DD260222A5 - A process for preparing an oral pharmaceutical preparation containing an acid labile compound - Google Patents

Abstract

The invention relates to a process for the preparation of an oral pharmaceutical preparation containing an acid-labile compound for use in human or veterinary medicine for therapeutic purposes. The method according to the invention consists in providing cores containing the acid-impermeable compound in admixture with at least one alkaline-reacting compound or an alkaline salt of the acid-impermeable compound first with one or more intermediate inert layers and then with an intestinal coating layer Preparation containing acid-resistant compound and alkaline-reacting compound, one or more inert intermediate layers, intestinal coating layer}

Description

Field of application of the invention

The pharmaceutical preparations produced by the process of the invention can be used in human and veterinary medicine for the oral administration of acid-labile substances.

Characteristic of the known technical solutions

Acid-resistant substances pose a problem for the galenic when preparing a pharmaceutical dosage form for oral use. In order to prevent the substances from coming into contact with the acidic gastric juice after oral ingestion, the usual way of solving this problem is to provide the dosage form with a bowel coating. The coating consists of a group of substances / polymers with the common feature that they are practically insoluble in acidic media while being soluble in neutral to alkaline media. For substances that are unstable in acidic media, but have better stability in neutral to alkaline media, it is often advantageous to add alkaline reacting inactive ingredients to increase the stability of the drug during manufacture and storage.

A linking group showing these stability properties consists of substituted benzimidazoles of the general formula (N)

wherein A is an optionally substituted heterocyclic group and R ¹ , R ² , R ³ and R ^{4 are the} same or different and are as defined below and R ^{5 is} H or a low molecular weight alkyl group. This linking group also includes 2 - [(2-dimethylaminobenzyl) sulfinyl] benzimidazole.

The compounds of general formula I are virtually biologically inactive as such, but are degraded or converted in acidic media to active inhibitors of certain enzyme systems.

As examples of compounds having the mentioned properties, those described in US-A-4045563, EP-BI-005129 and BE-898880 and EP-85850258.6, EP-AI-080602, EP-0127736, the EP-0134400, EP-0130729, EP-0150586, DE-3415971, GB-2082580 and SE-A-8504048-3. The last-mentioned application describes 2- (2-disubstituted aminobenzyl-sulfinylbenzimidazoles, such as 2- (2-dimethylaminobenzyl) -sulfinylbenzimidazole, also called NC-1300, and described by Prof. S. Okabe at the Symposium on Drug Activity, Am

October 17, 1985 in Nagoya, Japan, which interacts with the H ⁺ K ⁺ ATPaSe after acid degradation in the wall cells (see, for example, B. Wallmark, A. Brändström and H.Larsson "Evidence for acid-induced transformation of omeprazole into an active inhibitor of H ⁺ K ⁺ -ATPaSe within the parietal cell ", Biochemica et Biophysica Acta 778, pages 549 to 558, 1984.) Other compounds having similar properties are further described in US Patent 4,182,766 and GB-A A common feature of these compounds is that they are converted in the biologically active compounds via rapid degradation and rapid transformation in acidic media.

The stability profile of some compounds having general formula I above is shown by way of example in Table I below where the half life of the degradation / conversion reaction in solution at pH 2 and 7 is given.

Table I

Degradation / conversion of compounds of the general formula

A-CHO S -

0 π N ^ * ^ Il S - J N ¹ V ^ " H

Connection no.

R ² R ³ half-life (min) for the

Conversion of the active radical pH = 2 pH = 7

CH.

"N

5-COOCH ₃ ; 6-CH ₃ 11

150

CH

5-CH ₃ ; H 5.4

1700

122

8.8

C ₂ H ₅

1620

5-0CH ₃ ; H

3900

not determined

Substituted sulfoxides, such as the substituted benzimidazoles described in EP-BI-005129, are potent inhibitors of gastric acid secretion. The substituted benzimidazoles undergo degradation and conversion in acidic and neutral media.

It is an inherent property of these compounds to be activated in the wall cells in the acidic environment to the active residue. The activated compound interacts with the enzyme in the wall cells, mediating the production of hydrochloric acid in the gastric mucosa. All of the compounds of the class of substituted benzimidazoles containing a sulfoxide moiety which interfere with the H ⁺ K ⁺ ATPaSe in the wall cells known to date are also degraded in acidic media.

