Oral pharmaceutical dosage forms comprising a proton pump inhibitor and an antacid agent or alginate

An oral pharmaceutical dosage form comprising an acid susceptible proton pump inhibitor and one or more antacid agents or an alginate in a fixed formulation, wherein the proton pump inhibitor is protected by an enteric coating layer and an optional separating layer in between the proton pump inhibitor and the enteric coating. The fixed formulation is in the form of multilayered tablets, sachets or multiple unit tableted dosage forms. The multiple unit dosage form is most preferred. The new fixed formulation is especially useful in the treatment of disorders associated with dyspepsia such as heartburn.

FIELD OF THE INVENTION
 The present invention is related to new oral pharmaceutical preparations
 especially for use in the prevention and treatment of dyspeptic symptoms
 like upper abdominal pain/discomfort and heartburn. The present
 preparations comprise a combination of different gastric acid suppressing
 agents, such as an acid susceptible proton pump inhibitor and antacid
 agent(s) and/or an alginate in a new fixed unit dosage form, especially a
 tableted dosage form. Furthermore, the present invention refers to a
 method for the manufacture of such preparations and the use of such
 preparations in medicine, especially in the treatment of dyspeptic
 symtoms.
 BACKGROUND OF THE INVENTION
 Dyspepsia is a common disorders and patients are seeing both
 gastroenterologists and general practicians because of it. Heartburn is a
 symptom of dyspepsia, and it is estimated that 44% of Americans have
 heartburn at least monthly and some has to contact a doctor about the
 problem, but only around 25% of the patients are seeing the doctor because
 of their dyspepsia problem. Symtoms associated with dyspepsia symtom are
 for instance upper abdominal pain/discomform and heartburn, indigestion,
 sour stomach, heartburn and other gastrointestinal disorders including
 gastro oesophageal reflux. The wide diversity of symptoms and disease
 severity produced by gastro oesophageal reflux has led to the need for
 more individualized treatment strategies.
 Therapeutic agents effective in the treatment of dyspepsia include gastric
 acid suppressing agents, such as H.sub.2 receptor antagonists, proton pump
 inhibitors, other agents of interest are antacids/alginates and prokinetic
 agents. These agents can be distinguished by their mechanisms of action,
 safety profile, pharmacokinetics and indications. WO 95/017080 describes a
 composition for use in the treatment of for instance heartburn, the
 composition comprises a H.sub.2 receptor antagonist, such as famotidine,
 and an alginate and optionally simethicone.
 Antacid agents and alginates may be used alone in the treatment of
 heartburn. They have a short duration of action but are seen as
 inexpensive and safe. Antacid agents work locally through a neutralisation
 of gastric acid. Alginates further give some mechanical protection against
 reflux or gastric acid into the oesophagasus. The main advantages of
 antacid agents and alginates are, that they provide fast relief of
 symtoms. The main disadvantage of antacid agents and alginates is that,
 dosing has to be repeated frequently to keep the patients free of symtoms,
 further that antacids in many cases do not provide symtom resolution, i.e.
 complete relief of symtoms.
 H.sub.2 receptor antagonists are widely prescribed for reducing gastric
 acid secretion systemically. Proton pump inhibitors, such as omeprazole,
 are rapidly taking share from H.sub.2 receptor antagonists. Omeprazole is
 known to offer significant gain over H.sub.2 receptor antagonists in terms
 of symptom resolution, healing and prevention of relapse. Proton pump
 inhibitors provide symtom resolution, but normally not immediately.
 Proton pump inhibitors have in clinical studies been proven to be very
 effective in providing symtom resolution (usually within 24-48 hours) in
 patients with dyspepsia associated with gastric ulcers, duodenal ulcers,
 reflux oesophagitis and gastro oesophageal reflux without oesophagitis. It
 is for instance established that omeprazole is superior to H.sub.2
 receptor antagonists regarding healing of gastroduodenal and oesophageal
 lesions as well as providing dyspeptic symtom resolution in these
 conditions, See Eriksson S., Euro Journ of Gastroenterology & Hepatology
 1995, 7:465.
 EP 338861 describes a solid pharmaceutical preparation of an antacid and
 excipients. It is proposed to use this preparation in combination with a
 proton pump inhibitor or any other substance inhibit gastric acid
 secretion. There is no suggestion to combine these substances in one fixed
 unit dosage form.
 U.S. Pat. No. 5,244,670 describes an ingestible pharmaceutical composition
 comprising a substance selected from the group consisting of antacid
 agents, acid secretion prevention agents, bismuth-containing agents, and
 mixtures thereof, and the excipient 3-1-menthoxy propane 1,2-diol. There
 are no specific arrangements discussed in neither of these references, to
 solve the problem with one of the component being an acid susceptible
 proton pump inhibitor.
 A combination therapy of a proton pump inhibitor and an antacid or an
 alginate would provide immediate symtom relief, provided by the local
 effect of the antacid agent or the alginate, combined with a long-lasting
 symtom resolution provided by the systemically acting proton pump
 inhibitor. Such a combination would be ideal for "on-demand treatment " of
 dyspepsia as well as for symtom resolution. The combination therapy
 comprising an acid suppressing agent, for instance a proton pump
 inhibitor, together with an antacid agent or an alginate could also be an
 alternative to each of them separately in case of failure. It is well
 known that patient compliance is a main factor in receiving good results
 in medical treatments. Administration of two or even more different
 tablets to 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 active substances combined in one fixed unit
 dosage form, preferably a tablet.
