COMPRESSED ORAL PHARMACEUTICAL DOSAGE FORM, WITH AN ENTERIC COATING, WHICH CONTAINS AN ACID-LABILE BENZIMIDAZOLE COMPOUND

Description

FIELD OF THE INVENTION

[0001] The invention relates to new tableted pharmaceutical dosage forms, covered with an enteric coating, consisting of a plurality of units containing a benzimidazole compound labile in an acid medium, suitable for oral administration. The invention also relates to the process for preparing said pharmaceutical dosage forms and to their use in human and animal health care.

BACKGROUND OF THE INVENTION

[0002] Omeprazole, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole, is a benzimidazole compound that can inhibit gastric secretion in mammals, so that it is useful for preventing and treating disorders related to secretion of gastric acid, such as gastric ulcers, duodenal ulcers, reflux oesophagitis, Zolliger-Ellison syndrome, etc. Other benzimidazole compounds with antiulcerous activity are pantoprazole, lansoprazole and rabeprazole.

[0003] Omeprazole, as other benzimidazole compounds of therapeutic interest, is labile in an acid medium, which creates a great number of problems when developing a pharmaceutical form meant for oral administration as said compound breaks down upon contact with the stomach contents, a strongly acidic medium. Its labile nature may be responsible for the variability in the intra- and inter-individual therapeutic response of omeprazole.

[0004] To prevent contact between compounds labile in an acid medium and gastric juice after oral administration of said compounds, solid pharmaceutical forms have been developed that comprise a core containing the compound labile in an acid medium and an outer layer that provides a gastro-resistant coating, which can be separated by one or more intermediate layers. In certain cases it is not possible to use conventional enteric coatings of acidic nature as the active compound would break down upon direct or indirect contact with said coating, as made manifest by a change in color and a degradation of the active compound over time.

[0005] There exist several ways of solving the problem of stability of the active compound. One of them consists of creating an alkaline environment around the benzimidazole compound labile in an acid medium, which is achieved by using alkaline salts of the benzimidazole compound and/or by incorporating an alkaline reacting compound in the gastro-resistant pharmaceutical preparation [see, for example, European Patent Application EP 0 244 380 and American Patent US 4,786,505]. Another way of solving the problem of stability of the active compound is the creation of a physical barrier that manages to separate completely the active compound and the enteric layer, thereby preventing any degradation of the active compound, and involves the use of pharmaceutically acceptable excipients with the exception of those giving an alkaline reaction [see, for example, European Patent EP 0 773 025].

[0006] Patent application WO 96/01623 describes a multiple unit tableted dosage form containing omeprazole or an alkaline salt thereof, consisting of units arranged in layers containing the active compound and individually coated with an enteric coating. Such units arranged as enteric coated layers are mixed with excipients for tablets and are tableted together.

SUMMARY OF THE INVENTION

[0007] The invention addresses the problem of developing new pharmaceutical dosage forms, enteric coated, for oral administration, meant to increase the number of available means for the effective administration of benzimidazole compounds labile in an acid medium.

[0008] The solution provided by this invention is based on the inventors' observation that tableted oral pharmaceutical dosage forms covered with an enteric coating and consisting of multiple units containing a benzimidazole compound labile in an acid medium are stable and useful for effective administration of benzimidazole compounds labile in an acid medium.

DETAILED DESCRIPTION OF THE INVENTION

[0009] The invention provides a tableted oral pharmaceutical dosage form, covered with an enteric coating, consisting of a plurality of units containing a benzimidazole compound labile in an acid medium as the active principle, hereinafter referred to as the dosage form of the invention, that comprises:

(a) A plurality of units containing a benzimidazole compound labile in an acid medium as the active principle that comprise:

i) an inert core;

ii) an active layer deposited on said inert core i), formed by a benzimidazole compound labile in an acid medium, a non-alkaline water-soluble inert polymer and one or more pharmaceutically acceptable inert excipients; and

iii) an intermediate layer comprising an inert non-alkaline coating formed by a non-alkaline, water-soluble inert polymer and one or more pharmaceutically acceptable inert excipients, with said intermediate layer being disposed over the aforementioned active layer ii) that covers the inert core i);

(b) one or more pharmaceutically acceptable inert excipients, of which one or more are compression excipients; and

(c) an enteric coating layer that coats said plurality of units containing a benzimidazole compound labile in an acid medium as the active principle and said pharmaceutically acceptable inert excipients (b).

