AU776079B2 - New pharmaceutical formulation - Google Patents

Description

WO 00/35448 PCT/SE99/02315 NEW PHARMACEUTICAL FORMULATION Field of the invention S This invention is related to new oral pharmaceutical dosage forms comprising a H K ATPase inhibitor, a gastric antisecretory prostaglandin analogue compound, and optionally an additional drug such as a calcium channel blocking agent, especially for use in the treatment and prophylaxis of gastrointestinal disorders. More specifically the invention is related to new dosage forms comprising omeprazole and misoprostol. The invention is also to related to a combination of the three categories of drugs, i.e. the H K -ATPase inhibitor, the gastric antisecretory prostaglandin analogue and the calcium channel blocking agent.

Furthermore, the invention refers to a method for the manufacture of the described dosage forms and their use in medicine, as well as blisterpacks comprising these medicaments.

Background of the invention and prior art H K -ATPase inhibitors, such as the the proton pump inhibitors known under the generic names omeprazole, lansoprazole, pantoprazole, rabeprazole and leminoprazole are for instance described in EP 5129, EP 174 726, EP 166 287, GB 2 163 747 and WO 90/06925.

The expression H K -ATPase inhibitors and proton pump inhibitors are interchangable with each other within the context of the present application. Proton pump inhibitors are generally known to be useful for inhibiting gastric acid secretion in mammals and man by controlling gastric acid secretion in the final step of the secretory pathway. They heal gastric as well as duodenal ulcers in patients on continuous treatment with Non-steroidal anti-inflammatory drugs (NSAID) as in non-NSAID users. WO 96/01735 describes new fixed dosage forms comprising a proton pump inhibitor and an NSAID and their use in the treatment or prevention of gastrointestinal side-effects associated with NSAID treatment.

Prostaglandin analogue compounds, such as the ones known under the generic names misoprostol, enoprostil, enisoprost, rosaprostol and miraprostal are orally active PGEI WO 00/35448 PCT/SE99/02315 2 analogues with mucosal protective and antisecretory properties, and these type of compounds are for instance described in US 3,965,143 and US 4,178,457. They are mainly used for prevention of gastric and duodenal ulcers associated with NSAID treatment.

Usually they are administered in separate, single unit dosage form, and sometimes in Scombination with an NSAID in a fixed dosage form.

For gastric antisecretory prostaglandin analogues there are adverse drug reactions reported.

The use of misoprostol for instance, may cause diarrhoea, abdominal pain and other adverse effects connected to the gastrointestinal system. Dosage regimen for misoprostol to includes frequently intake of a dosage form, sometimes up to 4 times a day. This frequent intake, in addition to the undesired gastrointestinal side-effects with gastric antisecretory prostaglandin analogues implicates problems with compliance. On the other hand, the proton pump inhibitor, omeprazole, has only few dosage related adverse effects.

A combination of two or more active agents achieving similar physiological effect, but working through different mechanisms, usually gives a possibility to reduce the doses of each single drug and still achieve the desired effect. This will reduce the risk for dose dependent adverse side-effects. Furthermore, if one of the drugs fails due to individual patient response, the other component of the treatment regimen may be successful.

These factors implicates advantages of combining two or more antiulcerative drug in general, and to combine misoprostol with other antiulcerative drugs in particular.

Administration of two or even more different dosage forms to the patient is not convenient or satisfactory for achieving the most optimal result. As patient compliance is a major factor in receiving a good medical result, it would be advantageous to combine the different drugs into one single pharmaceutical dosage unit, which reduces the number of pills for the patient at each dosing occasion. If one or more of the drugs can be provided in dosage forms with extended release the efficacy may be further enhanced.

WO 00/35448 PCT/SE99/02315 Previously suggested combination therapies comprising antiulcerative agents are for instance combinations of a histamine H 2 receptor antagonist, such as cimetidine or ranitidine, and sucralfate. Other proposed therapies are for instance a combination of omeprazole and sucralfate, a combination of ranitidine and cimetidine, or a combination of S ranitidine and misoprostol. See for instance Van Deventer GM et al., Am J Med 1985; 79: 39 44, and Houston LJ et al, Am J Gastroenterol 1993; 88: 675 679.

A combination therapy of misoprostol and a calcium channel blocking agent, such as verapamil, has been proposed and tested with respect to mucosal-protective effects in rats 0o by reducing leukotriene synthesis and increasing prostaglandin synthesis. See Fedorak, R.N. et al, Gastroenterology 1992;102: 1229-35.

To combine the proton pump inhibitor omeprazole and the gastric antisecretory prostaglandin analogue enprostil for the treatment of gastrointestinal disorders is known from Tari, A. et al, Digestive Diseases and Sciences, 1997; 42: 1741-1746 and from Meijer, J.L. et al, Digestive Diseases and Sciences, 1994; 39: 609-616.

However, a fixed unit dosage form comprising a H K -ATPase inhibitor in combination with a gastric antisecretory prostaglandin analogue has so far not been suggested.

Furthermore, there is no suggestion or description in the prior art of a combination comprising a H K -ATPase inhibitor, a gastric antisecretory prostaglandin analogue and a calcium channel blocking agent. Neither is the Applicant aware of any oral pharmaceutical dosage forms comprising such a combination, especially not in the form of a blister pack or a fixed unit dosage form.

Summary of the invention WO 00/35448 PCT/SE99/02315 4 One aspect of the present invention is to provide a fixed unit dosage form for oral administration comprising a H K -ATPase inhibitor and a gastric antisecretory prostaglandin analogue.

SA further aspect of the invention is to provide dosage forms of aH K -ATPase inhibitor and a gastric antisecretory prostaglandin analogue, wherein the latter is in a form which provides extended release, such a dosage form reduces dosing frequency and dose related adverse side-effects.

o0 An additional aspect of the invention is to provide a combination therapy of aH K ATPase inhibitor, a gastric antisecretory prostaglandin analogue, and a component which potentiates the effect of the prostaglandin analogue, e.g. a calcium channel blocking agent.

The combination may be provided in the form of fixed unit dosage forms.

1i Detailed description of the invention According to the present invention, a fixed dosage form comprising a H K -ATPase inhibitor, a gastric antisecretory prostaglandin analogue compound, and optionally a calcium channel blocking agent, may principally be constructed in the form of a two-layer tablet, or a tablet core layered with a coating layer, or a press-coated tablet, wherein the different drugs are situated in different parts of the tablet. Alternatively, the dosage form may be a tablet or a capsule comprising either two or three populations of units each one containing one of the drugs, or a population of multiple layered units comprising a combination of the different drugs, or they may be constructed as a capsule containing one or two of the drugs as a population of units and the other drug as a single unit also positioned within the same capsule.

Preferred types of dosage forms according to the invention are described more in detail below under separate headings, and in the following examples.

WO 00/35448 PCT/SE99/02315 Two-layer tablet One layer comprises the proton puimp inhibitor as a multitude of enteric coated pellets dispersed in pharmaceutically acceptable excipients. These pellets may have the characteristics of immediate release, delayed pulsed release, delayed dual pulsed release, delayed multiple pulsed release or extended release, or any combination thereof. If the proton pump inhibitor is to be constructed as an extended release part layer, it may be designed in the form of a hydrophilic matrix layer comprising the proton pump inhibitor.

In this latter situation appropriate measures for protecting the proton pump inhibitor from contact with acidic fluids has to be taken.

The other layer comprises a gastric antisecretory prostaglandin analogue, and optionally a calcium channel blocking agent. This layer may be formulated to provide immediate or extended release of the drug(s). The extended release characteristics may be achieved by using membrane coated extended release pellets dispersed in pharmaceutically acceptable excipients or by dispersing the drug in a hydrophilic or hydrophobic matrix with extended release properties. Immediate release characteristics may be achieved by using a conventional tablet granulation procedure, or by incorporating the prostaglandin analogue in fast dissolving pellets, which are dispersed in pharmaceutically acceptable excipients. It is also possible in a first layer to include the proton pump inhibitor pellets together with the pellets comprising the prostaglandin analogue, and optionally in a second layer include a calcium channel blocking agent.

