MXPA00005896A - Oral pharmaceutical extended release dosage form - Google Patents

Abstract

An enteric coated pharmaceutical extended release dosage form of an H+,K+-ATPase inhibitor giving an extended plasma concentration profile of an H+,K+-ATPase inhibitor. The extended plasma profile is obtained by a pharmaceutical composition which comprises a core material of a hydrophilic or hydrophobic matrix, and the H+,K+-ATPase inhibitor and optionally pharmaceutically acceptable excipients. The dosage form may be administered once daily.

Description

ORAL PHARMACEUTICAL DOSAGE FORM OF PROLONGED RELEASE Field of the Invention The present invention relates to new forms of pharmaceutical dosages comprising a proton pump inhibitor, i.e. an inhibitor of H +, K + -ATPase. The new dosage forms are enteric coated formulations that provide a prolonged and continuous release of the H + inhibitor, K + -ATPase in the small and / or large intestines, resulting in a prolonged blood plasma profile. The formulations comprise a hydrophilic or hydrophobic matrix resulting in a prolonged release of the H + inhibitor, K + -ATPase, preferably for a minimum of 2 and a maximum of 12 hours. In addition, the present invention relates to the manufacture of such sustained release pharmaceutical formulations, and their use in medicine.

Background of the invention and prior art Inhibitors of H +, K + -ATPase of labile acid also called as inhibitors of the proton pump REF .: 120793 gastric are for example, compounds known under the generic names of omeprazole, lansoprazole, pantoprazole, rabeprazole and leminoprazole. Some of these compounds are described in EP-A1-0005129, EP-A1-124495, EP-A1-174726, EP-A1-166287 and GB 2163747.

These pharmaceutical substances are useful for inhibiting the secretion of gastric acid in mammals including man, controlling the secretion of gastric acid in the final stage of the acid secretion route and in this way, reducing the secretion of basal and stimulated gastric acid without consideration to stimulus. In a more general sense, they could be used for the prevention and treatment of diseases related to gastric acid in mammals and man, including e.g. reflux esophagitis, gastritis, duodenitis, gastric ulcer, duodenal ulcer and Zollinger-Ellison syndrome. In addition, they could be used for the treatment of other gastrointestinal conditions wherein the inhibitory effect of gastric acid is desirable, e.g. in patients on NSAID therapy, in patients with non-ulcer dyspepsia and in patients with symptomatic gastroesophageal reflux disease (GORD). They could also be used for patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre- and post-operatively to prevent aspiration of gastric acid and to prevent and treat ulceration of nervous tension. In addition, they could also be used in the treatment of psoriasis as well as in the treatment of Helicobacterium infections and related diseases.

The therapeutic control of gastric acid secretion is essential in all these diseases, but the degree and duration of acid inhibition required for the optimal clinical effect is not fully understood.

It has been proposed by the Applicant at 097/48380 (published on December 24, 1997, ie after the priority date of the present application), that a regimen that gives blood plasma levels ranging from 2 to 12 hours (by any of several means) will result in a larger fraction of the proton pump being inhibited. In this way, an extended blood plasma level should result in more effective inhibition of acid secretion resulting in improved efficiency in GORD, faster healing of gastric ulcer and improved H eradication. Pyl or ri. The present invention provides the pharmaceutical dosage forms that achieve such plasma levels extended by a prolonged release of the drug.

A pharmaceutical dosage form comprising omeprazole or any other proton pump inhibitor, is better protected from contact with acidic gastric juice by an enteric coating layer. In US 4,786,505 and US 4,853,230, such enteric coated preparations are described. These preparations have a center comprising an alkaline salt of the drug or a center comprising the drug together with an alkaline reaction compound., the center is coated with a water soluble or rapidly disintegrating layer in water and then with an enteric coating layer. WO 96/01623 and WO 96/01624 describe dosage forms of omeprazole tablets and other proton pump inhibitors, wherein the enteric coating layer pills are compressed into a multiple tablet forming unit dosage form. . It is essential in these tabletting formulations that the enteric coating layer be able to withstand the compressive forces. None of these formulations previously described by the Applicant gave a prolonged release of the drug that resulted in a prolonged blood plasma profile.

WO 97/02020 describes a dosage form for pantoprazole together with an antibiotic substance, the dosage form having a slow release membrane placed as an intermediate layer. The membrane comprises a water insoluble film forming agent as an important feature of the dosage forms. WO 97/02021 describes the same type of dosage form for a reversible proton pump inhibitor in combination with an antibiotic substance.

A facilitated way to produce sustained release dosage forms compared to the application of a semipermeable membrane is to produce a dosage form comprising a matrix unit. Some advantages of such matrices are, for example, easier processing methods mainly through the use of granulation equipment and common tablet formation and sometimes, also with respect to the gain of time in the handling of solvents, energy and production, etc. .

The use of hydrophilic matrix tablets as a principle for the prolonged release of the drug was first described at the beginning of the 60's, see for example US Patent 3,065,143. Also the principle of the hydrophobic matrix tablet for prolonged release originated in the 60's, for example, without hardness quinidine, was on the market in 1963.

