WO2000035448A1 - Nouvelle formulation pharmaceutique - Google Patents

Nouvelle formulation pharmaceutique Download PDF

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Publication number
WO2000035448A1
WO2000035448A1 PCT/SE1999/002315 SE9902315W WO0035448A1 WO 2000035448 A1 WO2000035448 A1 WO 2000035448A1 SE 9902315 W SE9902315 W SE 9902315W WO 0035448 A1 WO0035448 A1 WO 0035448A1
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WO
WIPO (PCT)
Prior art keywords
dosage form
tablet
pellets
form according
atpase inhibitor
Prior art date
Application number
PCT/SE1999/002315
Other languages
English (en)
Inventor
Arne Eek
Lars Josefsson
Per Johan Lundberg
Åke PILBRANT
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to EP99963820A priority Critical patent/EP1150677A1/fr
Priority to JP2000587768A priority patent/JP2002532425A/ja
Priority to BR9916224-5A priority patent/BR9916224A/pt
Priority to NZ511999A priority patent/NZ511999A/xx
Priority to KR1020017007344A priority patent/KR20010093822A/ko
Priority to IL14338699A priority patent/IL143386A0/xx
Priority to AU20186/00A priority patent/AU776079B2/en
Priority to CA002352613A priority patent/CA2352613A1/fr
Publication of WO2000035448A1 publication Critical patent/WO2000035448A1/fr
Priority to NO20012915A priority patent/NO20012915L/no
Priority to HK02103023.3A priority patent/HK1041224A1/zh