A pharmaceutical dosage form of acid labile substances which prevents the substances from coming into contact with acid gastric juice must have a bowel coating. Usually, however, intestinal coatings consist of acidic compounds. When the acid-impermeable substance is provided with such a usual intestinal coating, it decomposes rapidly by direct or indirect contact with it, with the result that the preparations discolor badly and lose their content of the active ingredient over time.

In order to improve the shelf life, the cores containing the acid-impermeable substance must also contain alkaline reacting ingredients. When such an alkaline core has a gut coating with an amount of a conventional enteric coating polymer, such as cellulose acetate phthalate, this allows dissolution of the coating and the nuclide-containing agent in the proximal part of the small intestine, and also allows some diffusion of water or gastric juice the intestinal lining into the nuclei during the time that the dosage form lingers in the stomach before it is delivered to the small intestine. The diffused water or gastric juice dissolves portions of the nucleus in the immediate vicinity of the intestinal coating layer and forms an alkaline solution within the coated dosage form. The alkaline solution affects the intestinal lining and dissolves it if necessary.

In DE-AI-3046559 a way of coating a dosage form is described. First, the dosage form is coated with a water-soluble layer containing microcrystalline cellulose and then coated with a second lining of the intestine with the aim of obtaining a dosage form which delivers the active ingredient in the colon. This preparation method does not give the desired release of the compounds of general formula I above in the small intestine. US-A-2540979 describes an intestinal-coated oral dosage form in which the intestinal lining is combined with a second and / or first coating of a water-insoluble "wax" layer, This preparation method is not applicable to cores containing a compound of the general formula I, since a direct contact between substances such as cellulose acetate phthalate (CAP) and a compound of formula I causes degradation and discoloration of the compounds of formula I.

DE-B2-2336218 describes a process for preparing a dialysis membrane which consists of a mixture of one or more conventional intestinal coating polymers and one or more insoluble cellulose derivatives. Such a membrane does not provide suitable protection of the acid-labile compounds of formula I in gastric juice. DE-AI-1204363 describes a three-layer coating process. The first layer is soluble in the gastric juice but insoluble in the intestinal juice. The second layer is water-soluble, regardless of pH, and the third layer is a bowel coating. This preparation and its preparation, which are described in DE-AI-1617615, lead to a dosage form that is not dissolved in gastric juice and dissolves only slowly in intestinal juice. Such preparations can not be used for the compounds of formula I where rapid release of the drug in the small intestine is required. DE-AI-1204363 describes a coating with three layers to achieve the release of a drug in the ileum, a goal which is outside the scope of the present invention. GB-A-1485676 describes a way to obtain a preparation which is effervescent in the small intestine. This is accomplished by providing one with a bowel coating agent containing the active ingredient and an effervescent system, such as a combination of carbonate and / or bicarbonate salt and a pharmaceutically acceptable acid. This formulation can not be applied to a pharmaceutical dosage form containing a compound of formula I since the presence of an acid in contact with a compound of formula I in the cores would result in the degradation of the compound of formula I.

WO 85/03436 describes a pharmaceutical preparation in which cores containing mixed active ingredients, for example with buffering components such as sodium dihydrogen phosphate, with the aim of maintaining a constant pH and a constant rate of diffusion, are provided with a first coating which controls the diffusion. This formulation can not be taken for acidic compounds where rapid clearance in the small intestine is desired. Direct application of a gut coating to the cores would adversely affect the shelf life of such dosage forms containing acid labile compounds.

Object of the invention

The aim of the invention is the preparation of novel storage-stable pharmaceutical preparations for oral administration.

Explanation of the essence of the invention

The object of the invention is a process for the preparation of oral pharmaceutical preparations which are storage stable, although they contain at least one acid-resistant substance. In particular, the pharmaceutical preparations produced by the process according to the invention are intended to influence gastric acid secretion and to have a cytoprotective effect in the gastrointestinal tract.

