HK1034668B - Oral pharmaceutical pulsed release dosage form - Google Patents

Description

Oral pharmaceutical pulsatile release dosage form

Technical Field

The present invention relates to novel oral pharmaceutical dosage forms comprising a proton pump inhibitor, i.e. H⁺、K⁺-an ATPase inhibitor. The new dosage form is an enteric coated formulation which provides H⁺、K⁺-two or more discrete release pulses of the atpase inhibitor in discrete types of small and/or large intestine. These pulses may be spaced apart by a time period of 0.5 to 12 hours, preferably 0.5 to 6 hours, more preferably 0.5 to 4 hours. The invention also relates to the production of such pulsed delayed release pharmaceutical formulations and their use in medicine.

Background of the invention and Prior Art

Acid labile H, also known as gastric proton pump inhibitors⁺、K⁺ATPase inhibitors are, for example, the compounds known under the generic names omeprazole, lansoprazole, pantoprazole, rabeprazole and leminoprazole. Some of these compounds are disclosed in EP-A1-0005129, EP-A1-124495, WO94/27988, EP-A1-174726, EP-A1-166287 and GB 2163747.

These pharmaceutical substances can be used to inhibit gastric acid secretion in mammals (including humans) by controlling gastric acid secretion in the last step of the acid secretion pathway and thereby reduce basal gastric acid not associated with irritation and stimulated gastric acid secretion. In a more general sense, they may be used for the prevention and treatment of gastric acid related diseases in mammals and man, including for example reflux esophagitis, gastritis, duodenitis, gastric ulcer, duodenal ulcer and Zollinger-Ellison syndrome. Furthermore, they may also be used for the treatment of other gastrointestinal diseases where gastric acid inhibitory effect is required, such as in NSAID-treated patients, in patients with non-ulcer dyspepsia and in patients with symptomatic gastroesophageal reflux disease (GORD). In addition, they can also be used in intensive care patients, in patients with pre-and post-operative acute upper gastrointestinal bleeding to prevent gastric acid aspiration and to prevent and treat pressure ulcers. They are also useful in the treatment of psoriasis and in the treatment of helicobacter infections and diseases associated therewith.

Therapeutic control of gastric acid secretion is the basis for the treatment of all these diseases, but the extent and duration of acid inhibition required for optimal clinical effects is not fully understood.

Applicants propose in WO97/48380 (published 24/12/1997, i.e. after the priority date of this application) that a dosing regimen that extends plasma levels for 2-12 hours (in any of several ways) can result in a greater fraction of proton pump inhibition. Thus, prolonged plasma levels should result in more effective inhibition of acid secretion, resulting in increased efficacy, more rapid healing of gastric ulcers and increased eradication of helicobacter pylori in GORD. The present invention provides pharmaceutical dosage forms that can achieve such extended plasma levels by releasing the drug in two or more separate pulses.

The pharmaceutical dosage form of omeprazole or any other proton pump inhibitor is best protected from contact with acidic gastric juice by applying an enteric coating layer. Such enteric coating formulations are described in US4,786,505 and US4,853,230. These preparations have a core containing an alkaline salt of the drug or a core containing the drug and an alkaline-reacting compound, which may be coated with a water-soluble or rapidly water-disintegrable separating layer and then with an enteric coating layer. Tablet dosage forms of omeprazole and other proton pump inhibitors are described in WO96/01623 and WO96/01624, wherein pellets with an enteric coating layer are compressed into a multiple unit tablet dosage form. The enteric coating layer must be able to withstand the pressure in these tablet formulations. None of these formulations previously described by the applicant can provide two or more pulses separated by a time, i.e. a pulsed release of the proton pump inhibiting agent that can produce a prolonged plasma profile.

The prior art describes various techniques and pharmaceutical formulations aimed at delayed release administration of drugs. Such pharmaceutical formulations are, for example, formulations that provide different delay times, constructs based on osmotic pressure differences, slowly eroding/dissolving layers, burst systems for controlled time, or any combination thereof. Some of these principles are described below.

Gazzaniga et al (proceed.12th pharm. int. Techn. Conf, 1993, 1, 400-8) describe spray-or press-coating with HPMC layers to obtain delayed release tablets of ketoprofen or verapamil formulations. The HPMC layer may also contain an insoluble filler. Gazzaniga et al also describe antipyrine press coated tablets containing an HPMC layer to obtain a delayed release, coated with an outer enteric coating layer containing Eudragit L30D (Proc. Inter. Symp. control. Rel. Bioact. Mater.1996, 23, 571-2).

EP-A1-0629398 describes dosage forms containing a drug and an organic acid in a core surrounded by a controlled release onset membrane and further covered with an enteric coating. This dosage form is not suitable for substances that are sensitive to acid degradation, because the core contains organic acids.

Fox describes an Osmotic System ("colloid-Targeted osmoticum System for oral delivery of Peptides and Proteins" in the oral delivery of Proteins, Peptides and other biological drugs; Proceedings Technology Management Group, Wakefield, MA, USA, 9 months 1991). The colonic release system OROS-CT was used to obtain delayed release after a delay time. The dosage form has an enteric coating that dissolves in the small intestine, the release of the drug begins after a desired delay time, and the release is sustained for several hours.

EP 0384642 and EP 0384646 (and pharm. J., 1991, 27.7.137-9) describe PULSINCAP for enteric and parenteral coating systems^TMThe preparation is prepared. The system comprises a gel consisting of a water-insoluble capsule body and a water-soluble capA bladder. The drug components are contained in capsules and sealed in the capsules with a hydrogel plug.

Conte et al (Drug Development and Industrial Pharmacy, 1989, Vol.15, pp.2583-96) describe three-layer tablets which provide a suitable dual pulse system for ibuprofen. The first layer contains a fast-release component and is separated from the layer containing the second dose by a swellable polymeric barrier layer. The second dose was coated with an ethylcellulose impermeable film. The construct can release the drug in an acidic medium.

In US5,567,441, a dosage form of diltiazem * is described which comprises a slow release enteric coated pellet portion and another delayed pulse release film coated pellet portion, the latter pellet portion not being enteric coated. Such dosage forms are not suitable for acid sensitive drugs such as omeprazole and the like.

There have been two recent published patent applications which both propose controlled release formulations containing proton pumps, namely pantoprazole in combination with an antibacterial in WO 97/02020. Wherein at least a portion of pantoprazole is released continuously over a period of time in a slow-release form. The formulation has an intermediate layer that remains intact and allows continuous release of pantoprazole at a dose such that pantoprazole plasma levels are maintained for as long a period as possible. WO97/02021 discusses a very similar dosage form of a reversible proton pump inhibitor in combination with an antibacterial agent.

