HK1017991B - Oral pharmaceutical dosage forms comprising a proton pump inhibitor and a nsaid - Google Patents

Description

Oral pharmaceutical dosage form comprising a proton pump inhibitor and an NSAID

Technical Field

The present invention relates to novel oral pharmaceutical formulations which are particularly useful in the treatment and prevention of gastrointestinal disorders associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs). The formulations of the present invention comprise an acid susceptible proton pump inhibitor in combination with an NSAID(s) in a novel fixed unit dosage form, particularly a tablet dosage form, and furthermore, the present invention relates to a process for the preparation of such formulations and the use of these formulations in medicine.

Background

NSAIDs including acetylsalicylic acid are the most commonly used drugs by physicians and patients worldwide. Although NSAIDs have one therapeutic benefit, their use is often limited due to the increased risk of gastrointestinal side effects. These gastrointestinal side effects are mainly those occurring in the upper part of the gastrointestinal tract such as peptic ulcer and dyspepsia.

The relative risk of developing gastric ulcers during NSAID treatment is well increased by 40-50, while the relative risk of developing duodenal ulcers is well increased by 8-10(McCarty DM. gastroenterology 1989; 96: 662). The relative risk of developing ulcer complications such as gastrorrhagia and perforations has increased by 1.5-5(Hawkey c.bmj 1990, 300: 278). Furthermore, 30-60% of the population treated with NSAIDs exhibit symptoms of dyspepsia (Larkai EN J.US. gastroenterology 1978; 82: 1153)

In the uk, it is officially statistical that 25% of all reported side effects are caused by NSAIDs. The corresponding data in the United states is 21%, therefore, therapeutic approaches to prevent NSAID-induced gastrointestinal side effects are needed

Attempts to modify the structure of NSAIDs to prevent such side effects have been largely unsuccessful. The best approach to the treatment and prevention of NSAID-associated upper gastrointestinal disorders such as ulcers and dyspepsia in patients in need of continuous NSAID treatment is currently NSAID treatment in combination with anti-ulcer agents such as prostaglandins, H2 receptor antagonists or proton pump inhibitors for the treatment and/or prevention of NSAID-associated gastrointestinal side effects.

Risk factors for the development of NSAID-related upper gastrointestinal side effects and complications have been found to be, for example, advanced age, previous peptic ulcer and/or bleeding, high dose NSAIDs, combined therapy with steroids, combined therapy with anticoagulants, which indicate that frail and elderly patients are poorly tolerated for complications such as bleeding or perforation, who should be treated with NSAIDs in combination with prophylactic treatment.

NSAIDs are used primarily for the treatment of chronic diseases such as rheumatoid arthritis and osteoarthritis, the most common of which in the elderly. Chief complaints are particularly important in elderly and infirm patients, where there is a highest risk of life-threatening NSAID treatment complications such as bleeding or perforation. It is known that 50% of all peptic ulcer deaths occur in NSAID users, and 68% of them are patients over 75 years of age (Catford: health Act 1986; 18: 38). This fact was again confirmed in another study, with NSAID-related deaths occurring predominantly in patients over 75 years of age (Guess. J. Clin epidemiology 1988; 41: 35). This study further supports the importance of patient complaints that most peptic ulcers associated with NSAID treatment are asymptomatic prior to onset.

Omeprazole is a well-known proton pump inhibitor that prevents erosion of the stomach and duodenum of healthy volunteers during treatment with acetylsalicylic acid. Clinical studies have shown that omeprazole is able to cure gastric and duodenal ulcers with the same rate and effectiveness in patients treated with continuous NSAIDs as in non-NSAID users (Walan a. new england journal of medicine 1989; 320: 69). These results provide the basis for amending the recommended dose of omeprazole for use during continuous NSAID treatment for gastric and duodenal ulcers, agreed to by the british and swedish authorities.

Recent studies have demonstrated that omeprazole significantly reduces the risk of gastric ulcer, duodenal ulcer and dyspepsia symptoms in patients on continuous NSAID treatment.

EP0426479 describes tablets containing an NSAID such as ibuprofen and a gastric acid inhibiting drug such as cimetidine and the like. If the gastric acid suppressing agent is an acid sensitive compound such as a proton pump inhibitor, the measures taken to prevent degradation are not mentioned

In the treatment with proton pump inhibitors including NSAID(s) and acid labile, the different active substances are administered separately, and it is known that in medicine, patient compliance is a major factor in achieving satisfactory results: the present invention now provides new oral dosage forms containing two or more active substances, which are combined in a fixed unit dosage form, preferably a tablet, which is inconvenient or unsatisfactory for the patient to use two or even more different tablets for optimal results.

For stability reasons, it is clear that some antiulcer diseases, such as proton pump inhibitors, are susceptible to degradation and denaturation in acidic and neutral media, and that one of the active substances, the proton pump inhibitor, must be protected from contact with the acidic gastric juice by an enteric coating layer: various enterically coated proton pump inhibitor containing formulations are described in the prior art, e.g. US-A4786505 (AB-Grassle) describes omeprazole containing formulations

In the preparation of fixed unit dosage forms having relatively high active substance contents, there are problems, and the inclusion of substances having different physical properties in the same formulation poses further problems. The manufacture of multiple unit tableted dosage forms poses special problems when enteric coated layered pellets containing an acid susceptible proton pump inhibitor active substance are compressed into tablets. If the enteric coating layer is not able to withstand the pressure at which the pellets are compressed into tablets, the sensitive active substance will be destroyed when the drug passes through the acidic gastric juice upon administration. I.e. after compression, the enteric coating layer of the pellets in the tablet is not sufficiently resistant to acidic attack.

Summary of The Invention

The present invention provides layered preparations of oral, fixed unit dosage forms, i.e. multiple unit tableted dosage forms, comprising a core with an enteric coating layer, a multilayer tablet or a capsule filled with one or more pharmaceutically active compounds. The active compound is preferably an acid susceptible proton pump inhibitor in combination with one or more NSAIDs, and wherein at least the proton pump inhibitor is protected by an enteric coating layer. These new dosage forms would simplify the dosing regimen and allow better patient compliance.

Brief Description of Drawings

Figure 1 is a sectional view of a multiple unit tableted dosage form comprising an acid susceptible proton pump inhibitor in the form of enteric coating layered pellets (1) mixed with NSAID containing fast disintegrating granules (2). The tablets are optionally coated with a film coating (13).

Figure 2. a cross-sectional view of a multiple unit tableted dosage form wherein an acid susceptible proton pump inhibitor in the form of enteric coating layered pellets (1) and an NSAID (3) in the form of a cyclodextrin complex, the latter being present in rapidly disintegrating granules (4). The tablets are optionally coated with a film coating (13).

Figure 3 is a cross-sectional view of a tablet comprising two separate layers, one of which comprises enteric coated pellets (1) of an acid susceptible proton pump inhibitor in admixture with excipients (5) and the other of which comprises an NSAID (6) which is present in a gel matrix for extended release optionally separated in the two separate layers by a separating layer (12), the tablet being coated with a film coating layer (13).

Figure 4 is a sectional view of a multiple unit tableted dosage form of an acid susceptible proton pump inhibitor (1) in the form of enteric coating layered pellets and an NSAID (7) in the form of enteric coating layered pellets and excipients (5) mixed therewith. The tablets are optionally coated with a film coating (13).

Figure 5 is a cross-sectional view of an enteric coated layered tablet comprising an acid susceptible proton pump inhibitor (8) in admixture with NSAID(s) (9) and excipient (5). The tablets are coated with an enteric coating layer (11) and a separating layer separates them optionally between the core and the enteric coating layer.

Figure 6-schematic representation of a tablet comprising an enteric coating layered pellet acid susceptible proton pump inhibitor (1) in the core and rapidly disintegrating granules (4) admixed therewith, surrounded by a coating layer comprising an NSAID substance/granule (2). The tablets are optionally coated with a pigmented film coat.