The process according to the invention comprises cores containing the acid-labile compound in admixture with at least one alkaline-reacting compound or an alkaline salt of the acid-labile compound, optionally mixed with at least one alkaline-reacting compound, with at least one inert intermediate coating layer and then with an intestinal coating layer provides. _v

According to the invention it has been found that the known acid-labile compounds of the above general formula I, wherein R ¹ , R ² , R ³ and R ^{4 are the} same or different, and

a) hydrogen,

b) halogen, such as F, Cl, Br, I,

d) -CNO,

f) -CR ¹¹ ,

h) -CH (OR ¹³ I ₂ ,

i) - (Z) _n -BD,

j) aryl of up to 10 carbon atoms,

k) aryloxy of up to 10 carbon atoms, optionally substituted by alkyl of 1 to 6 carbon atoms,

I) alkylthio having 1 to 6 carbon atoms,

n) alkylsulfinyl having 1 to 6 carbon atoms, ο) or in which adjacent groups R ¹ , R ² , R ³ and R ⁴ together with the adjacent carbon atoms in the benzimidazole ring form a 5-, 6- or 7-membered monocyclic ring or a 9-, 10 or 11-membered bicyclic ring, which rings may be saturated or unsaturated and Obis may contain 3 heteroatoms N and / or O and wherein the rings optionally with 1 to 4 substituents from the group of alkyl groups having 1 to 3 carbon atoms, alkylene groups with 4 or 5 carbon atoms to form spiro compounds may be substituted, or two or four of these substituents together may form one or two oxo groups 0, where, if R ¹ and R ^2, R ² and R ³ or R ³ and R ⁴ adjacent zusammenmitden

Carbon atoms in the benzimidazole ring form two rings, they may be fused together, where in the formulas R ¹¹ and R ¹² , which are the same or different,

a) aryl of up to 10 carbon atoms,

b) alkoxy of 1 to 4 carbon atoms,

c) alkoxyalkoxymiti up to 3 carbon atoms in each alkoxy part,

d) arylalkoxymiti bis2carbon atoms in the alkoxy moiety and up to 10 carbon atoms in the aryl moiety /

e) aryloxymitbis to ^ carbon atoms,

f) dialkyamino having 1 to 3 carbon atoms in the alkyl parts or

g) pyrrolidino or piperidino, optionally substituted by alkyl of 1 to 3 carbon atoms, R ^{13 is} a) alkyl of 1 to 4 carbon atoms or

b) alkylene having 2 to 3 carbon atoms,

Is -0- or -C-,

η 0 or list,

B a) alkyls having 1 to 6 carbon atoms,

b) cycloalkylene having 3 to 6 carbon atoms,

c) alkylene having up to 6 carbon atoms,

d) cycloalkylene having 3 to 6 carbon atoms or

e) alkynylene having 2 to 6 carbon atoms, D a) H,

b) -CN

"9

-C-R

d) 0 means "

:-( Y) _m - (C) _r -R

in which

R ⁹ a) alkoxy having 1 to 5 carbon atoms or

b) dialkylamino having 1 to 3 carbon atoms in the alkyl moieties, m is 0 or 1, r is 0 or 1, Y a) -O-

b) -NH-

c) -NR ¹⁰ -is, R ¹⁰ is a) H,

b) alkyl of 1 to 3 carbon atoms,

c) Arylalkylmiti to 2 carbon atoms in the alkyl moiety and up to 10 carbon atoms in the aryl moiety or

d) aryl is up to 10 carbon atoms, R ^{5 is} H, CH ₃ or C ₂ H ₅ ,

A is in particular a pyridyl group

N means in which R ⁶ and R ^{8 are the} same or different and

a) H or

b) alkyl having 1 to 6 carbon atoms and R ⁷ a) H,

b) alkyl of 1 to 8 carbon atoms,

c) alkoxy having 1 to 8 carbon atoms,

d) alkenyloxy of 2 to 5 carbon atoms,

e) alkynyloxymit2 to 5 carbon atoms,

f) alkoxyalkoxy having 1 to 2 carbon atoms in each alkoxy group,

g) aryl with up to 10 carbon atoms,

h) arylalkylmethyl of up to 6 carbon atoms in the alkyl moiety and up to 10 carbon atoms in the aryl moiety,

i) aryloxy of up to 10 carbon atoms, optionally substituted by alkyl of 1 to 6 carbon atoms,

j) arylalkoxymiti up to 6 carbon atoms in the alkoxy part and up to 10 carbon atoms in the aryl part,

k) dialkylaminoalkoxy having 1 to 2 carbon atoms in the alkyl substituents on the amino nitrogen and 1 to 4 carbon atoms in the alkoxy group,