Prolonged-release dosage forms comprising different drugs in a matrix have been described in the prior art. However, none of these matrix dosage forms as such is appropriate for an H + inhibitor, K + -ATPase.

Some prolonged release hydrophilic matrix dosage forms are described in the literature for example: in Journal of Pharmaceutical Sciences vol. 84, No. 3, March 1995, in which Kim describes dosage forms comprising theophylline hydrochloride or diltiazem. US Pat. No. 5,273,758 describes dosage forms comprising, for example, clemastine fumarate. EP 0249587 discusses the formulations of felodipine. Dosage forms comprising a benzodiazepine derivative are described by Franz et al in Journal of Controlled Relay 1987, 5, 159-72.

Dosage forms comprising a hydrophobic prolonged release matrix have been described, for example, by Romero et al in International Journal of Pharmacy 1991, 73, 239-48.

Extended release tablets with an additional coating layer are also disclosed, for example by Sangalli et al in International Journal of Pharmaceutics, 91 (1993), 151-6. The drugs are metoprolol tartrate and benfluorex. The described dosage form has a waterproof coating that is drilled to achieve a hole in the middle of the tablet, exposing an initial surface area for dissolution of the inner center, i.e. dissolution of the active drug.

A more complicated dosage form was described in US Pat. No. 5,178,867. Dosage forms had a center comprising a drug, the center was coated with a semipermeable wall (maintaining its physical integrity during the lifetime of the 'dosage form) having at least one hole punched through it as a exit port for the dissolved drug. It is also mentioned that an enteric coating layer could be applied to restrict the release of the drug in the stomach and to provide release of the drug in the small intestine. This dosage form is much more complicated to elaborate than a matrix unit. There is no detailed description of a preferred dosage form, which comprises a proton pump inhibitor compound and testing such a dosage form to ensure that acidic gastric fluid is penetrating the semipermeable membrane, and that the active substance is released intact in the absorption site.

None of these dosage forms provides a form of matrix dosage easier to produce that protects an acid susceptible substance, such as a proton pump inhibitor against degradation that occurs in contact with an acidic environment, such as found in the stomach.

Brief Description of the Invention The present invention relates to an enteric coating formulation with prolonged release properties comprising a hydrophilic or hydrophobic matrix, in which an inhibitor of H +, K + -ATPase or a simple enantiomer thereof, or an alkaline salt of the inhibitor is incorporated. of H +, K + -ATPase or one of its simple enantiomers.

The present invention provides a solution to the problem of processing in a simplified manner, such prolonged dosage forms comprise an inhibitor of H +, K + -ATPase susceptible to acid, such as omeprazole or another proton pump inhibitor. A specific problem is that the pharmaceutical dosage forms according to the present invention satisfy certain requirements with respect to resistance to gastric acid for the enteric coated articles specified in the US Pharmacopoeia (Issue 23). Such a dosage form has to be protected by an enteric coating to ensure the safe release of the intact drug at the appropriate site in the gastrointestinal tract where it could be absorbed.

According to the present invention, the extended plasma profile is provided by once daily administration of an enteric coated dosage form that releases the proton pump inhibitor over an extended period of time, preferably for a minimum period of time. 2 hours and a maximum period of. 12 hours. In this way, the complete dosage will have to be released within 2 hours or to a minimum within 12 hours. The therapeutic effect of omeprazole and similar substances could be improved by providing an extended plasma profile and providing such a dosage form during a once-a-day administration.

The present sustained release formulations show improved patient compliance over a delivery regimen comprising the consecutive administration of two or more unit dosages during a day.

Detailed description of the invention The dosage forms that give the prolonged release according to the present invention are units in the form of enteric coating tablets. Alternatively, the units are enteric coating pills, the pills are filled in a capsule or together with compressed tablet excipients in a multiple unit tablet formation dosage form.

The individual units, i.e. tablets or pills, could be built as - a center material, optionally coated in a seed / sphere, the center material comprises a hydrophilic or hydrophobic matrix containing the active drug and optionally pharmaceutically acceptable excipients, and - an optional surrounding separation layer, and finally - an enteric coating layer Ma t eria l del cen t ro The center material for the units, i.e. Individual tablets or pills can be constituted according to different principles. The center material could be homogeneous or heterogeneous.

I) Ma th eria l de cen tro homogén eo If the material of the center is homogeneous, it has a homogeneous distribution of active substance through the material of the center The active substance is mixed with substances that form a hydrophilic or hydrophobic matrix and optionally pharmaceutically acceptable excipients. The center material should be free of the acidic substance. In this way, the hydrophilic or hydrophobic matrix in combination with another material in the center should not create an acid reaction in the core material, which would be detrimental to the acid-susceptible proton pump inhibitor compound. The micro environment around the proton pump inhibitor compound should preferably have a pH of not less than pH = 7, more preferably not less than 8, when water is absorbed into the particles of the mixture or when water is added in small amount to mix.