Detailed description of the drawings

The graphs shown in fig. 1-5 illustrate the dissolution profiles of a portion of the pharmaceutical formulation of the present invention prepared in the examples. These figures illustrate the amount of drug released over time. The amount of drug released is determined by measuring absorbance at 292nm in buffer.

Figure 1 shows the dissolution profile of the single dose layered pellets prepared in example 1.

Figure 2 shows the dissolution profile of the single dose layered pellets prepared in example 2.

Figure 3 shows the dissolution profile of the single dose layered pellets prepared in example 3.

Figure 4 shows the dissolution profile of the single dose layered tablet prepared in example 5.

Figure 5 shows the dissolution profile of the multi-dose layered tablet prepared in example 6.

Summary of The Invention

The therapeutic effect of omeprazole and similar substances can be enhanced by providing a prolonged plasma profile through once-daily administration of the dosage form. The present invention achieves an extended plasma profile by a pharmaceutical dosage form capable of releasing drug in separate pulses at certain time intervals, i.e., a dosage form having a discontinuous release type. The present invention provides compositions containing acid labile H⁺K⁺-such dosage forms of an atpase inhibitor such as omeprazole or any other proton pump inhibitor. One particular problem is that of H⁺K⁺This pharmaceutical dosage form of the atpase inhibitor must meet certain requirements of the united states pharmacopeia (23 rd edition) regarding resistance of enteric-coated dosage forms to gastric acid.

According to one aspect of the present invention, a prolonged plasma profile of the proton pump inhibitor is provided by once daily administration of a dosage form that can release the proton pump inhibitor in two or more separate pulses at intervals of 0.5 to 12 hours, preferably at intervals of 0.5 to 8 hours and more preferably at intervals of 0.5 to 4 hours in the small and/or large intestine (but not in the stomach).

According to another aspect of the present invention, a discontinuous release version of a proton pump inhibiting agent is provided for once daily administration of a dosage form in which one part of the dosage form provides a delayed pulsatile release and another part of the formulation provides an immediate release of the proton pump inhibiting agent. The dosage form provides at least two consecutive pulses of release of drug, the pulses being separated by a time interval of 0.5 to 12 hours, preferably 0.5 to 8 hours and more preferably 0.5 to 4 hours.

The pulsed release formulations of the present invention have improved patient compliance compared to a dosing regimen comprising two or more unit doses administered at specified time intervals.

Detailed Description

Active substance

The target compound for the new pharmaceutical preparation of the invention is a compound having the general formula I, a basic salt thereof, one of the single enantiomers or a basic salt of one of the enantiomers:

wherein

Het₁Is composed of

Or

Het₂Is composed of

Or

X＝

Or

Wherein

N of the benzimidazole moiety is optionally represented by R₆-R₉One of the substituted ring carbon atoms may be replaced with a nitrogen atom without any substituent;

R₁、R₂and R₃Identical or different, selected from hydrogen, alkyl, alkoxy optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and phenylalkoxy;

R₄and R₅Identical or different, selected from hydrogen, alkyl and arylalkyl;

R₆' is hydrogen, halogen, trifluoromethyl, alkyl or alkoxy;

R₆-R₉identical or different from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolinyl and trifluoroalkyl, or adjacent radicals R₆-R₉Forming a further substituted ring structure;

R₁₀is hydrogen or with R₃Together form an alkylene chain, and

R₁₁and R₁₂Identical or different, selected from hydrogen, halogen or alkyl.

Examples of particularly interesting compounds of formula I are:

the compounds suitable for use in the pulsed release formulations of the invention may be in neutral form or in basic salts such as, for example, Mg²⁺、Ca²⁺、Na⁺Or K⁺Salt, preferably Mg²⁺The salt form is used. These compounds may also be used in the form of one of their single enantiomers or a basic salt of a single enantiomer.

Particularly preferred compounds for use in oral pharmaceutical formulations according to the invention are omeprazole, a magnesium salt of omeprazole or a magnesium salt of the (-) -enantiomer of omeprazole. Omeprazole and related substances and processes for their preparation are described in EP 5129, EP 124495, WO95/01977, WO94/27988, the contents of which are incorporated herein by reference.

The above compounds are susceptible to degradation/conversion in acidic and neutral media. In general, the degradation reaction is catalyzed by acid reactive compounds, while the active compounds can be stabilized by basic reactive compounds. Different enteric-coated formulations containing omeprazole and other proton pump agents are described in the prior art, e.g. US-A4,853,230, WO 95/01783 and WO 96/01623. In particular in the latter, an additional manufacturing process for the preparation of enteric-coated layered pellet formulations containing omeprazole and similar compounds is described.

The dosage form according to the invention provides at least one dose portion with delayed pulsatile release of the drug and another portion of the formulation with rapid or immediate release. Immediate and delayed pulsatile release of drugs can be obtained according to different principles such as:

by single dose layering of pills or tablets,

by multi-dose layering of pills or tablets, or

By two or more different single-or multi-dose layered pellet or tablet portions, optionally in combination with an immediate release pellet or tablet.

The multi-dose layered pellets or a collection of two or more different single or multi-dose layered pellets (a formulation) prepared according to any of the principles described below are filled into capsules or compressed together with tablet excipients into multi-unit tablets. Alternatively, multi-dose layered tablets may be prepared.

Single dose layered pill or tablet

According to one aspect of the invention, pellets or tablets are prepared which provide a single delayed release pulse of the drug. The single dose layered pellets or tablets may be constructed so as to contain the following moieties:

-a core material, optionally layered on seeds/spheres, said core material comprising a drug, a water-swellable material and optionally pharmaceutically acceptable excipients, said core material being free of acidic compounds and comprising layers applied thereon in the following order:

-a surrounding delay time control layer, finally

-an enteric coating layer covering the lag time controlling layer.

According to another aspect of the invention, the layered pellets or tablets may also be constructed to contain the following moieties:

-a core substance, optionally layered on seeds/spheres, said core substance containing a drug and optionally pharmaceutically acceptable excipients, said core substance being free of acidic compounds and containing layers applied thereon in the following order:

-an envelope containing a water-swellable substance thereon

-a surrounding delay time control layer, finally

-an enteric coating layer covering the lag time controlling layer.

