WO2011080500A2

WO2011080500A2 - New pharmaceutical dosage form for the treatment of gastric acid-related disorders

Info

Publication number: WO2011080500A2
Application number: PCT/GB2010/002335
Authority: WO
Inventors: Andreas Fischer; Emil Schwan
Original assignee: Orexo AB
Current assignee: Orexo AB
Priority date: 2009-12-29
Filing date: 2010-12-24
Publication date: 2011-07-07
Anticipated expiration: 2012-06-29
Also published as: WO2011080500A3

Abstract

According to the invention there is provided a single unit oral dosage form comprising: (a) a first component comprising a proton pump inhibitor or a pharmaceutically acceptable salt thereof and an enteric substance positioned to protect the proton pump inhibitor from the acidic environment of the stomach; (b) a second component comprising an H2 receptor antagonist or a pharmaceutically acceptable salt thereof; and (c) a physical and/or chemical barrier located between the first and second components, and preventing said components from interacting with each other. The dosage forms of the invention are particularly useful in the treatment of gastric acid secretion-related disorders, such as gastro-esophageal reflux disease.

Description

NEW PHARMACEUTICAL DOSAGE FORM FOR THE TREATMENT OF GASTRIC ACID-RELATED DISORDERS

This invention relates to new pharmaceutical dosage forms that are useful in the delivery of drugs for the treatment of gastrointestinal disorders.

Gastric acid secretion-related conditions, such as dyspepsia, are common. For example, in the US, around 25% of the adult population experiences heartburn at least weekly. The symptoms of such conditions occur acutely and are at best uncomfortable and at worst extremely painful.

Dyspepsia is a multi-factorial disease and may be associated with organic pathology such as duodenal ulcer, gastric ulcer, esophagitis, Barrett's esophagus or gastro-duodenal inflammation (e.g. Helicobacter pylori infection). Dyspepsia also includes conditions where no organic pathology can be found, e.g. non-ulcer dyspepsia (NUD) or functional dyspepsia.

Gastro-esophagea) reflux disease (GERD) is a related chronic (but often intermittent) disorder typified by abnormal reflux in the esophagus. The disease is characterised by transient or permanent changes in the barrier between the esophagus and the stomach and can arise from a weakening or relaxation of the lower esophageal sphincter, impaired expulsion of gastric reflux from the esophagus or a hiatus hernia. Common symptoms of GERD include heartburn, regurgitation, dysphagia, upper abdominal pain and/or discomfort, excessive salivation and nausea.

It is important that patients obtain immediate relief from such symptoms and for that relief to be sustained for as long as those symptoms continue. Thus, there is a clear unmet clinical need for a rapidly acting, potent and sustained acid- reducing medicament for the symptomatic treatment of gastric acid secretion- related conditions, such as dyspepsia and GERD.

International patent applications WO 02/083132 and WO 2004/035090 disclose the simultaneous co-administration of two classes of anti-secretory agents, proton pump inhibitors (hereinafter "PPIs") and H2 receptor antagonists (hereinafter "H2RAs"), in the treatment of gastric acid related disorders, such as dyspepsia and GERD.

Simultaneous concomitant therapy, and/or combined dosage forms, comprising these two classes of active ingredients were previously considered counterintuitive in view of the respective mechanisms of actions of the drugs. In particular, as a PPI's effectiveness was considered to depend upon the degree of activation of acid secretion at the time of drug administration, co-administration with other anti-secretory drugs, such as H2RAs, was never considered appropriate. See, for example, Soil "Peptic Ulcer and Its Complications" in Schlesinger and Fordtran's Gastrointestinal and Liver Disease (Pathophysiology/Diagnosis/Management), 6^th Edition (1998) and Wolfe and Sachs "Acid Suppression: Optimizing Therapy for Gastroduodenal Ulcer Healing, Gastroesophageal Reflux Disease, and Stress-Related Erosive Syndrome" Gastroenterology (2000) 118, S9-S31), both of which strongly advise against simultaneous co-administration of PPIs and H2RAs.

PPIs are acid labile and therefore typically require protection from the acid environment in the stomach. This is often achieved by way of an enteric coating material.

In the formulation of drug compositions comprising H2RAs and enterically coated PPIs, we have found that the H2RAs may interact with commonly employed enteric coating materials and that, accordingly, it is necessary to employ a barrier between one component comprising PPI and enteric substance, and another comprising H2RA.

According to a first aspect of the invention there is provided a single unit oral dosage form comprising:

(a) a first component comprising a pharmacologically effective amount of a PPI or a pharmaceutically acceptable salt thereof and an enteric substance positioned to protect the PPI or salt thereof from the acidic environment of the stomach;

(b) a second component comprising a pharmacologically effective amount of an H2RA or a pharmaceutically acceptable salt thereof; and (c) a physical and/or chemical barrier located between the first and second components, and preventing said components from interacting with each other. The dosage forms are referred to hereinafter as "the dosage forms of the invention".

Dosage forms of the invention find particular utility in the field of combination therapies for use in the inhibition of gastric acid secretion. See for example international patent applications WO 02/083132 and WO 2004/035090. As described in those documents, it has been surprisingly found:

(i) firstly, that H2RAs do not compromise the onset of action of acid- susceptible PPIs; and

(ii) secondly, that PPI formulated for delayed and/or extended release may maintain a maximal acid suppression after the first dose and maintain a maximal acid suppression during the course of treatment. (See also Fandriks et al, Scandinavian Journal of Gasteroenterology (2007) 42, 689.) Prior to the publication of WO 2004/035090 in particular, it was not known that it. might be possible to achieve maximal inhibition of acid secretion with an initial PPI dose. However, the latter document describes how expanding the time over which PPI is released in the intestine unexpectedly results in almost complete inhibition of acid secretion as a result of the first dose of PPI. A sustained inhibition of acid secretion may be achieved whilst parietal cells are put into a non-secretory state by means of the rapidly released H2RA.

