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`Citation:
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`R. Lfberg, Oral formulation of budesonide for IBD, 15 RES. CLIN. FORUM, 91-96 (1996).
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`General Information
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`Cosmo Ex 2010-p. 3
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`|PR2017-01035
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`This material may be protected by Copyright law (Title 17 US. Code)
`
`Oral formulation of budesonide for IBD
`
`The oral fm'mulation of l'tialestmidefor the treatment ofinflammatory bowel disease was developed
`as a etmtintattion of the development of butlesonide enema for the treatment of distal ulceratiw
`colitis. An oral jormulation of budesonide has been designed with an acid’resistant coating to
`prevent release in the stomach. This fin'mulation, budesonide CIR (controlled ileal release)
`capsule, was designed for the treatment ofileocaecal Crohn's disease. Pharmacokinetic studies
`have shown that the mtljtflll’)‘ ofbudesmtide Cl R is absorbed in the terminal ileum and eaeeum.
`regardless of the food regimen. The tissue affinin of budesonide for the bowel mucosa has not yet
`been studied.
`('Ilinit‘al
`trials presently suggest
`that budesonide CIR is as efficacious as 0le
`prednisolone and causes fewer side effects and less adrenal gland suppression.
`It remains to be
`established whether this oral formulation of budesonide will be advantageous in the long/term
`treatment Ufat‘llllt’ ileocaet'al ( :rolm's‘ disease
`
`IPR2017-01035
`
`R. Lofberg, PhD, MD
`Unit of Gastroenterology
`Huddinge University Hospital
`Karolinska Institute
`
`Stockholm
`
`Sweden
`
`SUMMARY
`
`lNTROllUCTlON
`
`The anti~inflammatory eii‘ect oi. elucocorticosteroids (0C5) in inflammatory bowel
`disease (18D), part icularly in moderate and severe disease, is unsurpassed by any other type
`oi‘drue. The clinical response is substantial and usually rapid (within days). Unfortunately,
`loneaerm treatment with prednisolone doses oi'ereater than 7.540 tug/daily is precluded
`by the risk of hazardous complications such as osteoporosis, diabetes mellitus and
`hypertension. Systemic side effects are not uncotntnon, and may be troublesome, even
`during shortaerm treatment. ll these systemic problems could be overcome or markedly
`reduced, (JCS may become a tnore attractive option both for short, and long~term
`treatment of llll).
`
`The topically’aciint: steroid. budesonide, given as an enema, has been proven to be
`beneficial in mild to moderately active distal ulcerative colitis (UC) and proctitis and
`causes no, oronly limited, depression oiendoeenous plasma cortisol levels”. Furthermore,
`cortictisteroida'elated side eli‘ects associated with treatment with budesonide enema have
`
`been rare and mild“. The enema preparation however, is not suitable for patients with
`extensive llll), iei total U(Z or (Irohn's disease (CD) in the small bowel and/or proximal
`colon, because the active drug will not spread proximally beyond the splenic ilexure.
`lludesonide, given as a plain tablet, is rapidly and completely absorbed in the proximal
`small bowel and is extensively metabolist in the liver, via the cytochromerl”W 3A system.
`l lenee, the systemic availability of‘oral budesonide at approximately 641%, is BEN at
`l 2010_p 4
`enhances its therapeutic versatility. Budesonide may be useful in the tteattnent olTRlfiii’E VCOsmo
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`92
`
`R. L« ii-iiiéia;
`
`involving the small bowel and proximal and transverse colon, provided that it is delivered
`to the affected bowel segment(s) and at a sufficient dose. Since the intestinal blood flow
`is predominantly drained via the portal vein, the amount of laidesonide reaching the
`systemic circulation would be low due to the high first/pass metabolism in the liver.