Multi-dose layered pills or tablets

According to another aspect of the invention, multi-dose layered pellets or tablets are prepared that provide two or more delayed release pulses of the drug. These pellets or tablets may be constructed so as to contain the following moieties:

-a core material (I), optionally layered on seeds/spheres, said core material comprising a drug, a water-swellable material and optionally pharmaceutically acceptable excipients, said core material being free of acidic compounds and comprising layers applied thereon in the following order:

-a surrounding delay time control layer (II), and

-a layer (III) comprising a drug and optionally a water-swellable substance, and/or a pharmaceutically acceptable excipient; the layer being free of acidic compounds, and

-optionally a water-soluble or rapidly water-disintegrable separating layer (IV),

where layers II and III and optionally layer IV may occur in a repeating sequence (in this order), each combination of these layers (II + III) may provide another single pulse of the drug. Finally the dosage form is coated with an outer enteric coating layer (V).

Thus, a three-pulse delayed release pellet or tablet may be constructed containing the following sequence of layers: i + II + III + optionally layer IV and further an outer enteric coating layer (V).

According to another aspect of the invention, a multi-dose layered pellet or tablet may also be constructed to contain the following components:

-a core substance (I), optionally layered on seeds/spheres, said core substance containing a drug and optionally pharmaceutically acceptable excipients, said core substance being free of acidic compounds and containing layers applied thereon in the following order:

-an envelope layer (II) containing a water-swellable substance, followed by

-a surrounding delay time control layer (III), and

-a layer (IV) containing a drug and optionally pharmaceutically acceptable excipients; the layer being free of acidic compounds, and

-optionally a water-soluble or rapidly water-disintegrable separating layer (V),

where layers II, III, IV and optionally V may occur in a repeating sequence (in this order), each combination of these layers (II + III + IV) may provide another single pulse of the drug. Finally the dosage form is coated with an outer enteric coating layer (VI).

Thus, a tripulsatile pellet or tablet may be constructed containing the following sequence of layers: i + II + III + IV + optionally layer V and further an outer enteric coating layer (VI).

The core material containing the active drug may be prepared by layering the drug on a seed such as a sugar sphere or by extruding/spheronizing a mixture containing the drug and pharmaceutically acceptable excipients. The core material may also be prepared by compressing the drug particles and optionally pharmaceutically acceptable excipients into a tablet core using tablet technology.

For both types of pellets, i.e. single dose pellets or multi-dose pellets, where the drug is deposited on the seed/sphere by layering, it is also possible to have an optional water swellable material containing layer below the drug containing layer in the core material.

The prepared core material can be used in further processing. Different techniques for preparing the core material of the pellets or tablets are described below.

Core material

Depending on the composition, the core material of the individual pellets or tablets may be composed. Seeds/spheres layered with the active substance, optionally mixed with a water-swellable substance and/or a pharmaceutically acceptable excipient, can be used as core material for further processing. The core material does not contain acidic compounds unless the active material is weakly acidic. Acid-labile H when water is absorbed onto the core material mixture or when water is added in small amounts to the mixture⁺K⁺The microenvironment pH of the ATPase inhibitor is preferably not less than 7, more preferably not less thanAt 8.

The seeds/spheres may be water insoluble and may contain various oxides, celluloses, organic polymers and other materials (including alone or in mixtures); or water soluble materials, and may contain various organic salts, sugars, and other materials (including individual materials or mixtures thereof). Furthermore, the seeds/spheres may also contain the active substance in the form of crystals, agglomerates, compacts and the like. The size of the seeds may vary between about 0.1 to 2 mm. The seeds layered with the active substance can be produced by powder or solution/suspension layering with e.g. granulating or spray coating/layering equipment.

The active substance may be mixed with additional components to obtain preferred handling and processing properties and appropriate concentrations of the active substance in the final mixture prior to layering the seeds.

Such components may be binders, surfactants, fillers, disintegrants, alkaline additives or other pharmaceutically acceptable components (including alone and mixtures thereof). The binder is, for example, cellulose such as hydroxypropylmethyl cellulose, methyl cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose, polyvinylpyrrolidone, gelatin, sugar, starch and other pharmaceutically acceptable substances having binding properties. Suitable surfactants may be pharmaceutically acceptable non-ionic surfactants such as polysorbate 80 or ionic surfactants such as sodium lauryl sulphate.

Optionally, a penetrant is added to the core material. Such osmotic agents are water soluble and can provide osmotic pressure in the tablet. Examples of osmotic agents are magnesium sulfate, sodium chloride, lithium fluoride, potassium chloride, potassium sulfate, sodium carbonate, lithium sulfate, calcium bicarbonate, sodium sulfate, calcium lactate, urea, magnesium succinate, sucrose, or mixtures thereof.

Additionally, the active material, optionally in admixture with any of the components defined above, may be formulated in a core material. Such core materials may be produced by extrusion/spheronization, pelletizing or pressing using different processing equipment. For the extrusion/spheronization process, it is preferred to add microcrystalline cellulose and low substituted hydroxypropyl cellulose to the core material. The core material is formulated to have a size of about 0.1 to 4mm, preferably about 0.1 to 2mm for pellet formulations and 2 to 10mm, preferably 3 to 7mm for tablet formulations.

Suitable basic additives may be selected from, but are not limited to, phosphates, carbonates, citrates or other suitable weak inorganic or organic acids of sodium, potassium, calcium, magnesium and aluminium; aluminum hydroxide/sodium bicarbonate coprecipitate; substances conventionally used in antacid preparations such as aluminum hydroxide, calcium hydroxide and magnesium hydroxide; magnesium oxides or composite materials, e.g.

Al₂O₃·6MgO·CO₂·12H₂O、(Mg₆Al₂(OH)₁₆CO₃·4H₂O)、MgO·Al₂O₃·2SiO₂·nH₂O or a similar compound; organic pH-buffering substances such as tris, basic amino acids such as arginine and their salts or other similar pharmaceutically acceptable pH-buffering substances.

Alternatively, the above core material of the pellet formulation may be prepared by spray drying or congealing techniques.

Swelling layer

The swelling layer used may contain one or more water-swellable substances, suitable binders and optionally pharmaceutically acceptable excipients. Suitable water-swellable substances, binders and pharmaceutically acceptable excipients are described below. The swelling layer may swell when contacted with an aqueous solution, such as intestinal fluid.

Alternatively, a layer comprising an additional drug layered on the core material may be a drug-binding swelling layer.

Water-swellable substance

Water-swellable materials suitable for use in the dosage form of the present invention are materials that are capable of swelling when contacted with an aqueous solution, such as intestinal fluid.

