MX2008006727A - Oral pharmaceutical dosage form comprising as active ingredients a proton pump inhibitor together with acetyl salicyclic acid - Google Patents

Abstract

The present invention relates to an oral pharmaceutical preparation for use in the prevention and/or reduction of gastrointestinal complications associated with the use of acetyl salicylic acid. The present preparation comprises a fixed oral dosage form comprising a proton pump inhibitor in combination with acetyl salicylic acid. Furthermore, the present invention refers to a method for the manufacture thereof and the use thereof in medicine. The present invention also relates to a specific combination comprising esomeprazole, or an alkaline salt thereof or a hydrated form of any one of them, and acetyl salicylic acid for use as a medicament for the prevention of thromboembolic vascular events, such as myocardial infarction or stroke, and for the prevention and/or reduction of gastrointestinal complications associated with the use of acetyl salicylic acid.

Description

NEW PHARMACEUTICAL FORMS OF COMBINATION FIELD OF THE INVENTION The present invention relates to an oral pharmaceutical preparation for use in the prevention and / or reduction of gastrointestinal complications associated with treatment with acetylsalicylic acid. The present preparation comprises a fixed oral dosage form comprising a proton pump inhibitor (hereinafter also referred to as PPI, in this case Proton Pump Inhibitor) in combination with acetylsalicylic acid (hereinafter also referred to as AAS) or a derivative thereof. In addition, the present invention relates to a method for the manufacture thereof and its use in medicine. The present invention also relates to a specific combination comprising esomeprazole, or an alkaline salt thereof or a hydrated form of any of them and acetylsalicylic acid, in a pharmaceutically fixed oral combination form comprising a group of separate physical units. comprising esomeprazole, or an alkaline salt thereof or a hydrated form of any of them and one or more separate separate physical units comprising ASA or a derivative thereof, for use as a medicament in the prevention of thromboembolic vascular events, as myocardial infarction or cerebrovascular accident, whose risk increases in No. Ref.: 192861 the elderly population, and also in the prevention and / or reduction of gastrointestinal complications associated with treatment with acetylsalicylic acid (ASA). BACKGROUND OF THE INVENTION Acetylsalicylic acid (ASA) is one of the most frequently prescribed drugs and the most widely used in the world. Its use in the prevention of thromboembolic vascular events, such as myocardial infarction or cerebrovascular accident was described in "Collaborative overwiev of randomized triais of antiplatelet therapy Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients". [British Medical Journal 1994, 308, p. 81-106, by Antiplatelets triallists collaboration]. Despite the therapeutic benefits, its use is often limited by an increased risk of gastrointestinal side effects, mainly upper gastrointestinal side effects such as peptic ulcer and dyspeptic symptoms. The relative risk of developing a complication of an ulcer such as stomach or duodenal bleeding increases with all the doses of ASA studied. A peptic ulcer always precedes a bleeding peptic ulcer. Even a daily dose as low as 75 mg doubles this risk (eil et al BMJ 1995: 310; 827-830). The epidemiological data from the United Kingdom indicate that 18% of hospital admissions due to Adverse drug reactions are caused by AAS (Pirmohamed et al BMJ 2004: 329; 15-19). Therefore, treatments that avoid the gastrointestinal side effect caused by ASA are necessary. The most promising solution to the problem of curing and preventing the upper gastrointestinal side effects associated with ASA, such as ulcers and dyspeptic symptoms in patients who need continuous treatment, is to combine the treatment with ASA with an approved anti-ulcer medicine for healing and / or prophylaxis of gastrointestinal side effects associated with ASA, such as prostaglandin analogs, H2 receptor antagonists, or proton pump inhibitors. "Schutzwirkung von Omeprazol gegenuber niedrig dosierter Acetylsalicylsaure" by Simon et al in Arzneimittel-Forschung, 1995 val. 45 na. 6, p. 701-3, reports that the concomitant administration of omeprazole to patients treated with ASA reduces gastroduodenal lesions caused by ASA. In "Untersuchungen zur Schutzwirkung van Lanzoprazol auf die menschlische Magenschleimhaut gegenuber niedrig dosierter Acetylsalicylsáure" by Muller et al in Arzneimittel-Forschung, 1997 val. 47 no. 6, p. 758-60, it was reported that concomitant administration of lansoprazole or ranitidine to patients treated with ASA reduces the damage caused to the mucosa by ASA.

The established risk factors of suffering upper gastrointestinal side effects and complications associated with ASA are for example, advanced age, previous peptic ulcer and / or hemorrhage, a high dose of ASA and simultaneous treatment with other antithrombotic, anticoagulant or anti-inflammatory drugs. No Steroids (NSAIDs). This means that, for example, frail and elderly patients who suffer a complication such as hemorrhage or perforation, should receive prophylactic treatment in relation to their treatment with ASA. This has been suggested, for example, by A. Lanas in Digestive and Liver Disease, 2004, 36, p. 655-7. A low dose of ASA is used mainly for the prevention of thromboembolic vascular events, such as myocardial infarction or cerebrovascular accident, whose risk increases in the elderly population. Compliance with treatment is especially important in elderly and frail patients, who have the highest risk of suffering a life-threatening complication with ASA treatment, such as hemorrhage or perforation. The importance of compliance is further supported by the finding that peptic ulcers associated with ASA treatment are often asymptomatic until the episode. In the proposed treatments comprising ASA and a proton pump inhibitor, the different principles Active ingredients are often administered separately, as discussed in "Clopidogrel versus Aspirin and Esomprazole to prevent recurrent bleeding" in New England Journal of Medicine, 2005, 352, p. 238-44. It is well known that compliance by the patient is a fundamental factor in obtaining a good result in medical treatments. Therefore, the administration of two or even more tablets or capsules than the patient is not convenient or satisfactory to achieve optimal results. In US 2005/0227949 Al it is stated that a combination of an i NSAID and a histamine H2 receptor antagonist is an effective treatment against viral and bacterial infections. Among the particularly preferred histamine H2 receptor antagonists are omeprazole and esomeprazole. An assembly containing the compounds is claimed among other things. No fixed pharmaceutical form is disclosed. WO 97/25064 describes an oral dosage form comprising an inhibitor of the proton pump sensitive to acids and one or more NSAIDs in a fixed formulation, in which the proton pump inhibitor is protected by an enteric coating layer. . The fixed formulation is a layered enteric coated tablet, a capsule or a multi-unit tablet dosage form. The preferred pharmaceutical forms are those of multiple units.

Some proton pump inhibitors are sensitive to degradation in acidic and neutral reactive media. Regarding stability properties, it is obvious that when one of the active ingredients is an inhibitor of the proton pump sensitive to acids it must be protected from contact with the acidic gastric juice by an enteric coating layer. There are different preparations of the proton pump inhibitors with enteric coating in layers described in the prior art, see for example US-A 4,786,505 (AB Hássle) containing omeprazole. US 2002/0155153 Al discloses a fixed dosage form which may optionally be a capsule filled with more than one pharmaceutical active ingredient. The active ingredients are preferably an inhibitor of the proton pump sensitive to acids in combination with one or more NSAIDs, and at least the proton pump inhibitor is protected by an enteric coating layer. US 2003/0069255 Al, currently US Pat. No. 6,926,907, describes a single, coordinated, single dose product that combines an agent that actively elevates the intragastric pH and an NSAID, specially formulated so that they are released in a coordinated manner. The figures show that the NSAID is located within an enteric coating while the agent that actively elevates the intragastric pH is located outside or above the enteric coating.

