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`R. Lfberg, Oral formulation of budesonide for IBD, 15 RES. CLIN. FORUM, 91-96 (1996).
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`Research and Clinical
`Forums
`vorn
`
`Bio-Medical
`Library
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`VOLUME 15 NUMBER5 1993
`ISSN 0143-3083
`
`3/4 /96
`
`<)>)NTST fy
`SJ{
`jjZN—<——~<
`
`
`
`WELLS MEDICAL
`ENGLAND
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`Kent TNI I BP
`Eneland
`
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`Research and Clinical Forums
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`British Library Cataloguing in Publications Data
`Research and Clinical Forums
`Volume 15, No. 5
`1, Medicine—Periodicals 2. Inflammatory howel disease
`3, Ulcerative colitis 4. Crohn's disease 5. Corticosteroids
`610'.5 R31
`ISBN 1 869969 82 0
`ISSN 0143-3083
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`Research and Clinical Forums is indexed in Current Contents/ Clinical Practice, the Indexof Scientific and Technical
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`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Oral formulation of budesonide for IBD
`
`R. Lofberg, PhD, MD
`Unit of Gastroenterology
`Huddinge University Hospital
`KarolinskaInstitute
`Stockholm
`Sweden
`
`SUMMARY
`The oral formulationof budesonideforthe treatment ofinflammatory bowel disease was developed
`as a continuation of the development of budesonide enemaforthe treatment of distal ulcerative
`colitis. An oral formulation of budesonide has been designed with an acid-resistant coating to
`prevent release in the stomach. This formulation, budesonide CIR (controlled ileal release)
`capsule, was designed for the treatment ofileocaecal Crohn's disease. Pharmacokinetic studies
`have shownthat the majority of budesonide CIR is absorbedin the terminal ileum andcaecum,
`regardless ofthe food regimen. Thetissue affinity of budesonide for the bowel mucosahas not yet
`been studied. Clinical tials presently suggest
`that budesonide CIRis as efficacious as oral
`prednisolone and causes fewerside effects and less adrenal gland suppression.
`It remains to be
`established whetherthis oral formulation of budesonide will be advantageous in the long-term
`treatment ofactive ileocaecal Crohn's disease.
`
`INTRODUCTION
`The anti-inflammatory effect of glucocorticosteroids (GCS) in inflammatory bowel
`disease (IBD), particularly in moderate andseveredisease, is unsurpassedby any other type
`of drug. Theclinical responseis substantial andusually rapid (within days). Unfortunately,
`long-term treatment with prednisolone dosesof greater than 7.5-10 mg/dailyis precluded
`by the risk of hazardous complications such as osteoporosis, diabetes mellitus and
`hypertension. Systemic side effects are not uncommon, and may be troublesome, even
`during short-termtreatment. If these systemic problems could be overcome or markedly
`reduced, GCS may become a more attractive option both for short- and long-term
`treatment of IBD.
`The topically-acting steroid, budesonide, given as an enema, has been proven to be
`beneficial in mild to moderately active distal ulcerative colitis (UC) andproctitis and
`causes no, or onlylimited, depression of endogenous plasmacortisol levels!?. Furthermore,
`corticosteroid-related side effects associated with treatment with budesonide enema have
`been rare and mild!?. The enema preparation however, is not suitable for patients with
`extensive IBD, ie. total UC or Crohn's disease (CD) in the small bowel and/or proximal
`colon, because the active drug will not spread proximally beyond the splenic flexure.
`Budesonide, given as a plain tablet, is rapidly and completely absorbed in the proximal
`small bowel andis extensively metabolisedin the liver, via the cytochrome-P,,, 3A system.
`Hence,the systemic availability of oral budesonide at approximately 6-11%,is lowe and 2010-p. 4
`enhancesits therapeutic versatility. Budesonide may be useful in the treatment 0 a v Cosmo
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`02
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`R. Lorserc
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`involving the small bowel andproximal andtransverse colon, providedthatit is delivered
`to the affected bowel segment(s) andat a sufficient dose. Since the intestinal blood flow
`is predominantly drained via the portal vein, the amount of budesonide reaching the
`systemic circulation would be low due to the highfirst-pass metabolism in the liver.
`
`DEVELOPMENT OF AN ORAL FORMULATION OF BUDESONIDE
`Budesonide wasinitially developedfor use in the airways, but in 1986, an oral formulation
`for the treatmentof extensive IBD was produced. The developmentofsuch a formulation
`took place in parallel with the work on the budesonide enemafor the treatment ofdistal
`UC. Theprimary target for the oral formulation was CD, localised to the terminal ileum
`and proximal colon. Theonly efficacious treatmentfor this disease hitherto available, had
`been either surgery (ie. resection of the diseased bowel segment) or treatment with
`moderate to high doses of conventional GCS. The topically-acting steroid, budesonide,
`appeared tooffer potential for a better efficacy versus side effect ratio.