One or more water-swellable substances may be present in the core material together with the active substance and optionally pharmaceutically acceptable excipients. In addition, one or more water-swellable substances may also be contained in the swelling layer layered on the core substance. Furthermore, if layered seeds or spheres are used as the core material, the swellable material may also be present in an optional swelling layer located below the drug-containing layer.

The amount and technique of the water-swellable material present in the swelling layer or core material is selected so that the core material or swelling layer can expand to such an extent upon contact with an aqueous solution, such as intestinal fluid, that the surrounding delay time controlling membrane can rupture. Water-swellable substances may also be present in the drug-containing layer of a multi-layered pellet or tablet to increase the dissolution rate of the drug ingredient.

Suitable materials that can be used as water-swellable materials are e.g. low substituted hydroxypropyl cellulose pixels L-HPC; cross-linked polyvinylpyrrolidone (PVP-XL) like Kollidon^TMCL and Polyplasdone^TMXL; croscarmellose sodium like Ac-di-sol^TM、Primellose^TM(ii) a Sodium starch glycolate like Primojel^TM(ii) a Sodium carboxymethylcellulose like NymcelZSB 10^TM(ii) a Sodium starch glycolate like Explotab^TM(ii) a Ion exchange resins like Dowex^TMOr Amberlite^TM(ii) a Microcrystalline cellulose pixel Avicel^TM(ii) a Starch and pregelatinized Starch like Starch1500^TM、Sepistab ST200^TMAnd formalin-casein like Plas-Vita^TM. One of these materials or any combination or mixture thereof may be used, but it is contemplated that the use of any acidic material is not appropriate.

Delay time control layer

The retardation time control layer is a semipermeable membrane containing a water-resistant polymer, which is semipermeable to an aqueous solution such as intestinal fluid. Suitable polymers are cellulose acetate, ethyl cellulose, polyvinyl acetateAcid esters, cellulose acetate butyrate, cellulose acetate propionate, acrylic copolymers such as Eudragit^TMRS or RL. The polymer may optionally contain pore formers, such as water-soluble substances like sucrose, salts; or water-soluble polymers like polyethylene glycol. Pharmaceutically acceptable excipients such as fillers and film strength modifiers such as talc, aerosols or sodium aluminium silicate may also be included.

At least one delay time controlling layer is present in the dosage form of the present invention. The most recent delay time controlling layer located in the core material is constructed in the form of a semipermeable membrane so as to be ruptured within a desired time after ingestion.

The desired retardation time can be adjusted by adjusting the composition and thickness of the retardation time control layer. The amount of the material forming such a semipermeable fractured membrane, i.e., the retardation time-controlling layer, is generally 0.5 to 25% (based on the weight of the core material including the swelling material or swelling layer). Preferably, the amount of the retardation time control layer, i.e., the rupturable semipermeable membrane, is 2 to 20% by weight.

The preferred semipermeable rupture membrane, i.e., the retardation time control layer, is composed of a mixture of ethylcellulose and talc. Most preferably the mixture contains 10 to 80% (w/w) talc.

Any further delay time control layer is optionally constructed as a disruptive semipermeable membrane.

Enteric coating layer and isolation layer

Before applying the enteric coating layer to the layered pills or tablets, they may optionally be covered with one or more isolating layers containing pharmaceutically acceptable excipients, optionally including basic compounds such as pH-buffering compounds. The separating layer may separate the layered pill or tablet from the outer enteric coating layer.

Layering of barrier layers as well as other types of layers such as swelling layers and delay time control layers is performed by performing a coating or layering step using a water and/or organic solvent coating process in a suitable apparatus such as a coating pan, a coating granulator, a centrifugal granulator, or a fluidized bed apparatus (including Wurster types). Other layers may also be prepared by powder coating or press coating techniques.

Suitable substances for use in the optional separating layer are pharmaceutically acceptable compounds such as sugars, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and the like, which may be used alone or in admixture. Additives such as plasticizers, colorants, pigments, fillers, anti-tack and antistatic agents such as magnesium stearate, titanium dioxide, talc, pH buffering substances and other additives may also be included in the barrier layer.

When the optional barrier layer is applied to the layered pill or tablet, it may have a variable thickness. The maximum thickness of the optional spacer layer is normally limited only by processing conditions. The spacer layer may also act as a dispersion barrier and may act as a pH buffer. The optional barrier layer may improve the chemical stability of the active substance and/or the physical properties of the dosage form.

Finally, the layered pellets or tablets are covered with one or more enteric coating layers using suitable coating techniques. The enteric coating material may be dispersed or dissolved in water or a suitable organic solvent. As enteric coating layer polymers one or more (alone or in combination) of the following may be used: such as solutions or dispersions of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, polyethylene acetate phthalate, cellulose acetate 1, 2, 4-trimellitate, carboxymethyl ethyl cellulose, shellac, or other suitable enteric coating layer polymers.

Additives such as dispersants, colorants, pigments, additional polymers such as poly (ethyl acrylate, methyl methacrylate), anti-stick and anti-foam agents may also be included in the enteric coating layer. Additional compounds may be added to increase the membrane thickness and reduce the diffusion of acidic gastric juices into acid labile substances. The enteric coating layer has a thickness of at least about 10 μm, preferably greater than 20 μm. The maximum thickness of the enteric coating layer used is generally limited only by the processing conditions.

Any polymer-containing layer and in particular the enteric coating layer may also contain a pharmaceutically acceptable plasticizer to obtain the desired mechanical properties. Such plasticizers are plasticizers such as, but not limited to, triacetin, citrate, phthalate, dibutyl sebacate, cetyl alcohol, polyethylene glycol, monoglycerides, polysorbates, or others. The amount of plasticizer is preferably optimized for each formulation relative to the selected polymer, the selected plasticizer, and the amount of polymer used.

Final dosage form

The prepared layered pills, optionally mixed with tablet excipients, are filled into capsules or compressed into multiple unit tablet dosage forms. Or the dosage form is a multilayer tablet. The prepared tablet is optionally covered with a film-forming agent to obtain a tablet having a smooth surface and to increase stability in tablet packaging and transportation. Such tablet coatings may also contain additives such as anti-tacking agents, colorants and pigments, as well as other additives to obtain tablets with good appearance.

The dosage form of the present invention is suitable for oral administration. The dosage depends on the nature and severity of the disease to be treated. The dosage will also vary with the age, weight and response of the particular patient. The dose in children and patients with liver disease and patients undergoing long-term treatment is generally favoured by a slightly lower than the average dose. Higher than average doses may be used in the treatment of other conditions.

