WO2005046634A2 - Gastric juice-resistant form of administration - Google Patents

Gastric juice-resistant form of administration Download PDF

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Publication number
WO2005046634A2
WO2005046634A2 PCT/CH2004/000677 CH2004000677W WO2005046634A2 WO 2005046634 A2 WO2005046634 A2 WO 2005046634A2 CH 2004000677 W CH2004000677 W CH 2004000677W WO 2005046634 A2 WO2005046634 A2 WO 2005046634A2
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WO
WIPO (PCT)
Prior art keywords
core
cores
salt
compound
film coating
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PCT/CH2004/000677
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German (de)
French (fr)
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WO2005046634A3 (en
WO2005046634A8 (en
Inventor
Waltraud Bueb
Bilge Bilgin-Zetler
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Siegfried Generics International Ag
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Publication of WO2005046634A2 publication Critical patent/WO2005046634A2/en
Publication of WO2005046634A3 publication Critical patent/WO2005046634A3/en
Publication of WO2005046634A8 publication Critical patent/WO2005046634A8/en

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    • 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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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

Definitions

  • the present invention relates to an enteric administration form, preferably in the form of granules, pellets or tablets, preferably as a film tablet, for oral administration, containing at least one 2- [(2-pyridyl) methylsulfinyl] benzimidazole compound or a salt of this compound, in particular 5- (Difluoromethoxy) -2- [(3, 4, -dimethoxy-2-pyridyl) methylsulfinyl] -lH-benzimidazole) (pantoprazole) or a salt thereof.
  • 2- [(2-pyridyl) methylsulfinyl] benzimidazole compound or a salt of this compound in particular 5- (Difluoromethoxy) -2- [(3, 4, -dimethoxy-2-pyridyl) methylsulfinyl] -lH-benzimidazole) (pantoprazole) or a salt thereof.
  • salts of these 2- [(2-pyridyl) methylsulfinyl] benzimidazole compounds are, for example, the sodium, potassium, calcium or magnesium salts.
  • the benzimidazole compounds mentioned are comparatively unstable. In the solid state, their stability is influenced in particular by heat, moisture and light, so that the content of active substance in the pharmaceutical administration form decreases over time. Numerous additives, which are usually used for the formulation of active pharmaceutical ingredients, are unusable for the formulation of the benzimidazole compounds mentioned, in particular for the formulation of pantoprazole, for reasons of stability and compatibility. this applies equally for the production of enteric forms of administration.
  • EP-A-244 380 describes oral administration forms for 2- [(2-pyridyl) methylsulfinyl] benzimidazole compounds which have a core, one or more intermediate layers and an enteric-resistant outer layer.
  • Analogous formulations are known from EP 0 247 983. These formulations are complex to manufacture.
  • the water content of the pellets should not exceed 1.5% by weight, as stated in EP 0 247 983, which means that the production process must also be carried out with the lowest possible water content, which has a negative effect on the quality of the end product.
  • 5- (difluoromethoxy) -2- • [(3, 4, -dimethoxy-2-pyridyl) methylsulfinyl] -IH-benzimidazole) (pantoprazole) or the salts thereof are known for use as H + / K + -ATPase inhibitors.
  • Such an administration form can be in the form of granules or pellets. These can be compressed into a tablet.
  • the granules and the pellets consist of a core and an enteric film coating, the core optionally being able to additionally have an intermediate layer.
  • the gastric juice-resistant administration form according to the invention also has a surprisingly high physical and chemical stability.
  • the present invention relates to an enteric administration form, preferably in the form of granules, as pellets or as a tablet, for oral administration, containing at least one optionally substituted 2- [(2-pyridyl) methylsulfinyl] benzimidazole compound or a salt of this compound , characterized in that
  • the granules and the pellets consist of a core and an enteric film coating, the core having an inner and an outer phase and optionally an intermediate layer;
  • the inner phase of the core as active ingredient at least one of the benzimidazole compounds mentioned together with an inorganic, alkaline compound, preferably sodium carbonate, and / or a salt of one of the benzimidazole compounds mentioned; and a combination of at least one sugar alcohol with pregelatinized starch, preferably in a weight ratio of 1:10 to 10: 1, preferably in a weight ratio of 1: 1 to 5: 1; and optionally further additives;