Tablet core comprising one drug layered with a second drug Each tablet comprises a tablet core containing a proton pump inhibitor which tablet core is spray coated with a layer comprising a gastric antisecretory prostaglandin analogue. The tablet cores may be prepared as desciibed below under the heading "Press-coated/coated tablets". The prepared tablets which are enteric coated are further layered with a suspension comprising the prostaglandin analogue. Alternatively, the tablet cores are layered in the same way as described below for pellets preparation. However, a prepared WO 00/35448 PCT/SE99/02315 6 tablet core has a larger size than cores intended for pellets preparation, i.e. preferably the tablet core has a size of 3 12 mm in diameter.

Press-coated/ coated tablets An inner tablet core is prepared by tableting technique according to known art. The tablet core comprises one of the active ingredients, preferably a proton pump inhibitor, optionally in combination with a calcium channel blocking agent. This tablet core is then coated with an enteric coating layer, and optionally a separating layer has been applied before the enteric coating layer. The enteric coating layer protects the acidic susceptible proton pump 0to inhibitor from gastric acid, i.e. it is a layer not dissolving in gastric acid environment but dissolving or disintegrating in the small intestines. A further coating layer comprising the second active ingredient, optionally in combination with a calcium channel blocking agent, is applied on the enteric coating layer by compression. Either the tablet core or the outer layer may give the characteristics of an extended or immediate release preparation.

Tablet or capsule comprising a multitude ofdrug-containing units Such dosage forms my be divided into two principally different categories; e.g. onepopulation of multiple layered units, and (ii) two-populations of units.

One-population of multiple layered units intendedfor tablet or capsule formulations.

The first category comprising one population of equally constructed units or pellets, optionally dispersed in a pharmaceutically acceptable tablet excipient.

Each unit comprises a proton pump inhibitor and a gastric antisecretory prostaglandin analogue as the pharmaceutically active agents. The units contain multiple layers and the different active substances are situated in different layers. The proton pump layer is positioned on the inside of an enteric coating layer, optionally a separating layer may be positioned in between the proton pump layer and the enteric coating layer. The layer comprising a gastric antisecretory prostaglandin analogue, and optionally a calcium WO 00/35448 PCT/SE99/02315 7 channel blocking agent, is positioned exterior to the proton pump layer, but it may be positioned interior or exterior with regard to the enteric coating layer.

The proton pump inhibitor comprising layer may have characteristics of immediate release or extended release, which also is applicable for the layer comprising the gastric antisecretory prostaglandin analogue, though extended release is preferred. The prepared drug containing units may be filled in capsules or mixed with pharmaceutically acceptable tablet excipients and compressed to multiple unit tablets.

(ii) Two-populations of units intended for tablet or capsule formulations.

The second category comprises a mixture of two different populations of within each population equally constructed units or pellets, optionally dispersed in a pharmaceutically acceptable tablet excipients. One population comprises a proton pump inhibitor, and the other population comprises a gastric antisecretory prostaglandin analogue as the s1 pharmaceutically active agent. Optionally, a third population of units comprising a calcium blocking agent is included in the mixture.

These formulations are based on the mixing of a population of units comprising a gastric antisecretory prostaglandin analogue with a population of units comprising a proton pump inhibitor. The mixture is filled in capsules, or further mixed with pharmaceutically acceptable tablet excipients and compressed to a tablet. The tablet excipients may be previously granulated or just admixed to the layered units before the compression to tablets.

Units comprising a gastric antisecretory prostaglandin analogue.

These units may be prepared by prilling, extrusion and spheronization, congealing, direct pelletization in a mixer, melt granulation with suitable polymeric additives, by incorporation in porous carriers, or by layering on a starting seed, or any other suitable techniques known in the art. The units may be formulated with immediate or extended WO 00/35448 PCT/SE99/02315 8 release characteristics. If suitable, an additional coating layer providing extended release may be applied onto the units.

To increase the residence time in the stomach for the units comprising a gastric antisecretory prostaglandin analogue, the gastric antisecretory prostaglandin analogue is included in a hydrophilic matrix together with a suitable concentration of a sodium hydrogen carbonate and formulated to pellets. When the pellets come in contact with the acidic gastric environment they develop small bubbles of carbon dioxide making the density of these pellets to decrease, and the pellets to flow in the stomach.

Units having immediate release characteristics may be prepared by incorporating the active substance in porous amorphous silica particles or by layering the active substance on sugar seeds.

Units comprising a proton pump inhibitor.

These units may be prepared for either immediate release, extended release or delayed pulsed release of the proton pump inhibitor. WO 97/ 02020 describes pellets of pantoprazole coated with extended release membrane which technology is suitable also for other extended release units. Units suitable for immediate release of the proton pump inhibitor are described in EP 502 556 and units especially designed for use in tableted dosage form are described in WO 96/ 01624, hereby incorporated by references.

Capsule comprising two or more drugs in a single unit in combination with multiple units.

The capsule comprises one drug in a single unit, i.e. a tablet, and one or two drugs in the form of two populations of units, or one population of units and one or two single tablets.

Units suitable for a capsule formulation may be prepared as described above, i.e. onepopulation of multiple layered units comprising a proton pump inhibitor and a gastric antisecretory prostaglandin analogue, or (ii) two-populations of units. The capsule may WO 00/35448 PCT/SE99/02315 9 comprise two or three different drugs, i.e. a third population of units comprising a calcium channel blocking agent may be included.

The single unit may comprise any of the drugs, i.e. the proton pump inhibitor, the gastric antisecretory prostaglandin analogue, or optionally the calcium channel blocking agent.

When the single unit comprises the prostaglandin analogue, it may have immediate or extended release characteristics. Immediate release single units are preferably constructed according to principles known in the art. Extended release single units are preferably constructed as hydrophilic matrix units, or as hydrophobic matrix units, or as membrane 0o coated units.

Techniques for application of layers.

The layer can be applied by coating or layering procedures in suitable equipments such as a coating pan, a coating granulator or in a fluidized bed apparatus using water and/or organic solvents for the coating process. As an alternative the layer(s) may be applied by using powder coating or press-coating techniques.

Excipients.

Different pharmaceutically acceptable excipients may be used in combination with the active substances in the claimed dosage forms. Such excipients are for instance binding agents, fillers, pH-buffering substances, pigments and the like.

Separating layer(s).

Suitable materials for the separating layer are pharmaceutically acceptable compounds such as, for instance, sugar, or filmforming compounds as polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium and others, used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-tacking and anti-static agents, such as for instance magnesium stearate, titanium dioxide, talc, pH-buffering substances and other additives may also be WO 00/35448 PCT/SE99/02315 included into the separating layer. The separating layer is composed in such a way that it has properties to be water soluble or disintegrating in water.

Enteric coating layer(s).

s The enteric coating layer material may be dispersed or dissolved in water or dissolved in suitable organic solvents. As enteric coating layer polymers one or more, separately or dissolved in combination, of the following can be used, but are not restricted to; e.g.

methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethylcellulose, shellac or other suitable enteric coating layer polymer(s) known in the art.

Additives such as dispersants, colorants, pigments, additional polymers e.g.

poly(ethylacrylat, methylmethacrylat), anti-tacking and anti-foaming agents may also be is included into the separating layer and/or the enteric coating layer or in an additional tablet coat as described below. Other compounds may be added to increase film thickness and to decrease diffusion of acidic gastric juices into the acid susceptible core material. The enteric coating layer(s) constitutes a thickness of approximately at least 10 p.m, preferably more than 20 pm. The maximum thickness of the applied enteric coating layer(s) is normally only limited by processing conditions.

The enteric coating layers may also contain pharmaceutically acceptable plasticizers to obtain desired mechanical properties. Such plasticizers are for instance, but not restricted to, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, glycerol monoesters, polysorbates or other plasticizers and mixtures thereof. The amount of plasticizer is preferably optimized for each formula, in relation to the selected polymer(s), selected plasticizer(s) and the applied amount of said polymer(s).

Over-coating layer.

Pellets covered with enteric coating layer(s) may further be covered with one or more overcoating layer(s). The over-coating layer(s) can be applied to the enteric coating layered pellets by coating or layering procedures in suitable equipments such as coating pan, WO 00/35448 PCT/SE99/02315 11 coating granulator or in a fluidized bed apparatus using water and/or organic solvents for the coating or layering process. The materials for over-coating layers are chosen among pharmaceutically acceptable compounds such as, for instance sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methyl cellulose, carboxymethylcellulose sodium and others, used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-tacking and anti-static agents, such as for instance magnesium stearate, titanium dioxide, talc and other additives may also be included into the overcoating layer(s). The maximum thickness of the applied over-coating layer(s) is normally o0 only limited by processing conditions.