`
`DEVELOPMENT OF AN ORAL FORMULATION OE BUDESONIDE
`
`
`
`Budesonide was initially developed for use in the airways, but in 1986, an oral formulation
`for the treatment of extensive IBD was produced. The development ofsuch a formulation
`took place in parallel with the work on the budesonide enema for the treatment of distal
`UC. The primary target for the oral formulation was CI), localised to the terminal ileum
`and proximal colon. The only efficacious treatment for this disease hitherto available, had
`been either surgery (ie. resection of the diseased bowel segment) or treatment with
`moderate to high doses of conventional (3C8. The topicallyaacting steroid, budesonide,
`appeared to offer potential for a better efficacy versus side effect ratio.
`A primary aim of the oral formulation of budesonide was to deliver most of the active
`drug to the site of inflammation. The oral formulation of budesonide is therefore acid—
`
`the
`resistant to prevent release in the stomach and release should not begin until
`formulation had passed into the small bowel. For ileocaecal CI), the active drug ideally
`should be released in the terminal ileum and the proximal third of the colon.
`The gastric emptying of different dosage formulations is variable and dependent upon
`the type offormulation itselfand the type ofmeal taken at the time ofdosing. Heavy meals,
`high in fat content, increase the time of gastric emptying. Tablets may remain in the
`stomach for a substantial period of time, ie. several hours, whereas small pellets empty in
`a more rapid and regular fashion and are not greatly affected by the digestive state of the
`individuali. Pellets also spread into the small intestine. To prevent the release ofthe 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
`independent of the dosage or the calorific content of the concomitant meal“. The average
`small bowel transit time is between 3~4 hours (range: 25 hours) for solutions, pellets or
`Single units}. The transit time through the small bowel appears to be unchanged following
`ileocolonic resection“. In patients with active CD ofthe small bowel or with terminal ileal
`resection, no differences in gastric emptying or small bowel transit time compared with
`normal controls were detected in a scinrigraphic study using '“Indium 7. It appears that the
`small bowel transit time of patients with (ID confined to the ileocolonic region, with or
`Without previous ileocaecal resection, averages 3.5 hours.
`An oral formulation of budesonide destined for use in the treatment of ileocaecal (II)
`was designed to release the main proportion ofbudesonide approximately three hours after
`stomach emptying. This formulation consisted ofsustained-release pellets with an enteric
`coating which were called budesonide CIR (controlled ileal release)
`
`COMPOSITION OF BUDESONIDE CIR I’ELLETS
`The CIR pellets are about 1 mm in size and consist of a sugar core over which budesonide
`and an insoluble polymer is sprayed in a fluid bed dryer. The insoluble polymer serves as
`rate—control for the release ofbudesonide. A IO~ZO micron thick enteric coating (Eudragit
`L) is applied to the exterior, as enteric coating (Figure 1). This outer coating starts to
`dissolve above a pH of 5.5. Gelatine capsules are filled with the dried and sieved pellets.
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`Rizsi-xtiusu ,XNl‘rfeillislliIv‘xl litmus; Vigil, 15 NW 5
`
`Budesonide controlled
`ileal release
`
`Rate limiting polymer
`with budesonide (Sum)
`
`Enteric coating:
`/Eudragit L 100—55 (10—20um)
`
`absorbed in the terminal ileum and caecutn.
`
`l’i‘lARMACOKINETIC STUDIES
`The pharmacokinetic properties ofbudesonide CIR pellets have so far only been tested in
`healthy volunteers“. Four tnale subjects were given gelatine capsules containing 18 mg
`budesonide Cerpellets and also radioactively labelled Illindium pellets (3 MBq). Co;
`adtninistration of a TCL‘lllM‘tllllnggln solution. enabled visualisation by scintigraphy, of
`the outer lining of the stomach and the caecum. Hence the budesonide dose could be
`followed during transit from the stomach to the ileocaecal region.
`Plutrmacokinetic 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 gamma camera, and
`the time for 50% of the maximum activity to enter or leave different regions ofthe gastrw
`intestinal tract were determined. Urine was collected at Z4»hour intervals for cortisol
`measurements.
`
`Sugar core
`
`l<————>l
`Pellet size 0.2—1.0 mm
`
`Figure 1.
