MXPA96004354A - New form of pharmaceutical dosage or - Google Patents

Abstract

An oral pharmaceutical dosage form comprising an inhibitor of the proton pump, susceptible to the acid, and one or more antibacterial compounds in a fixed formulation is described. The fixed formulation is designed for oral use and in the form of a tablet with an enteric coating layer, a capsule or a multi-unit tablet dosage form. The dosage form of multiple units is most preferred. The new fixed formulation is especially useful in the treatment of disorders associated with Helicobact infections.

Description

NEW FORM - ORAL PHARMACEUTICAL DOSAGE FIELD OF THE INVENTION The present invention relates to new oral pharmaceutical preparations, especially for use in the treatment of disorders associated with Helicobacter infections. The present preparations comprise a proton pump inhibitor, susceptose to acid, in combination with one or more antibacterial compounds, and a new fixed unit dose form, especially a tablet dosage form. The present invention relates to a method for manufacturing such preparations and to the use of such preparations in medicine, especially in the treatment of Helicobacter pylori infections.

BACKGROUND OF THE INVENTION 'The relationship between gastrointestinal disorders and Helicobacter pylori infections proposed in 1983 by Warren (Warren JR Lancet 1983; 1.1273) is well established today. A number of different therapies have been proposed for the treatment of H infections. pylori. Most of these tera- REF: 23137 pias comprise different combinations of antibacterial compounds. Some of these therapies also comprise a bismuth compound, see for example World Patent WO 89/03219 (Borody). Other combination therapies include a proton pump inhibitor and one or more antibacterial compounds, for example a combined regimen of omeprazole and amoxicillin which has been approved by regulatory authorities for example in Greater Grenada and Sweden for the treatment of infections, by H. pylori. Different triple therapies, for example omeprazole, clarithromycin and amoxicillin or other antibacterial substances, have recently been reported at the 10th World Congress of Gastroenterology in October 1994. Some patent applications published in this field are for example: WO 93 / 00327, Astra A tiebolag, which describes the combination of a substance with an inhibitory effect on the secretion of gastric acid, which increases the intragastric pH and an antibacterial compound degradable by acid. The proposed combination is especially suitable for the treatment of H infections. pylori. W0 92/03135, Smithkline & French Laboratories, which describes a combination of a benzimidazole 1 and an anti-Helicobacter agent, for example, pantoprazole in combination with amoxicillin and / or metronidazole. In these proposed combination therapies, each simple actiya substance is administered separately in different dosage forms, each comprising only one simple active substance. It is well known that compliance of the patient is a major factor in receiving a good result in medical treatments, especially in the treatment of infections x0 by H. pylori. The administration of two, three or even more tablets different from the patient is not convenient or satisfactory to achieve the most optimal results. The present invention now provides new oral dosage forms, comprising two or more different active auctionabilities combined in a fixed unit dosage form, preferably one tablet. It is well known that proton pump inhibitors are susceptible to degradation / transformation in acid and neutral reaction media. With respect to the stability properties, it is obvious that one of the active substances which is a proton pump inhibitor should be protected from contact with acidic gastric juice by an enteric coating layer. There are different preparations for enteric coating layers of omeprazole, as well as for other proton pump inhibitors, described in the prior art, for example, in US Pat. No. 4,786,505 (AB Hassle). There are problems in producing a fixed unit dose form comprising a rather high amount of active substances. Different active substances in the same preparation give additional problems. The preparation of a dosage form of multiple unit tablets, produces specific problems when the enteric coated coating spheres containing inhibitors of the proton pump susceptible to the acid, as active substance, are compressed into tablets. If the enteric coating layer does not resist compression of the spheres in a tablet, the susceptible active substance will be destroyed after administration, by the penetration of acidic gastric juices, for example, the acid resistance of the enteric coating layer. of the spheres will not be enough in the tablet after compression.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides fixed, oral unit dose forms, for example, dosage forms in multiple unit tablets, enteric coated tablets, multi-layered tablets or a capsule filled with more than one pharmaceutically active compound. The active compounds present are preferably an inhibitor of the proton pump, susceptible to the acid and one or more antibacterial substances. These new dosage forms will simplify the regimen and improve patient compliance.

DESCRIPTION OF THE FIGURES Figure 1 illustrates a cross-sectional view of a dosage form of multiple unit tablets, comprising an acid-susceptible proto-pump inhibitor, in the form of spheres or pellets (1) with enteric coating layer, in a mixture with an antibacterial granulation (2). The tablet is covered by a coating layer (7).

Figure 2 illustrates a cross-sectional view of a tablet with two separate layers, a layer comprising the pellets with enteric coating layer of an inhibitor of the proton pump susceptible to acid (1) in admixture with excipients (3), and the other layer comprises the antibacterial compound or compounds (2). The tablet is covered with a overcoat layer (7).

The Figure > 3 illustrates a cross-sectional view of a tablet with enteric coating layers, comprising an inhibitor of the proton pump susceptible to acid, in admixture with one or more antibacterial substances (4). The tablet is covered by an enteric coating layer (7).

Figure 4 illustrates a tablet with enteric coating layers consisting of two separate layers, one layer comprising a proton pump inhibitor (5), susceptible to the acid, and the other layer comprising the antibacterial compound or compounds (6) .

DETAILED DESCRIPTION OF THE INVENTION An object of the invention is to provide an oral dosage form, in multiple unit tablets, comprising an acid-susceptible proton pump inhibitor, in the form of units with individual enteric coating layers, together with one or more compounds antibacterials in the form of a powder or granules compressed in a tablet. The layer or layers of enteric coating that cover the individual units of the proton pump inhibitor, susceptible to acid, has properties such that the compression of the units in a tablet does not significantly affect the acid resistance of the units with enteric coating layers, individually. In addition, the dosage form in multiple unit tablets provides good stability during long-term storage for the active substances. Alternatively, the prepared tablet has separate layers, one layer is in the form of compressed layered or enteric-coated units, comprising the proton pump inhibitor and another layer comprising the antibacterial compound or compounds. The new fixed dose form is preferably in the form of a multi-unit tablet dosage form, which comprises the enteric coating layer units of an active substance, which is susceptible to the acid, for example, the inhibitor of the proton pump, and granules of the other substance or active substances, for example, antibacterial granulation, as shown in Figures 1 and 2. Alternatively, the different active compounds can be intimately mixed with one another and tablets in one. conventional tablet, which is coated with enteric layer, as shown in Figures 3 and 4. As a further alternative, the different active substances are dry mixed and filled into a capsule. In the last preparation the inhibitor of the proton pump, susceptible to the acid, is in the form of units (1) with an enteric coating layer. Another object of the invention is to provide a preparation in the form of a tablet comprising a proton pump inhibitor., susceptible to acid, in admixture with one or more antibacterial substances compressed in a tablet, whose tablet is coated with enteric layer. Optionally, a separation layer is applied before the tablet is coated with enteric layers. Alternatively, the core of the prepared tablet has separate layers, each comprising different active substances. One of the layers comprises the inhibitor of the proton pump, susceptible to the acid and another layer or layers further comprises the antibacterial substance or substances, respectively. The prepared tablet is thereafter coated with enteric layers. A further object of the invention is to provide a dosage form that is divisible, such as divisible tablets. Yet another objective of the present invention is to provide a multi-unit tablet dosage form, which is divisible and easy to administer. drive. The multi-unit tablet dosage form can be dispersed in an aqueous liquid, and it can be administered to patients with disorders in swallowing and in the pediatric area. Such suspension of dispersed units / pellets of appropriate size can be used for oral administration and also for feeding through a naso-gastric tube. In addition, the present invention provides a capsule preparation comprising the proton pump inhibitor, susceptible to acid, in the form of pellets or spheres with enteric coating layers, mixed with one or more antibacterial compounds in the form of granules or pellets. The antibacterial components can be formulated in the form of instant release, sustained release or prolonged release formulations. Alternatively, the components can be formulated in an effervescent formulation. The new fixed unit dose forms comprise as active substances an inhibitor of the proton pump, susceptible to the acid, and one or more anbacterial compounds. The different active compounds used in the dosage form are defined below.