The proton pump inhibitor is preferably administered once daily in a dosage form of 1-500 mg. Suitable dosages include, for example, from about 5 to 100mg of the substance, more preferably from 10 to 80 mg. The dosage form may be administered with other suitable drugs such as antibacterial compounds, NSAIDs, dynamic stimulants and/or antacids.

Examples

The following examples describe the invention in more detail without restricting it.

Example 1

Pulsed single dose delayed release layered pellets containing magnesium salt of S-omeprazole (pellet strength about 44mg/g)

Preparation of core Material (drug-layered spheres)

Suspensions containing the drug were prepared according to the following composition:

magnesium salt of S-omeprazole 100g

HPMC，6cps 15g

Polysorbate 802 g

Purified Water 323g

The HPMC was dissolved in water with stirring, followed by the addition of polysorbate 80 and drug. The suspension was sprayed onto 290g of sugar spheres (Non-pareil) in a fluidised bed. The product obtained weighed 395 g.

Swelling layer of the bag

A suspension containing a water-swellable material (without water) was prepared according to the following composition:

low-substituted hydroxypropylcellulose (L-HPC) 162g

Hydroxypropyl cellulose LF (HPC-LF) 74g

Talcum powder 354g

3100g ethanol (99.5%)

HPC-LF is dissolved in ethanol with stirring, followed by the addition of talc and the swelling agent L-HPC. This suspension was sprayed on 175g of the core material from above in a Wurster fluidised bed. The obtained product weighed 711 g.

Delay time control layer (semipermeable membrane)

The coating suspension was prepared according to the following formulation:

ethyl cellulose, 10cps 10g

Talcum powder 23g

1000g ethanol (99.5%)

The ethyl cellulose was dissolved in ethanol with stirring, and then talc was added.

The suspension was sprayed on 150g of pellets from the above-described swelling layer layering (sieved to give pellets of 0.61-0.71 mm) on a Wurster fluidized bed. The obtained pellet weighed 176 g.

The pellets (corresponding to about 10mg of active substance) were analysed using usp dissolution apparatus No. 2 (paddle method) at 100rpm at 37 ℃ using a phosphate buffer solution of ph 6.8. After dissolution of the active substance, the absorbance was measured in a buffer at 292nm using a 0.5cm flow-through compact chamber. The dissolution profile at 292nm is shown in FIG. 1.

Example 2

Pulsed single dose delayed release layered pellets containing magnesium salt of S-omeprazole (pellet strength about 43mg/g)

Preparation of core Material (sphere layered with drug)

Suspensions containing the drug were prepared according to the following composition:

magnesium salt of S-omeprazole 100g

HPMC，6cps 15g

Polysorbate 802 g

Purified Water 323g

The HPMC was dissolved in water with stirring, followed by the addition of polysorbate 80 and drug. The suspension was sprayed onto 290g of sugar spheres (Non-pareil) in a fluidised bed. The product obtained after coating weighed 395 g.

Swelling layer of the bag

A suspension containing a water-swellable material (without water) was prepared according to the following composition:

low-substituted hydroxypropylcellulose (L-HPC) 162g

Hydroxypropyl cellulose LF (HPC-LF) 74g

Talcum powder 354g

3100g ethanol (99.5%)

HPC-LF is dissolved in ethanol with stirring, followed by the addition of talc and the swelling agent L-HPC. This suspension was sprayed onto 175g of the pellets from above on a Wurster fluidized bed. The obtained product weighed 711 g.

Delay time control layer (semipermeable membrane)

100g of the swollen layer-layered pellets obtained above were coated with the following suspension to obtain a retardation time-controlling layer:

ethyl cellulose, 10cps 8g

Talcum powder 9g

Magnesium stearate 2g

620g of ethanol (99.5%)

The suspension was prepared by dissolving ethylcellulose in ethanol with stirring, and then the other compounds were added. The suspension was sprayed onto the pellets on a Wurster fluidized bed. The obtained pellets weighed 116 g.

The pellets were analyzed according to the method described in example 1. The dissolution profile is shown in figure 2.

Example 3

Single dose delayed-release pellets containing the magnesium salt of S-omeprazole, i.e. enteric coated pulsed single dose delayed release pellets (pellet strength of about 37mg/g)

Enteric coating layer

Pellets from example 1 were enteric coated on a fluidized bed with a coating dispersion according to the following:

eudragit L30D-55 (30% w/w dispersion) 73.3g

6.6g triethyl citrate (TEC)

Glycerol Monostearate (GMS) 0.3g

Polysorbate 800.03 g

Purified water 40.4g

A homogeneous coating dispersion was prepared by dissolving polysorbate 80 and glycerol monostearate in water. Triethyl citrate was dissolved in the Eudragit dispersion, after which the two dispersions were mixed to obtain a coating dispersion.

The coating dispersion was layered onto 120g of pellets from example 1 using a Wurster fluid bed. The weight of the layered pill was 140 g.

The pellets (equivalent to about 10mg of active substance) were analysed using a usp dissolution apparatus No. 2 (paddle method) at 100rpm at 37 ℃. The pellets were first immersed in 0.1M HCl (pH1.2) for 2 hours, after which time phosphate buffer components were added to bring the pH to 6.8. The dissolution profile was determined as described in example 1 and is shown in figure 3. The pellets were checked for acid resistance. After 2 hours of contact with 0.1M HCl, 96% of the active remained intact.

Example 4

Single dose layered pellets containing the magnesium salt of S-omeprazole, i.e. enteric coated pulsed single dose delayed release pellets (pellet strength about 35mg/g)

Preparation of core Material (sphere layered with drug)

Suspensions containing the drug were prepared according to the following composition:

magnesium salt of S-omeprazole 100g

HPMC，6cps 15g

Polysorbate 802 g

Purified Water 323g

The HPMC was dissolved in water with stirring, followed by the addition of polysorbate 80 and drug. The suspension was sprayed onto 290g of sugar spheres (Non-pareil) in a fluidised bed. After coating, the obtained product weighed 395 g.

Swelling layer of the bag

A suspension containing a water-swellable material (without water) was prepared according to the following composition:

low-substituted hydroxypropylcellulose (L-HPC) 162g

Hydroxypropyl cellulose LF (HPC-LF) 74g

Talcum powder 354g

3100g ethanol (99.5%)

HPC-LF is dissolved in ethanol with stirring, followed by the addition of talc and the swelling agent L-HPC. This suspension was sprayed on 175g of the core material from above in a Wurster fluidised bed. The obtained product weighed 711 g.