Hydrophilic matrix.

The active substance, i.e. the drug, is embedded in a hydrophilic polymer optionally together with pharmaceutically acceptable excipients. Suitable hydrophilic polymers are for instance hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylhydroxy ethylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, poloxamer, polyethylene oxides, polyvinylpyrrolidone, polyvinyl alcohols, tragacanth, xanthan and guar gums or any other suitable hydrophilic polymer(s). These polymers can be used alone or in mixtures with each other.

The amount of hydrophilic polymer in the matrix is preferably 15 85 w/w (calculated on the unit weight) of a hydrophilic polymer(s) chosen among the above mentioned.

Especially preferred polymers in the hydrophilic matrix unit are hydroxypropyl methylcellulose or polyethylene oxides.

Excipients preferred in the matrix are fillers which will result in technically good tableting properties, i. e. sodium aluminium silicate, mannitol or calcium phosphate

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(Emcompress A preferred matrix comprises 15 85 w/w (calculated on the unit weight) of a hydrophilic polymer chosen as above, and 80 10 w/w (calculated on the

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unit weight) of sodium aluminium silicate or calcium phosphate (Emcompress WO 00/35448 PCT/SE99/02315 12 Hydrophobic matrix.

The active substance, i.e. the drug, is embedded in a hydrophobic matrix optionally together with pharmaceutically acceptable excipients. The hydrophobic matrix comprises a hydrophobizing agent and/or a hydrophobic polymer. Suitable material for the hydrophobic matrix are for instance a hydrophobizing agents such as cetanol, cetostearyl alcohol, cetyl palmitate, waxes like carnauba wax, paraffin, magnesium stearate, sodium stearyl fumarate, and medium- or long- chain glycerol esters alone or in any mixtures.

Hydrophobic polymers are exemplified by for instance polyvinyl chloride, ethyl cellulose,

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to polyvinyl acetate and acrylic acid copolymers, such as Eudragith RS and RL. The polymers may be used alone or as mixtures. Furthermore, the polymers may be combined with the hydrophobizing agent.

As binders for the hydrophobic matrix may be used either hydrophilic or hydrophobic s1 polymers.

It is important that the matrix comprises at least one component that is soluble in aqueous media such as the intestinal fluids. This component dissolves and leaves a porous network open for passage of dissolving fluids and dissolved drug. This soluble component may for instance be a sugar. It is preferred that the matrix comprises 10 70 w/w (calculated on the unit weight) of a hydrophobizing agent or a hydrophobic polymer and 10-70% w/w of a water soluble component, both described above, or any combinations thereof.

Another preferred matrix comprises as an additive a slightly soluble or less soluble component. As such components may any of the following be added: sodium aluminium silicate, calcium phosphate, aerosil, titanium dioxide, magnesium carbonates, or other neutral or alkaline compounds that are slightly soluble or less soluble, herein with regard to solubility in water. Slightly soluble is defined in compliance with the European Pharmacopea (Edition 3) under the heading "General notices". Such a matrix comprises preferably 10 70 w/w (calculated on the unit weight) of a hydrophobizing agent or a WO 00/35448 PCT/SE99/02315 13 hydrophobic polymer or any combinations thereof, together with preferably 10 70 w/w of a slightly soluble or less soluble component. As such a component is especially preferred sodium aluminium silicate.

The final dissolution profile may sometimes be adjusted by thermal treatment of the hydrophobic matrix unit for a short period, to achieve temperatures at or above the softening temperature of the hydrophobizing agents.

Particles comprising oily material, such as for instance misoprostol.

o0 One way of preparing a free-flowing particle of oily/greasy/sticky material is to incorporate it into inorganic porous particle material, such as for instance ceramic hydroxy apatite or amorphous silica. The ceramic hydroxy apatite has preferably a range particle diameter size between 5 250 jim, more preferably 80 150 pm, a nominal pore diameter between 50 1 000 A, more preferably 500 1 000 A; and a surface area between 40 m- The amorphous silica has preferably a median pore diameter between 50 1 000 A, more preferably 50 200 A; a pore volume of 0.8 1.2 ml/g; and a surface area between 500 600 m2g.

The incorporation of the oily material may be accomplished by known conventional methods, such as dissolve the oil in a suitable solvent and then add the porous particle material and dry the mixture. Alternatively, the oil may be mixed directly with the porous particle material, or the incorporation may be done using phase separation from solution containing particles accomplished by the addition of a non-solvent. The loaded porous particles can be filled into capsules or compressed to tablets.

Preparation of particles comprising oily material in small amot may also be accomplished by conventional methods, such as layering or coating on inert seeds or by extrusion/ spheronization.

WO 00/35448 PCT/SE99/02315 14 Tablet coat Prepared tablets are optionally covered with film forming agent(s) to obtain a smooth surface of the tablet and further enhance the stability of the tablet during packaging and transport. Such a tablet coat comprising a polymeric material may further comprise S additives like anti-tacking agents, colorants and pigments or other additives to obtain a tablet of good appearance. The tablet coat may especially comprise a pigment to protect light sensitive components of the dosage form.

Active ingredients.

I) H K -ATPase inhibitors, i.e. proton pump inhibitors suitable for the claimed therapies and the pharmaceutical formulations according to the present invention are compounds of the general formula I, an alkaline salt thereof, one of the single enantiomers thereof or an alkaline salt of one of the enantiomers 0 O

II

Het,-X-S-Het 2

I

wherein Hetj is R2 R4 R R3 or N 'R Het2 is WO 00/35448 PCT/SE99/02315

A

NS

H

H

-CH-

RIo wherein N in the benzimidazole moiety means that one of the ring carbon atoms substituted by R 6 R9 optionally may be exchanged for a nitrogen atom without any substituents; RI, R2 and R 3 are the same or different and selected from hydrogen, alkyl, alkoxy io optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and phenylalkoxy; R4 and R5 are the same or different and selected from hydrogen, alkyl and arylalkyl; R6' is hydrogen, halogen, trifluoromethyl, alkyl or alkoxy;

R

6

-R

9 are the same or different and selected from hydrogen, alkyl, alkoxy, halogen, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolinyl, trifluoroalkyl, or adjacent groups R 6 R9 form ring structures which may be further substituted; RI0 is hydrogen or forms an alkylene chain together with R3 and WO 00/35448 PCT/SE99/02315 16 R I and R 12 are the same or different and selected from hydrogen, halogen or alkyl.

Examples of specifically interesting compounds according to formula I are

OCH

3 omneprazole

OCH

2

CF

3

CH

3 N

N

H

lansoprazole pantoprazole

OCH

2

CH

2

CH

2

OCH

3

OH

3 N -CH2-S Nj

N

H

pariprazole WO 00/35448 WO 0035448PCT/SE99/02315

CH

3

H

2 C H(C H 3 2 leminoprazole CH

NC

N 0

N

H

OCH

3

H

3 C N CH 3 I 0 N N

CH'

2 -S I OCH 3

H

OCH

3

H

3 C

CH

3 0N N~ NNH--K NN N

H

WO 00/35448 PCT/SE99/02315 18 The compound suitable for the formulations according to the present invention may be 2+ 2+ used in neutral form or in the form of an alkaline salt, such as for instance the Mg Ca 2+ Na or K salts, preferably the Mg salts. The compounds may also be used in the form of one of its single enantiomers or an alkaline salt of the single enantiomer.

Preferred compounds for the oral pharmaceutical preparations according to the present invention are omeprazole, a magnesium salt of omeprazole or a magnesium salt of the enantiomer of omeprazole. Omeprazole and related substances as well as their preparations are described in EP 5129, EP 124 495, WO 95/01977, WO 94/27988 hereby incorporated in a whole by references.

The above compounds are susceptible to degradation/transformation in acidic and neutral media. Generally, the degradation is catalyzed by acidic reacting compounds and the active compounds are stabilized with alkaline reacting compounds. There are different enteric coating layered preparations comprising omeprazole as well as other proton pump inhibitors described in the prior art, see for instance US-A 4,853,230, WO 95/ 01783 and WO 96/ 01624. Especially, the latter describes alternative manufacturing methods for the preparation of enteric coating layered pellets comprising omeprazole and similar compounds. These patents are hereby incorporated in whole by references.