Active substances The proton pump inhibitors are, for example, compounds of the general formula I 0 Hetj-X-S- Het. where Y Het. is wherein N in the benzimidazole moiety means that one of the carbon atoms substituted by R, - RQ, can optionally be exchanged for a nitrogen atom without any substituent; R, R and R are the same or different and are selected from hydrogen, alkyl, alkoxy optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and phenylalkoxy; R, and e are the same or different and are selected from hydrogen, alkyl and aralkyl; R 'is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy; - R, -RQ are the same or different and are selected from hydrogen, alkyl, alkoxy, haloalkoxy, alkyl carbonyl, alkoxycarbonyl, oxazolyl, trifluoroalkyl, or adjacent groups R, -RQ form ring structures which may be adicionalmen and replaced; Rn is hydrogen or forms an alkylene chain together with R ~ and Rll and R12 are the same different degrees, and are selected from hydrogen, halogen or alkyl and alkyl groups, alkoxy groups and portions thereof can be linear chains or branched from 1 to 9 carbon atoms, or comprise citric alkyl groups, for example cycloalkylalkyl. Examples of proton pump inhibitors according to formula I are Omeprazole H - - Lansoprazole H H Pariprazole 0 H Leminoprazole 5 H CH / \ CH3 CHj H The inhibitors of the proton pump used in the dosage form of the invention can be used in neutral form or in the form of an alkaline salt, such as eg in the salts of Mg, Ca, Na, K or Li +, preferably the Mg2 + salts. Where they are additionally applicable, the compounds listed above may be used in racemic form or in the foram of a substantially pure enantiomer thereof, or alkali salts of the simple enantiomers. The proton-pump inhibitor, suitable, are described for example in European Patent EP-A1-0005129, EP-A1-174 726, EP-A1-166, 287, GB 2,163,747, GB 2,163,747 and British Patent World Patent W090 / 06925, W091 / 19711, W091 / 19712, and the especially suitable additional compounds are described in the World Patents W095 / 01977 and W094 / 27988. A wide variety of antibiotic compounds can be used in combination with a. proton pump inhibitor, appropriate, in the fixed unit dose form, according to the present invention. Such antibacterial compounds include for example nitroimidazole antibiotics type, tetracyclines, penicillins, inas cefalospor, carbopenems, aminoglycosides, macrolide antibiotics, lincosamide antibiotics type, 4-quinolones, rifamycins and nifrofurantoína. In the following examples of such antibacterial compounds are listed: ampicillin, amoxicillin, bencilpenicilin, fenoximetilpenicilir brs, bacampicillin, pivampicillin, carbenicillin, cloxacillin, cyclacillin, dicloxacillin, methicillin, oxacillin, p-peracilina, ticarcillin, f lucloxacilina, cefuroxi to, cefetamet , cefetram, cefimetim, cefoxitin, ceftazidime, ceftizoxime, latamoxef, cefoperazone, ceftriaxone, cefsulodin, cefotaxime, cephalexin, cefaclor, cefadroxil, cephalothin, cefazolin, cefpodoxime, ceftibuten, aztreonam, tegemonam, erythromycin, dirithromycin, roxithromycin, azithromycin, cyarithromycin , clindamycin, paldimycin, lincomycin, vancomycin, spectinomycin, tobramycin, paromomycin, metronidazole, tinidazole, ornidazole, amifloxacin, cinoxacin, ciprofloxacin, difloxacin, enoxacin, fleroxacin, ñor f loxacin, ofloxacin, teraafloxacin, doxycycline, minocycline , tetracycline, chlortetracycline, oxytetracycline, • metacycline, r olitetracycline, nitrofurantoin, nalidixic acid, gentamicin, rifampin, amikacin, netilmicin, imipenem, cilastatin, chloramphenicol, furazolidone, nifuroxazide, sulfadiazine, sulfamethoxazole, bismuth subsalicylate, colloid bismuth subcitrate, gramicidin, mecillinam, cloxyquine, chlorhexidine, dichlorobenzyl alcohol, methyl-2-pentyl- phenol. The active antibacterial agents could be in standard or used forms such as salts, hydrates, esters, etc. A combination of two or more of the drugs listed above may be used, for example to minimize the risk of developing resistance. Preferred antibacterial compounds for the new fixed dose form are clarithromycin, erythromycin, roxithromycin, azithromycin, amoxicillin, metronidazole, tinidazole and tetracycline. Clarithromycin and metronidazole alone or in combination are especially appropriate. The preferred multiple unit tablet dosage form comprising a proton pump inhibitor in the form of a racemate, an alkaline salt or one of its simple enantiomers and one or more antibacterial compounds is characterized in the following manner. Individual units of enteric coating layers (small spheres, granules or pellets) containing the proton pump inhibitor, susceptible to acid, and optionally containing alkaline reaction substances, are mixed with the antibacterial compound or compounds and with excipients for conventional tablets. Preferably, the antibacterial compound or compounds and the excipients for tablets are in the form of a granulation. The dried mixture of the units in enteric coating layers, the antibacterial granulation and optionally the excipients, are compressed in the dosage form into multiple unit tablets. The term "individual units" means small spheres, granules or pellets, referred to below as pellets of the proton pump inhibitor. The process of compaction (compression) for the formulation of the dosage form of multiple unit tablets should not significantly affect the acid resistance of the pellets with enteric coating layers. In other words the mechanical properties, such as the Flexibility and hardness as well as the thickness of the layer or layers of enteric coating, must ensure that the requirements on articles coated with enteric coating in the United States Pharmacopoeia, are complied with so that the acid resistance does not diminish further. 10% during compression of pellets in tablets. Acid resistance is defined as the amount of proton pump inhibitor in tablets or pellets after being exposed to USP simulated gastric fluid, or 0.1 M HCl (aqueous) relative to that of unexposed pellets and pellets, respectively. The test is carried out in the following manner. The tablets or individual pellets are exposed to simulated gastric fluid of a temperature of 37 ° C. The tablets disintegrate rapidly and release the pellets with enteric coating layer to the medium. After two hours the pellets with enteric coating layers are removed and analyzed for the contents of the proton pump inhibitor, using high-performance liquid chromatography (HPLC). The additional specific components, used in the fixed unit dose form of the present invention, are defined below.