Delay time control layer (semipermeable membrane)

120g of the swollen layer-formed pellets obtained above (fraction of 0.61mm to 0.71mm obtained by sieving) were coated with the following suspension:

ethyl cellulose, 10cps 8g

Talcum powder 18g

Ethanol (99.5%) 810g

The suspension was prepared by dissolving ethyl cellulose in ethanol with stirring. Talc was then added. The suspension was sprayed onto the pellets on a Wurster fluidized bed. The product obtained weighed 137 g.

Enteric coating layer

120g of the pellets from the above procedure were coated with an enteric coating solution according to the following:

HPMCP(HP-55) 33g

cetyl alcohol 2.4g

353g of acetone

Ethanol (99.5%) 151g

The coating solution was prepared by dissolving HPMCP and hexadecanol in a solvent mixture under stirring. The coating solution was coated on a Wurster fluidized bed. The weight of the layered pill was 149 g.

The layered pellets were checked for resistance to acid in 0.1M HCl. The acid resistance was 97%.

Example 5

Single dose layered tablet containing magnesium salt of S-omeprazole, enteric coated pulsed single dose layered delayed release tablet (tablet strength about 16mg)

Granules

Granules of homogeneous tablet cores were prepared according to the following composition:

229g of magnesium salt of S-omeprazole

Microcrystalline cellulose Avicel pH 101151 g

Microcrystalline cellulose Avicel pH102sp

L-HPC 256g

PVP-XL 302g

Sodium dodecyl sulfate (SLS) 30g

1060g of purified water

The granulation solution was prepared by dissolving SLS in 460g of purified water.

The above powders were mixed in a mixer, and then the above solution was fed. Thereafter, about 600g of water was added with continued mixing to give a satisfactorily homogeneous mass.

The mass was dried in a drying oven at 50 ℃ overnight.

Preparation of the tablet core

After comminution through a sieve of 1.0mm, the granules obtained are mixed with a tablet lubricant, sodium chloride and a further amount of swellable material according to the following composition:

tablet core granule 400g

80g of sodium chloride (0.3 mm over)

Sodium stearyl fumarate (Pruv)^*) 8g

Crosslinked polyvinylpyrrolidone (PVP-XL) 20g

Mixing was carried out in a Kenwood mixer until homogeneous.

The above mixture was compressed on a single punch tablet machine (Diaf) to 6mm diameter tablets with an average tablet weight of 126 mg.

Delay time control layer (semipermeable membrane)

The tablets obtained in the previous step were coated in a Wurster fluid bed coating apparatus with a coating suspension of the following composition:

EtOH99.5% (w/v) 291 parts by weight

Ethyl cellulose N-1011 weight parts

7 parts by weight of micronized talcum powder

Total amount: 309 parts by weight

The tablets were made with 200g and were coated continuously until the average tablet weight was 134 mg.

Enteric coating layer

The tablets obtained in the previous step were coated with an enteric coating layer on the same equipment as the previous coating step. The coating solution consisted of:

hydroxypropyl methylcellulose phthalate (HP-55 *) 16 parts by weight

Cetyl alcohol 1 part by weight

151 parts by weight of acetone

65 parts by weight of ethanol (95% w/v)

Total amount: 233 parts by weight

The coating was continued with 100g tablets until the average tablet weight was 148 mg.

Each tablet was analyzed using a usp dissolution apparatus No. 2 (paddle method) equipped with a fixed basket and operated at 100rpm and 37 ℃. The tablets were first contacted with 0.1M HCl for two hours (pH1.2), after which the dissolution medium was changed to phosphate buffer pH 6.8.

The dissolution profile obtained according to the method described in example 1 can be seen in figure 4.

Example 6

Multi-dose layered tablets, enteric-coated double-pulse multiple-release tablets (tablet strength about 2X 15mg)

Granules

Core granules were prepared according to the following composition:

229g of magnesium salt of S-omeprazole

Microcrystalline cellulose Avicel pH 101151 g

Microcrystalline cellulose Avicel pH102sp

L-HPC 256g

PVP-XL 302g

Sodium dodecyl sulfate (SLS) 30g

1060g of purified water

The granulation solution was prepared by dissolving SLS in 460g of purified water.

The above powders were mixed in a mixer, and then the above solution was fed. Thereafter, about 600g of water was added with continuous mixing to give a satisfactorily homogeneous mass.

The mass was dried in a drying oven at 50 ℃ overnight.

Preparation of the tablet core

After comminution through a sieve of 1.0mm, the granules obtained are mixed with a tablet lubricant, sodium chloride and a further amount of swellable material according to the following composition:

homogeneous tablet core granule 400

Sodium chloride (0.3 mm over) 80

Sodium stearyl fumarate (Pruv)^*) 8

Cross-linked polyvinylpyrrolidone (PVP-XL) 20

Mixing was carried out in a Kenwood mixer until homogeneous.

The above mixture was compressed on a single punch tablet machine (Diaf) to 6mm diameter tablets with an average tablet weight of 126 mg.

Delay time control layer (semipermeable membrane)

The tablets obtained in the previous step were coated in a Wurster fluid bed coating apparatus with a coating suspension of the following composition:

99.5% (w/v) 291 parts by weight of EtOH

Ethyl cellulose N-1011 weight parts

7 parts by weight of micronized talcum powder

Total amount: 309 parts by weight

The tablets were made with 200g and were coated continuously until the average tablet weight was 134 mg.

Comprises a medicine layer

The tablets obtained in the preceding step were coated in the same equipment as described above with a coating suspension of the following composition:

20 parts by weight of S-omeprazole magnesium salt

13 parts by weight of hydroxypropyl methylcellulose 6cps

128 parts by weight of 99% ethanol

Purified water 128 parts by weight

Total amount: 289 parts by weight

This was done with 99g tablets and continued coating until the average tablet weight was 162 mg.

Enteric coating layer

The tablets obtained in the previous step were coated with an enteric coating layer on the same equipment as the previous coating step. The coating solution consisted of:

hydroxypropyl methylcellulose phthalate (HP-55) 16 parts by weight

Cetyl alcohol 1 part by weight

153 parts by weight of acetone

65 parts by weight of ethanol (95% w/v)

Total amount: 235 parts by weight

This was done with 119g tablets and continued coating until the average tablet weight was 173 mg.

Each tablet was analyzed using a usp dissolution apparatus No. 2 (paddle method) equipped with a fixed basket and operated at 100rpm and 37 ℃. The tablets were first contacted with 0.1M HCl for two hours, after which the dissolution medium was changed to phosphate buffer at pH 6.8.