II) Gastric anti-secretory prostaglandin analogues suitable for the claimed therapies and formulations are for instance misoprostol, enprostil, enisoprost, rosaprostol, miraprostal and analogues with the following formulas WO 00/35448 WO 0035448PCT/SE99/023

-~~COOCH

3 misoprostol OOCH3 enprostil 0 If 1 0

OH

0 Ho

OH

enisoprost 0± WO 00/35448 PCT/SE99/02315 0 O -COOCH III) Calcium channel blockers which optionally may be used in combination with a proton pump inhibitor and a gastric antisecretory prostaglandin analogue are for instance the following ones known under the generic names verapamil, felodipin, nifedipin and to nisoldipine.

Use of the preparations The dosage forms according to the present invention, are suitable for oral administration.

s1 The dose will depend on the nature and severity of the disease to be treated. The dose may also vary according to the age, body weight, and response of the individual patient.

Children and patients with liver diseases as well as patients under long term treatment will generally benefit from doses that are somewhat lower than the average. In the treatment of other conditions higher doses than average will be used. The dosage forms may also be used in combinations with other dosage forms comprising for instance a calcium channel blocking agent, an NSAID, or other antiulcerative agents.

The dosage forms according to the invention are especially advantageous for patients experiencing gastrointestinal side-effects caused by gastric antisecretory prostaglandin analogues, when used alone. The new dosage forms are administered one to several times a day, preferably once or twice daily. The typical daily dose of the active substances varies and will depend on various factors such as the individual requirements of the patients, the WO 00/35448 PCT/SE99/02315 21 mode of administration and disease. In general each dosage form will comprise 1-200 mg of the H K -ATPase inhibitor and 80 1 000 ug of the gastric antisecretory prostaglandin analogue(-s). Preferably, each dosage form will comprise 5-80 mg of the H K -ATPase inhibitor and 100 800 gg of the gastric antisecretory prostaglandin analogue(-s), and S more preferably 10-40 mg of the H K -ATPase inhibitor and 150 600 pg of the gastric antisecretory prostaglandin analogue(-s), respectively. Especially preferred combinations comprise omeprazole and misoprotol in a range of 15: 1 to 400: 1, for instance 20 mg omeprazole together with 200 gg misoprostol, or 20 mg omeprazole and 400 ig misoprostol. In the latter one, misoprostol is preferably present in the form of an extended to release formulation.

The optional calcium channel blocking agent may be present in an amount of I 100 mg.

The multiple unit preparation, i.e. a capsule or a tableted dosage form, may also be suitable for dispersion in an aqueous liquid with slightly acidic pH-value. The dispension should be prepared just before being orally administered or fed through a naso-gastric tube.

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

Examples Example 1.

Two-layer tablet comprising misoprostol and omeprazole (magnesium salt).

Principle: one layer comprises 400 p.g misoprostol in a hydrophilic matrix, and the other layer comprises 20 mg omeprazole (magnesium salt) in the form of enteric coated pellets mixed with tableting excipients.

Extended release granules comprising misoprostol were prepared according to this recipe; WO 00/35448 PCT/SE99/02315 22 Misoprostol 0.4 parts by weight Ethanol 95% 410 parts by weight Hydroxypropyl methyl cellulose 50 cps 400 parts by weight Sodium stearyl fumarate 4 parts by weight The misoprostol was dissolved in half the amount of ethanol. This solution was poured on the HPMC powder during mixing. The rest of the ethanol was added to achieve a suitable consistence of the mass. The mass was dried under mild conditions, and the particle size of the dried granules was reduced until all granules passed a 0.8 mm sieve. 1% of sodium stearyl fumarate was admixed.

Enteric coated pellets comprising omeprazole magnesium salt was prepared according to the following recipe; to Core material Magnesium omeprazole 12.00 kg

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Sugar spheres (non-pareil 12.00 kg Hydroxypropyl methylcellulose 1.8 kg Water purified 35.4 kg Separating layer Core material (acc. to above) 23.50 kg Hydroxypropyl cellulose 2.35 kg Talc 4.03 kg Magnesium Stearate 0.34 kg Water purified 48.00 kg Enteric coating Coated pellets (acc. to above) 29.00 kg Methacrylic acid copolymer (30% suspension) 38.70 kg Triethyl citrate 3.48 kg WO 00/35448 PCr/S E99/0231 23 Mono- and diglycerides (NF) 0.58 kg Polysorbate 80 0.06 kg Water purified 22.68 kg Over-coating Enteric coated pellets 44.7 kg Hydroxypropyl methylcellulose 0.58 kg Mg-Stearate 0.017 kg Water purified 11.6 kg Suspension layering was performed in a fluid bed apparatus. Magnesium omeprazole was sprayed onto non-pareil from a water suspension containing the dissolved binder and magnesium omeprazole.

The prepared core material was coated in a fluid bed apparatus with the separating layer material. The enteric coating was sprayed onto the coated pellets in a fluid bed apparatus.

In the same type of apparatus the enteric coated pellets were coated with an over-coat. The over-coated pellets were classified by sieving.

Tableting excipient for mixing with enteric coated pellets was prepared by mixing the following ingredients to homogeneity; Tableting excipient; Microcrystalline cellulose special coarse grade PH 102 12.12 g Microcrystalline cellulose PH 101 6.06 g Polyvinyl pyrrolidone cross-linked 1.82 g Sum: 20.00 g Tablets were compressed on a tablet machine equipped with 9x17 mm oval punches (giving elliptically shaped tablets), by pre-compressing 404 mg of the misoprostolcontaining granules and then filling a mixture consisting of 100 mg omeprazole pellets (according to above) and 200 mg of the tableting excipient mix, and compressing. A two WO 00/35448 PCT/SE99/02315 24 layered tablet was obtained with an acid resistance of 91% (mean value of 4 tablets). The release of omeprazole at pH 6.8 from a tablet pre-exposed 2 h in 0.1 M HC1, spectrophotometric determination, was 89% within 30 min.

Example 2.

Enteric coated pellets comprising magnesium salt of S-omeprazole, layered with misoprostol.

Principle: enteric coated pellets comprising approx. 225 mg/g magnesium salt of Someprazole layered with an outer fast dissolving layer comprising approx. 3.6 mg/g misoprostol.

Enteric coated pellets comprising magnesium salt of S-omeprazole were prepared according to the following recipe; Core material S-omeprazole Mg-salt 20.0 kg

TM

Non-pareil 25.0 kg Hydroxypropyl methylcellulose (HPMC) 3.0 kg Polysorbate 80 0.4 kg Water purified 93.6 kg Separating layer Core material (ace. to above) 50.0 kg Hydroxypropyl cellulose 5.5 kg Talc 20.5 kg Magnesium Stearate 1.4 kg Water purified 193.8 kg WO 00/35448 PCTSE99/02315 Enteric coating Coated pellets (acc. to above) 30.0 kg Methacrylic acid copolymer (30% suspension) 30.0 kg Triethyl citrate 0.9 kg Mono- and diglycerides (NF) 0.5 kg Polysorbate 80 0.05 kg Water purified 12.9 kg Suspension layering was performed in a fluid bed apparatus. S-omeprazole magnesium salt was sprayed onto non-pareil from a water suspension containing the dissolved binder. The prepared core material was coated in a fluid bed apparatus with the separating layer material. The enteric coating was sprayed onto the coated pellets in a fluid bed apparatus.

The enteric coated pellets were classified by sieving.

The enteric coated pellets were further coated with a solution of HPMC and misoprostol in a fluid bed apparatus, using the following composition; Enteric coated pellets (according to above) 100 g Solution; EtOH 95% 125 g Misoprostol 0.46 g Water, purified 125 g Hydroxypropyl methyl cellulose (HPMC) 6 cps 5.3 g

TM

Colloidal silica (Aerosil 0.5 g First the misoprostol was dissolved in the ethanol and then the water was added. The

TM

HPMC was admixed and dissolved. Finally the Aerosil was dispersed in the solution.

The obtained pellets were classified by sieving. The acid resistance of the prepared pellets was 99.6%. The prepared pellets may be mixed with tablet excipients and compressed into WO 00/35448 PCT/SE99/02315 26 a multiple unit tablet as described in Example 5, or filled into a capsule suitable for the desired dose.

Example 3.

STwo-layer tablet with 400 p.g misoprostol and 10 mg of felodipine comprised in a hydrophilic matrix as one layer, and the other layer comprising 20 mg omeprazole (magnesium salt) in the form of enteric coated pellets mixed with tableting excipients.