I) oxacycloalkyl having one oxygen atom and 3 to 7 carbon atoms, m) oxacycloalkoxy having 2 oxygen atoms and 4 to 7 carbon atoms, n) oxacycloalkylalkyl having 1 oxygen atom and 4 to 7 carbon atoms, o) oxacycloalkyialkoxy having 2 oxygen atoms and 4 to 6 carbon atoms or p) R ⁶ and R ⁷ or R ⁷ and R ⁸ together with the adjacent carbon atoms in the pyridine ring represent a ring, wherein the part formed by R ⁶ and R ⁷ or R ⁷ and R ⁸

-CH = CH-CH = CH- O- (CH ₂ ) p -S - (CH ₂ ) _V - CH ₂ (CH ₂ ) p - O - CH = - CH - NH - CH = CH - -N-CH = CH-CH ₃

in which ρ is 2,3 or 4, ν is 2 or 3 and the O and N atoms are always attached at the 4-position to the pyridine ring, with no more than one of R ⁶ , R ⁷ and R ^{8 is} hydrogen, can be processed into a dosed form of dosage.

The object of the present invention is thus an intestinal-coated dosage form of acid-labile compounds having the general formula I as defined above except for the compound omeprazole, 5-methoxy-2 - [- -methoxy-SB-dimethyl-pyridinyl -methyll-sulfinyll-IH-benzimidazole. Another compound which can be provided with an intestinal lining according to the invention is 2 - [{2-dimethylaminobenzyl) sulfinyl] benzimidazole. The new compounds are resistant to dissolution in acid media, but dissolve rapidly in neutral to alkaline media and have good durability during long-term storage. The new dosage form is labeled as follows. Cores containing the acid labile compound in admixture with alkaline compounds or an alkaline salt of the acid labile compound, optionally in admixture with an alkaline compound, are coated with two or more layers, the first layer (s) being soluble in water or rapidly melting / melting in water and consisting of non-acidic, otherwise inert pharmaceutically acceptable substances. This first layer / layers separates / separates the alkaline core material from the outer layer, which is a bowel coating. The finished, bowel-coated dosage form is treated in a suitable manner to reduce the water content to a very low level in order to obtain good consistency of the dosage form during Larig time storage. As examples of compounds which are particularly suitable for the pharmaceutical dosage form according to the invention.

The half-life for the decomposition of compounds 1 to 6 in Table I in aqueous solution at pH values less than 4 is shorter than 10 minutes in most cases. Even at neutral pH values, the degradation reaction proceeds rapidly, z. For example, the half-life for decomposition at pH = 7 is between 10 minutes and 65 hours, while at higher pHs the stability in solution is much better for most compounds. The stability profile is similar in solid phase. The degradation is catalyzed by acidic substances. The acid-resistant compounds are stabilized in mixtures with alkaline substances. It can be seen from the above discussion of the stability properties of the acid labile compounds that an oral dosage form of these compounds must be protected from contact with the acidic gastric juice to reach the small intestine without degradation.

The acid-resistant active ingredient is blended with inert, preferably water-soluble, conventional pharmaceutical ingredients to obtain the preferred concentration of the active ingredient in the final mixture, and further mixed with an alkaline-reacting, otherwise inert, pharmaceutically-acceptable substance (s) around each particle of the active ingredient produces a "micro-pH" of not less than pH = 7, preferably not less than pH = 8, when water is adsorbed by the particles in the mixture or when small amounts of water are added to the mixture Such substances may be included among such as the sodium, potassium, calcium, magnesium and aluminum salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids, substances normally used in antacid preparations, such as aluminum , Calcium and magnesium hydroxides, magnesium oxide or composite substances, such as Al2O3 · 6MgO CO ₂ · 12H ₂ O, (Mg ₆ Al ₂ (OH) ₁₆ CO ₃ AH ₂ O), MgO · Al ₂ O ₃ · 2SiO ₂ · nH ₂ 0 wherein η is not an integer and less than 2, or similar compounds, organic pH buffering substances such as trishydroxymethylaminomethane or other similar pharmaceutically acceptable pH buffering substances are selected, but are not limited thereto. The stabilizing high pH in the powder mix may also be achieved by using an alkaline salt of the active ingredient, such as the sodium, potassium, magnesium, calcium and similar salts of acid labile compounds, either alone or in combination with a conventional buffering agent, as described above , be achieved. The powder mixture is then processed into small spheres, ie pellets, or tablets according to conventional pharmaceutical procedures. The pellets, tablets or gelatin capsules are used as cores for further processing.