Core material - for enteric-coated layer pellets comprising a proton pump inhibitor The core material for the pellets with enteric coating layer individually, can be constituted according to different principles. Seeds or nuclei in layers with the proton pump inhibitor, susceptible to acid, optionally mixed with alkaline substances *, can be used as the core material for further processing. The seeds that are going to be coated with layers with the proton pump inhibitor, suscep- tibie to the acid, can be seeds insoluble to water that comprise different oxides,. cellulos, organic polymers and other materials, alone or in mixtures, or water soluble seeds comprising different inorganic salts, sugars, unpaired and other materials, alone or in mixtures. In addition, seeds may comprise the proton pump inhibitor in the form of crystals, agglomerates, compacts, etc. The size of the seeds is not essential for the present invention, but may vary between about 0.1 and 2 mm. The seeds in layers with the proton pump inhibitor are produced either by conversion into powder or solution / suspension layers using for example granulation or formation equipment in spray coating layers. 'Before the seeds are covered with layers, the proton pump inhibitor can be mixed with additional components. Such components may be binders, surfactants, fillers, disintegrating agents, alkaline or other additives, and / or pharmaceutically acceptable ingredients alone or in mixtures: Binders are for example celluloses such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, (HPC), sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), sugar or starch or other pharmaceutically acceptable substances with cohesive properties. Suitable surfactants are found in pharmaceutically acceptable nonionic or ionic surfactant groups, such as, for example, sodium lauryl sulfate. Alternatively, the proton pump inhibitor optionally mixed with alkaline substances and further mixed with suitable constituents can be formulated into the core material. Said core material can be produced by extrusion / spheronization, pelletizing or compression using conventional process equipment. The size of the core material formulated is approximately between 0.1 and 4 mm, and preferably between 0.1 and 2 mm. The fabricated core material can also be layered with additional ingredients comprising the proton pump inhibitor and / or used for further processing. The proton pump inhibitor is mixed with pharmaceutical constituents to obtain the preferred handling and processing properties and an adequate concentration of the substance in the final mixture. Pharmaceutical constituents such as fillers, binders, lubricants, disintegrating agents, surfactants and other pharmaceutically acceptable additives can be added. In addition, the proton pump inhibitor can also be mixed with a pharmaceutically acceptable alkaline substance (or substances). Such substances may be chosen from, but are not restricted to, substances such as sodium, potassium, calcium, magnesium and aluminum salts of phosphoric acid, carbonic acid, citric acid or other suitable inorganic or weak organic acids; co-precipitated aluminum hydroxide / sodium bicarbonate, substances normally used in anti-acid preparations such as aluminum, calcium and magnesium hydroxides; magnesium oxide or compound substances, such as Al203.6MgO.C02.12H20, (Mg &Al2 (OH) 16C03.4H20), MgO. A1"0 ~ .2Si0". nH "0 or similar compounds; pH-buffering organic substances such as trihydroxy-methylaminomethane, basic amino acids and their salts or the like, pH-absorbing substances, pharmaceutically acceptable. Alternatively, the aforementioned core material can be prepared by the use of spray drying or the spray freeze technique.

Coating layer (s), enteric Prior to application of the enteric coating layer or layers on the core material, in the form of individual pellets, the pellets may optionally be coated with one or more separation layers comprising pharmaceutical excipients that optionally include alkaline compounds such as compounds pH buffers. This / these hoods), separates (n) the core material from the outer layers that are the layer or layers of enteric coating. The separation layer or layers can be applied to the core material by coating or layered coating processes in suitable equipment such as coating drum, coating granulator or in a fluidized bed apparatus using water and / or organic solvents for the coating. coating process. As an alternative, the separation layer or layers can be applied to the core material by the use of the powder coating technique. The materials for the separation layers are pharmaceutically acceptable compounds such as, for example, sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethyl cellulose, water soluble salts of enteric coating polymers and others, used alone or in mixtures. Additives such as plasticizers, colorants, pigments, anti-adhesion fillers and antistatic agents, such as for example magnesium stearate, titanium dioxide, talc and other additives may also be included within the separation layer or layers. 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 only limited by the process conditions. The separation layer can serve as a diffusion barrier and can act as a buffer zone of pH. The pH buffering properties of the separation layer or layers can be further strengthened by introduction into the layered substances, chosen from a group of compounds frequently used in antacid formulations such as, for example, oxides, hydroxides or carbonates. magnesium, hydroxide, carbonate 1 or aluminum silicate or ca * lcio; aluminum / magnesium compounds such as, for example, Al203.6MgO.C02.12H20, (Mg6Al2 (0H) 16C03.4H20), MgO. A L jO. .2Si02. nH20 ,, coprecipitate of aluminum hydroxide / sodium bicarbonate or similar compounds; or other pharmaceutically acceptable pH buffering compounds such as, e.g. example, sodium, potassium, calcium, magnesium and aluminum salts of phosphoric, carbonic, citric or other suitable acids, weak Q, inorganic or organic; or appropriate organic bases, including basic amino acids and salts thereof. Talc or other compounds can be added to increase the thickness of the layer or layers, and thereby strengthen the diffusion barrier. The optionally applied layer 5 or separation layers are not essential to the invention. However, the separation layer or layers can improve the chemical stability of the active substance and / or the physical properties of the dosage form in multiple unit tablets Q. Alternatively, the separation layer may be formed in situ by the reaction between an enteric coating polymer layer applied on the core material and an alkaline reaction compound in the core material. Thus, the separation layer formed comprises a water-soluble salt formed between the polymer or polymers in enteric coating layers and an alkaline reaction compound which is in the position to form a salt. One or more layers of enteric coating are applied to the core material or to the core material covered with the layer or layers of separation, by using an adequate coating technique. The enteric coating layer material can be dispersed or dissolved either in water or in suitable organic solvents. As polymers for enteric coating layer one or more, separately or in combination, of the following may be used, for example, solutions or dispersions of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, acetate succinate Hydroxypropyl methylcellulose, polyvinyl acetate phthalate, cellulose acetate tri-eluate, carboxymethylethylcellulose, shellac or other suitable enteric coating polymers. The enteric coating layers contain pharmaceutically acceptable plasticizers to obtain the mechanical properties, such as flexibility and hardness of the enteric coating layers. Such plasticizers are for example, but are not restricted to 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 of the enteric coating layer, selected, to the plasticizer or plasticizers selected and to the applied amount of the polymer or polymers, in such a way that the mechanical properties, for example, the flexibility and hardness of the enteric coating layer or layers, e.g., and employed as Vickers hardness, are adjusted so that the acid resistance of the pellets covered with the enteric coating layer or layers »Does not decrease significantly during compression of the pellets to form tablets. The amount of plasticizer is usually 'above 10% by weight of the polymer or polymers for the enteric coating layer, preferably 15 to 50%, and more preferably 20 to 50%. Also additives such as dispersants, colorants, pigments, polymers, for example, poly- (ethylacrylate, methyl methacrylate), antiadhesive and antifoaming agents may 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 into the material susceptible to acid. To protect the substance susceptible to acid, the proton pump inhibitor, and to obtain an acceptable acid resistance of the dosage form according to the invention, the enteric coating layer or layers constitutes a thickness of approximately 10. μm, preferably more than 20 μm. The maximum thickness of the enteric coating applied is normally only limited by the processing conditions. Alternatively, the enteric coating layer described above can be used for the formation in enteric coating layers of conventional tablets, comprising a composition of a proton pump inhibitor, susceptible to acid, and one or more antibacterial compounds. , optionally covered by one of the separation layers described above. As a further alternative, the proton pump inhibitor can be replaced in such a tablet by agents that suppress gastric acid, such as an H2 receptor antagonist, for example ranitidine, cimetidine or famothidine.

Layer of over-reverse The pellets covered with the enteric coating layer or layers may also be covered with one or more overcoating layers. The overcoating layer or layers can be applied to the pellets with enteric coating layers, by coating or layering methods in suitable equipment such as a coating drum, coating granulator or in a fluidized bed apparatus using water and / or organic solvents for the coating or layered process. The materials for the overcoat layers are chosen from pharmaceutically acceptable compounds such as, for example, sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and others, used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, release agents and antistatic agents, such as for example magnesium stearate, titanium dioxide, talc and other additives may also be included in the overcoat layer or layers. Said overcoat layer can further prevent the potential agglomeration of the pellets with enteric coating layers, and in addition it can protect the enteric coating layer against cracking during the compaction process, and improve the tabletting process. The maximum thickness of the applied overcoat layer or layers is normally only limited by the process conditions. The overcoat layer described above can also be used as a coating layer for tablets, to obtain good looking tablets.

Antibacterial granulation The active substance in the form of one or more antibacterial compounds is dry mixed with inactive excipients, and the mixture is kneaded in wet form with a granulation liquid. The wet mass is preferably dried to a loss on drying of less than 3% by weight. After this, the dry mass is milled to an appropriate size for the granules, such as smaller "4mm, and preferably smaller than 1mm inactive excipients suitable for antibacterial granulation are for example, sodium starch glycolate. , corn starch, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropylcellulose, microcrystalline cellulose and anhydrous colloidal silicon dioxide (Aerosil) R. The dry mixture comprising the antibacterial compound or compounds is mixed with a suitable granulation liquid, such as, for example, polyvinylpyrrolidone, hydroxypropylcellulose, and optionally wetting agents, such as sodium lauryl sulfate, dissolved in purified water The lubricants suitable for the tabletting process are, for example, sodium stearyl fumarate, magnesium stearate and talc.