Extended release granules comprising misoprostol and felodine are prepared according to the following recipe; parts by weight Misoprostol 0.4 Felodipine Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) Ethanol 95% 400 Hydroxypropyl methyl cellulose 50 cps 400 Sodium stearyl fumarate 4 The misoprostol is dissolved in half the amount of ethanol. Another solution is made by dissolving 10 parts of the felodipine and 10 parts of the Cremophor RH 40 in 60 parts of 1i ethanol. These solutions are poured on the HPMC powder during mixing. Additionally ethanol (approximately 140 parts) may be added to get satisfactory consistency of the mass. The mass is dried on a tray (under mild conditions). The particle size of the dried granules is reduced until all granules passed a 0.8 mm sieve. Thereafter 1% of sodium stearyl fumarate is admixed.

Enteric coated pellets comprising omeprazole magnesium salt was prepared and mixed with tabletting excipients according to Example 1. Two-layer tablets containing WO 00/35448 PCT/SE99/02315 27 misoprostol 400 4g, felodipin 10 mg, and omeprazole 20 mg were prepared as described in Example 1.

The tablets are coated with a solution of HPMC and PEG having pigments dispersed therein, in a suitable coating apparatus, e.g. rotating drum coater, using the following composition; Tablets (according to above) Solution; Water purified Hydroxypropyl methyl cellulose (HPMC) 6 cps Polyethylene glycol (PEG) 6000 Titanium dioxide Iron oxide yellow 724 parts by weight 122 parts by weight 14 parts by weight 4 parts by weight 2 parts by weight 2 parts by weight The coating is continued until average tablet weight has increased with 14 20 mg.

Example 4.

Capsule formulation comprising pantoprazole and misoprostol pellets. (40 mg pantoprazole and 200 pg misoprostol).

Pantoprazole enteric coated pellets is prepared according to the following recipe; Core material Pantoprazole 100 g

TM

Non-pareil 200 g Hydroxypropylcellulose LF 25 g Water purified 607 g WO 00/35448 PCT/SE99/02315 28 Separating layer Core material (acc. to above) 200 g Hydroxypropyl cellulose LF 20 g Talc 34.3 g Magnesium Stearate 2.9 g Water purified 400 g Enteric coating Coated pellets (ace. to above) 200 g o0 Methacrylic acid copolymer, 30% suspension 333 g Triethyl citrate 30 g Mono- and diglycerides (NF) 5 g Polysorbate 80 0.5 g Water purified 281.5 g Suspension layering is performed in a fluid bed apparatus. Pantoprazole is sprayed onto non-pareil from a water suspension containing the dissolved binder.

The prepared core material is coated in a fluid bed apparatus with the separating layer material. The enteric coating is sprayed onto the coated pellets in a fluid bed apparatus.

The pellets are classified by sieving.

Misoprostol pellets are prepared by coating inert sugar spheres in a fluid bed according to the following recipe;

TM

Sugar spheres (Non Pareil 100 g Solution; EtOH 95% 125 g Misoprostol 0.46 g Water, purified 125 g WO 00/35448 PCT/SE99/02315 Hydroxypropyl methyl cellulose (HPMC) 6 cps

TM

Colloidal silica (Aerosil 5.34 g 0.50 g First the misoprostol is dissolved in the ethanol and then the water is added. The HPMC is

TM

admixed and dissolved. Finally the Aerosil is dispersed in the solution. The obtained pellets are classified by sieving.

Capsule filling; 266 mg enteric coated pantoprazole pellets and pellets corresponding to 200 pg of misoprostol approx. 55 mg) are filled into a No. 1 hard gelatin capsule.

to Example Multiple unit tablet comprising lansoprazole and misoprostol pellets. (60 mg lansoprazole and 200 p.g of misoprostol).

Lansoprazole pellets are prepared according to the is Core material Lansoprazole

TM

Non-pareil Hydroxypropyl methylcellulose Sodium laurylsulphate Water purified following recipe; 370 g 400 g 76 g 2.8 g 1360 g Separating layer Core material (ace. to above) Hydroxypropyl cellulose Talc Magnesium Stearate Water purified 400 g 40 g 68.6 g 5.7 g 800 g WO 00/35448 PCT/SE99/02315 Enteric coating Coated pellets (acc. to above) Methacrylic acid copolymer 30% suspension (containing dry materials Triethyl citrate Mono- and diglycerides (NF) Polysorbate 80 Water purified Over-coating Enteric coated pellets Hydroxypropyl methylcellulose Mg-Stearate Water purified 400 g 667 g 200 g) 60 g lg 420 g 500 g 6.5 g 0.2 g 130 g The enteric coated pellets comprising lansoprazole are prepared as described in Example 1, with lansoprazole replacing omeprazole.

Tablets Pellets comprising lansoprazole (according to above) Pellets comprising misoprostol (according to Ex 4) Microcrystalline cellulose PH 102 Microcrystalline cellulose PH 101 Polyvinyl pyrrolidone cross-linked Sodium stearyl fumarate mg/tablet approx.

approx.

285 205 205 First the microcrystalline celluloses and polyvinyl pyrrolidone are mixed to homogeneity.

Then the lubricant sodium stearyl fumarate is admixed, and thereafter the lansoprazole comprising pellets and the misoprostol comprising pellets are added, and mixed until homogeneity.

WO 00/35448 PCT/SE99/02315 31 Compression to tablets is done by compressing the mixture on a tablet machine equipped with 9x21 mm oval punches.

Example 6.

Two-layer tablet with 200 p.g misoprostol in one layer, and the other layer comprises mg S-omeprazole (magnesium salt) containing delayed pulsed release pellets mixed with tableting excipients.

Granules comprising misoprostol are prepared according to this recipe; parts by weight Misoprostol 0.2 Ethanol 95% 300 Water purified 110 Hydroxypropyl methyl cellulose 6 cps Microcrystalline cellulose PH 101 350 Sodium stearyl fumarate 4 The misoprostol is dissolved in 200 parts of ethanol. This solution is poured on the HPMC and microcrystalline cellulose powders during mixing. Then a satisfactory amount of a mixture consisting of 100 parts of ethanol and 110 parts of water is admixed until is satisfactory consistency of the mass is obtained. The mass is dried under mild conditions.

The particle size of the dried granules is reduced until all granules pass a 0.8 mm sieve.

Thereafter 1% of sodium stearyl fumarate is admixed.

Preparation of delayed pulsed release pellets comprising magnesium salt of S-omeprazole (pellet strength approx. 44 mg/g).

Preparation of core material (spheres layered with drug).

A drug containing suspension is made according to the composition below; WO 00/35448 PCT/SE99/02315 32 S-omeprazole Mg-salt 100g HPMC, 6cps 15 g Polysorbate 80 2 g Purified water 323 g HPMC is dissolved in water during stirring with subsequent addition of Polysobate 80 and the drug. The suspension is sprayed onto 290 g of sugar spheres (Non-pareil) in a fluidized s bed. The product weight is approx. 395 g.

Application of swelling layer A (water free) suspension containing in water highly swellable substances is prepared according to the following composition; Low-substituted hydroxypropylcellulose (L-HPC) 162 g Hydroxypropylcellulose LF (HPC-LF) 74 g Talc 354 g EtOH 3100 g HPC-LF is dissolved in ethanol during stirring, then the talc and the swelling agent L-HPC are added. The suspension is sprayed onto 175 g drug containing pellets from above in a Wurster equipped fluidized bed. The weight of the product is usually approx. 710 g.

Application of lag time controlling layer (semipermeable membrane).

A coating suspension is made according to the following formula; Ethylcellulose, 10 cps 10 g Talc 23 g EtOH 1000 g WO 00/35448 PCT/SE99/02315 33 The ethylcellulose is dissolved in the ethanol during stirring, then the talc is added.

Spraying of the suspension onto 150 g of pellets from above (0.61-0.71 mm obtained by sieving) is done in a Wurster equipped fluidized bed. The weight of the obtained pellets is usually approx. 175 g.

Application of enteric coating layer.

Pellets from above are enteric coated in a fluidized bed with a coating dispersion according to below; Eudragit L30 D-55 (30 w/w dispersion) 73.3g Triethyl citrate (TEC) 6.6 g Glycerol monostearate (GMS) 0.3 g Polysorbate 80 0.03 g Purified water 40.4 g A homogenous coating dispersion is prepared by dispersing polysorbate 80 and glycerol monostearate in water. Tritehylcitrate is dissolved in the Eudragit dispersion and thereafter the two dispersions are mixed to obtain the coating dispersion.

