MXPA01005935A - New pharmaceutical formulation - Google Patents

Abstract

This invention is related to new oral pharmaceutical dosage forms comprising a proton pump inhibitor, i.e. a H+, K+ -ATPase inhibitor, a gastric antisecretory prostaglandin analogue compound, and optionally an additional drug such as a calcium channel blocking agent, especially for use in the treatment and prophylaxis of gastrointestinal disorders. More specifically the invention is related to new dosage forms comprising omeprazole and misoprostol. The invention is also related to a combination of the three categories of drugs, i.e. the H+, K+ -ATPase inhibitor, the gastric antisecretory prostaglandin analogue, and the calcium channel blocking agent. Furthermore, the invention refers to a method for the manufacture of the described dosage forms and their use in medicine, as well as blister packs comprising these medicaments.

Description

NEW PHARMACEUTICAL FORMULATION Field of Invention This invention relates to novel oral pharmaceutical dosage forms comprising an H + inhibitor, K + -ATPase, a gastric antisecretory prostaglandin analogue compound, and optionally an additional drug such as the blocking agent. of the calcium channel, especially for its use in the treatment and prophylaxis of gastrointestinal disorders. More specifically the invention relates to new dosage forms comprising omeprazole and misoprostol. The invention also relates to a combination of the three categories of drugs, that is, an inhibitor of H +, K + -ATPase, the analogue of the gastric antisecretory prostaglandin and the calcium channel blocking agent. Further. The invention relates to a method for the manufacture of the dosage forms and their uses in medicine, as well as to the packages of ampoules comprising these medicaments. BACKGROUND OF THE INVENTION Inhibitors of H +, K + -ATPase, such as proton pump inhibitors known under the generic names of omeprazole, lansoprazole, pantoprazole, rabeprazole REF: 129896 and leminoprazole are for example described in EP 5129, EP 174 726, EP 166 287, GB 2 163 747 and WO 90/06925. The expression of the H + inhibitors, K + -ATPase, and the proton pump inhibitors are interchangeable with each other within the context of the present application. Proton pump inhibitors are generally known to be useful for inhibiting the secretion of gastric acid in mammals and man controlling the secretion of gastric acid in the final step of the secretory pathway. Heals the gastric as well as duodenal ulcers in patients in continuous treatment with non-spheroidal anti-inflammatory drugs (NSAIDs) as well as non-NS ^ ID users. WO 96/01735 describes new fixed dosage forms comprising the proton pump inhibitor and an NSAID and its use in the treatment or prevention of gastrointestinal side effects associated with treatment with the NSAID. Analogous prostaglandin compounds, such as those known under the generic names of misoprostol, enoprostil, enisoprost, rosaprostol and miraprostal are orally active PGEi analogues with the protective and antisecretory properties of the mucosa, and these types of compounds are for example described in U.S. Patent 3,965,143 and U.S. Patent 4,178,457. These are mainly used for the prevention of gastric and duodenal ulcers associated with the treatment with the NSAID. Usually these are administered in a single, separate unit dosage form, and sometimes in combination with an NSAID in a fixed dosage form. For the analogues of the gastric antisecretory prostaglandin there are reported adverse reactions of the drug. The use for example of misoprostol, can cause diarrhea, abdominal pain and other adverse effects connected to the gastrointestinal system. The dosage regimen for misoproetol includes an input frequently of a dosage form, sometimes up to 4 times a day. This frequent intake or administration, in addition to unwanted gastrointestinal side effects with the gastric antisecretory prostaglandin analogues, implies problems with the subject's comfort. On the other hand, the inhibitor of the proton pump, omeprazole, has only a few adverse effects related to the dosage. A combination of two or more active agents achieves a similar psychological effect, but they work through different mechanisms, usually giving the possibility of reduce the doses of each single drug and still achieve the desired effect. This should reduce the risk of adverse side effects dependent on the dose. In addition, if one of the drugs fails due to the patient's individual response, the other component of the treatment regimen can be successful. In general, these factors involve advantages of combining two or more antiulcerative drugs, and combining misoprostol with other anti-ulcer drugs in particular. The administration of two or even more different dosage forms to the patient is not convenient or satisfactory to achieve the most optimal result. Since patient comfort is a major factor in receiving a good medical result, it may be advantageous to combine the different drugs into a single pharmaceutical dosage unit, which reduces the number of pills for the patient on each occasion of dosing. If one or more of the drugs can be provided in dosage forms with a prolonged release the efficiency can also be improved. The combination of the previously suggested therapies comprising the antiulcerative agents are for example the combinations of an H2 receptor antagonist of the histamine, such as cimetidine or ranitidine, and sucralfate. Other proposed therapies are for example a combination of omeprazole and sucralfate, a combination of ranitidine and cimetidine, or a combination of ranitidine and misoprostol. See for example Van Deventer GM et al., Am J. Med. 1985; 79: 39-44, and Houston LJ et al., Am J. Gastroenterol 1993; 88: 675-679. A combination therapy of misoprostol and a calcium channel blocking agent, such as verapamil, has been proposed and tested with respect to the mucosal protective effects in rats by reducing the synthesis of leukotriene and increase the synthesis of prostaglandin. See Fedorak, R. N. et al., Gastroenterology 1992; 102: 1229-35. The combination of the omeprazole proton pump inhibitor and the enprostil analog of the gastric antisecretory prostaglandin for the treatment of gastrointestinal disorders is known from Tari, A. et al., Digestive. Disseases and Sciences, 1997; 42: 1741-1746 and de Meijer, J.L. et al., Digestive Diseases and Sciences, 1994; 39: 609-616. However, until now a fixed unit dosage form comprising an inhibitor has not been suggested.

H +, K + -ATPase in combination with the analogue of the gastric antisecretory flandin prostaglandin. Acemas, there is no suggestion or description in the prior art of a combination comprising an H + inhibitor, K + -ATPase, a gastric antisecretory prostaglandin analogue and a calcium channel blocking agent. Especially, neither the Applicant knows of any of the oral pharmaceutical dosage forms comprising such a combination, nor in the form of a blister pack or a fixed unit dosage form. BRIEF DESCRIPTION OF THE INVENTION One aspect of the present invention is to provide a fixed unit dosage form for oral administration comprising an inhibitor of H +, K + -ATPase, and a gastric antisecretory prostaglandin analogue. A further aspect of the invention is to provide dosage forms of an H + inhibitor, K + -ATPase, and a gastric antisecretory prostaglandin analogue, wherein the latter is in a form that provides for prolonged release, such as a form of dosage that reduces adverse side effects related to dosage frequency and dose.

A further aspect of the invention is to provide a combination therapy of an H + inhibitor, K + -ATPase, a gastric anti-secretory prostaglandin analogue, and a component that enhances the effect of the prostaglandin analogue, eg, an anti-inflammatory agent. blocking the calcium channel. The combination can be provided in the fixed unit dosage forms. DETAILED DESCRIPTION OF THE INVENTION According to the present invention, a dosage form comprising an H + inhibitor, K + -ATPase, a gastric antisecretory prostaglandin analogue compound, and optionally a calcium channel blocking agent, can be mainly constructed in the form of a two layer tablet, or a stratified center tablet with a coating layer, or a pressure coated tablet, wherein the different drugs are located in different parts of the tablet. Alternatively, the dosage form may be a tablet or a capsule comprising either two or three populations of units each containing one of the drugs, or a population of multiple stratified units comprising a combination of different drugs, or these Can be built as a capsule which contains one or two of the drugs as a population of units and the other drugs as a single unit also positioned within the same capsule. The preferred types of the dosage forms according to the invention are described more in detail below by separate headers, and in the following examples. Two layer tablet One layer comprises the proton pump inhibitor as a multitude of enteric coated pellets or pellets dispersed in pharmaceutically acceptable excipients. These pellets can have the characteristics of immediate release, delayed pulsed release, dual delayed pulsed release, delayed multiple pulsed release or prolonged release, or any combination thereof. If the proton pump inhibitor is constructed as a layer with an extended release part, it can be designed in the form of a hydrophilic matrix layer comprising the proton pump inhibitor. In this last appropriate situation, measures are taken to protect the proton pump inhibitor from contact with acidic fluids.