 Some gastric acid suppressing agents, such as proton pump inhibitors, are
 susceptible to degradation/transformation in acid reacting and neutral
 media. In respect of the stability properties, it is obvious that the one
 of the active substances being a proton pump inhibitor must be protected
 from contact with acidic gastric juice by an enteric coating layer. There
 are different enteric coating layered preparations of proton pump
 inhibitors described in the prior art, see for example U.S. Pat. No.
 4,786,505 (AB Hassle) describing a preparation comprising omeprazole.
 There are problems to produce a fixed unit dosage form comprising a rather
 high amount of active substance. Different active substances in the same
 preparation give further problems. Preparation of a multiple unit tableted
 dosage form arises specific problems when enteric coating layered pellets
 comprising an acid susceptible proton pump inhibitor as active substance
 are compressed into tablets. If the enteric coating layer does not
 withstand the compression of the pellets into a tablet the susceptible
 active substance will be destroyed upon administration by penetrating
 acidic gastric juice, i.e. the acid resistance of the enteric coating
 layer of the pellets will not be sufficient in the tablet after
 compression.
 SUMMARY OF THE INVENTION
 The present invention provides oral, fixed unit dosage forms, i.e. multiple
 unit tableted dosage forms, layered formulations comprising an enteric
 coating layered tablet core, multilayered tablets or a sachet filled with
 more than one pharmaceutically active compound. The active compounds
 present in the dosage form are preferably an acid susceptible proton pump
 inhibitor and antacid agents. Alternatively, in some of the formulations
 the antacid agents may be replaced by an alginate. These new dosage forms
 will simplify the regimen and improve the patient compliance.

DETAILED DESCRIPTION OF THE INVENTION
 One object of the invention is to provide an oral, multiple unit tableted
 dosage form comprising an acid susceptible proton pump inhibitor in the
 form of individually enteric coating layered units together with one or
 more antacid agents in the form of a powder or granules compressed into a
 tablet. The enteric coating layer(s) covering the individual units of the
 acid susceptible proton pump inhibitor has properties such that the
 compression of the units into a tablet does not significantly affect the
 acid resistance of the individually enteric coating layered units.
 Furthermore, the multiple unit tableted dosage form provides a good
 stability to the active substances during long-term storage.
 A further object of the invention is to provide a multiple unit tableted
 dosage form, which is divisible and easy to handle. Such a multiple unit
 tableted dosage form comprising enteric coating layered pellets of a
 proton pump inhibitor and antacid agent(s) also may be dispersed in a
 slightly acidic aqueous liquid and can be given to patients with
 swallowing disorders and in pediatrics. Such a suspension of dispersed
 units/pellets of appropriate size can be used for oral administration and
 also for feeding through a naso-gastric tube.
 Another object of the invention is to provide a tablet preparation
 comprising a proton pump inhibitor in admixture with tablet excipients in
 a tablet core and a separate layer surrounding the tablet core, which
 layer comprises one or more antacid agent(s) in admixture with
 pharmaceutical excipients compressed onto the tablet core. The tablet core
 is enteric coating layered before the surrounding layer comprising the
 antacid agents is applied. Optionally a separating layer is applied on the
 tablet core before the core is enteric coating layered.
 Alternatively, the prepared tablet is sectioned in separate layers, each
 one comprising different active substances. One of the layers comprises
 the proton pump inhibitor in the form of enteric coating layered pellets
 in admixture with pharmaceutical excipients and the other layer(s)
 comprises(-e) the antacid agent(s)/alginate, respectively in admixture
 with pharmaceutical excipients. Optionally the two layers are separated by
 a separating layer to prevent tacking between the two layers.
 The new fixed unit dosage forms comprise as active substances one gastric
 acid suppressing agent, such as an acid susceptible proton pump inhibitor,
 and antacid agent(s)/alginate. Alternatively, the proton pump inhibitor in
 the form of enteric coating layered pellets may be mixed with an alginate
 and optionally pharmaceutical excipients to be administred in a sachet
 intended for oral administration after dispersion in a sligthly acidic
 aqueous solution. The new fixed dosage form is preferably in the form of a
 multiple unit tableted dosage form containing enteric coating layered
 units comprising the active substance being an acid susceptible proton
 pump inhibitor and granules comprising the other active substance(s), i.e.
 the antacid agent(s) as shown in FIG. 1.
 The antacid agent(s) may preferably be formulated in preparations intended
 for instant release. Alternatively, the components may be formulated in an
 effervescent formulation.
 The different therapeutically active components used in the dosage forms
 are defined below.
 Active Substances
 The gastric acid suppressing agent is preferably an acid susceptible proton
 pump inhibitor. Such proton pump inhibitors are for example compounds of
 the general formula I
 ##STR1##
 wherein
 N in the benzimidazole moiety means that one of the carbon atoms
 substituted by R.sub.6 -R.sub.9 optionally may be exchanged for a nitrogen
 atom without any substituents;
 R.sub.1, R.sub.2 and R.sub.3 are the same or different and selected from
 hydrogen, alkyl, alkoxy optionally substituted by fluorine, alkylthio,
 alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and
 phenylalkoxy;
 R.sub.4 and R.sub.5 are the same or different and selected from hydrogen,
 alkyl and aralkyl;
 R.sub.6 ' is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy;
 R.sub.6 -R.sub.9 are the same or different and selected from hydrogen,
 alkyl, alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl,
 oxazolyl, trifluoroalkyl, or adjacent groups R.sub.6 -R.sub.9 form ring
 structures which may be further substituted;
 R.sub.10 is hydrogen or forms an alkylene chain together with R.sub.3 and
 R.sub.11 and R.sub.12 are the same or different and selected from hydrogen,
 halogen or alkyl, alkyl groups, alkoxy groups and moities thereof, they
 may be branched or straight C.sub.1 -C.sub.9 -chains or comprise cyclic
 alkyl groups, such as cycloalkylalkyl.