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • 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
  • 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.
  • 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.
  • NSAID Non-steroidal anti-inflammatory drugs
  • 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.
  • misoprostol for instance, may cause diarrhoea, abdominal pain and other adverse effects connected to the gastrointestinal system.
  • Dosage regimen for misoprostol 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.
  • the proton pump inhibitor, omeprazole has only few dosage related adverse effects.
  • misoprostol and a calcium channel blocking agent such as verapamil
  • a calcium channel blocking agent such as verapamil
  • One aspect of the present invention is to provide a fixed unit dosage form for oral
  • 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.
  • 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.
  • a fixed dosage form comprising a H , K -ATPase inhibitor, a gastric antisecretory prostaglandin analogue compound, and optionally a calcium channel blocking agent
  • 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.
  • 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.
  • One layer comprises the proton mememp 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.
  • 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 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.
  • the tablet cores are layered in the same way as described below for pellets preparation.
  • a prepared 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.
  • 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 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.
  • 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 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.
  • 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 pharmaceutically active agent.
  • a third population of units comprising a calcium blocking agent is included in the mixture.
  • 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 release characteristics. If suitable, an additional coating layer providing extended release may be applied onto the units.
  • 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.
  • a suitable concentration of a sodium hydrogen carbonate is included in a hydrophilic matrix together with a suitable concentration of a sodium hydrogen carbonate and formulated to pellets.
  • 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.
  • 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. (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 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.
  • the single unit 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 coated units.
  • 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.
  • 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.
  • the layer(s) may be applied by using powder coating or press-coating techniques.
  • excipients may be used in combination with the active substances in the claimed dosage forms.
  • excipients are for instance binding agents, fillers, pH-buffering substances, pigments and the like.
  • Separating layer 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.
  • the enteric coating layer material may be dispersed or dissolved in water or dissolved in suitable organic solvents.
  • 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 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 ⁇ m, preferably more than 20 ⁇ m. 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.
  • 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, 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 only limited by processing conditions.
  • 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
  • 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
  • the active substance i.e. the drug
  • 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,
  • TM 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.
  • binders for the hydrophobic matrix may be used either hydrophilic or hydrophobic polymers.
  • 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.
  • 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.
  • a slightly soluble or less soluble component 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.
  • 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.
  • 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 ⁇ m, more preferably 80 - 150 ⁇ m, a nominal pore diameter between 50 - 1 000 A, more preferably 500 - 1 000 A; and a surface area between 40 - 50 2 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 2 /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.
  • 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 am ⁇ t 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.
  • 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.
  • 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
  • N in the benzimidazole moiety means that one of the ring carbon atoms substituted by R - R9 optionally may be exchanged for a nitrogen atom without any substituents;
  • Rl , R2 and R3 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 R5 are the same or different and selected from hydrogen, alkyl and arylalkyl;
  • Rg' is hydrogen, halogen, trifluoromethyl, alkyl or alkoxy
  • R ⁇ -Ro are the same or different and selected from hydrogen, alkyl, alkoxy, halogen, halo- alkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolinyl, trifluoroalkyl, or adjacent groups Rg- R9 form ring structures which may be further substituted;
  • RlO is hydrogen or forms an alkylene chain together with R3 and R l i and R1 2 are the same or different and selected from hydrogen, halogen or alkyl.
  • the compound suitable for the formulations according to the present invention may be any compound suitable for the formulations according to the present invention.
  • 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 124495, 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.
  • 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.
  • 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
  • the above compounds may be used in the form of their single enantiomers.
  • 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.
  • the dosage forms according to the present invention are suitable for oral administration.
  • 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.
  • each dosage form will comprise 1-200 mg of the H , K -ATPase inhibitor and 80 - 1 000 ⁇ g of the gastric antisecretory prostaglandin analogue(-s).
  • each dosage form will comprise 5-80 mg of the H , K -ATPase inhibitor and 100 - 800 ⁇ g of the gastric antisecretory prostaglandin analogue(-s), and more preferably 10-40 mg of the H , K -ATPase inhibitor and 150 - 600 ⁇ g 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 ⁇ g misoprostol, or 20 mg omeprazole and 400 ⁇ g 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.
  • Two-layer tablet comprising misoprostol and omeprazole (magnesium salt).
  • one layer comprises 400 ⁇ g misoprostol in a hydrophilic matrix
  • 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
  • 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
  • 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 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;
  • 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).
  • Enteric coated pellets comprising magnesium salt of S-omeprazole, layered with misoprostol.
  • 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;
  • HPMC Hydroxypropyl methylcellulose
  • Methacrylic acid copolymer (30% suspension) 30.0 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;
  • HPMC Hydroxypropyl methyl cellulose
  • misoprostol was dissolved in the ethanol and then the water was added.
  • HPMC 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 a multiple unit tablet as described in Example 5, or filled into a capsule suitable for the desired dose.
  • Example 3 Two-layer tablet with 400 ⁇ 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.
  • omeprazole magnesium salt
  • Extended release granules comprising misoprostol and felodine are prepared according to the following recipe;
  • 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 misoprostol 400 ⁇ g, 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;
