesonide absorption took place during the
`time tablets were passing the region between the ascend-
`ing and the descending/sigmoid colon, which underlines
`the efficiency of the colon targeting release kinetics of
`the new MMX® matrix structure.
`The systemic availability of budesonide from
`MMX®-tablets matches that of marketed formulations
`[3]. However, the time to reach maximum plasma con-
`centrations for the MMX®-tablets was prolonged from
`6 h [10] to 14 h, which might be a measure of the pro-
`jected slow and graded budesonide release throughout
`the colon. Furthermore, as reported previously for other
`formulations [11], the gastrointestinal-transit and sys-
`temic absorption of budesonide from MMX®-tablets
`
`Gastrointestinal budesonide transit
`
`were subject to a high interindividual variability with
`times of arrival in and times of leaving from some ROIs
`differing up to 10-fold between subjects.
`One factor, that might contribute to variable gas-
`trointestinal-transit times, is concurrent food and drug
`intake [12], which, together with tablet size, is known
`to affect gastric emptying. Tablets of 10 mm diameter
`or less empty from the fed stomach in a linear fashion
`[5], whereas an increase in tablet size and concomitant
`food intake lead to increased variability in gastric
`emptying. To test the effect of food on budesonide phar-
`macokinetics, plasma samples were taken after admin-
`istration of a high calorie, high fat breakfast according
`to FDA guidelines [8]. Food intake significantly
`decreased the rate and extent of budesonide absorption.
`MRT and tmax increased by up to 30% compared with
`fasted control subjects. Delayed gastric emptying might
`explain the observed retarded postprandial absorption of
`budesonide, a finding, which has also been described for
`controlled ileal budesonide formulations [13]. In turn,
`decreased plasma AUC and Cmax, may either result from
`a food–drug interaction affecting bioavailability or from
`increased presystemic metabolism due to postprandial
`changes in liver blood flow, which might affect drugs
`with high intrinsic hepatic clearance such as budes-
`onide. The significant decrease in systemic exposure,
`which may improve the safety profile of the drug, could
`justify the administration of MMX®-budesonide with a
`meal. Furthermore, the lack of drug accumulation and
`serious side-effects after a 7-day treatment period sup-
`ports the long-term treatment with the new drug formu-
`lation. The duration of remission in Crohn’s disease
`patients has recently been linked to the length of corti-
`costeroid treatment [14].
`The present study was performed in healthy subjects
`and disease activity and the possibility that disease
`activity and inflammation might affect gastrointestinal-
`transit and drug absorption should be considered.
`Although previous studies on the uptake of budesonide
`in the ileo-colonic region have shown no major differ-
`ences between patients and healthy subjects, a disease
`mediated influence on transit times should not be com-
`pletely ruled out [3]. In particular, inflammation has
`been reported to significantly affect colon transit, such
`that ascending colon transit shortens with more drug
`remaining to be delivered to and absorbed by the distal
`colon [15]. To what extent inflammation influences
`mucosal drug absorption of budesonide is currently a
`matter of debate, as systemic exposure in patients with
`active Crohn’s disease has been described to be either
`increased or decreased compared with healthy controls
`[10, 13]. Besides inflammation, the absorption of budes-
`
`Br J Clin Pharmacol
`
`61:1
`
`37
`
`Cosmo Ex 2001-p 7
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`M. Brunner et al.
`
`onide might also be affected by the expression of P-
`glycoprotein, an intestinal efflux pump, which actively
`secretes substrates into the gut lumen. Recently, budes-
`onide has been identified as a P-glycoprotein substrate
`and poor response to corticosteroid treatment in IBD has
`been related to increased efflux pump expression [16,
`17].
`In conclusion, MMX®-budesonide tablets appear
`suitable for targeted drug delivery to the colon. Transit
`parameters, low systemic bioavailability and a lack of
`significant side-effects after repeated administration
`support further studies on the effectiveness of this new
`formulation of budesonide in controlled clinical trials in
`IBD patients.
`
`Competing interests: None declared.
`
`References
`1 Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002;
`347 (6): 417–29.
`2 Navarro F, Hanauer SB. Treatment of inflammatory bowel disease:
`safety and tolerability issues. Am J Gastroenterol 2003; 98
`(12(Suppl): S18–23.
`3 Edsbäcker S, Andersson T. Pharmacokinetics of Budesonide
`(EntocortTM EC) Capsules for Crohn’s Disease. Clin Pharmacokin