Detailed Description

It is an object of the present invention to provide an oral, multiple unit tableted dosage form comprising an antiulcer agent, preferably an acid susceptible proton pump inhibitor and an NSAID in individual enteric coating layered units and tablet excipients compressed together into a tablet. The enteric coating layer(s) coating the individual units of the acid susceptible proton pump inhibitor has (have) properties which do not significantly affect the acid resistance of the individual enteric coating layer units when the unit pellets are compressed into tablets. In addition, the multiple unit tableted dosage form provides better stability of the active substance during long-term storage,

alternatively, tablets may be prepared having separate layers, one layer containing the acid susceptible proton pump inhibitor in the form of compressed enteric coated layered units and the other layer containing the NSAID(s).

The novel fixed dosage form is preferably in the form of a multiple unit tableted dosage form comprising enteric coated layered units of the acid sensitive substance and the other active substance(s) in the form of granules, the latter constituting the rest of the compressed tablet, as shown in figure 1

Alternatively, the different active substances can be mixed thoroughly with each other and compressed into conventional tablets, which are enteric coated (see fig. 5), or both active substances can be in the form of enteric coated layered pellets compressed into multiple unit tablets together with preferably inert excipient rapidly disintegrating granules (see fig. 4).

Alternatively, the multiple unit dosage form comprises individual proton pump inhibitors in the form of enteric coated layered units and a) NSAID(s) in the form of a complex to give improved bioavailability (see figure 2), or b) NSAID(s) in the form of a gel matrix to give the formulation extended release NSAID(s) (see figure 3). Alternatively, the proton pump inhibitor in the form of pellets containing individual enteric coating layers is compressed into a tablet, onto which the NSAID(s) are added by spraying onto the tablet separate layers of NSAID(s), which tablet is coated with a coloured film coating layer to protect the NSAID(s) (see fig. 6), since some NSAID(s) are photosensitive and require a light-shielding layer

In another option, different active substances are dry mixed and filled into capsules. In the latter formulation, the acid susceptible proton pump inhibitor is in the form of enteric coated layered units and the NSAID(s) are in the form of granules or modified release formulation unit such as enteric different layered units or units coated with a controlled release layer.

The NSAID(s) may be formulated for immediate release, sustained release or extended release. Alternatively, the composition can be made into effervescent preparations. Furthermore, since some NSAID(s) are photosensitive, the formulation is preferably protected from light by a colored tablet film coating (see FIG. 6), or by the addition of dyes to a coating applied to the tablet

It is another object of the present invention to provide a divisible dosage form, such as a divisible tablet.

It is a further object of the present invention to provide a multiple unit tableted dosage form that is divisible and easy to handle. Some multiple unit tablet dosage forms may be dispersed in a weakly acidic aqueous solution and may be administered to patients or children with dysphagia. Such suspensions of dispersed units/pellets of appropriate particle size can be administered either orally or via naso-gastric tubing.

The different therapeutically active substances used in the dosage forms are given below. Active substance

The gastric acid suppressing agent is preferably an acid susceptible proton pump inhibitor. For example, such proton pump inhibitors are compounds of the general formula I:wherein, Het₁Is thatOrHet₂Is thatOrOrX＝OrWherein N in the benzimidazole moiety represents that one of the carbon atoms substituted with R6-R9 may be optionally replaced by a nitrogen atom without any substituent; r1, R2 and R3 are the same or different and are selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group optionally substituted with fluorine, an alkylthio group, an alkoxyalkoxy group, a dialkylamino group, a piperidino group, a morpholino group, a halogen atom, a phenyl group and a phenylalkoxy group; r4 and R5 are the same or different and are selected from the group consisting of a hydrogen atom, an alkyl group and an aralkyl group; r¹ ₆Is a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkyl group and an alkoxy group; R6-R9 are identical or different and are selected from the group consisting of hydrogen, alkyl, alkoxy, halogen, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl, trifluoroalkyl, or adjacent radicals R6-R9 form a ring structure which may be further substituted; r10 is a hydrogen atom or forms an alkylene chain with R3; r11 and R12 are the same or different and are selected from the group consisting of hydrogen, halogen or alkyl, alkoxy and a portion thereof, which may be straight or branched C1-C9 chain or contain cycloalkyl, such as cycloalkylalkyl.

Examples of proton pump inhibitors of formula I are

The acid susceptible proton pump inhibitors useful in the dosage forms of the present invention may be neutral or basicIn the form of salts, e.g. Mg²⁺、Ca²⁺、Na⁺、K^-Or Li⁺Preferably Mg²⁺Salts, and in addition, when used, the above compounds may be used in the form of the racemate or in the form of substantially pure enantiomers thereof or as the basic salt of a single enantiomer.

Suitable proton pump inhibitors are, for example, those disclosed in EP-A1-0005129, EP-A1174726, EP-A1-166287, GB2163747 and WO90/06925, WO91/19711, WO91/19712, particularly suitable compounds being described in WO95/01977 and WO 94/27988.

A variety of NSAIDs may be used in combination with suitable proton pump inhibitors and any pharmaceutically acceptable excipients in the fixed unit dosage form of the present invention, such NSAIDs including, for example, propionic acid derivatives, oxithiazines (oxicams), acetic acid and acetamide derivatives, salicylic acid derivatives and pyrazolidine derivatives.

Future NSAIDs such as Cyclooxygenase (COX)2 selective NSAIDs and NO-releasing NSAIDs (de Soldato P, NO-releasing NSAIDs, a new class of safe anti-inflammatory analgesic and antipyretic agents; anti-inflammatory side effects fifth International conference on 1995, 8.7-9.8.9 (NO-refining NSAIDs, A new class of drug anti-inflammatory and anti-viral agents: The IV International on side-effects of anti-inflammatory drugs, of drug-inhibitory drugs August 7-9, 1995)).

The following are examples of some suitable NSAIDs: acetylsalicylic acid, indomethacin, diclofenac, piroxicam, tenoxicam, ibuprofen, naproxen, suprofen, nabumetone, ketorola, indomethacin, mefenamic acid, meclofenamic acid, sulindac, diflunisal, phenylpropionic acid, podophyllotoxin derivatives, acemetacin, aceclofenac, indoxicam, oxaprozin, fluquinamine phenyl ester, phenylbutazone, valprozin, flurbiprofen, toluoylpipecolic acid, and phenylbutyric acid.

The active NSAID may be in the standard form or in the form of salts, hydrates, esters, and the like. Combinations of two or more of the above agents may be used. Preferred NSAIDs in the new fixed dosage form are diclofenac, ibuprofen, naproxen and piroxicam.

A preferred multiple unit tablet dosage form comprising a proton pump inhibitor (in the form of a racemate, a basic salt or one of its single enantiomers) in combination with an NSAID has the following characteristics. Comprising an acid susceptible proton pump inhibitor and optionally individual enteric coated units (beads, granules or pellets) containing a basic substance, are mixed with the NSAID(s) and conventional tablet excipients. Preferably the NSAID(s) and tablet excipients are granules. A dry blend of the enteric coated units, NSAID granules and any excipients is compressed into a multiple unit tableted dosage form. The term "individual unit" refers to beads, granules or pellets, hereinafter to pellets of the acid susceptible proton pump inhibitor.

The compression process (tableting) to prepare a multiple unit tableted dosage form should not significantly affect the acid resistance of the enteric coating layered pellets as much as possible. In other words, the mechanical properties such as flexibility and hardness and the thickness of the coating layer(s) have to comply with the requirements of the United states pharmacopoeia on enteric coating provisions, i.e. the reduction of acid resistance when compressing pellets into tablets cannot exceed 10%.

Acid resistance is defined as the amount of proton pump inhibitor in a tablet or pellet after contact with simulated gastric fluid USP or 0.1M HCl (aqueous solution), respectively, compared to a tablet or pellet without contact. The experiment was performed in the following manner. The individual tablets or pellets were exposed to simulated gastric fluid at a temperature of 37 ℃. The tablets disintegrate rapidly and release the enteric coated layered pellets into the medium. After 2 hours, the enteric coated layered pellets were removed and analyzed for proton pump inhibitor content by High Performance Liquid Chromatography (HPLC).

In addition, the particular components used in the fixed unit dosage form of the present invention are defined below. Tablet core material-layered pellets/units for enteric coating

The core material for the individual enteric coated layered pellets may be composed according to different principles. The core, optionally mixed with alkaline substance, coated with proton pump inhibitor on the outside can be used as a core material for further processing.