The coating dispersion is applied onto 120 g pellets, using a Wurster equipped fluidized bed. The weight of the enteric coated pellets is usually approx. 140 g.

Preparation of tablets Tableting excipient for mixing with enteric coated pellets is prepared by mixing the following ingredients to homogeneity; Tableting excipient; Microcrystalline cellulose special coarse 12.12 g grade PH 102 Microcrystalline cellulose PH 101 6.06 g WO 00/35448 PCTSE99/02315 34 Polyvinyl pyrrolidone cross-linked 1.82 g Sum: 20.00 g Compression to tablets is done on a tablet machine equipped with 9x21 mm oval punches (giving elliptically shaped tablets). The tablets are prepared by first pre-compressing 404 mg of the misoprostol-containing granules and then filling a mixture consisting of approx.

s 270 mg S-Omeprazole magnesium salt comprising pellets (according to above) and 270 mg of the tableting excipient mix.

Example 7.

Enteric coated tablet comprising 45 mg omeprazole (magnesium salt) in a hydrophilic matrix, having an outer fast dissolving coat upon the enteric coat, the outer coat comprises approx. 220 p.g of misoprostol.

Extended release tablets comprising omeprazole Mg-salt (approx. 45 mg).

Granules for tablet cores are made according to the following composition (parts by weight); Omeprazole Mg-salt Hydroxypropyl methylcellulose 50 cps 300 Polyvinyl pyrrolidone (PVP) K-90 Ethanol 99.5% 400 The PVP is dissolved in the alcohol. The other two ingredients are mixed and then moistened with the PVP-solution in a mixer. Thereafter the obtained mass is dried in a drying oven at 50 0 C. After milling in an oscillating mill through a 1.0 mm screen the obtained granules are mixed with tablet lubricant, according to the following composition (parts by weight); WO 00/35448 PCT/SE99/02315 Granules for tablet core Sodium stearyl fumarate (Pruv®) The ingredients are mixed whereafter the mixture is compressed to tablets (9 mm in diameter) having an average weight of 265 mg, on a tableting machine.

s Separating layer coated tablets Obtained tablets are coated first with a separating layer in e.g. a rotating drum coating apparatus, with a coating suspension of the following composition; EtOH 99.5% (w/v) Water purified Hydroxypropyl methylcellulose 6 cps Talc, micronized 85 parts by weight 85 parts by weight 10 parts by weight 2 parts by weight 182 parts. Sum: 0o The coating of the tablets is continued until average tablet weight is approx 274 mg.

Enteric coated tablets The tablets coated with a separating layer are coated with an enteric coating layer in the same equipment as for the preceeding coating step. The coating solution to be used has the following composition; Hydroxypropyl methylcellulose phtalate (HP-55®) Cetanol Acetone Ethanol (95% w/v) 19 parts by weight 1 parts by weight 182 parts by weight 78 parts by weight 280 parts Sum: WO 00/35448 PCT/SE99/02315 36 Separating layer coated tablets are processed and the coating is continued until average tablet weight is 293 mg.

Enteric coated tablets coated with misoprostol layer The enteric coated omeprazole Mg-salt tablets are coated with a solution of HPMC and misoprostol in e.g. a rotating drum coating apparatus, using the following composition; Dispersion EtOH 95% (w/v) Misoprostol Water, purified Hydroxypropyl methyl cellulose (HPMC) 6 cps Colloidal silica (Aerosil RTM) 125 parts by weight 0.46 parts by weight 125 parts by weight 5.34 parts by weight 0.50 parts by weight First the misoprostol is dissolved in the ethanol and then the water is added. The HPMC is

TM

admixed and dissolved. Finally the Aerosil is dispersed in the solution.

The coating is continued, until the average tablet weight is 296 mg.

Example 8.

is Enteric coated tablet comprising 20 mg omeprazole (magnesium salt) in a hydrophilic matrix, having an outer hydrophilic matrix layer upon the enteric coat, the outer layer comprises 200 pg misoprostol.

Granules comprising omeprazole Mg-salt are prepared according to this recipe; mg/tablet Omeprazole Mg-salt 22.5 Ethanol 95% Hydroxypropyl methyl cellulose (HPMC) 50 cps WO 00/35448 PCT/SE99/02315 37 Hydroxypropyl methyl cellulose (HPMC) 10000 cps Polyvinyl pyrrolidone (PVP) K-90 The PVP is dissolved in the ethanol. This solution is poured on the mixed powders of the HPMC's and Omeprazole Mg-salt powder during continued mixing. The mass is dried on a tray at 50 0 C in a drying oven. After milling through a 0.8 mm screen the obtained Sgranules are mixed with tablet lubricant according the following composition; Granules 119 g Sodium stearyl fumarate (Pruv®) 1 g The mixing is performed in to homogeneity in a mixer, e.g. Kenwood. Then it is compressed to 6 mm in diameter tablets having an average weight of 120 mg on a tableting machine. The tablets are coated with a separating layer by using a solution of HPMC and coating, e.g. in a fluid bed coating apparatus or rotating drum coater, using the following composition; EtOH 95% 125 parts by weight Water, purified 125 parts by weight Hydroxypropyl methyl cellulose (HPMC) 6 cps 5.3 parts by weight The HPMC is dissolved in the ethanol/water mixture. The coating is continued until average tablet weight has increased with 4 mg if starting average weight is 120 mg, to 124 mg).

The obtained separating layer coated tablets are coated with an enteric coating layer in the same equipment as for the preceeding coating step. The coating solution has the following composition; Hydroxypropyl methylcellulose phtalate (HP-55) 16 parts by weight WO 00/35448 PCT/SE99/02315 Cetanol Acetyl tributyl citrate Acetone Ethanol (95% w/v) 1 parts by weight 1 part by weight 153 parts by weight 65 parts by weight 236 parts by weight Sum: The tablets are coated until average tablet weight is 133 mg. The obtained enteric coated extended release omeprazole Mg salt tablets are dry coated in a suitable tableting machine with a granulate comprising HPMC and misoprostol prepared using the following composition; Misoprostol Ethanol 95% (w/v) Hydroxypropyl methyl cellulose (HPMC) 50 cps 0.2 parts by weight 200 parts by weight 200 parts by weight First the misoprostol is dissolved in the ethanol. Then the solution is poured on the HPMC powder during mixing. The mass is dried using mild conditions. Obtained dried granules 0o are milled in an oscillating granulator equipped with a 1.0 mm screen.

For the manufacturing of each dry coated extended release tablet, one enteric coated omeprazole Mg-salt tablet and 200 mg of misoprostol comprising extended release granulate is used, and compressed with 10 mm diameter punches.

Example 9.

Capsule formulation comprising 20 mg pantoprazole and 400 p.g of misoprostol, the latter comprised in a hydrophilic matrix plug.

Pantoprazole pellets are prepared as described in Example 5, with lansoprazole replacing pantoprazole.

WO 00/35448 PCT/SE99/02315 39 Extended release plug comprising misoprostol is prepared by first making a granulation according to this recipe; Misoprostol Ethanol 95% (w/v) Hydroxypropyl methyl cellulose 50 cps 0.4 parts by weight 110 parts by weight 118 parts by weight s The misoprostol is dissolved in 110 parts of ethanol. This solution is poured on the HPMC powder during mixing. The mass is dried under mild conditions. The particle size of the dried granules is reduced until all granules pass a 0.8 mm sieve. Thereafter the lubricant sodium stearyl fumarate is admixed, according to following recipe; Granules according to above Sodium stearyl fumarate sum 118.4 parts by weight 1.6 parts by weight 120.0 parts by weight The mixing is performed to homogeneity in a mixer. Then it is compressed to 6 mm in diameter plugs (tablets) having an average weight of 120 mg on a tableting machine.

Capsule filling; is One plug according to above and 95 mg pantoprazole comprising pellets are filled into a hard gelatine capsule of size no 1.

Example Enteric coated, layered tablet with dual pulsed release of S-omeprazole magnesium salt (2 x approx.15 mg), having an outer fast dissolving coat upon the enteric coat, the outer layer comprises 220 p.g of misoprostol.