The other layer comprising an analogue of the gastric antisecretory prostaglandin, and optionally a calcium channel blocking agent. This layer can be formulated to provide an immediate or prolonged release of the drug (s). The characteristics of the prolonged release can be achieved by using the pellets or prolonged release coated pellets in the membrane dispersed in the pharmaceutically acceptable excipients or by dispersing the drug in a hydrophilic or hydrophobic matrix with prolonged release properties. The characteristics of immediate release can be achieved by using a conventional tablet granulation process, or by incorporating the prostaglandin analog in fast dissolving pellets, which are dispersed in pharmaceutically acceptable excipients. This is possible in a first layer to include pellets of the proton pump inhibitor together with the pellets comprising the prostaglandin analogues, and optionally in a second layer including a calcium channel blocking agent. The center of the tablet comprising a drug stratified with a second drug Tablet fall comprises a tablet center containing a proton pump inhibitor as the center of the tablet is coated with a spray with a layer comprising an analogue of the gastric antisecretory prostaglandin. The centers of the tablet can be prepared as described below by the heading "pressure coated / coated tablets". The prepared tablets which are enteric coated are further laminated with a suspension comprising the prostaglandin analogue. Alternatively, the centers of the tablets are stratified in the same manner as described below by pellet preparation. However, a prepared tablet center has a size larger than that of the centers intended for pellet preparation, for example, preferably the center of the tablet has a size of 3-12 mm in diameter. Pressure Coated / Coated Tablets Ur inert tablet center is prepared by the tabletting technique according to the known art. The center or core of the tablet comprises active ingredients, preferably a proton pump inhibitor, optionally in combination with the calcium channel blocking agent. This center or core of the Tablet is then coated with an enteric coating layer. The enteric coating layer protects the proton pump inhibitor susceptible to acid from gastric acid, ie, this is a layer that does not dissolve in the gastric acid environment but dissolves or disintegrates in the small intestine. The additional coating layer comprises the second active agent, optionally in combination with the calcium channel blocking agent, is applied to the enteric coating layer by means of compression. Either the center of the tablet or the outer layer can give the characteristics of a prolonged or immediate release preparation. The tablet or capsule comprising a plurality of units containing the drug. Such dosage forms can be divided mainly into two different categories; for example (i) a population of multiple coated units, and (ii) two populations of units. (i) a - population of multiple coated units intended for the tablet or capsule formulations The first category comprises a population of units or pellets constructed equally, optionally dispersed in a pharmaceutically acceptable tablet excipient. Each unit comprises a proton pump inhibitor and a gastric antisecretory prostaglandin analogue as pharmaceutically active agents. The units containing the multiple layers and the different active substances are located in different layers. The proton pumpFor example, it is positioned on the inside of an enteric coating layer, optionally a separating layer can be positioned between the proton pump layer and the enteric coating layer. The layer comprising a gastric antisecretory prostaglandin analogue, and optionally a calcium channel blocking agent, is positioned externally to the proton pump layer, but it can be positioned on the inside or outside with respect to the enteric coating layer. The proton pump inhibitor comprising the layer may have the characteristics of an immediate release or a prolonged release, which is also applicable to the layer comprising the gastric anti-secretory prostaglandin analog, although prolonged release is preferred. The prepared drug containing the units can be filled into capsules or mixed with excipients of the pharmaceutically acceptable tablet and compressed into multiple unit tablets. (ii) Two populations of intended units for the tablet or capsule formulations The second category comprises a mixture of two different populations within each population of equally constructed units or pellets, optionally dispersed in excipients of the pharmaceutically acceptable tablets. A population comprising a proton pump inhibitor, and the other population comprising an analogue of the gastric antisecretory prostaglandin as the pharmaceutically active agent. Optionally, a third population of units comprising a blocking agent of the calcium channel in the mixture is included. These formulations are based on the mixing of a population of units comprising a gastric anti-secretory prostaglandin analogue with a population of units comprising a proton pump inhibitor. The mixture is filled into capsules, or else mixed with the pharmaceutically acceptable tablet excipients and compressed into a tablet. The excipients of the tablet can be previously granulated or only mixes with coated units before compression to tablets. Units comprising an analog of gastric antisecretory prostaglandin These units can be prepared by granulation, extrusion and sphering, coagulation, direct pelletizing in a mixer, granulation with fusion with suitable polymeric additives, by incorporation into porous carriers, or by stratification in a seed start, or by any other suitable techniques known in the art. The units can be formulated with the characteristics of immediate or prolonged release. If adequate, an additional coating layer that provides prolonged release can be applied within the units. Increase the residence time in the stomach for the units comprising the gastric antisecretory prostaglandin analogue, the gastric antisecretory prostaglandin analog is included in a hydrophilic matrix together with a suitable concentration of sodium acid carbonate and formulated to pellets. When the pellets are in contact with the gastric acid environment they develop small bubbles of dioxide carbon reducing the density of these pellets, and the pellets flow in the stomach. The units having the characteristics of immediate release can be prepared by incorporating the active substance into the porous amorphous silica particles or by coating the active substance in seeds or sugar starting particles. Units comprising a proton pump inhibitor These units can be prepared for either prolonged release, immediate release or delayed pulsed release of the proton pump inhibitor. WO 97/02020 describes pantoprazole pellets coated with a prolonged release membrane whose technology is also suitable for the other extended release units. Suitable units for immediate release of the proton pump inhibitor are described in EP 502 556 and units specially designed for use in the tablet dosage form are described in WO 96/01624, incorporated herein by reference. Capsule comprising two or more drugs in a single unit in combination with multiple units.

