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

Process for the preparation of pharmaceutical compositions containing acid labile compounds for oral administration

Field of the invention

The present invention relates to novel pharmaceutical preparations containing acid labile substances for oral administration, a method for their preparation and a method of acting on gastric acid secretion and providing gastrointestinal eight-protective action by means of their use. use.

Background of the invention

Labile acidic substances present a problem for the formulator when formulating a pharmaceutical composition for oral administration. To avoid contact of the substances with the acidic gastric juice that reacts after oral ingestion, there is a conventional way to solve this problem by coating the dosage form with an enteric coating. 0 The coating is comprised of a group of substances / polymers with the common feature of being practically insoluble, acidic and soluble in neutral or alkaline.

For acid-labile substances, but which have better stability in neutral or alkaline media, it is often advantageous to add alkaline reaction inert compounds in order to increase the stability of the active ingredient during preparation and storage. .

<img file="PT84786B_D0001.tif" />

A group of compounds having these stability properties are substituted benzimidazoles of formula

A-CH * 5

<img file="PT84786B_D0002.tif" />

in which

A represents an optionally substituted heterocyclic group j

Ej, Rg * ^ 3 ^{and R}4 * same or different have the meaning defined later; and

R4 represents a hydrogen atom or a lower alkyl group or the 2- [2- (2-dimethyloylobenzyl) sulfinyl] benzimidazole compound.

The compounds of formula I are virtually biologically inactive as such, but they degrade / become active inhibitors of certain enzyme systems in acidic media.

Examples of compounds having the above properties include the compounds described in U.S. Patent A-4O45563, B1-OOO5129 and Belgian -898880 and European patent applications. 85850258.6, EF-Al.008.602, /

fw

EP-0127.736, EP-0134.400, EF-0130729, EP-0150.586, Federal German Patent Application 3,415 * 971, English Patent Application 2,082,580 and the Swedish Patent Application A-8504048.

The last patent application describes the

2- (2-disubstituted-aminobenzyl) sulfinylbenzimidazoles, for example 2- (2-dimethylaminobenzyl) sulfinylbenzimidazole, also referred to as NC-1300 and presented by Prof. S. Okabe at the Symposium on Drug Activity, held October 17, 1985 in Nagoya, Japan and interfering with H⁺K⁺-ATPase after acid degradation in parietal cells. (See, for example, B. Wallmark,

A. Brãndstrãm and H. Earsson Evidence for acid-induced transforX X mation of omeprazole into an active inhibitor of-K -ATi and within the parietal cell ”, Biochemica et Biophysica Acta 778,

549-558, 1984).

Other compounds with similar properties are further disclosed in U.S. Patent 4,182,766 and Great Britain Patent Applications 2141 429 and 2082580 and European Patent Application 0 146 370,

A characteristic of these compounds is that they are transformed into biologically active compounds by degradation / transformation into acidic medium.

The stability profile of some of the compounds of formula I above is shown in Table I below, where the half-life of the degradation / transformation reaction in pH 2 and pH 7 solution is given.

-4 Table 1. Rate of degradation / transformation of compounds of general formula -and structure

<img file="PT84786B_D0003.tif" />

Compound

No R₂ R₃

THE

Half-life (minutes) .for transformation of active radical at pH = 2 to pH = 7

1.

Vice^CH3

5-COOCH₃6-CH₃

150

<img file="PT84786B_D0004.tif" />

5-CH₃;H

5-CF₃;H

5.4

1.9

1700

122

<img file="PT84786B_D0005.tif" />

2.0

8.8

<img file="PT84786B_D0006.tif" />

3.7

1620

Account.

<img file="PT84786B_D0007.tif" />

Compound

N9 R₂ R₃

THE

Half-life (minutes) for transformation of active radical at pH - 2 at pH = 7

<img file="PT84786B_D0008.tif" />

4.0

3900 not determined

CH₃

Substituted sulphoxides, such as for example substituted benzimidazoles described in European Patent B1-OOO5129 are potent inhibitors of gastric acid secretion. Substituted benzimidazoles are likely to be degraded and transformed into acidic and neutral medium.