Interface

The alkaline reacting cores containing an acid labile compound must be separated from the intestinal coating polymer (s) containing free carboxy groups which would otherwise cause degradation / discoloration of the acid labile compound during the coating process or during storage. The intermediate coating layer (separating layer) also serves as a pH-buffering zone in which hydrogen ions diffusing from outside to the alkaline core can react with hydroxyl ions which diffuse from the alkaline core to the surface of the coated particles. The pH-buffering properties of the release layer can be further enhanced by introducing into the layer selected substances selected from a linking group commonly used in antacid formulations, such as magnesium oxide, hydroxide or carbonate. Aluminum or calcium hydroxide, carbonate or silicate, compound aluminum / magnesium compounds such as Al ₂ O ₃ - 6 MgOCO ₂ - 12H ₂ O ₁ (Mg ₆ Al ₂ (OH) ₁₆ CO ₃ -4H ₂ O), MgO -Al ₂ O ₃ - 2SiO ₂ - nH ₂ O, where η is not an integer and less than 2, or similar compounds or other pharmaceutically acceptable pH buffering substances, such as the sodium, potassium, calcium, magnesium and aluminum salts of phosphoric acid, citric acid or other suitable weak inorganic or organic acids.

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

The release layer (s) may be applied to the cores - pellets or tablets - by conventional coating techniques in a suitable coater or fluidized bed apparatus using water and / or conventional organic solvents for the coating solution. The material for the release layer will be selected from the pharmaceutically acceptable, water-soluble inert compounds or polymers used for film-like coatings, such as sugar, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropylmethyl cellulose or the like. The thickness of the separating layer is not less than 2 μm, for small spherical pellets preferably not less than 4 μm, for tablets preferably not less than 10 μm.

In the case of tablets, another method of applying the coating according to the dry coating technique may be used. First, a tablet containing the acid labile compound is compressed as described above. To this tablet, another layer is pressed using a suitable tableting machine. The outer release layer consists of pharmaceutically acceptable, water-soluble or rapidly disintegrating in water tablet carriers. The separation layer has a thickness of not less than 1 mm. Ordinary plasticizers, pigments, titanium dioxide, talc and other additives can also be incorporated into the release layer. In the case of gelatin capsules, the gelatin capsule itself serves as a separating layer.

Enteric coating layer

The enteric coating layer is applied to the intercoated cores by conventional coating techniques, such as by particle coating or fluidized bed coating, using solutions of polymers in water and / or suitable organic solvents, or using latex suspensions of these polymers. For example, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, copolymerized methacrylic acid / methyl methacrylate, such as compounds known under the trade designation Eudragit® L 12.5 or Eudragit® L100 (Röhm Pharma), or similar compounds used to obtain intestinal coatings may be used as the enteric coating polymers can be used

 The intestinal cover may also be applied using water-based polymer dispersions, such as

for example from Aquateric (FMC Corporation), Eudragit® L100-55 (Röhm Pharma) or Coating CE 5142 (BASF). The enteric coating layer may optionally contain a pharmaceutically acceptable plasticizer such as cetanol, triacetin, citric acid esters such as those known by the trade name Citroflex® (Pfizer), phthalic acid esters, dibutylsuccinate or similar plasticizers.

The amount of plasticizer is usually optimized for each enteric polymer and is usually in the range of 1 to 20% of the enteric polymers. Dispersants such as talc, dyes, and pigments can also be incorporated into the bowel coating layer.