The active substance could be mixed with additional components to obtain the preferred handling and processing properties and an appropriate concentration of the active substance in the final mixture. Such components may be binders, surfactants, lubricants, slip agents, fillers, alkaline additives or other pharmaceutically acceptable ingredients, alone or in mixtures.

The center material could be produced either by direct compression of the mixed ingredients or by granulation of the ingredients followed by compression of the dry granulated material.

In direct compression, the ingredients are mixed and compressed using the ordinary tablet-forming equipment.

For the granulation there are numerous alternatives of granulation procedures mentioned in the literature, dry methods such as roller compaction (Chilsonator) and wet methods that use granulation solutions with and without the addition of binders. A variant of the wet methods is to make a sprayable granulation in a fluidized bed.

For wet granulation methods, either organic solvents, aqueous solutions or pure water could be used to prepare the granulation solutions. Due to environmental considerations, pure water is preferred. However, for some of the materials used as hydrophilic matrix components, the technical properties of the granules produced could be better when organic solvents such as alcohols are used, this is especially notable for hydroxypropyl methycelluloses.

For the granulation of the hydrophobic matrix components, it is also preferred to use alcoholic solvents in the wet granulation methods. As binders in this solution, one or more of the aforementioned polymers could be chosen as matrix-forming polymers.

As a general principle, the active ingredients are mixed and granulated together with the matrix forming polymers and optionally the pharmaceutically acceptable excipients. The dried granules are optionally mixed with pharmaceutically acceptable excipients, and then compressed into tablets using common equipment.

The size of the materials of the center formulated is approximately between 2 and 14 mm, preferably between 3 and 9 mm for a tablet preparation, and between 0 '.1 and 4 mm, preferably between 0.1 and 2 mm for a pill preparation.

II) Ma t eria l heterogeneous center.

Alternatively, the center material could be heterogeneous with an internal zone, for example a seed or sphere, that does not contain the active substance. This seed or sphere is surrounded by a hydrophilic or hydrophobic matrix layer containing the active substance, and optionally the pharmaceutically acceptable excipients are incorporated into the matrix.

The seed or sphere could be soluble or insoluble. Optionally, the seed or sphere (inner zone) could be coated with an inert layer to prepare a smooth surface, before the layer containing the active substance and the hydrophilic or hydrophobic wear substance is applied to the seed / sphere.

The insoluble spheres / seeds could comprise different oxides, celluloses, organic polymers and other materials, alone or in mixtures. Soluble seeds / mixtures could comprise different inorganic salts, sugars and other materials, alone or in mixtures. The size of the seeds could vary between approximately 0.1 and 2 mm. The seeds of layers with the matrix containing the active substance are produced either by formation of powder layers or solution / suspension using, for example, granulation equipment or spray coating / layering.

Adi ti vos fa rma c u u ti camen t e a ceptabl es The binders for a hydrophilic matrix can be chosen from the hydrophilic wear matrices mentioned below, and in addition to sugars, polyvinyl pyrrolidine, starches and gelatin.

The binders for a hydrophobic matrix can be chosen from the hydrophobic wear matrices mentioned below.

The additives listed among the following components are suitable for a hydrophilic as well as a hydrophobic matrix.

Suitable alkaline additives may be chosen from, but not restricted to, substances such as sodium, potassium, calcium, magnesium and aluminum salts of phosphoric acid, carbonic acid, citric acid or other weak inorganic or organic acids; aluminum hydroxide / sodium bicarbonate coprecipitate; substances normally used in antacid preparations such as aluminum, calcium and magnesium hydroxides; magnesium oxide or compound substances, such as Al 203 • 6M gO • C02-12H20, (Mg5Al2 (OH) 16C03- 4H20), MgO • 1203 • 2Si02 • nH20 or similar compounds; organic pH buffer substances such as trihydroxymethallylamine, basic amino acids such as arginine and its pharmaceutically acceptable salts or other buffer substances.

Suitable surfactants are in the groups of pharmaceutically acceptable nonionic surfactants, such as polysorbate 80, or nonionic surfactants such as, for example, sodium lauryl sulfate.

The lubricants are for example magnesium stearate, sodium stearyl fumarate (Pruv ™) and cetyl palmitate.

The fillers are, for example, sodium silicate aluminum, lactose, calcium phosphate and others.

The glidants are, for example, talc and aerosil.

Antioxidants could be added when appropriate.

Active substance The compounds of interest for the new sustained release dosage forms according to the present invention are compounds of the formula I, an alkaline salt thereof, one of the simple enantiomers thereof or an alkaline salt of one of the enantiomers Het -X-S-Het2 where Het, it's X = wherein N in the benzimidazole radical means that one of the ring carbon atoms substituted by R6-R9 could optionally be exchanged for a nitrogen atom without any substituent.

R1 R2 and R3 are the same or different and are selected from hydrogen, alkyl, alkoxy optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and phenylalkoxy; R4 and R5 are the same or different and are selected from hydrogen, alkyl and arylalkyl; R6 'is hydrogen, halogen, trifluoromethyl, alkyl or alkoxy.