Multiple unit tablets The pellets with enteric coating layers comprising a proton gum inhibitor are mixed with the granules comprising antibacterial compounds and excipients for tablets. The dried mixture is compressed into a multiple unit tablet dose form. The compressed tablet is optionally coated with a film-forming agent or agents, to obtain a smooth surface of the tablet, and further increase the stability of the tablet during packaging and transport. Such a coating layer of the tablet may also comprise additives such as anti-adherent agents, colorants and pigments or other additives, to obtain a good looking tablet. The pellets coated with enteric coating with or without an overcoat, and the antibacterial granulation, are mixed with the tablet excipients such as fillers, binders, disintegrators, lubricants and other pharmaceutically acceptable additives., and compress to form tablets. The amount of the pellets with enteric coating layers constitutes less than 75% by weight of the total weight of the tablet, and preferably less than 60%. By choosing the pellets with small enteric coating layer, in the formulation according to the present invention, the number of pellets in each tablet can be kept high, which in turn makes the tablet divisible with the precision of conserved dosage. A larger amount of the granulation comprising the antibacterial compound or compounds may reduce the amount of the enteric coated layer pellets in the multiple unit dose, tablet form. Thus, the preferred multiple unit tablet formulation consists of pellets with enteric coating layers containing an active substance in the form of an inhibitor of the proton pump, susceptible to the acid, optionally mixed with a compound or reaction compounds. alkaline, compressed to a tablet, together with a granulation containing the antibacterial compound or compounds and optionally tablet excipients. The addition of an alkaline reaction material for the proton pump inhibitor is not necessary, in any sense, but such a substance can further improve the stability of the proton pump inhibitor or some of the alkaline reaction compounds can react in in situ with the enteric coating material to form a separation layer. The enteric coating layer or layers make the pellets in the dosage form insoluble in acid media, but disintegrate / dissolve in almost neutral alkaline media such as, for example, liquids present in the proximal part of the small intestine, where the dissolution of the proton pump inhibitor is desired. The antibacterial substance or substances can be released into the stomach.

The pellets with enteric coating layer may also be coated with an overcoat layer before being formulated into the tablet, and these may also contain one or more separation layers optionally containing the alkaline substance or substances.

Process The process for manufacturing the dosage form represents a further aspect of the invention. After the formulation of the pellets by spray coating or layered formation of the proton pump inhibitor on seeds, or by extrusion / spheronization or granulation, for example, rotary granulation of the homogeneous pellets, the pellets are first, optionally coated with the separation layer or layers and then with the enteric coating layer or layers, or a separation layer is spontaneously developed in situ between an alkaline core material and the enteric coating layer material. The coating is carried out as described above in the appended examples. The prep-aracióp of the granulation comprising the antibacterial compound or compounds is also described above in the examples. The pharmaceutical processes can preferably be completely water-based. Pelofilias with enteric coating layers, with or without an overcoat, are mixed with the prepared granules, with the excipients for tablet and other pharmaceutically acceptable additives, and compressed to form tablets. The tablet can be in the form of a two-layer tablet, wherein one layer comprises the pellets with enteric coating layer optionally mixed with the inactive excipient, and another layer comprising the prepared granules of the antibacterial substance or substances. Alternatively, the different active substances in the powder form can be intimately dry mixed with tablet excipients, formed in wet mass and compressed into conventional tablets before the application of an optional separation layer and a coating layer. enteric. The tablet can be in the form of a tablet with two-layer enteric coating layers, wherein one layer comprises one of the active substances and the other layer comprises the other active substance. As a further alternative, the proton pump inhibitor in the form of pellets with enteric coating layers can be filled into a capsule together with the antibacterial substance or substances, in the form of a granulation optionally mixed with pharmaceutical excipients. .

Use of preparation The dosage forms according to the invention are especially advantageous in the treatment of H infections. pylori. These are administered one to several times a day, preferably once or twice a day. The typical daily dose of the active substances varies and will depend on various factors such as the individual requirements of the patients, the mode of administration and the disease. In general, each dosage form will comprise 0.1 to 200 mg of the proton pump inhibitor and 0.1 mg to 1.2 g of the antibacterial compound or compounds. Preferably, each dosage form will comprise from 10 to 80 mg of the proton pump inhibitor and 100 to 900 mg of the antibacterial compounds or compounds, and more preferably from 20 to 40 mg of the proton pump inhibitor and from 250 to 650 mg of the antibacterial compound or compounds, respectively. The preparation of tablets in multiple units is also suitable for dispersion in an aqueous liquid with a neutral or slightly acidic pH value, before being orally administered or fed through a nasogastric tube. The invention is illustrated in more detail in the following examples.

Eg emplos Example 1 : Multiple unit dose form comprising omeprazole and metronidazole (tablets, lot size equal to 10,000).

Core material Omeprazole magnesium 12.00 kg Spherical sugar seeds 12.00 kg Hydroxypropyl methylcellulose 1.8 kg Purified water 35.4 kg Separation layer Core material (according to the above) 23.50 kg Hydroxypropyl cellulose 2.35 kg Talc 4.03 kg Magnesium stearate 0.34 kg Purified water 48.00 kg Enteric coating layer Pellets coated with the separation layer (according to the above) 29.00 kg Methacrylic acid copolymer (30% suspension) 38.70 kg Triethyl citrate 3.48 kg Mono- and diglycerides (NF) 0.58 kg Polysorbate 80 0.06 kg Purified water 22.68 kg Overcoat layer Pellets with enteric coating layer (according to the above) 44.7 kg Hydroxypropyl methylcellulose 0.58 kg Purified water 11.6 kg Tablets Pellets prepared comprising omeprazole as prepared above 933 g Metronidazole 4000 g Sodium starch glycolate 500 g D Aerosil 25 g Sodium lauryl sulfate 20 g Polividone K90 253.1 g Microcrystalline cellulose 1181 g Purified water 2278 g Sodium stearyl fumarate 66.5 g Coating solution for tablets (for 10 kg of tablets).

Hydroxypropyl methylcellulose 250 g Polyethylene glycol 6000 62.5 g Titanium dioxide 62.5 g Purified water 2125 g Hydrogen peroxide 0.75 g The layering of the suspension is carried out in a fluidized milk apparatus. The magnesium omepra-zol is sprayed onto the spherical sugar seeds from an aqueous suspension containing the dissolved binder. The size of the spherical sugar seeds is in the range of 0.25 to 0.35 mm. The prepared core material is covered with a separation layer in a fluidized bed apparatus with a solution of hydroxypropylcellulose containing talc and magnesium stearate. The enteric coating layer consisting of the copolymer of methacrylic acid, mono- and diglycerides, triethyl citrate and polysorbate, is sprayed onto the pellets covered with a separation layer, in a fluidized bed apparatus. In a fluidized bed apparatus the pellets with enteric coating layer are coated with hydroxypropylmethylcellulose solution. The pellets with overcoating layers are classified by sieving. Sodium lauryl sulfate and polyvidone K90 are dissolved in purified water to form the granulation liquid. The metronidazole, the sodium starch glycolate and the Aerosil are mixed dry. The granulation liquid is added to the powder mixture and the mass is mixed in wet form. The wet mass is dried in a steam oven at 50 ° C. The prepared granulation is milled through the one millimeter sieve in an oscillating mill stock. The pellets with enteric coating layer with an overcoat layer, the prepared granules, the microcrystalline cellulose and the sodium styrene fumarate are mixed and compressed into tablets, using a rotary, tablet-forming machine, equipped with oval punches of 8.5 x 17 mm. The amount of omeprazole in each tablet is approximately 20 mg and the amount of metronidazole is approximately 400 mg. The speed of tablet formation is adjusted to 50 rpm and the force of the upper punch is adjusted to 20 kN. The hardness of the measured tablet is 150-164 N. The obtained tablets are coated with a conventional layer for coating tablets.