US 6,554,556 Bl presents an invention that points to a solid oral dosage form comprising a prolonged release NSAID tablet and an enteric coated proton pump inhibitor prepared without applying a separation layer between the proton pump inhibitor and the enteric coating. US 2002/0051814 Al, currently US Patent 7,029,701 B2, points to formulations having omeprazole and aspirin comprised in the same core and also some type of coating around the core. FR 2845917 refers to a pharmaceutical combination comprising tenatoprazole and an NSAID or a COX-2 inhibitor. Another patent application, US 2004/0121004 A1, presents a fixed pharmaceutical form for an NSAID, a proton pump inhibitor and a buffer. The pharmaceutical forms do not have enteric coating. Another patent application disclosing a fixed pharmaceutical form that does not have enteric coating, is US 2005/0147675 Al. This reference discloses a rapid dissolving tablet comprising AAS and esomeprazole. SUMMARY OF THE INVENTION The present invention relates to an oral pharmaceutical dosage form containing a proton pump inhibitor together with acetylsalicylic acid and, optionally, pharmaceutically acceptable excipients, which characterized in that the dosage form is in the form of an oral fixed combination dosage form comprising a group of separate physical units containing a proton pump inhibitor and one or more separate separate physical units containing acetylsalicylic acid or one of its derivatives. In the present invention, the dosage form is a capsule formulation, a multi-unit tablet formulation or an envelope formulation, which will simplify the regimen and improve patient compliance and which will also provide good stability to the active ingredients during the treatment. long-term storage. The dosage forms according to the invention are suitable for use especially in the prevention of thromboembolic vascular events, such as myocardial infarction or cerebrovascular accident, whose risk increases in the elderly population, and also in the prevention and / or reduction of gastrointestinal complications associated with treatment with acetylsalicylic acid (ASA). DETAILED DESCRIPTION THE INVENTION A first embodiment of the present invention relates to an oral pharmaceutical dosage form comprising as active ingredients an inhibitor of the proton pump (PPI) sensitive to acids together with acetylsalicylic acid (AAS) or a derivative thereof and, optionally, pharmaceutically acceptable excipients, which are characterized in that the dosage form is in the form of an oral fixed combination dosage form composed of a group of separate physical units containing the inhibitor of the acid-sensitive proton pump and one or more separate separate physical units containing acetylsalicylic acid or one of its derivatives, and wherein at least the proton pump inhibitor is protected by an enteric coating layer. In a second embodiment of the present invention the oral pharmaceutical dosage form is composed of an acid-sensitive proton pump inhibitor together with acetylsalicylic acid and, optionally, pharmaceutically acceptable excipients, characterized in that the dosage form is the form of an oral fixed combination dosage form composed of a group of separate physical units containing the acid-sensitive proton pump inhibitor and one or more separate separate physical units containing the acetylsalicylic acid or a derivative thereof , and wherein at least the proton pump inhibitor is protected by an enteric coating layer and in which the acetylsalicylic acid or a derivative thereof has no enteric coating.

In a third embodiment of the present invention the oral pharmaceutical dosage form is composed of an acid-sensitive proton pump inhibitor together with acetylsalicylic acid or a derivative thereof and, optionally, pharmaceutically acceptable excipients, characterized in that the The dosage form is in the form of an oral fixed combination dosage form composed of a group of separate physical units containing the acid-sensitive proton pump inhibitor and one or more separate separate physical units containing the acetylsalicylic acid. or a derivative thereof, and wherein at least the proton pump inhibitor is protected by an enteric coating layer and in which the acetylsalicylic acid or its derivative is not enteric coated and is also present in a release form immediate A fourth embodiment of the invention is directed to an oral pharmaceutical dosage form which is composed of an acid-sensitive proton pump inhibitor together with acetylsalicylic acid or a derivative thereof and, optionally, pharmaceutically acceptable excipients, which are characterized because the dosage form is in the form of a fixed oral combination dosage form composed of a group of separate physical units containing the proton pump inhibitor sensitive to the acids and one or more separate separate physical units containing the acetylsalicylic acid or a derivative thereof, and wherein the units containing the proton pump inhibitor are protected by an enteric coating layer and the unit containing the acid acetylsalicylic acid or a derivative thereof is compressed in the form of a tablet and also does not have an enteric coating. A fifth embodiment of the invention is directed to an oral pharmaceutical dosage form which is composed of an acid-sensitive proton pump inhibitor together with acetylsalicylic acid or a derivative thereof and, optionally, pharmaceutically acceptable excipients, which are characterized because the dosage form is in the form of an oral fixed combination dosage form comprising a group of separate physical units containing the acid-sensitive proton pump inhibitor and one or more separate separate physical units containing the acetylsalicylic acid or its derivative, and wherein the units containing the acid-sensitive proton pump inhibitor are protected by an enteric coating layer and the unit containing the acetylsalicylic acid or a derivative thereof is compressed slightly in plug form and also has no enteric coating. Light compression of AAS is beneficial for its stability and dissolution rate.

In a special embodiment of the invention, the slightly compressed AAS cap has a friability as measured for the tablets in the US Pharmacopoeia 24, official as of January 1, 2000, in the range of 2% -50% ( p / p), preferably 2% -30% (w / w) and more preferably 2% -10% (w / w). In another special embodiment of the invention, the slightly compressed AAS cap has a friability as measured for the tablets in the US Pharmacopoeia 24, official as of January 1, 2000, in the range of 4% -50% ( p / p), preferably 4% -30% (w / w) and more preferably 4% -10% (w / w). In yet another special embodiment of the invention, the slightly compressed AAS plug has a friability as measured for the tablets in the US Pharmacopoeia 24, official as of January 1, 2000, in the range of 6 X 50% (w / w), preferably from 6% -30% (w / w) and more preferably from 6% -10% (w / w). Terms used: Physical units, when used as a starting material for the coating, are also referred to as "cores" or "core material". The term "dosage form" as used herein is limited to capsules, tablets, "multi-unit tablets" (see page 22) or envelopes.

Therefore, the term "fixed combination dosage form" in the present invention excludes a standard package arrangement comprising separate dosage forms of IBP and AAS respectively, for example, a capsule or a tablet containing the inhibitor of the proton pump sensitive to acids and another capsule or tablet containing acetylsalicylic acid, packaged together. This does not exclude the possibility of packaging the dosage forms of the invention in blister packs. The term "unit" or "units", as used herein, is intended to include "dragee (s)", "granule (s)", "pearl (s)", "cap or plugs slightly compacted (s)" and "tablet (s)". The term "tablet" is normal, meaning any compressed tablet, which also meets the requirement that its friability be less than 1% (w / w), as measured and required for the tablets in the US Pharmacopoeia. , official since January 1, 2000. The expression "slightly compacted plug" takes into account a material that has been compressed into a unit such as a tablet, but not enough to meet the requirement of friability for tablets from US Pharmacopoeia 24, official as of January 1, 2000. The slightly compacted tampons have a friability as measured for the tablets, in the US Pharmacopoeia 24, official as of January 1, 2000, of 2% ( p / p) or more.

