MODIFIED RELEASE ORAL PHARMACEUTICAL COMPOSITION CONTAINING 5-ASA AND METHOD FOR THE TREATMENT OF BOWEL DISEASES

Abstract: Modified release pharmaceutical composition and method for the treatment of inflammatory bowel diseases (IBD) such as Crohn's disease and Colitis Ulcerosa, said compositions comprising as active the ingredient 5-aminosalicyclic acid (5-ASA), and being adapted for modified and targeted release so as to obtain a clinically important localized effect profile of 5-ASA by means of releasing an appropriate amount of 5-ASA in both the small and large bowel.

Description: MODIFIED RELEASE ORAL PHARMACEUTICAL COMPOSITION CONTAINING 5-ASA AND METHOD FOR THE TREATMENT OF BOWEL DISEASES FIELD OF THE INVENTION The present invention provides improved oral pharmaceutical compositions for the tieatment of inflammatory bowel diseases (fBD) such as Crohn ' s disease. Colitis Ulceiosa and related diseases, e g an unclassifiable form of said diseases or a diagnosed subtype of one of said diseases The invention also provides a method for the treatment of IBD The composition of the present invention comprises as e lngie ient 5- ammosalicylic acid (5-ΛSΛ) or pharmaceutically acceptable salts oi esters thereof and is adapted for modified and targeted release of said 5-ΛSΛ in the diseased parts of the intestine, so as to obtain an advantageous and clinically important lelease and effect profile of 5-ASΛ Thus, said admmisti tion form and release are improved compared to known therapy regimens BACKGROUND OF THE INVENTION The composition of the invention is individually coated gianules adapted foi oral admmistiation as such, I e the composition is a "granulate " composition ready for use The granule composition of the invention is an advantageous administration foim m many clinical situations, e g with lespect to patient having difficulties in swallowing and with respect to children not wanting to swallow tablets A further advantage is that the granules of the invention may be packaged in unit dosage forms comprising larger amounts of active 5-ΛSA. c u m sachets or sticks In punciple. there is. in contrast to the maximal content of tablets and capsules no uppet limit to the amount of active ingredients in a unit dosage form of the composition according to the invention Thus, an advantage of the granule composition of the present invention is that it enables improved compliance values with respect to the therapy regimen, a clinically important parameter for the treatment of chronic diseases Overall, it should be noted that the question of a satisfactory compliance is especially important in the case of IBD, since failure to respond to medical treatment in many cases necessitates surgery, with the standard surgical operation in the treatment of ulcerative colitis in many cases being total proctocolectomy (removal of the colon and the rectum) US patents 4.496,553 and 4,980, 1 73 (Halskov) provide a method for the treatment of IBD by oral administration of 5-ΛSΛ compositions consisting essentially of free 5-ΛSΛ and carriers which will control the release of an effective amount of 5-ASA However, as opposed to the present invention, no mention of the administration of 5-ΛSΛ granules as such was disclosed, and the compositions described for clinical use were all in the form of tablets The disclosure of said US patents, including the examples, is totally silent about the provision of a specific type of granule composition for direct oral intake Nowhere in said patent specification is it suggested to develop or administer a granule composition Thus, in the examples of the above US patents, preparations of granulates pressed to form tablets with a diameter of 13.5 mm and a weight of 650 mg/tablet containing 250 mg of 5-ASA The resulting tablets were used in clinical tests In the examples of the US patents, two intermediary preparations of granulates were described, one of them comprising 5-ΛSΛ, and the other being a "helper " granulate without 5-ASΛ , said "helper " granulate being prepared and admixed in order to facilitate the tablet compression involving the addition of laic and a lubricant mixture The 173 patent more specifically claims a method for the preparation of sustained-release tablets, useful for the treatment of colitis ulcerosa or Crohn's disease, comprising the steps of a) preparing a first granulate fiom 5-ASA or a pharmaceutically acceptable salt or ester theieof and bout 10% by weight (solids content based on the 5-ASA) of polvvmylpyrrolidone in an otgamc solvent thereby to provide granules of a paiticle size from about 0 7 to 1 mm. upon evapoiation of the solvent b) applying onto said granules a coating composition, compnsmg a solution in an organic solvent of a pharmaceutically acceptable coating material which will gradually lelease the active ingredient upon amval at the small intestine, theieby to piovide coated gianules upon evaporation of the solvent, c) mixing the fust gianulale with about ^° o b\ weight, calculated