The dissolution profile obtained according to the method described in example 1 can be seen in figure 5. The acid resistance of the tablets was checked and found to be 98%.

Example 7

A multi-dose capsule formulation containing (2 x 20) mg omeprazole in the form of an enteric coated pellet mixed with a delayed release enteric coated tablet.

Layering of suspensions

Omeprazole magnesium salt 5kg

Sugar ball core (0.25-0.355mm) diameter 10kg

Hydroxypropyl methylcellulose 0.8kg

20kg of purified water

Insulating layer

The medicated core (above) 14.6kg

Hydroxypropyl cellulose 1.5kg

Talcum powder 2.5kg

Magnesium stearate 0.2kg

29kg of purified water

Sausage coating

Pill (above) 9kg

15kg of methacrylic acid copolymer (30% suspension)

Triethyl citrate 1.4kg

0.2kg of monoglyceride and diglyceride (NF)

800.02 kg of polysorbate

9kg of purified water

Outer coating(over-coating)

Enteric coated pill 9kg

Hydroxypropyl methylcellulose 0.2kg

Magnesium stearate 0.005kg

3.6kg of purified water

Layering of the suspension was performed on a fluidized bed apparatus. The magnesium salt of omeprazole is sprayed onto the inert sugar ball cores from an aqueous suspension containing dissolved binding agent.

An enteric coating solution containing methacrylic acid copolymer, mono-and diglycerides, triethyl citrate and polysorbate was sprayed onto the inner coated (sub-coated) pellets on a fluid bed apparatus. Enteric coated pellets were coated with a hydroxypropyl methylcellulose/magnesium stearate suspension on the same type of equipment. The externally coated pellets were classified by sieving through a 0.71mm sieve.

The product was analyzed and found to contain 209mg of magnesium omeprazole salt per gram.

Single dose layered tabletI.e. enteric coated delayed release tablets containing the magnesium salt of omeprazole (tablet strength about 16mg)

Granules

Tablet core granules (in parts by weight) were prepared according to the following composition:

229g of omeprazole magnesium salt

Microcrystalline cellulose Avicel pH 101145 g

Microcrystalline cellulose Avicel pH102sp

L-HPC 251g

PVP-XL 302g

Hydroxymethyl cellulose 6cps 11g

Sodium dodecyl sulfate (SLS) 30g

Purified Water 960g

The granulation solution was prepared by dissolving SLS in 460g of purified water.

The above powders were mixed in a mixer, and then the above solution was fed. After which about 500g of water was added with continuous stirring to give a satisfactorily homogeneous mass. The mass was dried in a drying oven at 50 ℃ overnight.

Preparation of the tablet core

After comminution through a sieve of 1.0mm, the granules obtained are mixed with a tablet lubricant, sodium chloride and a further amount of swellable material according to the following composition:

tablet core granule 400g

80g of sodium chloride (0.3 mm over)

Sodium stearyl fumarate (Pruv)^*) 8g

Crosslinked polyvinylpyrrolidone (PVP-XL) 20g

Mixing was carried out in a Kenwood mixer until homogeneous.

The above mixture was compressed on a single punch tablet machine (Diaf) to 6mm diameter tablets with an average tablet weight of 126 mg.

Delay time adjusting layer (semipermeable membrane)

The tablets obtained in the previous step were coated in a Wurster fluid bed coating apparatus with a coating suspension of the following composition:

EtOH99.5% (w/v) 291 parts by weight

Ethyl cellulose N-1011 weight parts

7 parts by weight of micronized talcum powder

Total amount: 309 parts by weight

The tablets were made with 200g and were coated continuously until the average tablet weight was 134 mg.

Enteric coating layer

The tablets obtained in the previous step were coated with an enteric coating layer on the same equipment as the previous coating step. The coating solution consisted of:

hydroxypropyl methylcellulose phthalate (HP-55 *) 16 parts by weight

Cetyl alcohol 1 part by weight

151 parts by weight of acetone

65 parts by weight of ethanol (95% w/v)

Total amount: 233 parts by weight

The coating was continued with 100g tablets until the average tablet weight was 148 mg.

Filling capsule

0.10g of the above-prepared pellet and one of the above-obtained layered tablets were filled in a No. 1 hard gelatin capsule.

The best mode for carrying out the invention is the mode carried out according to the description of example 6.

Claims (24)

1. Comprising H⁺、K⁺-an ATPase inhibitor, a rupturable semi-permeable membrane and an enteric coated pharmaceutical dosage form of one or more swellable substances, wherein the dosage form has an immediate release inhibitor portion and at least one delayed release inhibitor portion and the formulation is capable of discontinuous release of H in the form of continuous pulses of at least two time intervals of 0.5-12 hours⁺、K⁺-an ATPase inhibitor, wherein the rupturable semi-permeable membrane comprises 0.5-25% by weight based on the weight of a core material comprising a water-swellable material or swelling layer, said core material containing a portion of H⁺、K⁺-an ATPase inhibitor, and said H⁺、K⁺-the atpase inhibitor is a compound having formula I, a basic salt of compound I, a single enantiomer of compound I or a basic salt of a single enantiomer of compound I:

wherein

Het₁Is composed of

Or

Het₂Is composed of

Or

X＝

Or

Wherein

N of the benzimidazole moiety is optionally represented by R₆-R₉One of the substituted ring carbon atoms may be replaced with a nitrogen atom without any substituent;

R₁、R₂and R₃Identical or different, selected from hydrogen, alkyl, alkoxy optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and phenylalkoxy;

R₄and R₅Identical or different, selected from hydrogen, alkyl and arylalkyl;

R₆' is hydrogen, halogen, trifluoromethyl, alkyl or alkoxy;

R₆-R₉identical or different from hydrogen, alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolinyl and trifluoroalkyl, or adjacent radicals R₆-R₉Forming a ring structure which may be further substituted;

R₁₀is hydrogen or with R₃Together form an alkylene chain, and

R₁₁and R₁₂Identical or different, selected from hydrogen, halogen or alkyl.

2. The dosage form of claim 1, characterized in that said H⁺、K⁺-the ATPase inhibitor is omeprazole, an alkaline salt of omeprazole, the (-) -enantiomer of omeprazole or an alkaline salt of the (-) -enantiomer of omeprazole.

3. The dosage form of claim 2, characterized in that the basic salt is a magnesium salt.

4. The dosage form of claim 1, characterized by H⁺、K⁺-the ATPase inhibitor is lansoprazole, an alkaline salt thereof, a single enantiomer thereof, or an alkaline salt thereof.