[0010] In the sense used in this specification, the term "benzimidazole compound labile in an acid medium" includes benzimidazole compounds of therapeutic interest with a half-life under 10 minutes in an aqueous solution of pH less than 4, and/or a half-life between 10 minutes and 65 hours in an aqueous solution with a pH of 7, such as for example omeprazole, lansoprazole, pantoprazole and rabeprazole or their corresponding enantiomers.

[0011] In a specific embodiment, said benzimidazole compound labile in an acid medium is a compound of 2-[(2-pyridyl)methylsulfinyl]benzimidazole with the formula (I) or its enantiomers

wherein
R¹ is hydrogen, methoxy or difluoromethoxy,
R² is methyl or methoxy,
R³ is methoxy, 2,2,2-trifluoroethoxy or 3-methoxypropoxy, and
R⁴ is hydrogen or methyl.

[0012] The inert core (i) is a pharmaceutically inert substance in relation to the active principle. That is, it does not react with the active principle under the conditions used to cause its decomposition, and may consist of a sugar, such as saccharose, starch and the mixtures thereof. In a specific embodiment, said inert cores consist of a mixture of saccharose and corn starch, and have an average grain size of between 0.25 and 1.4 mm and meet the requirements of the USP (United States Pharmacopoeia) [Monograph on Sugar Spheres, USP NF 18]. In a specific embodiment, the inert cores (i) are present in the unit constituting the dosage form of the invention in an amount between 5% and 35% by weight with respect to the total weight of the unit.

[0013] The active layer (ii) comprises a benzimidazole compound labile in an acid medium, preferably a compound of formula (r), for example, omeprazole or one of its individual R or S enantiomers, a non-alkaline, water-soluble inert polymer such as hydroxypropylmethyl cellulose (HPMC) or hydroxypropyl cellulose (HPC). In the sense used in this specification the term "inert" applied to a polymer or excipient indicates that said compound does not react under the conditions used. In a particular embodiment, the active layer (ii) is present in the unit constituting the dosage form of the invention in an amount between 1.6% and 35% by weight with respect to the total weight of the unit.

[0014] The intermediate layer (iii) comprises an inert non-alkaline coating consisting of an inert, non-alkaline water-soluble polymer such as HPMC or HPC, and one or more pharmaceutically acceptable inert excipients, such as a pigment, for example titanium dioxide. In a specific embodiment, the intermediate layer (iii) is present in the unit constituting the dosage form of the invention in an amount between 0.5% and 15% by weight with respect to the total weight of the unit.

[0015] The dosage form of the invention additionally comprises one or more pharmaceutically acceptable inert excipients of which one or more are compression excipients, such as diluents, for example microcrystalline cellulose, disintegrants, for example, crospovidone, and lubricants, for example, magnesium stearate. In a specific embodiment, said compression excipients are present in the dosage form of the invention in an amount between 40% and 80% by weight with respect to the total weight of the dosage form.