R6-R9 are the same or different and are selected from hydrogen, alkyl, alkoxy, halogen, haloalkoxy, alkoxycarbonyl, alkoxycarbonyl, oxazolinyl, trifluoroalkyl or adjacent groups R6-R9 which form ring structures which could also be substituted; R10 is hydrogen or forms an alkylene chain together with R3 and R? l and R12 are the same or different and are selected from hydrogen, halogen or alkyl.

Examples of compounds specifically of interest according to formula I are ) The compound suitable for use in the sustained release formulations according to the present invention could be used in the neutral form or in the form of an alkaline salt, such as for example the salts of Mg2 +, Ca2 +, Na + or K +, preferably the salts of Mg2 +. The compounds could also be used in the form of one of their simple enantiomers or an alkaline salt of the single enantiomer.

Preferred compounds for oral pharmaceutical preparations according to the present invention are omeprazole, a magnesium salt of omeprazole or a magnesium salt of the (-) -enantiomer of omeprazole. Omeprazole and related substances, as well as their preparations are described in EP 5129, EP 124 495, WO 95/01977, WO 94/27988 whereby they are incorporated in their entirety by references.

The above compounds are susceptible to degradation / transformation in acidic and neutral medium. In general, the degradation is catalyzed by the acid reaction compounds and the active compounds are stabilized with alkaline reaction compounds. There are different preparations of enteric coating layers comprising omeprazole, as well as other proton pump inhibitors described in the prior art, see for example US-A 4,853,230, WO 95/01783 and WO 96/01623.

Especially, the latter describes alternative processing methods for the preparation of enteric coating layer pills comprising omeprazole and the like compounds. These patents are incorporated herein in their entirety by the references.

Ma t ri z h i drofí l i ca The active substance, i.e. the drug is optionally coupled together with pharmaceutically acceptable excipients in a hydrophilic polymer. Suitable hydrophilic polymers are for example, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylhydroxy ethylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, polyethylene oxides, polyvinyl alcohols, tragacanth, and xanthan. These polymers can be used alone or in mixtures of one another.

The amount of the hydrophilic polymer in the matrix is preferably 15-80% (calculated in the weight unit), and the hydrophilic polymer (s) is selected from those mentioned above.

Especially preferred polymers in the hydrophilic matrix unit are hydroxypropyl methylcellulose or polyethylene oxides.

Preferred excipients in the matrix are fillers that result in good tabletting technical properties, i.e. aluminum sodium silicate, mannitol or calcium phosphate (Emcompres s ™). A preferred matrix comprises 15-80% w / w (calculated on the weight unit) of a hydrophilic polymer chosen as above, and 10-60% w / w (calculated on the weight unit) of aluminum sodium silicate or phosphate of calcium (Emcompress ™).

Hydrophobic ma t ri z The active substance, i.e. the drug is optionally coupled together with pharmaceutically acceptable excipients in a hydrophobic matrix. The hydrophobic matrix comprises a hydrophobicizing agent and / or a hydrophobic polymer. Suitable materials for the hydrophobic matrix are, for example, hydrating agents such as cetanol, cetostearyl alcohol, cetyl palmitate, waxes such as carnauba wax, paraffin, magnesium stearate, sodium stearyl fumarate and glycerol esters. of medium or long chain alone or in any of the mixtures. Hydrophobic polymers are exemplified by for example, polyvinyl chloride, ethyl cellulose, polyvinyl acetate and acrylic acid copolymers, such as Eudragith ™ RS and RL. The polymers can be used alone or as mixtures.

As agglutinants for the hydrophobic matrix, either hydrophilic or hydrophobic polymers could be used.

It is important that the matrix comprises at least one component that is soluble in medium such as intestinal fluids. This component dissolves and leaves an open porous network for the passage of dissolution fluids and dissolved drug. This soluble components could be the active drug itself, or a soluble component such as s. Preferably, the soluble component is present in an amount of not less than 2% w / w (calculated on the weight unit) and up to 60%.

It is preferred that the matrix comprises not less than 10% w / w (calculated on the weight unit) and up to 80% of a hydrophobicizing agent or a hydrophobic polymer, both described above, or any combination thereof.

Another preferred matrix comprises as an additive a slightly soluble or less soluble component. As such components could be added any of the following: aluminum sodium silicate, calcium phosphate, aerosil, titanium dioxide, magnesium carbonates or other neutral or alkaline compounds that are slightly soluble or less soluble, with respect to water solubility. Slightly soluble is defined according to the European Pharmacopoeia (Edition 3) under the heading "General notices". Such a matrix comprises 10-80% w / w (calculated on the weight unit) of a hydrophobic agent or a hydrophobic polymer or any combination thereof, together with 10% -60% of a slightly soluble component or less soluble. Sodium silicate aluminum is especially preferred as such component.

The final dissolution profile could sometimes be adjusted by thermal treatment of the hydrophobic matrix unit for a short period, to reach temperatures at or above the softening temperature of the hydrophobicizing agents. Such treatment is most appropriately carried out after the enteric coating has been completed.