Granules WO 00/35448 PCT/SE99/02315 Granules for tablet cores are made according to the following composition; S-omeprazole Mg-salt Microcrystalline cellulose, Avicel PH 101 Microcrystalline cellulose, Avicel PH 102 sp. Coarse grade

L-HPC

PVP-XL

Sodium laurylsulphate (SLS) Water purified parts by weight 229 151 400 256 302 1060 A granulating solution is prepared by dissolving the SLS in 460 parts of purified water.

s The powders above are mixed in a mixer after which the solution is added in an even stream. Thereafter approx. 600 parts of water is added during continued mixing, to give satisfactory consistence to the mass. The mass is dried in a drying oven at 50 0 C over night.

Preparation of tablet cores After milling through a 1.0 mm screen the obtained granules are mixed with tablet lubricant, sodium chloride, and an additional amount of swellable substance, according the following composition; Granules for homogenous tablet core Sodium chloride (passing 0.3 mm) Sodium stearyl fumarate (Pruv®) Polyvinyl pyrrolidone cross-linked (PVP-XL) parts by weight 400 8 WO 00/35448 PCT/SE99/02315 41 The mixing is performed in to homogeneity in a mixer, e.g. Kenwood. Then it is compressed to 6 mm in diameter tablets having an average weight of 126 mg on a tableting machine.

Application of lag time controlling layer (semipermeable membrane).

The tablets are coated in a Wurster equipped fluidized bed coating apparatus with a coating suspensiol following composition; EtOH 99.5% (w/v) Ethyl cellulose N-10 Talc, micronized 291 parts by weight 11 parts by weight 7 parts by weight Sum: 309 parts The tablets are coated and the coating is continued until average tablet weight is 134 mg.

Application of drug containing layer is The obtained tablets are coated in the same equipment as above with a coating suspension of the following composition; S-omeprazole Mg-salt Hydroxypropyl methylcellulose 6 cps Ethanol 99% Water purified Sum: 20 parts by weight 13 parts by weight 128 parts by weight 128 parts by weight 289 parts.

The tablets are coated and the coating is continued until the average tablet weight is 162 mg.

WO 00/35448 PCT/SE99/02315 42 Separating layer coated tablets Obtained tablets are coated first with a separating layer, in e.g. a rotating drum coating apparatus, with a coating suspension of the following composition; EtOH 99.5% (w/v) Water purified Hydroxypropyl methylcellulose 6 cps Talc, micronized 85 parts by weight 85 parts by weight 10 parts by weight 2 parts by weight 182 parts. Sum: The coating of the tablets is continued until average tablet weight is approx 166 mg.

Application of enteric coating layer o0 The obtained tablets are coated with an enteric coating layer in the same equipment as for the preceeding coating step. The coating solution has the following composition; Hydroxypropyl methylcellulose phtalate (HP-55) Cetanol Acetone Ethanol (95% w/v) Sum: 16 parts by weight 1 parts by weight 153 parts by weight 65 parts by weight 235 parts by weight The tablets are coated and the coating is continued until average tablet weight is 177 mg.

The enteric coated dual pulsed release S-omeprazole Mg salt tablets are coated with a solution of HPMC and misoprostol e.g. in a fluid bed coating apparatus or rotating drum coater, using the following composition; Tablets (according to above) 100 parts by weight WO 00/35448 PCT/SE99/02315 Solution; EtOH 95% (w/v) Misoprostol Water, purified Hydroxypropyl methyl cellulose (HPMC) 6 cps

TM

Colloidal silica (Aerosil 125 0.46 125 5.34 0.50 parts by weight parts by weight parts by weight parts by weight parts by weight First the misoprostol is dissolved in the ethanol and then the water is added. The HPMC is

TM

admixed and dissolved. Finally the Aerosil is dispersed in the solution.

The coating is continued until average tablet weight has increased with 3 mg if starting average weight is 177 mg, to 180 mg).

Example 11.

Two-layer tablet with pellets comprising 200 pg misoprostol and pellets comprising 20 mg to omeprazole (magnesium salt) mixed with tableting excipients in one layer, and the other layer comprises 30 mg nifedipine in a hydrophilic matrix.

Extended release granules comprising nifedipine was prepared according to this recipe; Nifedipine Polyoxyl 40 hydrogenated castor oil Ethanol 99.5% (w/v) Ethyl cellulose N-10 Propyl gallate Hydroxypropyl methyl cellulose 50 cps Sodium aluminium silicate Sodium stearyl fumarate 30 g 30 g 300 g 20 g 0.06 g 175 g 75 g 6 g WO 00/35448 PCT/SE99/02315 44 Nifedipine, polyoxyl 40 hydrogenated castor oil and propyl gallate are charged into the ethanol. This mixture is heated and stirred until a solution is formed, keeping the temperature of the mixture/solution at maximum 70 0 C. Then the ethyl cellulose is added s and dissolved. The obtained solution is poored on a mixture of the HPMC and the sodium aluminium silicate powders during mixing. The mass is dried in an explosion safe drying cabinet, whereafter it is milled in an oscillating granulator having a screen with 1 mm openings. The obtained granules are mixed with the lubricant sodium stearyl fumarate for 2 minutes.

Enteric coated pellets comprising omeprazole magnesium salt were prepared as described in Example 1.

Misoprostol pellets are prepared by dissolving misprostol in ethanol and then mixing is porous silica particles with this solution, according to the following recipe; Misoprostol Silica particles, porous, appr diameter 150 pm Ethanol 95% (w/v) 0.16 parts by weight 53.14 parts by weight 42.5 parts by weight The mass is dried under mild conditions. Obtained misoprostol pellets contain approx. 3.75 mg misprostol per gram.

Tableting excipients for mixing with omeprazole and misoprostol pellets are prepared by mixing the following ingredients to homogeneity; Tableting excipient; Microcrystalline cellulose special coarse grade PH 102 Microcrystalline cellulose PH 101 Polyvinyl pyrrolidone cross-linked 12.12 parts by weight 6.06 parts by weight 1.82 parts by weight WO 00/35448 PCT/SE99/02315 Sum: 20.00 parts by weight Compression to tablets is done on a tablet machine equipped with 9x17 mm oval punches (giving elliptically shaped tablets). The tablets are prepared by first pre-compressing 336 mg of the nifedipine containing granules and then filling a mixture consisting of 100 mg omeprazol magnesium salt comprising pellets (according to above), 53 mg misoprostol containing pellets and 200 mg of the tableting excipient mix, giving a total tablet weight of 689 mg.

To protect the nifedipine in the tablets against photolytic degradation, the tablets are coated 0o with a solution of HPMC and PEG having pigments dispersed therein, in a fluid bed coating apparatus or rotating drum coater, using the following composition; Tablets (according to above) Solution; Water purified Hydroxypropyl methyl cellulose (HPMC) 6 cps Polyethylene glycol (PEG) 6000 Titanium dioxide Iron oxide yellow 336 parts by weight 12 parts by weight 14 parts by weight 4 parts by weight 2 parts by weight 2 parts by weight The coating is continued until average tablet weight has increased with 15 20 mg.

Example 12.

Enteric coated pellets comprising approx. 225 mg/g S-omeprazole magnesium salt and misoprostol, approx. 3.5 mg/g pellet wherein the latter is positioned in an outer extended release layer.

Enieric coated pellets comprising S-omeprazole magnesium salt wtere prepared as described in Example 2.

The enteric coated pellets are coated with a solution of H-PMC and mi:;oprostol in a fluid bed apparatus, using the following composition; Enieric coated pellets (according to above) Solution; ErOR 95% (wv/v) Water, purified Misoprostol HYdzoxypropyl methyl cellulose (HPMC) 50 cps Colloidal silica (Aerosil") 100 parts by weight 300 parts by weight 50 paits by weight 0.46 paxts by weight 5.3 4 parts by weight 0.50 peats by weight First the rnisoprostol is dissolved in the ethanol and then the water is added. Therea Aer the HPMC is admaixed and dissolved. Finally the Aerosil is dispersed in the Solution.- The obtained pellets are classified by sieving. The prepared pellets may be compressed to a multiple unit Tablet as described in Example 5, or filled into a capsule suitable for tle desired dose.

It will be understood that the term "comprises" or its grammatical variants as used herein is equivalent to the term "includes" and is not to be taken as excluding the presence of other elements or features.

