ZA200104273B

ZA200104273B - New pharmaceutical formulation.

Info

Publication number: ZA200104273B
Application number: ZA200104273A
Authority: ZA
Inventors: Arne Eek; Lars Josefsson; Per Johan Lundberg; Aake Pilbrant
Original assignee: Astrazeneca Ab
Priority date: 1998-12-14
Filing date: 2001-05-24
Publication date: 2002-08-26
Also published as: EP1150677A1; AU776079B2; WO2000035448A1; IL143386A0; NO20012915D0; CN1334731A; CA2352613A1; NO20012915L; JP2002532425A; AU2018600A; BR9916224A; HK1041224A1; NZ511999A; KR20010093822A; SE9804314D0

Description

* "a 1}

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 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 PGE, -

® 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 combination 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. (5 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.

k 2

J

Previously suggested combination therapies comprising antiulcerative agents are for instance combinations of a histamine Hj- receptor antagonist, such as cimetidine or ranitidine, and sucralfate. Other proposed therapies are for instance a combination of omeprazole and sucralfate, 2 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 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. etal, 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 2s a blister pack or a fixed unit dosage form.

Summary of the invention

+

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.

A further aspect of the invention is to provide dosage forms of a H, 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. to An additional aspect of the invention is to provide a combination therapy of a H, 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.

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.

+ ) L WO 00/35448 s 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, s 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

SE conventional tablet granulation procedure, or by incorporating the prostaglandin analogue in fast dissolving pellets, which are dispersed in pharmaceutically acceptable excipients. It

CL 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 2s spray coated with a layer comprising a gastric antisecretory prostaglandin analogue. The tablet cores may be prepared as described 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 p - 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 io 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 of drug-containing units : Such dosage forms my be divided into two principally different categories; e.g. (i) one- . population of multiple layered units, and (ii) two-populations of units. (i) One-population of multiple layered units intended for 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 N comprising a gastric antisecretory prostaglandin analogue, and optionally a calcium

: . t WO 00/35448 PCT/SE99/02315 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 s 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

ES acceptable tablet excipients. One population comprises a proton pump inhibitor, and the : other population comprises a gastric antisecretory prostaglandin analogue as the 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. 2s 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

: 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 5s 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. ts 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 3 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 3s 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. (i) one- population of multiple layered units comprising a proton pump inhibitor and a gastric =~ antisecretory prostaglandin analogue, or (ii) two-populations of units. The capsule may i WO 00/35448 PCT/SE99/02315 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 s antisecretory prostaglandin analogue, or optionally the calcium channel blocking agent. Ce

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 to 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 t5 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). 2s 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 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, 10 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 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 um, preferably more than 20 um. 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. - 30 Pellets covered with enteric coating layer(s) may further be covered with one or more over- coating 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,

; . ) 3 WO 00/35448 PCT/SE99/02315 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, s methylcellulose, ethylcellulose, hydroxypropyl methyl cellulose, carboxymethylicellulose 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 over- coating layer(s). The maximum thickness of the applied over-coating layer(s) is normally to 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, oo polyvinyl alcohols, tragacanth, xanthan and guar gums or any other suitable hydrophilic polymers). These polymers can be used alone or in mixtures with each other. ) 20

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 (Ermcompress )- 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 unit weight) of sodium aluminium silicate or calcium phosphate (Emcompress )-

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

As binders for the hydrophobic matrix may be used either hydrophilic or hydrophobic 15. 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 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.

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 pm, more preferably 80 - 150 pum, a nominal pore diameter between 50 - 1 000 A, more preferably 500 - 1 000 A; and a surface area between 40 - 50 m’ /g. 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 m’/g. . 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 amowst may also be accomplished by conventional methods, such as layering or coating on inert seeds or by extrusion/ spheronization.

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 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. - + _ + _ . Cg ere . .

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 4

Het;—X—S—Het, I wherein i

Het is

Ry Ra

Ry R N pa 3 ~ or Rs ra

N R'¢

Het; is

) 4 WO 00/35448 PCT/SE99/02315

Re R 7

N N— Ss

A Rs or A —

N \

MW Rg H

X= . —¢ H— Ry 1 . or

Rio pe , wherein

N in the benzimidazole moiety means that one of the ring carbon atoms substituted by Rg- " Rg optionally may be exchanged for a nitrogen atom without any substituents;

R1, Ry and Rj are the same or different and selected from hydrogen, alkyl, alkoxy ~ optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and phenylalkoxy;

R4 and Rs are the same or different and selected from hydrogen, alkyl and arylalkyl;

Rg’ is hydrogen, halogen, trifluoromethyl, alkyl or alkoxy;

Rg-Rg are the same or different and selected from hydrogen, alkyl, alkoxy, halogen, halo- alkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolinyl, trifluoroalkyl, or adjacent groups Rg-

Rg form ring structures which may be further substituted;

Rg is hydrogen or forms an alkylene chain together with R3 and f ¥

R11 and Ry; are the same or different and selected from hydrogen, halogen or alkyl.