 Examples of proton pump inhibitors according to formula I are
 ##STR2##
 ##STR3##
 The proton pump inhibitors used in the dosage forms of the invention may be
 used in neutral form or in the form of an alkaline salt, such as for
 instance the Mg.sup.2+ Ca.sup.2+ 'Na.sup.+, K.sup.+ or Li.sup.+ salts,
 preferably the Mg .sup.2+ salts. Further where applicable, the compounds
 listed above may be used in racemic form or in the form of a substantially
 pure enantiomer thereof, or alkaline salts of the single enantiomers.
 Suitable proton pump inhibitors are for example disclosed in EP-A1-0005129,
 EP-A1-174 726, EP-A1-166 287, GB 2 163 747 and WO90/06925, WO91/19711,
 WO91/19712, and further especially suitable compounds are described in
 WO95/01977 and WO094/27988.
 The gastric acid suppressing agent is preferably an acid susceptible proton
 pump inhibitor but H.sub.2 receptor antagonists such as ranitidine,
 cimetidine or famotidine may be used in the pharmaceutical compositions
 with an alginate as proposed in WO 95/017080 or together with antacid
 agent(s).
 A wide variety of antacid agent(s) and/or alginates may be used in
 combination with a suitable proton pump inhibitor in the fixed unit dosage
 form according to the present invention. Such antacid agents include for
 example aluminium hydroxide, calcium carbonate, magnesium hydroxide,
 magnesium carbonate and aluminium magnesium hydroxide carbonate
 (hydrotalcit) taken alone or in combinations with each other. The
 alginates may be an alginate selected from alginic acid or sodium alginate
 or other pharmaceutically acceptable alginate salts, hydrates, esters etc.
 Especially preferred antacid agents are magnesium or calcium based antacid
 agents and aluminium hydroxide/magnesium carbonate complex. Suitable
 antacid agents are for instance described in U.S. Pat. No. 5,409,709.
 The preferred multiple unit tableted dosage form comprising a proton pump
 inhibitor in the form of a racemat, an alkaline salt or one of its single
 enantiomers in combination with antacid agent(s), is characterized in the
 following way. Individually enteric coating layered units (small beads,
 granules or pellets) containing the acid susceptible proton pump inhibitor
 and optionally containing alkaline reacting substances, are mixed with the
 antacid(s) and conventionally tablet excipients. The antacid(s) and tablet
 excipients may be dry mixed or wet-mixed into granules. The mixture of
 enteric coating layered units, antacid agent(s) and optionally excipients
 are compressed into the multiple unit tableted dosage forms. With the
 expression "individual units" is meant small beads, granules or pellets,
 in the following referred to as pellets of the proton pump inhibitor.
 The compaction process (compression) for formulating the multiple unit
 tableted dosage form must not significantly affect the acid resistance of
 the enteric coating layered pellets. In other words the mechanical
 properties, such as the flexibility and hardness as well as the thickness
 of the enteric coating layer(s), must secure that the requirements on
 enteric coated articles in the United States Pharmacopeia are accomplished
 in that the acid resistance does not decrease more than 10% during the
 compression of the pellets into tablets.
 The acid resistance is defined as the amount of proton pump inhibitor in
 the tablets or pellets after being exposed to simulated gastric fluid USP,
 or to 0,1 M HCl (aq) relative to that of unexposed tablets and pellets,
 respectively. The test is accomplished in the following way. Individual
 tablets or pellets are exposed to simulated gastric fluid of a temperature
 of 37.degree. C. The tablets disintegrate rapidly and release the enteric
 coating layered pellets to the medium. After two hours the enteric coating
 layered pellets are removed and analyzed for content of the proton pump
 inhibitor using High Performance Liquid Chromatography (HPLC).
 Further specific components used in the fixed unit dosage forms of the
 present invention are defined below.
 Core Material--for Enteric Coating Layered Pellets Comprising a Proton Pump
 Inhibitor
 The core material for the individually enteric coating layered pellets can
 be constituted according to different principles. Seeds layered with the
 proton pump inhibitor, optionally mixed with alkaline substances, can be
 used as the core material for the further processing.
 The seeds which are to be layered with the proton pump inhibitor can be
 water insoluble seeds comprising different oxides, celluloses, organic
 polymers and other materials, alone or in mixtures or water-soluble seeds
 comprising different inorganic salts, sugars, non-pareils and other
 materials, alone or in mixtures. Further, the 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 approximately 0.1 and 2 mm. The seeds layered with the proton
 pump inhibitor are produced either by powder or solution/suspension
 layering using for instance granulation or spray coating layering
 equipment.