Example 2 • Multiple unit dose forms, comprising omeprazole and clarithromycin (lot size, 10,000 tablets).

Tablets Pellets with enteric coating layer with a coating overcoat 978 g (manufacture and composition as in example 1) Claritromiclna 2500 g Microcrystalline cellulose 3000 g Sodium starch glycolate 350 g p Aerosil 40 g Sodium lauryl sulfate 12.5 g Polividona K90 384.8 g Purified water 3463 g Magnesium stearate 105 g Tablet coating solution (per 10, kg tablets) Hydroxypropyl methylcellulose 250 g Polyethylene glycol 6000 62.5 g Titanium dioxide 62.5 g Purified water 2125 g Hydrogen peroxide 0.75 g Sodium lauryl sulfate and polyvidone K90 are dissolved in purified water to form the granulation liquid. The clarithromycin, the microcrystalline cellulose, the sodium starch glycolate TJ and the Aerosil are mixed dry. The granulation liquid is added to the powder mixture and the mass is mixed wet.

The wet mass is dried in a steam oven. The prepared granulation is milled through a 1 mm sieve in an oscillating mill equipment. The pellets with enteric coating layer with a supercoating layer, the prepared granules and the magnesium stearate are mixed and compressed to form tablets as in example 1. The amount of omeprazole in each tablet is approximately 20 mg, and the Amount of cyarithromycin is approximately 250 mg. The speed of tablet formation is adjusted to 50 rpm and the force of the upper punch is adjusted to 14 kN. The hardness of the tablets measured is 178-189 N. The tablets obtained are covered with a conventional coating layer for tablets.

Example 3: Dosage form of multiple units comprising 'omeprazole and clarithromycin (batch size, 10,000 tablets).

Tablets Pellets with enteric coating layer 978 g with an overcoat layer (manufacture and composition as in example 1) Ciar itromycin 5000 g Microcrystalline cellulose 2500 g Sodium starch glycollate 350 g Aerosil 40 g Sodium lauryl sulfate 25 g Polividona K90 361.9 g Purified water 3257 g Magnesium stearate 91.7 g Coating solution for tablets (for 10 kg of tablets) Hydroxypropyl methylcellulose 250 g Polyethylene glycol 6000 62.5 g Titanium dioxide 62.5 g Purified water 2125 g Hydrogen peroxide 0.75 g The antibacterial granulation is manufactured as in Example 2. The pellets with enteric coating layer with an overcoating layer, the prepared granules and the magnesium stearate are mixed and compressed to form tablets using a rotary, tablet-forming machine. equipped with oval punches of 10 x 21 mm. The amount of omeprazole in each tablet is approximately 20 mg, and the amount of clarithromycin is approximately 500 mg. The speed of tablet formation is adjusted to 50 rpm, and the force of the upper punch is adjusted to 20 kN. The hardness of the tablets measured is 105-128 N. The tablets obtained are covered with a conventional coating layer for tablets.

Example 4 Dosage form of multiple units, comprising clarithromycin (batch size, 2,500 tablets).

Core material Omeprazole Magnesium 15.00 kg Spherical sugar seeds 15.00 kg Hydroxypropyl methylcellulose 2.25 kg Purified water 40.25 kg - Separation layer Core material (according to the above) 15.00 kg Hydroxypropyl cellulose 1.5 kg Talc 2.57 kg Magnesium stearate 0.21 kg Purified water 30.00 kg Enteric coating layer Pellets covered with separation layer 18.00 kg (according to the above) Copolymer of methacrylic acid (30% suspension 30 kg) Triethyl citrate 2.7 kg Mono- and diglycerides (NF) 0.49 kg Polysorbate 80 0.05 kg Purified water 19.00 kg Tablets Pellets with enteric coating layer 246 (according to the above) Clarithromycin 625 8 Metronidazole 1000 g Microcrystalline cellulose 375 g Sodium starch glycolate 125 g Aerosil 10 g Sodium lauryl sulphate 8 g Polividone K90 117. 8 g Purified water 1060 g Sodium stearyl fumarate 48. 2 g The formation of layers in suspension is carried out in a fluidized bed apparatus. Magnesium omeprezole is sprayed onto spherical sugar seeds from an aqueous suspension containing the dissolved binder. The prepared core material is covered with a separating layer in a fluidized bed apparatus with a solution of hydroxypropyl cellulose containing talc and magnesium stearate. The enteric coating layer consisting of methacrylic acid copolymer, mono- and diglycerides, triethyl citrate and polysorbate, is sprayed onto the pellets covered with a separating layer in a fluidized bed apparatus. The pellets in enteric coating layers are classified by sieving. Sodium lauryl sulfate and polyvidone K90 are dissolved in purified water to form the granulation liquid. Clarithromycin, metronidazole, microcrystalline cellulose, sodium starch glycolate and Aerosil are mixed dry. The granulation liquid is added to the powder mixture and the mass is mixed in wet form. The wet mass is dried in a steam oven. The prepared granulation is milled through a 1 mm sieve in an oscillating mill equipment. The pellets with enamel coating, the prepared granules and the sodium stearyl fumarate are mixed and compressed into tablets as in Example 3. The amount of omeprazole in each tablet is approximately 20 mg, the amount of Metronidazole is 400 mg, and the amount of clarithromycin is 250 mg. The speed of tablet formation is adjusted to 50 rpm, and the force of the upper punch is adjusted to 24 kN. The hardness of the tablets, measured is 130 - 142 N.

Example 5 Multiple unit dose form, comprising lansoprazole and clarithromycin (batch size 1000 tablets).

Core material Lansoprazole 400 g Spherical seeds of sugar 400 g Hydroxypropyl methylcellulose 80 g Purified water 1 200 g Separation layer Core material (according to the above) 400 Hydroxypropyl cellulose 40 Talcum 69 Magnesium stearate 6 g Purified water 800 g Enteric coating layer Pellets covered with a separating layer (according to the above) 400 g Methacrylic acid copolymer (30% suspension) Triethyl citrate bU g Mono- and diglycerides (NF) 10 g Polysorbate 80 1 g Purified water 391 g Tablets Pellets with cover layer enté89.8 g rich (according to the above) Clarithromycin 250 g Microcrystalline cellulose 300 g Sodium starch glycolate 35 g Aerosil 4 g Sodium lauryl sulfate 1.25 g Polividona K90 45.2 g Purified water 406.8 g Magnesium stearate 10.1 g The formation in suspension layers is carried out in a fluidized bed apparatus. Lansoprazole is sprayed onto the spherical sugar seeds from a suspension containing the binder dissolved in an aqueous solution. The pellets covered with separation layer and with enteric coating layer are produced as in example 1. The antibacterial granulation is manufactured as in example 2. The pellets with enteric coating layer, the prepared granules and the magnesium stearate are mixed and compressed to form tablets using a rotary tablet-forming machine, equipped with 8.5 x 17 mm oval punches. The amount of lansoprazole in each tablet is approximately 20 mg and the amount of clarithromycin is approximately 250 mg. The force of the upper punch is adjusted to 5.8 kN, and the measured hardness of the tablets is 63 N.

Example 6 Multiple unit dosage form comprising magnesium salt of (s) -omeprazole, metronidazole and clarithromycin (batch size of 200 tablets).