The core coated with the proton pump inhibitor may be a water-soluble core containing different oxides, celluloses, organic polymers and others alone or in combination, or a water-soluble core containing different inorganic salts, sugars, pellets (non-pareil) and others alone or in combination. Furthermore, the core may contain the proton pump inhibiting agent in the form of crystals, agglomerates, compacts, and the like. The size of the core is not a necessary limitation of the present invention, but may vary between about 0.1 and 2 millimeters. The cores coated with the proton pump inhibiting agent may be coated by powder or solution/suspension using an immediate granulation or spray coating apparatus.

The proton pump inhibitor may be mixed with other components prior to core coating. Such components may be individual binders, surfactant fillers, disintegrants, alkaline additives or other and pharmaceutical components and mixtures thereof. Binders are, for example, Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), sodium carboxymethylcellulose, polyvinylpyrrolidone (PVP), sugars, starches or other pharmaceutically acceptable substances with adhesive properties. Suitable surfactants are pharmaceutically acceptable non-ionic or ionic surfactants such as sodium lauryl sulphate.

Alternatively, a proton pump inhibiting agent optionally mixed with an alkaline substance and further mixed with a suitable component may be compressed into a tablet core. The core material may be prepared by extrusion/spheronization, spheronization or compression using conventional equipment. The core material is produced in a size of about 0.1 to 4mm, preferably 0.1 to 2 mm. The resulting tablet core material may be coated and/or further processed with additional components including a proton pump inhibitor.

The proton pump inhibiting agent is mixed with the pharmaceutical component to achieve preferred handling and processing properties and to achieve the appropriate concentration in the final mixture. The medicine components comprise a filling agent, a bonding agent, a lubricating agent, a disintegrating agent, a surfactant and other medicinal additives.

Furthermore, the proton pump inhibitor may be mixed with a base, a pharmaceutical substance(s). Such a substance may be in (but is not limited to)Selected from sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; aluminum hydroxide/sodium bicarbonate coprecipitation; general substances for antacid preparations, for example, aluminum hydroxide, calcium hydroxide and magnesium hydroxide; magnesium oxide or composites such as Al₂O₃·6MgO·CO₂·12H₂O，(Mg₆Al(OH)₁₆CO₃·4H₂O)，MgO·Al₂O₃·2SiO₂·nH₂O or a similar compound; organic pH buffer substances such as tris, basic amino acids and their salts or other analogues, pharmaceutically acceptable pH buffer substances.

Alternatively, the above-described core material may be prepared by spray drying or spray congealing techniques. Enteric coating layer (one or more layers)

The pellets or tablets may optionally be coated with one or more separating layers(s) containing any pharmaceutical excipients including basic compounds such as pH buffering compounds, before the enteric coating layer(s) are applied to the cores of the individual pellets or tablets. This/these separating layer(s) separate the core from the outer enteric coating layer. The barrier layer(s) protecting the proton pump inhibitor should be water soluble or rapidly degradable in water.

The separating layer(s) may be applied to the core by coating or coating techniques using water and/or organic solvents used in the coating process in a suitable apparatus such as a coating pan, a coating granulator or a fluidized bed. Additional barrier layer(s) may be added to the core by using powder coating techniques. The substance used for the separation layer is a pharmaceutical compound such as sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and others, which can be used alone or in combination. Additives such as plasticizers, colorants, pigments, fillers, anti-tacking agents, and antistatic agents, for example, magnesium stearate, titanium dioxide, talc, and other additives may also be included in the barrier layer(s).

The thickness of the optional barrier layer may vary when it is applied to the core material. The maximum thickness of the barrier layer(s) is generally limited only by processing conditions. The isolation layer may act as a diffusion barrier and may act as a pH buffer. The pH buffering properties of the barrier layer(s) may be further enhanced by incorporating compounds commonly used as antacids into the barrier layer(s) material. Such compounds include, for example, magnesium oxide, hydroxide or carbonate, hydroxide or hydroxide, carbonate or carbonate, silicate or silicate; composite aluminium/magnesium compounds such as Al₂O₃·6MgO·CO₂·12H₂O，(Mg₆Al(OH)₁₆CO₃·4H₂O)，MgO·Al₂O₃.2SiO₂·nH₂O, aluminum hydroxide/sodium bicarbonate coprecipitate or similar compounds; or other pharmaceutically acceptable pH buffering compounds such as phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; or suitable organic bases including basic amino acids and salts thereof. Talc or other compounds may increase the consistency of the coating layer(s) and thus enhance the diffusion barrier. Any added barrier layer(s) is not required for the present invention. However, the separating layer(s) may improve the chemical stability of the active substance and/or the physical properties of the new multiple unit tableted dosage form.

Alternatively, the separating layer may be formed in situ by reaction between an enteric coating polymer layer on the core and a basic reactive compound in the core material. Thus, the separating layer formed contains a salt which is formed between the enteric coating layer polymer(s) and the alkaline-reacting compound, just at the site where the salt is formed.

One or more enteric coating layers may be added to the core material or to the core material coated with the separating layer(s) by suitable coating techniques. The enteric coating layer material may be dispersed or dissolved in water or a suitable organic solvent. The following materials may be used as enteric coating layer polymer(s) (either separately or in combination), such as a solution or dispersion of methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethyl cellulose ester, shellac, or other suitable enteric coating polymer(s).

The enteric coating layer may contain pharmaceutically acceptable plasticizers to achieve desired mechanical properties, such as flexibility and hardness of the enteric coating layer. Such plasticizers are, but not limited to, for example, triacetin, citrate, phthalate, dibutyl sebacate, cetyl alcohol, polyethylene glycol, tween or other plasticizers.

For each enteric coating layer, the amount of plasticizer is suitably determined in accordance with the enteric coating layer polymer(s) selected, the plasticizer(s) and the amount of said polymer(s) added, the principle being to adjust the mechanical properties of the enteric coating layer(s), such as flexibility and hardness (as expressed by Vicker's hardness), such that the acid resistance of the pellets coated with the enteric coating layer(s) is not significantly reduced when the pellets are compressed into tablets. Plasticizers are generally used in amounts of about 10%, preferably 15-50%, more preferably 20-50% by weight of the enteric coating layer polymer(s). Additives such as dispersants, colorants, pigment polymers such as poly (ethyl acrylate, methyl methacrylate), anti-adherents, and anti-foaming agents may also be included in the enteric coating layer(s). Other compounds may be added to increase the thickness of the film coating and thereby reduce the diffusion of acid gastric juices into acid sensitive substances. In order to protect the acid labile substance (proton pump inhibitor) and render the acid resistance of the dosage form of the present invention acceptable, the enteric coating layer(s) have a thickness of about at least 10 μm, preferably greater than 20 μm. The maximum thickness of the enteric coating is generally limited by the preparation conditions and the desired solubility.

The enteric coating layer may also be due to NSAID(s) coating. Alternatively, the enteric coating layer described above may also be used for enteric coating of conventional tablets containing an acid susceptible proton pump inhibitor and an NSAID, and the optionally prepared core may also be coated with an isolating layer as described above to separate the core from the enteric coating layer. Outer coating layer

The pellets coated with the enteric coating layer(s) may be further coated with one or more outer coating layer(s). The outer coating layer(s) should be water soluble or disintegrate rapidly in water. The outer coating layer(s) may be added by a coating or coating process using suitable equipment such as a coating pan, a coating granulator or a fluidized bed in the presence of water and/or organic solvent used in the coating or coating process. The substances used for the outer coating layer are pharmaceutical compounds such as sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and others, which may be used alone or in admixture. Additives such as plasticizers, colorants, pigments, fillers, anti-adherents and antistatic agents, for example, magnesium stearate, titanium dioxide, talc and other additives may also be included in the outer coating layer(s). The outer coating layer may further prevent agglomeration of the enteric coating layered pellets, further protect the enteric coating layer during tableting and facilitate tableting. The maximum thickness of the outer coating layer(s) is generally limited by the processing conditions and the desired solubility. The coating layer may also be used as a film coating layer for the tablet. NSAID formulations

The active substance(s) in the form of an NSAID substance is dry blended with inert excipients, wherein the excipient(s) is/are optionally a disintegrant. The mixture is softened with a granulation liquid. The damp mass is dried, preferably with less than 3% of the weight lost during drying. Thereafter, the dried material is ground to a suitable particle size, such as less than 4mm, and preferably less than 1 mm. Suitable inert excipients are, for example, sodium starch glycolate, corn starch, potato starch, crosslinked polyvinylpyrrolidone, low-substituted hydroxypropylcellulose, microcrystalline cellulose, mannitol, and anhydrous colloidal silicon dioxide (Aerosil ), and the like. The dry blend containing the NSAID(s) is mixed with a suitable granulation liquid containing, for example, polyvinylpyrrolidone, hydroxypropylcellulose, polyethylene glycol, hydroxypropylcellulose and optionally a wetting agent such as sodium dodecylsulphonate dissolved in purified water or ethanol or a mixture thereof.