The Capsule comprises a drug in a single unit, for example, a tablet and one or two drugs in the form of two populations of units, or a population of units and one or two tablets alone. Suitable units for the formulation of the capsule can be prepared as described above, i.e., (i) a population of multiple stratified units comprising a proton pump inhibitor and a gastric antisecretory prostaglandin analogue, or (i) two populations of units. The capsule may comprise two or three different drugs, that is, a third population of units comprising a calcium channel blocking agent may be included. The unit alone can comprise any of the drugs, i.e., the proton pump inhibitor, the gastric antisecretory prostaglandin analog, or optionally the calcium channel blocking agent. When the unit alone comprises the prostaglandin analog, it may have the characteristics of immediate or prolonged release. The immediate release single units are preferably constructed according to the principles known in the art. Single-time extended-release units are constructed preferably as the hydrophilic matrix units, or as the hydrophobic matrix units, or as membrane coated units. Techniques for the application of the layers The layer can be applied by the coating or stratification procedures in suitable equipment such as the coating vessel, a coating granulator or in a fluidized bed apparatus using water and / or organic solvents for the process of coating. As an alternative, the layer (s) can be applied using powder coating or pressure coating techniques. Excipients The various pharmaceutically acceptable excipients can be used in combination with the active substances in the claimed dosage forms. Such excipients are, for example, binders, fillers, pH buffering agents, pigments and the like. Separation layer (s) Suitable materials for the separation or separating layer are pharmaceutically acceptable compounds such as, for example, sugar, or the forming compounds of films such as polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and others, used alone or in admixture. Additives such as plasticizers, colorants, pigments, fillers, anti-tack and anti-static agent, such as, for example, magnesium stearate, titanium dioxide, talcum, pH-buffering substances and other additives may also be included inside the separating layer. The separating layer is composed in such a way that it has the properties of being soluble in water or disintegrating in water. Enteric coating layer (s) The material of the enteric coating layer can be dispersed or dissolved in water or dissolved in suitable organic solvents. As one or more of the polymers of the enteric coating layer, they may be used separately or dissolved in combination, of the following, but not restricted to; for example, the copolymers of rrethacrylic acid, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxyioropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethylcellulose, shellac or other polymer (s) of the suitable enteric coating layer known in the art. Additives such as dispersants, colorants, additional polymers, for example, poly (ethylacrylate, methyl methacrylate), anti-tack agents and defoamers can also be included within the separating layer and / or enteric coating layer or a coating of the additional tablet as described above. Other compounds can be added to increase the thickness of the film and decrease the diffusion of acid gastric juices within the core material or nucleus susceptible to acid. The enteric coating layer (s) constitutes a thickness of at least 10 μm, preferably greater than 20 μm. The maximum thickness of the enteric coating layer (s) is normally only limited by the process conditions. The enteric coating layers may also contain pharmaceutically acceptable plasticizers to obtain suitable mechanical properties. Such plasticizers are, for example, but not restricted to, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates or other plasticizers and mixtures of the same. The amount of the plasticizers is preferably optimized for each formula, in relation to the selected polymer (s), selected plasticizer (s) and the applied amount of said polymer (s). Overcoating layer (s) The pellets or pellets covered with the enteric coating layer (s) can also be covered with one or more overcoating layer (s). The overcoating layer (s) can be applied to the enteric coating coated pellets by means of the coating or stratification procedures in suitable equipment such as the coating vessel., coating granulate, or in a fluidized bed apparatus using water and / or organic solvents for the coating process or cover with one layer. The materials for the overcoat layer (s) are chosen from pharmaceutically acceptable compounds such as, for example, sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methyl cellulose. , sodium carboxymethylcellulose and others, used alone or in mixtures. Additives such as plasticizers, dyes, pigments, fillers, antifog agents and anti-foaming agents, such as, for example, magnesium stearate, titanium dioxide, talc and other additives may also be included within the overcoat layer (s). The maximum thickness of the applied overcoat layer (s) is usually only limited by the process conditions. Hydrophilic Maker The active substance, ie the drug, is embedded in a hydrophilic polymer optionally together with the pharmaceutically acceptable excipients. Suitable hydrophilic polymers are, for example, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylhydroxyl ethylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, poloxamer, polyethylene oxides, polyvinyl pyrrolidone, polyvinyl alcohols, tragacanth, xanthan and guar gums. or any other hydrophilic polymer (s). These polymers can be used alone or in mixtures with some of the others. The amount of the hydrophilic polymer in the matrix is preferably 15-85% w / w (calculated on the weight of the unit) of a hydrophilic polymer (s) chosen from those mentioned above. The polymers that are particularly preferred in the hydrophilic matrix unit are hydroxypropyl methylcellulose or polyethylene oxides. The preferred excipients in the matrix are fillers that result in technically good tabletting properties, for example, sodium aluminum silicate, mannitol or calcium phosphate (Emcompress ™). A preferred matrix comprises 15-85% w / w (calculated on the weight of the unit) of a hydrophilic polymer chosen as above, and 80-10% w / w (calculated on the unit weight) of aluminum silicate and sodium or calcium phosphate (Emcompress ™). The Hydrophobic Matrix The active substance, i.e. the drug, is embedded is a hydrophobic matrix optionally together with the pharmaceutically acceptable excipients. The hydrophobic matrix comprises a hydrophobicizing agent and / or a hydrophobic polymer. Suitable materials for the hydrophobic matrix are, for example, cetanol, cetostearyl alcohol, cetyl palmitate, waxes similar to carnauba wax, paraffin, magnesium stearate, sodium stearyl fumarate, and medium chain glycerol esters. long alone or in any mixture. Hydrophobic polymers are exemplified by, for example, polyvinyl chloride, ethyl cellulose, polyvinyl acetate and copolymers of acrylic acid, such as Eudragith ™ RS and RL. The polymers can be used alone or as mixtures. In addition, the polymer can be combined with the hydrophobicizing agent. A binder for the hydrophobic matrix can use either hydrophilic or hydrophobic polymers. It is important that the matrix comprises at least one compound that is soluble in an aqueous medium such as the fluids of the intestine. This component dissolves and allows an opening in the porous network for the passage of the dissolved fluids and the dissolved drug. This soluble component can be, for example, sugar. It is preferable that the matrix comprises 10-70% w / w (calculated on unit weight) of the hydrophobicizing agent or a hydrophobic polymer and 10-70% w / w of a water-soluble compound, both described above, or any of the combinations of these. Another preferred matrix comprises as an additive, a slightly soluble or less soluble component. How any of the following components can be added: aluminum and sodium silicate, calcium phosphate, aerosil, titanium dioxide, magnesium carbonates, or other neutral or alkaline compounds, which are slightly soluble or less soluble, at this point with respect to solubility in water. Slightly soluble is defined as in accordance with the European Pharmacopoeia (3rd Edition) under the heading of "General News". Such a matrix preferably comprises 10-70% w / w (calculated on the weight of the unit) of a hydrophobicizing agent or a hydrophobic polymer or any of combinations thereof, together with preferably 10-70% w / w of a slightly soluble or less soluble component. As such component the sodium aluminum silicate is especially preferred. The profile of the final solution can sometimes be adjusted by thermal treatment of the hydrophobic matrix unit for a short period, to achieve temperatures at or above the softening or softening temperature of the hydrophobicizing agents. Particles that comprise oily material, such as for example the misoprost One way to prepare a particle that flows free of oily / greasy / sticky material is to incorporate this within the material of the inorganic porous particle, such as, for example, hydroxy apatite ceramic or amorphous silica. The ceramic hydroxyl apatite preferably has a particle size range between 5-250 μm, more preferably 80-150 μm, a nominal pore diameter of 50-1000 μm, more preferably 500-1000 μA; and a surface area between 40 - 50 m2 / g. The amorphous silica preferably has a mean pore diameter between 50-1000 A, more preferably 50-200 A; a pore volume of 0.8 -1.2 ml / g; and a surface area between 500 - 600 m2 / g. The incorporation of the oily material can be carried out by known conventional methods, such as dissolving the oil in a suitable solvent and then adding the porous particle material and drying the mixture. Alternatively, the oil can be mixed directly with the material of the porous particle, or the incorporation can be done using the phase separation of the solution containing the finished particles by the addition of a non-solvent. The particles of the charged pores can be filled into the capsule or compressed into tablets. The preparation of the particles comprising the oily material in small quantities can also be carried out by conventional methods, such as stratification or coating on inert seeds or by extrusion / spheronization. Tablet coating The prepared tablets are optionally coated with an agent (s) that forms the film to obtain a smooth surface of the tablet and further increase the stability of the tablet during packaging and transport. Such a coating of the tablet comprises a polymeric material which may further comprise additives similar to anti-tack agents, dyes and pigments or other additives to obtain a good looking tablet. The coating of the tablet may especially comprise a pigment to protect the slightly sensitive components of the dosage form. Active Ingredients I) the H +, K + -ATPase inhibitors, for example the proton pump inhibitors for the claimed therapies and the pharmaceutical formulations according to the present invention are the compounds of the general formula I, an alkaline salt thereof , one of the individual enantiomers thereof or an alkaline salt of one of the enantiomers.

Het? -X-S-Het2 Where Het2 is X = Where N in the benzimidazole portion means one of the ring carbon atoms substituted by R6-R_ may optionally be exchanged for a nitrogen atom outside any substituent. Ri, R2 and R3 are the same or different and are selected from hydrogen, alkyl, alkoxy, optionally substituted by fluorine, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and phenyloalkoxy; R4 and R5 are the same or different and are selected from hydrogen, alkyl and arylalkyl; R is hydrogen, halogen, trifluoromethyl, alkyl or alkoxy; R6-R. they are the same or different and are selected from the hydrogen, alkyl, alkoxy, halogen, haloalkoxy, alkylcarbonyl, oxazolinyl, trifluoroalkyl, or ring structures that form the adjacent groups R6-R9 which may also be substituted. Rio is hydrogen or which forms an alkylene chain together with R 3 and R n and R 2 are the same or different and are selected from hydrogen, halogen or alkyl. Examples of the compounds of particular interest according to formula I are prazol r.so; »Razol paiuoprazole piíriprazole leminoprazoi Suitable compounds for the formulations according to the present invention can be used in a neutral form or in the form of an alkaline salt, such as, for example, the Mg2 +, Ca2 +, Na + or K + salts, preferably the Mg2 + salts. . The compounds can also be used in the form of one of their individual enantiomers or an alkali salt of a single enantiomer. The preferred compounds for the 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 incorporated herein by reference.

The above compounds are susceptible to degradation / transformation in the acidic and neutral environment.