[0016] The outer layer of the dosage form of the invention comprises an enteric coating that comprises a gastro-resistant polymer, such as a methacrylic copolymer, for example a copolymer formed by methacrylic acid and esters of methacrylic acid, a plasticiser such as triethyl acetate or the like, and one or more pharmaceutically acceptable inert excipients, such as talc. In a specific embodiment, said outer enteric coating is present in the dosage form of the invention in an amount between 4% and 30% by weight with respect to the total weight of the dosage form. The outer layer of the dosage form of the invention can contain, in addition, a colored coating comprising a mixture of colorants and opacifiers together with other pharmaceutically acceptable excipients, such as a mixture of polydextrose, HPMC, titanium dioxide, PEG 400 and colorants. The colored coating layer can be mixed with the outer enteric coating layer to define a single outer layer. In a specific embodiment, said colored layer is present in the dosage form of the invention in an amount between 1.5% and 15% by weight with respect to the total weight of the dosage form.

[0017] The units containing a benzimidazole compound labile in an acid medium as the active principle can be obtained by conventional techniques. A review of the various techniques for preparing said units with therapeutic applications can be found in the book Pharmaceutical Pelletization Technology, published by Isaac Ghebre-Sellassie, Marcel Dekker, Inc., 1989. In a specific embodiment, said units are obtained applying the various layers with conventional fluidised bed coating techniques, using aqueous solutions or suspensions of the components of said layers. In short, in a fluidised bed apparatus the inert cores are covered with a first layer containing the benzimidazole compound labile in an acid medium and a non-alkaline, water-soluble inert polymer, such as HPMC or HPC. Afterwards said active layer is covered with an intermediate layer containing a non-alkaline inert coating formed by a non-alkaline, water-soluble inert polymer, such as HPMC or HPC, and one or more pharmaceutically acceptable inert excipients, for example a pigment such as titanium dioxide.

[0018] The dosage form of the invention can be obtained by conventional techniques by a process that involves mixing a plurality of units containing a benzimidazole compound labile in an acid medium as an active principle with one or more compression excipients, and compressing the resulting mixture. Compression can be effected by dry or wet methods. A review of the various methods for preparing tablets is mentioned, for example, in the Tratado de Farmacia Galénica (Treatise of Gallenic Pharmacy), C. Faulí i Trillo, Luzán 5, S.A. de Ediciones (1993), Chapter 36, pages 521-541.

[0019] The active principles can be administered in the same doses and with the same protocols as those of the commercially available pharmaceutical forms. In general, the dose of active principle is between approximately 5 mg/day and 100 mg/day, adjusted to the individual needs of the patient and according to the specialist's considerations.

[0020] The dosage form of the invention is resistant to solution in an acid medium, stable when passing through the gastric juice and allows liberating the active principle in an alkaline or neutral aqueous medium, the characteristic conditions of the proximal area of the small intestine.

[0021] The invention also provides the use of the pharmaceutical dosage form of the invention for the manufacture of a medicament for preventing and treating disorders related to an abnormal secretion of gastric acid.

[0022] The following example is shown by way of illustration of the invention, and should not be understood as limiting its scope.

EXAMPLE

Enteric tablets comprising multiple units containing omeprazole

[0023] A suspension of the active principle is prepared dispersing 1,250 g of the active principle [omeprazole or lansoprazole] and 478.73 g of HPMC in 4,033 g of purified (deionised) water.

[0024] In a fluidised bed apparatus are introduced 2,791.69 g of inert cores, spherical, of uniform size 0.25-0.355 mm of saccharose, over which the suspension obtained previously is sprayed.

[0025] In 2,855.5 g of purified water are dispersed 427.26 g of HPMC and 56.83 g of titanium dioxide and the resulting aqueous suspension is sprayed over the spheres obtained previously. After spraying and before applying the next layer the spheres thus obtained are dried.

[0026] Then 1,988 g of said spheres are mixed with 4,783.7 g of microcrystalline cellulose, 403.4 g of crospovidone and 24.8 g of magnesium stearate and compressed.

[0027] In 331.04 g of purified water are dispersed 33.104 g of a mixture of polydextrose, HPMC, titanium dioxide, PEG 400 and colorants E110/E124/E132 and the resulting suspension is sprayed over 800 g of the previously obtained tablets. After spraying and before applying the next layer the spheres thus obtained are dried.