 Before the seeds are layered, the proton pump inhibitor may be mixed with
 further components. Such components can be binders, surfactants fillers,
 disintegrating agents, alkaline additives or other and/or pharmaceutically
 acceptable ingredients alone or in mixtures. The binders are for example
 polymers such as hydroxypropyl methylcellulose (HPMC),
 hydroxypropyl-cellulose (HPC), carboxymethylcellulose sodium, polyvinyl
 pyrrolidone (PVP), sugars, starches or other pharmaceutically acceptable
 substances with cohesive properties. Suitable surfactants are found in the
 groups of pharmaceutically acceptable non-ionic or ionic surfactants such
 as for instance sodium lauryl sulfate.
 Alternatively, the proton pump inhibitor optionally mixed with alkaline
 substances and further mixed with suitable constituents can be formulated
 into a core material. Said core material may be produced by
 extrusion/spheronization, balling or compression utilizing conventional
 process equipment. The size of the formulated core material is
 approximately between 0.1 and 4 mm and preferably between 0.1 and 2 mm.
 The manufactured core material can further be layered with additional
 ingredients comprising the proton pump inhibitor and/or be used for
 further processing.
 The proton pump inhibitor is mixed with pharmaceutical constituents to
 obtain preferred handling and processing properties and a suitable
 concentration of the substance in the final mixture. Pharmaceutical
 constituents such as fillers, binders, lubricants, disintegrating agents,
 surfactants and other pharmaceutically acceptable additives.
 Further, the proton pump inhibitor may also be mixed with an alkaline,
 pharmaceutically acceptable substance (or substances). Such substances can
 be chosen among, but are not restricted to substances such as the sodium,
 potassium, calcium, magnesium and aluminium salts of phosphoric acid,
 carbonic acid, citric acid or other suitable weak inorganic or organic
 acids; aluminium hydroxide/sodium bicarbonate coprecipitate; substances
 normally used in antacid preparations such as aluminium, calcium and
 magnesium hydroxides; magnesium oxide or composite substances, such as
 Al.sub.2 O.sub.3.6MgO.CO.sub.2.12H.sub.2 O, (Mg.sub.6 Al.sub.2 (OH).sub.16
 CO.sub.3.4H.sub.2 O), MgO.Al.sub.2 O.sub.3. 2SiO.sub.2.nH.sub.2 O or
 similar compounds; organic pH-buffering substances such as
 trihydroxymethyl-aminomethane, basic amino acids and their salts or other
 similar, pharmaceutically acceptable pH-buffering substances.
 Alternatively, the aforementioned core material can be prepared by using
 spray drying or spray congealing technique.
 Enteric Coating Layer(s)
 Before applying the enteric coating layer(s) onto the core material in the
 form of individual pellets or tablets, the pellets or tablets may
 optionally be covered with one or more separating layer(s) comprising
 pharmaceutical excipients optionally including alkaline compounds such as
 pH-buffering compounds. This/these separating layer(s), separate(s) the
 core material from the outer layers being enteric coating layer(s). The
 separating layer(s) protecting the proton pump inhibitor should be water
 soluble or rapidly disintegrating in water.
 The separating layer(s) can be applied to the core material by coating or
 layering procedures in suitable equipments such as coating pan, coating
 granulator or in a fluidized bed apparatus using water and/or organic
 solvents for the coating process. As an alternative the separating
 layer(s) can be applied to the core material by using powder coating
 technique. The materials for the separating layers are pharmaceutically
 acceptable compounds such as, for instance, sugar, polyethylene glycol,
 polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl
 cellulose, methylcellulose, ethyl-cellulose, hydroxypropyl methyl
 cellulose, carboxymethylcellulose sodium and others, used alone or in
 mixtures. Additives such as plasticizers, colorants, pigments, fillers
 anti-tacking and anti-static agents, such as for instance magnesium
 stearate, titanium dioxide, talc and other additives may also be included
 into the separating layer(s).
 When the optional separating layer, is applied to the core material it may
 constitute a variable thickness. The maximum thickness of the separating
 layer(s) is normally only limited by processing conditions. The separating
 layer may serve as a diffusion barrier and may act as a pH-buffering zone.
 The pH-buffering properties of the separating layer(s) can be further
 strengthened by introducing into the layer(s) substances chosen from a
 group of compounds usually used in antacid formulations such as, for
 instance, magnesium oxide, hydroxide or carbonate, aluminium or calcium
 hydroxide, carbonate or silicate; composite aluminium/magnesium compounds
 such as, for instance Al.sub.2 O.sub.3.6MgO.CO.sub.2 12H.sub.2 O,
 (Mg.sub.6 Al.sub.2 (OH).sub.16 CO.sub.3.4H.sub.2 O), MgO.Al.sub.2
 O.sub.3.2SiO.sub.2.nH.sub.2 O, aluminium hydroxide/so bicarbonate
 coprecipitate or similar compounds; or other pharmaceutically acceptable
 pH-buffering compounds such as, for instance the sodium, potassium,
 calcium, magnesium and aluminium salts of phosphoric, carbonic, citric or
 other suitable, weak, inorganic or organic acids; or suitable organic
 bases, including basic amino acids and salts thereof. Talc or other
 compounds may be added to increase the thickness of the layer(s) and
 thereby strenghten the diffusion barrier. The optionally applied
 separating layer(s) is not essential for the invention. However, the
 separating layer(s) may improve the chemical stability of the active
 substance and/or the physical properties of the novel multiple unit
 tableted dosage form.