Generally, the degradation is catalyzed by acidic reaction compounds and the active compounds are stabilized with the alkaline reaction compounds. There are different stratified enteric coating preparations comprising the omeprazole as well as the proton pump inhibitors described in the prior art, see for example US-A 4,853,230, WO 95/01783 and WO 96/01624. Especially, the latter discloses alternative manufacturing methods for the preparation of enteric coated stratified pellets comprising omeprazole and similar compounds. These patents are incorporated into a set of references. II) Analogs of the gastric anti-secretory prostaglandin suitable for the claimed therapies and formulations are for example, misoprostol, enprostil, enisoprost, rosaprostol, miraprostal and the analogs with the following formulas misoprostol enprostil enisoprost twenty The compounds above can be used in the form of their individual enantiomers. II E) Calcium channel blockers that can optionally be used in combination with the proton pump inhibitor and a prostaglandin anti-secretory gastric analogue are, for example, the following known under the generic names of verapamil, felodipine , nifedipine and nisoldipine. The use of the preparations The dosage forms according to the present invention are suitable for oral administration. The dosage will depend on the nature and severity of the disease to be treated. The dose may also vary according to age, body weight, and individual patient's response. Children and patients with liver diseases as well as patients under a long-term treatment will generally benefit from the dose being somewhat lower than average. They will be used in the treatment of other conditions doses greater than the average. The dosage forms can also be used in combinations with other dosage forms comprising, for example, a calcium channel blocking agent, an NSAID, or other antiulcer agents. Dosage forms according to the invention are especially advantageous for patients who experience gastrointestinal side effects caused by gastric anti-secretory prostaglandin analogues, when used alone. The new dosage forms are administered several times a day, preferably once or twice daily. The typical daily dose of the active substances varies and depends on several factors such as the individual requirements of the patients, the mode of administration and the disease. In general, each dosage form will comprise 1-200 mg of the H + inhibitor, K + -ATPase and 80-1000 μg of the analogue (s) of the gastric anti-secretory prostaglandin. Preferably, each dose will comprise 5-80 mg of the H + inhibitor, K + -ATPase and 100-800 μg of the analogue (s) of the gastric anti-secretory prostaglandin, and more preferably 10-40 mg of the H + inhibitor, K + -ATPase. and 150-600 μg of the anti-secretory gastric prostaglandin analog (s), respectively. The combinations especially preferred comprise omeprazole and misoprostol in a range of 15: 1 to 400: 1, for example 20 mg of omeprazole together with 200 μm of misoprostol, or 20 mg of omeprazole and 400 μg of misoprostol. In the latter, misoprostol is preferably present in the form of a prolonged release formulation. The calcium channel blocking agent can be present in an amount of 1-100 mg. The preparation of the multiple unit, for example, a capsule or a tablet dosage form, may also be suitable for dispersion in an aqueous liquid with a slightly acidic pH value. The dispersion should be prepared just before it is orally administered or fed through a naso-gastric tube. The present invention is illustrated in more detail in the following non-limiting examples. Example Example 1 The two-layer tablet comprises misoprostol and omeprazyl (magnesium salt). The principle: one layer comprises 400 μg of misoprostol in a hydrophilic matrix, and the other layer comprises 20 mg of omeprazl (magnesium salt) in pellet form enteric coated mixed with the excipients in tablets. The extended release granules comprising misoprostol are prepared according to this formula: Misoprostol 0.4 parts by weight 95% Ethanol (weight / weight) 410 parts by weight Hydroxypropyl methyl cellulose 50 400 parts by weight cps Estearii sodium fumarate 4 parts by weight The misoprostol dissolved in half the amount of ethanol. This solution was poured into the HPMC powder during mixing. The rest of the ethanol was added to achieve the proper consistency of the dough. The mass was dried under the harsh conditions, and the particle size of the dried granules was reduced until all the granules passed in a 0.8 mm sieve. The 1% (weight / weight) of the sodium stearyl fumarate was mixed. The enteric coated pellets comprising the magnesium salt of omeprazole were prepared according to the following formula; Core or center material Magnesium omeprazole 12.00 kg Sugar spheres (non-pareil ™) 12.00 kg hydroxypropyl methylcellulose 1.8 kg Purified water 35.4 kg Separating layer Material of the center (according to 23.50 kg with the above) Hydroxypropyl cellulose 2.35 kg Talc 4.03 kg Magnesium stearate 0.34 kg Purified water 48.00 kg Enteric coating Coated pellets (29.00 kg according to the above) Methacrylic acid copolymer 38.70 kg (suspension at 30%) Triethyl citrate 3.48 kg Mono- and diglycerides (NF) 0.58 kg Polysorbate 80 0.06 kg Purified water 22.68 kg On coating Enteric-coated pellets 44.7 kg Hydroxypropyl methyl cellulose 0.58 kg Magnesium stearate 0.017 kg Purified water 11.6 kg The stratification of the suspension was carried out in an apparatus fluidized bed. Magnesium omeprazole was sprayed onto the non-pareil of a suspension in water containing the dissolved binder and magnesium omeprazole. The prepared core material was coated in a fluidized bed apparatus with the material of the separating layer. The enteric coating was sprayed onto the coated pellets in a fluidized bed apparatus of the same type of apparatus in which the enteric coated pellets were coated with an overcoat. The coated pellets were classified by sieving.

The tabletting excipient for mixing with the enteric coated pellets was prepared by mixing the following ingredients to homogeneity; Excipierte of formation of tablets Cellulose microcrystalline special coarse grade PH 102 12.12 g microcrystalline cellulose PH 101 6.06 g Crosslinked polyvinyl pyrrolidone 1.82 g sum: 20.00 g The tablets were compressed in a tablet machine, equipped with oval punches of 9x17 mm (giving tablets of elliptical form), or by precompression of 404 mg of the rulules containing misoprostol and then filling a mixture consisting of 100 mg of meprazole pellets (according to above) and 200 mg of the tablet-forming excipient mixture , and compressing. Two-layer tablets with an acid resistance of 91% (mean value of 4 tablets) were obtained. The release of omeprazole at pH 6.8 from a pre-exposed tablet 2 h in 0.1 N HCl, spectrophotometric determination, was 89% in 30 minutes.

EXAMPLE 2 Enteric-coated pellets containing the magnesium salt of S-omeprazole, stratified with misoprosol. Principle: Enteric-coated pellets comprising approx. 225 mg / g of magnesium salt of S-omeprazole, stratified with an outer layer of fast dissolution, comprising approx. 3.6 mg / g of misoprostol. The enterically coated pellets comprising the magnesium salt of S-omeprazole were prepared according to the following recipe; Core material Mg salt of S-omeprazole 20.0 kg Non-pareil ™ 25.0 kg Hydroxypropyl methylcellulose (HPMC) 3.0 kg Polysorbate 80 0. kg Purified water 93.6 kg Separating layer Core material (according to above) 50.0 kg Hydroxypropyl cellulose 5.5 kg Talc 20.5 kg Magnesium stearate 1.4 kg Purified water 193.8 kg Enteric coating Pelotil Coated (according to the above) 30.0 kg Methacrylic acid copolymer (30% suspension) 30.0 kg Triethyl citrate 0.9 kg Mono- and diglycerides (NF) 0.3 kg Polysorbate 80 0.05 kg Purified water 12.9 kg The stratification of the suspension was carried out in a fluidized bed apparatus, the magnesium salt of S-omeprazole was pulverized in non-pareil, from a suspension of water containing the dissolved binder. The prepared core material was coated with the material of the separating layer in a fluidized bed apparatus. The enteric coating was sprayed onto the coated pellets in a fluidized bed apparatus. The enteric coated pellets were classified by sieving. The enteric coated pellets were further coated with a solution of HPMC and misoprostol in a fluidized bed apparatus, using the following composition; Enteric-coated pellets (according to above) 100 g Solution; 95% EtOH (w / v) 125 g Misoprcstol 0.46 g Purified water 125 g Hydroxypropyl methyl cellulose (HPMC) 6 cps. 5.3 g Colloidal silica (Aerosil ™) 0.5 g First the misoprostol was dissolved in the ethanol and after the water was added. The HPMC was mixed and dissolved. Finally the Aerosil ™ was dispersed in the solution. The pellets obtained were classified by sieving. The acid resistance of the pellets prepared was 99.6%. The pellets can be mixed with excipients of tablets and tablets in a multi-unit tablet, as described in Example 5, or filled into a capsule for the desired dose. Example 3 The two-layer tablets with 400 μg of misoprostol and 10 mg of felodipine comprised in a hydrophilic matrix as one layer, and the other layer comprising mg of omeprazole (magnesium salt) in the form of enteric-coated pellets mixed with a tabletting excipient. Prolonged-release granules comprising misoprostol and felodipine are prepared according to the following recipe; Parts by weight Misoprostol 0.4 Felodipine 10 Castor oil (Cremofor RH 40) Hydrogenated polyoxyl 40 10 95% Ethanol (w / v) 400 Hydroxypropyl methyl cellulose 50 cps 400 Stearyl fumarate sodium 4 Misoprostol dissolves in the middle of the amount of ethanol. Another solution is made by dissolving 10 parts of the felodipine and 10 parts of the Cremophor RH 40 in 60 parts of ethanol. These solutions are poured into the HPMC powder during mixing. Additionally, ethanol (approximately 140 parts) can be added to obtain a satisfactory dough consistency. The dough is dried on a tray (under mild conditions). The particle size of dry granules is reduced until all the granules pass a 0.8 mm sieve. Then, 1% sodium stearyl fumarate is mixed. Coated pellets comprising magnesium salt of omeprazole were prepared and mixed with the tablet-forming excipients, according to Example 1. The two-layer tablets containing 400 μg of misoprostol, 10 mg of felodipine and 20 mg of omeprazole , were prepared as described in Example 1. The tablets were coated with a solution of HPMC and PEG having pigments dispersed therein, in a suitable coating apparatus, for example, a rotating drum coating, using the following composition; Tablets (according to the above) 724 parts by weight Solution; Purified water 122 parts by weight Hydroxypropyl methyl cellulose (HPMC) 6 cps 14 parts by weight polyethylene glycol (PEG) 6000 4 parts by weight titanium dioxide 2 parts by weight yellow iron oxide 2 parts by weight The coating is continued until the average weight of the tablets has been increased to 14-20 mg. Example 4 Formulation of capsules comprising pellets of pantoprazole and misoprostol, (40 mg of pantoprazole and 200 μg of misoprostol). The enterically coated pantoprazole pellets are prepared according to the following formula; Materia], from the core Pantoprazole 100 g Non-pareil ™ 200 g Hidroxip > ropilcelulosa LF 25 g Purified water 607 g Separating layer Core material (according to the above) 200 g Hydroxypropyl cellulose LF 20 g Talc 34.3 g Magnesium stearate 2.9 g Purified water 400 g Enteric coating Coated pellets (according to above) 200 g Methacrylic acid copolymer, 30% suspension 333 g Triethyl citrate 30 g Mono- and diglycerides (NF) 5 g Polysorbate 80 0.5 g Purified water 182.5 g The stratification of the suspension is carried out in a fluidized bed apparatus. Pantoprazole is sprayed or sprayed non-pareil from a suspension of water containing the dissolved binder. The prepared core material is coated with the material of the separating layer in a fluidized bed apparatus. The enteric coating is sprayed onto the coated pellets in a fluidized bed apparatus.