`
`Schematic VlL‘W ofhudesonide CIR (controlled ileal release) pellets.
`
`The pellets have been tested in ’UllTl), both in a simulated gastric fluid (SGF) and in a
`simulated intestinal fluid (51F). Not more than 2% of budesonide is released after 2 hours
`in SGF (pH 1.2). In $11: at a pH of 7.5, the release is 35% after 1 hour, 55% after 2 hours
`and 80% after 4 hours. 111 mm scintigraphic studies show that it takes approximately 2 hours
`for the first pellets to reach the ileocaecal region.
`
`The systemic availability ofbudesonide was 1 1.9% (range 10.6—14.8) with breakfast and
`9.3."0 (range 78—109) in the fasting state. The tnean absorption time was 6.4 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 absorbed in different segments was assessed by deconvolution,
`combined with transit data. As shown in Table 1, most of the dose was absorbed in the distal
`small bowel and caectun when the test subjects had eaten breakfast. Only a small amount
`of budesonide was absorbed in the rest of the colon. The amount absorbed in the colon
`increased in the fasting state, but was less than 20% of the given dose. Urine cortisol
`excretion fell, but was within the normal range in all subjects for both dosings. The
`pharmacokinetic study shows that the major part of the budesonide ClRévreparation is
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`94
`
`R, L1 Niki-RH
`
`Table l. Ahsorbtion of oral hudesonide in CIR pellets in different segments of the gastro’intestinal
`tract. Mean percentage of given dose in four healthy volunteers’.
`
`Upper small
`bowel
`
`Ileum +
`caeeum
`
`With breakfast
`
`Fasting
`
`~
`
`'
`
`63%
`
`59%
`
`Rest of
`colon
`
`41%,
`
`18%
`
`The tissue affinity ofhudesonide is high, due to its lipophilic properties. This enables the
`active drug to come into contact with the (JCS receptor for a relativer 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 heen performed.
`
`.- O
`
`CIR food
`
`CLINICAL EXPERIENCE WITH BUDESONIIE CIR
`In 1988, for the first time, three patients with CI) were treated with a low to moderate dose
`of budesonide CIR capsules (L6 mg/day). Beneficial results of this study led to the
`initiation ofa larger, open and uncontrolled trial”. Budesonide treatment was evaluated in
`20 patients with active CD localised to the distal ileum, ileocaecai region or ascending
`colon during a 24—week treatment period. The patients selected for this trial were either
`candidates for aggressive immunosuppression therapy or were awaiting surgery. IIthleonidL‘
`CIR was given at a dose of9 mg/day for the first 12 weeks, followed hy a dose reduction to
`6 mg/day for the next 6 weeks and then reduced to 3 mg/day for the lzlsl 6 weeks. I’rimary
`variables evaluated were: the modified CI) activity index (mCl)/\I), hasic lahoratory
`parameters and plasma cortisol levels. The patients in this series had had ( II) for an average
`duration of 8 years and 6500 had terminal ileitis.
`
`|PR2017-01035
`
`
`
`
`
`Plasmaconcentration(nmol/L)
`
`9
`
`12
`
`15
`
`18
`
`21
`
`24
`
`Time (hours)
`Figure 2. Dose—normalised curves oprasma levels ofhudesonide given orally as CIR or}
`fest? ’10-p. 7
`(CIR fast) and CIR capsules with food (CIR food)“. Reproduced with kint
`“
`an v Cosmo
`V
`pernmslon 0
`(:zlstroenteralogy.
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`III'HI'MU’II .-\NI)CIINIL:\1, Fr am 1:1». Voi. 15 No, 5
`
`95
`
`The tnean inCI)AI at entry was 268, falling to 146 after 4 weeks Oftreatment an it 122
`after a total of 12 weeks with 9 mg budesonide CIR/day (P <0.001) After [hL dk 0
`a
`.