In special modalities the friability is in a range that can be located starting at 2% (p / p) or more and upwards. The term "gastrointestinal complications," as used herein, was intended to include ulcers in the stomach or duodenum, complications of ulcers, such as hemorrhage, perforation and / or obstruction, and dyspeptic symptoms, such as epigastric pain and / or discomfort. The term "prevention", as used herein, also includes the inhibition of "gastrointestinal complications". The term "reduction" as used here, was intended to also include the reduction of the risk of "Gastrointestinal complications". The term "ASA", as used herein, is an abbreviation for acetylsalicylic acid. The term "IBP", as used herein, is an abbreviation of proton pump inhibitor and therefore encompasses esomeprazole, or one of its alkaline salts or a hydrated form of any of them, as well as omeprazole, or one of its alkaline salts or a hydrated form of any of them. The expressions "low doses of acetylsalicylic acid", or "low doses of ASA", as used herein, is defined in a modality as a dose in the range of 10 mg to 500 mg of ASA. In another modality, it is defined as dose in the range of 25 mg to 450 mg of ASA. In yet another embodiment, it is defined as a dose in the range of 60 mg to 350 mg of AAS Active ingredients; Acid-sensitive proton pump inhibitors suitable for the present invention are inhibitors of H + K + ATPase and are selected from: omeprazole esomeprazole Esomeprazole magnesium Iansoprazole rabeprazole (pariprazole) Leminoprazole pantoprazole Tenatoprazole ilaprazole The acid-sensitive proton pump inhibitors that are used in the pharmaceutical form of the present invention can be used in their neutral form or in the form of a pharmaceutically acceptable salt as an alkaline salt selected from any of its Mg2 + salts, Ca2 +, Na +, K +, Li + or TBA (tert-butyl ammonium). In addition a given chemical formula or name will encompass all stereoisomers and optical isomers and racemates thereof as well as mixtures in different proportions of the separated enantiomers, wherein such isomers and enantiomers exist, as well as pharmaceutically acceptable salts thereof and solvates of them, such as for example hydrates. The compounds indicated above can also be used in their tautomeric form. Also included in the present invention are derivatives of the compounds indicated above that have the biological function of the indicated compounds, like the prodrugs. Proton pump inhibitors are described, for example, in EP-A1-0005129, EP-A1-174 726, EP-A1-166 287, GB 2 163 747 and WO90 / 06925, W091 / 19711, W091 / 19712, W095 / 01977, W098 / 54171 and W094 / 27988. Acetylsalicylic acid (ASA) can be selected from its free acid form, derivatives thereof or any other possible form, for example, but without limiting the scope of the present invention, acetylsalicylic amide or acetylsalicylic complexes. In another special embodiment of the present invention, acetylsalicylic acid is in its free acid form. In yet another special embodiment of the present invention, acetylsalicylic acid is present as an acetylsalicylic amide or acetylsalicylic complex (s), such as, for example, a cyclodextrin complex. Any of the different forms of AAS can be combined with any of the embodiments of the oral pharmaceutical dosage form of the invention presented above. According to one embodiment of the invention, the acid-sensitive PPI is omeprazole or an alkaline salt or the acid-sensitive PPI is esomeprazole, an alkaline salt thereof or a hydrate of any of them. In accordance with another embodiment of the invention, the acid-sensitive PPI is omeprazole or an alkaline salt thereof. Consistently with yet another embodiment of the present invention the acid-sensitive PPI is esomeprazole, an alkaline salt thereof or a hydrate of any of them. According to another additional embodiment of the present invention the acid-sensitive PPI is lansoprazole or a pharmaceutically acceptable salt thereof or a single enantiomer of any of them. In another embodiment of the present invention the acid-sensitive PPI is pantoprazole or a pharmaceutically acceptable salt thereof or a single enantiomer of any of them. In yet another embodiment of the present invention, the acid sensitive PPI is rabeprazole or a pharmaceutically acceptable salt thereof or a single enantiomer of any of them. In a further embodiment of the present invention, the acid sensitive PPI is ilaprazole or a pharmaceutically acceptable salt thereof or a single enantiomer of any of them. In yet another embodiment of the present invention, the acid sensitive PPI is tenatoprazole or a pharmaceutically acceptable salt thereof or a single enantiomer of any of them. Any of the different forms of acid sensitive PPI can be combined with any of the ASA modalities presented above in any of the previously presented embodiments of the oral pharmaceutical dosage form of the invention. A combination of active ingredients that was specially anticipated to be included in any of the modalities presented before the dosage form Oral pharmaceutical is esomeprazole, an alkaline salt thereof or a hydrate of any of them and acetylsalicylic acid in its free acid form. Another combination of active ingredients that was especially anticipated to be included in any of the modalities presented before the oral dosage form is omeprazole, an alkaline salt thereof or a hydrate of any of them and acetylsalicylic acid in its free acid form. Core material The core material of the individually coated units with enteric coating in layers can be formed according to different principles. Granules distributed in layers with the proton pump inhibitor, optionally mixed with alkaline substances, can be used as a core material for further processing. The grains that will be distributed in layers with the proton pump inhibitor can be insoluble grains in water of different oxides, celluloses, organic polymers and other materials, alone or in mixtures. The grains can also be water-soluble grains of different inorganic salts, sugars, granulates and other materials, alone or in mixtures. In addition, the grains may comprise the proton pump inhibitor in the form of crystals, agglomerates, compacts, etc. The size of the grains is not essential for the present invention but may vary from about 0.1 to 2 mm. In a preferred embodiment of the invention the average diameter of the grains is from 0.1 mm to 1.0 mm. The grains distributed in layers with the proton pump inhibitor are produced by distribution in powder or solution / suspension layers. Equipment for coating in granulation or spray layers can be used. Before the grains are distributed in layers, you can mix the proton pump inhibitor with other components. Such components may be binders, surfactants, fillers, disintegrants, alkaline additives and / or other pharmaceutically acceptable ingredients, alone or in mixtures. Binders are for example polymers such as hydroxypropylmethylcellulose (RMCM), hydroxypropylcellulose (RPC), sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP) or sugars, starches or other pharmaceutically acceptable substances with cohesive properties. Suitable surfactants are found in pharmaceutically acceptable nonionic or ionic surfactant groups such as sodium lauryl sulfate. Alternatively, the proton pump inhibitor optionally mixed with alkaline substances and further mixed with suitable constituents can be formulated as core material. Extrusion / spheronization, Agglomeration or compression using conventional processing equipment can produce the core material. The size of the core material formulated is, in one embodiment of the invention, from about 0.1 mm to 4 mm in diameter and in another embodiment of the invention from 0.1 mm to 2 mm in diameter. The fabricated core material can be layered with other ingredients comprising the proton pump inhibitor and / or used for further processing. The proton pump inhibitor is mixed with pharmaceutical constituents to obtain adequate handling and processing properties and an adequate concentration of the proton pump inhibitor in the final preparation. Pharmaceutical constituents can be used as fillers, binders, lubricants, disintegrants, surfactants and other pharmaceutically acceptable additives. In addition, the proton pump inhibitor can also be mixed with one or more pharmaceutically acceptable alkaline substances. Such substances may be chosen, but not only, from substances such as sodium, potassium, calcium, magnesium and aluminum salts, from phosphoric, carbonic, citric or other suitable weak inorganic or organic acids; co-precipitated sodium aluminiolbicarbonate hydroxide; substances normally used in antacid preparations such as aluminum hydroxides, calcium and magnesium; magnesium oxide or compound substances, such as A1203 6MgO. C02.12H20, (Mg6Al2 (OH)? 6C03.4H20), MgO. A1203.2 Si02nH2U or similar compounds; pH-buffering organic substances such as trihydroxymethylaminomethane, basic amino acids and their salts or other similar pharmaceutically acceptable pH-absorbing substances. Alternatively, the aforementioned core material can be prepared using the spray-drying or spray-and-freeze technique. Enteric Coating Layer (s) Before applying the enteric coating layer (s) on the core material in the form of individual units, the units may optionally be covered with one or more separation layers containing the pharmaceutical excipients. , optionally including, alkaline compounds such as pH buffering compounds. This separation layer or layers separate the core material from the outer layers which are enteric coating layers. This separation layer or layers that protect the core material of the proton pump inhibitor must be soluble in water or rapidly disintegrate in water. The separation layer or layers can be applied to the core material by coating or layering procedures in suitable equipment, such as a pallet. of coating or coating granulator or in a fluidized bed equipment using water and / or organic solvents for the coating process. Alternatively, the separation layer or layers can be applied to the core material using the powder coating technique. The materials for the separation layers are pharmaceutically acceptable compounds selected from any of the following: sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, water soluble salts of coating polymers. enteric and others, used alone or in mixtures. Also additives such as plasticizers, colorants, pigments, fillers, antiadherents and antistatics (such as magnesium stearate, titanium dioxide, talcum) and other additives in the separation layer or layers may be included. When the optional separation layer is applied to the core material, it can constitute a variable thickness. The maximum thickness of the separation layer or layers is normally limited only by the processing conditions. The separation layer can serve as a diffusion barrier and can also act as a buffer zone for pH. The buffering properties of the separation layers can be further enhanced by introducing them into the layers substances chosen from a group of compounds generally used in formulations of antacids such as, for example, magnesium oxide, hydroxide or carbonate, hydroxide, carbonate or aluminum or calcium silicate; aluminum / magnesium compounds such as A1203.6MgO. C02.12H20, (Mg6Al2 (OH)? 6CO34H20), MgO. A1203.2Si02. nH20, co-precipitated from aluminum hydroxide / sodium bicarbonate or similar compounds; or other pharmaceutically acceptable pH buffering compounds such as, for example, sodium, potassium, calcium, magnesium and aluminum salts of phosphoric, carbonic, citric acid or other suitable weak, inorganic or organic acids; or suitable organic bases, including basic amino acids and salts thereof. Can talcum be added too? other compounds to increase the thickness of the layer or layers and thereby strengthen the diffusion barrier. Optionally applied separation layers are not essential to the invention. However, the separation layer or layers can (n) improve the chemical stability of the active principle and / or the physical properties of the claimed fixed oral pharmaceutical dosage form. Alternatively, the separation layer can be formed in situ by reaction between a layer of the enteric coating polymer applied on the core material and an alkaline reactive compound of the core material. By therefore, the separation layer formed comprises a water-soluble salt formed between the polymer (s) of the enteric coating layer and an alkaline reactive compound, which is capable of forming a salt. One or more enteric coating layers are applied on the core material or on the core material covered with a separation layer or layers using a suitable coating technique. The material of the enteric coating layer can be dispersed or dissolved in water or in suitable organic solvents or in suitable mixtures of water plus solvent when applicable, as for example water can be used plus ethanol in certain proportions to dissolve the phthalate of hydroxypropylmethylcellulose. As polymers of the enteric coating layer, one or more of the following can be used, separately or in combination, for example, solutions or dispersions of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimethylate, carboxymethyl ethyl cellulose, lacquer or other suitable polymer or polymers for enteric coating. The enteric coating layers may contain pharmaceutically acceptable plasticizers to obtain the desired mechanical properties, such as flexibility and hardness of the enteric coating layers. Such plasticizers are they select, for example, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates or other plasticizers. The amount of plasticizer is optimized for each enteric coating layer formula, relative to the polymer or polymers selected for the enteric coating layer, the selected plasticizer and the applied amount of such polymer, such that the mechanical properties are say flexibility and hardness of the enteric coating layer or layers meet the desired requirements. The amount of plasticizer is generally above 10% by weight of the polymer or polymers of the enteric coating layer, alternatively from 15% -50%, or alternatively from 20% -50%. Also additives such as dispersants, colorants, pigments, polymers for example, poly (ethylacrylate, methylmethacrylate), antiadhesives and antifoams can be included in the enteric coating layer or layers. Other compounds can be added to increase the thickness of the film and to decrease the diffusion of acidic gastric juices in the acid-sensitive material. To protect the acid sensitive substance, the proton pump inhibitor, and to obtain an acceptable acid resistance of the pharmaceutical form according to the invention, the enteric coating layer or layers form (n) a thickness of approximately at least 10 μm or alternatively more than 20 μm, The maximum thickness of the applied enteric coating is normally limited only by the processing conditions and the desired dissolution profile . In one embodiment of the invention, the thickness of the enteric coating layer is in the range of 15-45 microns. In a preferred embodiment of the invention the thickness of the enteric coating layer is in the range 20-35 microns. Overcoating layer Units comprising a proton pump inhibitor or AAS and coated with one or more enteric coating layers may also be coated with one or more overcoating layers. The overcoat layer or layers must (are) soluble in water or rapidly disintegrated in water. The overcoat layers can be applied to the enteric coated units in layers by coating or layering methods in suitable equipment, such as coating pan, coating granulator or fluidized bed equipment using water and / or organic solvents for the process of coating or distribution in layers. The materials for the overcoat layers are they choose from pharmaceutically acceptable compounds selected from any of the following: sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and others, used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, antiadherents and antistats (such as magnesium stearate, titanium dioxide and talcum) and other additives may also be included in the overcoat layers. Such an overcoating layer can furthermore prevent the possible agglomeration of the enteric coated units in layers. The maximum thickness of the overcoating layers applied is normally limited by the processing conditions and the desired dissolution profile. In one embodiment of the present invention, the proton pump inhibitor is protected by two layers, an enteric coating layer and a coating layer that separates the enteric coating from the proton pump inhibitor. For filling capsules with enteric coated units or enteric coated units, it is sometimes advantageous to mix a lubricant or a glidant. Such lubricants or gliders include magnesium stearate, sodium stearyl fumarate, glyceryl behenate, talc and fumed silica, without excluding the possibility of using other pharmaceutically acceptable lubricants or glidants not mentioned. In one embodiment of the invention, the lubricant is magnesium stearate. In another embodiment of the invention, the lubricant is sodium stearyl fumarate. In yet another embodiment of the invention, the lubricant is glyceryl behenate. The different forms of acetylsalicylic acid (ASA) ASA can be present in the following forms: - AAS powder (the substance AAS as such); - AAS agglomerates; - Spherical agglomerates of AAS; - Dispersions or solid solutions of AAS in polymers; These dispersions or solid solutions can be carried out by melting the dispersing / dissolving agent and adding the AAS, or by dissolving the dispersing agent / solution and AAS in a common solvent, and then evaporating the solvent. - AAS cyclodextrin complexes (as a powder); These complexes may comprise α-cyclodextrin, β-cyclodextrin, and-cyclodextrin or derivatives thereof such as, for example, β-hydroxypropyl cyclodextrin. The cyclodextrin complexing agent can be chosen so as to affect the rate of release, for example, to obtain a prolonged release (β-hydroxypropyl cyclodextrin) or an immediate release (β-cyclodextrin). - Dextrin cycle complexes of granulated AAS together with pharmaceutical excipients; These complexes may comprise α-cyclodextrin, β-cyclodextrin, β-cyclodextrin or derivatives thereof such as, for example, β-hydroxypropyl cyclodextrin. The cyclodextrin complexing agent can be chosen so as to affect the rate of release, for example, to obtain a prolonged release (β-hydroxypropyl cyclodextrin) or an immediate release (β-cyclodextrin). - Units for immediate release, comprising AAS together with pharmaceutical excipients; - Units for prolonged release, comprising AAS together with pharmaceutical excipients. These units can be made in accordance with the principle of hydrophilic gel matrix, the principle of hydrophobic matrix or the principle of membrane diffusion of coated tablets / granules; - Units for enteric release (granules or lozenges with enteric coating), containing AAS together with pharmaceutical excipients; Units for delayed release in time independent of pH (granules or dragees (without enteric coating)), containing ASA together with pharmaceutical excipients; Units comprising AAS together with effervescent pharmaceutical excipients for immediate release; - Units distributed in layers with an enteric coating layer, such as the enteric coating layer described above, comprising AAS; - Minitabletas that comprise AAS; - Coated minitablets comprising AAS - Slightly compacted AAS cap, which takes into account a material that has been compressed in the form of a unit eg a tablet, with a friability that does not meet the friability requirements for US Pharmacopoeia tablets. , official since January 1, 2000 (requirement: less than 1%). See the previous explanations. Process for the preparation of the claimed fixed pharmaceutical form The present invention also relates to a process for the manufacture of a fixed combination oral dosage form containing an inhibitor of the proton pump sensitive to acids and acetylsalicylic acid, which is characterized in that the proton pump inhibitor is prepared in the form of enteric coated units in layers and that the units are mixed with acetylsalicylic acid and this mixture is optionally mixed with pharmaceutically acceptable excipients and then with the obtained mixture a capsule or an envelope is filled. The acetylsalicylic acid can be in any of the forms described above. One embodiment of the present invention relates to a process for the manufacture of a fixed combination oral dosage form containing an inhibitor of the proton pump sensitive to acids and acetylsalicylic acid, which is characterized in that such an inhibitor of the The protons are prepared in the form of layered enteric-coated units and in that the units are filled with a capsule or an envelope together with one or more separate separate physical units containing acetylsalicylic acid optionally mixed with pharmaceutically acceptable excipients. An example of a manufacturing process of the present fixed pharmaceutical form, but which should in no way limit the scope of the present invention, is to dry mix the PPI and the AAS and then fill with those active compounds a capsule or an envelope . The proton pump inhibitor is in the form of layered enteric-coated units and the acetylsalicylic acid is in the form of units that can be used as such or in the form of units formulated for modified release as enteric coated units in layers or in the form of units formulated to achieve prolonged release for example, when coated with a release coating layer prolonged Another example of a manufacturing process, but which should in no way limit the scope of the present invention, is wet granulation. The acetylsalicylic acid is dry mixed with excipients, in which one or more of these is optionally a disintegrant. Suitable excipients for the granulation of acetylsalicylic acid can be selected from any of the following: sodium starch glycolate, corn starch, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropylcellulose, microcrystalline cellulose, mannitol, lactose and anhydrous colloidal silicon dioxide (Aerosil®) . The mixture is wet kneaded with a granulation liquid comprising a binder selected from any of the following: polyvinylpyrrolidone, hydroxypropylmethylcellulose, polyethylene glycol, hydroxypropylcellulose and optionally one or more humectants, such as sodium lauryl sulfate and a solvent such as purified water or a suitable alcohol or a mixture of these. In one embodiment of the invention, the wet mass is dried to a drying loss of less than 3% by weight. In another embodiment of the invention, the wet mass is dried to a drying loss of less than 2% by weight. After drying the dry mass is ground to a size suitable for granules, such as smaller than 4 mm, alternatively smaller than 1 mm. The dried granules are then mixed with the proton pump inhibitor, which is in the form of layered enteric coated units and then filled with a capsule or an envelope or compressed, optionally together with suitable pharmaceutical excipients in the form of "multi-unit tablet". In an alternative manufacturing process the AAS, or AAS granules and optionally pharmaceutical excipients, are compressed into a slightly compacted cap (definition according to the previous one) and a capsule is filled with it, together with the IBP where the latter it is in the form of units with enteric coating in layers. The cap can be placed in the lower part of the capsule, that is to say in the body, or in the upper part of the capsule, that is to say in the cap. In both situations the plug is in close contact with the inner walls of the capsule, restricting free movement of the IBP composite units within the capsule. This is favorable to reduce intracapsular wear. The IBP composite units can be placed under or over the plug (in both cases inside the capsule). Therefore, in one embodiment of the invention, the stopper AAS compound is placed in the body of the capsule in close contact with the internal walls thereof and the composite units of IBP are placed above the cap inside the capsule. In another embodiment of the invention, the AAS composite cap is placed in the body of the capsule in close contact with the internal walls thereof and the composite PPI units are placed under the cap within the capsule. In still another embodiment of the invention, the AAS composite cap is placed on the cap (ie the upper part) of the capsule in close contact with the inner walls of the cap thereof and the composite units of IBP are placed under the plug inside the body of the capsule. The acetylsalicylic acid can also be mixed during the granulation with a gelling agent, such as a hydrophilic polymer or polymers to obtain a prolonged release. Suitable hydrophilic gelling polymers can be selected from any of the following: hydroxypropylmethylcellulose with a viscosity greater than or equal to 50 mPas (cps), polyoxyethylene (polyethylene glycol) with a molecular weight above 50,000 u, hydroxypropylcellulose with the exception of the poorly substituted hydroxypropylcellulose , hydroxyethylcellulose and xanthan or combinations of the same.