The pellets are classified by sieving. The pellets are prepared by coating them with inert sugar spheres in a fluidized bed, according to the following formula; Sugar spheres (Non-pareil ™) 100 g Solution; 95% EtOH (w / v) 125 g Misoprostol 0.46 g Purified water 125 g Hydroxypropyl methyl cellulose 5.34 g Colloidal silica 0.50 g First dissolve the misoprostol in the ethanol and then add the water. The HPMC is mixed and dissolved. Finally the Aerosil ™ is dispersed in the solution. The pellets obtained are classified by sieving. Filling the capsules; 266 mg of enteric-coated pantoprazole pellets or pellets and pellets corresponding to 200 μg of misoprostol (i.e., about 55 mg) were filled into No. 1 hard gelatin capsules. Example 5 Multi-unit tablets comprising pellets of lansoprazole and misoprostol (60 mg of lansoprazole and 200 μg of misoprostol). The pellets of lansoprazole are prepared according to the following formula; Core material Lansoprazole 370 g Non-pare: .l ™ 400 g Hydroxioropyl methyl cellulose 76 g Sodium lauryl sulfate 2.8 g Purified water 1360 g Separating layer Core material (as above) 400 g Hydroxypropyl cellulose 40 g Talcum 68.6 g Stear: o Magnesium 5.7 g Purified water 800 g Enteric coating PelotilLas coated (according to the above) 400 g Copolymer of methacrylic acid, 30% suspension 667 g (containing dry materials 200g) Triethyl citrate 60 g Mono- and diglycerides (NF) 10 g Polysorbate 80 1 g Purified water 420 g On coating Enteric-coated pellets 500 g Hydroxypropyl methylcellulose 6.5 g Magnesium stearate 0.2 g Purified water 130 g The enteric-coated pellets comprising lansoprazole are prepared as described in Example 1, with lansoprazole replacing omeprazole. Tablets mg / tablet PelotilLas that comprise lansoprazole (according to the above) approx. 285 Pellets comprising misoprostol (according to Ex. 4) approx. 55 microcrystalline cellulose PH 102 205 microcrystalline cellulose PH 101 205 polyvinyl pyrrolidone crosslinked 30 stearyl .. sodium fumarate 4 First, the microcrystalline celluloses and the polyvinyl pyrrolidone are mixed homogeneously. The sodium stearyl fumarate lubricant is then mixed, and then the pellets comprising the lansoprazole and the pellets comprising the misoprostol are added and mixed until homogeneous. Compression for tablets is made by compressing the mixture in a tablet machine equipped with 9x21 mm oval punches.

EXAMPLE 6 The two-layer tablet with 200 μg in one layer, and the other comprises 10 mg of S-omeprazole (magnesium salt) containing pulsed release, delayed pellets mixed with tablet-forming excipients. The granules comprising misoprostol are prepared according to this formula; Parts by weight Misoprostol 0.2 95% (w / v) ethanol 300 Purified water 110 Hydroxypropyl methyl cellulose 6 cps 50 Microcrystalline cellulose PH 101 350 Sodium stearil fumarate 4 Misoprostol is dissolved in 200 parts of ethanol. This solution is poured into the HPMC and the microcrystalline cellulose powders during mixing. Then, a satisfactory amount of a mixture consisting of 100 parts of ethanol and 110 parts of water is mixed until a satisfactory consistency of the mass is obtained. The dough is dried under mild conditions. The particle size of the dried granules is reduced until all the granules pass a 0.8 mm sieve. Then 1% stearyl fumarate sodium (w / w) is mixed. The preparation of delayed pulsed release pellets, comprising magnesium salt of S-omeprazole (pellet strength about 44 mg / g). Preparation of core material (spheres stratified with drug) A drug containing a suspension is prepared according to the composition below; Mg salt of S-omeprazole 100g HPMC, 6 cps 15g Polysorbate 80 2g Purified water 323g HPMC is dissolved in water during agitation with the subsequent addition of Polysorbate 80 and the drug.

The suspension is pulverized in 290 g of sugar spheres (non-pareil) in a fluidized bed. The weight of the product is approx. 395g. Application of the inflation layer A suspension (free of water) containing highly inflatable substances is prepared according to the following composition; Little substituted hydroxypropylcellulose (L-HPC) 162g Hydroxypropylcellulose LF (HPC-LF) 74g Talc 354g EtOH (99.5%) 3100g The HPC-LF dissolves during the stirring, then the talc and the swelling agent L-HPC are added. The suspension is sprayed on 175g pellets containing the drug from above in a fluidized bed equipped with Wurster. The weight of the product is usually approximately 710 g. Application of the delay time controlling layer (semipermeable membrane). A coating suspension is prepared according to the following formula. Ethylcellulose, 10 cps lOg Talc 23g EtOH (99.5%) lOOOg Ethylcellulose is dissolved in the ethanol during stirring, then the talc is added. The pulverization of the suspension in 150g of pellets from above (0.61-0.71 mm, obtained by sieving), is done in a fluidized bed equipped with Wurster. The weight of the pellets obtained is usually 175g approx. Application of the enteric coating layer.