These compounds have the common property of being activated to an active group in the acidic environment of the parietal cells, activated compound interferes with the enzyme in the parietal cells that intervene in the production of hydrochloric acid in the gastric mucosa. All compounds of the imidazole class dis; that contain a sulfoxide group that interferes with

I I. '

Η K -ATPase in the parietal cells known to date are all degradable in acidic medium.

A pharmaceutical dosage form of acid labile substances which prevents the substances from contacting with acid gastric juice must have an enteric coating. Ordinarily, enteric coatings are, however, made up of acidic compounds. If coated with such an enteric coating, the acid-labile substances decompose rapidly upon direct or indirect contact with it, resulting in unpleasantly discolored preparations with loss of active ingredient over time.

In order to enhance stability during storage, nuclei containing the acid-labile substance should also contain alkaline reaction constituents. When one of these alkaline cores is protected with an amount of a conventional enteric coating polymer for example,

<img file="PT84786B_D0009.tif" />

Cellulose acetophthalate, which allows the dissolution of the lining and active ingredient contained in the nucleus in the region near the small intestine, will also allow the diffusion of some water or gastric juice through the enteric lining into the nuclei during the dose period. remains in the stomach before transitioning to the small intestine.

Water or diffused gastric juice will dissolve parts of the nucleus closest to the enteric layer and form an alkaline solution within the coated dose form therein. The alkaline solution will interfere with the enteric coating and eventually dissolve it.

In German patent A-1-3O46559, a route for coating a dosage form is described. This is first coated with a water-insoluble layer containing microcrystalline cellulose and then with a second enteric coating for the purpose of achieving a dosage form which yields the active ingredient in the colon region. This preparation method will not allow the desired yield of the compounds of formula I in the small intestine.

U.S. Patent A-2-540,979 discloses an enteric coating of an oral dosage form wherein the enteric layer is associated with a second and / or first coating layer of a water-insoluble wax layer.

This preparation method is not applicable to cores containing a compound of formula I, provided that in direct contact with substances such as cellulose acetophthalate (GAP) and a compound of formula I which causes degradation.

<img file="PT84786B_D0010.tif" />

and discoloration of these.

Federal German Patent B2-2336218 describes a process for the preparation of a dialyzing membrane consisting of a mixture of one or more conventional enteric coating polymers and one or more insoluble cellulose derivatives. Such a membrane will not provide adequate protection for the acid labile compounds of general formula I in the gastric juice.

German Patent 1,204,363 describes an enteric coating process consisting of three layers.

The first is soluble in gastric juice but insoluble in in testinal juice; the second is water soluble according to pH and the third layer forms an enteric coating.

This preparation, as well as the preparation described in German Patent A-11617615 results in a dosage form which does not dissolve in the gastric juice and which only dissolves slowly in the intestinal juice. Such preparations cannot be used for compounds of general formula I, where rapid release of the drug into the small intestine is required.

German patent Al 1204363 describes re. three-layer coating to achieve drug release in the ileum, an object that is outside the scope of the present invention.

British Patent A-1485676 discloses a form for obtaining a preparation which becomes effervescent in the small intestine, which is obtained by an enteric coating of a core containing the active ingredient and an active ingredient. effervescent system, such as a combination of carbonate and / or bicarbonate and a pharmaceutically acceptable acid.

This composition cannot be adopted for a pharmaceutical dosage form containing a compound of formula I, such as the presence of an acid in contact with a compound of formula I, in the core, which would result in the breakdown of the compound.

West German Patent 85/03436 discloses a pharmaceutical preparation wherein the cores containing the active ingredients are mixed, for example, with buffering agents, such as sodium dihydrogen phosphate, the purpose of which is to maintain a constant pH value, and a constant diffusion rate, are coated with a first coat that controls diffusion.

This composition cannot be adopted for acid labile compounds which require rapid release into the small intestine. Direct application of an enteric coating to the cores would also adversely influence the storage stability of such dosage forms containing acid labile compounds.

Scheme of the Invention

According to the present invention it has been found that acid labile compounds of general formula • 10 '

A-CH-3

NH

<img file="PT84786B_D0011.tif" />

'5

<img file="PT84786B_D0012.tif" />

R.