 Alternatively, the separating layer may be formed in situ by a reaction
 between an enteric coating polymer layer applied on the core material an
 alkaline reacting compound in the core material. Thus, the separating
 layer formed comprises a salt formed between the enteric coating layer
 polymer(s) and an alkaline reacting compound which is in the position to
 form a salt.
 The separating layer may also be used to separate two different layers of a
 tablet, as described in FIG. 2.
 One or more enteric coating layers are applied onto the core material or
 onto the core material covered with separating layer(s) by using a
 suitable coating technique. The enteric coating layer material may be
 dispersed or dissolved in either water or in suitable organic solvents. As
 enteric coating layer polymers one or more, separately or in combination,
 of the following can be used, e.g. solutions or dispersions of methacrylic
 acid copolymers, cellulose acetate phthalate, hydroxypropyl
 methylcellulose phthalate, hydroxypropyl methylcellulose acetate
 succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate,
 carboxymethylethylcellulose, shellac or other suitable enteric coating
 polymer(s).
 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 for instance, but 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, in relation to selected enteric coating layer polymer(s),
 selected plasticizer(s) and the applied amount of said polymer(s), in such
 a way that the mechanical properties, i.e. flexibility and hardness of the
 enteric coating layer(s), for instance exemplified as Vickers hardness,
 are adjusted so that the acid resistance of the pellets covered with
 enteric coating layer(s) does not decrease significantly during
 compression of pellets into tablets. The amount of plasticizer is usually
 above 10% by weight of the enteric coating layer polymer(s), preferably
 15-50% and more preferably 20-50%. Additives such as dispersants,
 colorants, pigments polymers e.g. poly (ethylacrylat, methylmethacrylat),
 anti-tacking and anti-foaming agents may also be included into the enteric
 coating layer(s). Other compounds may be added to increase film thickness
 and to decrease diffusion of acidic gastric juices into the acid
 susceptible material.
 To protect the acid susceptible substance, the proton pump inhibitor, and
 to obtain an acceptable acid resistance of the dosage form according to
 the invention, the enteric coating layer(s) constitutes a thickness of
 approximately at least 10 .mu.m, preferably more than 20 .mu.m. The
 maximum thickness of the applied enteric coating is normally limited by
 processing conditions and the desired dissolution profile.
 Alternatively, the enteric coating layer described above may also be used
 for enteric coating of conventional tablets comprising an acid susceptible
 proton pump inhibitor. Said enteric coating layered tablet is thereafter
 presscoated with antacid granules and pharmaceutical excipients.
 Over-coating Layer
 Pellets covered with enteric coating layer(s) may further be covered with
 one or more over-coating layer(s). The over-coating layer(s) should be
 water soluble or rapidly disintegrating in water. The over-coating
 layer(s) can be applied to the enteric coating layered pellets by coating
 or layering procedures in suitable equipments such as coating pan, coating
 granulator or in a fluidized bed apparatus using water and/or organic
 solvents for the coating or layering process. The materials for
 over-coating layers are chosen among pharmaceutically acceptable compounds
 such as, for instance sugar, polyethylene glycol, polyvinylpyrrolidone,
 polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose,
 methylcellulose, ethylcellulose, hydroxypropyl methyl cellulose,
 carboxymethylcellulose sodium and others, used alone or in mixtures.
 Additives such as plasticizers, colorants, pigments, fillers, anti-tacking
 and anti-static agents, such for instance magnesium stearate,
 titaniumdioxide, talc and other additives may also be included into the
 over-coating layer(s). Said over-coating layer may further prevent
 potential agglomeration of enteric coating layered pellets, further
 protect the enteric coating layer towards cracking during the compaction
 process and enhance the tableting process. The maximum thickness of the
 applied over-coating layer(s) is normally limited by processing conditions
 and the desired dissolution profile.
 The above described over-coating layer may also be used as a tablet
 filmcoating layer to obtain tablets of good appearance.
 Antacid Agent(s) or Alginate Preparation
 The active substance in form of one or more antacid agent(s) are dry mixed
 with inactive excipients such as fillers, binders, disintegrants, and
 other pharmaceutically acceptable additives. The mixture is wet massed
 with a granulation liquid. The wet mass is dried preferably to a loss on
 drying of less than 3% by weight. Thereafter the dry mass is milled to a
 suitable size for the granules, such as smaller than 4 mm, and preferably
 smaller than 1 mm. Suitable inactive excipients are for instance mannitol,
 corn starch, potato starch, low substituted hydroxypropylcellulose,
 microcrystalline cellulose and crosslinked polyvinylpyrrolidone. The dry
 mixture comprising antacid agent(s) is mixed with a suitable granulation
 liquid comprising for instance hydroxypropylcellulose or
 polyvinylpyrrolidone dissolved in purified water or alcohol or a mixture
 thereof.
 Alternatively, the antacid agent(s) are dry mixed with pharmaceutically
 acceptable excipients according to the above. The alginate preparation
 should also be prepared by dry mixing with pharmaceutically acceptable
 excipients.
 Multiple Unit Tablets
 The enteric coating layered pellets comprising a proton pump inhibitor are
 mixed with the prepared antacid granules or with the prepared dry mixture
 comprising the antacid agent(s). The mixture is admixed with lubricant(s)
 and compressed into a multiple unit tableted dosage form. Suitable
 lubricants for the tableting process are for instance sodium stearyl
 fumarate, magnesium stearate and talc. The compressed tablet is optionally
 covered with a filmforming agent(s) to obtain a smooth surface of the
 tablet and further enhance the stability of the tablet during packaging
 and transport Such a coating layer may further comprise additives such as
 anti-tacking agents, colorants and pigments or other additives to obtain a
 tablet of good appearance.