on ihe total solids content, of a lubiicant and a conventional phaimaceutical tablet caiuei tn an amount in accordance with the desned size and active ingredient content of the tablet, and d) forming tablets fiom the resulting mixture Preferably the coating material is a cellulose denvative International application WO 94/2891 1 descnbes i a oial pharmaceutical compositions having pi I legulating effect in pai ticulai f i laising a subnoimal pH in the intestine comprising a coated pl l regulated alkaline malenal, pieferably calcium caibonate The composition may be oimulated as enteio- coated granulates oi tablets The composition may furthei comprise a therapeutically actn e ingredient, e g 5-ΛSΛ Such compositions may be formulated as combination gianulates, where the 5-ΛSΛ is coated as described above with lefeience to US patent no 4,496,553 or as combination tablets The specific recμmements to the 5-ASA release pi operties of the granule composition as identified by the piesent invenloi s and defined by the present invention, were nowheie described or suggested in said US patents or WO 94/2891 1 , let alone any hint or guidance as to how to ainve at the specific embodiments of the lm ention, said embodiments ing the problems identified and thus providing advantages in a non-predictable way SUMMARY OF THE INVENTION Suiprisingly, according to the present invention, particular geometi ical shapes of each of the gianules in combination with the choice of and mixing of particular types of helper ingredients, provide granules w it an especially advantageous and clinically important 5-ΛSΛ gastio-intesti al release Surprisingly, the gianule composition of the piesent i emion provides an advantageous release profile securing a clinically impoi tant ailabihty Such a useful bio-availability is obtained due to the following characteristics only a minor release of 5-ASA in the stomach is obtained whereas a considerable amount of 5-ASA is available foi an appiυpnate period of time in the small intestine, and also a consideiablv amount of aιlable in the large intestine Thus, in one of its mam aspects, the invention pi vides a composition for oral administration, said composition being an oral modified release composition ensuimg bioavailabilitv of said 5-ΛSA in both the small and laige intestine, and comprising individually coated granules, each granule comprising • a core compnsmg 5-aminosahcyhc acid (5-ΛSΛ) (υi a salt or an ester thereof) and a physiologically acceptable fust helper ingiedient. pieferably a cellulose derivativ e, in particular miciociystallme cellulose, and • a coating confining said core, said coating compiising a second helpei ingredient, preferably a semi-permeable polymei, in particular, elhvlcellulose, and the majority of the granules, pieferably moie than 80% mote prefeiably moie than 90%. of the gianules being essentially spherical as defined bv an aspect ratio within I 00-1 25, preferably within I 00-1 20, moie pie erabK within 1 00-1 15. and the majority of Ihe granules, preferably more than 70% , more preferably more than 90%, of the granules of the composition exerting sieve values in the range of 0 5 mm - 2.0 mm, pieferably in the range of 0 7 mm - 1 1 mm; and the composition exerting the following in vitro dissolution rates [when measured in a model system using simulated intestinal fluid in USP Paddle System 2 operated at 37 °C with stirring speed 100 rpm] a) within 2-20%, preferably within 5- 15 %, of the total 5-ΛSA is released after 15 minutes in the model system. b) within 20-50%, preferably within 25-45%, of the total 5-ΛSA is released after 60 minutes in the model system. c) within 30-70%. preferably within 40-60% of the total 5-ΛSΛ is released after 90 minutes in the model system. d) within 50-90%, preferably within 55-80%, of the total 5-ASA is released after 150 minutes in the model system, e ) within 75-100% of the total 5-ΛSA is released after 240 minutes in the model system. In the present context "5-ASΛ" is used as also encompassing pharmaceutically acceptable salts and esters thereof The salts of 5-ΛSΛ may be acid addition salts, in particular the hydrochloride. but any pharmaceutically acceptable, non-toxic organic or inorganic acid may be used Also salts formed with the carboxylic acid group may be used As examples may be mentioned alkali metal salts (K. Na), alkaline earth metal salts (Ca, Mg). but again any pharmaceutically acceptable, non-toxic salt may be used The Na- and Ca-salts are preferred Applicable esters are e straight chain or branched Cι-Cικ alkyl esters, e methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, heptyl, octyl, nonyl. decyl, lauiyl, myristyl, cetyl, and stearyl, etc., straight chain or branched C 2 -C| 8 alkenyl esters, e g. vinyl, allyl, undecenyl, oleyl, linolenyl, etc., C 8 cycloalkyl esters, e cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl cycloheptyl and cyclooctyl, etc., aryl estei s. e g phenyl. tυluyl, xylyl. naphthyl. etc . alicyclic estei s, e