R in which

RpRg » ^and 'same or different, reprehends. seat each

a) a hydrogen atom

b) a halogen atom such as chlorine, fluorine, bromine or iodine;

c) a cyan group,

d) a radical - CHO,

e) a trifluoromethyl (cF1) group; O

f) a radical - A_p,

g) a radical -OCR4₂,

h) a group - CH (OR ^)₂,

(i) one group (Z_no) -BD,

j) an aryl group of more than 10 carbon atoms;

(h) an aryloxy group of more than 10 carbon atoms, optionally substituted by one O 1 -C 6 alkyl group

l) an alkylthio group of 1-6 carbon atoms,

m) a group -N0₂,

<img file="PT84786B_D0013.tif" />

n) a sulfinyl group of 1-6 carbon atoms; o) but the groups Rp Rg »^{and R}4 taken together with the adjacent carbon atoms of the benzimidazole ring constitute a 5-, 6- or 7-membered monocyclic ring or an optionally saturated 9-, 10- or 11-membered bicyclic ring, optionally containing from 0-3 heteroatoms selected from an oxygen atom to a nitrogen atom and wherein the nuclei may optionally have as substituent (s)

1-4 group (s) chosen from an alkyl group of 1-3 carbon atoms, alkylene of 4-5 carbon atoms, forming spiro compound, or two or four of these substituents constitute one or two oxo (—0—) groups if R ^ and Rg, Rg θ Rj or R e and R ^ considered together with the adjacent carbon atom in the imidazole ring form two nuclei which can be condensed into each other, in which form the symbols R ^ ® ®. The same or different R 2 are:

a) an aryl group of more than 10 carbon atoms;

b) an alkoxy group of 1-4 carbon atoms;

c) an alkoxyleoxy group having 1 to 3 carbon atoms in each alkoxy group;

d) an arylalkoxy group having 1-2 carbon atoms in the alkoxy radical and more than 10 carbon atoms.

-12% in the aryl radical;

e) an aryloxy group of more than 10 carbon atoms;

f) a dialkylamine group having 1-3 carbon atoms in the alkyl group; or

g) a pyrrolidino or piperidino group optionally having as an substituent an alkyl group of 1-3 carbon atoms;

<img file="PT84786B_D0014.tif" />

represents

a) an alkyl group of 1 to 4 carbon atoms;

or

b) an alkylene group of 2 to 3 carbon atoms;

Z represents an oxygen atom or a group -Cn represents zero or the number 1;

B represents

a) an alkylene group of 1 to 6 carbon atoms

b) a cycloalkylene group having 3-6 carbon atoms

c) alkylene of 2-6 carbon atoms;

d) cycloalkylene having 3-6 carbon atoms; or

e) alkynylene of 2-6 carbon atoms;

D represents

a) a hydrogen atom

b) a -CN group

θ) - C - Rg

d) a group of formula - (Y)_m '- °) r - * L0

13 '~ X.

in which

Rg stands for

a) an alkoxy group of 1-5 carbon atoms} or

b) dialkylamino having 1-3 carbon atoms in the alkyl group ra represents zero or 1;

r represents zero or Ij

And represents

a) an oxygen atom}

b) an -NH group

c) a group of formula -NR in which io &amp; L0 represents

a) a hydrogen atom

b) an alkyl group of 1-3 carbon atoms

c) an aralkyl group having 1-2 carbon atoms in the alkyl moiety and having more than 10 carbon atoms in the aryl moiety;

d) an aryl group of more than 10 carbon atoms;

R5 represents a hydrogen atom or a methyl or ethyl group

A represents, particularly a pyridyl group of general formula

<img file="PT84786B_D0015.tif" />

<img file="PT84786B_D0016.tif" />

in which

The same or different Rg and Rg each represent

a) a hydrogen atom;

b) an alkyl group of 1-6 carbon atoms;