The present invention is thus especially suitable for "on demand" treatment of gastroesophageal reflux complaints e.g. heartburn, where potent acid reduction is needed for a reasonably short period of time, that is where a rapid onset of action is important, and maximal acid reduction is preferred. We have found that the maximal acid inhibitory effect may be maintained over a 7 day period in contrast to the "fade-off' phenomenon seen when H2RA is given alone. This is of importance as this aspect of the invention enables a reduction in the time for the treatment of stomach ulcers, acid-related lesions in the esophagus and Helicobacter pylori eradication.

The term "PPI" will be understood by those skilled in the art to include any compound that is capable of inhibiting gastric H+,K+-ATPase to a measurable degree. Gastric H+,K+-ATPase is the proton-transporting enzyme involved in the production of hydrochloric acid in the stomach. The action of gastric H+.K+- ATPase represents the final step in the sequence of events resulting in secretion of hydrochloric acid by the parietal cell. Thus, inhibition of this enzyme is the most effective and specific means of controlling acid secretion regardless of the nature of the stimulus to secretion. As would be expected with such a mechanism of action, PPIs have been shown to inhibit both basal and stimulated acid secretion. Particular PPIs that may be utilised in dosage forms of the invention include acid- susceptible PPIs. The term "acid-susceptible PPI" will be understood by those skilled in the art to include a PPI that acts as a prodrug, in that it accumulates in the acidic milieu of the secretory membrane of the parietal cell before undergoing a chemical transformation in that acid environment to form an active sulphenamide, which irreversibly binds to H+,K+-ATPase by interacting with sulphydryl groups of the acid pump.

As their name suggests, "acid-susceptibie PPJs" are generally sensitive to acid and therefore need to be administered in a form which protects them from degradation in the stomach, and to ensure that they are passed into the small intestine where they are absorbed. The term will thus be understood to comprise benzimidazole derivatives, such as omeprazole, pantoprazole, lansoprazole, rabeprazole, pariprazole, tenatoprazole, ilaprazole and leminoprazole, as well as enantiomerically enriched versions of the foregoing, such as dexlansoprazole, estenatoprazole and esomeprazole, and pharmaceutically acceptable salts of any of the foregoing, in addition to compounds disclosed in international patent applications WO 97/25066 (see pages 7 to 1 1), WO 90/06925, WO 91/1971 1 , WO 91/19712, WO 94/27988 and WO 95/01977, European patent applications EP 005 129 A1 , EP 174 726 A1 and EP 166 287 A1 , and UK patent application GB 2 163 747, the compounds disclosed generically and specifically in all of which documents are hereby incorporated by reference. Preferred PPIs include esomeprazole, rabeprazole, more preferably dexlansoprazole and particularly lansoprazole or a pharmaceutically acceptable salt thereof. The term "H2RA" will be understood by those skilled in the art to include any compound that is capable of binding to histamine type 2 (H2) receptors, for example those on the surfaces of parietal cells, thereby inhibiting the action of histamine on such receptors and decreasing basal and nocturnal gastric acid secretion, as well as that stimulated by food, insulin and pentagastrin, to a measurable degree.

The term will thus be understood to comprise compounds such as cimetidine, ranitidine, nizatidine, lafutidine, ebrotidine and famotidine, and diastereoisomers and/or enantiomers thereof, and pharmaceutically acceptable salts (e.g. hydrochloride salts) of any of the foregoing. Preferred H2RAs include famotidine or a pharmaceutically acceptable salt thereof.

There are numerous formulation/dosing principles that may be employed in order to prepare dosage forms of the invention and these are described in a non- limiting sense hereinafter.

Pharmaceutically active ingredients) may be presented within dosage forms of the invention in association with commonly employed pharmaceutical additives and/or excipients used in the art for such preparations (vide infra and/or, for example, Pharmaceutical Dosage Forms: Tablets. Volume 1, 2^nd Edition, Lieberman et al (eds.), Marcel Dekker, New York and Basel (1989) p. 354-356 and the documents cited therein). In accordance with the invention, either or both active ingredients may firstly be mixed with appropriate excipients, such as fillers, binders, disintegrants and/or other pharmaceutically acceptable additives known to those skilled in the art.

Fillers may be defined as any inert material that is capable of increasing the mass of a dosage form of the invention, or a component thereof, in order to provide an appropriately handleable dosage form. Suitable fillers therefore include (optionally silicified) microcrystalline cellulose, sugars and sugar alcohols (such as lactose, mannitol, xylitol and/or isomalt), calcium phosphate dihydrate and the like. If present, filler is preferably employed in an amount of between about 5% and about 95% by weight based upon the total weight of the dosage form. A preferred range is from about 20% to about 80% by weight. Binders may be defined as materials that are capable of acting as bond formation enhancers, which may facilitate the compression of a powder mass into coherent compacts. Suitable binders include polyvinylpyrrolidone, gelatin, sodium alginate, cellulose derivatives, such as low substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose gum, (optionally silicified) microcrystalline cellulose, and the like. If present, binder is preferably employed in an amount of between about 2% and about 50% by weight based upon the total weight of the dosage form. A preferred range is from about 5% to about 30% by weight. Preferred binders include cellulose derivatives, such as microcrystalline cellulose, which, as stated above, may also function as a filler, and low substituted hydroxypropyl cellulose.

Disintegrants or disintegrating agents may be defined as materials that are capable of accelerating to a measurable degree the disintegration/dispersion of a dosage form of the invention. This may be achieved, for example, by the material being capable of swelling and/or expanding when placed in contact with aqueous media (particularly bodiiy fluids including those found in the gastrointestinal tract), thus causing at least part of a dosage form to disintegrate when so wetted. Suitable disintegrants include cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose (e.g. Ac-Di-Sol, F C Corp., USA), carboxymethyl starch, natural starch, pre-gelatinised starch, corn starch, potato starch, sodium starch glycolate (Primojel®, DMV International BV, Netherlands), low substituted hydroxypropyl cellulose and the like. If present, disintegrant is preferably employed in an amount of between about 1 % and about 25% by weight based upon the total weight of the dosage form. A preferred range is from about 2% to about 15% by weight.