The units obtained may also comprise suitable buffer substances. Capsule material or envelope The capsule or envelope comprises any polymeric material soluble in water or in gastric juice, such as gelatin or hydroxypropylmethylcellulose. However, this list should not be interpreted as exhaustive. The capsules or the envelope can be produced by molding. Use of the claimed invention The dosage forms according to the present invention are especially advantageous in the prevention and / or reduction of gastrointestinal complications caused by acetylsalicylic acid, for example in a continuous treatment with the acid. According to one embodiment of the present invention, the claimed pharmaceutical form has an amount of proton pump inhibitor in the range of 5 to 300 mg and an amount of acetylsalicylic acid in the range of 10 to 500 mg. According to another embodiment, the amount of proton pump inhibitor is in the range of 10 to 200 mg or 10 to 100 mg or 10 to 80 mg. In an alternative embodiment of the present invention the amount of proton pump inhibitor is selected from about: 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 and 100 mg. In accordance with yet another embodiment of the present invention, the amount of proton pump inhibitor is selected between 20, 40 and 80 mg. In other embodiments of the present invention the amount of acetylsalicylic acid is in the range of 25 to 450 mg, 50 to 400, 60 to 350 mg or 75 to 325 mg.In an alternative embodiment of the present invention the amount of acetylsalicylic acid is selected from about: 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, and 325 mg, for example 81, 101, 124, 126, 181, 204, 301, 311, and 321. In another embodiment of the present invention the oral fixed combination dosage form contains 20 mg of esomeprazole and 325 mg of acetylsalicylic acid In a second embodiment of the present invention, the oral combination dosage form contains 20 mg of esomeprazole and 75 mg of acetylsalicylic acid In a third embodiment of the present invention The fixed-dose oral dosage form contains 40 mg of esomeprazole and 325 mg of acetylsalicylic acid. In a fourth embodiment of the present invention the fixed combination oral dosage form contains 40 mg of esomeprazole and 75 mg of acetylsalicylic acid.