Examples of specifically interesting compounds according to formula I are

OCHa;

O N OCHs;

TN 1

N CHy—5—¢ 1r

N

/ omeprazole -

H

OCH,CF, oN

SN Il

N” CcH,—s—¢ 1)

N . /

H lansoprazole

OCH; : 7 OCH,

ON OCHF, }

N cH,—S—¢ IT

N

/

H : pantoprazole

OCH,CH,CH,0CH;4 % CHs

B IY

NT CH—s—<¢ 1 /

H . oo _pariprazole

‘ cr

N—CH,CH(CHs),

SY

CH,—s—¢

N od leminoprazole

A

\ Q N wT J

N

/

H

: CH;

N

Ss 4

CHa. / I

N O

— H

OCH,

Oo N i =

NT 1

Ne

NNT Noch,

H

OCH, 2» B xX fl X

N" cH,—s—¢ OR \

H

The compound suitable for the formulations according to the present invention may be used in neutral form or in the form of an alkaline salt, such as for instance the Mg”, ca™t,

Na orK' 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 to 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.

IT) 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

) of WO 00/35448 PCT/SE99/02315

Oo

SNS COO0CH, (2) : y 7 misoprostol flo OH 0]

SINT" Co0CH, =) OPh ) ~~ : enprostil

Ho OH 0) (4) COOCH,

R y ~ enisoprost

B fo OH 0)

INT Te . ) OOCH, : vd ~~ . Ho OH ®)

SISN=—"""co0CH, (2) : ’ ~~

Ho OH

Oo

ISNT" coocH, (2) : ’d

Ao OH

K rs 0

SINT" Co0CH, (1) : e (CH )n n=1-3 2 OH 2

Ho

The above compounds may be used in the form of their single enantiomers.

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 nisoldipine.

Use of the preparations

The dosage forms according to the present invention, are suitable for oral administration. 1s. 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 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 pg 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 pg 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 pg misoprostol, or 20 mg omeprazole and 400 pug misoprostol. In the latter one, misoprostol is preferably present in the form of an extended release formulation.

The optional calcium channel blocking agent may be present in an amount of 1 - 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 pg 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;

: Misoprostol 0.4 parts by weight

Ethanol 95% (w/v) 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% (w/w) of sodium stearyl fumarate was admixed.

Enteric coated pellets comprising omeprazole magnesium salt was prepared according to the following recipe;

Core material

Magnesium omeprazole 12.00 kg

Sugar spheres (non-pareil ) 12.00 kg

Hydroxypropyl methylcellulose 1.8 kg .

Water purified 354 kg 15 .

Separating layer

Core material (acc. to above) 23.50 kg

Hydroxypropyl cellulose 235kg

Talc 4.03 kg

Magnesium Stearate 0.34 kg

Water purified 48.00 kg

Enteric coating ~ Coated pellets (acc. to above) So 29.00kg ]

Methacrylic acid copolymer (30% suspension) 38.70 kg

Triethyl citrate 3.48 kg

' A WO 00/35448 PCT/SEY99/02315

Mono- and diglycerides (NF) 0.58 kg

Polysorbate 80 0.06 kg

Water purified 22.68 kg s 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 misoprostol- containing 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 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 HCl, 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 S- omeprazole 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 .

Non-pareil 25.0kg

Hydroxypropyl methylcellulose (HPMC) 3.0kg }

Polysorbate 80 0.4 kg

Water purified 93.6 kg

Separating layer

Core material (acc. to above) 50.0 kg

Hydroxypropyl cellulose 5.5 kg

Talc 20.5 kg

Magnesium Stearate 1.4 kg

Water purified oo oo 1938 kg

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 129 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. ve 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% (w/v) 125 g

Misoprostol 046 ¢

Water, purified 125 g

Hydroxypropyl methyl cellulose (HPMC) 6 cps 53 g

Colloidal silica (Aerosil 05 g

First the misoprostol was dissolved in the ethanol and then the water was added. The

HPMC was admixed and dissolved. Finally the Aerosil was dispersed in the solution. 1s 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

> a multiple unit tablet as described in Example 5, or filled into a capsule suitable for the desired dose.