Active ingredients may be dry mixed, dry granulated and/or or wet granulated along with excipients. Alternatively, melt granulation, thermoplastic pelletising, spray granulation or extrusion/spheronisation may be employed. A preferred technique is dry granulation.

Wet granulation techniques are well known to those skilled in the art and include any technique involving the massing of a mix of dry primary powder particles using a granulating fluid, which fluid comprises a volatile, inert solvent, such as water, ethanol or isopropanol, either alone or in combination, and optionally in the presence of a binder or binding agent. The technique may involve forcing a wet mass through a sieve to produce wet granules which are then dried, preferably to a loss on drying of less than about 3% by weight.

Dry granulation techniques are also well known to those skilled in the art and include any technique in which primary powder particles are aggregated under high pressure, including slugging and roller compaction, for example as described hereinafter.

Melt granulation will be known by those skilled in the art to include any technique in which granules are obtained through the addition of a molten binder, or a solid binder which melts during the process. After granulation, the binder solidifies at room temperature. Thermoplastic pelletising will be known to be similar to melt granulation, but in which plastic properties of the binder are employed. In both processes, the agglomerates (granules) obtained comprise a matrix structure.

Spray granulation will be known by those skilled in the art to include any technique involving the drying of liquids (solutions, suspensions, melts) while simultaneously building up granulates in a fluid bed. The term thus includes processes in which foreign seeds (germs) are provided upon which granulates are built up, as well as those in which inherent seeds (germs) form in the fluid bed due to abrasion and/or fracture, in addition to any spray coating granulation technique generally. The sprayed liquid coats the germs and assists further agglomeration of particles. It is then dried to form granules in the form of a matrix.

Extrusion/spheronisation will be well known to those skilled in the art to include any process involving the dry mixing of ingredients, wet massing along with a binder, extruding, spheronising the extrudate into spheroids of uniform size, and drying. Primary particles of ingredients (e.g. active ingredients and excipients) may be processed by techniques, such as grinding, dry milling, jet milling, wet milling, precipitation, etc, prior to granulation. Granulates may be further processed following formation by mixing with other ingredients (e.g. excipients). For example, a dry granulate may be broken, ground or milled using a suitable milling technique to produce particulate material of a smaller size, which may also be sieved to separate the desired size fraction. Wet granulate may be screened to break up agglomerates of granules and remove fine material. In either case, the unused undersized (fine), and oversized, material may be reworked to avoid waste. Suitable average granulate particle sizes are in the range of about 0.02 mm to about 3 mm, such as about 0.03 mm to about 1 mm. Particle sizes are expressed herein as weight based mean diameters. The term "weight based mean diameter" will be understood by the skilled person to include that the average particle size is characterised and defined from a particle size distribution by weight, i.e. a distribution where the existing fraction (relative amount) in each size class is defined as the weight fraction, as obtained e.g. by sieving.

PPI in the form of a powder may alternatively be mixed with excipients as described above and processed into small pellets and/or granules, for example by compression and/or by extrusion/spheronisation. Alternatively, pellets and/or granules comprising PPI (and optional excipients) may be blended with further excipients and thereafter compacted into one or more cores. Mixtures/granules may be compressed/compacted using techniques such as those described in, for example, Pharmaceutical Dosage Forms: Tablets, Volume 1 , 2^nd Edition, Lieberman et al (eds.), Marcel Dekker, New York and Basel (1989) p. 354-356 and the documents cited therein. Suitable compacting equipment includes standard tabletting machines, such as the Kilian SP300 or the Korsch E 0. In order to assist in the compaction process, the first component may further comprise one or mote lubricants or glidants (such as stearic acid, sodium stearyl fumarate, anhydrous colloidal silica, talc or, preferably, magnesium stearate). When a lubricant is employed it should be used in very small amounts (e.g. up to about 3%, and preferably up to 2%, by weight based upon the total weight of the first component).

In the context of the present invention, the "enteric" substance is employed and arranged in a dosage form of the invention such that it is capable of substantially preventing the PPI or salt thereof within that dosage form from being released, and/or coming into contact with gastric juices, until the dosage form reaches the small intestine. By "substantially preventing" we include that no more than about 20%, such as about 15%, for example about 10%, or more particularly no more than about 5%, of PPl/salt is released within the acid environment of the stomach.

Typical enteric coating materials include the following: cellulose acetate, cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate tetrahydrophthalate, polyvinyl acetate phthalate, hydroxyethyl ethyl cellulose phthalate, methacrylic acid copolymers, polymethacrylic acid/acrylic acid copolymers, styrol maleic acid copolymers, hydroxypropyl methyl cellulose phthalate, acrylic resins, cellulose acetate trimellitaie, hydroxypropyl methylcellulose trimellitate, shellac, hydroxyethyl ethyl cellulose phthalate, carboxymethylcellulose and hydroxypropyl methyl cellulose acetate succinate. Preferred enteric substances include methacrylic acid copolymers.

Although it is not excluded that the enteric substance is included within (e.g. admixed with) the PPI and other excipients (as present) to form the first component of a dosage form of the invention in the form of a matrix, we prefer that the enteric substance is presented as a discrete coating on the exterior of at least one core comprising PPI or salt thereof.

In this respect, in the first component of a dosage form of the invention, PPl/salt thereof may be presented as a powder, or compacted either in pelletised form, i.e. as multiple units (pellets or granules) comprising individual cores of PPl/salt thereof, or as a single unitary central core.