`A
`'
`’
`()S
`g
`‘
`reduced, the meaii inLDAI was slightly elevated after 18 and 24 weeks of treatiriente'livlis
`ESR fell significantly during the study period. 13 patients completed the full 34-weeklmlle
`' on
`htit 7 patients were withdrawn during the course of the study due to clinical deteriorati
`after dose reduction. Four of those patients had to be treated surgically No serious sil
`effects or significant CUI‘I’ICOSI'CI‘OILI’HSIRECLI problems occurred. Mean plasma cortisol
`levels
`.
`,
`i
`,
`I
`‘
`(
`‘
`were depressed compared to the initial values, but remained Within normal limits through mt
`the study. However, the plasma cortisol levels of four patients taking the highest dose )f
`.
`e
`K
`hudcsonide, were markedly suppressed
`
`EUROPEAN MULTICENTRE TRIAL
`During 1991—19?2 a European miilticentre, double»blind 10—week trial10 was conducted,
`comparing the efficacy and safety of hudesonide CIR (9 tug/day) with oral prednisolone (40
`mg/day). The hiidesonide dose was tapered to 6 iitg daily after 8 weeks of treatment and
`prednisolone was tapered beginning at 2 weeks and Continued down to 5 mg during the last
`treatment week. A total of 176 patients with active ileocaecal CI) (CDAI>ZOO) were
`randomised to treatment and the two groups were similarly matched.
`After 10 weeks oftreatmenr, 5 3% ofpatients treated with budesonide, compared to 66%
`of the patients in the prednisolone group, were in clinical remission defined by a CDA] of
`less than 150, htit the difference was not statistically significant. The CDAI ofboth groups
`were significantly lower than the pretreatment values. At 10 weeks, the mean CDAIofthe
`hudesonide group had decreased by 100 points compared to 143 points by the prednisoloi'ie
`group (P <0.001
`Investigators observed significantly fewer GCS associated side effects in
`the hudesonide group compared to the prednisolone group. (Twelve patients versus 25 at
`four weeks, 14 wrsux 30 at 8 weeks, 12 versus 27 at 10 weeks). Plasma cortisol levels of the
`l7llthSU11lth’U'c‘éll'Ctl group were significantly less depressed than in the prednisolone'
`treated group (maximum decrease was 40 it 39% versus 84 i 20% for budesonide versus
`prednisolone, I’ <0.00I ). Two patients from the prednisolone group had to be withdrawn
`due to serious adverse events (bowel perforation, enterocutaneous fistula).
`This large controlled trial demonstrates the efficacy of budesonide CIR in inducing
`remission in active ileocaecal CI), with a result comparable to that obtained with oral
`pI'CLlnlS( )loiie htit with fewer UCS side effects and significantly less adrenal gland suppression.
`
`
`
`CONCLUSIONS
`
`The clinical trials performed indicate that hudesonide CIR may play an important role in
`the treatment of active ileocaecal CD. Ongoing trials 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.
`Other formulations ofbudesonide, eg. for extensive UC, are currently in the development
`
`phase.
`Experience so far, indicates that budesonide induces less depression of plasma cortisol
`levels and is associated with less GCS induced side effects compared to orally administered
`prednisolone. There is also a potential role for hudesonide treatment in Iongaterm relapse
`prevention, particularly in CI). Several maintenance studies are currently being performed
`to compare various doses of hudesonide CIR to placebo treatment.
`
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`R. L« ititttto
`
`For the patient, the advantages of a powerful anti»inflammatory drug are apparent.
`Budesonide, associated with fewer side effects than prednisolone, can he used hoth for the
`induction of remission in active disease and later, at a lower dose, can he used for
`maintaining quiescent disease. Sl‘torvterm studies in healthy volunteers suggest
`that
`inhaled budesonide causes fewer negative effects on hone turnover 1 han oral prednisolone’ 1.
`However, prolonged treatment with conventional steroids even at low doses is known to
`cause adverse effect on bone metabolism and therefore it remains to he determined hy
`prospective trials whether hudesonide offers any advantage in this respect, for long—term
`treatment.