In some cases, a complex is formed between the NSAID(s) and the complex-forming agent by mechanical treatment, such as β -hydroxypropyl cyclodextrin in example 3 below. Cyclodextrin complexes of NSAID(s) appear to increase the bioavailability of NSAID(s), see, for example, Drug Dev. Ind. pharm.19(7), 843 and 852 (1993).

In addition, the NSAID may be mixed with a gelling agent such as hydrophilic polymer(s) in the granulation. Suitable gelling hydrophilic polymers are, for example, hydroxypropylmethylcellulose, polyoxyethylene (polyethylene glycol), hydroxypropylcellulose, hydroxyethylcellulose and gum tragacanth (xantan). The particles may also contain a buffer. See, for example, example 4 below. Some NSAIDs irritate the gastric mucosa and so protection with an enteric coating layer is advantageous and enteric coated layered pellets can be made. Multiple unit tablet

Enteric coated layered pellets containing a proton pump inhibitor are mixed with NSAID(s) -containing granules and tablet excipients. The blend is compressed into a multiple unit tablet dosage form. The compressed tablets may optionally be coated with a film coating agent(s) to smooth the tablet surface and further improve the stability of the tablets during storage and transport. Such film coatings may further contain additives such as anti-tacking agents, colorants and pigments or other additives to give the tablet a better appearance, as well as a light protective layer for the light sensitive substance.

Enteric coated pellets with or without an outer coating and NSAID granules are mixed with tablet excipients and compressed into tablets. Excipients such as fillers, binders, disintegrants, lubricants and other pharmaceutical additives, suitable lubricants in tableting being, for example, sodium stearyl fumarate, magnesium stearate and talc.

Alternatively, the NSAID(s) may be mixed with enteric coated layered pellets containing the proton pump inhibitor and any inert excipients and compressed into tablets (direct compression), or the different active substances may be formulated in different layers, optionally in the form of a controlled release layer.

In addition, the NSAID(s) and the proton pump inhibitor in the form of enteric coated layered pellets may be mixed with inert tablet excipients and compressed into tablets. The compressed tablets are optionally coated with a tablet film coating to give a good tablet appearance.

Alternatively, the proton pump inhibitor-containing multiple unit tablets are spray coated with a suspension or solution containing the NSAID(s). The tablets prepared were then coated with a colored tablet film coating layer.

The enteric coating layered pellet fraction should not exceed 75% of the total tablet weight, preferably not exceed 60% by increasing the amount of NSAID(s) -containing particles, the enteric coating layered pellet fraction of the proton pump inhibitor in a multiple unit tableted dosage form can be correspondingly decreased. By selecting small enteric coating layered pellets in the preparation of the formulation of the present invention, the number of pellets per tablet can be larger, which allows the tablet to be divided and dosed accurately.

Thus, a preferred multiple unit tableted formulation consists of enteric coated layered pellets containing an acid susceptible proton pump inhibitor, optionally mixed with a basic compound(s) and compressed into a tablet together with NSAID(s) containing granules and optionally tablet excipients. From any viewpoint, it is not necessary to add an alkaline substance to the proton pump inhibiting agent, but such a substance may further enhance the stability of the proton pump inhibiting agent, or some alkaline substance may react with the enteric coating substance in situ to form a separate layer. The enteric coating layer(s) render the pellets of this dosage form insoluble in acidic media, but disintegrate/dissolve in a near neutral to alkaline medium, such as the liquid in the proximal small intestine, where the proton pump inhibitor needs to dissolve. The NSAID(s) may be released in the stomach. The enteric coated layered pellets may be further coated with an outer coating layer before being tableted, and wherein one or more separating layer(s) may also be present between the core material and the enteric coating layer. Method of producing a composite material

The process for preparing the dosage form is another aspect of the present invention. After the proton pump inhibitor has been added to the core by spray coating or coating to form pellets, or after forming uniform pellets by extrusion/spheronization or granulation, i.e. rotary granulation, the pellets are optionally coated with a separating layer(s) followed by an enteric coating layer(s), or the separating layer is automatically formed in situ between the core material and the enteric coating layer material. Coatings were made as described above and with reference to the examples. Pellets containing NSAID(s) granules and enteric coating layered NSAID are prepared as described above and in the examples. The pharmaceutical process may preferably be entirely aqueous.

Enteric coated layered pellets (with or without an outer coating) are mixed with the prepared granules, tablet excipients or other pharmaceutical additives and compressed into tablets. Alternatively, the different active substances in powder form are thoroughly dry-mixed with tablet excipients, made into a soft mass and compressed into conventional tablets before the addition of any separating layer and enteric coating layer. The NSAID(s) may also be incorporated into the coating layer and added to the multiple unit dosage form containing the proton pump inhibitor, or the NSAID(s) and the proton pump inhibitor may be mixed in the form of enteric coated layered pellets with inert tablet excipients and compressed into a multiple unit tablet dosage form.

Different active substances may also be made in different layers, wherein the layer(s) containing the NSAID(s) may be in the form of a controlled release formulation. Or alternatively, the proton pump inhibitor in the form of enteric coating layered pellets may be filled into a capsule together with the NSAID(s) in the form of granules or enteric coating layered pellets, optionally mixed with pharmaceutically acceptable excipients. Use of formulations

The dosage forms of the present invention are particularly advantageous for the treatment of NSAID(s), such as gastrointestinal side effects caused by continued treatment with NSAID(s). The new dosage forms are administered from 1 to several times per day, preferably once or twice per day. Typical dosages of the active substance to be administered will vary depending on factors such as the individual needs of the patient, the mode of administration and the disease. In general, each dosage form contains 0.1-200mg of the proton pump inhibitor and 0.1-1000mg of the NSAID(s), respectively. Preferably each dosage form contains 10-80mg of the proton pump inhibitor and 10-800mg of the NSAID(s), respectively, and more preferably 10-40mg of the proton pump inhibitor and 10-500mg of the NSAID(s), respectively. Particularly preferred are compositions containing, for example, 10mg omeprazole in combination with 50mg diclofenac, 10mg omeprazole and 250mg naproxen, 10mg omeprazole and 10mg piroxicam, or 10mg omeprazole and 400mg ibuprofen.

Multiple unit tablet formulations are also suitable for dispersion in aqueous solutions of mildly acidic pH and subsequent administration orally or via naso-gastric tubing.

The present invention is illustrated in more detail by the following examples.

Examples

Example 1

Rapidly disintegrating multiple unit tablet dosage form comprising magnesium omeprazole salt and ibuprofen.Tablet core material12.00kg of omeprazole magnesium salt pellet 12.00kg of hydroxypropyl methylcellulose 1.8kg of pure water 35.4kgInsulating layerCore material (as described above) 23.50kg hydroxypropyl cellulose 2.35kg talc 4.03kg magnesium stearate 0.34kg purified water 48.00kgEnteric coating layerPellets coated with a separating layer (as described above) 29.00kg methacrylic acid copolymer (30% suspension) 38.70kg triethyl citrate 3.48kg mono and diglycerides (NF)0.58kg Tween 800.06 kg pure water 22.68kgOuter coating layerEnteric coated layered pellets (as described above) 44.7kg hydroxypropyl methylcellulose 0.58kg magnesium stearate 0.017kg purified water 11.6kgTablet formulationmg/tablet of omeprazole-containing coated pellets 47.85 ibuprofen 400 microcrystalline cellulose (MCC) 273.6 crospovidone 100.4 polyvinylpyrrolidone K-2533.3 sodium dodecyl sulfate 26.7 pure water 297 sodium stearyl fumarate 4.0

The suspension coating is carried out in a fluidized bed. The magnesium salt of omeprazole is sprayed onto the pellet from an aqueous suspension containing the dissolved binding agent.