Thereafter, PPI salt thereof may be mixed with the enteric substance, or individual pellets/multiple units may be individually coated with, or surrounded by, the enteric substance. Alternatively, PPI or salt thereof may be presented as a central unitary PPI-containing core, mixed together with, or, more preferably, coated with a layer comprising, the enteric substance. The unit(s) comprising PPI/salt thereof may be covered with a separating layer prior to mixing with, or application of, the enteric substance. The separating layer may serve to provide a moisture barrier and/or a barrier to protect acid susceptible PPI/salt from chemical decomposition brought on by the enteric coatings, which may comprise acidic components. Such a barrier may comprise a sugar, a sugar alcohol, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, hydroxymethyl cellulose and/or hydroxypropyl methylcellulose, prior to coating with enteric substance. A preferred material is polyvinyl alcohol (part hydrolysed). The separating layer may by applied using various techniques, but is preferably applied by a spray-coating technique. In this regard a film-forming agent, such as one of those described above is applied by pre-dissolving or pre-dispersing it in a solvent, for example an organic solvent, such as acetone, methanol, ethanoJ, isopropyl alcohol, ethyl acetate and/or methylene chloride or, preferably, an aqueous solvent, such as purified water, followed by spraying, the use of a rotating pan and/or a fluid-bed spray coater. If necessary, pH may be controlled by the polymer or combination of polymers selected and/or ratio of pendant groups in order to control dissolution. Plasticisers, such as triacetin, dibutyl phthalate, polyethylene glycols (e.g. macrogols), triethyl citrate, etc may be included in the spray-coating solution, as well as wetting agents (i.e. surfactants), including polysorbates, sodium lauryl sulphate, lecithin and/or bile acid salts, and glidants and/or lubricants (e.g. talc).

The first component of a dosage form of the invention may also comprise one or more further excipient materials to provide for a delayed and/or, preferably, an extended release of PPI or salt thereof in the intestines.

The term "extended release" is intended to be synonymous with "prolonged release" and/or "sustained release", whereby the rate of release of active ingredient is altered, i.e. at a sufficiently retarded rate to produce a therapeutic response over a required period of time. The term "delayed" release is intended to mean the delay of release of active substance for a pre-determined time within the gastrointestinal tract. A substance that provides for a delayed release does not necessarily also provide for an extended release. The essential enteric substance that is included within a dosage form of the invention provides for enteric release, which is in itself a form of delayed release in that the active substance (PPI) is not released for absorption in the stomach, but rather release is delayed until PPI reaches the small intestine. The excipient that provides for a delayed and/or extended release of PPI or salt thereof may be associated with the first component of a dosage form of the invention and may therefore be associated (e.g. admixed) with the enteric substance or may comprise a separate, discrete coating. Further, it may be applied to PPI in the form of a membrane or may be admixed together with the PPI to form a matrix, in the same way as described hereinafter for the enteric substance.

Such materials, which are we}} known to those skiJJed in the art, and may be inert and/or lipid-based. The excipient(s) may therefore comprise non-polymeric or polymeric materials, such as calcium phosphate, ethyl cellulose, methyl cellulose, methacrylate copolymer, hydroxypropyl methylcellulose (hypromellose) polyamide, polyethylene, polyvinyl alcohol or polyvinyl acetate. Lipid-based excipient(s) may comprise non-polymeric or polymeric materials based on fats, such as carnauba wax, cetyl alcohol, hydrogenated vegetable oils, microcrystalline waxes, mono-, di- and triglycerides, polyethylene glycol or polyethylene glycol monostearate. Hydrophilic, pore-forming excipients, such as alginates, carbopol, gelatin, hydroxypropyl cellulose or hydroxypropyl methylcellulose, may also be added. The enteric substance or enteric substance-containing mixtures, may be applied to the surfaces of the PPI/salt thereof (in the form of a powder, pellets/multiple units or central cores) using techniques that will be well known to those skilled in the art. Enteric substance may thus be applied by way of a processing step that comprises press-coating, which will be understood by the skilled person to involve any technique in which a dry powder is compressed in the substantial absence of solvent (although a lubricant may be employed to assist the compaction process) onto another substance (optionally in the presence of other ingredients) using suitable compacting equipment. Appropriate equipment includes standard tabletting machines, such as the Kilian SP300, the Korsch E 0 or the Manesty DryCota Model 900 core and coating tablet press. See, for example, Clausen et a/, J. Control. Release (2001 ) 75, 93 and Schiermeier and Schmidt, Eur. J. Pharm. Sci. (2002) 15, 295.

However, the enteric substance may also be applied by pre-dissolving or pre- dispersing it in a solvent, followed by spraying, application as a chemical vapour, or the use of a rotating pan or a fluid-bed spray coater, using the same techniques as described hereinbefore. In addition to piasticisers, wetting agents and glidants that may be employed in spray-coating solutions that may be employed to make dosage forms of the invention, such solutions may further comprise buffering agents, such as sodium bicarbonate or other alkaline-reacting substances, including those described below.

An essential feature of the invention is that there is a physical and/or chemical barrier located between the first and second components of the dosage forms of the invention. We have unexpectedly found that placing H2RA in direct contact with the enteric substance that is an essential element of the first component of a dosage form of the invention has a deleterious effect on that substance, drastically reducing its chemical stability and physical integrity. This has been found to have a profound negative effect on both the performance (with PPI not being fully protected from the acid environment in the stomach), and the storage capability, of a corresponding dosage form that does not include such a physical and/or chemical barrier.

A chemical barrier may comprise an acid, such as a fruit acid (e.g. glycolic acid, lactic acid, mandelic acid or, preferably, citric acid). A physical barrier may comprise a sugar, a sugar alcohol, or a polymer substance, such as a polymer coating, which may comprise e.g. polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose or, preferably, polyvinyl alcohol (e.g. part- hydrolyzed polyvinyl alcohol). The physical barrier may be located adjacent to (e.g. on the periphery of and/or surrounding) the first component. The physical barrier may thus be in physical contact with the first component. Such a physical barrier may thus be applied to the first component of the dosage form of the invention as a coating using techniques such as those described hereinbefore.