  • HPMC Hydroxypropyl methyl cellulose
  • Titanium dioxide 2 parts by weight
  • the coating is continued until average tablet weight has increased with 14 - 20 mg.
  • Capsule formulation comprising pantoprazole and misoprostol pellets. (40 mg pantoprazole and 200 ⁇ g misoprostol).
  • Pantoprazole enteric coated pellets is prepared according to the following recipe
  • Coated pellets (ace. to above) 200 g Methacrylic acid copolymer, 30% suspension 333 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;
  • misoprostol is dissolved in the ethanol and then the water is added.
  • the HPMC is
  • enteric coated pantoprazole pellets and pellets corresponding to 200 ⁇ g of misoprostol are filled into a No. 1 hard gelatin capsule.
  • Multiple unit tablet comprising lansoprazole and misoprostol pellets. (60 mg lansoprazole and 200 ⁇ g of misoprostol).
  • Lansoprazole pellets are prepared according ; to the following recipe:
  • the enteric coated pellets comprising lansoprazole are prepared as described in Example 1 , with lansoprazole replacing omeprazole.
  • Tablets mg/tablet Pellets comprising lansoprazole (according to above) approx. 285
  • microcrystalline celluloses and polyvinyl pyrrolidone are mixed to homogeneity.
  • lubricant sodium stearyl fumarate is admixed, and thereafter the lansoprazole comprising pellets and the misoprostol comprising pellets are added, and mixed until homogeneity.
  • Compression to tablets is done by compressing the mixture on a tablet machine equipped with 9x21 mm oval punches.
  • Two-layer tablet with 200 ⁇ g misoprostol in one layer and the other layer comprises 10 mg S-omeprazole (magnesium salt) containing delayed pulsed release pellets mixed with tableting excipients.
  • S-omeprazole magnesium salt
  • Granules comprising misoprostol are prepared according to this recipe; parts by weight Misoprostol 0.2
  • 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 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 % (w/w) of sodium stearyl fumarate is admixed.
  • a drug containing suspension is made according to the composition below; S-omeprazole Mg-salt lOOg
  • 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 bed.
  • the product weight is approx. 395 g.
  • a (water free) suspension containing in water highly swellable substances is prepared according to the following composition
  • Hydroxypropylcellulose LF (HPC-LF) 74 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.
  • a coating suspension is made according to the following formula
  • EtOH 99.5%) 1000 g
  • the ethylcellulose is dissolved in the ethanol during stioing, 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.
  • Pellets from above are enteric coated in a fluidized bed with a coating dispersion according to below;
  • 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.
  • Tableting excipient for mixing with enteric coated pellets is prepared by mixing the following ingredients to homogeneity;
  • 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. 270 mg S-Omeprazole magnesium salt comprising pellets (according to above) and 270 mg of the tableting excipient mix.
  • 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 ⁇ 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);
  • 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°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); Granules for tablet core 412
  • 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.
  • 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;
  • the coating of the tablets is continued until average tablet weight is approx 274 mg.
  • 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;
  • 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;
  • HPMC Hydroxypropyl methyl cellulose
  • Colloidal silica (Aerosil RTM) 0.50 parts by weight
  • misoprostol is dissolved in the ethanol and then the water is added.
  • the HPMC is
  • the coating is continued, until the average tablet weight is 296 mg.
  • Example 8 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 ⁇ g misoprostol.
  • Granules comprising omeprazole Mg-salt are prepared according to this recipe; mg/tablet Omeprazole Mg-salt 22.5
  • HPMC Hydroxypropyl methyl cellulose
  • HPMC Hydroxypropyl methyl cellulose
  • HPMC Hydroxypropyl methyl cellulose
  • 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°C in a drying oven. After milling through a 0.8 mm screen the obtained granules are mixed with tablet lubricant according the following composition;
  • 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;
  • HPMC Hydroxypropyl methyl cellulose
  • the HPMC is dissolved in the ethanol/water mixture.
  • the coating is continued until average tablet weight has increased with 4 mg (i.e. 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
  • 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;
  • HPMC Hydroxypropyl methyl cellulose
  • 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 are milled in an oscillating granulator equipped with a 1.0 mm screen.
  • 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.
  • Capsule formulation comprising 20 mg pantoprazole and 400 ⁇ g of misoprostol, the latter comprised in a hydrophilic matrix plug.
  • Pantoprazole pellets are prepared as described in Example 5, with lansoprazole replacing pantoprazole.
  • Extended release plug comprising misoprostol is prepared by first making a granulation according to this recipe;
  • 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;
  • 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.
  • Granules Granules for tablet cores are made according to the following composition
  • a granulating solution is prepared by dissolving the SLS in 460 parts of purified water.
  • 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°C over night.
  • Polyvinyl pyrrolidone cross-linked (PVP-XL) 20 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.
  • lag time controlling layer (semipermeable membrane).
  • the tablets are coated in a Wurster equipped fluidized bed coating apparatus with a coating suspe following composition
  • the tablets are coated and the coating is continued until average tablet weight is 134 mg.
  • the obtained tablets are coated in the same equipment as above with a coating suspension of the following composition;
  • the tablets are coated and the coating is continued until the average tablet weight is 162 mg. 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;
  • the coating of the tablets is continued until average tablet weight is approx 166 mg.
  • 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;
  • the tablets are coated and the coating is continued until average tablet weight is 177 mg.
  • 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;
  • HPMC Hydroxypropyl methyl cellulose
  • misoprostol is dissolved in the ethanol and then the water is added.
  • the HPMC is
  • the coating is continued until average tablet weight has increased with 3 mg (i.e. if starting average weight is 177 mg, to 180 mg).
  • omeprazole magnesium salt
  • Extended release granules comprising nifedipine was prepared according to this recipe;
  • 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 porous silica particles with this solution, according to the following recipe;
  • 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;
  • 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.
  • the tablets are coated 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;
  • HPMC Hydroxypropyl methyl cellulose
  • Titanium dioxide 2 parts by weight
  • the coating is continued until average tablet weight has increased with 15 - 20 mg.
  • 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.
  • Enteric coated pellets comprising S-omeprazole magnesium salt were prepared as described in Example 2.
  • the enteric coated pellets are coated with a solution of HPMC and misoprostol in a fluid bed apparatus, using the following composition;
  • HPMC Hydroxypropyl methyl cellulose
  • misoprostol is dissolved in the ethanol and then the water is added. Thereafter the
  • HPMC HPMC is admixed and dissolved. Finally the Aerosil is dispersed in the solution. The obtained pellets are classified by sieving. The prepared pellets may be compressed into a multiple unit tablet as described in Example 5, or filled into a capsule suitable for the desired dose.