`A primary aimof the oral formulation of budesonide was to deliver mostofthe active
`drug to the site of inflammation. The oral formulation of budesonide is therefore acid-
`resistant to prevent release in the stomach and release should not begin until
`the
`formulation hadpassed into the small bowel. For ileocaecal CD, the active drug ideally
`shouldbereleasedin the terminal ileum and the proximal third of the colon.
`The gastric emptying of different dosage formulationsis variable and dependent upon
`the type of formulationitself and the type of meal takenat the time of dosing. Heavy meals,
`high in fat content, increase the time of gastric emptying. Tablets may remain in the
`stomachfor a substantial period of time,ie. several hours, whereas small pellets empty in
`a more rapid andregular fashion andare notgreatly affected by the digestive state of the
`individual’, Pellets also spreadinto the small intestine. To prevent the release of the active
`drug in the stomach,pellets are covered with an acid-resistant layer called an enteric
`coating,
`In contrast to gastric emptying, small bowel transit time appears to be constant and
`independentofthe dosageor thecalorific content of the concomitant meal!. The average
`small boweltransit time is between 3—4 hours (range: 2—5 hours) for solutions, pellets or
`single units’. The transit time throughthe small bowel appears to be unchangedfollowing
`ileocolonic resection®. In patients with active CDofthe small bowel or with terminal ileal
`resection, nodifferences in gastric emptying or small bowel transit time compared with
`normal controls were detectedina scintigraphic study using !!'Indium!. It appears that the
`small bowel transit time of patients with CD confinedto the ileocolonic region, with or
`withoutprevious ileocaecal resection, averages 3.5 hours.
`Anoral formulation of budesonide destinedfor use in the treatment ofileocaecal CD
`wasdesignedtorelease the main proportion of budesonide approximately three hours after
`stomachemptying. This formulation consistedofsustained-release pellets with an enteric
`coating which werecalled budesonide CIR (controlledileal release).
`
`COMPOSITION OF BUDESONIDE CIR PELLETS
`The CIRpellets are about | mmin size andconsist ofa sugar core over which budesonide
`andan insoluble polymeris sprayedinafluid bed dryer. The insoluble polymerserves as
`rate-controlfor the release of budesonide. A 10-20 micronthick enteric coating (Eudragit
`L) is applied to the exterior, as enteric coating (Figure |). This outer coating starts to
`dissolve above a pHof5.5. Gelatine capsules arefilled with the dried andsievedpellets.
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`RESEARCH AND CLINICAL Forums Vor. 15 No. 5
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`93
`
`Budesonidecontrolled
`ileal release
`
`Rate limiting polymer
`(Sum)
`with budesonide (5um
`
`Enteric coating:
`= g
`(
`um)
`Eudragit L 100-55 (10-20,1m
`
`Sugar core
`
`Say
`Pellet size 0.2-1.0 mm
`
`Figure 1,
`
`Schematic view of budesonide CIR (controlled ileal release) pellets.
`
`The pellets have been testedin vitro, both in a simulatedgastric fluid (SGF) andin a
`simulatedintestinalfluid (SIF). Not more than 2%of budesonideis released after 2 hours
`in SGF (pH 1.2). In SIF at a pHof7.5, the releaseis 35%after | hour, 55%after 2 hours
`and 80%after 4 hours. In vivoscintigraphic studies showthatit takes approximately 2 hours
`for the first pellets to reach the ileocaecal region.
`
`PHARMACOKINETIC STUDIES
`The pharmacokinetic properties of budesonide CIRpellets havesofar only been tested in
`healthy volunteers®. Four male subjects were given gelatine capsules containing 18 mg
`budesonide CIR-pellets andalso radioactively labelled "Indiumpellets (3 MBq). Co-
`administration of a Technetium-99msolution, enabledvisualisation by scintigraphy, of
`the outer lining of the stomach and the caecum. Hence the budesonide dose could be
`followed during transit from the stomach totheileocaecal region.
`Pharmacokinetic studies were performed both in the fasting state and after a heavy
`breakfast, by taking multiple blood samples. Intravenous dosing of budesonide was used as
`reference. The transit time of the drug formulation was assessed by a gammacamera, and
`the time for 50%of the maximumactivity toenterorleave different regionsof the gastro-
`intestinal tract were determined. Urine was collected at 24-hourintervals for cortisol
`measurements.