R? represents

a) a hydrogen atom;

b) an alkyl group of one to 8 carbon atoms;

c) an alkoxy group of 1-8 carbon atoms;

d) an alkenyloxy group having 2-5 carbon atoms;

e) an alkynyloxy group having 2-5 carbon atoms;

f) alkoxyalkoxy of 1-2 carbon atoms in each of the alkoxy groups;

g) aryl of more than 10 carbon atoms;

h) arylalkyl of 1-6 carbon atoms in the alkyl radical and more than 10 carbon atoms in the aryl radical;

(i) aryloxy of more than 10 carbon atoms

<img file="PT84786B_D0017.tif" />

optionally containing as an substituent an alkyl group of 1-6 carbon atoms;

j) an arylalkoxy group having 1-6 carbon atoms in the alkoxy group and more than 10 carbon atoms in the aryl group;

k) dialkylaminoalkoxy of 1-2 carbon atoms in the alkyl substituent groups of the amino nitrogen atom and 1-4 carbon atoms in the alkoxy group;

1) an oxa cycloalkyl group having one oxygen atom and 3-7 carbon atoms. at the;

m) an oxycycloalkoxy group having two oxygen atoms and 7 carbon atoms;

n) an oxycycloalkylalkyl group having one oxygen atom and 4-7 carbon atoms; or

o) oxacycloalkylalkoxy having two oxygen atoms and 4 to 6 carbon atoms;

or

p) Rg and Ry or Ry or Rg, taken together with the adjacent carbon atoms in the pyridine nucleus, form a nucleus in which the fraction represented by Rg and Ry or Ry and Rg represents a group.

-CH = CH ~ CH-CH-,

-0-(0¾ )_P-16

THE

-s- (oh₂)_v-oh₂(ch₂)_P-O-CH = CH-NH-CH = CH-N-CH-CH

I

CH₃ where p represents a number 2, 3 or 4, v represents a number 2 or 3, and oxygen and nitrogen atoms are always bonded at position 4 in the pyridine nucleus, provided that no more than one of Kg, R ? and Kg represents a hydrogen atom, may be incorporated into an enteric coated dosage form.

It is therefore an object of the present invention to obtain an enteric coated dosage form of acid labile compounds of general formula I as defined above except for the compound omeprazole, 5-methoxy-2- (4-methoxy-3, 5-dimethyl) -2-pyridinyl-methylsulfinyl-1H-benzimidazole. Another compound which may have an enteric coating according to the present invention is 2- (2-dimethylaminobenzyl) sulfinylbenzimidazole.

The novel preparations are resistant to acid dissolution, dissolve rapidly in neutral or alkaline media and have good stability during storage.

The new dosage form is characterized by the following mo-17-

<img file="PT84786B_D0018.tif" />

Nuclei containing the acid-labile compound mixed with alkali or alkaline salt of a labile compound, optionally mixed with an alkaline compound are coated with one or more layers wherein the first layer / layers is / are soluble in water or rapidly disintegrates in water and is a pharmaceutically inert substance (s).

This first layer separates the alkaline core from the outer layer consisting of an enteric coating. The final enteric coated dosage form is suitably treated to reduce the water content to a very low level in order to achieve good stability of the dosage form during long term storage.

The compounds referred to in Table I may be mentioned by way of example of compounds especially suitable for the pharmaceutical dosage forms according to the present invention.

The degradation half-life of compounds 1-6 listed in Table I in aqueous solution with pH values ​​below four is in many cases less than ten minutes. Also at neutral pH values ​​the degradation reaction proceeds rapidly, for example at pH 7 the degradation half-life is between 10 minutes and sixty-five hours, while at pH values ​​greater than stability in solution is much better. 0 Stability profile is similar in the solid phase. Degradation is catalyzed by acid reaction substances. The acid-labile compounds are stabilized by mixing with alkaline reaction substances.

From the foregoing on the stability properties of acid labile compounds it is obvious that an oral dosage form of said compounds must be protected from contact with the acid reaction of the gastric juice in order to pass to the small intestine. free from degradation.