Thus, the specific preparation according to the invention consists of cores containing the acid-labile compound in admixture with an alkaline-reacting compound, or cores containing an alkaline salt of the acid-labile compound, optionally in admixture with an alkaline-reacting compound. The cores suspended in water form a solution or suspension having a pH higher than that of a solution in which the polymer used for the intestinal coating is just soluble. The cores are provided with a water-soluble or water-fast decomposing coating, optionally containing a pH-buffering substance, and this coating separates the alkaline cores from the intestinal cover. Without this release layer, gastric juice resistance would be too short and the shelf life of the dosage form would be unacceptably short. Finally, the intermediate coated dosage form is provided with a bowel coating which renders the dosage form insoluble in acidic media in neutral to alkaline media, such as those in the proximal part of the small intestine, the site where dissolution is desired but rapidly disintegrates or dissolves.

Finished dosage form

The finished dosage form is either a bowel-coated tablet or capsule or, in the case of intestinal-coated pellets, consists of pellets in hard gelatin capsules or sachets or pellets processed into tablets. For long-term stability during storage, it is essential that the water content of the finished dosage form containing the acid-resistant compound (coated tablets, capsules or pellets) be kept low, preferably at most 1.5% by weight.

method

After the cores have been produced, they are first provided with the separating layer and then with the intestinal coating layer. The coating takes place in the manner described above.

The preparation according to the invention is particularly advantageous for the reduction of gastric juice secretion and / or for the production of cell protective effect in the gastrointestinal tract. It is usually given once or several times a day. The typical daily dose of the drug will vary and depend on various factors, such as the individual requirements of the patient, the mode of administration and the disease. In general, the dose is in the range of 1 to 400 mg per day of active ingredient. A method for treating such conditions using the new oral dosage form is another aspect of the invention.

embodiment

Examples 1 to 3 illustrate the invention.

Example 1 Uncoated pellets

Lactose

I lactose, anhydrous hydroxypropyl cellulose

Compound 1, Table I Sodium Lauryl Sulfate

II disodium hydrogen phosphate sodium dihydrogen phosphate distilled water

The dry ingredients (I) were premixed in a mixer. Addition of a granulating liquid (II) containing the suspended active ingredient was carried out, and the mass was wet-blended to a suitable consistency. The wet mass was pressed through an extruder and pelletized. The pellets were dried and classified to suitable particle size ranges.

Intermediate coated pellets

Uncoated pellets 500 g

Hydroxypropylmethyl cellulose 20 g

distilled water 400 g

The polymer solution (III) was sprayed onto the uncoated pellets in a fluid bed apparatus. The spray guns were located above the fluidized bed.

253 G ig 167 G 9 25 9 50 9 5 9 1.5g 0 / 125

Encased pellets

Intermediate coated pellets 500 g

Hydroxypropylmethylcellulose phthalate 57 g

Cetyl alcohol 3 g

Acetone 540 g

Ethanol 231 g

The polymer solution (IV) was sprayed onto the intermediate coated pellets in a fluidized bed apparatus with spray guns above the layer. After drying to a water content of 0.5%, the intestinal-coated pellets were classified and filled into hard gelatin capsules in an amount of 284 mg corresponding to 25 mg of Active Compound I. 30 capsules were packaged together with a desiccant in tight containers.

Example 2

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

Uncoated pellets

Compound 2, Table I, sodium salt 339 g

Mannitol powder 2422 g

I lactose, anhydrous 120 g

Hydroxypropyl cellulose 90 g

Microcrystalline cellulose 60 g

Sodium lauryl sulfate 7 g

distilled water 650 g

The preparation was prepared as described in Example 1, except that the sodium salt of the compound was added together with the other ingredients in mixture I.

Intermediate coated pellets

Uncoated pellets 500 g

Hydroxypropylmethyl cellulose 20 g

In aluminum hydroxide / magnesium carbonate 4g

distilled water 400 g

With IM intercoated pellets 500 g

Hydroxypropylmethyl cellulose 20 g

distilled water 400 g

The two intermediate layers III and IV were applied to the uncoated pellets in a fluidized bed apparatus in succession as described above.

Encased pellets

Intermediate coated pellets 500 g

Hydroxypropylmethylcellulose phthalate 57 g

Cetyl alcohol 3 g

Acetone 540 g

Ethanol 231 g

The preparation of intestinal-coated pellets was carried out as described in Example 1.