The pellets above were enterically coated in a fluidized bed with a coating dispersion according to the one below; Eudragit L30 D-55 (30% dispersion w / w) 73g Triethyl citrate 6.6g Glycerol monostearate (GMS) 0.3g Polysorbate 80 0.03g Purified Water 40.4g A homogeneous coating dispersion is prepared by dispersing the polysorbate 80 and the glycerol monostearate in water. The triethyl citrate is dissolved in the Eudragit dispersion and then the two dispersions are mixed to obtain the coating dispersion. The coating dispersion is applied on 120g pellets, using a fluidized bed equipped with Wurster. The weight of the enteric coated pellets is usually approximately 140g. Preparation of the tablets. The tablet-forming excipient for mixing with enteric-coated pellets is prepared by mixing the following ingredients in homogeneity; Tablet forming excipient; Microcrystalline cellulose coarse grade 12.12g special PH 102 Microcrystalline cellulose pH 101 6.06g Crosslinked polyvinyl pyrrolidone 1.82g Sum: 20.00g The compression for the tablets is done in a tablet machine equipped with 9x21 mm oval punches (giving elliptical tablets). The tablets are prepared by first pressing 404 mg of the granules containing misoprostol and then filling a mixture consisting of 270 mg approx. of magnesium salt of S-Omeprazole comprising the pellets (according to the above) and 270 mg of the mixture of the tablet-forming excipient. EXAMPLE 7 Enterally-coated tablets, containing 45 mg of omeprazole (magnesium salt), in a hydrophilic matrix, having an enteric coating of fast dissolution on the enteric coating, the outer coating, comprises 220 μg approx. of misoprostol. Prolonged-release tablets containing the magnesium salt of omeprazole (45 mg approx.) Granules for tablet cores according to the following composition (parts by weight); Magnesium salt of omeprazole 80 Hydroxypropyl methyl cellulose 50 cps 300 Polyvinyl pyrrolidone (PVP) K-90 40 Ethanol 99.5% (w / v) 400 PVP dissolves in alcohol. The other two ingredients are mixed and then moistened with the PVP solution in a mixer. Then, the mass obtained is dried in a drying oven at 50 ° C. After grinding in an oscillating mill through a 1.0 mm sieve, the obtained granules are mixed with tablet lubricant, according to the following composition (parts by weight); Granules for tablet core 412 Sodium stearyl fumarate (Pruv®) 4 The ingredients are mixed, then the mixture is compressed into tablets (9 mm diameter) having an average weight of 265 mg, in a tablet-forming machine. Tablets covered with separating layers. The tablets obtained are first coated with a separating layer in, for example, an apparatus for coating the rotating drum with a coating suspension of the following composition; 90.5% EtOH (w / v) 85 parts by weight Purified water 85 parts by weight Hydroxypropyl methylcellulose 6 cps 10 parts by weight Talc, micronized 2 parts by weight Sum: 182 parts. The coating of the tablets is continued until the average weight of the tablets is approximately 264 g. Enteric coated tablets The tablets coated with a separating layer are coated with an enteric coating layer in the same pack as for the preceding coating step. The coating solution to be used has the following composition; Hydroxypropyl methylcellulose phthalate (HP-55®) 19 parts by weight Cetanol 1 part by weight Acetone 182 parts by weight Ethanol (95% w / v) 78 parts by weight Sum: 280 parts i The tablets with coating of separating layers are processed and the coating is continued until the average weight of the tablets is 293 mg. Enteric coated tablets, coated with a layer of misoprostol. Enteric coated omeprazole magnesium salt tablets are coated with a solution of HPMC and misoprostol in, for example, a rotating drum coating apparatus, using the following composition; Dispersion EtOH 95% (w / v) 125 parts by weight Misoprostol 0.46 parts by weight Purified water 125 parts by weight Hydroxypropyl methyl cellulose (HPMC) 6 cps 5.34 p. in P. Colloidal silica (Aerosil RTM) 0.50 parts by weight First the misoprostol dissolves in the ethanol and then the water is added. The HPMC is mixed and dissolved. Finally the Aerosil ™ is dispersed in the solution. The coating is continued until the average weight of the tablets is 296 mg. Example 8 Enteric coated tablets, comprising 20 mg of omeprazole (magnesium salt), in a hydrophilic matrix, having an outer layer of the hydrophilic matrix on the enteric coating, the outer layer comprising 200 μg of misoprostol. Granules comprising magnesium salt of omeprazole are prepared according to this recipe; Mg / tablet Magnesium salt of omeprazole 22. 5 95% ethanol (w / v) 90 Hydroxypropyl methyl cellulose (HPMC) 50 cps 50 Hydroxypropyl methyl cellulose (HPMC) 1000 cps 40 Polyvinyl pyrrolidone (PVP) K-90 6. 5 PVP dissolves in ethanol. This solution is poured into the mixed powders of the HPMCs and the powder of the magnesium salt of omeprazole during continuous mixing. The dough is dried in a tray at 50 ° C in a drying oven. After grinding through a 0.8 mm sieve, the obtained granules are mixed with the tablet lubricant according to the following composition; Granules 119 g Stearyl fumarate sodium 1 g The mixing is carried out in homogeneity, for example, in a Kenwood mixer. It is then compressed into 6 mm diameter tablets having an average weight of 120 mg, in a tablet machine. The tablets are coated with a separating layer using an HPMC solution and coating, for example in a fluidized bed coating apparatus or a rotating drum coater, using the following composition; 95% (w / v) EtOH 125 parts by weight Purified water 125 parts by weight Hydroxypropyl methyl cellulose (HPMC) 6 cps 5.3 parts by weight HPMC is dissolved in the ethanol / water mixture. The coating is continued until the average weight of the tablets has been increased with 4 mg (ie, if the initial average weight is 120 mg, to 124 mg). The separating layer coated tablets are coated with an enteric coating layer in the same equipment as for the preceding coating step. The coating solution has the following composition; Hydroxypropyl methyl cellulose phthalate (HP-55) 16 parts by weight Cetanol 1 part by weight Acetyl tributyl citrate 1 part by weight Acetone 153 parts by weight Ethanol (95% w / v) 65 parts by weight Sum: 236 parts by weight The tablets are coated until the average weight of the tablets is 133 mg. The obtained, enteric-coated omeprazole magnesium salt tablets obtained are dry-coated in a suitable tablet-forming machine with a granulate comprising HPMC and misoprostol, prepared using the following composition; Misoprostol 0.2 parts by weight 95% ethanol (w / v) 200 parts by weight Hydroxypropyl methyl cellulose (HPMC) 50cps 200 parts by weight First dissolve misoprostol in ethanol.

The solution is then poured into the HPMC powder during mixing. The dough is dried using mild conditions.

The obtained dry granules are milled in an oscillating granulator equipped with a 1.0 mm sieve. For the manufacture of each dry-coated prolonged-release tablet, one enteric-coated omeprazole magnesium salt tablet and 200 mg of misoprostol, comprising the prolonged release granulate, and compressed with 10 mm diameter punches. Example 9 Formulation of capsules comprising 20 mg of pantoprazole and 400 μg of misoprostol, the latter comprised in a plug of hydrophilic matrix. The pantoprazole pellets are prepared as described in Example 5, with lansoprazole replacing pantoprazole. The prolonged release cap comprising misoprostol is prepared by first making a granulation according to this recipe; Misoprostol 0.4 parts by weight 95% ethanol (w / v) 110 parts by weight Hydroxypropyl methyl cellulose 50 cps 118 parts by weight Misoprostol is dissolved in 110 parts of ethanol. This solution is poured into the HPMC powder during mixing. The dough is dried under mild conditions. The particle size of the dried granules is reduced until all the granules pass through a 0.8 mm sieve. Then, the stearyl sodium fumarate lubricant is mixed, according to the following recipe; granules according to above 118.4 parts by weight stearyl sodium fumarate 1.6 parts by weight sum: 120.0 parts by weight The mixing is carried out homogeneously in a mixer. Then they are compressed to 6mm diameter plugs (tablets) that have an average weight of 120 mg, in a tablet-forming machine. Filling the capsules; A cap according to the above and 95 mg pantoprazole pellets are filled into a capsule of hard gelatin of size no. 1. EXAMPLE 10 Tablet with enteric coating, stratified with dual pulsed release of magnesium salt of omeprazole (2 x about 15 mg), which has a fast dissolving outer coating on the enteric coating, the outer layer 'comprises 220 μg of misoprostol. Granules The granules for the cores of the tablets are prepared according to the following composition; Parts by weight Mg salt of omeprazole 229 Microcrystalline cellulose, Avicel PH 101 151 Microcrystalline cellulose, Avicel PH 102 sp coarse grade 400 L-HPC 256 PVP-XL 302 Sodium lauryl sulfate 30 Purified water 1060 A granulation solution is prepared by dissolving the SLS in 460 parts of purified water. The above powders are mixed in a mixer after which the solution is added to a leveled stream. Then add approx. 600 parts of water during continuous mixing, to give a satisfactory consistency to the dough. The dough is dried in a drying oven at 50 ° C overnight. Preparation of tablet cores. After grinding through a 1.0 mm sieve, the obtained granules are mixed with tablet lubricant, sodium chloride and an additional quantity of the inflatable substance, according to the following composition; Parts by weight Granules for homogeneous tablet cores 400 sodium chloride (passing through 0.3 mm) 80 sodium stearyl fumarate (Pruv®) 8 cross-linked polyvinyl pyrrolidone (PVP-XL) 20 Mixing is carried out in a homogeneous mixer, for example, Kenwood. It is then compressed into 6 mm diameter tablets having an average weight of 126 mg in a tablet-forming machine. Application of a time delay controller layer (semipermeable membrane). The tablets are coated in a fluidized bed apparatus, equipped with Wurster with a coating suspension, following the following composition; 99.5% EtOH (w / v) 291 parts by weight Ethyl cellulose N-10 11 parts by weight Talc, micronized 7 parts by weight Sum: 309 parts The tablets are coated and the coating is continued until the average weight of the tablets it is 134 mg.