Detailed Description of the Present Invention

Cores

The labile acid active compounds are mixed with conventional, preferably water-soluble pharmaceutical ingredients to obtain the preferred concentration of the active compound in the final mixture and with alkaline reaction ie pharmaceutically acceptable inert substance (s) which creates a micro-pH 'around each particle of the active compound having a value of not less than 7, preferably a pH value of not less than 8, when the particles in the mixture absorb water or when small amounts of water are added to the mixture.

Such substances are not limited to substances chosen from sodium salts, potassium salts, calcium salts, magnesium salts and aluminum salts of phosphoric acid, carbonic acid, citric acid or other weak organic or inorganic acids. used in antacid preparations such as aluminum hydroxide, calcium hydroxide and magnesium hydroxide; magnesium oxide or compound substances such as AlgO ^, δΤ ^ Ο C0₂, 12H₂0 (Mgg Alg (0H)_lg CO₃4H₂O). MgO, Al_g 0 ^ 2SiOiH₂Where n is not an integer and is less than 2 and other organic pH buffer substances such as tris

-hydroxymethylaminoethane or equivalent, pharmaceutically acceptable, as buffer substances.

Stabilization of a high pH value in the paddle mixture can also be achieved by using an alkaline reaction salt of the active compound, such as sodium salts, potassium salts, magnesium salts, calcium salts, etc. of the acid labile compounds either alone or in combination with a conventional buffer substance as described above.

The standing mixture is then formulated into small beads, for example granules or tablets, by conventional methods. Granule granules, tablets or capsules are then used as cores for further preparation.

Separation Range

Alloaline reaction nuclei containing an acid labile compound should be separated from the enteric coating polymer layer (s) containing free carboxylic groups which would otherwise cause degradation / discoloration of the labile acid compounds during the coating process. or during storage.

The sublayer (separating layer) also serves as a pH buffer zone, in which hydrogen ions diffusing from the outside toward the alkaline nucleus can react with hydroxyl ions that diffuse from the nucleus toward the surface of the compounds that make up the hydrocarbon. coating.

The pH buffer properties of the separating layer may be further enhanced by introducing substances chosen from the number of compounds commonly used in antacid compositions, such as magnesium oxide, magnesium hydroxide or magnesium carbonate. aluminum hydroxide or calcium hydroxide, aluminum carbonate or calcium carbonate or aluminum or calcium silicate Aluminum / magnesium compounds such as, for example, AlgO 4, 6MgO00₂, 12H₂O. (MggAl₂ (OHCOp 4H₂O), Μ ^ Ο, ^ e ^ ίΟ ^ η ^ Ο, where n is not an integer, and represents a decimal number of less than 2 or similar compounds; or other pharmaceutically acceptable pH buffer substances such as, for example, sodium, potassium, calcium, magnesium and aluminum salts of phosphoric acid or citric acid or other suitable inorganic salts or organic acids.

The separating layer consists of one or more inert, water-soluble layers which optionally contain pH buffering substances.

The separation layer (s) may (Q). It may be applied to the core, granules or tablets by conventional coating processes in a suitable drageifier or fluid bed apparatus using water and / or appropriate organic solvents as a coating solution.

The separating layer material is selected from pharmaceutically acceptable, water-soluble, inert, II, or film-applying polymers such as polyethylene glycol sugar, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropylcellulose, hydroxymethylcellulose or the like.

The thickness of the separation layer is not less than 2

For the spherical granules, preferably not less than 4 yAm θ for tablets not less than 10ynm.

For tablets other coating methods may be applied by dry coating techniques. First the tablet containing the acid labile compound is compressed as described above. Around this tablet, another layer is printed by means of an appropriate compression machine. Outside, the separating layer is comprised of pharmaceutically acceptable, water-soluble or rapidly disintegrable excipients. The separating layer has a thickness of not less than 1 mm. Commonly, plasticizing agents, pigments, titanium dioxide, talc and other additives may be inoluted.

In the case of gelatin capsules this itself serves as a separating layer.

Enteric Coating Layer

The enteric coating layer is applied to the core sublayer by conventional re-techniques. for example, such as in a drainage basin or fluid bed apparatus, using polymer solutions in water or / and in appropriate organic solvents or by latex suspensions of said polymers.