Core material Magnesium salt of (s) -omeprazole 120 g Spherical sugar seeds 150 g Hydroxypropyl methylcellulose 18 g Polysorbate 80 2.4 g Purified water 562 g Separation layer Core material (according to the previous 200 Hydroxypropyl cellulose 30 g Talc 51.4 g Magnesium stearate 4.3 g Purified water 600 g Enteric coating layer Pellets covered with separation layer (according to the above) 250 g Methacrylic acid copolymer (30% suspension 333.7 g) Triethyl citrate 30 g Mono- and diglycerides (NF) 5 g Polysorbate 80 0.5 g Purified water 196 g Granulation of methoxydazole and clarithromycin Clarithromycin 3500 g Metronidazole 5600 g Microcrystalline cellulose 1400 g Sodium starch glycolate 700 g Aerosil 56 g Polividona K90 511 g Purified water 4600 g Tablets Pellets comprising magnesium salt 25.5 g of (s) -omeprazole (according to the above) Granulation containing clarithromycin and metronidazole. (previous) 16 8. 1 g Microcrystalline cellulose 40 g Sodium stearyl fumarate 4.7 g Coating solution for tablets (for 10 kg of tablets) Hydroxypropyl methylcellulose 250 g Polyethylene glycol 6000 62.5 g Titanium dioxide 62.5 g Purified water 2125 g Hydrogen peroxide 0.75 g The layering in suspension is carried out in a fluidized bed apparatus. The magnesium salt of the (s) -omeprazole is sprayed onto the spherical sugar seeds from an aqueous suspension containing the dis >binder. uelto and polysorbate 80. The size of the spherical sugar seeds is in the range of 0.25 to 0.35 mm. The prepared core material is covered with a separating layer in a fluidized bed apparatus with a solution of hydroxypropyl cellulose containing talc and magnesium stearate. The enteric coating layer consisting of copolymer of methacrylic acid, mono- and diglycerides, triethyl citrate and polysorbate, is sprayed onto the pellets covered with a separation layer in a fluidized bed apparatus. The pellets with enteric coating layers are classified by sieving. Polyvidone K90 is dissolved in purified water to form the granulation liquid. Clarithromycin, metronidazole, microcrystalline cellulose, sodium starch glycolate and Aerosil are mixed dry. The granulation liquid is added to the powder mixture and the mass is mixed in wet form. The wet mass is dried in a steam oven. The prepared granulation is ground through a 1 mm sieve in an oscillating mill equipment.

The pellets with the enteric coating layer, the prepared granules, the microcrystalline cellulose and the magnesium stearate are mixed and compressed into tablets on a tablet-forming machine, equipped with 10 x 21 mm oval punches. The amount of (s) -omeprazole is about 20 mg, the amount of metronidazole is about 400 mg and the amount of clarithromycin is about 250 mg. The proven hardness of the tablets with the Schleuniger apparatus was 140-150 N. The obtained tablets are coated with a conventional coating layer for tablets. The results of the tests on the acid resistance of the compressed tablets are described in Table 1, below.

Table 1 Example No Acid resistance Tablets (%), n = 3 1 95 2 99 3 91 4 92 5 90 6 93 Example 7 A tablet with an enteric coating layer comprising omeprazole magnesium, clarithromycin and metronidazole (batch size, 1,000 tablets).

Tablets Magnesium Omeprazole 20 g Clarithromycin 250 g Metronidazole 400 g Microcrystalline cellulose 150 g Sodium starch glycolate 50 g A Aerosi-l? R 4 g Sodium lauryl sulphate 3.2 g Polividone K90 50 g Purified water 450 g Sodium stearyl fumarate 18 g Solution for the separation layer - (for 10 kg of tablets) Hydroxypropyl methylcellulose 300 g Hydrogen peroxide (30%) 0.003 g Purified water 2700 ß Solution for enteric coating layer (for 10 kg of tablets) Dispersion of copolymer of methacrylic acid 2450 g (at 30%) Polyethylene glycol 400 80 g Titanium dioxide 100 g Purified water 1960 g Sodium lauryl sulfate and polyvidone K90 are dissolved in purified water to form the granulation liquid. Magnesium omeprazole, clarithromycin, metronidazole, microcrystalline cellulose, sodium starch glycolate and Aerosil are mixed dry. The granulation liquid is added to the powder mixture and the mass is mixed in wet form. The wet mass is dried in a steam oven. The prepared granulation is milled through a 1 mm sieve in an oscillating mill equipment. The prepared granules and the sodium stearyl fumarate are mixed and compressed to form tablets, using a rotary tablet-forming machine, equipped with oval punches of 8.5 x 19 mm. The amount of omeprazole in each tablet is 20 mg, the amount of clarithromycin is 250 mg, and the amount of metronidazole is 400 mg.

The tablets obtained are covered with a separation layer and an enteric coating layer for tablets.

Example 8 A tablet with an enteric coating layer comprising sunflower and clarithromycin (lot size, 1,000 tablets).

Tablets Lansoprazole 20 g Clarithromycin 250 g Microcrystalline cellulose 150 g Sodium starch glycolate 50 g A Aerosi • ltR 4 g Sodium lauryl sulfate 3.2 g Polividona K90 50 g Purified water 450 g Sodium stearyl fumarate 18 g Solution for the separation layer (for 10 kg of tablets) Hydroxypropyl cellulose 300 g Hydrogen peroxide (30%) 0.003 g Purified water 2700 Solution for the enteric coating layer (for 10 kg of tablets) Dispersion of 2450 methacrylic acid copolymer (30%) Polyethylene glycol 400 80 g Titanium dioxide 100 g Purified water 960 g Sodium lauryl sulfate and polyvidone K90 are dissolved in purified water to form the granulation liquid. Dry lansoprazole, clarithromycin, microcrystalline cellulose, sodium glycollate and Aerosil are mixed dry. The granulation liquid is added to the powder mixture and the mass is mixed in wet form. The wet mass is dried in a steam oven. The prepared granulation is milled through a 1 mm sieve in an oscillating mill equipment. The prepared granules and the sodium stearic fumarate are mixed and compressed to form tablets using a rotary tablet-forming machine equipped with 8.5 x 19 mm oval punches. The amount of lansoprazole in each tablet is 20 mg, the amount of clarithromycin is. of 250 mg. The tablets obtained are covered with a separation layer and an enteric coating layer for tablets. > Example 9 A formulation of capsules comprising omeprazole and metronidazole.

Core material Omeprazole magnesium 10.00 kg Spherical seeds of sugar 10.00 kg Hydroxypropyl methylcellulose 1.5 kg Purified water 29.65 kg Separation layer Core material (according to 20.00 kg previous) • Hydroxypropyl cellulose 2.00 kg Talc 3.43 kg Magnesium stearate 0.29 kg Purified water 40.00 kg Enteric coating layer Pellets covered with a 24.00 kg layer separation (according to the above) Copolymer of methacrylic acid 40.00 kg (30% suspension) Triethyl citrate 3.6 kg Mono- and diglycerides (NF) 0.6 kg Polysorbate 80 0.06 kg Purified water 24.45 kg Granulation of metronidazole Metronidazole 5000 g Polyvidone K90 62.6 g Purified water 562.9 g Polyvidone K90 is dissolved in purified water to form the granulation liquid. The liquid is added to the metronidazole and the mass is mixed in wet form. The wet mass is dried in a steam oven. The prepared granulation is milled through a 1 mm sieve in an oscillating mill equipment.

Capsules Metronidazole granulation (according to 1250.8 g above) Pellets with coating layer 104 / mg capsule (according to the above) (manufacture as in Example 4) Magnesium stearate 24.8 g The granulation of metronidazole is mixed with magnesium stearate. The prepared granules and pellets with enteric coating layer are filled into capsules, size 0, using a capsule filling machine equipped with the powder dosing unit and pellet filler. The amount of omeprazole in each capsule is 20 mg, and the amount of metronidazole is 400 mg. The capsule filling speed is adjusted to 61 rpm.

Example 10 A formulation of capsules comprising omeprazole and clarithromycin.