Application of the layer containing the drug. The obtained tablets are coated in the same equipment as above, with a coating suspension of the following composition; Mg salt of S-omeprazole 20 parts by weight Hydroxypropyl methylcellulose 6 cps 13 parts by weight 99% ethanol 128 parts by weight purified water 128 parts by weight sum: 289 parts. The tablets are coated and the coating is continued until the average weight of the tablets is 162 mg. Tablets coated with separating layers The obtained tablets are first coated with a separating layer in, for example, a rotary tamber coating apparatus, with a coating suspension of the following composition; 99.5% EtOH (w / v) 85 parts by weight Purified water 85 parts by weight Hydroxypropyl methyl cellulose 6 cps 10 parts by weight talc, micronized 2 parts by weight sum: 182 parts. The coating of the tablets is continued until the average weight of the tablets is approx. 166 mg. Application of the enteric coating layer. The obtained tablets are coated with an enteric coating layer in the same equipment as for the preceding coating step. The coating solution has the following composition; Hydroxypropyl methyl cellulose phthalate (HP-55) 16 parts by weight Cetanol 1 part by weight acetone 153 parts by weight ethanol (95% w / v) 65 parts by weight sum: 235 parts by weight The tablets are coated and the coating continue until the average weight of the tablets is 177 mg. The enteric-coated dual-release S-omeprazole magnesium salt tablets are coated with a solution of HPMC and misoprostol, for example, in a fluidized bed coating apparatus. or rotating drum coater, using the following composition; Tablets (according to the above) 100 parts by weight Solution; 95% EtOH (w / v) 125 parts by weight Misoprostol 0.46 parts by weight Purified water 125 parts by weight Hydroxypropyl methyl cellulose (HPMC) 6 cps 5.34 parts by weight Colloidal silica (Aerosil ™) 0.50 parts by weight First, the misoprostol in the ethanol, and then the water is added. The HPMC is mixed and dissolved. Finally the Aerosil ™ is dispersed in the solution. The coating is continued until the average weight of the tablets has been increased by 3 mg (ie, if the initial average weight is 177 mg, to 180 mg). EXAMPLE 11 The two-layer tablets, comprising 200 μg of misoprostol and pellets of 20 mg of omeprazole (magnesium salt), are mixed with the tabletting excipients, in one layer, and the other layer, comprises 30 mg of nifedipine in a hydrophilic matrix.

Prolonged-release granules containing nifedipine were prepared according to this formula; Nifedipine 30 g Castor oil Polyoxyl 40 Hydrogenated 30g Ethanol 99.5% (w / v) 300g Ethyl cellulose N-10 20g Propyl gallate 0.06g Hydroxypropyl methyl cellulose 50 cps 175g Sodium aluminum silicate 75g Sodium stearil fumarate 6g nifedipine, hydrogenated polyoxyl 40 castor oil and propyl gallate are loaded into ethanol. This liquid is heated and stirred until a solution is formed, maintaining the maximum temperature of the mixture at 70 ° C. Then ethyl cellulose is added and dissolved. The solution obtained is poured into a mixture of HPMC and sodium aluminum silicate during mixing. The mass is dried in a safe blast-drying cabinet, then ground in an oscillating granulator, which has a sieve with 1 mm openings. The obtained granules are mixed with the stearyl fumarate sodium lubricant for 2 minutes. The enterically coated pellets comprising the magnesium salt of omeprazole were prepared as described in Example 1. The pellets of misoprostol were prepared by dissolving misoprostol in ethanol and then mixing the porous silica particles with this solution according to the following recipe; Misoprostol 0.16 parts by weight Silica particles, Porous, diameter Of apr. 150 μm 53.14 parts by weight 95% ethanol (w / v) 42.5 parts by weight The mass is dried under mild conditions. The obtained misoprostol pellets contain approx. 3.75 mg of misoprostol per gram. The excipients for tabletting for blending with omeprazole pellets and misoprostol are prepared by mixing the following ingredients to homogeneity; Excipients for tablet formation special grade coarse-grained microcrystalline cellulose PH 102 12.12 parts by weight microcrystalline cellulose pH 101 6.06 parts by weight crosslinked pyrrolidone polyvinyl chloride 1.82 parts by weight sum: 20.00 parts by weight Tablet compression is done in a tablet machine equipped with 9x17 mm oval punches (giving elliptical tablets). The tablets are prepared by first pre-compressing 336 mg of the granules containing nifedipine and then filling a mixture consisting of 100 mg of the pellets comprising magnesium salt of omeprazole (as above), 53 mg of pellets containing misoprostol and 200 mg of the mixture of excipients for tabletting, giving a total weight of 689 mg tablets. To protect nifedipine in the tablets against proteolytic degradation, the tablets are coated with a solution of HPMC and PEG, having pigments dispersed therein, in a fluidized bed coating apparatus or a rotating drum coater, using the following composition; Tablets (according to above) 336 parts by weight Solution; purified water 122 parts by weight hydroxypropyl methyl cellulose (HPMC) 6 cps 14 parts by weight polyethylene glycol (PEG) 6000 4 parts by weight titanium dioxide 2 parts by weight yellow iron oxide 2 parts by weight the coating is continued until that the average weight of the tablets has increased with 15-20 mg. Example 12 Enteric coated pellets, comprising approximately 225 mg / g of magnesium salt of S-omeprazole and misoprostol, approx. 3.5 cm / g of pellets where the last one is placed in a prolonged release layer. The enterically coated pellets comprising the magnesium salt of S-omeprazole are prepared as described in Example 2. The enteric-coated pellets are coated with a solution of HPMC and misoprostol in a fluidized bed apparatus, using the following composition; Entotically coated pellets (according to above) 100 parts by weight Solution; 95% EtOH (w / v) 300 parts by weight Purified water 50 parts by weight Misoprostol 0.46 parts by weight Hydroxypropyl methyl Cellulose (HPMC) 50 cps 5.34 parts by weight Colloidal silica (Aerosil ™) 0.50 parts by weight First, dissolves the misoprostol in the ethanol and then the water is added. The HPMC is then mixed and dissolved. Finally the Aerosil ™ is dispersed in the solution. The pellets obtained are classified by sieving. The pellets prepared can be compressed into a multi-unit tablet as described in Example 5, or filled into a capsule suitable for the desired dose. It is noted that with respect to this date, the best method known to the applicant to carry out the present invention is that which is clear from the present description of the invention.