The prepared core material was coated with a separating layer in a fluidized bed with a solution of hydroxypropylcellulose containing talc and magnesium stearate. In a fluidized bed, an enteric coating layer consisting of methacrylic acid copolymer, mono and diglycerides, triethyl citrate and tween was sprayed onto the pellets (coated with a separating layer). The enteric coating layered pellets were coated with a hydroxypropylmethylcellulose/magnesium stearate containing suspension in the same model machine. The resulting pellets were classified by sieving.

26.7 parts of sodium lauryl sulfate and 33.3 parts of polyvinylpyrrolidone K-25 were dissolved in 267 parts of pure water to form a tablet granulation liquid. 400 parts ibuprofen, 226 parts MCC and 10.4 parts crospovidone are dry blended. The granulation liquid was added to the powder mixture and the material was wet mixed. To equilibrate to a sufficient amount 30 parts water were added.

The soft mass was dried in an oven at 60 ℃ for about 6 hours. The dry granules were milled through a 0.8mm screen.

Enteric coated layered omeprazole pellets, milled ibuprofen granules, 47.6 parts MCC, 4.0 parts sodium stearyl fumarate and 90 parts cross-linked polyvinylpyrrolidone were mixed and compressed into tablets with a tableting machine equipped with a punch 15mm in diameter. The hardness of 866mg tablets was between 5.3 and 5.9kP as measured by a Schleuniger apparatus. Disintegration times measured in simulated gastric fluid (USP, no enzyme) were 49-52 seconds (n ═ 2).

Example 2 a rapidly disintegrating multiple unit tablet dosage form containing magnesium salt of S-omeprazole and naproxen.Tablet core material120g of S-omeprazole magnesium salt, 150g of pellet, 8024 g of Tween, 18g of hydroxypropyl methylcellulose, 18g of pure water and 562gInsulating layerCore material (as described above) 200g hydroxypropyl cellulose 30g talc 51.4g magnesium stearate 4.3g purified water 600gEnteric coating layerPellets coated with a separating layer (as described above) 250g methacrylic acid copolymer (30% suspension) 333.7g triethyl citrate 30g mono and diglycerol (NF) 5.0g Tween 80 (Tween 80) 0.5g pure water 195.8gOuter coating layerEnteric coating layered pellet 371g sodium carboxymethylcellulose 5.0g pure water 191gTablet formulationmg/tablet outer coating containing S-omeprazole magnesium saltPellet 55 nepson 250 microcrystalline cellulose (MCC) 150 Low substituted hydroxypropyl cellulose 40 polyvinylpyrrolidone K-905.0 pure Water 250

The suspension coating is carried out in a fluidized bed. The magnesium salt of S-omeprazole is sprayed onto an inert sugar core (pellet) from an aqueous suspension containing dissolved binder and tween.

The prepared core material was coated with a separating layer in a fluidized bed with a solution of hydroxypropylcellulose containing talc and magnesium stearate. In a fluidized bed, an enteric coating layer consisting of methacrylic acid copolymer, mono and diglycerides, triethyl citrate and tween was sprayed onto the pellets (coated with a separating layer). The enteric coating layered pellets were coated with a sodium carboxymethyl cellulose solution in the same type of machine. The resulting pellets were classified by sieving.

5 parts polyvinylpyrrolidone K-90 were dissolved in 150 parts pure water to form a tablet granulation liquid. Naproxen, MCC and low-substituted hydroxypropyl cellulose were dry blended. The granulation liquid was added to the powder mixture and the material was wet mixed. 100 parts of water were added to equilibrate to capacity.

The soft mass was dried in an oven at 60 ℃ for about 5-6 hours. The dry granules were milled through a 1.0mm screen.

Enteric coated layered omeprazole pellets, milled granules were mixed and compressed into tablets with a tabletting machine equipped with a 18 x 8.5mm punch. The average hardness of the 500mg tablets, measured with a Schleuniger instrument, was 9.4 kP. The disintegration time measured in pure water at 37 ℃ is 15-30 seconds (n-2).

Example 3 a rapidly disintegrating multiple unit tablet dosage form containing pantoprazole and piroxicam- β -hydroxypropyl cyclodextrin.Tablet core materialPontoprazole 100g pellet200g of hydroxypropyl cellulose LF 25g of pure water 607gInsulating layerTablet core material (as described above) 200g hydroxypropyl cellulose LF 20g talc 34.3g magnesium stearate 2.9g pure water 400gEnteric coating layerPellets coated with a separating layer (as described above) 200g methacrylic acid copolymer (30% suspension) 333g triethyl citrate 30g mono and diglyceride (NF) 5g Tween 800.5 g purified water 281.5gTablet formulationmg/tablet of pills containing pantoprazole 133 piroxicam 20 beta-hydroxypropyl cyclodextrin (90%) 72 microcrystalline cellulose (MCC) 276 crosslinked polyvinylpyrrolidone 36.8 pure water 2 Stearyl Sodium Fumarate (SSF) 3.9

The suspension coating is carried out in a fluidized bed. Pantoprazole is sprayed onto inert sugar cores (pellets) from an aqueous suspension containing dissolved binder.

The prepared core material was coated with a separating layer in a fluidized bed with a solution of hydroxypropylcellulose containing talc and magnesium stearate. In a fluidized bed, an enteric coating layer consisting of methacrylic acid copolymer, mono and diglycerides, triethyl citrate and tween was sprayed onto the pellets (coated with a separating layer). The resulting pellets were classified by sieving.

Piroxicam was added to the β -hydroxypropyl cyclodextrin while mechanically treated and humidified with water. The soft mass was dried in an oven at 50 ℃ and then ground through a 0.8mm screen.

Piroxicam-beta-hydroxypropyl cyclodextrin, MCC, crosslinked polyvinylpyrrolidone and SSF were dry blended, and this mixture was then mixed with pantoprazole pellets.

Tablets were compressed using a tablet machine equipped with an 18X 8.5mm punch. The average hardness of the 577mg tablets, measured along the longest axis using a Schleuniger instrument, was 16.7kP and varied between 14.8 and 18.7 kP. The disintegration time measured in water was about 4 minutes.

The tablets were coated with the pigmented dispersion as in example 7

Example 4

A two-layered tablet dosage form, one of which is a rapidly disintegrating portion containing 20mg lansoprazole in the form of enteric coated pellets, and the other of which is an extended release portion in the form of a hydrophilic gel matrix containing 250mg naproxen.

Lansoprazole enteric coated pellet Tablet core materialLansoprazole 400g pellet 400g hydroxypropyl methylcellulose 80g sodium dodecyl sulfate 3g pure water 1360gSub-coating (Sub-coating)Core material (as described above) 100g hydroxypropyl methylcellulose 9g polyethylene glycol 60001 g talc 18g 95% ethanol250g of pure waterEnteric coating layerSubcoated pellets (described above) 100g hydroxypropyl methylcellulose phthalate 39.9g acetyl tributyl citrate 8g cetyl alcohol 2.1g 95% ethanol 162g acetone 378g

The suspension coating is carried out in a fluidized bed. Lansoprazole is sprayed onto inert pellet sugar from an aqueous suspension containing a binder and a wetting agent.

The prepared core material was subcoated with talc suspended in an HPMC/PEG solution in a fluid bed equipped with Wurster. PEG also functions as a plasticizer for HPMC.

Enteric coating is carried out in the same machine with a solution of the enteric coating layer-forming substance in an organic solvent.Tablet formulationmg/tablet of lansoprazole-containing pellets 94 microcrystalline cellulose 181.8 crospovidone 18.2 neproxen 250 polyoxyethylene (molecular weight about 4000000) 200 sodium aluminum silicate 50L-arginine 19095% ethanol about 280

Naproxen, Polyox WSR 301 , L-Arginin and sodium aluminum silicate were dry blended. The granulation liquid, ethanol, was added to the powder mixture and wet mixed. The soft mass was dried in an oven at 60 ℃ for about 8 hours. The dried granules were milled through a 1.0mm screen.