`
`ACKNOWLEDGEMENTS:
`
`Staffan Edshacker and Jan Ulmius at Astra Draco AB are gratefully acknowledged for their
`assistance in preparation of this paper.
`
`
`
`. Tttt [)ANistt BitntzsoNint; Stow URUIJI‘. Budesonide enema in distal tilt'erative t'ttlitls. /\ randomized dose—
`response trial with prednisolone enema as positive control. Strand. ]. (iztsimeniyml., 19121;.)6: 1225 712 $0.
`. El)Si'iA(1KER. 8., DAt ItsTitoM, K. and Cotttmnsstw, 1.17:. Rectal
`and oral hioavailahi 1in t )fliudesonitle in man.
`Hellenic. J. Gastmentemlngy, 1992; 5(Suppl. 75): A 297.
`€, R. l’hartnacolx'iltet to
`. RYintizipr, A, Antitzitssow, [’., Etistmtzixtiztt, 5., ToNNtr».soN, M, Davtta, 1). and 1‘,\I “WM
`and metaholism ofhudesonide, a selective glucocorticoid, 15141:]. Resp. I)is., 1932; 62(514Mtl. 1231‘ H(3’93-
`. DAVIS, 33., HARDY, J1). and TARA,
`Transit of pharm
`acetitical dosage forms through the small
`intestine. Gut, 1986; 27: 8867892.
`_ Punt. A., S’HEADMAN, (3.1., PHILIPS, S,F.,C/\MH.1.E1U, M, littoww, M.L., ll/\|!11./\11, A. and Titania/Iii. UM
`lleoeolonic transit does not change after right sith hemicolectoniy. ( irist7'uertle1‘nlu;W, 1992; 1031 79‘1 799‘
`. MILLER, L.R.,Vl'l't'1,R.,M/\Uitt£1t,A.,Slii<iiil.,l.,(itil./\71:‘»§iCI,T.. KMEVHKY. 11. and Frantic. RS. Small intestinal
`transit in symptomatic (Irohn's disease. ()astmemerulogy, 1990; 90: A 54-}.
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`V
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`x
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`' Ll.)5llN‘Km' 5” Will-['Mlill" ll'i N115” ’Nv A‘ 'Ilml N115"‘i‘ ’N. M. l’harinacokinetics and gastrointestinal it‘tllhii
`of hudesonide controlled i
`leal release (CIR) capsules. (iastroen[urology, 199’); 104: Al‘t‘ulrllL’l.
`. LOFBERU, R., DANitissoN, A. and Samar, L. Oral liudesonide in am We ileotaeeal Crohli's disease — a pilot
`trial with a topically acting steroid. (,ittstroenterology, 1991; 100: A226.
`in, A, i Pr tutti I.
`. RU'ruttit'rs, P., Lot-titan, R,, M,\t.t:t low, 11., LAM]:1’.S, (1., ()1./\l‘~i"w" w, U.,J[:WI£1.I , 1)., Daria-t
`11.,(13‘1'115111i/\A1(1)T11()MSEN,O.,LURIENZ'MEYER,H.,l lulxi‘ittN, H., l’iziwotifi'. antlSHItI-t i.\11.lt.( I. Birdcsonidc
`versus prednisolone for the treatment of
`active ileocecal (Irohn's disease: A European multicenter trial.
`(iastroentcmlngy, 1993; 104: Abstract.
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`. Toowon, J.1~1., Calm. R.G., Jonas, (1., NAI'IIEAH,
`. and Wilts, (LA. Effect at high dose inhaled
`hudesonide on calcium and phosphate metaholism
`and the risk of Osteoporosis. Am. Rev. Remit. 121V.
`1988;158:57—61,
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`1. DANastson, A, LUI-‘HIERU, 11., Pizttssow, '17, 51\1.[)1£. L., Sumo] iii, K, Sorta, 0. and Wu 11:4, R. A act-mid
`enema, hudesonide, lacking systemic effects forthe treatment ofdistal ulcerat iv
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`]. Gastroenterul., 1992; 27: 9-12.
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`'
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