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Abstract

La présente invention concerne de nouvelles formes posologiques pharmaceutiques par voie orale comprenant un inhibiteur de pompe à protons, c.-à-d. un inhibiteur de H+, K+ ATPase, un composé analogue de prostaglandine antisécrétoire gastrique et éventuellement un médicament supplémentaire tel qu'un agent bloquant des canaux calciques, ces nouvelles formes posologiques étant spécialement destinées au traitement et à la prophylaxie de troubles gastro-intestinaux. Plus spécifiquement, l'invention concerne de nouvelles formes posologiques comprenant l'oméprazole et le misoprostol. L'invention concerne également une combinaison des trois catégories de médicaments, c.-à-d. l'inhibiteur de H+, K+ ATPase, l'analogue de prostaglandine antisécrétoire gastrique et l'agent bloquant des canaux calciques. En outre, l'invention concerne une méthode de fabrication des formes posologiques décrites et leur utilisation dans le domaine médical, ainsi que des plaquettes sous blister comprenant ces médicaments.
PCT/SE1999/002315 1998-12-14 1999-12-10 Nouvelle formulation pharmaceutique WO2000035448A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
EP99963820A EP1150677A1 (fr) 1998-12-14 1999-12-10 Nouvelle formulation pharmaceutique
JP2000587768A JP2002532425A (ja) 1998-12-14 1999-12-10 新規な医薬製剤
BR9916224-5A BR9916224A (pt) 1998-12-14 1999-12-10 Forma de dosagem farmacêutica oral, processos para a manufatura de uma forma de dosagem fixa, para o tratamento e a profilaxia de distúrbios gastrintestinais e para evitar efeitos colaterias gastrintestinais, uso de uma forma de dosagem, combinação, e, embalagem tipo ampola
NZ511999A NZ511999A (en) 1998-12-14 1999-12-10 Pharmaceutical formulation comprising a H+,K+-ATPase inhibitor and a gastric antisecretory prostaglandin analogue
KR1020017007344A KR20010093822A (ko) 1998-12-14 1999-12-10 신규한 제약 제형
IL14338699A IL143386A0 (en) 1998-12-14 1999-12-10 Pharmaceutical dosage form comprising a h+, k+ -atpase inhibitor and gastric antisecretory prostaglandin analogue compound
AU20186/00A AU776079B2 (en) 1998-12-14 1999-12-10 New pharmaceutical formulation
CA002352613A CA2352613A1 (fr) 1998-12-14 1999-12-10 Nouvelle formulation pharmaceutique
NO20012915A NO20012915L (no) 1998-12-14 2001-06-13 Ny farmasöytisk formulering
HK02103023.3A HK1041224A1 (zh) 1998-12-14 2002-04-22 新的藥物製劑

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SE9804314A SE9804314D0 (sv) 1998-12-14 1998-12-14 New pharmaceutical formulation
SE9804314-4 1998-12-14

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CN (1) CN1334731A (fr)
AU (1) AU776079B2 (fr)
BR (1) BR9916224A (fr)
CA (1) CA2352613A1 (fr)
HK (1) HK1041224A1 (fr)
IL (1) IL143386A0 (fr)
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EP1150677A1 (fr) 2001-11-07
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ZA200104273B (en) 2002-08-26
KR20010093822A (ko) 2001-10-29
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AU776079B2 (en) 2004-08-26
NZ511999A (en) 2002-10-25
CA2352613A1 (fr) 2000-06-22
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JP2002532425A (ja) 2002-10-02

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