5. Dosage form according to any one of claims 1 to 4, characterized in that it comprises

a) Containing a portion of H⁺、K⁺A core material of an ATPase inhibitor, a water swellable material and optionally pharmaceutically acceptable excipients,

b) layers covering the core material in the following order

b1) A delay time control layer which is a rupturable semi-permeable membrane,

b2) h containing a second moiety⁺、K⁺At least one further layer of an ATPase inhibitor, and

b3) an enteric coating layer.

6. Dosage form according to any one of claims 1 to 4, characterized in that it comprises

a) Containing a portion of H⁺、K⁺-a core material of an ATPase inhibitor and optionally pharmaceutically acceptable excipients,

b) layers covering the core material in the following order

b1) A swelling layer comprising a water-swellable substance,

b2) a delay time control layer which is a rupturable semi-permeable membrane,

b3) h containing a second moiety⁺、K⁺At least one further layer of an ATPase inhibitor, and

b4) an enteric coating layer.

7. Dosage form according to any one of claims 1 to 4, characterized in that it comprises at least two general pellets or tablets or any combination thereof, characterized in that it comprises

a) A first body having a structure containing a portion of H⁺、K⁺-a core material of an atpase inhibitor, a water swellable material and optionally pharmaceutically acceptable excipients, wherein said core material is covered by a delay controlling layer which is a rupturable semi-permeable membrane and an enteric coating layer, and

b) a second population of pellets or tablets having a second fraction H⁺、K⁺-a core material of an atpase inhibitor and optionally pharmaceutically acceptable excipients, and which core material is covered by an enteric coating layer.

8. Dosage form according to any one of claims 1 to 4, characterized in that it comprises at least two general pellets or tablets or any combination thereof, characterized in that it comprises

a) A first body having a structure containing a portion of H⁺、K⁺-an atpase inhibitor and optionally pharmaceutically acceptable excipients, wherein the core material is covered by a swelling layer comprising a water-swellable substance, a delay controlling layer which is a rupturable semi-permeable membrane, and an enteric coating layer, and

b) a second population of pellets or tablets havingHaving a second part H⁺、K⁺-a core material of an atpase inhibitor and optionally pharmaceutically acceptable excipients, and which core material is covered by an enteric coating layer.

9. Dosage form according to claim 1, characterised in that it will contain a further fraction of H⁺、K⁺-one or more further layers of atpase inhibitors are placed under the enteric coating layer of the first population a).

10. The dosage form of claim 1, characterized in that said H⁺、K⁺-the two portions of ATPase inhibitor are released in two discrete pulses with a time interval of 0.5-4 hours.

11. The dosage form of claim 5, characterized in that said H⁺、K⁺-the ATPase inhibitor further comprises a mixture of alkaline additives.

12. The dosage form according to claim 5, characterised in that the water-swellable substance is selected from the group consisting of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and sodium starch glycolate.

13. The dosage form of claim 5, characterized in that the delay time controlling layer is a rupturable semi-permeable membrane, including a water-resistant membrane, which is a semi-permeable membrane of an aqueous solution.

14. The dosage form of claim 7, characterized in that two or more general pellets or tablets or any combination thereof are filled into a capsule.

15. The dosage form of claim 7, characterized in that two or more populations having different H's are combined⁺、K⁺-pellets or tablets of the atpase inhibitor release type are mixed with pharmaceutically acceptable excipients and compressed into a multiple unit tablet dosage form.

16. Dosage form according to claim 5, characterised in that a separating layer is present below the enteric coating layer.

17. The dosage form of claim 5, characterized in that the core material comprises H⁺、K⁺-nuclei of layering of ATPase inhibitors.

18. A layered pill or tablet of a dosage form as defined in claim 6, characterized in that said pill or tablet comprises a core comprising a portion of H⁺、K⁺-a core material of an atpase inhibitor, a water swellable material and optionally pharmaceutically acceptable excipients, wherein said core material is covered by a delay time controlling layer being a rupturable semi-permeable membrane, optionally will contain a further portion of H and an enteric coating layer⁺、K⁺-at least one further layer of an ATPase inhibitor is placed under the enteric coating layer.

19. A layered pill or tablet of the dosage form of claim 6, characterized in that the pill or tablet comprises a core comprising a portion of H⁺、K⁺-an ATPase inhibitor and optionally pharmaceutically acceptable excipients, wherein the core material is covered by a swelling layer comprising a water-swellable substance, a delay time controlling layer which is a rupturable semi-permeable membrane, optionally will contain a further portion of H, and an enteric coating layer⁺、K⁺-at least one further layer of an ATPase inhibitor is placed under the enteric coating layer.

20. Preparation of a catalyst containing H⁺、K⁺-a method for enteric coating dosage forms of an atpase inhibitor, wherein the inhibitor compound is present in the dosage form in a pulsed release providing H at least two intervals⁺、K⁺-at least two parts of an atpase inhibitor, said method comprising the following steps:

a) shaping a core material comprising a portion of H⁺、K⁺-an ATPase inhibitor, a water-swellable substance and optionally pharmaceutically acceptable excipients,

b) the core material was covered with the following layers:

b1) a delay time control layer which is a rupturable semi-permeable membrane,

b2) containing a second part H⁺、K⁺-a layer of an ATPase inhibitor, and

b3) the enteric coating layer.

21. Preparation of a catalyst containing H⁺、K⁺-a method for enteric coating dosage forms of an atpase inhibitor, wherein the inhibitor compound is present in the dosage form in a pulsed release providing H at least two intervals⁺、K⁺-at least two parts of an atpase inhibitor, said method comprising the following steps:

a) shaping a core material comprising a portion of H optionally mixed with a pharmaceutically acceptable excipient⁺、K⁺-an ATPase inhibitor, which is,

b) the core material was covered with the following layers:

b1) a swelling layer comprising a water-swellable substance,

b2) a delay time control layer which is a rupturable semi-permeable membrane,

b3) containing a second part H⁺、K⁺-a layer of an ATPase inhibitor, and

b4) the enteric coating layer.

22. A process for the preparation of a dosage form according to claim 20 or 21, wherein the application of the H-containing layer precedes the application of the enteric coating layer⁺、K⁺-a further layer of an ATPase inhibitor.

23. Use of an enteric coated pharmaceutical dosage form as defined in claim 1 for the manufacture of a medicament for increasing inhibition of gastric acid secretion.

24. Use of a pharmaceutical dosage form as defined in claim 1 for the manufacture of a medicament for the treatment of gastrointestinal disorders associated with hyperacidity secretion.