g menlhyl, etc., or aralkyl esters, e g benzyl, phenethyl, etc DETAILED DESCRIPTION OF THE INVENTION The present invention provides for an oral composition in the form of granules designed for direct oral administration, i e the granules satisfy the pharmaceutical requirements without being foimulaled e g as tablets or e g formulated in capsules Specific problems had to be overcome, first of all the individual granules should be able to pass relatively quickly through the ventricle without any significant dissolution of 5-ΛSΛ, and subsequently a fraction of the 5-ΛSA should be distributed both in the small and large intestine and reside there in sufficient time for exerting the localized effect The present invention provides a modified release oral composition for the treatment of inflammatory bowel diseases, said composition ensuring bio- availability of 5-aminosalicylic acid (5-ΛSA) in both the small and laige intestine, and comprising individually coated granules, each granule comprising • a core comprising 5-aminosalicylic acid (5-ΛSΛ) or a pharmaceutically acceptable salt or ester thereof and a physiologically acceptable first helper ingredient, preferably a cellulose derivative, in particular microcrystalline cellulose, and • a coating confining aid core, said coating comprising a second helper ingredient, preferably a semi-permeable polymer, in particular ethylcellulose. and the majority of the granules, pieferably more than 80%, more preferably more than 90%, of the granules being essentially spherical as defined by an aspect ratio within I 0- 1 25, preferably within 1 .00-1 .20. more pieferably within I 00-1 1 5; and the majority of the granules, preferably more than 70% . more preferably more than 90%, of the granules of the composition exerting sieve values in the range of 0.5 mm - 2 0 mm, preferably in the range of 0 7 m - 1 . 1 mm. and the composition exerting the following in vitro dissolution rales [when measured in a model system using simulated intestinal fluid in USP Paddle System 2 operated at 37 °C with stirring speed 100 rpmj a) within 2-20%. pieferably within 5- 1 %, of ihe total 5-ΛSΛ is released after 15 minutes in the model system, b) within 20-50%, pieferably within 25-45%, of the total 5-ΛSΛ is released after 60 minutes in the model system; c) within 30-70%. pieferably within 40-60% of the total 5-ΛSA is released after 90 minutes in the model system, d) within 50-90%, pieferably within 55-80%, of the total 5-ΛSA is released after 150 minutes in the model system; e) within 75- 100% of the total 5-ASA is released after 240 minutes in the model system In the present context "first helper ingredient" is a sphero ization aid, preferably miciocrystalline cellulose A "second helper ingi edient" is a coating material which pieferably acts as a diffusion-rate limiting bamer, but may also act as erodable degi adable rate-limiting ban lei 1 he pi efei i ed ingi cdieiit is ethylcellulose The composition of the invention exerts the following 5-ASA leiease parameters provided the gastric emptying is within the noimal lange, ">0% of the granules have left the stomach within 60 minutes after intake of the composition piefeiably within 30 minutes Fuithei ore the composition exeits the following in VIN O ^-ΛSΛ iclease parameters provided the small bowel tiansit time is within the noimal range 50% of the granules is present in the small bowel 3-6 houis aftei intake of the composition Fuitheimore the composition exerts the following in vivo 'ϊ-ASΛ leiease parameters piovided the laige bowel tiansit time is within the noi mal lange ^0% of the gianules is piesent in the large bowel 12-50 hours after intake of the composition The transit time of va ous phaimaceutical foi mulations has been the subject of numeious studies Bechgaaid, I I , Λcta Phaimaceutica Technologi s 28(2), 1982, studied the critical factors influencing gastrointestinal absorption and focused on the gastiointestinal transit time and pH She pointed to ihe marked diffeience in transit time between single-unit dosages, i e υial phaimaceutical formulations consisting of one non-disintegrating unit and multiple-unit dosage i e oral phaimaceutical foi mulations consisting of a unit which disintegrates in the stomach into a lame number of sub-units For single-unit dosage forms Bechgaard repoits gastric emptying in the range from 0 to 24 houi s. while the most recent studies cited (Bogentoft et al ) for multiple-unit dosage forms varies from 1 5 to 2 5 hours in fasting condition to 2.3 to 3 hours in non-fasting condition Bechgaard does not report overall intestinal transit time but only the transit time from mo th to caecum Again there is a v ery considerable vaiiation for single-unit dosages ranging fiom 5 to 40 hours, while the transit time for multiple units lie within a more narrow range Bechgaard obtained results showing a laige variation as a function of the density of the pellets, which, however, could not be verified by Bogentofl (6, l ± 0.9 to 7. 