The second, H2RA-containing, component of a dosage form of the invention is thus presented in a form that is entirely separated by the aforementioned physical and/or chemical barrier from the first component. H2RA is not prevented from being released from the second component of a dosage form of the invention until the latter reaches the small intestine. In this respect, H2RAs may be formulated, optionally along with pharmaceutically acceptabie excipienis that do not affect the rate of release or absorption (such as those described below), in, and/or as part of, a dosage form of the invention, without the need for any kind of delayed and/or extended release component. It is preferred that the H2RA is formulated for rapid release. H2RA may thus be formulated with one or more excipients that provide for rapid release, such as the disintegrants mentioned hereinbefore. The second component may be located adjacent to (e.g. on the periphery of and/or surrounding) the first component. The second component may thus be in physical contact with the physical (and/or chemical) barrier that protects the first component. In this respect, dosage forms of the invention may be provided in the form of an oral, multiple-unit dosage form, in which PPI is provided in the form of a multitude of small units (e.g. pellets) individually or collectively coated with an enteric substance, which may then be combined with a H2RA in the form of a powder or granules. Such a combination may then be packaged and presented for example in a suitable e.g. hard gelatin capsule as a single unit dosage form. In a more preferred embodiment, we have found that H2RA may be advantageously applied as a separate coating, or layer in a bilayer formulation (e.g. tablet).

The second, H2RA-containing component may thus be:

(a) "coated" onto individual, or collective, enteric substance-coated PPI units that are pre-protected with the physical and/or chemical barrier, using an appropriate technique;

(b) mixed together with the enteric substance-coated PPI units pre-protected with the physical and/or chemical barrier, and thereafter compressed into a tablet. In order to achieve this, the mixture may be admixed with lubricant(s), such as sodium stearyl fumarate, magnesium stearate and talc, prior to compression;

(c) added to the enteric substance-coated PPI units pre-protected with the physical and/or chemical barrier, which units have already been compressed as described in (b) above, and then the entire tablet mass finally compressed into a tablet (e.g. a bilayer tablet); or

(d) added to the enteric substance-coated PPI units pre-protected with the physical and/or chemical barrier in the form of a dry mixture, which is then loaded into capsules made from an appropriate material (e.g. hard gelatin) that, once administered, causes its contents to be released immediately into the stomach so that the H2RA can exert its effect.

Multiple unit tableted dosage forms, such as those described under (b) and (c) above, may have the advantage that compressing individual enteric substance- coated units of PPI does not significantly affect the acid resistance of those units, and may provide improved long-term storage properties.

Multiple unit dosage forms (for example those described under (d) above) may also contain effervescent components to make them disintegrate rapidly in an aqueous environment prior to administration either perorally or via a nasogastric tube. The pH of the aqueous environment must be made slightly acidic (e.g. by the addition of citric acid) to prevent dissolution of the enteric substance. Such dosage forms, which may be useful for administration to patients with swallowing disorders and/or in pediatrics, may be provided in a sachet intended for oral administration after dispersion in a slightly acidic aqueous solution. In relation to the preparation of multiple unit dosage forms, reference may be made to the relevant disclosures in international patent application WO 97/25066 (page 13, second to last paragraph, to page 15, end of second paragraph, page 15, second to last paragraph, to page 18, end of second paragraph and page 18, last paragraph, to page 19, end of first paragraph), US patent No. 6,274,173, and "Pharmaceutics. The Science of Dosage Form Design", 1^st edition; Ed. M.E. Aulton, Churchill Livingstone, Edinburgh, 1988 (pages 289-305). H2RA is preferably employed in compositions of the invention in micronised form. Primary particles of H2RA may be micronised by techniques that are well known to those skilled in the art, such as grinding, dry milling, jet milling, wet milling, crushing, cutting, precipitation (e.g. by way of dissolution in a supercritical fluid under pressure, followed by rapid expansion) etc, prior to granulation.

In a preferred embodiment of the invention, however, PPI is firstly formulated in admixture with excipients, such as those described above. This mixture may thereafter be processed as a dry powder or granulated, as described hereinbefore, optionally mixed with further excipients, and then optionally compressed, to form a single tablet core. Compression may be achieved by addition of lubricants as described hereinbefore.

The PPI core is then coated with the enteric substance, using an appropriate coating technique, such as one of those described hereinbefore, to form a first component of a dosage form of the invention.

Optionally, prior to compression and/or application of the enteric substance:

(i) a separating layer may be applied, as described above, to the PPI/salt core; and/or

(ii) PPI/salt thereof be blended with a basic/alkaline-reacting substance e.g. as described herein in order to neutralise the small amounts of protons that may be released from the enteric substance during storage and/or may pass through the enteric substance during passage through the stomach; (iii) a further excipient that provides for a delayed and/or (preferably) extended release may be added to the PPI/salt thereof, as described hereinbefore; and/or

(iv) other excipients(s) that provide for rapid release (e.g. disintegrants, as described in more detail herein).

The resultant first component may thereafter be over-coated with the physical and/or chemical barrier, for example as described hereinbefore. The second component (e.g. a coating surrounding or, in the case of a bilayer tablet, a layer adjacent to the tablet core) comprising H2RA, optionally in admixture with pharmaceutical excipients, such as a disintegrant, may then be applied using techniques such as those described above. The second component is preferably applied to the exterior of the first component over-coated with the physical and/or chemical barrier.

Coating principles such as those described hereinbefore may be employed in order to make such a dosage form of the invention. However, we prefer that a combined preparation comprising a PPI and a H2RA is prepared by a process of spray-coating:

(a) the physical barrier onto the first component; and/or

(b) the second component onto the physical barrier.

Dosage forms of the invention may, if necessary, finally be coated with an appropriate material in order to obtain a smooth surface. Such a coating layer may comprise additives such as anti-tacking agents, colourants, pigments or other additives. The fraction of the first component of a dosage form of the invention preferably constitutes less than 90% by weight of the total weight of the dosage form, whether in the form of a tablet or otherwise.