Claims (38)

1. An oral pharmaceutical dosage form comprising a K'-ATPase inhibitor and a gastric antisecretory prostaglandin analogue compound and optionally pharmaceutically acceptable excipients, wherein the dosage form is in the form of a fixed unit dosage form comprising at least these two pharmaceutically active components.

2. A dosage form according to claim 1, wherein the dosage form is a tablet formation.

3. A dosage form according to claim 1, wherein the dosage form is a 10 capsule formulation.

4. A dosage form according to any one of claims 1-3, wherein the H+, K+-ATPase inhibitor compound is protected by an enteric coating layer, and optionally a separating layer is applied under the enteric coating separating the H K+-ATPase inhibitor from the enteric coating layer.

5. A dosage form according to claim 1, wherein the fixed dosage form in addition to the K*-ATPase inhibitor and the gastric antisecretory prostaglandin analogue comprises a calcium channel'blocking agent.

6. A dosage form according to any one of claims 1-5, wherein the H*, K',-ATPase inhibitor is omeprazole, an alkaline salt thereof, one of its single enantiomers or an alkaline salt thereof.

7. A dosage form according to claim 6, wherein the K-ATPase inhibitor is omeprazole magnesium salt.

8. A dosage form according to claim 6, wherein the K+-ATPase inhibitor is S-omeprazole magnesium salt. 003980860 48

9. A dosage form according to any one of claims 1-5, wherein the H+, K -ATPase inhibitor is lansoprazole, one of its single enantiomers or a pharmaceutically acceptable salt thereof.

A dosage form according to any one of claims 1-5, wherein the H+, K-ATPase inhibitor is pantoprazole, one of its single enantiomers or a pharmaceutically acceptable salt thereof.

11. A dosage form according to any one of claims 1-10, wherein the gastric antisecretory prostaglandin analogue compound is misoprostol, enisoprost, enprostil or one of the single enantiomers thereof or a pharmaceutical acceptable 10 salt thereof.

12. A dosage form according to any one of claims 1-11, wherein the amount of the H K-ATPase inhibitor is in the range of 1-200 mg and the amount of the gastric antisecretory prostaglandin analogue is in the range of 80 1 000 jg. 15

13. A dosage form according to any one of claims 1-12, wherein the amount of the K-ATPase inhibitor is in the range of 5-80 mg and the amount of the gastric antisecretory prostaglandin analogue is in the range of 100-800 [ig.

14. A tableted dosage form according to claim 2, wherein the tablet consists of two different layers, a first layer comprising the H K-ATPase inhibitor and a second layer comprising the gastric antisecretory prostaglandin analogue.

A tableted dosage form according to claim 2, wherein the tablet formulation is a multiple unit tableted dosage form comprising a) the K'-ATPase inhibitor in the form of enteric coating layered pellets, b) the gastric antisecretory prostaglandin analogue compound and optionally c) pharmaceutically acceptable excipients 003980860 49 compressed together into a tablet, whereby the enteric coating layer covering the individual pellets has mechanical properties such that the tableting of the pellets together with the gastric antisecretory prostaglandin analogue and optionally pharmaceutically acceptable excipients does not significantly affect the acid resistance of the enteric coating layered pellets.

16. A tableted dosage form according to claim 15, wherein the enteric coating of the individual pellets comprises a plasticized enteric coating layer material.

17. A tableted dosage form according to claim 15, wherein the enteric 10 coating layered pellets are further covered with an over-coating layer comprising a *--"film forming polymer and pharmaceutically acceptable excipients. eeeee

18. A tableted dosage form according to any one of claims 15-17, wherein the tablet is divisible.

19. A tableted dosage form according to claim 2, wherein at least one part of the tablet is in the form of an extended release formulation. S°

20. A tableted dosage form according to claim 19, wherein the part of the tablet giving extended release is a hydrophilic matrix.

21. A tableted dosage form according to claim 19, wherein the part of the tablet giving extended release is a hydrophobic matrix.

22. A tableted dosage form according to claim 2, wherein the tablet consists of two different layers, a first layer comprising the K -ATPase inhibitor in the form of enteric coating layered pellets compressed with tablet excipients into a layer; and a second layer giving an extended release of the incorporated gastric antisecretory prostaglandin analogue. 003980860

23. A tableted dosage form according to claim 2, wherein the tablet comprises enteric coating layered pellets of the K'-ATPase inhibitor layered with a further layer comprising the gastric antisecretory prostaglandin analogue, and the layered pellets are compressed with tablet excipients to a tablet.

24. A tableted dosage form according to claim 23, wherein the pellets before compression to a tablet is covered by a pigmented film coating layer, or the compressed tablet is covered by a pigmented tablet coat.

A tableted dosage form according to claim 2, wherein the tablet consists of two types of layered pellets, the first type consists of enteric coating 10 layered pellets comprising the K -ATPase inhibitor and the second type consists of pellets comprising the gastric antisecretory prostaglandin analogue, all pellets are compressed together with tablet excipients to a tablet.

26. A tableted dosage form according to claim 22, wherein the tablet consists of enteric coating layered pellets comprising the H K-ATPase inhibitor, 15 and pellets comprising the gastric antisecretory prostaglandin analogue incorporated in a matrix giving an extended release of the prostaglandin analogue.

27. A dosage form according to claim 3, wherein the capsule comprises two types of layered pellets, the first type consists of enteric coating layered pellets comprising the K+-ATPase inhibitor and the second type consists of pellets comprising the gastric antisecretory prostaglandin analogue, all pellets and optionally pharmaceutically acceptable excipients are filled in the capsule.

28. A process for the manufacture of a fixed dosage form comprising a H K+-ATPase inhibitor and one or more gastric antisecretory prostaglandin analogue(s) in a capsule, characterized in that the H K+-ATPase inhibitor is prepared in the form of enteric coating layered pellets, and the gastric antisecretory prostaglandin analogue is prepared in the form of pellets coating layered with an extended release film, the pellets are mixed, optionally with pharmaceutically acceptable excipients, and the mixture is filled in to capsules. 003980860 51

29. A process for the manufacture of a fixed dosage form comprising a K -ATPase inhibitor and one or more gastric antisecretory prostaglandin analogues in a multiple unit tableted dosage form, characterized in that the H K+-ATPase inhibitor is prepared in the form of enteric coating layered pellets and these pellets are mixed with pellets comprising the gastric antisecretory prostaglandin analogue, and optionally pharmaceutically acceptable tablet excipients, whereafter the mixture is compressed into multiple unit tablets without causing any significant change of the acid resistance of the enteric coating layered pellets.

30. A process for the manufacture of a fixed dosage form comprising a Ht, K+-ATPase inhibitor and one or more gastric antisecretory prostaglandin analogues in a multiple unit tableted dosage form, characterized in that the H+, K'-ATPase inhibitor is prepared in the form of enteric coating layered pellets and the gastric antisecretory prostaglandin analogue is prepared in the form of coating layered pellets wherein the coating layer is an extended release layer, the pellets are mixed, optionally with pharmaceutically acceptable tablet excipients, and compressed into tablets without causing any significant change of the acid resistance of the enteric coating layered pellets.

31. A method for the treatment and profylaxis of gastrointestinal 20 disorders by administering to a host in need thereof a therapeutically effective Sdosage form according to any one of claims 1-27.

32. A method for avoiding gastrointestinal side-effects normally associated with gastric antisecretory prostaglandin analogue medicament treatment in mammals and man by administering to a host in need thereof a therapeutically effective dosage form according to any one of claims 1-27.

33. Use of a dosage form according to any one of claims 1-27 in the manufacture of a medicament for treatment of profylaxis of gastrointestinal diseases. SUUt l UDJ 52

34. Use of a dosage from according to any one of claims 1-27 in the manufacture of a medicament for avoiding gastrointestinal side-effects normally associated with gastric antisecretory prostaglandin analogue treatment.

A combination of a H K'-ATPase inhibitor, a gastric antisecretory prostaglandin analogue and a calcium channel blocking agent in the treatment of gastrointestinal diseases.

36. A blister pack comprising a fixed dosage form comprising a H K'- ATPase inhibitor medicament and a gastric antisecretory prostaglandin analogue medicament.

37. A blister pack according to claim 36 comprising an additional medicament which is a calcium channel blocking agent.

38. A dosage form according to claim 1 substantially as hereinbefore described with reference to any one of the Examples. AstraZeneca AB By their Registered Patent Attorneys Freehills Carter Smith Beadle 9 July 2004 o oooo oo *o go *0o o *•go