`Thesystemic availability ofbudesonide was | 1.9%(range 10.6-14.8) with breakfast and
`9.3.%(range 7.8-10.9) in the fasting state. The mean absorption time was6.4 hours (range
`5.9-6.8) with breakfast and 5.4 hours without breakfast (range 4.5-6.1) ( Figure 2). The
`percentage of budesonide absorbedin different segments wasassessed by deconvolution,
`combinedwithtransit data. As shownin TableI, mostof the dose wasabsorbed in the distal
`small bowel and caecumwhenthetest subjects had eaten breakfast. Only a small amount
`of budesonide was absorbedin the rest of the colon. The amountabsorbedin the colon
`increasedin the fasting state, but was less than 20%of the given dose. Urine cortisol
`excretionfell, but was within the normal range in all subjects for both dosings. The
`pharmacokinetic study shows that the major part of the budesonide CIR preparationis
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`94
`
`R. LOEBERG
`
`Table I. Absorbtion of oral budesonide in CIR pellets in different segments of the gastro-intestinal
`tract. Meanpercentageof given dose in four healthy volunteers’,
`
`Dosing:
`
`With breakfast
`
`Fasting
`
`Upper small
`bowel
`
`Tleum +
`caecum
`
`24%
`
`21%
`
`68%
`
`59%
`
`Rest of
`colon
`
`4%
`
`18%
`
`Thetissue affinity ofbudesonideis high,dueto its lipophilic properties. This enables the
`active drug to comeintocontact with the GCSreceptorfora relatively long period oftime
`(high constant of association/low constant of dissociation). However, studies elucidating
`these properties of the drug in the gut mucosa have not yet been performed.
`
`CLINICAL EXPERIENCE WITH BUDESONIDE CIR
`In 1988,forthefirst time, three patients with CD weretreated with a low to moderate dose
`of budesonide CIR capsules (3-6 mg/day). Beneficial results of this study led to the
`initiation of alarger, open and uncontrolledtrial’. Budesonide treatment was evaluatedin
`20 patients with active CDlocalisedto the distal ileum, ileocaecal region or ascending
`colon during a 24-week treatmentperiod. The patients selectedfor this trial were either
`candidatesfor aggressive immunosuppression therapyor were awaiting surgery. Budesonide
`CIR wasgiven at a dose of 9 mg/dayforthe first 12 weeks,followed by a dose reductionto
`6 mg/day for the next 6 weeks and then reducedto3 mg/day for the last 6 weeks. Primary
`variables evaluated were: the modified CD activity index (mCDAIT), basic laboratory
`parameters andplasmacortisol levels. The patients in this series had had CD foran average
`duration of 8 years and 65%hadterminal ileitis.
`
`= oO
`
`(nmol/L)
`
`Plasmaconcentration
`
`0
`
`3
`
`6
`
`9
`
`12
`
`15
`
`18
`
`21
`
`24
`
`Figure 2. Dose-normalised curvesofplasmalevelsofbudesonide givenorally asCIR cer
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`DETIMISSJON O
`(CIR fast) and CIR capsules with food (CIR food)’. Reproduced with kind
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`RESEARCH AND CLINICAL Forums Voi. 15 No. 5
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`7
`
`The mean mCDAIat entry was 268, falling to 146 after 4 weeks of treatmentand t 122
`after a total of 12 weeks with 9 mg budesonide CIR/day (P <0.001). After the dlése
`as
`reduced, the mean mCDAIwasslightly elevatedafter 18 and 24 weeks of treatment ci
`ESRfell significantly during the study period. 13 patients completed thefull SAidvesdariel
`but 7 patients were withdrawnduring the course of the study duetoclinical deterianacion
`after dose reduction. Four of those patients hadto be treatedsurgically. Noserious side
`effects or significant corticosteroid-related problems occurred. Meanplasmacortisol —
`were depressed comparedtotheinitial values, but remained within normallimits throughout
`the study. However,the plasmacortisol levels of four patients taking the highest dose of
`budesonide, were markedly suppressed.
`:
`
`EUROPEAN MULTICENTRE TRIAL
`During 1991-1992 a European multicentre, double-blind 10-week trial"? was conducted,
`comparingtheefficacy andsafety of budesonide CIR (9 mg/day) withoral prednisolone (40
`me/day). The budesonide dose was tapered to 6 mgdaily after 8 weeks of treatment and
`prednisolone was tapered beginningat 2 weeks and continued downto 5 mg during thelast
`treatment week. A total of 176 patients with active ileocaecal CD (CDAI>200) were
`randomisedto treatment andthe twogroups were similarly matched.