1 ± 0.8 hours) The Pentasa formulation according to the above-mentioned US patents is a multiple unit foimulation and the release of 5-ΛSΛ fiom Pentasa during noimal and accelerated intestinal transit time in 7 healthy volunteei has been investigated by Chi istensen, L A et al , Br, J Gin Pharmac ( 1987). 23, 365- 369 Daily dose was 1500 Pentasa, normal transit time (NTT) was 24 h ( 16-26 h) and accelerated transit time (ATT), caused by a laxative, was 5 h (4-9 h) Median total lecovery (24 h, 4-ΛSA + acetyl-5-ΛSΛ) was 87% ( 1-129%) (NTT) and 81% (56- 100%) (ΛTT), lespectivclv. (P > 0 10) An almost complete release of 5-ΛSΛ fiom Pentasa takes place during NTT Λt ΛTT conditions about 88% is released, indicating Pentasa to be an acceplable source of 5-ASΛ also in diarrhoeal states While only a lelatively small group of volunteers were investigated 6 of the volunteers had NTT's in the lange from 24 lo 26 houi s and I had an NTT of 16 hours The pH-profile and regional transit times of the normal gut has been measured by a radiotelemetiv device by Fallingborg, J , et al , Aliment Pharmacol therap ( 1989) 3, 605-613 The pi I of the gut lumen was measured in 39 healthy persons using a pH-scnsitive, radiotransmitting capsule Thirteen persons were studied twice The location of the capsule was determined by X- ray The pl l rose from 6 4 in the duodenum to 7 3 in the distal part of the small intestine In 17 persons the pH diopped by 0 1 -0 8 pi I units during the last hours of the small intestinal transit The pH was 5 7 in the caecum, but rose to 6 6 in the rectum Gastric residence time was I l h. small intestinal transit was 8 h, and colonic transit time was 17.5 h (median values) The results provide a firmer basis for prediction of the level, and the rate of release of active substance from pH-dependent sustained-release oral preparations and confirm the data obtained by Christensen op cit Further advantages of the composition of the invention are related to improvements with respect to compliance and reproducibility of pharmaceutical characteristics, including laboratory characteristics, especially reproducibility of coating technique parameters DESCRIPTION OF THE MANUFACTURING PROCESS 5-ASΛ and the first helper ingredient are weighed out in Ihe predetermined ratio, e wherein the % by weight of 5-ΛSA of the total weight of said granule ranging from 30-90%, preferably from 40-80%. more preferably from 50-60%, most preferably about 50% The ingredients are thoroughly mixed in a mixing container The next step is a granulating process comprising mixing the ingredients with a granulating agent, preferably water, e g in the range of 70-90% by weight of the water of the total amount of 5-ASΛ and helper ingredients Preferably (he granulation is carried out in the mixing container An advantage of this step of the process is that it may be performed with water, thus avoiding using organic solvents In a subsequent step, an extrusion may be performed by extruding (he above- mentioned mixture through sieves with pores of a diameter of e g I 0 mm The subsequent step involves spheronizaliυn of the mixture by applying the mixture on a spheronizing apparatus, pieferably a N1CΛ spheronizer The process is carefully monitored, and the speed and the employed time interval adjusted according to the instmctions of the apparatus, e g operated at the maximally allowed speed, and so as to obtain the size and shape of the 5-ASΛ granules as specified herein After the spheionizmg step, the granules aie transfened lo a fluid-bed drying system and after diymg the granules are indiv iduallv coaled with the second helpei ingredient, pieferably ethylcellulose, said helpei ingredient being dissolved in e g an organic solvent, prefeiablv acetone in pai ticular in a concentration of from 0 I - 5 % w/w The monitonng of the obtamment of granules having the specified shapes and sizes may be pei foimed by the following piocedure I Image processing and analysis A commeiciallv available microscope and analysis softwai e w s obtained fiom Leica ("Leica Q500MC Image Analysis System ) and was used to clcteimine the dimensions and the aspect ratio of the piepaied gi anules The aspect ratio as used heiein is defined as the ratio of the length div ided by the bieadth 1 he length is defined as the length of the longest dimension of the granule The bieadth is defined as the length of the shoitest dimension of the granule Samples weie taken up randomly, e g in tnplicate The compositions accoiding to the invention should meet the following criteria the majority of the granules, pi eferably moie than 80%, moie prefeiabh moie than 90%, of the gianules aie essentially spherical as defined bv an aspect latiυ I 00- 1 25, pi efeiabh within l 00- l 20, moie preferably within I 00-1 1 II Furtheimoie the particle size distribution of thc gianules of the composition can be detei mined by the LEICA ANALYSIS SYS I EM as described abov e and also in the following way Repiesentativ e samples of a granule pieparation aie sieved o er a siev e-stack of varying sieves, using fixed time and oscillation, the sieves typically being 1 40 mm - 1 25 mm - 1 12 mm - 1 00 mm - 0 710 mm - 0 50 mm - 0 355 mm - 0 250 mm The compositions according to the invention should meet the following criteria the majority of the granules, prefeiably moie than 70° o , more preferably more than 90%, of the granules of the composition exerting sieve values in the range of 0 5 mm - 2 0 mm. pieferably in the range of 0 7 mm - I 1 mm Furthermore, the piepared granule preparations aie tested in an in vitro model system foi dissolution profiles and using simulated intestinal fluid. 0 I M Na phosphate buffer, pH 7 5, in USP Paddle System 2 opei ated at 37 °C with stirring speed 100 ipm Batches exerting the dissolution profiles de ciibed below are selected for clinical pui poses The piefened dissolution profiles of the granules of the invention are as follows a) within 2-20%, preferably within 5-15 %, of the total 5-ΛSA is released after 15 minutes in the model system, b) within 20-50%, preferably within 25-45%, of the total 5-ΛSΛ is leleased aftci 60 minutes in the model system. c) within 30-70%, pieferably within 40-60% of the total 5-ΛSΛ is released after 90 minutes in the model system. d) within 50-90%. preferably within 55-80%, of the total 5-ΛSA is released after 1 0 minutes in the model system, e) within 75- 100 % of the total 5- ASA is l eleased after 240 minutes in the model system DETAILED DESCRIPTION OF THE GEOMETRICAL/STRUCTURAL CHARACTERISTICS OF THE GRANULES Granules of the invention aie selected so as to exert the following geometrical/structui al characteristics the majority of the granules, pieferably more than 80%, more preferably more than 90%, of the granules being essentially spherical as defined by an aspect ratio within l 00- 1 .25. preferably within I 00- 1 20, more preferably within 1.00-1. 15; and the majority of the granules, preferably more than 70% , more preferably more than 90%, of the granules of the composition exerting sieve values in the range of 0 5 mm - 2 0 mm, preferably in the range of 0 7 mm - 1 1 mm PREFERRED EMBODIMENT OF THE INVENTION (BATCH 322202) - see Figure 2 For preferred gi anules according to the invention, the following results weie obtained (measurements based on 75 measurements on granules obtained by random sampling) LENGTH With respect to the length of the granule as defined herein as the length of the longest dimension of (he granule, the following values were obtained. Minimum = 0 751 mm - maximum = I 101 mm, i e the range was from 0 75 lo I 10 mm The granules showed length values varying within (mean ± I SD) 0 88 I mm ± 0 068 mm = from 0.813 mm to 0 949 mm - and the granules had maximal length varying within mean ± 2 SD 0 881 mm ± 0 136 mm = from 0 745 mm to 1 017 mm Thus, the majority (95%) of the granules showed a length (the lenuth of the longest dimension) of from 0.75 mm to 1.02 mm. BREADTH With respect to the breadth of the granules defined herein as the length of the shortest dimension of the granule, the following values were obtained Minimum = 0 674 mm - maximum = 0 920 mm, i e the range was from 0 67 lo 0 92 mm The granules had breadth values varying within (mean ± I SD) 0 800 mm ± 0 058 mm = from 0 742 mm to 0 858 mm - and within (mean ± 2 SD) 0 800 mm ± 0 1 16 mm = from 0 684 mm to 0 916 mm As seen, the majoiity 95%) of the granules showed breadth (the lcimth of the shortest dimension) of fiom 0.68 mm lo 0.92 mm. ASPECT RATIO With lespect to the aspect ratio defined heiein as the ratio of the length divided by the breadth, (the length being defined as the length of the longest dimension of the gi anule, and the breadth being defined as ihe length of the shortest dimension of the gianule), the following values ei e obtained Minimum = I 029 - maximum = l 250 i e the range of aspects ratios was from I 03 to l 25 The granules showed aspect ratios varying within (mean ± I SD) I 102 ± 0 044 = from I 058 to I 146 - and within (mean ± 2 SD) = I 102 0 088 mm = from I 014 to I 190 As seen, the majority, 97 %) of the granules showed aspect ratios of fiom 1.01 to 1.19. PREFERRED EMBODIMENT OF THE INVENTION (BATCH 437601 ) - see Figure 4 For pieferred gianules according to the invention, the following results weie obtained (measurements based on 75 measurements on granules obtained by random sampling) LENGTH With lespect to the length of the granule as defined herein as the length of the longest dimension of the granule, the following values were obtained Minimum = 0 712 mm - maximum = I 01 O mm, i e the range was fiom 0 71 to 1 01 mm The granules had length values varying within (mean ± 1 SD) 0 834 mm ± 0 070 mm = from 0 764 mm to 0 904 mm. and within (mean ± 2 SD) 0 834 mm ± 0 140 mm = from 0 694 mm to 0 974 mm As seen, the majoiity, 98 %) of the granules showed a length (the lenuth of lυimest dimension) C from 0.69 mm to 1.02 mm. BREADTH With respect to the breadth of the granules defined herein as the length of the shoitest dimension of the gianule. the following v alues wei e obtained Minimum = 0 648 mm - maximum = 0 907 mm. i e the range was from 0 65 to 0 91 mm The gianules had bieadth values varying within (mean ± 1 SD) = 0 759 mm ± 0 069 mm = from 0 690 mm to 0 828 mm, and within (mean ± 2 SD) 0 759 mm ± 0 138 mm = fiom 0 621 mm to 0 897 mm Λs seen, the majoiity 95%) of the gianules showed breadth (the length of the shoi test dimension) of from 0.62 mm to 0.90 mm. ASPECT RATIO With respect to the aspect ratio defined herein as the ratio of the length divided by the bieadth. (the length being defined as the length of the longest dimension of the granule, and the breadth being defined as the length of the shoitest dimension of the granule), the following v alues were obtained Minimum = 1 016 - maximum = 1 266 i e the range of aspects ratios was from I 02 to 1 27 The granules showed aspect ratios varying within (mean ± 1 SD) I 100 ± 0 046 = from 1 054 to I 146. and within (mean ± 2 SD) I 100 ± 0 092 mm - from 1 008 to 1 192 As seen, the majority (apprυx 95%) of the granules showed aspect ratios of from 1.01 to 1.1 . TREATMENT OF INFLAMMATORY BOWEL DISEASES A main aspect of the invention is a method for the treatment of inflammatory bowel diseases (IBD) in particular Crohn's disease, colitis ulcerosa. an unclassified form of said diseases, or a diagnosed subtype of said disease comprising orally administering a pharmacologically effective amount of the composition according to the invention The term "pharmacologically effective amount " as used heiein, repi esents an amount of a compound of ihe invention which is capable of inducing the desired therapeutical effect in the individual in need theieof The pai ticular dose of 5-ASΛ administered according to the pi esent invention will, of course, be determined by the particular circumstances i elating lo the case, including the paiticulai condition and pathological site to be treated, the sex, age, and weight of the individual, and similar considerations The piesent invention is also useful in a maintenance treatment of more or less chronic inflammatory bowel disease, inter alia because systemic effects and other adverse effects due to the 5-ΛSA aie negligible Thus, relativ ely long treatment cycles employing relatively high total amounts of drugs may be pre- scribed with the concomitant reduced risk of advei se effects The target part of the gastrointestinal tract is a target pai l in the pioximal small intestine, Ihe mid small intestine, the distal small intestine, the caecum, the ascending colon, the transverse colon, the descending colon, the sigmoid colon and/or the rectum An aspect of the invention is a composition, wheiein Ihe 5-ΛSΛ is in a unit dosage form and comprises 5-ASA in amounts suitable for the administration of fiom 250 mg to 12 g, preferably from 500 mg to 6 g, more preferably from 500 mg to 4 g, e g in unit dosage form each comprising 500 mg, I g, 2 g, 5 g, or 6 g The term "unit dosage form " refers to physically discrete units suitable as unitary dosages for clinical use, each unit containing a predetermined quantity of 5-ASA calculated to produce the desired therapeutic effect Furthermore, the composition is preferably a composition . wherein the 5-ASA is supplied as a unit dosage forms in sealed packages to be opened immediately prior to use, e g sachets or sticks BRIEF DESCRIPTION OF THE DRAWINGS FIG I shows an image analysis of spherical granules of a preferred embodiment of the invention prepared as described below FIG 2 shows the corresponding aspect ratio determinations, obtained by LEICA Q500MC Image Analysis System FIG 3 and 4 show similar data obtained from anothei batch FIG 5 is a graphical depiction of the preferred dissolution rate intervals of the granules according to the invention. FIG. 6 is a graphical depiction showing the same dissolution rate intervals as in FIG 5. but also showing data obtained from a comparison experiment It is seen that the dissolution profile of the conventional granules are very different from the profiles of the granules of the invention FIG. 7 is a graphical depiction of data obtained from spherical granules of the invention The test procedure was as in FIG 6 Results aie within the preferred limits FIG 8 is a graphical depiction of data obtained from spherical granules of the invention. The test procedure was as in FIG 6 Results are within the preferred limits FIG 9 is a graphical depiction showing the results described in FIG 6 an 7 and 8 on the same graph FIG 10 shows a table relating to in vivo gasti ic emptying time and colon arrival time of spherical granules. FIG. 1 I and FIG 12 show results from the same clinical study as described in FIG 10 plasma concentration curves of 5-ASΛ EXAMPLE 1 THE MANUFACTURE OF GRANULE COMPOSITIONS ACCORDING TO THE INVENTION 5000 g 5-ΛSΛ and 5000 g microcrystalline cellulose were weighed out and carefully mixed at a fixed lime and speed 8000 g purified water was poured into the blending container and the ingiedients weie mixed The mixture was extruded through l 0 mm sieves, and spheronized at fixed time and speed After carefully monitored spheionization. using maximal speed (790 rpm) of the NICΛ spheronizing apparatus (NICΛ S2-450) for a fixed interval of time, e 5 minutes, being adapted to the amount of granule mixture applied to the apparatus, the spheronized granules were transferred to a fluid-bed drying system After drying, the pellets were spray-coated with ethyl cellulose dissolved in acetone Finally, the granules were analyzed and selected as described above, with respect to the geometrical properties For determination of the particle size distribution, typically 400 grams of granules were used. The determination was carried out with a Retsch laboratory sieving machine type VIBRO ( I 400 - I 250 - 1. 120 - I 000 - 0.710 - 0.500 - 0 355 - 0 250 mm) The oscillation amplitude control regulation was set at 60. for 10 minutes The specific batches of granules prepared as described above are further characterized by the accompanying drawings DESCRIPTION OF THE TESTS AND RESULTS An image analysis of spheiical granules of a piefened embodiment (batch 322201 ) of the invention is shown in FIG I FIG 2 is a table showing corresponding geometiical characteristics obtained from the same batch , including data repiesentmg length, bieadth, and aspect ratio determinations - all obtained by the LEICΛ Q500MC Image Analysis System Typically approximately 3 x 300 mg of gianules ai e taken l ndomly for image piocessmg and analysis FIG 3 and 4 show image analysis and geometiical data obtained fiom batch 43760 I Test pioceduie for dissolution rates The in vitio dissolution rates were tested in simulated intestinal fluid using a USP Paddle system 2 Dissolution System The following conditions were applied Dissolution Fluid 0 I M Na-phosphate buf ei pi I = 7 5 Fluid Volume 1000 ml Tempeiatuie 37 °C Stirling speed 100 rpm A graphical depiction of the prefeired dissolution l ate intervals of the granules accoi ding to the invention is shown in fig 5 COMPARISON STUDY A comparison study was pei foimed using a poi tion of some granules representing a 5-ΛSΛ granulate piepared as an inteimediaiy pioduci pnor to the addition of tablet ingredients and compiession into tablets, i e an lntermediaiy 5-ΛSΛ gianulate as prepared prior to the formulation of conventional 5-ΛSA tablets The comparison lesults showed that such "conventional " gianules did not provide the pioperties characteristic of the granules of the present invention. The conventional granules employed in the comparison study were granules made from a homogenous mixture of 5% polyvinylpyrrolidone and 95% 5-ASA, and granulated and extruded ( 1 0 mm sieve), and subsequently coated with ethylcellulose - 6 batches were tested FIG 6 is a graphical depiction showing the same dissolution rate inlervals as in FIG 5, but also showing data obtained from a comparison experiment It is seen that the dissolution profile of the conventional granules is very different from the profiles of the granules of the invention FIG 7 is a graphical depiction of data obtained fiom spiicrical granules of the invention (batch 322202) The test procedure was as in FIG 6 Results are within the preferred limits FIG 8 is a graphical depiction of data obtained from spherical granules of the invention (batch 437601 ) The test procedure was as in FIG 6 Results are within the preferred limits FIG 9 is a graphical depiction showing the results described in FIG 6 (comparison data) and FIG 7 and FIG 8 on Ihe same graph Test procedure in vivo The dispositions of spherical granules were investigated in eight healthy volunteers. The experiments were performed according to a Clinical Study Protocol employed at Pharmaceutical Profiles l td, Nottingham, UK . using radiolabelled ,5, Sm granules for the localization of the position of ihe disposed composition The results are shown in FIG. I0, which is a table showing the gastric emptying time and colon arrival time of the tested spherical granules FIG 1 1 and FIG 12 show further results from the clinical study; plasma concentration curves of 5-ΛSA after administration ( 1000 mg single dose) of the granule composition of the invention

Claims: C A I M S I A modified release oral composition for the tieatment of inflammatory bowel diseases, said composition ensuring bioavailabilitv of 5-ammosalιcylιc acid (5-ASA) in both the small and large intestine, and comprising individually coated granules, each granule compnsmg - a core compiising 5-amιnosahcγlιc acid (5-ASA) oi a pharmaceutically acceptable salt or ester thereof and a physiologically acceptable first helpei ingredient, prefeiably a cellulose derivative, in particulai miciocivstall e cellulose, and - a coating confining said core, said coating compi ising a second helpei ingredient, prefeiably a semi-pei meable poiymei in particular ethylcellulose, and the majority of the granules, pieferably more than 80%, moie preferably