[0028] In 170.67 g of purified water are dispersed 176.28 g of methacrylic acid - ethyl acrylate copolymer of USP/Ph.Eur. grade, 7.4 g of triethyl citrate and 5.31 g of talc, and the resulting aqueous suspension is sprayed over the tablets coated with the colored layer previously obtained. After spraying and applying this enteric coating layer the resulting tablets, with an enteric coating layer, are dried.

Claims

1. A tableted oral pharmaceutical dosage form, covered with an enteric coating, consisting of a plurality of units containing a benzimidazole compound labile in an acid medium as the active principle, that comprises:

(a) A plurality of units containing a benzimidazole compound labile in an acid medium as the active principle that comprise:

i) an inert core;

ii) an active layer deposited on said inert core i), formed by a benzimidazole compound labile in an acid medium, a non-alkaline water-soluble inert polymer and one or more pharmaceutically acceptable inert excipients; and

iii) an intermediate layer comprising an inert non-alkaline coating formed by a non-alkaline, water-soluble inert polymer and one or more pharmaceutically acceptable inert excipients, with said intermediate layer being disposed over the aforementioned active layer ii) that covers the inert core i);

(b) one or more pharmaceutically acceptable inert excipients, of which one or more are compression excipients; and

(c) an enteric coating layer that coats said plurality of units containing a benzimidazole compound labile in an acid medium as the active principle and said pharmaceutically acceptable inert excipients (b).

2. Tableted oral pharmaceutical dosage form according to claim 1, wherein said benzimidazole compound labile in an acid medium is a compound of 2-[(2-pyridyl)methylsulfinyl]benzimidazole of formula (I) or its enantiomers

wherein
R¹ is hydrogen, methoxy or difluoromethoxy,
R² is methyl or methoxy,
R³ is methoxy, 2,2,2-trifluoroethoxy or 3-methoxypropoxy, and
R⁴ is hydrogen or methyl.

3. Tableted oral pharmaceutical dosage form according to claim 1, wherein said benzimidazole compound labile in an acid medium is selected from the group consisting of omeprazole, lansoprazole, rabeprazole and pantoprazole or their corresponding enantiomers.

4. Tableted oral pharmaceutical dosage form according to any of claims 1 a 3, wherein said non-alkaline, water-soluble inert polymer present in the active layer ii) is selected from among hydroxypropylmethyl cellulose (HPMC) and hydroxypropyl cellulose (HPC).

5. Tableted oral pharmaceutical dosage form according to any of claims 1 a 3, wherein said non-alkaline, water-soluble inert polymer present in the intermediate layer iii) is hydroxypropylmethyl cellulose (HPMC).

6. Tableted oral pharmaceutical dosage form according to claim 1, wherein said compression excipients are selected from among the group formed by diluents, disintegrants, lubricants and their mixtures.

7. Tableted oral pharmaceutical dosage form according to claim 1, wherein said enteric coating layer (c) that covers the aforementioned plurality of units containing a benzimidazole compound labile in an acid medium as the active principle and said pharmaceutically acceptable excipients (b), comprises a gastro-resistant polymer, a plasticiser and one or more pharmaceutically acceptable inert excipients.

8. A process for preparing a tableted oral pharmaceutical dosage form, covered with an enteric coating, consisting of multiple units containing a benzimidazole compound labile in an acid medium as the active principle, according to any of claims 1 a 7, involving:

applying on an inert core an aqueous suspension of a benzimidazole compound labile in an acid medium, a

non-alkaline, water-soluble inert polymer, and one or more pharmaceutically acceptable inert excipients to obtain an active layer that coats the inert core,

applying on said active layer an intermediate layer containing a non-alkaline inert coating consisting of a non-alkaline, water-soluble inert polymer and one or more pharmaceutically acceptable inert excipients to obtain a unit containing a benzimidazole compound labile in an acid medium as the active principle;

mixing a plurality of said units containing a benzimidazole compound labile in an acid medium as the active principle with one or more pharmaceutically acceptable inert excipients, of which one or more are compression excipients, and compressing said mixture to obtain a tablet; and

covering said tablet with an aqueous suspension comprising a gastro-resistant polymer, a plasticiser and one or more pharmaceutically acceptable inert excipients to form an outer enteric coating layer.