Example 3. 5s Two-layer tablet with 400 pg 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 04 ’ Felodipine _ 10

Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) 10

Ethanol 95% (w/v) 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 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% (w/w) 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

Claims

_- » - Claims

1. An oral pharmaceutical dosage form comprising a H, K'-ATPase inhibitor and a s 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.

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

3. A dosage form according to claim 1, wherein the dosage form is a capsule formulation. 15

4. A dosage form according to any of claims 1-3, wherein the H, K -ATPase inhibitor compound is protected by an enteric coating layer, and optionally a separating + os layer is applied under the enteric coating separating the H, K -ATPase inhibitor from the ] enteric coating layer. 20

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

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

. . . + + eget

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

“or (Sy “ 48

+

8. A dosage form according to claim 6, wherein the H , K'-ATPase inhibitor is S- omeprazole magnesium salt. :

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

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

11. A dosage form according to 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 salt thereof.

12. A dosage form according to any 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 pg. . +

13. A dosage form according to any of claims 1-12, wherein the amount of the H , 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 pg.

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.

15. A tableted dosage form according to claim 2, wherein the tablet formulation is a multiple unit tableted dosage form comprising

. E a) the H, K -ATPase inhibitor in the form of enteric coating layered pellets, b) the gastric antisecretory prostaglandin analogue compound and optionally c) pharmaceutically acceptable excipients compressed together into a tablet, whereby the enteric coating layer covering the individual 5s 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 coating layered pellets are further covered with an over-coating layer comprising a film forming polymer and pharmaceutically acceptable excipients. :

18. A tableted dosage form according to any 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.

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

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

22. A tablet dosage form according to claim 2, wherein the tablet consists of two different layers, a first layer comprising the H, 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. s

23. A tableted dosage form according to claim 2, wherein the tablet comprises enteric coating layered pellets of the H, 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.

25. A tablet dosage form according to claim 2, wherein the tablet consists of two types of layered pellets, the first type consists of enteric coating layered pellets comprising the H, 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 tablet dosage form according to claim 22, wherein the tablet consists of enteric coating layered pellets comprising the H, K'-ATPase inhibitor, and pellets comprising the gastric antisecretory prostaglandin analogue incorporated in a matrix giving an extended release of the prostaglandin analogue. 2s 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 H, 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.

PCT/SE99/02315

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.

29. A process for the manufacture of a fixed dosage form comprising a H*, 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 tablets 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 H*, 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 prophylaxis of gastrointestinal disorders by administering to a host in need thereof an effective dosage form according to any of claims 1 to 27. AMENDED SHEET

LC PCT/SE99/02315

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 an effective dosage form according to any one of claims 1 to 27.

33. Use of dosage form according to any of claims 1 to 27 in the manufacture of a preparation for treatment or prophylaxis of gastrointestinal diseases.

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

35. 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 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 substance or composition for use in a method for treatment or prophylaxis of gastrointestinal diseases, said substance or composition comprising a dosage form according to any of claims 1 to 27, and said method comprising administering said substance or composition.

39. A substance or composition for use in a method for avoiding gastrointestinal side-effects normally associated with gastric antisecretory prostaglandin analogue AMENDED SHEET

PCT/SE99/02315 treatment, said substance or composition comprising a dosage form according to any of claims 1 to 27, and said method comprising administering said substance or composition.

40. A dosage form according to claim 1, substantially as herein described and illustrated.

41. A process according to claim 28, claim 29 or claim 30, substantially as herein described and illustrated.

42. A method according to claim 31, or claim 32, substantially as herein described and illustrated.

43. Use according to claim 33, or claim 34, substantially as herein described and illustrated.

44. A combination according to claim 35, substantially as herein described and illustrated.

45. A blister pack according to claim 36 or claim 37, substantially as herein described and illustrated.

46. A substance or composition for use in a method of treatment according to claim 38 or claim 39, substantially as herein described and illustrated.

47. A new dosage form, a new process for the manufacture of a dosage form, a new non-therapeutic method of treatment, a new use of a dosage form as claimed in any one of claims 1 to 27, a new combination, a new blister pack, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET