Use of specific core material and layers to obtain pharmaceutical formulations stable to discolouration of acid labile compounds

Descrlptlon

The present invention is related to new pharmaceutical preparations containing acid labíle substances for oral use and, to amethod for the manufacture of such preparations.

Acid labile substances present a problsm to the formulator when formulating a pharmaceutical dosage form for oral use. In order to prevent the substances from contact with the acid reacting gastric juice after oral intake, the conventlonal way to solve this probtem is to coat the dosage form with an enteric coating. Tha coating is a group of substances/polymers with the common feature of baing practically insolublð in acid media, white they are soluble in neutral to alkaline media. For substancas that are labile in acid media, but have better stability in neutral to alkaline media, it is often advantageous to add alkaline reacting inactive consfrtuents in order to increase tha stability of the active compound during manufacture and storaga.

A group of compounds axerting thase stability properties are substituted benzimidazoles with the general formula I <img file="IS1918B_D0001.tif" /> wherein A is an optionally substituted heterocyclic group and R', R’, R³, and R‘, are the same or different as deflned below and R⁵ is H or a lower alkyl, or the compound 2-[(2-dimethylaminobenzyl)sulfinyl]-benzimidazole.

The compounds with the general formula I are virtually biologically inactive as such, but degrade/transform to activa inhibitors of certain enzyme systems in acid media.

As examples of compounds with the mentioned properties the compounds described in the patents US-A-4045 563, EP-B1-0 005 128 and BE-898 880 and tha patent applications, EP-A-173664, EP-A1-0 080 602, EP-0127 763, EP-0 134 400, EP-0 130 729, EP-0 150 586, DE-3415971 GB-2 082 580 and SE-A-8504048-3 may be mentiorwd. The last applicatlon descrlbes 2- (2-disubstitutad-aminobenzyl)sulfinyl benzimidazoles, e.g. 2- (2-di-methylaminobenzy))sulfinyl benzimidazole, also called, NC-1300 and presented by Prot S. Okabe at the Symposlum on Drug Actlvlty held on Oct 17th 1985 in Nagoya, Japan, and which interacts with the Η’κ’-ATPase after acid degradation within the parietal cells. (See for instance B. Wallmark, A. Brándström and H. Larsson "Evidence for acid-induced transformation of omeprazole into an activa inhibitor of H*K*-ATPase within the parietal cell", Biochemica et Biophysica Acta 778, 549-558, 1984). Other compounds with similar properties are further mentioned In the patant UST~182 766 and tha patent applications GB-2 141 429, EP-0 146 370 and GB-2 082 580. A common feature of these compounds is that thay are transformed into tha biologically active compounds via rapid degradation/transformation in acid media.

The stability profila ot soma compounds wlth the genaral formula I abova Is exemplilied in tha Table 1 below, where the half-life of tha degradation/transformation reaction in solution at pH 2 and 7 are given.

<img file="IS1918B_D0002.tif" />

iablt 1. Rate of degradation/transfonnation of cowpounðs with the general structure <img file="IS1918B_D0003.tif" />

Compound Half-Hfe (ninutes) for the

No transformation to the actfve moiety

A R² R³ at pH = 2 at pH - 7

11150

5.41700

1.9122

2.08.8

3.71620

Cont.

<img file="IS1918B_D0004.tif" />

<img file="IS1918B_D0005.tif" />

Compound Half-life (minutesj for the

No transfornation to the active moiety

A R² R³ at pH = 2 at pH = 7

6. 4.0 3900

7. 33 not determined

Substituted sulfoxides, such as for instance the substituted benzimidazoles described in EP-B1-0005129 are potent Inhlbitors of gastric acid secretion. Tha substituted benzimidazolas are susceptibla to degradationflranstormation in acid reacting and neutral media.

It is an inhsrent property of these compounds to be activated to tha active moiaty in the acid environment within the parietal cells. The activated compound interacts with the enzyme in the parietal cells, which madiates ths production of hydrochloric acid in the gastric mucasa. All compounds of tíia class of substituted benzimidazoles, containing a sulfoxide grouping, which interferes with the H*K*-ATPase in the parietal cells hitherto known are all also degradad In acld madla.

A pharmaceutical dosage form of acid labile substances, which prevents the substances from contact wlth acidic gastric juice, must be enteric coated. Ordinary enteric coatings, however, are made of acidic compounds. If covered with such a conventional enteric coating, the acid labile substance rapldily decomposas by direct or indirect contact with it, with the rasult that the preparations become badly discoloured and lose in content of the activs compound with the passage of tima.

In order to enhance the storage stability. the cores which contain the add labile substance must also contain alkaline reacting constituents. When such an alkaline core is enteric coated with an amount of a conventional enteric coating polymer such as. for axample, callulosa acelate phthalata, that parmits the dissolution of the coating and the active drug contained in tha cores in the proximal part of the small intestine. It also will allow some diffusion of watar or gastric juice through the enterlc coating into the cores, during the tima the dosage form resides in the stomach before it is amptied into the small intestina. The diffused water or gastric juice will dissolva parts of the cora in the close praximity of the enteric coatlng layar and there torm an alkaline solution inside the coated dosage fbrm. The alkaline solution will interfere with tha enteric coating and eventuaily dissolva it.

In DE-A1-3 046 559 a way to coat a dosaga form is described. First the dosage form i$ coated with a water insolubla layer containing microcrystalline cellulosa and then wlth a sacond enteric coating with the aim to achieve a dosage Form which raleases the activa drug in the colon. This method of preparation will not give the dasired rateasa of tha compounds with the general formula) abova in the small intastine.

US-A-2 540 979 describes an enteric coated oral dosage form, where the entaric coating is combined with a second and/or first coating of a waler Insoluble "wax” layer. This mathod of preparation is not applicable on cores containing a compound with the ganeral formula I sinca direct contact betwean substances such as cellulosa acetate phthalate (CAP) and a compound of formula I causes degradation and discolouration of the campounds of the formula I.

DE-B2-23 36 218 describes a method to praduce a dialysis membrana consisting of a mixture of one or more conventional enteric coating polymers and one or more insoluble cellulosa derivativas. Such a

<img file="IS1918B_D0006.tif" />

membrane will not give a proper proteclion of the acid labile compounds of the formula I in gastric juice.

DE-A1-1 204 363 dBScribes a three-layer coating procedure. The first layer is soluble in gastric but is insoluble in intestinal juice. The second is water solubla regardless of pH and the third layar is an entsric coating. This preparation as well as the preparation described in DE-A1-1 617 615 result in a dosage form which is not dissolved In gastric juice and whlch only dissolves slowly in intestinal juice. Such preparations cannot ba used for the compounds of the formula I, where a rapid release of the drug in tha small intestine is needed. DE-A1 12 04 363 describes coadng with three layers to achieve release of a drug in the iteum, an alm which Is outside the scope of the present invention. GB-A-1 485 676 describes a way to obtain a praparation which effarvascas in the small intestine. This is obtained by the enteric coating of a core containing the actlve drug and an effervescing system such as a combination of carbonate and/or bicarbonate salt and a pharmaceutically acceptabla acid. This formulation cannot be adopted for a pharmacButical dosage form containing a compound of formula I as the presenca of an acid In contact wlth a compound of formula I in the cores would give as a result that the compound of formula I was dagraded.

WO 85/03436 describes a pharmaceutical preparation, wherein cores containing active drugs mixed with for Instance buffaring components such as sodlum dihydrogen-phosphate with the alm of maintaining a constant pH and a constant rate of diffusion, are coated with a first coating which controls the diffusion. This fbrmulation cannot bs adopted for acid labite compounds where a rapid release in the small intestive is wanted. Dlrsct appllcatlon of an enterlc coatlng onto the cores would also adversely Influence the storage stability of such dosaga forms containing acid labile compounds.

EP-A-124 495 and EP-A-173 664 describa enteric coated granules without subcoaling or a powder that are filled irrta hard gslatine capsules or a solution that is filled into a soft capsule.

The object of tha prasant inventíon is to provide an oral, pharmaceutical preparation stabls to discolouration containing an acid labile compound of the gönaral formula I above wharein A is an optionally subatituted heterocyclic group, R', R^z, R³ and R‘, ara the same or different and preferably hydrogen, lower alkyl, lower alkoxy, -CFa,

-O-L-lower alkyl or halogan and R⁵ is H or a lower alkyl group wherein 'lower" denotes 1-6 carbon atoms except the compound omeprazote, mettioxy-2[[(4-methoxy-3,5 dlmethyl-2-pyridlnyl) methyl] sulfinyl]-! H-benzimldazole; or the acid labile compound is 2-[(2-dlmethylaminobenzyl)sulfinyl]-bensimida2ole as the active ingredient. The core material is in the form of small beads or tablets containing the active ingredienl togather with an alkaline reacting compound, or an alkaline salt of the acliva ingrediant optionally together with an alkaline reacting compound, and on said cora matsrial one or more inert reacting subcoating layers comprising tablet excipients which ara solubla or rapidly disintegratlng in water, or polymaric, water solubla, filmforming compounds, optionally containing pH-buffering, alkaline compounds between the alkaline reacting cora and an outar layer, which is an enterlc coating.

R¹, R², R³ and R^l, which are the sama or different and especially (a) hydrogen (b) halogsn, e.g. F, Cl, Br, I (c) -CN (d) -CHO (e) -CF_a(0 " 11

-C-R¹¹ (g) -O-C-R¹² (h) -CH(OR^,3)s ÖHZVB-D (j) aryl containing up to 10 carbon atoms (k) aryloxy containing up to 10 carbon atoms, optlonally substitutsd by alkyl contalning 1-6 carbon atoms (l) -alkylthio containing 1-6 carbon atoms (m)-NOs (π) -alkylsuHinyl containing 1-6 carbon atoms (o) or wherein adjacant groups R¹ R² R³ and R* together with the adjacent carbon atoms in the benzlmidazole ring form a 5-, 6- or 7-membered monocyclic ring or a 9-, 10- or 11-membered blcyclic ring, which rings may be saturated or unsaturated and may contain 03 hetero atoms selected from -N-and -0-, and which rings may be optionally substituted with 1-4 substituents selected from alkyl groups with 1-3 carbon atoms, alkylene radlcals containing 4-5 carbon atoms giving spiro compounds, or two or four of thesa substituants togethar form one or two oxo groups (-C-), whereby if R’ and R², R² and R³ or R³ and R* together w'rth the adjacent carbon atoms In tha benzimidazole ring form two rings they may be condensed with each other, in which formulas R" and R¹², which are the same or different, are (a) aryl containing up to 10 carbon atoms (b) alkoxy containing 1-4 carbon atoms (c) alkoxyalkoxy contalning 1-3 carbon atoms in each alkoxy part (d) arylalkoxy containing 1-2 carbon atoms in tha alkoxy part and up to 10 carbon atoms in the aryl part (e) aryloxy containing up to 10 carbon atoms (f) dialkylamlno containing 1-3 carbon atoms in the alkyl parts, or (9) pyrrolidino or piperldino. optionally substituted with alkyl containing 1-3 carbon atoms;

R” is (a) alkyl containing 1-4 carbon atoms, or (b) alkylena containing 2-3 carbon atoms;

Z is -O or

II -c- ;

nis 0 or 1;

Bis (a) alkylene containing 1-6 carbon aloms (b) cycloalkylena containing 3-6 carbon atoms (c) alkenylene containing 2-6 carbon atoms (d) cycloalkylBne containing 3-6 carbon atoms, or (e) alkynylene containing 2-6 carbon atoms;

D is (a) H (b) -CN (0 ¹¹ 9

-c-ir

II

-(c)_r

-R10 wherein

R* is (a) alkoxy containing 1-5 carbon atoms, or (b) dialkylamino containing 1-3 carbon atoms in the alkyl parts;

m is 0 or 1;

risOorl;

Yis (a)-O- (b)-NH- (c) -NR'⁰-;

R'° is (a)H (b) alkyl containing 1-3 carbon aloms (c) arylalkyl containing 1-2 carbon atoms in tha alkyl part and up to 10 carbon atoms in the aryl part (d) aryl containing up to 10 carbon atoms;

R⁵ is H, CH₃ or CíHs;

A ls especlally a pyridyl group in whlch R^s and R* are the same or different, are <img file="IS1918B_D0007.tif" /> (a) H or (b) alkyl containing 1-6 carbon atoms;

R⁷ is (a) H (b) alkyl containing 1-8 carbon atoms (c) alkoxy containing 1-8 carbon atoms (d) alkenyloxy containlng 2-5 carbon atoms (e) alkynyloxy containing 2-5 carbon atoms (f) alkoxyalkoxy containing 1-2 carbon atoms in each alkoxy group (g) aryl containing up to 10 carbon atoms (h) arylalkyl containing 1-6 carbon atoms in tha alkyl part and up to 10 carbon atoms in ttia aryl part (i) aryloxy containing up to 10 carbon atoms, optionally substituted by alkyl containing 1-6 carbon atoms (j) arylalkoxy containing 1-6 carbon atoms in the alkoxy part and up to 10 carbon atoms in the aryl part (k) dialkylamlnoalkoxy contalning 1-2 carbon atoms In the alkyl substituents on the amino nitrogen and 1-4 carbon atoms in the alkoxy group (l) oxacycloalkyl containing one oxygen atom and 3-7 carbon atoms (m) oxacycloalkoxy containing two oxygen atoms and 4-7 carbon atoms (n) oxacycloalkylalkyl containing one oxygen atom and 4-7 carbon atoms (o) oxacycloalkylalkoxy containing two oxygen atoms and 4-6 carbon atoms, or (p) R⁶ and R⁷, or R⁷ and R* together with Ihe adjacant carban atoms In tha pyridina rlng form a rlng wherein the part constituted by R⁶ and R’, or R⁷ and R’, is

-CH = CH-CH = CH-O-(CH₂)_p-S-(CH₂),-

<img file="IS1918B_D0008.tif" />

-CH^CHaV O-CH = CH--NH-CH=CH-p-CH=CH-CH₃ wherein p is 2,3 or 4, v is 2 or 3 and the 0 and N atoms always are attached to posrtion 4 in tha pyridine ring; provided that not mora than one of R*. R⁷ and R^B Is hydrogen can ba formulated into an entaric coated dosage fomn.

The object of the present inventlon Is thus an enterlc coated dosage form ol acld labile compounds with the general fomnula I dafined above axcapt the compound omeprazole, 5-methoxy-2-[[(4-methoxy-3,5 dimethyfö-pyridlnyljmathyllsulfinyl] -IH-benzlmldazole. Another compound, whlch may be enteric coated according to The invention is 2- (2-dimethylaminobenzyl)sulfinyl -benzimidazole. The new preparations are resistant to dissolution in acid media, dissolve rapidly in neutral to alkalina media and have a good stability during long-term storage. The new dosage form is characterized in the following way. Cores containing the acid labile compound mixed with alkaiine compounds or an alkaline saft of the acid labile compound optionally mixad with an alkalina compound are coated w'rth two or more layers, in which the first layer/layers is/are soluble in water or rapídly disintegrating in watar and consist(s) of non-acidic. otherwise inert pharmaceutically acceptable substances. This/these first layer/layers separates/separate tha alkaline core material from the outar layer, which is an enteric coating. Tba final, errteric coated dosage tarm is treated ln a suitable way to reduce the water content to a vary low leval in order to obtain a good stability with virtually no discolouration of the dosaga form during long-tarm storage.

As examples of compounds espacially suitable for the pharmaceutical dosage form according to The invention the compounds listed in Table 1 can be mentioned.

The half-lite of degradation of the compounds 1-6 in Tabla 1 in water solution at pH-values less than four Is in most cases shorter than tan minutes. Also at neutral pH-values the degradation raaction proceads rapidly, e.g. at pH=7 the half-life of degradation is between 10 minutes and 65 hours while at higher pH-values the stability in solution for most compounds is much better. The stability profile is similar in solid phasa. The degradation is catalyzed by acid reacting substances. The acid labile cornpounds are stabilized in mixtures with alkaline reacting substances.

From what is said about the stability propertias of the acid labile compounds listad above it is obvious that an oral dosage form of tha said compounds must be protected from contact with tha acid reacting gastrlc juica in order to reach the small intestina without degradation.

Cores

The acid labile active compound is mixed witti inert, prefarably water solubla, conventional pharmaceutical constituents to obtain the prefarred concentration of the active compound in the final mixture and with an alkaline reacting, otherwise inert, pharmaceuticaHy acceptable substance (or substances), which creates a "micro-pH’ around each particle of active compound of not less than pH=7, preferably not less than pH=B, when water is adsorbed to the particles of the mixture or when water Is added In small amounts to tha mixture. Such substancas can ba chosen among substances such as the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other sultable weak inorganic or organic acids; substances normaily used in antacid preparafions such as aluminium, calclum and magnesium hydroxides; magnesium oxlde or composite substances such as AhOj.eMgO CO2.12HjO, (MgsA1₂(OH)i6CO3 4H₂O), MgO.AI2O3.2SiQ2.nH2O, wharein n not is an intager and less than 2 or similar compounds; organic pH-buffering substances such as trishydroxymethylaminomethane or other similar, pharmaceutically acceptable pH-buffaring substances. The stabilizing, high pH-value in the powder mixture can also be achieved by using an alkaline reacting, salt of the activa compound such as the sodium, potasslum, magnesium, calcium salts of acid labile compounds, either alone or in combination with a convantional buffering substance as previously described.