Dosage forms of the invention may further comprise, or be co-administered with, a gastric acid-suppressing agent and/or an alginate. If employed in the dosage form 100 mg to 1000 mg of antacid agent and/or alginate may be added. The antacid agent may comprise aluminum hydroxide, calcium carbonate, magnesium carbonate, basic magnesium carbonate, magnesium hydroxide, magnesium oxide and sodium hydrogen carbonate.

Dosage forms of the invention may also comprise further additives and/or excipients, such as:

(a) flavourings (e.g. lemon, menthol or peppermint powder), sweeteners (e.g. neohesperidin, sucralose or acesulfame potassium) and dyestuffs;

(b) surfactants;

(c) antioxidants; and/or

(d) other ingredients, such as preservatives and buffering agents.

Suitable final formulation (e.g. tablet/capsule) weights are in the range about 10 mg to about 2 g, such as about 50 mg to about 600 mg. Suitable final tablet diameters are in the range about 3 mm to about 20 mm, such as about 5 mm to about 12 mm.

PPIs and H2RAs are employed in pharmacologically effective amounts in dosage forms of the invention. Typically, the first component of a dosage form of the invention comprises a pharmacologically effective amount of a PPI or a pharmaceutically acceptable salt thereof and the second component of a dosage form of the invention comprises a pharmacologically effective amount of an H2RA or a pharmaceutically acceptable salt thereof. The term "pharmacologically effective amount" refers to an amount of active ingredient, which is capable of conferring the desired therapeutic effect on a treated patient, depending upon the drug that is employed, whether administered alone or in combination with another active ingredient. Such an effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of, or feels, an effect).

Thus, amounts of PPI and/or H2RA that may be employed in dosage forms of the invention may be determined routinely by the physician or the skilled person, in relation to what will be most suitable for an individual patient. This is likely to vary with the mode of administration, the nature and severity of the condition that is to be treated, as well as the age, weight, sex, renal function, hepatic function and response of the particular patient to be treated. However, it is preferred that an H2RA is provided in a dosage form of the invention in an amount that is effective to reduce acidity in the stomach after administration. It is further preferred that an (acid-susceptible) PPI is provided in such a dosage form of the invention in an amount that is effective to sustain the reduced acidity effected by the H2RA over an extended period of time. In this respect, it is preferred that the respective amounts are those which are capable of raising gastric pH to a value of above about 3 (preferably above about 4) within about 2 hours of administration, in addition to maintaining this pH level for at least about 4 hours, preferably for at least about 8 hours, more preferably for at least about 16 hours.

Thus, the H2RA may be provided in an amount which is capable of providing at least about 80% (e.g. about 95%) of maximal reduction of the acidity in the stomach within about 2 hours. The term "maximal reduction" will be understood by the skilled person to include the reduction of acidity that can be obtained as a maximum when an equivalent H2RA is administered alone in an equivalent dose in a therapeutically acceptable amount (i.e. an amounts that are accepted dosages in the prior art). Thus, a dosage form of the invention may comprise between about 1 mg and about 800 mg of H2RA or salt thereof, more preferably between about 5 mg and about 400 mg. Preferred dosages for cimetidine are between about 250 mg and about 900 mg; preferred dosages for ranitidine are between about 100 mg and about 400 mg; preferred dosages for famotidine are between about 5 mg and about 50 mg; and preferred dosages for nizatidine are between about 50 mg and about 400 mg.

Accordingly, the PPI may be provided in an amount which is capable of maintaining the low acidity effected by the H2RA over at least about 6 hours. Thus, a dosage form of the invention may comprise between about 1 mg and about 100 mg, more preferably between about 5 mg and about 75 mg, per single dose of PPI or salt thereof. Preferred dosages for omeprazole and tenatoprazole are between about 5 mg and about 30 mg; preferred dosages for lansoprazole are between about 10 mg and about 40 mg; preferred dosages for pantoprazole are between about 20 mg and about 50 mg; and preferred dosages for esomeprazofe are between about 10 mg and about 50 mg; and preferred dosages for dexlansoprazole are between about 20 mg and about 70 mg. Dosage forms of the invention are preferably administered by way of a dosing regimen that is capable of maintaining gastric pH above about 3 (e.g. about 4, such as about 5) for at least about 95% of the time, from about 2 hours after administration of the first dose until about 6 hours after the administration of the last dose. Particularly preferred dosing regimens include those in which the dosing period is at least about 1 day (e.g. use on an "as required" basis), e.g. at least about 1 week, preferably about 2 weeks, such as about 4 weeks. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

Dosage forms of the invention may be administered once or several times a day, for example perorally by way of appropriate dosing means known to the skilled person. In this respect, the dosage forms of the invention may be incorporated into various kinds of pharmaceutical preparations intended for oral administration using standard techniques (see, for example, Lachman et al, ''The Theory and Practice of Industrial Pharmacy", Lea & Febiger, 3^rd edition (1986) and "Remington: The Science and Practice of Pharmacy", Gennaro (ed.), Philadelphia College of Pharmacy & Sciences, 19^th edition (1995)).

Wherever the word "about" is employed herein in the context of dimensions (e.g. sizes, weights, pH values, time intervals, etc.), amounts (e.g. relative amounts of individual constituents in a dosage form or a component of a dosage form, absolute doses of active ingredient, degrees of release of active ingredients, reductions in gastric acidity and other percentages), it will be appreciated that such variables are approximate and as such may vary by ± 10%, for example ± 5% and preferably ± 2% (e.g. ± 1%) from the numbers specified herein.

Dosage forms of the invention may be employed to provide both rapid onset of inhibition of gastric acid secretion, followed by maintenance of such inhibition as long as desired (for example by repeated administration of PPI preferably in the form of a dosage form of the invention). Thus, dosage forms of the invention are useful in the (e.g. symptomatic) treatment of dyspepsia and other gastrointestinal disorders related to the production of gastric acid, such as dyspepsia, GERD, etc.