In a fifth embodiment of the present invention the fixed combination oral dosage form contains 20 mg of esomeprazole and 81 mg of acetylsalicylic acid. In a sixth embodiment of the present invention the fixed combination oral dosage form contains 40 mg of esomeprazole and 81 mg of acetylsalicylic acid. The present invention also relates to a method for the prevention of thromboembolic vascular events, such as myocardial infarction or cerebrovascular accident, and the reduction and / or prevention of gastrointestinal complications associated with treatment with acetylsalicylic acid, such as, for example, associated esophagitis to treatment with low doses of ASA, in mammals or humans, by administration to mammals or humans in need of a therapeutically effective dose of the claimed fixed combination oral dosage form. In accordance with other embodiments of the present invention, the complication is an upper gastrointestinal complication, a peptic ulcer in the stomach or a peptic ulcer in the duodenum. Upper gastrointestinal complications include hemorrhage, perforation, and obstruction of gastric outflow. In accordance with another embodiment of the present invention, the human is a patient 60 years of age or older. In accordance with an alternative modality of the present invention the claimed method comprises the administration of a capsule or an envelope containing acetylsalicylic acid and proton pump inhibitor. The administration is once or twice a day. The present invention also relates to the use of a dosage form containing a proton pump inhibitor and acetylsalicylic acid for the manufacture of a medicament for the prevention of thromboembolic vascular events, such as myocardial infarction or cerebrovascular accident, and for the prevention and / or reduction of gastrointestinal complications associated with treatment with acetylsalicylic acid. In accordance with other embodiments of the present invention, the complication is, as mentioned above, an upper gastrointestinal complication or a peptic ulcer in the stomach or a peptic ulcer in the duodenum. The present invention also relates to a fixed pharmaceutical oral dosage form containing esomeprazole or an alkaline salt thereof or a hydrated form of any of them and acetylsalicylic acid, for the prevention of thromboembolic vascular events, such as myocardial infarction or stroke, and for the prevention and / or reduction of gastrointestinal complications associated with treatment with acetylsalicylic acid. Any oral dosage form is it can be used for the administration of this pharmaceutical combination, for example, a capsule, an envelope, a tablet or a multi-unit tablet, including its effervescent forms. However, this list should not be interpreted as exhaustive. An alternative embodiment of the present invention relates to an oral pharmaceutical dosage form of a fixed combination containing esomeprazole or an alkaline salt thereof or a hydrated form of any of them and acetylsalicylic acid, wherein the pharmaceutical dosage form is composed of a group of separate physical units containing the acid-sensitive proton pump inhibitor and one or more separate separate physical units containing the acetylsalicylic acid or one of its derivatives and in which at least the proton pump inhibitor is protected by an enteric coating layer, for the prevention of thromboembolic vascular events, such as myocardial infarction or cerebrovascular accident, and for the prevention and / or reduction of gastrointestinal complications associated with treatment with acetylsalicylic acid. In another alternative embodiment of the invention, the unit (the unit composed of ASA mentioned in the previous paragraph) that contains acetylsalicylic acid is compressed and used for the prevention of thromboembolic vascular events, such as myocardial infarction or cerebrovascular accident, and for the prevention and / or reduction of gastrointestinal complications associated with treatment with acetylsalicylic acid. In yet another alternative embodiment of the invention, the unit (the unit composed of ASA mentioned in the penultimate previous paragraph) comprising the acetylsalicylic acid is slightly compressed in the form of a stopper and is used for the prevention of thromboembolic vascular events, such as infarction to the myocardium or cerebrovascular accident, and for the prevention and / or reduction of chronic complications associated with treatment with acetylsalicylic acid. In one embodiment of the present invention, the claimed pharmaceutical combination has an amount of esomeprazole or an alkaline salt thereof or a hydrated form of any of them in the range of 5 to 300 mg and an amount of acetylsalicylic acid between 10 and 500 mg . According to another embodiment of the present invention, the amount of esomeprazole or an alkaline salt thereof or a hydrated form of any of them is in the range of 10 to 80 mg. According to yet another embodiment, the amount of esomeprazole or an alkaline salt thereof or a hydrated form of any of them is selected from 20, 40 or 80 mg. In other embodiments of the present invention the amount of acetylsalicylic acid is in the range of 25 to 450 mg, 50 to 400, 60 to 350 mg or 75 to 325 mg. In an alternative embodiment of the present invention the amount of acetylsalicylic acid is selected from about: 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, and 325 mg, for example 81, 101, 124, 126, 181, 204, 301, 311, and 321. Another embodiment of the present invention concerns to a method for the prevention of thromboembolic vascular events, such as myocardial infarction or cerebrovascular accident, and for the prevention and / or reduction of gastrointestinal complications, associated with treatment with acetylsalicylic acid in mammals or humans by administration to mammals or to the human in need of the claimed pharmaceutical combination. EXAMPLES The present invention is described in more detail by the following examples, which should not in any way limit the scope of the present invention. Example 1 Randomized, double-blind, multicenter, placebo-controlled patients, male or female patients negative for the presence of Heli cobacter pylori of 60 years of age or older, who presented a moderate to high risk of presenting gastroduodenal ulcers. Patients were randomized to receive esomeprazole 20 mg (administered as esomeprazole magnesium, ie Nexium® from AstraZeneca AB) or placebo once a day for 26 weeks. The primary endpoint was the endoscopic detection of gastric and / or duodenal ulcers in the 26-week period. A total of 991 patients, who all received ASA at doses ranging from 75-325 mg / day (57.1% human, mean age 69.3 years, mean dose of acetylsalicylic acid (AAS) 124.0 mg / day) were included in the population with intention to treat. The cumulative proportion of patients without gastric or duodenal ulcer at 26 weeks was 98.2% with esomeprazole, compared to 93.8% with placebo (calculations from the survival table, p = 0.0007). The incidence of gastric ulcers was lower in patients taking esomeprazole than in those taking placebo (1.2% versus 3.8%), as was the incidence of duodenal ulcers (0.4% and 1.6% for esomeprazole and placebo, respectively) . Eight patients (1.6%) presented an ulcer, in the esomeprazole group at 6 months, compared with 27 patients (5.4%) in the placebo group. This corresponded to a relative reduction of presenting an ulcer of 70% when esomeprazole was taken instead of placebo. A total of 95.6% of patients treated with esomeprazole had no esophageal injury at week 26, compared to 81.7% of patients treated with placebo (p <0.0001). The proportion of patients without esophageal lesions at 6 months was higher with esomeprazole than with placebo for patients without lesions and for those with lesions of Los Angeles grade A at the beginning. The resolution, evaluated by the investigator, of upper gastrointestinal symptoms was higher with esomeprazole than with placebo for all symptoms. Esomeprazole was safe and well tolerated. Example 2 Capsule comprising 20 mg of Esomeprazole and 325 mg of AAS granules. Principle: enteric coated lozenges containing esomeprazole magnesium trihydrate corresponding to 20 mg esomeprazole were prepared and mixed with magnesium stearate. Hard gelatin capsules were filled with this mixture and the AAS granules. Manufacture of esomeprazole coated tablets with core coating Core material Spherical sugar grains from 0.25 to 0.35 mm 300 g in diameter (Suspension for) active layer Esomeprazole-Mg trihydrate 445 g Hydroxypropylmethylcellulose 67 g Polysorbate 80 9 g Purified water 2100 g (Suspension for) sub-coating layer Hydroxypropyl cellulose 90 g Talcum 340 g Magnesium stearate 22 g Purified water 3100 g (Dispersion for) enteric coating layer Type C methacrylic acid copolymer, 1270 g 30% dispersion Triethyl citrate 38 g Mono and diglycerides 19 g Polysorbate 80 2 g Purified water 500 g Esomeprazole magnesium trihydrate was suspended in an aqueous solution containing the binder dissolved in hydroxypropylmethylcellulose and the surfactant polysorbate 80. The suspension was sprayed onto the spherical sugar grains in a fluidized bed coating equipment using the lower spraying technique (Wurster).