Claims (35)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A pharmaceutical oral dosage form, characterized in that it comprises an inhibitor of H +, K + -ATPase and a gastric antisecretory prostaglandin analogue compound and optionally pharmaceutically acceptable excipients, wherein the dosage form is in the form of a fixed dosage form comprising at least these two pharmaceutically active components.
2. 2. A dosage form according to claim 1, characterized in that, the dosage form is a tablet formulation.
3. 3. A dosage form, according to claim 1, characterized in that, the dosage form is a capsule formulation.
4. 4. A dosage form according to any of claims 1-3, characterized in that, the H + inhibitor compound, K + -ATPase is protected by an enteric coating layer, and optionally a separating layer. applied under the enteric coating, separating the H + inhibitor, K + -ATPase from the enteric coating layer.
5. 5. A dosage form according to claim 1, characterized in that the fixed dosage form, in addition to the H + inhibitor, K + -ATPase and the gastric antisecretory prostaglandin analogue, comprises a calcium channel blocking agent.
6. 6. A dosage form according to any of claims 1-5, characterized in that the inhibitor of H +, K + -ATPase is omeprazole, an alkaline salt thereof, one of its enantiomers alone or an alkaline salt thereof.
7. 7. A dosage form according to claim 6, characterized in that the inhibitor of H +, K + -ATPase is the magnesium salt of omeprazole.
8. 8. A dosage form according to claim 6, characterized in that, the inhibitor of the H +, K + -ATPase is the magnesium salt of S-omeprazole.
9. 9. A dosage form according to any of claims 1-5, characterized in that, the inhibitor of H +, K + -ATPase is lansoprazole, or one of its enantiomers alone or a pharmaceutically acceptable salt thereof.
10. 10. A dosage form according to any of claims 1-5, characterized because, the inhibitor of H +, K + -ATPase is pantoprazole, or one of its enantiomers alone or a pharmaceutically acceptable salt thereof.
11. 11. A dosage form according to one of claims 1-10, characterized in that the gastric antisecretory prostaglandin analogue compound is misoprostol, enisoprost, enprostil or one of the single or single enantiomers thereof or a pharmaceutically acceptable salt of the same.
12. 12. A dosage form according to any of claims 1-11, characterized in that, the amount of inhibitor of H +, K + -ATPase is in the range of 1-200 mg and the amount of analogous compound of gastric antisecretory prostaglandin. It is in the range of 80-1000 μg.
13. 13. A dosage form according to any of claims 1-12, characterized in that, the amount of inhibitor of H +, K + -ATPase is in the range of 5-80 mg and the amount of analogous compound of gastric antisecretory prostaglandin. It is in the range of 100-800 μg.
14. 14. A dosage form in tablet form according to claim 2, characterized in that, the tablet consists of two different layers, a first layer that cotiprende inhibitor of H +, K + -ATPase and a second layer comprising the analogous compound of prostaglandin gastric antisecretory.
15. 15. A tablet dosage form according to claim 2, characterized in that the tablet formulation is a multi-unit tablet dosage form, comprising a) the inhibitor of the H +, K + -ATPase pellet form stratified with enteric coatingb) the gastric antisecretory prostaglandin analogue compound and optionally, c) the pharmaceutically acceptable excipients comprised together in a tablet, whereby the enteric coating layer covering the individual pellets has mechanical properties such that the formation of tablets of the pellets together with the gastric antisecretory prostaglandin analog and optionally the pharmaceutically acceptable excipients do not significantly affect the acid resistance of the enteric coated laminated pellets or pellets.
16. 16. A tablet dosage form according to claim 15, characterized in that the enteric coating of the individual pellets comprises a plasticized material in the enteric coating layer.
17. 17. A tablet dosage form according to claim 15, characterized in that the enteric coated stratified pellets are further coated with an overcoat layer, comprising a film forming polymer and pharmaceutically acceptable excipients.
18. 18. A tablet dosage form according to any of claims 15-17, characterized in that the tablet is divisible.
19. 19. A tablet dosage form according to claim 2, characterized in that at least a part of the tablet is in the form of a sustained release formulation.
20. 20. A tablet dosage form according to claim 19, characterized in that the part of the tablet that gives the prolonged release is a h: .drofílica matrix.
21. 21. A tablet dosage form according to claim 19, characterized in that the part of the tablet that gives the prolonged release is a hydrophobic matrix.
22. 22. A tablet dosage form according to claim 2, characterized in that the tablet consists of two different layers, a first layer comprising the H + inhibitor, K + -ATPase, in the form of enteric coated, layered pellets, compressed with the excipients of the tablet in one layer, and a second layer which gives a prolonged release of the gastric anti-secretory prostaglandin analogue.
23. 23. A tablet dosage form according to claim 2, characterized in that the tablet comprises enteric-coated stratified pellets of the H + inhibitor, K + -ATPase, layered with another layer comprising the gastric antisecretory prostaglandin analog, and the stratified pellets are compressed with the excipients of the tablet to a tablet.
24. 24. A tablet dosage form according to claim 23, characterized in that, the pellets before compression to a tablet are covered by a coating layer of a pigmented film or the compressed tablet is covered with a pigmented coating of the tablet.
25. 25. A tablet dosage form according to claim 2, characterized in that the tablet consists of two types of laminated pellets, the first type consisting of enteric coated laminated pellets, comprising the inhibitor of H +, K + -ATPase and the second type, consists of pellets that comprise the gastric antisecretory prostaglandin analogue, all the pellets are compressed together with the excipients of tablets to a tablet.
26. 26. A tablet dosage form according to claim 22, characterized in that the tablet consists of enteric coated stratified pellets, comprising the H + inhibitor, K + -ATPase, and pellets comprising the built-in gastric antisecretory prostaglandin analogue. in a matrix, giving a prolonged release of the prostaglandin analog.
27. 27. A dosage form according to claim 3, characterized in that the capsule comprises two types of laminated pellets, the first type consis: e of enteric coated stratified pellets, comprising the H + inhibitor, K + -ATPase and the second type, consists of pellets comprising the gastric antisecretory prostaglandin analog, all the pellets and optionally pharmaceutically acceptable excipients are filled in the capsule
28. 28. A process for the manufacture of a fixed dosage form, comprising an inhibitor of H +, K + -ATPase and one or more analogue (s) of gastric antisecretory prostaglandin, in a capsule, characterized in that the H + inhibitor, K + -ATPase is prepared in the form of layered enteric coating pellets and the gastric antisecretory prostaglandin analog is prepared in the form of stratified pellets coated with an extended release film, the pellets are optionally mixed with the pharmaceutically acceptable excipients, and the mixture It is filled in capsules.
29. 29. A process for the manufacture of a fixed dosage form, comprising an inhibitor of H +, K + -ATPase and one or more gastric antisecretory prostaglandin analogs in a multi-unit tablet dosage form, characterized in that the inhibitor of the H +, K + - ATPase is prepared in the form of enteric coated pellets and these pellets are mixed with the pellets comprising the gastric antisecretory prostaglandin analog, and optionally the pharmaceutically acceptable excipients, then the mixture is compressed into multiple unit tablets without causing any significant change in the acid resistance of stratified pellets.
30. 30. A process for the manufacture of a fixed dosage form, comprising an inhibitor of H +, K + -ATPase and one or more gastric antisecretory prostaglandin analogs in a multi-unit tablet dosage form, characterized in that the inhibitor of the H +, K + -ATPase is prepared in the form of enteric coated pellets and the gastric antisecretory prostaglandin analog is prepared in the form of coated pellets, wherein the coating layer is an extended release layer, the pellets are mixed , optionally with the pharmaceutically acceptable excipients of tablets, and compressed into tablets without causing any significant change in the acid resistance of the enriched, layered, pelletized pellets.
31. 31. The use of a dosage form according to any of claims 1-27, in the manufacture of a medicament for the treatment or prophylaxis of gastrointestinal diseases.
32. 32. The use of a dosage form according to any of claims 1-27 in the manufacture of a medicament to avoid collateral gastrointestinal effects, usually associated with treatment with a secretory gastric prostaglandin analogue.
33. 33. A combination of an H + inhibitor, K + -ATPase, a gastric antisecretory prostaglandin analogue and a calcium channel blocking agent, in the treatment of gastrointestinal diseases.
34. 34. A bubble pack, characterized in that, I understood, an inhibitor drug of H +, K + -ATPase and an analogous drug of gastric antisecretory prostaglandin.
35. 35. A bubble pack according to claim 34, characterized in that it comprises an additional medicament, which is a calcium channel blocking agent. NEW PHARMACEUTICAL FORMULATION SUMMARY OF THE INVENTION This invention relates to new oral pharmaceutical dosage forms comprising a proton pump inhibitor, for example an inhibitor H +, K + -ATPase, an analogous compound of the gastric anti-secretory prostaglandin, and optionally a drug additional agent such as the calcium channel blocking agent, especially for its use in the treatment of the prophylaxis of gastrointestinal disorders. More specifically the invention relates to new dosage forms comprising omeprazole and misoprostol. The invention also relates to a combination of three drug categories, for example, the H + inhibitor, K + -ATPase, the gastric anti-secretory prostaglandin analogue, and the calcium channel blocking agent. Furthermore, the invention relates to a method for the manufacture of the dosage forms described and their uses in medicine, as well as to the packages of bubbles or ampoules comprising these medicaments.