Dosage forms of the invention may also be useful in a treatment program designed for the healing of gastric and duodenal ulcers, and esophagitis, for which the maintenance of intragastric pH above 4 for a maximal duration should be attained (see Huang J Q and Hunt R H, pH, Healing Rate and Symptom Relief in Patients with GERD, Yale J Biol Med 1999, 72:181-94). Dosage forms of the invention may also be used, in association with one or more antibiotic agent(s), for the eradication of Helicobacter pylori.

According to a further aspect of the invention, there is provided a method of treatment of a disorder associated with gastric acid secretion, such as dyspepsia, GERD, gastric ulcers, duodenal ulcers, oesophagitis, Barrett's oesophagus, oesophageal adenoma, gastric cancer and the like, which method comprises administration of a dosage form of the invention to a patient in need of such treatment. Dosage forms of the inventions are particularly useful in the treatment (such as the "on demand" treatment) of GERD, and in particular treatment of the symptoms thereof, including heartburn, regurgitation, indigestion, dysphagia, upper abdominal pain and/or discomfort, excessive salivation, sour stomach and nausea.

For the avoidance of doubt, by "treatment" we include the therapeutic treatment, as well as the symptomatic treatment, the prophylaxis, or the diagnosis, of a condition. The dosage forms of the invention are easy and inexpensive to manufacture, and enable the rapid and sustained relief of the symptoms described hereinbefore.

Dosage forms of the invention comprising micronised H2RA in combination with one or more disintegrants may exhibit a rapid rate of dissolution of H2RA at high pHs. Firstly, this means that such dosage forms of invention may exhibit a rapid dissolution of H2RA that is independent of pH. Rapid dissolution (and therefore availability for absorption) may therefore take place over a wider region of the gastrointestinal tract (e.g. both the stomach and in the smaller intestine). Secondly, this means that such dosage forms of invention may exhibit a rapid dissolution of H2RA that is not compromised in patients exhibiting high pH values in the stomach, for example because they are receiving gastric acid suppression therapy (and particularly a more effective therapy such as one comprising a combination of H2RA and PPI, as described hereinbefore). Dosage forms of the invention may also have the advantage that they may be prepared using established pharmaceutical processing methods and employ materials that are approved for use in foods or pharmaceuticals or of like regulatory status. Dosage forms of the invention may aiso have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile than, and/or have other useful pharmacological, physical, or chemical properties over, pharmaceutical dosage forms known in the prior art, whether for use in the treatment of gastrointestinal disorders related to the production of gastric acid (e.g. dyspepsia and GERD), the eradication of Helicobacter pylori, or otherwise.

The invention is illustrated by way of the following example, in which Figures 1 to 3 show pH profiles (y-axis) over several days (hours represented on x-axis) as a consequence of concomitant co-administration of H2RA and PPIs (omeprazole, esomeprazole and lansoprazole, respectively).

Example 1

A Spray-Coated Tablet Comprising Lansoprazole and Famotidine

A tablet core was prepared as follows.

Lansoprazole (15 mg; Hetero Drugs Ltd., India), magnesium carbonate (3 mg; Merck KGaA, Germany), isomalt (26 mg; BENEO-Palatinit GmbH, Germany), croscarmellose sodium (3 mg; F C Biolpolymer, Ireland) and microcrystalline cellulose (3 mg; FMC Biopolymer, Ireland) were dry mixed together for 20 minutes in a low intensive tumbling mixer (Sewin, Sweden). The resultant mixture was then dry granulated by roller compaction and sieving in a dry granulator (W120 Pharma, Alexanderwerk GmbH, Germany) using roller speed of 7 rpm, roller pressure of 7 kN/cm, wafer thickness of 2 mm, screen mill impeller speed 50 rpm and pore sizes of primary and secondary screens of 2 mm and 0.63 mm respectively.

The resultant granulate was then dry mixed with the following additional excipients: magnesium carbonate (2 mg; Merck KGaA, Germany), microcrystalline cellulose (44 mg; FMC Biopolymer, Ireland), croscarmellose sodium (3 mg; FMC Biopolymer, Ireland), anhydrous colloidal silica (0.5 mg; EVONIK Degussa GmbH, Germany) and magnesium stearate (0.5 mg; Peter Greven, the Netherlands). (Anhydrous colloidal silica and magnesium stearate were sieved whilst being added to the powder blend.)

The resultant mixture was then subjected to compaction on a rotary tablet press (XL100, Korsch AG, Germany), with round 6.5 mm diameter punches, which were convex with a 5.6 mm radius.

The tablet core was then spray coated with five coatings in the order described below for a total amount of active spray time of approx. 8.5 hours to give a coating in the amounts indicated below. Coating liquids were prepared by dispersing the various agents into purified water with stirring in an amount between 10 % and 20 % w/w, depending on coating layer. All coating liquids are stirred continuously during the process to avoid sedimentation. 1. A sub-coat comprising Opadry II clear (3 mg; Colorcon Inc.; West Point, PA; comprises part-hydrolyzed polyvinyl alcohol).

2. An enteric coating with Acryl-EZE clear (15 mg; Colorcon Inc.; comprises methacrylic copolymer type C). This was sieved before use to remove lumps. 3. An over-coat comprising Opadry II clear (3 mg). This provides a physical barrier separating the famotidine-containing layer from the enteric coating.

4. A coating made by mixing Opadry II clear with famotidine (5 % w/w in coating liquid, Gedeon Richter PLC, Hungary) to provide a layer with 10 mg of famotidine and 20 mg of Opadry II clear.