690mg of neprosyn-containing granules were first compressed and then filled with 81mg lansoprazole pellets and 181.8mg MCC and 18.2mg of crospovidone on each tablet. These were then compressed together into two-layered tablets in a Diaf tablet press equipped with a 9 x 20mm punch. The tablet hardness along the longest axis measured in a Schleuniger instrument was about 14 kP.

The dissolution of naproxen was detected in phosphate buffer (ph6.8) and the results were as follows: 1 hour 14% dissolution 3 hour 34% dissolution 5 hour 58% dissolution 7 hour 79% dissolution 24 hour 102% dissolution

Example 5

Rapidly disintegrating multiple unit tablets containing a magnesium salt of omeprazole and piroxicam.Tablet core material (omeprazole)Omeprazole magnesium salt 500kg sugar pill 10.00kg hydroxypropyl methyl cellulose 0.75kg pure water 19.65kgIsolation layer (omeprazole)Core material (as described above) 14.60kg hydroxypropyl cellulose 1.46kg talc 2.5kg magnesium stearate 0.21kg purified water 29.2kgEnteric coating layer (omeprazole)Pellets with isolation layer (as described above) 9.00kg methacrylic acid copolymer (30% suspension) 15.00kg triethyl citrate 1.35kg mono and diglycerides (NF) 0.22kg Tween 800.02 kg pure water 8.8kgOuter coating layer (omeprazole)Enteric coated layered pellet9.0kg of hydroxypropylmethylcellulose 0.18kg of magnesium stearate 0.005kg of purified water 3.6kg

The suspension coating is carried out in a fluidized bed. The magnesium salt of omeprazole is sprayed onto an inert sugar core (pellet) from an aqueous suspension containing dissolved binding agent.

The prepared core material was coated with a separating layer in a fluidized bed with a solution of hydroxypropylcellulose containing talc and magnesium stearate. In a fluidized bed, an enteric coating layer consisting of methacrylic acid copolymer, mono-and diglycerides, triethyl citrate and tween was sprayed onto the subcoated pellets. The enteric coating layered pellets were coated with a hydroxypropylmethylcellulose/magnesium stearate suspension in the same model machine. The resulting coated pellets were classified by sieving.Tablet core material (piroxicam)Micronized piroxicam 35g sugar core 100g hydroxypropyl methylcellulose (6cps), 25g pure water 250g 99% ethanol (w/v) 250gEnteric coating layer (Piloxiazine)Piloxiazine pellets (as described above) 100g were coated with a suspension of the following components to give a product content of 163 mg/g. Hydroxypropyl methylcellulose acetate succinate LF 14.38 parts, triethyl citrate 2.87 parts, sodium dodecyl sulfate 0.43 parts, talc 4.32 parts, pure water 183.3 parts

The suspension coating is carried out in a fluidized bed. Micronized piroxicam is sprayed onto inert pellets from an aqueous suspension containing dissolved binder.

In a fluidized bed, the acetic acid succinic acid hydroxylAn enteric coating layer consisting of propylmethylcellulose, triethyl citrate, sodium dodecyl sulfate and talc was sprayed onto the piroxicam pellets.Tablet (1000 tablets per batch)Omeprazole pellets 95.7g piroxicam pellets 122.7g microcrystalline cellulose (MCC) 240g crospovidone (PVP-XL) 20g low substituted hydroxypropyl cellulose (L-HPC) 40g sodium dodecyl sulfate (SSF) 4.6g

MCC, L-HPC and PVP-XL were mixed together and homogenized. The two enteric coated layered pellets were then mixed. Finally, the lubricant SSF was mixed and the mixture was compressed into tablets on a tabletting machine equipped with 8.5 x 16mm punches. The hardness of the 523mg tablet was measured to be 8 to 9kP using a Schleuniger instrument. 2 disintegration time in water at 37 ℃ is less than 1 minute.

The tablets were coated with the pigmented dispersion as in example 7.

Example 6

Rapidly disintegrating enteric coated layered tablets containing magnesium omeprazole salt and diclofenac.Tablet (2000 tablets per batch)Magnesium omeprazole salt (equivalent to 20mg omeprazole) 45.0g sodium diclofenac (equivalent to 20mg diclofenac) 43.2g microcrystalline cellulose (MCC), 110g crospovidone (PVP-XL), 50g low-substituted hydroxypropyl cellulose (L-HPC), 50g sodium dodecyl sulfate (SSF), 8.6g pure water, about 170g

Omeprazole, diclofenac, MCC, L-HPC, 30g PVP-XL and 5.6g SSF were mixed together and then water was added while mixing continuously. The pellets were dried in an oven at 60 ℃ for about 1.5 hours. The dried granules were milled through a 1.0mm screen.

The milled particles were mixed with 20g PVP-XL and 30.g SSF. The mixture was compressed into 153mg tablets on a tablet machine using a punch with a diameter of 7 mm. The average hardness of the tablets was 7.4kP (n ═ 6). The disintegration time in water at 37 ℃ was 1 min 20 sec.

The tablets were coated with a separating layer consisting of Hydroxypropylmethylcellulose (HPMC) and talc in a fluid bed equipped with Wurster.Addition of a separating layer7mm tablet 100.1g coating Dispersion HPMC (6cps) 5.5g talc 1.15g 99% ethanol (w/v) 46.7g pure Water 46.7g

The resulting coated layered tablets are further coated with an enteric coating layer in the same machine.Addition of enteric coating layerTablet with isolation layer 100g coating dispersion methacrylic acid copolymer (30% suspension) 26.4g (dry weight 7.92g) polyethylene glycol 4000.9 g titanium dioxide 0.83g red brown iron oxide 0.28g pure water 55.1g

The tablet weight increased by about 11 mg/tablet in the enteric coating step, corresponding to 7% of the total tablet weight.

The pigment in the enteric coating layer plays a role of keeping out light.

Example 7

Rapidly disintegrating multiple unit tablet dosage form comprising a magnesium salt of omeprazole and an inner coating layer of sodium diclofenac and an outer coloured coating layer providing protection from light.

Enteric coated layered pellets of the magnesium salt of omeprazole were obtained from example 5.Tablet formulationmg/tablet omeprazole pellets 83.3 microcrystalline cellulose (MCC) 181.4 Cross-Linked polyvinylpyrrolidone 3.7 sodium stearyl fumarate 0.4

Pellets were prepared as in example 5.

MCC, cross-linked polyvinylpyrrolidone and omeprazole pellets were dry blended. And then mixed with SSF.

This mixture was compressed into tablets on a tablet machine equipped with a punch of diameter 9 mm. The hardness of 269mg tablets, measured with a Schleunger instrument, is 8 to 9 kP.

The tablets were coated in a fluidized bed with the following solution until the average weight of the tablets was 298mg, sodium diclomortate 20.0 parts by weight HPMC (6cps) 11.4 parts by weight 99% ethanol (w/v) 113.6 parts by weight pure water 113.6 parts by weight

Finally, the tablets are coated with the colored suspension in the same machine. The composition of the coating suspension was: HPMC (6cps) 10 parts polyethylene glycol 60002.5 parts titanium dioxide 1.83 parts yellow iron oxide 0.40 parts 99% ethanol (w/v) 85 parts pure water 85 parts

Tablets with an average weight of 303mg were obtained. The disintegration time measured in water at 37 ℃ was less than 4 minutes (n-4).

Example 8

Capsules containing omeprazole magnesium salt and piroxicam.CapsuleEnteric coated layered omeprazole pellets (preparation and composition as in example 5)95.7 mg/capsule enteric coated layered piroxicam pellets (preparation and composition as in example 5)122.7 mg/capsule

The prepared pellets were filled into No. 3 hard capsules. Optionally, a small amount of lubricant is added before filling the capsules. The amount of omeprazole contained in each capsule was about 20mg and the amount of piroxicam contained in each capsule was about 20 mg.

Example 9

A capsule formulation comprising magnesium salt of S-omeprazole and naproxen.CapsuleEnteric coated layered pellets (preparation and composition as in example 2) 55.2 mg/capsule naproxen particles (preparation and composition as in example 2) 445 mg/capsule

The prepared granules and enteric coating layered pellets were filled into size 00 hard gelatin capsules. Optionally, a small amount of lubricant is added before filling the capsules. The amount of S-omeprazole contained in each capsule is about 10mg and the amount of naproxen contained in each capsule is about 250 mg.