moie than 90%. of the granules being essentially sphencal as defined bv an aspect ratio withm I 00- I 25, preferably within l 00-1 20, moie pieferably within I 00- 1 15, and the majontv of the gianules, piefeiably moie than 70% moie pieleiablv moie than 90%, of the gianules of the composition exeiting siev e values in the range of 0 5 mm - 2 0 mm, piefeiably in the lange of 0 7 mm - 1 1 mm and the composition exerting the following in vitro dissolution rates [when measured in a model system using simulated intestinal fluid in USP Paddle System 2 opeiated at 37 °C with stiinng speed 100 rpm] a) within 2-20%, piefeiably within 5- 1 %, of the total 5-ASA is released aftei 1 minutes in the model system. b) within 20-50%, piefeiably within 25-45% of the total -ΛSA is released after 60 minutes in the model system. c) within 30-70%, ptefeiablv within 40-60% of the total 5-ΛSΛ is released after 90 minutes m the model system. d) within 0-90%, preferably within 55-80%, of the total 5-ΛSA is leleased after I 50 minutes in the model system e) within 75- 100% of the total 5-ASΛ is leleased after 240 minutes in the model system 2 A composition according to claim I exeiting the following in vivo 5-ASA release parameters provided the gastnc emptying is within the normal lange. 50% of the gianules have left the stomach within 60 minutes aftei intake of the composition, prefeiably within 30 minutes 3 A composition accoiding to claim I exei ting the following in v i 5-ASA release paiameteis provided the small bowel transit time is within the noimal range, 50% of the granules is piesent in the small bowel 3-6 houi s after intake of the composition 4 A composition accoiding to claim I exeiting the following in vivo 5-ΛSΛ release parameters provided the laige bowel transit time is within the noimal lange, ^ of the granules is piesent in the laige bowel 12-50 houis after intake of the composition 5 A composition accoiding to claim I, heiein the % by weight of 5-ASΛ of the total weight of said granule ranging fiom 30-90%, pieferably from 40- 80%, more prefeiably fiom 50-60% 6 Λ composition according to claim 1 , wherein the 5-ΛSΛ is in a unit dosage foim and compnses 5-ΛSA in amounts suitable foi the admmistiation of fiom 250 mg to 12 g, piefeiably from 500 mg to 6 g, moie prefeiably from 500 mg to 4 g, e g in unit dosage form each compnsmg 500 mg, 1 g, 2 g, 5 g, or 6 g 7 Λ composition according to claim I , wherein the 5-ASA is supplied as unit dosage forms in sealed packages to be opened immediately pnor to use, e g sachets or sticks 8 A composition according to claim 1, wherein the inflammatory bowel disease is Crohn's disease, colitis ulcerosa, an unclassified form of said diseases, oi a diagnosed subtype of said disease 9 Use of 5-ΛSA or a pharmaceutically acceptable salt oi ester theieof and a first and second helpei ingiedient for the manufacluie of a medicament for the tieatment of inflammatoiy bowel diseases (IBD). in paiticular Ciohn's disease, colitis ulceiυsa, an unclassified foi in of said diseases, or a diagnosed subtype of said disease, said medicament compiising individually coated gi anules, each gianule compiising - a coie comprising 5-aminosalιcylic acid (5-ΛSΛ) (oi a salt or an ester theieof) and a physiologically acceptable first helper ingiedient, pieferably a cellulose derivative, in paiticular miciocrystalline cellulose, and - a coaling confining said coie. said coating compiising a second helpei ingiedient, preferably a semi-pei meable polymei , in paiticulai ethylcellulose, and the majoiity of the gianules, pieferably moie than 80%, more preferably moie than 90%, of the granules being essentially spheiical as defined by an aspect ratio within I 00- 1 25, pieferably within I 00- 1 20, moie piefeiably within 1 00-1 15, and the majoiity of the gianules, pieferably moie than 70° n , moie preferably moie than 90%, of the gianules of the composition exerting sieve values in the range of 0 5 mm - 2 0 mm, piefeiably in the range of 0 7 mm - 1 I mm, and the composition exeiting the following m vitio dissolution rates [when measured in a model system using simulated intestinal fluid in USP Paddle System 2 operated al 37 °C with stirring speed 100 rpm] a) within 2-20° o, preferably within 5-15 %, of the total 5-ASA is released after 1 minutes in the model system. b) within 20-50%, preferably within 25-45%, of the total 5-ΛSΛ is released after 60 minutes in the model system, 5 c) within 30-70%, preferably within 40-60% of the total 5-ASA is released after 90 minutes in the model system. d) within 50-90%, preferably within 55-80%, of ihe total 5-ΛSΛ is released after 150 minutes in the model system. e) within 75- 100% of the total 5-ΛSΛ is released after 240 minutes in 10 the model system

Inventors: HALSKOV SOEREN, JEPSEN SVENN KLUEVER, HALSKOV, SOEREN, JEPSEN, SVENN, KLUEVER
Applicants: FERRING FARMA LAB, FARMACEUTISK LABORATORIUM FERRING A/S
Application year: 1996
Main classification: A61K9
IPC codes: A61K9, A61K31, A61K47, A61P1, A61P37