5. A final top coating comprising Opadry II clear (1 mg).

Clinical Data

In support of the efficacy of the claimed invention, reference is made to Fandriks et al, Scandinavian Journal of Gasteroenterology (2007) 42, 689-694, the clinical protocols and data presented in which are hereby incorporated by reference, which demonstrate, in the clinical setting, that famotidine (H2RA) and omeprazole (PPI) may be co-administered, and actually provide an additive benefit in the early days of treatment. The data compare the control arms omeprazole alone; famotidine alone; and coadministration of omeprazole and famotidine. The data show for Day 1 (i) omeprazole alone controlled stomach acid pH >4 for 27% of the day, (ii) famotidine alone controlled stomach acid pH >4 for 54% of the day; and (iii) the co-administration of omeprazole and famotidine controlled the stomach acid pH >4 for 67% of the day.

A surprising effect is therefore observed on Day 1 , given the traditional view that an adverse effect would be observed due to the co-administration, because of the contemporaneous co-administration of a PPI and an H2RA.

On Day 8, when the steady state for the omeprazole had been reached, the percentage of time that omeprazole alone was controlling stomach acid was 78% of the day (which is in keeping with the pharmacological profile of a PPI); famotidine alone was controlling stomach acid for 48% of the day, which is similar to the 54% on Day 1, but showing evidence of physiological tolerance (also in keeping with the pharmacological profile of a H2RA). The co-administration of PPI and H2RA was controlling stomach acid for 78% of the day, showing none of the expected diminished PPI activity compared to Day 1.

According to the prior conventional wisdom, on Day 1 and Day 8 the control percentages for the co-administered dose would be expected to be lower than the individual doses. At the very least, the co-administered dose would be expected to be lower on Day 8 compared to the omeprazole alone, because the effectivness of omeprazole would be expected to be inhibited by the presence of H2RA.

Subsequent studies have demonstrated that the co-administration of other PPIs with famotidine provide similar surprising results. Studies of the PPI esomeprazole co-administered with famotidine and of the PPI lansoprazole coadministered with famotidine, each pair being administrated simultaneously or concomitantly on a once daily basis for eight days, demonstrate that the coadministration of these PPIs with an H2RA simultaneously or concomitantly gives an early and clinically important intragastric pH increase within two hours after coadministration of the first dose, and that the acid-suppressive effect is maintained throughout the eight days treatment period. The results are shown in Figures 1 to 3, respectively.

Claims

1. A single unit oral dosage form comprising:

(a) a first component comprising a pharmacologically effective amount of a proton pump inhibitor or a pharmaceutically acceptable salt thereof and an enteric substance positioned to protect the proton pump inhibitor or salt thereof from the acidic environment of the stomach;

(b) a second component comprising a pharmacologically effective amount of an H2 receptor antagonist or a pharmaceutically acceptable salt thereof; and

(c) a physical and/or chemical barrier located between the first and second components, and preventing said components from interacting with each other.

2. A dosage form as claimed in Claim 1 , wherein the barrier is a physical barrier which prevents the first and second components from being in contact with each other physically.

3. A dosage form as claimed in Claim 1 or Claim 2, wherein the barrier comprises a polymer.

4. A dosage form as claimed in Claim 3, wherein the polymer comprises polyvinyl alcohol.

5. A dosage form as claimed in any one of the preceding claims, wherein the second component surrounds, or is located adjacent to, the barrier.

6. A dosage form as claimed in any one the preceding claims, wherein the second component and the barrier physically contact each other.

7. A dosage form as claimed in any one of the preceding claims, wherein the barrier surrounds, or is located adjacent to, the first component.

8. A dosage form as claimed in any one of the preceding claims, wherein the barrier and the first component physically contact each other.

9. A dosage form as claimed in any one of the preceding claims, wherein the first component comprises at least one core containing proton pump inhibitor or salt thereof and the enteric substance is in the form of a coating surrounding said core.

10. A dosage form as claimed in Claim 9, wherein the barrier is in the form of a coating surrounding the first component.

1 1. A. dosage form as claimed in Claim 10, wherein the second component is in the form of a coating surrounding the barrier.

12. A dosage form as claimed in any one of the preceding claims, wherein the proton pump inhibitor is omeprazole, pantoprazole, lanzoprazole, rabeprazole, pariprazole, tenatoprazole, ilaprazole or leminoprazole, or an enantiomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

13. A dosage form as claimed in Claim 12, wherein the enantiomer is estenatoprazole, dexlansoprazole or esomeprazole, or a pharmaceutically acceptable salt thereof.

14. A dosage form as claimed in Claim 12, wherein the proton pump inhibitor is lansoprazole or a pharmaceutically acceptable salt thereof.

15. A dosage form as claimed in any one of the preceding claims, wherein the H2 receptor antagonist is cimetidine, ranitidine, nizatidine, lafutidine, ebrotidine or famotidine, or a diastereoisomer or an enantiomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

16. A dosage form as claimed in Claim 15, wherein the H2 receptor antagonist is famotidine or a pharmaceutically acceptable salt thereof.

17. A dosage form as claimed in any one of the preceding claims, wherein the second component is formulated for rapid release of the H2 receptor antagonist.

18. A dosage form as defined in any one of the preceding claims for use in the treatment of gastric acid secretion.

19. The use of a dosage form as defined in any one of Claims 1 to 17 for the manufacture of a medicament for the treatment of gastric acid secretion.

20. A method of treatment of gastric acid secretion, which method comprises administration of a dosage form as defined in any one of Claims 1 to 17 to a patient in need of such treatment.

21. A dosage form as claimed in Claim 18, a use as claimed in Claim 19, or a method as claimed in Claim 20, wherein the treatment is of gastro-esophageal reflux disease.

22. A process for the preparation of a dosage form as defined in any one of Claims 1 to 17, which comprises applying the physical barrier to the first component followed by applying the second component to the physical barrier.

23. A process as claimed in Claim 22 wherein the physical barrier is spray- coated onto the first component.

24. A process as claimed in Claim 22 or Claim 23 wherein the second component is spray coated onto the physical barrier.