The prepared core material was covered with the subcoating layer in a fluidized bed equipment by spraying a solution of hydroxypropylcellulose containing talc and magnesium stearate in suspension. The enteric coating layer was sprayed as a dispersion in water on the subcoating tablets obtained before, in a fluid bed equipment. Esomeprazole dragee mixture with enteric coating and magnesium stearate. Enteric-coated tablets were mixed, in accordance with the aforementioned, with magnesium stearate in the proportions by weight given below; Esomeprazole tablets, gastroresistant 100 Magnesium stearate 0.2 Capsule filling Per capsule Esomeprazole dragee mixture with 86.2 mg enteric coating and magnesium stearate (according to the above) ASS granules * 325 mg Hard gelatin capsule size 0 1 piece * granules of AAS Rhodine ® 3118, Ba 0407231, from Rhodia France. The majority of the granules goes through a sieve with openings of 1000 microns and is retained in a sieve that has openings of 125 microns. Capsules, in accordance with the aforementioned, were placed in plastic jars (High Density Polyethylene, also known as HDPE) with desiccant and with proven stability. The results obtained can be seen in the table below; * AS = salicylic acid NA = not analyzed ** The esomeprazole solution was measured in the dissolution apparatus No. 2 of the USP (paddle, 100 rpm) after the previous exposure to 300 ml of 0.1 M HCl for 2 hours, where 700 ml of phosphate buffer was then added yielding 1000 ml of pH 6.8 test medium. After 30 minutes at pH 6.8 the amount released from the nominal dose was measured.

Example 3 Capsule containing 20 mg of Esomeprazole and 325 mg of AAS powder. Principle: Enteric-coated lozenges containing esomeprazole magnesium trihydrate corresponding to 20 mg of esomeprazole were prepared and mixed with magnesium stearate, in accordance with example 2. Hard gelatin capsules were filled with this mixture and AAS powder.