 Further, the different active substances may be formulated into different
 layers, wherein the layer comprising the proton pump inhibitor preferably
 is in the form of a multiple unit tableted dosage form layered with the
 prepared mixture of the antacid agent(s) or an alginate preparation. The
 two layers may be separated by a third layer comprising antitacking
 agents.
 The fraction of enteric coating layered pellets constitutes less than 75%
 by weight of the total tablet weight and preferably less than 60%. By
 increasing the amount of the granules comprising the antacid agent(s) and
 excipients, the fraction of enteric coating layered pellets of the proton
 pump inhibitor may be reduced in the multiple unit tableted dosage form.
 By choosing small enteric coating layered pellets in the formulation
 according to the present invention, the number of pellets in each tablet
 can be held high which in turn makes the tablet divisible with retained
 dosing accuracy.
 Thus, the preferred multiple unit tablet formulation consists of enteric
 coating layered pellets containing the acid susceptible proton pump
 inhibitor, optionally in admixture with alkaline reacting compound(s),
 compressed into tablets together with the prepared antacid mixture and
 optionally tablet excipients. The addition of an alkaline reacting
 material to the proton pump inhibitor is not necessary, in any sense, but
 such a substance may further enhance the stability of the proton pump
 inhibitor or some of the alkaline reacting compounds may react in situ
 with the enteric coating material to form a separating layer. The enteric
 coating layer(s) is making the pellets of the dosage form insoluble in
 acidic media, but disintegrating/dissolving in near neutral to alkane
 media such as, for instance the liquids present in the proximal part of
 the small intestine, where dissolution of the proton pump inhibitor is
 desired. The enteric coating layered pellets may further be covered with
 an overcoating layer before being formulated into the tablet and they may
 also contain one or more separating layer(s) in between the core material
 and the enteric coating layer(s).
 Process
 The process for the manufacture of the dosage form represents a further
 aspect of the invention. After formulation of the pellets by spray coating
 or layering of the proton pump inhibitor onto seeds, or by
 extrusion/spheronization or granulation, e.g. rotor granulation of
 homogeneous pellets, the pellets are first optionally covered with the
 separating layer(s) and then with the enteric coating layer(s) or a
 separating layer is spontaneously developed in situ between the core
 material and the enteric coating layer material. The coating is carried
 out as described above and in the accompanying examples. The preparation
 of the antacid mixture is also described above and in the examples. The
 pharmaceutical processes can preferably be completely water-based.
 The enteric coating layered pellets, with or without an over-coat, are
 mixed with the prepared antacid granules, tablet excipients and other
 pharmaceutically acceptable additives and compressed into tablets.
 Alternatively, the enteric coating layered pellets may be intimately mixed
 with tablet excipients and precompressed and further layered with the
 antacid or alginate preparation and finally compressed into a tablet. As a
 further alternative the proton pump inhibitor in form of a powder may be
 mixed with tablet excipients and compressed into a tablet which is
 optionally layered with a separating layer and thereafter enteric coating
 layered. Said tablet core is then presscoated with the antacid
 preparation. Finally the tablet may be covered by a tablet coat.
 As a further alternative, the proton pump inhibitor in the form of enteric
 coating layered pellets may be filled in a sachet together with an
 alginate optionally mixed with excipients.
 Use of the Preparation
 The dosage forms according to the invention are especially advantageous in
 the treatment of dyspepsia and other gastrointestinal disorder to provide
 an immediate symptom relief and a long-lasting symptom resolution. The
 dosage forms are administered one to several times a day, preferably once
 or twice daily. 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 disease. In general each dosage
 form will comprise 0.1-200 mg of the proton pump inhibitor and 0.1-1000 mg
 of the antacid agent(s)/alginate. Preferably, each dosage form will
 comprise 5-80 mg of the proton pump inhibitor and 100-900 mg of the
 antacid agent(s)/alginate, and more preferably 10-40 mg of proton pump
 inhibitor and 250-650 mg of the antacid agent(s)/alginate, respectively.
 The multiple unit tablet preparation is also suitable for dispersion in an
 aqueous liquid with slightly acidic pH-value before being orally
 administered or fed through a naso-gastric tube.
 The invention is illustrated more in detail in the following examples.
 EXAMPLES
 Example 1
 Multiple unit tableted dosage form comprising magnesium omeprazole and
 antacid agents (batch size 400 tablets).

Core material
 Magnesium omeprazole 5.0 kg
 Sugar sphere seeds 10.0 kg
 Hydroxypropyl methylcellulose 0.75 kg
 Water purified 20.7 kg
 Separating layer
 Core material (acc. to above) 10.2 kg
 Hydroxypropyl cellulose 1.02 kg
 Talc 1.75 kg
 Magnesium stearate 0.146 kg
 Water purified 21.4 kg
 Enteric coating layer
 Pellets covered with separating layer (acc. to above) 11.9 kg
 Methacrylic acid copolymer (30% suspension) 19.8 kg
 Triethyl citrate 1.79 kg
 Mono- and diglycerides (NF) 0.297 kg
 Polysorbate 80 0.03 kg
 Water purified 11.64 kg
 Over-coating layer
 Enteric coating layered pellets (acc. to above) 20.0 kg
 Hydroxypropyl methylcellulose 0.238 kg
 Magnesium stearate 0.007 kg
 Water purified 6.56 kg
 Tablets
 Prepared pellets comprising omeprazole Mg-salt 31.3 g
 (acc. to above)
 Microcrystalline cellulose 140.0 g
 Calcium carbonate 100.0 g
 Aluminium hydroxide/magnesium carbonate 100.0 g
 Potato starch 46.4 g
 Water purified 314 g
 Polyvidone crosslinked 38.0 g
 Sodium stearyl fumarate 4.6 g
 Suspension layering was performed in a fluid bed apparatus. Magnesium
 omeprazole was sprayed onto sugar sphere seeds from a water suspension
 containing the dissolved binder. The size of sugar sphere seeds were in
 the range of 0.25 to 0.35 mm.