`After 10 weeks of treatment, 53%ofpatients treated with budesonide, compared to 66%
`ofthe patientsin the prednisolone group, werein clinical remission defined by a CDAIof
`less than 150,but the difference wasnotstatistically significant. The CDAI of both groups
`weresignificantly lowerthanthe pretreatmentvalues. At 10 weeks, the mean CDAofthe
`budesonide group had decreasedby 100 points comparedto 143 points by the prednisolone
`group (P <0.001). Investigators observedsignificantly fewer GCSassociatedsideeffects in
`the budesonide group comparedto the prednisolone group. (Twelvepatients versus 25 at
`four weeks, 14 versus 30 at 8 weeks, 12 versus 27 at 10 weeks). Plasmacortisol levels ofthe
`budesonide-treated group were significantly less depressed than in the prednisolone-
`treated group (maximumdecrease was 40 + 39% versus 84 + 20%for budesonide versus
`prednisolone, P <0.001). Twopatients fromthe prednisolone group hadto be withdrawn
`due to serious adverse events (bowel perforation, enterocutaneousfistula).
`This large controlled trial demonstrates the efficacy of budesonide CIR in inducing
`remission in active ileocaecal CD, with a result comparable to that obtained withoral
`prednisolonebut with fewer GCSside effects andsignificantly less adrenal glandsuppression.
`
`CONCLUSIONS
`Theclinical trials performedindicate that budesonide CIR mayplay an importantrole in
`the treatment ofactive ileocaecal CD. Ongoingtrials in North America, Australia and
`Europe are being carried out to investigate whether different doses and/or dosing can
`enhance the clinical efficacy of the formulation.
`Otherformulations ofbudesonide,eg. for extensive UC,are currently in the development
`phase.
`Experiencesofar, indicates that budesonide inducesless depression of plasmacortisol
`levels andis associatedwith less GCSinducedside effects comparedtoorally administered
`prednisolone. Thereis also a potentialrole for budesonide treatmentin long-termrelapse
`prevention, particularly in CD.Several maintenancestudiesare currently being performed
`to compare various doses of budesonide CIR toplacebo treatment.
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`96
`
`R. LorperG
`
`For the patient, the advantages of a powerful anti-inflammatory drug are apparent.
`Budesonide, associated with fewerside effects than prednisolone, can be used both for the
`induction of remission in active disease and later, at a lower dose, can be used for
`maintaining quiescent disease. Short-term studies in healthy volunteers suggest
`that
`inhaled budesonide causes fewer negativeeffects on bone turnover than oral prednisolone!!.
`However,prolonged treatment with conventional steroids even at low doses is knownto
`cause adverse effect on bone metabolism andtherefore it remains to be determined by
`prospective trials whether budesonide offers any advantage in this respect, for long-term
`treatment.
`
`ACKNOWLEDGEMENTS:
`Staffan Edsbacker andJan Ulmius at Astra Draco ABare gratefully acknowledgedfor their
`assistance in preparation of this paper.
`
`REFERENCES
`1. DANIELSSON, A. LorberG, R., Persson, T., SALDE, L., Scorer, R., Sunr, O. and Witten, R. A steroid
`enema, budesonide, lacking systemic effects for the treatment ofdistal ulcerativecolitis or proctitis. Scand.
`J. Gastroenterol., 1992; 27: 9-12.
`2. Tut DANIsH Bubesonipe Stupy Grour. Budesonide enemaindistal ulcerative colitis. A randomized dose-
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`aceutical dosage forms through the small
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`» Ficu, A., Srzapman, C.J., Puiuips, S.F., Camitteri, M., Bown, M.L., Happap, A. and THomrorpe, G.M.
`Heocolonic transit does not changeafterright side hemicolectomy. Gastroenterology, 1992; 103: 794-799.
`7. Mitver, L.R., Virti, R., Maurer, A., Steet,J., GOLAzEsKI, T., Krevsky, B. and FISHER, R.S. Small intestinal
`transit in symptomatic Crohn's disease. Gastroenterology, 1990; 96: A344,
`8. EDSBACKER,S., Wottmer, P., Nitsson, A. and Ninssc oN, M. Pharmacokinetics andgastrointestinal transit
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`H., CESTERGAARDTHOMSEN, O., Lorenz-Meyer, H., Hopson, H., Persson, T. and SemecArp, C. Budesonide
`versus prednisolone for the treatmentofactive ileocecal Crohn's disease: A European multicentertrial.
`Gastroenterology, 1993; 104: Abstract.
`. and Weis, G.A. Effect at high dose inhaled
`Toocoon, J.H., Crit, R.G., Jones, G., NAbeau,
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`budesonide oncalcium and phosphate metabolism
`and the risk of osteoporosis. Am. Rev. Respir. Dis.,
`1988; 138: 57-61.
`
`I,
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