Capsule filling per capsule Mix of esomeprazole tablets with 86.2 mg enteric coating and magnesium stearate (according to example 2 above) ASS powder 325 mg Hard gelatin capsule size 0 1 piece Capsules were placed in accordance with the above in plastic bottles (High Density Polyethylene, also called HDPE) with desiccant and proven stability. The results obtained can be seen in the table below; NA = Not analyzed Example 4 Capsule containing 20 mg of Esomepra zol and 75 mg of ASA (in the form of a compressed tablet). Principle: Enteric-coated lozenges containing esomeprazole magnesium trihydrate corresponding to 20 mg of esomeprazole were prepared and mixed with magnesium stearate, according to example 2. With this mixture and the AAS tablets, hard gelatine capsules were filled. Capsule filling Per capsule Mix of esomeprazole tablets with 86. 2 mg enteric coating and magnesium stearate (according to example 2 above) AAS tablets with 75 mg of AAS * Approx. 97 mg Hard gelatin capsule size 1 1 piece * Trombyl ®, Ba B 811A from Pfi zer. Flat tablets, heart-shaped uncoated, approximate size 6-7 mm in diameter, weight 97 mg (average of 10 tablets). Capsules were placed, as mentioned above, in plastic jars (High Density Polyethylene, also called HDPE) with desiccant and proven stability. The results obtained can be seen in the table below; ** The esomeprazole solution was measured in the No. 2 dissolution apparatus of the USP (paddle, 100 rpm) after the previous exposure to 300 ml of 0.1 M HCl for 2 hours, where 700 ml of solution was then added phosphate buffer producing 1000 ml of pH 6.8 test medium.

After 30 minutes at pH 6.8 the amount released from the nominal dose was measured. Example 5 Capsule containing 20 mg Esomeprazole and AAS (enteric-coated tablet content) 100 mg. Principle: enteric-coated tablets containing esomeprazole magnesium trihydrate corresponding to 20 mg of esomeprazole were prepared and mixed with magnesium stearate, according to example 2. With this mixture and coated enteric-coated AES tablets, hard gelatine capsules were filled .