9. Use of the pharmaceutical dosage form according to any of claims 1 a 8, for the manufacturing of a medicament.

Ansprüche

1. Tablettierte, oral, pharmazeutische Dosierungsform, beschichtet mit einer enterischen Beschichtung, bestehend aus einer Vielzahl von Einheiten, enthaltend eine Benzimidazolverbindung, die in einem sauren Medium labil ist, als Wirkstoff, folgendes umfassend:

(a) eine Vielzahl von Einheiten, enthaltend eine Benzimidazolverbindung, die in einem sauren Medium labil ist, als Wirkstoff, folgendes umfassend:

(i) einen inerten Kern;

(ii) eine aktive Schicht, abgemagert auf dem inerten Kern (i), gebildet durch eine Benzimidazolverbindung, die in einem sauren Medium labil ist, ein nicht-alkalisches, wasserlösliches, inertes Polymer und ein oder mehrere pharmazeutisch annehmbare inerte Exzipienten; und

(iii) eine Zwischenschicht, umfassend eine inerte nicht-alkalische Beschichtung, gebildet durch ein nicht-alkalisches, wasserlösliches, inertes Polymer und ein oder mehrere pharmazeutisch annehmbare, inerte Exzipientien, wobei die Zwischenschicht über der vorher genannten aktiven Schicht (ii), die den inerten Kern (i) bedeckt, angeordnet ist;

(b) ein oder mehrere pharmazeutisch annehmbare, inerte Exzipientien, wobei ein oder mehrere Kompressionsexzipientien sind; und

(c) eine enterische Beschichtung, die die Vielzahl von Einheiten, enthaltend eine Benzimidazolverbindung, die in einem sauren Medium labil ist, als Wirkstoff, und die pharmazeutisch annehmbare inerte Exzipientien (b) bedeckt.

2. Tablettierte, orale, pharmazeutische Dosierungsform gemäss Anspruch 1, wobei die Benzimidazolverbindung, die in einem sauren Medium labil ist, eine Verbindung von 2-[(2-Pyridyl)methylsulfinyl]benzimidazol der Formel (I) oder der Enantiomere davon ist:

- worin

R¹ Wasserstoff, Methoxy oder Difluormethoxy ist,

R² Methyl oder Methoxy ist,

R³ Methoxy, 2,2,2-Trifluorethoxy oder 3-Methoxypropoxy ist, und

R⁴ Wasserstoff oder Methyl ist.

3. Tablettierte, orale, pharmazeutische Dosierungsform gemäss Anspruch 1, wobei die Benzimidazolverbindung, die in einem sauren Medium labil ist, gewählt ist aus der Gruppe, bestehend aus Omeprazol, Lansoprazol, Rabeprazol und Pantoprazol oder ihren korrespondierenden Enantiomeren.

4. Tablettierte, orale, pharmazeutische Dosierungsform gemäss einem der Ansprüche 1 bis 3, wobei das nicht-alkalische, wasserlösliche, inerte Polymer, das in der aktiven Schicht (ii) vorliegt, gewählt ist aus Hydroxypropylmethylcellulose (HPMC) und Hydroxypropylcellulose (HPC).

5. Tablettierte, orale, pharmazeutische Dosierungsform gemäss einem der Ansprüche 1 bis 3, wobei das nicht-alkalische, wasserlösliche, inerte Polymer, das in der Zwischenschicht (iii) vorliegt, Hydroxypropylmethylcellulose (HPMC) ist.