Example 10

Rapidly disintegrating multiple unit tablet dosage form comprising magnesium omeprazole salt and sodium diclofenac.Tablet core material5kg of omeprazole magnesium salt, 10kg of round sugar core, 0.75kg of hydroxypropyl methyl cellulose, and 19.7kg of pure waterInsulating layerCore material 10.2kg hydroxypropyl cellulose 1.02kg talc 1.75kg magnesium stearate 0.146kg purified water 21.4kg pellets of enteric coating layer coated with isolating layer 11.9kg methacrylic acid copolymer (30% suspension) 19.8kg triethyl citrate 1.79kg mono and diglycerides (NF) 0.297kg Tween 800.03 kg purified water 11.64kgOuter coating layerEnteric coating layered pellet 20.0kg hydroxypropyl methylcellulose 0.238kg magnesium stearate 0.007kg pure water 6.65kgTablet formulationmg/tablet of omeprazole containing sodium diclomortate 82.4 50.0 microcrystalline cellulose (MCC) 261 Cross-Linked polyvinylpyrrolidone 5.6 sodium stearyl fumarate 0.56

The suspension coating is carried out in a fluidized bed. The magnesium salt of omeprazole is sprayed onto the round sugar cores from an aqueous suspension containing dissolved binding agent. The particle size of the round sugar cores is 0.25 to 0.35 mm.

The prepared cores were coated in a fluid bed with a solution of hydroxypropylcellulose containing talc and magnesium stearate. In a fluidized bed, an enteric coating layer consisting of methacrylic acid copolymer, mono-and diglycerides, triethyl citrate and tween was sprayed onto the pellets coated with the separating layer. The enteric coating layered pellets are coated with a hydroxypropylmethylcellulose solution containing magnesium stearate in a fluidized bed. The resulting coated pellets were classified by sieving.

Enteric coated layered pellets with an outer coating layer, sodium diclomortate, MCC, cross-linked polyvinylpyrrolidone and sodium stearyl fumarate were dry blended and tableted on an outer core tablet machine equipped with an 11mm punch. The amount of omeprazole contained in each tablet was about 10mg and the amount of sodium diclofenac was about 50 mg. The hardness of the tablets was measured to be 80N.

Example 11

Rapidly disintegrating multiple unit tablet dosage form comprising a magnesium salt of omeprazole and piroxicam.Tablet core material10.0kg of magnesium omeprazole salt, 10.0kg of round sugar core, 1.0kg of hydroxypropyl methyl cellulose, 1.5kg of pure water and 29.9kg of pure waterInsulating layerCore material 20.0kg hydroxypropyl cellulose 2.0kg talc 3.43kg magnesium stearate 0.287kg purified water 41.0kg pellet of enteric coating layer isolation layer 24.5kg methacrylic acid copolymer (30% suspension) 32.7kg triethyl citrate 2.94kg mono and diglycerides (NF)0.49kg of Tween 800.049 kg of pure water 19.19kgOuter coating layerEnteric coating layered pellet 37.8kg hydroxypropyl methylcellulose 0.49kg magnesium stearate 0.0245kg pure water 11.6kgTablet formulationmg/tablet of omeprazole containing 94.9 piroxicam 20.0 microcrystalline cellulose (MCC) 280 crospovidone 5.6 sodium stearyl fumarate 0.56

Enteric coated layered pellets of omeprazole with an outer coating layer were prepared as in example 10.

Enteric coated layered pellets with outer coating layer, piroxicam, MCC, cross-linked polyvinylpyrrolidone and sodium stearyl fumarate were dry blended and tableted on an outer core tablet machine equipped with an 11mm punch. The amount of omeprazole contained in each tablet was about 20mg and the amount of sodium diclofenac was about 20 mg. The hardness of the tablets was measured to be 110N.Results"acid resistance", i.e. the residual amount after 2 hours of contact with 0.1N hydrochloric acid

Tablet example 195% example 295% example 399% example 491% example 592% example 696% example 793% example 1091% example 1191%

The best mode of carrying out the invention is the dosage form described in examples 5, 7, 10.

Enteric coated layered pellets containing proton pump inhibitors may also be prepared as described in the following examples. Example 12

Enteric coated pellets were prepared by extrusion/spheronization.Tablet core material600g of magnesium omeprazole salt, 1000g of mannitol, 300g of microcrystalline cellulose, 100g of hydroxypropyl cellulose, 6g of sodium dodecyl sulfate, 6g of pure water and 802g of pure waterInsulating layerCore Material (as described above) 400g hydroxypropyl methylcellulose 48g purified Water 960gEnteric coating layerPellets coated with a separating layer (as described above) 200g methacrylic acid copolymer 100g triethyl citrate 30g mono and diglycerides (NF) 5g Tween 800.5 g pure water 309g

Sodium dodecyl sulfate was dissolved in purified water to form a granulation liquid. The magnesium salt of omeprazole, mannitol, microcrystalline cellulose and hydroxypropyl cellulose are dry blended. The granulation liquid is added to the powder mixture and the material is wet mixed.

The soft material was passed through an extruder equipped with a 0.5mm screen. The extrudate is spheronized on a friction disk on a spheronizer. The core material was dried and separated in a fluid bed dryer. The prepared core material was coated with an isolation layer in a fluid bed with hydroxypropyl methylcellulose/water solution.

To the aqueous dispersion of methacrylic acid copolymer plasticized by triethyl citrate was added the mono and diglyceride/tween dispersions, whereby the enteric coating layer was applied thereto to the pellets coated with the isolating layer. The pellets were dried in a fluidized bed.

Example 13

Enteric coated layered pellets were prepared by powder coating of a round sugar core.Tablet core materialMagnesium omeprazole 1500g round sugar core 1500g hydroxypropyl methyl cellulose 420g aerosil  8g pure water 4230gInsulating layerTablet core material (as described above) 500g hydroxypropyl cellulose 40g talc 67g magnesium stearate 6g pure water 800gEnteric coating layerBarrier coated pellets (as described above) 500g methacrylic acid copolymer 200g triethyl citrate 60g pure water 392g

The magnesium salt of omeprazole, a portion of hydroxypropylcellulose and Aerosil  are dry blended to form a powder. This powder was coated onto round sugar cores (0.25-0.4mm) while spraying with a hydroxypropylmethylcellulose solution (6%, w/w) in a centrifugal fluidized coating granulator.

The prepared core material was dried and coated with an isolation layer in a centrifugal fluidized coating granulator. The fluidized bed is used for enteric coating.

Example 14

Enteric coated layered pellets containing a silica core were prepared.Tablet core materialOmeprazole magnesium salt 8.00kg silicon dioxide 8.00kg hydroxypropyl methyl cellulose 1.41kg sodium dodecyl sulfate 0.08kg pure water 28.00kgInsulating layerCore material (as above) 10.00kg hydroxypropyl methylcellulose 0.80kg pure water 10.00kgEnteric coating layerPellets coated with a separating layer (see above) 300g methacrylic acid copolymer 124g polyethylene glycol 40025 g mono-and diglyceride (NF) 3g Tween 801 g pure water 463g

The suspension coating is carried out in a fluidized bed. The magnesium salt of omeprazole is sprayed onto the silica core from an aqueous suspension containing dissolved binder and surfactant.

The prepared core material was coated with an isolation layer in a fluidized bed using hydroxypropyl methylcellulose solution. An enteric coating layer consisting of methacrylic acid copolymer, mono-and diglycerides, polyethylene glycol 400 and tween is sprayed onto the pellets coated with the isolating layer in a fluidized bed.