The powder mixtura is than formulatad into small beads i.a. pellets or tablets, by conventional pharmaceutical procedures. The pellats or tablets are used as cores for further processing.

Separating layer

The alkaline reacting cores containing an acid labila compound must be separated from the enteríc coating polymer(s) containing frea carboxyl groups, which otherwise causes degradation/discolouration of the acid labile compound during the coating process or during storage. The subcoatlng layer, (the separating layer), also serves as a pH-buffering zone in which hydrogen ions diffuslng from the outside in towards tha alkaline core can raact with hydroxyl ions diffusing from the alkaline core towards the surface of the coated particles. The pH-buffering propartias of the separating layer can ba further strengthanad by introducing in the layer substances chosen frorn a group of compounds usually used in antacid formulations such as, for instance, magnesium oxide, hydroxida or carbonate, aluminium or calcium hydroxide, carbonate or silicate; composite aluminium/magnesium compounds such as, tar Instance AhO3.6MgO CO2.12H2O, (Mg6A1₂(OH)_lECO3,4H₂O), MgO.AI2O3.2SiO2.nH2O, wherein n not is an intager and less than 2 or similar compounds; or other pharmaceutically accaptable pH-buffering substances such as, for instance the sodlurn, potassium, calclum, magnesium and alumlnium salts of phasphoric, citric or other suitable, weak, inorganic or organic acids.

The separating layer consists of one or more water soluble inert layers, optionally containing pH-buffering subslances.

The separating layer(s) can be applied to the cores - pellets or tablets - by conventional coating procedures in a suitable coating pan or in a fluidized bad apparatus using water and/or conventional organic solvents for the coating solution. The material for the separating laysr is chosen among the pharmaceutically acceptabla, watar soluble, inert compounds or polymers usad for film-coating applications such as, for instance sugar, polyethylene glycol, polyvinyIpyrolíidone. polyvinyI alcohol, hydroxypropyl cellulose, hydroxymethyl cellulose or hydroxypropyl methylcellulose. The thickness of the separating layer is not less than 2 um, for small spherical pellets prefarably not less than 4 um, for tablets prelerably not Isss than 10 um.

In the case of tablets another method to apply the coating can be performed by the drycoating tachniqua. First a tablet containing the acid labila compound Is comprassed as describad above. Around this tablet another layer is compressad usíng a suitable tableting machine. The outer, separating layer, consists of phamaceutically acceptable, in water soluble or in water rapidly disintegrating tablet excipients. Tha separating layer has a thickness of not less than 1 mm. Ordinary plasticizers, pigments, titanium dioxide talc and other additives may also be included ínto the separating layer.

The entsric coating layer Is appliad on to the sub-coatad cores by convantional coating techniques such as, for instanca, pan coating or fluidized bad coating using solutions of polymars in water and/or sultablð organic solvents or by using latex suspensions of said polymars. As enteric coating polymers can be used, for Bxample, cellulosa acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetata phthalate, co-polymerizsd methacrylic acid/methacrylic acid methyl esters such as, for instanca, campounds known under the trada nama Eudragit” L 12,5 or Eudragit" L 100, (Röhm Pharma) or similar compounds used to obtain enteric coatings.

The enteric coatlng can also be applied using water-basad polymer dispersions, a.g. Aquateric (FMC Corporation), Eudragit^R L 100-55 (Röhm Pharma), Coating CE 5142 (BASF). The enteric coating layer can optionally contain a pharmaceutically acceptable plasticizer such as, tor instance, cetanol, triacetin, citric acid esters such as, for instance, those known under the trade name Citroflex^R (Pfizer) phthalic acid esters, dibutyl succinata or similar plasticizers.

The amourrt of plasticizer is usually optimized for each enteric coating polymer(s) and is usually in the range of 1-20 % of the enteric coating polymerfs). Dispersants such as talc, colourants and pigments may also be Included Into the enterlc coating layer.