 The prepared core material was covered with a separating layer of a
 hydroxypropyl cellulose solution containing talc and magnesium stearate.
 The enteric coating layer consisting of methacrylic acid copolymer, mono-
 and diglycerides, triethyl citrate and polysorbate was sprayed onto the
 pellets covered with a separating layer in a fluid bed apparatus. In a
 fluid bed apparatus enteric coating layered pellets were coated with a
 hydroxypropyl methylcellulose containing magnesium stearate. The
 over-coating layered pellets were classified by sieving.
 A small amount of the potato starch was dissolved in purified hot water to
 form the granulation liquid. Calcium carbonate, aluminium
 hydroxide/magnesium carbonate, potato starch and microcrystalline
 cellulose are dry-mixed. The granulation liquid was added to the dry
 mixture and the mass was wet-mixed. The wet mass was dried in a steamoven
 at 50.degree. C. The prepared granulation was milled through sieve 1 mm in
 an oscillating mill equipment.
 The enteric coating layered pellets with an over-coating layer, prepared
 granules, polyvidone crosslinked and sodium stearyl fumarate were mixed
 and compressed into tablets using a tableting machine equipped with
 9.times.20 mm oval punches. The amount of omeprazole in each tablet was
 approx. 10 mg and the amount of antacid agents were approx. 500 mg in
 total. Tablet hardness was measured to 110N.
 Optionally the obtained tablets were covered with a tablet coating layer.
 Results

"Acid resistance" i.e. %
 left after exposure to 0.1N
 HCl for 2 hrs
 Tablets
 Ex 1 93%
 Example 2
 Multiple unit tableted dosage form comprising magnesium omeprazole and
 antacid agents (batch size 500 tablets).

Core material
 Magnesium omeprazole 10.0 kg
 Sugar sphere seeds 10.0 kg
 Hydroxypropyl methylcellulose 1.5 kg
 Water purified 29.9 kg
 Separating layer
 Core material (acc. to above) 20.0 kg
 Hydroxypropyl cellulose 2.0 kg
 Talc 3.43 kg
 Magnesium stearate 0.287 kg
 Water purified 41.0 kg
 Enteric coating layer
 Pellets covered with separating layer (acc. to above) 24.5 kg
 Methacrylic acid copolymer (30% suspension) 32.7 kg
 Triethyl citrate 2.94 kg
 Mono- and diglycerides (NF) 0.49 kg
 Polysorbate 80 0.049 kg
 Water purified 19.19 kg
 Over-coating layer
 Enteric coating layered pellets (acc. to above) 37.8 kg
 Hydroxypropyl methylcellulose 0.49 kg
 Magnesium stearate 0.0245 kg
 Water purified 11.6 kg
 Tablets
 Prepared pellets comprising magnesium omeprazole 47.45 g
 (acc. to above)
 Calcium carbonate 123.9 g
 Magnesium hydroxide 123.9 g
 Potato starch 52.2 g
 Water purified 435 g
 Microcrystalline cellulose 175 g
 Polyvidone crosslinked 50 g
 Sodium stearyl fumarate 6.0 g
 Enteric coating layered pellets of magnesium omeprazole with an overcoating
 layer were prepared as in Example 1.
 A small amount of the potato starch was dissolved in hot purified water to
 form the granulation liquid. Calcium carbonate, magnesium hydroxide and
 potato starch were dry-mixed. The granulation liquid was added to the dry
 mixture and the mass was wet-mixed. The wet mass was dried in a steamoven
 at 40.degree. C. The prepared granulation was milled through sieve 1 mm in
 an oscillating mill equipment.
 The enteric coated layered pellets with an over-coating layer, prepared
 granules, microcrystalline cellulose, polyvidone crosslinked and sodium
 stearyl fumarate were mixed and compressed into tablets using a tableting
 machine equipped with 9.times.20 mm oval punches. The amount of omeprazole
 in each tablet was approx. 20 mg and the amount of antacid agents were
 approx. 500 mg in total. Tablet hardness was measured to 30-40N.
 Optionally the obtained tablets were covered with a tablet coating layer.
 Example 3
 Multiple unit tableted dosage form comprising S-omeprazole magnesium salt
 and antacid agents (batch size 500 tablets).