As enteric coating polymers can be used, for example, cellulose acetophthalate, hydroxypropyl methylcellus phthalate, polyvinyl acetophthalate, polymerized methacrylic acid / methacrylic acid methyl esters, such as for example commercially designated compounds

Eudragii L 12.5 or Eudragii L 100, (Röhm Pharma) or similar compounds used to obtain enteric coatings.

Enteric coating can be applied by using polymer dispersions in water such as

Aquateric (FMC Corporation), Eudragit L 100-55 (R8hm Pharma), Coating CE 5142 (BASF).

The enteric coating layer may optionally contain pharmaceutically acceptable plasticizing agents such as, for example, kethanol, triacetine, citric acid esters such as, for example, compounds known under the name Citrofle® (Pfizer), phthalic acid esters, dibutyl succinate or equivalent plasticizers.

The amount of plasticizer is optimized for each enteric coating polymer (s) and usually in a ratio of 1 to 20% polymer (s). Dispersing agents such as talc, coloring agents or pigments may also be included in the enteric coating layers.

Therefore, according to the present invention, the special preparation consists of nuclei containing the acid labile compound mixed with alkaline reaction compounds or nuclei containing a salt of the acid labile compound optionally mixed with alkaline reaction compounds.

The cores suspended in water form a solution or suspension that has a pH higher than the pH of a solution in which the polymer used for the enteric coating is exactly soluble. The cores are coated with a water-soluble coating or undergo rapid breakdown in water.

optionally having pH buffer substances which separate the alkaline nuclei from the enteric coating.

Without this separation phase, the resistance to the gas juice would be too low and the storage stability of the form would be too short to be acceptable.

The dosage form with the subcoating is finally covered with an enteric layer which makes it acid insoluble, but which rapidly disintegrates / dissolves in neutral or alkaline media such as liquids in the small intestine near the site. where dissolution is required.

Final Dosage Form

The final dosage form consists of an enteric coated tablet or capsule or, in the case of enteric coated granules, consists of a hard gelatin capsule containing such granules or compressed sachets or granules in tablet form.

For long term storage stability it is essential that the water content of the final dosage form containing the acid labile compound (enteric coated tablets, capsules or granules) is low, preferably not exceeding 1.5% of its Weight.

Process The process of preparing oral dosage forms represents another aspect of the present invention. After formation of the nuclei they are first covered with a separating layer and then with an enteric coating. 0 revs-24-

<img file="PT84786B_D0019.tif" />

Enteric treatment is obtained according to the process described above.

The preparation according to the present invention is especially advantageous for reducing gastric acid secretion and / or providing a cytoprotective gastrointestinal effect. It is usually given one or more times a day.

The typical daily dose of the active substance depends and varies according to various factors such as, for example, the individual need of the patient, the form of administration and the disease.

In general the dose should be in a range of 1 to 400 mg per day of active ingredient. The process for treating such conditions using the new oral dosage form represents a further aspect of the present invention.

The present invention is described in detail by the following examples:

Examples 1-3 exemplify the present

Examples

<td colspan="4">invention.</td>

<td>Example 1</td><td></td><td></td><td></td>

<td>Beads not</td><td colspan="2">coated</td><td></td>

<td></td><td></td><td>* standing lactose</td><td> 253</td>

<td>I</td><td> &lt;</td><td>Anhydrous lactose</td><td> 167</td>

<td></td><td></td><td>Hydroxypropyl Cellulose</td><td> 25</td>

gg

g

Compound 1 Table I Sodium lauryl sulphate Disodium hydrogen phosphate Monosodium dihydrogen phosphate Distilled water g

g

1.5 g

0.1 g

125 g

In a mixer the dry ingredients (I) will be mixed. Then, the granulation liquid (11) containing the suspended active compound is added and a mass is formed which is wet mixed to an appropriate consistency. The wet mass is compressed through an effector and forms small spherical granules which are dried and separated into appropriate size classes.

Sublayer granules uncoated granules 500 g / hydroxypropyl methylcellulose 20 g distilled water 400 g

The solution containing polymer (XII) is sprayed onto the uncoated granules in a fluid bed chamber. Sprinkler jets are placed above the fluid bed.