Capsule filling per capsule Blend of esomeprazole tablets with 86.2 mg enteric coating and magnesium stearate (according to example 2 above) enteric-coated AAS tablets with 117.9 mg 100 mg of ASA * Hard gelatin capsule size 1 1 piece * content of "Astrix®" capsules, ba 298140, manufactured by Faulding & Co Ltd, Australia. Capsules were placed, according to the aforementioned, in plastic jars (Polyethylene High Density, also called HDPE) with desiccant and proven stability. The results obtained can be seen in the table below; ** The esomeprazole solution was measured in the No. 2 dissolution apparatus of the USP (paddle, 100 rpm) after the previous exposure to 300 ml of 0.1 M HCl for 2 hours, where 700 ml of solution was then added phosphate buffer producing 1000 ml of pH 6.8 test medium. After 30 minutes at pH 6.8 the amount released from the nominal dose was measured. Example 6 Capsule comprising 20 mg of Esomeprazole and 75 mg of AAS granules. Principle: Enteric-coated tablets containing esomeprazole magnesium trihydrate corresponding to 20 mg of esomeprazole were prepared and mixed with magnesium stearate, according to example 2. With this mixture and a slightly compacted cap of AAS, hard gelatine capsules were filled. . Production of esomeprazole coated tablets with enteric coating It was carried out according to example 2. Mix of esomeprazole tablets with enteric coating and magnesium stearate. Enteric coated tablets according to the above were mixed with magnesium stearate in the proportions by weight given below; Esomeprazole tablets, gastroresistant 100 Magnesium stearate 0.2 Capsule filling Per capsule Esomeprazole dragee mixture with 86.2 mg enteric coating and magnesium stearate (according to the above) ASS granules, compacted in the form of a cap * 75 mg Hard gelatin capsule size 0 1 piece * granules of AAS Rhodine ® 3118, Ba FRH 0528131, from Rhodia France. The majority of the granules passes through a sieve with openings of 1000 microns and is retained in a sieve having openings of 125 microns. The stopper was placed in the lower part of the capsule, that is to say in the body, in close contact with the internal walls of the capsule. The capsules, of conformity as described above, were packed in blister packs, which had three layers of PVC / Aclar® * / PVC film and an aluminum foil as backing sheet. (* = Aclar® film is a polychlorotrifluoroethylene film that is currently manufactured by Honeywell International Inc.) Such capsules were also placed in plastic bottles (High Density Polyethylene also known as HDPE) with desiccant and proven stability. The results obtained can be seen in the table below; * AS = salicylic acid NA = not analyzed Example 7 Tablet comprising 20 mg of Esomeprazole and 100 mg of ASA. Principle: Enteric-coated lozenges containing esomeprazole magnesium trihydrate corresponding to 20 mg of esomeprazole and overcoated with a layer of hydroxypropylmethylcellulose were then prepared and then mixed with AAS granules and tablet excipients and compressed in the form of multiple-unit dragees. Manufacture of esomeprazole coated tablets with enteric coating Core material Spherical sugar grains from 0.25 to 0.35 mm 300 g in diameter (Suspension for) active layer Esomeprazole-Mg trihydrate 445 g Hydroxypropylmethylcellulose 67 g Polysorbate 80 9 g Purified water 2100 g (Suspension for) subcoating layer Hydroxypropylcellulose 90 g Talcum 340 g Magnesium stearate 22 g Purified water 3100 g (Dispersion for) enteric coating layer Type C methacrylic acid copolymer, 1270 g 30% dispersion Triethyl citrate 114 g Mono and diglycerides 19 g Polysorbate 80 2 g Purified water 500 g Esomeprazole magnesium trihydrate was suspended in an aqueous solution containing the binder hydroxypropyl methylcellulose and the polysorbate 80 surfactant. The suspension was sprayed onto the spherical sugar grains in a fluidized bed coating equipment using the lower spraying technique (Wurster). The prepared core material was covered with the layer of subcoating in a fluidized bed equipment by spraying a solution of hydroxypropylcellulose containing talc and magnesium stearate in suspension. The enteric coating layer was sprayed as a dispersion in water on the subcoating tablets obtained before, in a fluid bed equipment. (Solution for) overcoat layer Hydroxypropyl methylcellulose 5-6 cps (mPas) 90 g Purified water 2400 g The enteric coated tablets prepared in Example 2 are covered with the overcoating layer in a fluidized bed equipment by spraying hydroxypropylmethylcellulose solution according to the above described on them and drying when the spraying is complete. Overcoated enteric-coated tablets are used to obtain tablets; Ingredients For 1000 tablets Esomeprazole coated tablets 103 g enteric coated AAS granules * 100 g Microcrystalline cellulose (Avicel PH 102) 100 g Sodium stearyl fumarate (Pruv®) 2.9 g Sum 305.! 3 g * given example, Rhodia granules as in example 2 The above ingredients are mixed in a laboratory mixer, Kenwood type for 3-4 minutes then compressed into tablets in a suitable compressor machine, a non-limiting example of which is Korsch Pharmapress 106, using circular biconvex punches of 9 mm , adjusting the average weight of the tablets to 306 mg / tablet. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (40)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. An oral pharmaceutical dosage form comprising as active ingredients an inhibitor of the proton pump (PPI) sensitive to acids together with acetylsalicylic acid (AAS) or a derivative thereof and optionally pharmaceutically acceptable excipients, characterized in that it is in the form of a fixed oral combination comprising a group of separate physical units containing the proton pump inhibitor sensitive to acids and one or more separate separate physical units containing the acetylsalicylic acid or a derivative thereof and wherein at least the proton pump inhibitor is protected by an enteric coating layer.
2. 2. A dosage form according to claim 1, characterized in that the proton pump inhibitor is protected by an enteric coating layer and the acetylsalicylic acid or its derivative has no enteric coating.
3. 3. A dosage form according to claim 2, characterized in that the acetylsalicylic acid or a derivative thereof are further present in an immediate release form.
4. 4. A dosage form according to claim 3, characterized in that the inhibitor of the proton pump comprising is in units protected by an enteric coating layer and the unit composed of acetylsalicylic acid or its derivative is compressed into a tablet.
5. 5. A dosage form according to claim 4, characterized in that the unit comprising acetylsalicylic acid or its derivative is compressed slightly in the form of a stopper.
6. 6. A dosage form according to claim 5, characterized in that the AAS plug has a friability in the range of 2% - 50% (w / w).
7. 7. A dosage form according to any of claims 1 to 6, characterized in that it is a capsule formulation or an envelope formulation.
8. 8. A dosage form according to any of claims 1 to 3, characterized in that it is a tablet formulation of multiple units.
9. 9. A dosage form according to any of claims 1 to 8, characterized in that the proton pump inhibitor is protected by two layers, an enteric coating layer and a subcoating layer separating the enteric coating of the inhibitor from the proton pump.
10. 10. A dosage form according to any of claims 1 to 9, characterized in that the proton pump inhibitor is omeprazole or an alkaline salt thereof.
11. 11. A dosage form according to any of claims 1 to 9, characterized in that the proton pump inhibitor is esomeprazole or an alkaline salt thereof or a hydrated form of any of them.
12. 12. A dosage form according to any of claims 1 to 9, characterized in that the proton pump inhibitor is lansoprazole or a pharmaceutically acceptable salt thereof or a single enantiomer of any of them.
13. 13. A dosage form according to any of claims 1 to 9, characterized in that the proton pump inhibitor is pantoprazole or a pharmaceutically acceptable salt thereof or a single enantiomer of any of them.
14. 14. A dosage form according to any of claims 1 to 9, characterized in that the proton pump inhibitor is rabeprazole or a pharmaceutically acceptable salt thereof or a single enantiomer of some of them.
15. 15. A dosage form according to any of claims 1 to 9, characterized in that the proton pump inhibitor is ilaprazole or a pharmaceutically acceptable salt thereof or a single enantiomer of some of them.
16. 16. A dosage form according to any of claims 1 to 9, characterized in that the proton pump inhibitor is tenatoprazole or a pharmaceutically acceptable salt thereof or a single enantiomer of some of them.
17. 17. A dosage form according to any of claims 1 to 16, characterized in that the amount of proton pump inhibitor is in the range of 5 to 300 mg and the amount of acetylsalicylic acid is in the range of 10 to 500 mg.
18. 18. A dosage form according to any of claims 1 to 17, characterized in that the amount of proton pump inhibitor is in the range of 10 to 200 mg.
19. 19. A dosage form according to any of claims 1 to 18, characterized in that the amount of proton pump inhibitor is selected from 5, 10, 20,30,40,50,60, 70, 80, 90 and 100 mg.
20. 20. A dosage form according to any of claims 1 to 19, characterized in that the amount of acetylsalicylic acid is in the range of from 25 to 450 mg.
21. 21. A dosage form according to any of claims 1 to 20, characterized in that the amount of acetylsalicylic acid is in the range from 50 to 400.
22. 22. A dosage form according to any of claims 1 to 21, characterized in that the amount of acetylsalicylic acid is in the range from 60 to 350 mg.
23. 23. A dosage form according to any of claims 1 to 22, characterized in that the amount of acetylsalicylic acid is in the range from 75 to 325 mg.
24. 24. A process for the manufacture of a fixed-dose oral dosage form comprising an inhibitor of the proton pump sensitive to acids and acetyl 1-organic acid, characterized in that the proton pump inhibitor is prepared in the form of units with enteric coating in layers and because with those units a capsule or an envelope is filled together with one or more separate separate physical units containing acetylsalicylic acid optionally mixed with pharmaceutically acceptable excipients.
25. 25. A method for the prevention of thromboembolic vascular events, such as myocardial infarction or accident cerebrovascular disease, and the reduction and / or prevention of gastrointestinal complications associated with treatment with acetylsalicylic acid in mammals or humans, characterized in that a therapeutically effective dose of a fixed dosage form is administered to the host in need thereof in accordance with any of the claims 1 to 23.
26. 26. A method according to claim 25, characterized in that it comprises the administration of a capsule or an envelope containing acetylsalicylic acid and proton pump inhibitor.
27. 27. A method according to claim 26, characterized in that the capsule or the envelope is administered once a day.
28. 28. A method according to claim 26, characterized in that the capsule or envelope is administered twice a day.
29. 29. The use of a pharmaceutical form according to any of claims 1 to 23, for the manufacture of a medicament for the prevention of thromboembolic vascular events, such as myocardial infarction or cerebrovascular accident, and for the prevention and / or reduction of Gastrointestinal complications associated with treatment with acetylsalicylic acid.
30. 30. An oral pharmaceutical form of fixed combination that comprises esomeprazole or an alkaline salt thereof or a hydrated form of any of them and acetylsalicylic acid, characterized in that it is comprised of a group of separate physical units containing the inhibitor of the proton pump sensitive to acids and one or more physical units separate spreads comprising acetylsalicylic acid or a derivative thereof and wherein at least the proton pump inhibitor is protected by an enteric coating layer, wherein the pharmaceutical form is for the prevention of thromboembolic vascular events, such as infarction to the myocardium or cerebrovascular accident, and for the prevention and / or reduction of gastrointestinal complications associated with treatment with acetylsalicylic acid.
31. 31. A dosage form according to claim 30, characterized in that the unit containing the acetylsalicylic acid or a derivative thereof is compressed, and the dosage form is for the prevention of thromboembolic vascular events, such as myocardial infarction or cerebrovascular accident. , and for the prevention and / or reduction of gastrointestinal complications associated with treatment with acetylsalicylic acid.
32. 32. A dosage form according to any of claims 30 or 31, characterized in that the amount of esomeprazole or an alkaline salt thereof or a hydrated form of any of them is in the range of 5 to 300 mg and the amount of acetylsalicylic acid is in the range of 10 to 500 mg.
33. 33. A dosage form according to any of claims 30 to 32, characterized in that it comprises 20 mg of esomeprazole and 325 mg of acetylsalicylic acid.
34. 34. A dosage form according to any of claims 30 to 32, characterized in that it comprises 20 mg of esomeprazole and 75 mg of acetylsalicylic acid.
35. 35. A pharmaceutical form according to any of claims 30 to 32, characterized in that it comprises 40 mg of esomeprazole and 325 mg of acetylsalicylic acid.
36. 36. A dosage form according to any of claims 30 to 32, characterized in that it comprises 40 mg of esomeprazole and 75 mg of acetylsalicylic acid.
37. 37. A dosage form according to any of claims 30 to 32, characterized in that it comprises 20 mg of esomeprazole and 81 mg of acetylsalicylic acid.
38. 38. A dosage form according to any of claims 30 to 32, characterized in that it comprises 40 mg of esomeprazole and 81 mg of acid acetylsalicylic.
39. 39. The use of a dosage form according to any of claims 30 to 38 for the manufacture of a medicament for administration to a mammal or a human, wherein the medicament is for the prevention of thromboembolic vascular events, such as infarction. to the myocardium or stroke, and for the prevention and / or reduction of gastrointestinal complications associated with acetylsalicylic acid treatment.
40. 40. A method for the prevention of thromboembolic vascular events, such as myocardial infarction or cerebrovascular accident, and for the prevention and / or reduction of gastrointestinal complications, characterized in that it is associated with treatment with acetylsalicylic acid in mammals or humans, by administration to a mammal or human in need of a therapeutically effective dose of a combination according to any of claims 30 to 38.