Core material Omeprazole magnesium 15.00 kg Spherical seeds of sugar 15.00 kg Hydroxypropyl methylcellulose 2.25 kg Purified water 44.00 kg Separation layer Core material (according to the above) 30.00 kg Hydroxypropyl cellulose 3.00 kg Talc '5.14 kg Magnesium stearate 0.43 kg Purified water 60.00 kg Enteric coating layer Pellets covered with a 750 separation layer (according to the above) Methacrylic acid copolymer 322.5 Triethyl citrate 96.8 Mono- and diglycerides (NF) 16.1 Polysorbate 80 1.61 Purified water 631.4 Overcoat layer Hydroxypropyl methylcellulose 22.5 g Purified water 427.5 g Granulation of clarithromycin Clarithromycin 5000 g Ethanol (99.5%) 2064 g Sodium lauryl sulfate 50 g Sodium lauryl sulfate is dissolved in ethanol to form the granulation liquid. The liquid is added to the clarithromycin and the mass is mixed in a moist form. The wet mass is dried in a steam oven. The prepared granulation is milled through a 1 mm sieve in an oscillating mill equipment.

Capsules Clarithromycin granulation (according to 1 500 g as above) Hydroxypropyl cellulose (L-HPC) 7 5 g Magnesium stearate 31. 5 g Pellets coated with a layer of 9S .7 mg / capsule overcoat (according to the above and to the manufacture as in example 1) The granulation of clarithromycin is mixed with L-HPC and magnesium stearate, and the size 00 capsules are filled as in example 8. The amount of omeprazole in each capsule is 20 mg, and the amount of clarithromycin is 500 mg .

Example 11 A formulation of capsules comprising omeprazole, clarithromycin and meth »ronidazole.

Capsules clarithromycin granulation 1805 (manufacture and composition as in example 9) Hydroxypropyl cellulose (L-HPC) 90.3 g Metronidazole 2670 g Magnesium stearate 91.3 g Pellets coated with a layer of 96.7 mg / overcoat capsule (manufacture and composition as in example 1) The granulation of clarithromycin is mixed with metronidazole, L-HPC and magnesium stearate. The capsules of size 00 are filled as in example 8. 'The amount of omeprazole in each capsule is 20 m, the amount of metronidazole is 400 mg and the amount of clarithromycin is 250 mg.

Example 12: A dosage form comprising lansoprasol and clarithromycin, filled «inside capsules in the form of granules.

Core material Lansoprazole 400 g Spherical seeds of sugar 400 g Hydroxypropyl methylcellulose 80 g Purified water 1200 g Separation layer Core material (according to the above) 400 g Hydroxypropyl cellulose 40 g Talc 69 g Magnesium stearate 6 g Purified water 800 g Enteric coating layer Pellets covered with a 400 separation layer (according to the above) Methacrylic acid copolymer 667 g (30% suspension) Triethyl citrate 60 g Mono- and diglycerides. (NF) 1 0 g Polysorbate 80 1 g Purified water 391 g Granulation of clarithromycin Clarithromycin 5000 Ethanol (99.5%) 2064 Sodium lauryl sulfate 50 The sodium lauryl sulfate is dissolved in ethanol to form the granulation liquid. The liquid is added to the clarithromycin and the mass is mixed in a moist form. The wet mass is dried in a steam oven. The prepared granulation is milled through a 1 mm sieve in a rotary mill equipment.

Capsules Clarithromycin granulation (according to 1500 to the above) Hydroxypropyl cellulose (L-HPC) 75 g Magnesium stearate 31.5 g Pellets with coating layer 94 mg / enteric capsule (according to the above and manufacture as in example 5) Clarithromycin granulation is mixed with L-HPC and magnesium stearate, and the size 00 capsules are filled as in example 8. The amount of lansoprazole in each capsule is 20 mg and the amount of clarithromycin is 500 mg. The best mode for carrying out the invention are dosage forms of the compositions described in Examples 3, 4 and 6. The pellets with enteric coating layer and other intermediates used in the compositions described above, can also be prepared as described in the following examples.

Example 13 Preparation of pellets with enteric coating layer by extrusion / spheronization.

• Core material Omeprazole magnesium 6UU g Mannitol 1000 g Microcrystalline cellulose 300 g Hydroxypropyl cellulose 100 g Sodium lauryl sulfate 6 g Purified water 802 Separation layer Core material (»according to the above) 400 g Hydroxypropyl methylcellulose 48 g Purified water 960 g Enteric coating layer Pellets covered with 200 separation layer (according to the above) Methacrylic acid copolymer 100 g Triethyl citrate 30 g Mono- and diglycerides (NF) 5 g Polysorbate 80 0.5 Purified water 309 g The sodium lauryl sulfate is dissolved in purified water to form the granulation liquid. Magnesium omeprazole, mannitol, microcrystalline cellulose and hydroxypropyl cellulose are mixed dry. The granulation liquid is added to the powder mixture and the mass is mixed in wet form. The wet mass is forced through an extruder equipped with mesh size 0.5 mm. The extrudate is spheronized on a friction plate in a spheronization apparatus. * The core material is dried in a fluidized bed dryer and sorted. The prepared core material is covered by a separating layer, in a fluidized bed apparatus with a solution of hydroxypropyl-ethylcellulose / water. The enteric coating layer is applied to the pellets covered with a separation layer from an aqueous dispersion of methacrylic acid copolymer plasticized with triethyl citrate to which a dispersion of mono- and diglycerides / polysorbate has been added. The pellets are dried in a fluidized bed apparatus.

Example 14 Preparation of pellets with enteric coating layer, using powder.

Core material Omeprazole Magnesium 1500 g Spherical sugar seeds 1500 g Hydroxypropyl methylcellulose 420 g A Aerosi • l! R 8 g Purified water 4230 g Separation layer Core material (according to the above) 500 g Hydroxypropyl cellulose 40 g Talcum > 67 g Magnesium stearate 6 g Purified water 800 g Enteric coating layer Pellets covered with 500 separation layer (according to the above) Methacrylic acid copolymer 200 g Triethyl citrate 60 g Purified water 392 8 The magnesium omeprazole, part of the hydroxypropyl methylcellulose and the Aerosil are mixed dry to form a powder. The spherical sugar seeds (0.25 - 0.40 mm) are covered with powder layers in a centrifugal fluidized coating granulator, • with a solution of hydroxypropyl methylcellulose (at 6%, w / w). The prepared core material is dried and covered by a separating layer in a centrifugal fluidized coating granulator. A fluidized bed apparatus is used for the formation of enteric coating layers Example 15 Preparation of pellets with enteric coating layer with silicon dioxide seeds.

Core material Omeprazole magnesium 8.00 kg Silicon dioxide 8.00 kg Hydroxypropyl methylcellulose 1.41 kg Sodium lauryl sulfate 0.08 kg Purified water 28.00 kg Separation layer Core material (according to the above) 10.00 kg Hydroxypropyl methylcellulose 0.80 kg Purified water 10.00 kg 'Enteric coating layer Pellets covered with 300 separation layer (according to the above) Methacrylic acid copolymer 24 g Polyethylene glycol 400 25 g Mono- and diglycerides (NF) 3 g Polysorbate 80 1 Purified water 463 The formation of layers in suspension is carried out in a fluidized bed apparatus. The magnesium omeprazole is sprayed onto the silicon dioxide seeds from an aqueous suspension containing the dissolved binder and an active surface ingredient. The prepared core material is covered with a separating layer in a fluidized bed apparatus with a solution of hydroxypropyl methylcellulose. The enteric coating layer consisting of copolymer of methacrylic acid, mono- and diglycerides, polyethylene glycol 400 and polysorbate, is sprayed onto pellets covered with the separation layer in a fluidized bed apparatus.

Example 16 Preparation of the pellets with enteric coating layer.