Enteric Coated Beads

Sublayer granules 500 g Hydroxypropyl methyl cellulose 57 g Cetyl alcohol 3 g Acetone 540 g Ethyl alcohol 231 g

The solution containing polymer (IV) is sprayed onto the sublayer pellets in a fluid bed chamber with the spray placed above the bed.

After drying the water content to about 0.5%, the enteric coated granules are classified and filled into hard gelatin capsules in an amount of 284 mg, corresponding to 25 mg of the active compound of general formula I. · Each 30 capsules are packed in thin containers together with a drying agent.

Example 2

Composition with a sedic salt of compound 2 shown in Table I

Uncoated granules

Sodium salt of compound 2, Table I Standing Mannitol Anhydrous lactose Hydroxypropyl cellulose Microcrystalline cellulose

II

Sodium Lauryl Sulphate Distilled Water

339 g

422 g 120 g 90 g 60 gg 650 g

The preparation is carried out according to the description of example I, except for the sodium salt of compound 2 which is added together with the other ingredients in the mixture I.

<img file="PT84786B_D0020.tif" />

<td colspan="7">Sublayer Beads</td>

<td></td><td></td><td>Uncoated granules</td><td></td><td></td><td> 500</td><td>g</td>

<td></td><td></td><td>Hydroxypropyl methylcellulose</td><td></td><td></td><td> 20</td><td>g</td>

<td>III</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Aluminum hydroxide / carbonate</td><td colspan="2">magnesium</td><td> 4</td><td>g</td>

<td></td><td></td><td>Distilled water</td><td></td><td></td><td> 400</td><td>g</td>

<td></td><td></td><td>Sub-layered Granules III</td><td></td><td></td><td> 500</td><td>g</td>

<td>IV</td><td></td><td>Hydroxypropylmethylcellulose</td><td></td><td></td><td> 20</td><td>g</td>

<td></td><td></td><td>Distilled water</td><td></td><td></td><td> 400</td><td>g</td>

<td></td><td></td><td>The two sub-layers III and</td><td>IV, are</td><td colspan="3">applied to grains</td>

<td colspan="3">uncoated voids in a</td><td>bed</td><td>fluid</td><td colspan="2">in the order of</td>

<td colspan="3">previously written.</td><td></td><td></td><td></td><td></td>

<td colspan="3">Enteric Coated Beads</td><td></td><td></td><td></td><td></td>

<td></td><td>r</td><td>Beads with subcoating</td><td></td><td></td><td> 500</td><td>g</td>

<td></td><td></td><td colspan="2">Hydroxypropyl methylcellulose</td><td></td><td> 57</td><td>g</td>

<td>v -</td><td></td><td>Cetyl alcohol</td><td></td><td></td><td> 3</td><td>g</td>

<td></td><td></td><td>Acetone</td><td></td><td></td><td> 540</td><td>g</td>

<td></td><td></td><td>Ethyl alcohol</td><td></td><td></td><td> 231</td><td>g</td>

The preparation of the enteric coated granules is as described in Example I.

Example 3

Composition with compound 6, shown in Table I.

This example provides the composition of a unit dose according to the present invention.

Core —— tablet

Compound 6, Table I Lactose

Hydroxypropylcellular se (low compression)

Hydroxypropylcellulose

Talc Mg (OH)₂Total mg

119 mg mg 1 mg 5 mg mg

160 mg

Tablets (cores) of the above composition and individual weight of 160 mg are prepared according to conventional techniques.

Separation layer (innermost)

Hydroxypropylcellulose 2 mg

Synthetic hydrotalcite 0.3 mg

AlgOy 6Mg0. C0₂.12H₂0 _/

Separation layer (more external)

Hydroxypropylcellulose 2 mg

The two layers of separation were applied to the cores by conventional coating techniques.

<img file="PT84786B_D0021.tif" />

Enteric layer

Hydroxypropylroethylcellulose phthalate 7 _mg

Cetyl alcohol 0.5 mg

The enteric coating solution is sprayed onto the cores coated with the two separating layers by standard enteric coating techniques.