6. Tablettierte, orale, pharmazeutische Dosierungsform gemäss Anspruch 1, wobei die Kompressionsexzipientien gewählt sind aus der Gruppe, bestehend aus Verdünnungsmitteln, Desintegrantien, Gleitmitteln und ihren Mischungen.

7. Tablettierte, orale, pharmazeutische Dosierungsform gemäss Anspruch 1, wobei die enterische Beschichtung (c), die die vorher genannte Vielzahl von Einheiten, enthaltend eine Benzimidazolverbindung, die in einem sauren Medium labil ist, als Wirkstoff, und die pharmazeutisch annehmbare inerte Exzipientien bedeckt (b), ein magensaftresistentes Polymer, einen Weichmacher und ein oder mehrere pharmazeutisch annehmbare, inerte Exzipientien umfasst.

8. Verfahren zur Herstellung einer tablettierten, oralen, pharmazeutischen Dosierungsform, bedeckt mit einer enterischen Beschichtung, bestehend aus multiplen Einheiten, enthaltend eine Benzimidazolverbindung, die in einem sauren Medium labil ist, als Wirkstoff, gemäß einem der Ansprüche 1 bis 7, das folgendes beinhaltet:

Aufbringen einer wässrigen Suspension einer Benzimidazolverbindung, die in einem sauren Medium labil ist, eines nicht-alkalischen, wasserlöslichen, inerten Polymers und ein oder mehreren pharmazeutisch annehmbaren, inerten Exzipientien auf einen inerten Kern zum Erhalt einer aktiven Schicht, die den inerten Kern beschichtet;

Aufbringen einer Zwischenschicht, enthaltend eine nicht-alkalische inerte Beschichtung, bestehend aus einem nicht-alkalischen, wasserlöslichen, inerten Polymer und ein oder mehreren pharmazeutisch annehmbaren, inerten Exzipientien auf die aktive Schicht, um eine Einheit zu erhalten, enthaltend eine Benzimidazolverbindung, die in einem sauren Medium labil ist, als Wirkstoff;

Vermischen einer Vielzahl, der Einheiten, enthaltend eine Benzimidazolverbindung, die in einem sauren Medium labile ist, als Wirkstoff, mit ein oder mehreren pharmazeutisch annehmbare, inerten Exzipientien, wovon ein oder mehrere Kompressionsexzipientien sind, und Komprimieren der Mischung, um eine Tablette zu erhalten; und

Bedeckung der Tablette mit einer wässrigen Suspension, umfassend ein magensaftresistentes Polymer, einen Weichmacher und ein oder mehrere pharmazeutisch annehmbare, inerte Exzipientien zur Bildung einer äusseren enterischen Beschichtung.

9. Verwendung der pharmazeutischen Dosierungsform gemäss einem der Ansprüche 1 bis 8 für die Herstellung eines Medikaments.

Revendications

1. Une forme pharmaceutique de comprimé oral revêtu d'un enrobage gastrorésistant et entérosoluble, constituée d'une multitude d'unités contenant un composé benzimidazole labile en milieu acide comme principe actif, comprenant :

(a) Une multitude d'unités contenant un composé benzimidazole labile en milieu acide comme principe actif, constituées de :

i) un noyau inerte ;

ii) une couche active déposée sur ledit noyau inerte i), constituée d'un composé benzimidazole labile en milieu acide, d'un polymère inerte hydrosoluble non alcalin et d'un ou plusieurs excipients inertes pharmaceutiquement acceptables ; et

iii) une couche intermédiaire formant un enrobage inerte non alcalin constitué d'un polymère inerte hydrosoluble non alcalin et d'un ou plusieurs excipients inertes pharmaceutiquement acceptables, ladite couche intermédiaire étant déposée sur la couche active ii) susmentionnée couvrant le noyau inerte i) ;

(b) un ou plusieurs excipients inertes pharmaceutiquement acceptables, dont un ou plusieurs sont des excipients de compression ; et

(c) une couche d'enrobage gastrorésistant et entérosoluble enrobant ledit multitude d'unités contenant un composé benzimidazole labile en milieu acide comme principe actif et ledit plusieurs excipients inertes pharmaceutiquement acceptables (b).