Example 3

Formulation with Compound 6 according to Table I. This example gives the composition of a dosage unit according to the invention.

tablet core

Compound 6, Table I Lactose Hydroxypropylcellulose (low substitution) Hydroxypropylcellulose Talc Mg (OH) ₂ Sum

Tablet cores having the above composition and each weighing 160 mg were first prepared by known techniques. -

Separating layer (inner)

Hydroxypropylcellulose 2 mg

Synthetic hydrotalcite 0.3 mg [Al ₂ O ₃ -6MgO-CO ₂ -12H ₂ ]

Separating layer (outer)

Hydroxypropylcellulose 2 mg

The two release layers were applied to the cores according to the known coating methods.

Enteric coating layer

Hydroxypropyl methyl cellulose phthalate 7 mg

Ceryl alcohol 0.5 mg

The intestinal coating solution was sprayed onto the cores coated with the two release layers by known intestinal coating techniques.

Claims (12)

A process for the preparation of an oral pharmaceutical preparation containing as an active ingredient an acid-labile compound, characterized in that cores containing the acid-labile compound in admixture with at least one alkaline-reacting compound or an alkaline salt of the acid-labile compound, optionally in admixture with at least an alkaline-reacting compound, provided with at least one inert intermediate coating layer and thereafter provided with an intestinal coating layer. 2. The method according to claim 1, characterized in that for the intermediate coating layers, tablet carriers which are soluble in water or decompose rapidly, or polymeric water-soluble film-forming compounds, optionally containing at least one pH-buffering alkaline compound used. 3. The method according to claim 1 or 2, characterized in that the acid-resistant compound is one of the general formula I. where A is an optionally substituted heterocyclic group, R ¹ , R ₂ , R ³ and R ^{4 are} identical or different and are preferably hydrogen, low molecular weight alkyl, low molecular weight alkoxy, -CF ₃ ,
O -OC- is lower alkyl or halogen and R ^{5 is} H or a low molecular weight alkyl group, in which "low molecular weight" denotes 1 to 6 carbon atoms, with the exception of the compound omeprazole, 5-methoxy-2 - [[(4-methoxy-3,5-) dimethyl-2-pyridinyl) -methyl] -sulfinyl] -1H-benzimidazole, or by using as the acid-labile compound 2 - [(2-dimethylaminobenzyl) -sulfinyl] -benzimidazole. 4. Process according to one of Claims 1 to 3, characterized in that magnesium oxide, magnesium hydroxide and / or a composite substance [Al ₂ O ₃ .6MgO. CO ₂ .12H ₂ O or MgO. Al ₂ O ₃ for the intermediate coating layer 2SiO ₂ .nH ₂ 0], wherein η is not an integer and less than 2 is used. 5. The method according to any one of claims 1 to 4, characterized in that the intermediate coating layer has two or more sub-layers. 6. The method according to any one of claims 1 to 5, characterized in that one uses for the intermediate coating layers hydroxypropylmethylcellulose, hydroxypropylcellulose or polyvinylpyrrolidone. Process according to any one of Claims 1 to 6, characterized in that alkaline cores containing the acid-labile compound and at least one pH-buffering alkaline compound giving a pH of 7 to 12 to the microenvironment of the acid-labile compound are used , 8. The method according to claim 7, characterized in that as the alkaline compound magnesium oxide, hydroxide or carbonate, aluminum hydroxide, aluminum, calcium, sodium or potassium carbonate, phosphate or citrate and / or the composite aluminum / magnesium compounds AI ₂ O ₃ .6MgO. CO ₂ .12H ₂ O or MgO. Al ₂ O ₃ .2SiO ₂ .nH ₂ O, wherein η is not an integer and less than 2. Process according to any one of Claims 1 to 8, characterized in that alkaline cores containing an alkaline salt of the acid-labile compound, such as the sodium, potassium, magnesium, calcium or ammonium salt, are used. 10. The method according to claim 8, characterized in that one uses alkaline cores containing an alkaline salt of acid-resistant compound in admixture with an inert alkaline compound. 11. The method according to any one of claims 1 to 10, characterized in that hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, copolymerized methacrylic acid / methyl methacrylate or polyvinyl acetate phthalate, optionally with a content of plasticizer used for the intestinal lining. 12. The method according to any one of claims 1 to 11, characterized in that one adjusts the water content of the finished dosage form containing the acid-resistant compound to at most 1.5 wt .-%.