Coating layer (s) in terms of material and separation layer (s) Before applying an enteric coating layer on the core material, the pill or tablet could optionally be covered with one or more layers of * & • separation comprising pharmaceutical excipients, which optionally include alkaline compounds such as, for example, buffering compounds. This separation layer separates the active substance in the pills or tablets from the outer enteric coating layer.

This separation layer can be applied by the methods of coating or layering in the appropriate equipment, such as. coating tank, coating granulator, centrifugal granulator in a fluidized bed apparatus (including the Wuster type) using water and / or organic solvents for the coating process. As an alternative, the layer could be applied using powder coating or coating techniques.

Suitable materials for the separation layer are pharmaceutically acceptable compounds, such as, for example, sugar, polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and others, used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-sticking and anti-static agents, such as, for example, magnesium stearate, titanium dioxide, talcum, pH-buffering substances and other additives, could also be included in the layer of separation.

When the optimal separation layer is applied to the pills or tablets, it could constitute a variable thickness. The maximum thickness of the separation layer is usually only limited by the processing conditions. The separation layer could serve as a diffusion barrier and could act as a buffer zone of pH. The separation layer could optionally improve the chemical stability of the active substances and / or the physical properties of the dosage form.

Finally the units, í.e. The tablets or pills are covered by one or more layers of enteric coating using an appropriate coating technique. The material of the enteric coating layer could be dispersed or dissolved in water or in suitable organic solvents. As enteric coating layer polymers, one or more, separately or in combination, the following may be used; e.g. solutions or dispersions of copolymers of methacrylic acid, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethylcellulose, shellac or other suitable steric coating layer polymers.

Additives such as dispersants, dyes, pigments, additional polymers e.g. poly (ethylacrylate, methylmethacrylate), anti-adherent and anti-foaming agents could also be included in the enteric coating layer. Other compounds could be added to increase the thickness of the film and to decrease the diffusion of the acidic gastric juices in the material susceptible to acid. The enteric coating layer constitutes a thickness of at least 10 μm, preferably more than 20 μm. The maximum thickness of the enteric coating layer applied is normally limited only by the processing conditions.

The enteric coating layers could also contain pharmaceutically acceptable plasticizers to obtain the desired mechanical properties. Such plasticizers are for example, but are not restricted to, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, glycerol monoesters, polysorbates or other plasticizers and mixtures thereof. The amount of plasticizer is preferably optimized for each formula, in relation to the selected polymer, selected plasticizers and the applied amount of the polymer.

Final dosage form The enteric coated tablet or pill optionally mixed with the tablet excipients is filled into a capsule or compressed into a multiple tablet unit dosage form. The prepared enteric coating tablets are optionally coated with film-forming agents to obtain a smooth surface of the tablet and further, improve the stability of the tablet during packaging and transport. Such a tablet coating layer could further comprise additives such as anti-tackifying agents, dyes and pigments or other additives to obtain a good looking tablet.

The dosage forms according to the invention are suitable for oral administration. The dosage will depend on the nature and severity of the disease to be treated. The dosage could also vary according to the age, body weight and response of the individual patient. Children and patients with liver diseases, as well as patients under long-term treatment in general, will benefit from dosages that are much lower than the average. In the treatment of other conditions higher than average dosages will be used. The dosage form could also be used in combinations with other dosage forms for example NSAID (s), motility agents, antibacterial substances and / or antacids.

A unit dosage of the proton pump inhibitor is administered at least once a day. The oral pharmaceutical formulation will maintain a prolonged release of the pharmaceutical substance from a minimum of 2 and a maximum of 12 hours, preferably it is maintained for a minimum of 4 and a maximum of 8 hours. Such a sustained release preparation could comprise up to about 5-100 mg of the substance and more preferably 10-80 mg.

The emplos The invention is described more in detail by the following non-limiting examples.

Ei emplo 1 Prolonged-release matrix tablets comprise omeprazole-Mg (approximately 20 mg).

The granules for the centers of the tablets were made according to the following composition (parts by weight); Omeprazole-Mg 45 Polyethylene oxide (molecular weight approx 4000,000), Poiyox® WSR 301 195 95% (w / v) 97 The powders were mixed in a mixer after which the ethanol was added in a uniform stream. The mass was dried in a drying oven at 50 ° C.

After grinding in an oscillating mill through a 1.0 mm screen, the obtained granules were mixed with the tablet lubricant, according to the following composition (parts by weight); Granules per tablet center 235 Stearyl sodium fumarate (Pruv®) The mixing was carried out in a Kenwood mixer, and the mixture was compressed to tablets (6 mm diameter) having an average weight of 123 mg, in a simple perforation tablet forming machine.

(Diaf) The rate of dissolution was tested by analyzing the individual tablets, using the dissolution apparatus USP No. 2 (alabe) equipped with a stationary basket operated at 100 rpm and 37 ° C. The dissolution medium was phosphate buffer pH 6.8. The release rate obtained (n = 2) is shown in the following table; The prepared tablets can also be processed according to Example 3 or 4, i.e. applying an enteric coating on the tablet.