Thus the spadal preparation according to The invention consists of cores containing the acid labila compound mixed with an alkaline reacting compound or cores containing an alkaline salt of the acid labile compound optianally mixed wíth an alkallns reacting compound. The cores suspended in water forms a solution or a suspansion which has a pH, which is higher than that of a solution in which the polymer used for enteric coating is just soluble. The cores are coated with a water soluble or in water rapidly dlsintegrating coating, optlonally containing a pH-buflering substanca, which separates the alkaline cores from the enteric coating. Without this separating layer the resistance towards gastric juice would ba too short and the storage stability of the dosage form would ba unacceptably short. The sub-coated dosage form is finally coated with an enteric coating rendering the dosage form Insoluble in acid medla, but rapidly disjntegrating/dissolving in neutral to alkaline media such as, for instanca the liquids present in the proximal part of the small intestine, the site where dissolution is wanted.

Final dosage form

The final dosage form is either an enteric coated tablet or In the case of enteric coated pellets, pellets dispansad in hard galatin capsulas or sachets or pellets formulaied into tablets. It Is essential for the long tarm stability durlng storage that the water content of the final dosage form containing acid labile compound (entaric coated tablats, capsules or pella(s) Is kept low, preferably not exceeding 1.5 % by weight.

A process íor the manufacture of the oral dosage form represents a further aspect of The invention. After tha forming of the cores the cores are first coated with the separating layer and than with the enteric coating layer. The coating is carried out as described above.

The preparation according to The invention Is especially advantageous In reducing gastric acid secretion and/or pravldlng a gastrolntestlnal cytoprotective affact. It is usually administered one to several times a day. The typical daily dose of the aclive substance varies and will depend on various factors such as for example the individual requirement of the patients, the mode of admlnistration and the disease. In generai the dosage will be in the range of 1 to 400 mg per day of active substance.

The invention is dascribed in detail in the following examples:

EXAMPLES

Examples 1 - 3 exemplify The invention.

Example 1

Uncoated pellets

253 g

167 g

I 25g

50g

II1.5 g

0.1 g

125 g

The dry ingredients (I) were premixad in a mixer. Addition of a granulation llquid (II) containing the suspended actlve compound was made and the mass was wet-mixed to a proper consistency. The wet mass was pressed through an axtruder and spheronized to pellets. The pallats wera dried and classified into sultabla partlcie slza ranges.

Subcoated pellats

500 g

III 20 g

400 g

<img file="IS1918B_D0009.tif" />

<img file="IS1918B_D0010.tif" />

The polymer solution (III) was sprayed onto the uncoated pallets in a fluidizad bed apparatus. The spray iuns were placed above tha fluidized bed.

•nteric coated pellets

500 g g

IV 3 g

540 g

231 g

The polymer solution (IV) was sprayed on the subcoated pellets in a fluldized bed apparatus with spray juns placad above tha bed. Aftar drying to a water content of 0.5 % tha antaric coated pallets wera :lassified and filted into hard gelatin capsulas in an amount of 284 mg, corresponding to 25 mg of activa ;ompound 1.30 capsules were packad in tight containers together with a desiccant.

íxample 2

Formulation with tha sodium salt of compound 2 according to Table I.

Jncoated pellets

339 g

422 g

120 g ^I 90 g g

^II 7 g

650 g

The preparation was made as described in Exampla 1 with tha exception that the sodium salt of nmpound 2 was added togathar with the other ingredlents in mixture I.

Subcoated pellets

<img file="IS1918B_D0011.tif" />

<img file="IS1918B_D0012.tif" />

500 g g

III g

400 g

500 g

IV 20 g

400 g

The twa subcoat layers, III and IV, were applied to the uncoated pellets in a fluidized bed apparatus in consecutive order as previously described.

Entaric coated pellets

500 g g

V 3 g

540 g

231 g

The praparation of entaric coated pellets was performed as describad in Example 1.

Example 3

Formulation with compound 8, according to Table 1. This axample gives the composition of one unit dose according to The invention.

Tablet core <img file="IS1918B_D0013.tif" />

Tablat cores having the composition above and each weighing 160 mg ware first made by known tachniques.

Separating layer (innar)

<img file="IS1918B_D0014.tif" />

<img file="IS1918B_D0015.tif" />

<img file="IS1918B_D0016.tif" />

<img file="IS1918B_D0017.tif" />

Saparating layer (outer) <img file="IS1918B_D0018.tif" />

The two saparating layers were appliad to the coras by known coating techniquas.

Enterlc caatlng layer <img file="IS1918B_D0019.tif" />

The enteric coating solution was sprayed on tha cores coated by the two separating layers by known enteric caating tachniquas.

<img file="IS1918B_D0020.tif" />

<img file="IS1918B_D0021.tif" />

<img file="IS1918B_D0022.tif" />