Example 15

Enteric coated layered pellets were prepared.Enteric coating layerPellets coated with a separating layer (preparation and composition as in example 12) 500g methacrylic acid copolymer 250g polyethylene glycol 600075 g mono-and diglyceride (NF) 12.5g Tween 801.2 g pure Water 490g

Example 16 enteric coated layered pellets were prepared.Enteric coatingPellets coated with a separating layer (preparation and composition as in example 1) 500g of hydroxypropylmethylcellulose phthalate 250g of cetyl alcohol 50g of ethanol (95%) 1000g of acetone 2500g

Example 17 enteric coated layered pellets were prepared.Tablet core materialOmeprazole 225g mannitol 1425g hydroxypropyl cellulose 60g microcrystalline cellulose 40g anhydrous lactose 80g sodium dodecyl sulfate 5g disodium hydrogen phosphate dihydrate 8g pure water 350gInsulating layerCore material (as described above) 300g hydroxypropyl cellulose 30g talc 51g magnesium stearate 4gEnteric coating layerPellets coated with a separating layer (as described above) 300g methacrylic acid copolymer 140g citric acid triglyceride 42g mono-and diglyceride (NF) 7g Tween 800.7 g

The dry ingredients for making the core material are thoroughly mixed in a mixer. The granulation liquid is added and the mixture is kneaded and granulated to a suitable density. The soft material is pressed out through the screen of the extruder and the particles are transformed into round shapes in a spheronizer. The core material is dried in a fluidized bed and divided into a suitable particle size range, e.g. 0.5-1.0 mm. The prepared tablet core material was coated with a separating layer and an enteric coating layer as described in the above examples. Preparation of active substances

The magnesium salt of omeprazole used in some examples is prepared according to the method described in WO95/01977, the single enantiomer of the omeprazole salt is prepared according to the method disclosed in WO94/27988 and omeprazole is prepared according to the method disclosed in EP-a 1-0005129. All of these documents are incorporated herein by reference.

Claims (29)

1. A multiple unit tableted dosage form comprising an acid susceptible proton pump inhibitor in the form of individually enteric coating layered pellets compressed together with particles comprising one or more non-steroidal anti-inflammatory drugs into a tablet, wherein the individually coated pellets have a plasticized enteric coating layer thickness of at least about 10 μm and mechanical properties such that the acid resistance of the individually enteric coating layered pellets does not decrease by more than 10% when the pellets are tableted with particles of a non-steroidal anti-inflammatory drug and optionally pharmaceutically acceptable excipients.

2. The dosage form of claim 1, wherein the proton pump inhibitor is protected by two layers, an enteric coating layer and a separating layer separating the enteric coating and the proton pump inhibitor.

3. The dosage form of claim 1, wherein the dosage form comprises an acid susceptible proton pump inhibitor and a nonsteroidal anti-inflammatory drug.

4. A dosage form according to claim 1, wherein the proton pump inhibitor is omeprazole or an alkaline salt thereof, one of its single enantiomers or an alkaline salt thereof.

5. A dosage form according to claim 4, wherein the proton pump inhibitor is the magnesium salt of S-omeprazole.

6. The dosage form of claim 1, wherein the proton pump inhibitor is lansoprazole, one of its single enantiomers, or a pharmaceutically acceptable salt thereof.

7. The dosage form of claim 1, wherein the proton pump inhibitor is pantoprazole, one of its single enantiomers or a pharmaceutically acceptable salt thereof.

8. A dosage form according to any one of claims 4 to 7 wherein the non-steroidal anti-inflammatory drug is ibuprofen, diclofenac, piroxicam or naproxen, or a pharmaceutically acceptable salt thereof.

9. The dosage form of any one of claims 4-7 wherein the non-steroidal anti-inflammatory drug is diclofenac or piroxicam, or a pharmaceutically acceptable salt thereof.

10. The dosage form of any one of claims 4-7 wherein the amount of the nonsteroidal anti-inflammatory drug component is NO-releasing nonsteroidal anti-inflammatory drug.

11. The dosage form of any one of claims 4-7, wherein the amount of the nonsteroidal anti-inflammatory drug component is Cyclooxygenase (COX)₂A selective non-steroidal anti-inflammatory drug.

12. The dosage form of claim 1, wherein the amount of proton pump inhibitor is 10-80mg and the amount of the one or more nonsteroidal anti-inflammatory drugs is 10-800 mg.

13. The dosage form of claim 1, wherein the proton pump inhibitor is present in an amount of 10-40mg and the one or more nonsteroidal anti-inflammatory drugs are present in an amount of 10-500 mg.

14. A tableted dosage form according to claim 1, wherein the enteric coating layer of the individual pellets contains a plasticizer in an amount of more than 10 wt% of the enteric coating layer material.

15. A tableted dosage form according to claim 1, wherein the pellets of the enteric coating layer are further coated with an outer coating layer comprising pharmaceutical excipients.

16. The tableted dosage form of claim 1, wherein the tablet is divisible.

17. A tableted dosage form according to claim 16, wherein the tablet is dispersed as an aqueous suspension of the pellets comprising the enteric coating layer of the non-steroidal anti-inflammatory drug(s) and the proton pump inhibitor.

18. A tableted dosage form according to claim 1, wherein the tablet consists of two separate layers, one of which comprises the proton pump inhibitor in the form of pellets compressed with tablet excipients into an enteric coating layer of one layer, and the other layer in which the admixed non-steroidal anti-inflammatory drug or drugs has extended release properties.

19. The tableted dosage form of claim 18, wherein the layer comprising one or more nonsteroidal anti-inflammatory drugs is a gel matrix with extended release characteristics.

20. A tableted dosage form according to claim 1, wherein the tablet is an enteric coated tablet comprising a mixture of proton pump inhibitor and non-steroidal anti-inflammatory drug particles, optionally comprising a water soluble or rapidly disintegrating separating layer in water between the core and the enteric coating layer.

21. A tableted dosage form according to claim 1, wherein the tablet comprises pellets compressed into a tablet having an enteric coating layer of the proton pump inhibitor, the tablet being coated with a separate layer comprising one or more non-steroidal anti-inflammatory drugs.

22. A tableted dosage form according to claim 21, wherein the tablet is coated with a coloured tablet film coating layer.

23. A tableted dosage form according to claim 1, wherein the tablet consists of two types of enteric coating layered pellets, one containing the proton pump inhibitor and the other containing the one or more non-steroidal anti-inflammatory drugs, which are compressed into a tablet together with tablet excipients.

24. A tableted dosage form according to claim 1, wherein the tablet consists of enteric coating layered pellets of the proton pump inhibitor and one or more non-steroidal anti-inflammatory drug pellets coated with an extended release film, the layered pellets being compressed into a tablet together with tablet excipients.

25. A process for the manufacture of a fixed dosage form comprising an acid susceptible proton pump inhibitor and one or more non-steroidal anti-inflammatory drugs in the form of a multiple unit tablet, characterized in that the proton pump inhibitor is formulated in the form of pellets of a plasticized enteric coating layer, wherein the enteric coating layer has a thickness of at least about 10 μm and the pellets are mixed with granules of the non-steroidal anti-inflammatory drug prepared and optionally pharmaceutical tablet excipients, after which the dry mixture is compressed into a multiple unit tablet, and the acid resistance of the enteric coating layer does not decrease more than 10%.

26. A process for the preparation of a fixed dosage form comprising an acid susceptible proton pump inhibitor and one or more non-steroidal anti-inflammatory drugs in the form of a multiple unit tablet, characterized in that the proton pump inhibitor is prepared in the form of pellets having an enteric coating layer, wherein the enteric coating layer has a thickness of at least about 10 μm and the one or more non-steroidal anti-inflammatory drugs are prepared in the form of pellets having a coating layer, wherein the coating layer is an extended release layer or an enteric coating layer, and the prepared pellets are mixed with tablet excipients and compressed into a tablet.

27. A process for the preparation of a fixed dosage form comprising an acid susceptible proton pump inhibitor and one or more non-steroidal anti-inflammatory drugs in the form of an enteric coating layer tablet, characterized in that the proton pump inhibitor is mixed with one or more non-steroidal anti-inflammatory drugs and a pharmaceutically acceptable excipient, after which the mixture is compressed into a tablet, which is coated with an enteric coating layer, wherein the enteric coating layer has a thickness of at least about 10 μm and is optionally coated with a separating layer before the enteric coating layer is coated.

28. Use of a dosage form according to any one of claims 1 to 24 in the manufacture of a medicament for the treatment or prevention of gastrointestinal side effects associated with the treatment of a disease with one or more non-steroidal anti-inflammatory drugs.

29. The use according to claim 28 wherein the disorder is a disorder of the upper gastrointestinal tract associated with treatment with a non-steroidal anti-inflammatory drug.