Example 2 Prolonged-release matrix tablets comprise the Mg salt of S-omeprazole (about 32 mg).

The granules for the centers of the tablets were made according to the following composition (parts by weight); Sodium salt of S-omeprazole 300 Hydroxypropyl methylcellulose 50 cps 80 95% ethanol (w / v) 356 Polyvinyl pyrrolidone K-90 40 The powders were mixed in a mixer after which the ethanol was added in a uniform stream. The mass was dried in a drying oven at 50 ° C.

After grinding in an oscillating mill through a 1.0 mm screen, the obtained granules were mixed with the tablet lubricant, according to the following composition (parts by weight); Granules for tablet center 380 Sodium stearyl fumarate (Pruv®; Mixing was carried out in a Kenwood mixer, after which the mixture was compressed to tablets (7 mm diameter) having an average weight of 175 mg, in a simple perforation tablet machine ( Diaf).

The tablets prepared in addition can be processed according to Example 3 or 4 i.e. applying an enteric coating on the tablet. 3 The enteric coated prolonged release matrix tablets comprise the Mg salt of S-omeprazole (about 32 mg).

The tablets of Example 2 were first coated with a separating layer in a fluidized bed coating apparatus with a coating suspension of the following composition; 99.5% EtOH (w / v. 5 parts by weight Purified water 5 parts by weight Hydroxypropyl methylcellulose 6 cps 10 parts by weight Talc, micronized 2 parts by weight Sum 182 parts 200 grams of tablets were processed and the coating was continued until the average weight of the tablet was 181 mg.

The tablets coated with a separation layer were coated with an enteric coating layer in the same equipment according to the preceding coating step. The coating solution used had the following composition; Hydroxypropyl phthalate 19 parts by weight methylcellulose (HP-55®) Cet anol 1 part by weight Acetone 182 parts by weight Ethanol (95% w / v) 78 parts by weight Sum: 280 parts 100 grams of the tablets coated with the separation layer were processed and the coating was continued until the average weight of the tablet was 194 mg.

Tablets were exposed to 0.1 M HCl for 2 hours. The acid resistance was determined to be 98%.

The 4 Enteric coated prolonged release matrix tablets comprise the Mg salt of S-omeprazole (about 32 mg) The tablets obtained from Example 2 were directly coated with an enteric coating layer in a fluidized bed coating apparatus. The coating solution used had the following composition; Hydroxypropyl phthalate 19 parts by weight methylcellulose (HP-55®) Cetanol 1 part by weight Acetone 182 parts by weight Ethanol (95% w / v) 78 parts by weight Sum 280 parts 100 grams of the tablets were processed and the coating was continued until the average weight of the tablet was 187 mg.

Tablets were exposed to 0.1 M HCl for 2 hours. The acid resistance was determined to be 99%.

Example 5 Prolonged-release matrix tablets comprise the Mg salt of S-omeprazole (about 45 mg).

The granules for the tablet centers were made according to the following composition (parts by weight); Mg salt of S-omeprazole 45 Polyethylene oxide (approx. Pm. 4000 000), 145 Poiyox® WSR 301 Sodium silicate alum 50 Propyl gallate 0.1 99.5% Ethanol (w / v) 140 The powders were mixed and humidified with ethanol in a mixer, after which the mass was dried in a drying oven at 50 ° C.

After grinding in an oscillating mill through a 1.0 mm screen, the obtained granules were mixed with the tablet lubricant, according to the following composition (parts by weight); Granules for the tablet center 232 Sodium stearyl fumarate (Pruv®) 1 The ingredients were mixed, after which the mixture was compressed to the tablets (10 mm diameter) having an average weight of 241 mg, in a simple perforation tabletting machine (Diaf).

The dissolution rate was tested as described in example 1.

The release rate obtained (n = 2) is shown in the following table; ) Comment: full dosing has been released Example 6 Prolonged-release matrix tablets comprise the Mg salt of S-omeprazole (about 45 mg).

The granules for the tablet centers were made according to the following composition (parts by weight); Mg salt of S-omeprazole 45 Polyethylene oxide (approx. Pm. 4000 000), 72.5 Poiyox® WSR 301 Polyethylene oxide (approx. P.M. 100 000), 72.5 Poiyox® WSR N10 Sodium silicate alum 50 Propyl gallate 0.1 99.5% Ethanol (w / v) 140 The powders were mixed and humidified with ethanol in a mixer, after which the mass was dried in a drying oven at 50 ° C.

After grinding in an oscillating mill through a 1.0 mm screen, the obtained granules were mixed with the tablet lubricant, according to the following composition (parts by weight); Granules for the center of the tablet 234 Sodium stearyl fumarate (Pruv®) The ingredients were mixed, after which the mixture was compressed to the tablets (10 mm diameter) having an average weight of 241 mg, in a simple perforation tabletting machine (Diaf).

The rate of dissolution was tested as described in Example 1 above.

The release rate obtained (n = 2) is shown in the following table; Comment: The full dosage has been released 7 Prolonged-release matrix tablets comprise the Mg salt of S-omeprazole (about 45 mg).