Core material
 S-omeprazole magnesium salt 120 g
 Sugar sphere seeds 150 g
 Hydroxypropyl methylcellulose 18 g
 Polysorbate 80 2.4 g
 Water purified 562 g
 Separating layer
 Core material (acc. to above) 200 g
 Hydroxypropyl cellulose 30 g
 Talc 51.4 g
 Magnesium stearate 4.3 g
 Water purified 600 g
 Enteric coating layer
 Pellets covered with separating layer (acc. to 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
 Water purified 196 g
 Tablets
 Prepared pellets comprising (s)-omeprazole Mg-salt 63.7 g
 Calcium carbonate 123.9 g
 Magnesium hydroxide 123.9 g
 Potato starch 52.2 g
 Water purified 435 g
 Microcrystalline cellulose 175 g
 Polyvidone crosslinked 50.0 g
 Sodium stearyl fumarate 6.0 g
 Suspension layering was performed in a fluid bed apparatus. S-omeprazole
 magnesium salt was sprayed onto sugar sphere seeds from a water suspension
 containing the dissolved binder and polysorbate 80. The size of sugar
 sphere seeds were in the range of 0.25 to 0.35 mm.
 The prepared core material was covered with a separating layer in a fluid
 bed apparatus with hydroxypropyl cellulose solution containing talc and
 magnesium stearate. The enteric coating layer consisting of methacrylic
 acid copolymer, mono-and diglycerides, triethyl citrate and polysorbate
 was sprayed onto the pellets covered with a separating layer in a fluid
 bed apparatus. The enteric coating layered pellets were classified by
 sieving.
 A small amount of the potato starch was dissolved in hot purified water to
 form the granulation liquid. Calcium carbonate, magnesium hydroxide and
 potato starch were dry-mixed. The granulation liquid was added to the dry
 mixture and the mass was wet-mixed.
 The wet mass was dried in a steamoven at 40.degree. C. The prepared
 granulation was milled through sieve 1 mm in an oscillating mill
 equipment.
 The enteric coating layered pellets, prepared granules, polyvidone
 crosslinked, microcrystalline cellulose and sodium stearyl fumarate were
 mixed and compressed into tablets using a tableting machine equipped with
 9.times.20 mm oval punches. The amount of S-omeprazole in each tablet was
 approx. 20 mg and the amount of antacid agents were approx. 500 mg in
 total. Tablet hardness was measured to 30N.
 Optionally the obtained tablets were covered with a tablet coating layer.
 Example 4
 Three-layered tableted dosage form with a fast disintegrating layer
 comprising omeprazole, a separating layer and a layer comprising alginic
 acid. (batch size 1,000 tablets)

Core material
 Magnesium omeprazole 1500 g
 Sugar sphere seeds 1500 g
 Hydroxypropyl methylcellulose 420 g
 Aerosil .RTM. 8 g
 Water purified 4230 g
 Separating layer
 Core material 500 g
 Hydroxypropyl cellulose 40 g
 Talc 67 g
 Magnesium stearate 6 g
 Water purified 800 g
 Enteric coating layer
 Pellets covered with separating layer 500 g
 Methacrylic acid copolymer 200 g
 Triethyl citrate 60 g
 Water purified 392 g
 Magnesium omeprazole, part of the hydroxypropyl methylcellulose and
 Aerosil.RTM. are dry-mixed forming a powder. Sugar sphere seeds (0.25-0.40
 mm) are layered with the powder in a centrifugal fluidized coating
 granulator while spraying a hydroxypropyl methylcellulose solution (6%,
 w/w).
 The prepared core material is dried and covered by a separating layer in a
 centrifugal fluidized coating-granulator. A fluid bed apparatus is used
 for enteric coating layereing.
 Example 7
 Preparation of enteric coating layered pellets with cores of silicon
 dioxide seeds.

Core material
 Magnesium omeprazole 8.00 kg
 Silicon dioxide 8.00 kg
 Hydroxypropyl methylcellulose 1.41 kg
 Sodium lauryl sulphate 0.08 kg
 Water purified 28.00 kg
 Separating layer
 Core material (acc. to above) 10.00 kg
 Hydroxypropyl methylcellulose 0.80 kg
 Water purified 10.00 kg
 Enteric coating layer
 Pellets covered with separating layer (acc. to above) 300 g
 Methacrylic acid copolymer 124 g
 Polyethylene glycol 400 25 g
 Mono- and diglycerides (NF) 3 g
 Polysorbate 80 1 g
 Water purified 463 g
 Suspension layering is performed in a fluid bed apparatus. Magnesium
 omeprazole is sprayed onto the silicon dioxide seeds from a water
 suspension containing the dissolved binder and a surface active
 ingredient.
 The prepared core material is covered with a separating layer in a fluid
 bed apparatus with a hydroxypropyl methylcellulose solution. The enteric
 coating layer consisting of methacrylic acid copolymer, mono- and
 diglycerides, polyethylene glycol 400 and polysorbate is sprayed onto the
 pellets covered with separating layer in a fluid bed apparatus.
 Example 8
 Preparation of enteric coating layered pellets.

Enteric coating layer
 Pellets covered with separating layer 500 g
 (manufacturing and composition
 as in example 10)
 Methacrylic acid copolymer 250 g
 Polyethylene glycol 6000 75 g
 Mono- and diglycerides (NF) 12.5 g
 Polysorbate 80 1.2 g
 Water purified 490 g
 Example 9
 Preparation of enteric coating layered pellets.

Enteric coating
 Pellets covered with separating layer 500 g
 (manufacturing and composition as in example 1)
 Hydroxypropyl methylcellulose phthalate 250 g
 Cetanol 50 g
 Ethanol (95%) 1000 g
 Acetone 2500 g
 Example 10
 Preparation of enteric coating layered pellets.