Enteric coating layer Pellets covered with separation layer 500 (manufacture and composition as in example 13) Methacrylic acid copolymer 250 g Polyethylene glycol 60C, 0 75 g Mono- and diglycerides (NF) 12.5 g Polysorbate 80 1.2 g Purified water 490 g Example 17 Preparation of pellets with enteric coating layer Enteric coating Pellets covered with separation layer 500 (manufacture and composition as in example 1) Hydroxypropyl methylcellulose phthalate 250 g Cetanol 50 g • Ethanol (95%) 1000 g Acetone 2500 g Example 18 Preparation of pellets with enteric coating layer Core material Omeprazole 225 g Mannitol 1425 g Hydroxypropyl cellulose 60 g Microcrystalline cellulose 40 g Lactose anhydrous 80 g Sodium lauryl sulfate 5 g Disodium acid phosphate, dihydrate 8 g Purified water 350 R Separation layer Core material (according to the above) 300 g Hydroxypropyl cellulose 30 g Talc 51 g • Magnesium stearate 4 g Enteric coating layer Pellets covered with 300 g layer separation (according to the above) Methacrylic acid copolymer 140 g Triethyl citrate. 42 g Mono- and diglycerides (NF) 7 g Polysorbate 80 0.7 g The dry ingredients for the production of the core material are mixed perfectly in a mixer. The granulation liquid is added and the mixture is kneaded and granulated to a suitable consistency. The wet mass is pressed through an extruder mesh and the granules are converted to a spherical shape in a spheronizer. The core material is dried in a fluidized bed apparatus, and is classified into a range of appropriate particle size, for example, from 0.5 to 1.0 mm. The prepared core material is covered with a separation layer and with the enteric coating layer as described in the previous examples.

Preparation of the active substance, The magnesium omeprazole used in the examples is produced according to the process described in the World Patent W0 / SE94 / 00680, the omeprazole is produced according to the process described in the European Patent EP-A 1,0005,129, and the enantiomers simple of the omeprazole salts are produced as described in the World Patent W0 / SE94 / 00509.These documents are incorporated herein by reference, in their entirety.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (30)

.REIVINDICATION? S

1. An oral pharmaceutical dosage form, comprising an inhibitor of the proton pump, susceptible to acid, together with at least one antibacterial compound and optionally pharmaceutically acceptable excipients, characterized the dosage form, because it is in the fixed unit dose form that comprises at least two pharmaceutically active components.

2. A dosage form according to claim 1, characterized in that the dosage form is a tablet formulation.

3. A dosage form according to claim 1, characterized in that the dosage form is a capsule formulation.

4. A dosage form according to claim 1, characterized in that the dosage form comprises a proton pump inhibitor, susceptible to the acid and two antibacterial compounds.

5. A dosage form according to claim 1, characterized in that the proton pump inhibitor is omeprazole or its simple enantiomers, or an alkaline salt thereof.

6. A dosage form according to claim 1, characterized in that the proton pump inhibitor is the magnesium salt of (s) -omeprazole.

7. A dosage form according to claim 1, characterized in that the proton pump inhibitor is lansoprazole.

8. A dosage form according to any of claims 5 to 7, characterized in that the antibacterial compound is clarithromycin and / or metronidazole.

9. A dosage form according to any of claims 5 to 7, characterized in that the antibacterial compound is amoxicillin and / or clarithromycin or metronidazole.

10. A dosage form according to claim 1, characterized in that the amount of the proton pump inhibitor is in the range of 10 to 80 mg, and the amount of the antibacterial compound or compounds is in the range of 100 to 900 mg .

11. A dosage form according to claim 1, characterized in that the amount of the proton pump inhibitor is in the range of 20 to 40 mg, and the amount of the antibacterial compound or compounds is in the range of 250 to 650 mg.

12. A tablet dosage form according to claim 2, characterized in that the dosage form consists of two separate layers, each comprising different active substances.

13. A tablet dosage form according to claim 2, characterized in that the tablet formulation is a multi-unit tablet dosage form, comprising the proton pump inhibitor, susceptible to acid, in the form of pellets with enteric coating layers, individually, compressed together with an antibacterial granulation inside a tablet, whereby the enteric coating layer covering the individual pellets has mechanical properties such that the tabletting of the pellets together with the antibacterial granulation and optionally pharmaceutically acceptable excipients, does not significantly affect the acid resistance of pellets with enteric plating layer, individually.

14. A dosage form in tablets according to claim 13, characterized in that the acid resistance of the pellets with enteric coating layer individually, is consistent with the requirements in articles with enteric coating layer defined in the United States Pharmacopoeia. .

15. A dosage form in tablets according to claim 13, characterized in that the acid resistance of the pellets with enteric coating layer individually, does not decrease more than 10% during the compression of the individual pellets in dosage form in unit tablets. multiple

16. A dosage form "in tablets according to claim 13, characterized in that the enteric coating of the individual pellets comprises an enteric coating material, plasticized.

17. A dosage form in tablets according to claim 13, characterized in that the pellets with enteric coating layer individually, are further covered with an overcoat layer comprising pharmaceutically acceptable excipients.

18. A dosage form in tablets according to claim 13, characterized in that the pellets with enteric coating layer consist of a seed or core coated with the proton pump inhibitor.

19. A tablet dosage form according to claim 13, characterized in that the tablet is divisible.

20. A dosage form in tablets according to claim 19, characterized in that the tablet is dispersible to a suspension of pellets with enteric coating layer, individually, in an aqueous liquid.

21. A tablet dosage form according to claim 2, characterized in that the tablet is a tablet with an enteric coating layer, optionally with a separation layer under the enteric coating layer, and the tablet comprises at least two different pharmaceutically active substances , in mixture with each other.

22. A process for the manufacture of a fixed dose form, comprising an inhibitor of the proton pump, susceptible to acid, and one or more antibacterial compounds in a capsule, characterized the process because the inhibitor of the proton pump is prepared in the pellet form with enteric coating layer, individually, and the pellets are • filled into a capsule together with the antibacterial compound or compounds, optionally mixed with pharmaceutically acceptable excipients.

23. A process for the manufacture of a fixed dose form, comprising an inhibitor of the proton pump, susceptible to acid, and one or more antibacterial compounds in a dosage form of multiple unit tablets, characterized the process because the inhibitor, of the proton pump is prepared in the form of pellets with enteric coating layer, individually, and these pellets are mixed with an antibacterial granulation prepared and optionally with pharmaceutically acceptable tablet excipients, after which, the dry mixture is compressed to form a multi-unit tablet without giving any significant change in acid resistance to the enteric coating layer covering the pellets with enteric coating layer, individually.

24. A process for the manufacture of a fixed dose form, comprising an inhibitor of the proton pump, susceptible to acid, and one or more antibacterial compounds in a tablet with enteric coat coating, characterized the process because the inhibitor of the The proton pump is mixed with the antibacterial compound or compounds and pharmaceutically acceptable excipients, after which the dry mixture is compressed in the form of a tablet, which tablet is covered with an enteric coating layer and optionally a separation layer is applied. on the tablet before the enteric coating layer.

25. A dosage form according to any one of claims 1 to 21, characterized in that it is for use in the treatment of disorders associated with Helicobacter infections in mammals and in man.

26. A dosage form according to claim 25, characterized in that the disorder is a gastric disorder associated with Helicobacter pylori infections.

27. A method for the treatment of disorders associated with Helicobacter pylori infections in mammals and man, characterized in that it is, by administering to a host in need thereof, a therapeutically effective dose of a multi-unit tablet dosage form according to any one of claims 1 to 21.

28. A method according to claim 27, characterized in that the disorder is a gastric disorder associated with Helicobacter pylori infections > _

29. The use of a dosage form according to any of claims 1 to 21, characterized in that it is for the manufacture of a medicament for the treatment of disorders associated with Helicobacter infections in mammals and in man.

30. The use of a dosage form according to claim 29, characterized in that the disorder is a gastric disorder associated with Helicobacter pylori infections.