The granules for the tablet centers were made according to the following composition (parts by weight); Mg salt of S-omeprazole 45 Polyethylene oxide (approx.P.M. 100 000), 145 Poiyox® WSR N10 Sodium silicate alum 50 Propyl gallate 0.1 99.5% ethanol (w / v; 140) The powders were mixed and humidified with ethanol in a mixer, after which the mass was dried in a drying oven at 50 ° C.

After grinding in an oscillating mill through a 1.0 mm screen, the obtained granules were mixed with the tablet lubricant, according to the following procedure (parts by weight); Granules for tablet center 229 Sodium stearyl fumarate (Pruv®) The ingredients were mixed, after which the mixture was compressed to the tablets (10 mm diameter) having an average weight of 241 mg, in a simple perforation tabletting machine (Diaf).

The dissolution rate was tested as described in example 1.

The release rate obtained (n = 2 is shown in the following table; *) Comment: The complete dosage has been released.

Example 8 Prolonged-release matrix tablets comprise the Mg salt of omeprazole (about 45 mg).

The granules for the tablet centers were made according to the following composition (parts by weight); Mg salt of omeprazole 80 Hydroxypropyl methylcellulose 50 cps 300 Polyvinyl pyrrolidone K-90 40 99.5% Ethanol (w / v; 400) The polyvinyl pyrrolidone (PVP) was dissolved in the alcohol. The other two ingredients were mixed and then humidified with the PVP solution in a mixer. Subsequently, the mass obtained was dried in a drying oven at 50 ° C.

After grinding in an oscillating mill through a 1.0 mm screen, the obtained granules were mixed with the tablet lubricant, according to the following composition (parts by weight); Granules for the tablet center 412 Sodium stearyl fumarate (Pruv®) The ingredients were mixed, after which the mixture was compressed to tablets (9 mm diameter) having an average weight of 265 mg, in a simple perforation tablet machine (Diaf).

Example 9 Prolonged-release matrix tablets comprise the Mg salt of S-omeprazole (about 45 mg).

The granules for the tablet centers were made according to the following composition (parts by weight); Mg salt of S-omeprazole 74 Hydroxypropyl methylcellulose 50 cps 210 Hydroxypropyl methylcellulose 10000 cps 90 Polyvinyl pyrrolidone K-90 40 99.5% Ethanol (w / v) 400 The polyvinyl pyrrolidone (PVP) was dissolved in the alcohol. The other ingredients were mixed and then humidified with the PVP solution in a mixer. Subsequently, the mass obtained was dried in a drying oven at 50 ° C.

After grinding in an oscillating mill through a 1.0 mm screen, the obtained granules were mixed with the tablet lubricant, according to the following composition (parts by weight) Granules for the center of the tablet 378 Sodium stearyl fumarate (Pruv®) The mixing was carried out in a mixer, and the mixture was compressed to tablets (9 mm diameter) having an average weight of 261 mg, in a simple perforation tablet forming machine (Diaf).

The rate of dissolution was tested in phosphate buffer pH 6.8 as described in example 1. The release rate obtained (n = 6) is shown in the following table; Example 10 Prolonged-release matrix tablets comprise the Mg salt of S-omeprazole (about 55 mg).

The granules for the tablet centers were made according to the following composition (parts by weight); Mg salt of S-omeprazole 40 Polyvinyl alcohol PM 22000, 160 hydrolysis grade 97.5-99.5% Polyvinyl pyrrolidone K-90 14 99.5% ethanol (w / v) 49 The polyvinyl pyrrolidone (PVP) was dissolved in the alcohol. The other two ingredients were mixed and then humidified with the PVP solution in a mixer. Subsequently, the mass obtained was dried in a drying oven at 50 ° C.

After grinding in an oscillating mill through a 1.0 mm screen, the obtained granules were mixed with the tablet lubricant, according to the following composition (parts by weight); Granules for tablet center 215 Sodium stearyl fumarate (Pruv®) The ingredients were mixed, after which the mixture was compressed to tablets (9 mm diameter) having an average weight of 310 mg, in a simple perforation tablet machine (Diaf).

The rate of dissolution was tested in phosphate buffer pH 6.8 as described in example 1. The release rate obtained (n = 2) is shown in the following table; It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (23)

REIVIND CATIONS

1. A pharmaceutical prolonged release dosage form of enteric coating of an H + inhibitor, K + -ATPase, characterized in that the dosage form comprises a central material of a hydrophilic matrix or a hydrophobic matrix and the H + inhibitor, K + -ATPase, and the H + inhibitor, K + -ATPase is a compound of the formula I, an alkaline salt thereof, one of the simple enantiomers thereof or an alkaline salt of one of the enantiomers of a compound of the formula I He ^ - X-S-Het2 where H e t j e s R, O Het2 is X = where N in the benzimidazole radical means that one of the ring carbon atoms substituted by R6-R9 could optionally be exchanged for a nitrogen atom without any substituent; Rlf R2 and R3 are the same or different and are selected from hydrogen, alkyl, alkoxy optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and phenylalkoxy; R4 and R5 are the same or different and are selected from hydrogen, alkyl and arylalkyl; R6 'is hydrogen, halogen, trifluoromethyl, alkyl or alkoxy. R6-R9 are the same or different and are selected from hydrogen, alkyl, alkoxy, halogen, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolinyl, trifluoroalkyl or adjacent groups R6-R9 which form ring structures which could also be substituted; R10 is hydrogen or forms an alkylene chain together with R3 and R n and R 2 are the same or different and are selected from hydrogen, halogen or alkyl.