2. Une forme pharmaceutique de comprimé oral selon la revendication 1, dans laquelle ledit composé benzimidazole labile en milieu acide est un composé de 2-[(2-pyridyl)méthylsulfinyl]benzimidazole de formule (I) ou ses énantiomères

dans lequel
R¹ est un hydrogène ou un groupe méthoxy ou difluorométhoxy,
R² est un groupe méthyl ou méthoxy,
R³ est un groupe méthoxy, 2,2,2-trifluoroéthoxy ou 3-méthoxypropoxy, et
R⁴ est un hydrogène ou un groupe méthyl.

3. Une forme pharmaceutique de comprimé oral selon la revendication 1, dans laquelle ledit composé benzimidazole labile en milieu acide est sélectionné dans un groupe constitué d'oméprazole, lansoprazole, rabéprazole et pantoprazole ou leurs énantiomères respectifs.

4. Une forme pharmaceutique de comprimé oral selon une des revendications 1 à 3, dans laquelle ledit polymère inerte hydrosoluble non alcalin présent dans la couche active ii) est choisi entre l'hydroxypropylméthylcellulose (HPMC) et l'hydroxypropylcellulose (HPC).

5. Une forme pharmaceutique de comprimé oral selon une des revendications 1 à 3, dans laquelle ledit polymère inerte hydrosoluble non alcalin présent dans la couche intermédiaire iii) est l'hydroxypropylméthylcellulose (HPMC).

6. Une forme pharmaceutique de comprimé oral selon la revendication 1, dans laquelle lesdits excipients de compression sont sélectionnés dans un groupe constitué de diluants, désagrégeant, lubrifiants et leurs mélanges.

7. Une forme pharmaceutique de comprimé oral selon la revendication 1, dans laquelle ladite couche d'enrobage gastrorésistant et entérosoluble (c) enrobant ledit multitude d'unités contenant un composé benzimidazole labile en milieu acide comme principe actif et ledit plusieurs excipients inertes pharmaceutiquement acceptables (b), comprend un polymère gastrorésistant, un plastifiant, et un ou plusieurs excipients inertes pharmaceutiquement acceptables.

8. Un processus de préparation d'une forme pharmaceutique de comprimé oral revêtu d'un enrobage gastrorésistant et entérosoluble, constituée de multiples unités contenant un composé benzimidazole labile en milieu acide comme principe actif, selon une des revendications 1 à 7, comportant :

l'application sur un noyau inerte d'une suspension aqueuse d'un composé benzimidazole labile en milieu acide, d'un polymère inerte hydrosoluble non alcalin et d'un ou plusieurs excipients inertes pharmaceutiquement acceptables, pour l'obtention d'une couche active enrobant le noyau inerte,

l'application sur ladite couche active d'une couche intermédiaire formant un enrobage inerte non alcalin constitué d'un polymère inerte hydrosoluble non alcalin et d'un ou plusieurs excipients inertes pharmaceutiquement acceptables, pour l'obtention d'une unité contenant un composé benzimidazole labile en milieu acide comme principe actif ;

le mélange d'une multitude desdites unités contenant un composé benzimidazole labile en milieu acide comme principe actif avec un ou plusieurs excipients inertes pharmaceutiquement acceptables, dont un ou plusieurs excipients sont de compression, et la compression dudit mélange pour l'obtention d'un comprimé ; et

le revêtement dudit comprimé pair une suspension aqueuse comprenant un polymère gastrorésistant, un plastifiant et un ou plusieurs excipients inertes pharmaceutiquement acceptables, pour la formation d'une couche extérieure d'enrobage gastrorésistant et entérosoluble.

9. l'utilisation de la forme pharmaceutique de comprimé oral selon une des revendications 1 à 8, pour la fabrication d'un médicament.