2. A dosage form according to claim 1, characterized in that the inhibitor of H +, K + -ATPase s a compound selected from the group of omeprazole, an alkaline salt of omeprazole, the (-) - enantiomer of omeprazole and an alkaline salt of ( -) - enantiomer of omeprazole.

3. A dosage form according to claim 2, characterized in that the alkaline salt is a magnesium salt.

4. A dosage form according to claim 1, characterized in that the H + inhibitor, K + -ATPase is a compound selected from the group of lansoprazole, pantoprazole, alkaline salts thereof, a simple enantiomer thereof and an alkaline salt thereof. same.

5. A dosage form according to claims 1-4, characterized in that the center material is formed in layers with a separation layer, which is present under the enteric coating layer.

6. A dosage form according to claims 1-5, characterized in that the center material further comprises pharmaceutically acceptable excipients.

7. A dosage form according to claims 1-6, characterized in that the center material also comprises alkaline additives.

8. A dosage form according to claims 1-7, characterized in that the center material comprises a seed placed in layers with the H + inhibitor, K + -ATPase and the hydrophilic or hydrophobic matrix and optionally the pharmaceutically acceptable excipient.

9. A dosage form according to claims 1-8, characterized in that the center material creates a micro-environment around the H + inhibitor, K + -ATPase of not less than pH = 7.

10. A dosage form according to claims 1-9, characterized in that the hydrophilic matrix comprises a hydrophilic polymer selected from the group of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylhydroxy ethylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, polyethylene oxides, polyvinylpyrrolidone, polyvinyl alcohols, tragacanth, and xanthan or any mixture of the same.

11. A dosage form according to claim 10, characterized in that the hydrophilic matrix further comprises a filler, such as aluminum sodium silicate.

12. A dosage form according to any of claims 1-9, characterized in that the hydrophobic matrix comprises a hydrophobic polymer and a hydrophobic agent, the hydrophobic agent being selected from the group of: cetanol, keto-stearic alcohol, cetyl, waxes such as carnauba wax, paraffin, magnesium stearate, sodium stearyl fumarate and medium or long chain glycerol esters alone or mixtures thereof.

13. A dosage form according to claim 12, characterized in that the hydrophobic polymer is selected from the group of: polyvinyl chloride, ethyl cellulose, polyvinyl acetate and copolymers of acrylic acid.

14. A dosage form according to any of claims 12 or 13, characterized in that the hydrophobic matrix further comprises a slightly soluble or less soluble component selected from the group of: aluminum sodium silicate, calcium phosphate, aerosil, titanium dioxide and carbonates of magnesium.

15. A process for the preparation of an enteric coating dosage form, comprising an inhibitor of H +, K + -ATPase and a hydrophilic matrix or a hydrophobic matrix and optionally t the pharmaceutically acceptable excipient, characterized in that the process comprises the following steps: a) a center material comprising the H + inhibitor, K + -ATPase and the hydrophilic matrix or the hydrophobic matrix and optionally the pharmaceutically acceptable excipient is formed, b) optionally a separation layer is applied on the center material, and c) an enteric coating layer is applied on the material of the center of step a) or step b).

16. A dosage form according to any of claims 1-14, characterized in that the prolonged release is maintained for a minimum of 2 hours and a maximum of 12 hours.

17. A dosage form according to any of claims 1-14, characterized in that it is used in therapy

18. The use of an oral pharmaceutical composition as claimed in any of claims 1-14, characterized in that it is the manufacture of a medicament with improved inhibition of gastric acid secretion.

19. The use of an oral pharmaceutical composition as claimed in any of claims 1-14, characterized in that it is the preparation of a medicament with improved therapeutic effect in the treatment of gastrointestinal disorders associated with excess acid secretion.

20. The use of the H + inhibitor, K + -ATPase with the formula I defined in claim 1, characterized in that it is the preparation of a pharmaceutical composition with prolonged release.

21. A method for improving the inhibition of gastric acid secretion, characterized in that it comprises administering to a patient with need thereof, an oral pharmaceutical composition as claimed in any of claims 1-14.

22. A method for improving the therapeutic effect in the treatment of gastrointestinal disorders associated with excess acid secretion, characterized in that it comprises administering to a patient with the need thereof an oral pharmaceutical composition as claimed in any of claims 1-14 .

23. A method for receiving a prolonged plasma profile of an H + inhibitor, K + -ATPase, characterized in that a pharmaceutical preparation with prolonged release of the H + inhibitor, K + -ATPase as defined in any one, is administered to a patient in need thereof. of claims 1-14.