  • the outer phase of the core from at least one additive selected from the group comprising fillers Substances, flow regulators, lubricants and mold release agents is formed;
  • the intermediate layer optionally present consists of at least one polymeric polyol and / or a polyalkylene oxide and optionally further substances such as preferably hydroxypropyl cellulose (HPC), levothoxypropyl cellulose
  • Both the inner and / or the outer phase of the granule cores and / or the pellet cores, the intermediate layer which may be present, and the enteric coating film may optionally contain further additives.
  • the granules and pellets are preferably filled in sachets or hard gelatin capsules or compressed into tablets. Tablets, in particular film-coated tablets, are preferred.
  • the invention further relates to a method for producing the granules or pellets according to the invention [previously defined under (A)] consisting of a core and an enteric film coating, the core of which has an inner and an outer phase, which is characterized in that preferably in the granulation process, first of all the inner phase of the core, then the connections of the outer phase, optionally the connections of the intermediate layer and then the connections for the build-up of the gastric juice-resistant layer.
  • the invention further relates to a method for producing the tablet according to the invention [previously defined under (B)], which is characterized in that (i) granules and / or pellets which are provided with an enteric film coating, as described under (A ) (i), (A) (ii), (A) (iii) and (A) (iv) is defined, pressed; or (ii) granule cores and / or pellet cores (without their enteric film coating) according to the definition under (A) (i), (A) (ii) and (A) (iii) pressed into a tablet core and an enteric-resistant material thereon Apply film coating as defined in (A) (iv). Techniques known per se can be used for this.
  • the present invention also relates to granule cores and / or pellet cores (without their enteric film coating) as defined under (A) (i), (A) (ii) and ( ⁇ ) (iii) as starting materials for the production of the granules according to the invention, pellets [as defined under (A)] and tablets [as defined under (B)] and the use of these granule cores and / or pellet cores (without their enteric film coating) as defined under (A) (i), (A) (ii) and (A) (iii) for the manufacture of tablet cores.
  • the present invention also relates to the use of the administration forms according to the invention as H + / K + -ATPase inhibitors.
  • the administration forms according to the invention preferably contain the compound in salt form, preferably as an alkali or alkaline earth salt, e.g. as the sodium, potassium, calcium or magnesium salt, preferably as the sodium salt.
  • the administration form according to the invention preferably contains 5- (difluoromethoxy) -2- [(3,, -dimethoxy-2-pyridyl) methylsulfinyl] - 1H-benzimidazole) (pantoprazole) or a salt thereof, preferably pantoprazole sodium, preferably pantoprazole Sodium sesquihydrate.
  • 2- [(2-pyridyl) methylsulfinyl] benzimidazole compounds preferably contains 2- [(2-pyridyl) methylsulfinyl] benzimidazole compounds.
  • the administration form according to the invention contains or contains the cores, ie the granule cores, pellet cores and tablet cores, preferably as an admixture, an inorganic pharmaceutically acceptable basic reacting compound, preferably a Salt of a cation with an anion of a weak acid or a hydroxide, for example salts of sodium, potassium, calcium or magnesium, in each case as carbonate or as hydroxide, preferably sodium carbonate, sodium hydrogen carbonate or sodium hydroxide.
  • the molar ratio of the free base to the basic compound is preferably in the range from 1: 0.5 to 1: 3.5, preferably in the range from 1: 1.5 to 1: 3.
  • the administration form or the cores mentioned preferably contain both the 2- [(2-pyridyl) methylsulfinyl] benzimidazole compound in salt form and also an inorganic pharmaceutically acceptable basic salt.
  • the administration form or the named cores preferably contain the benzimidazole compound together with the basic salt, preferably pantoprazole sodium salt sesquihydrate (pantoprazole sodium sesquihydrate) together with an alkali salt or alkaline earth salt, in the weight ratio of the benzimidazole compound to the basic reacting compound of 1: 1 to 10: 1, preferably from 3: 1 to 10: 1.
  • the amount of 2- [(2-pyridyl) methylsulfinyl] benzimidazole compound and / or a salt thereof, e.g. on the tablet core is in the range of about 1% to 50%, preferably from 5% to 30%, based on the total weight of the tablet core.
  • the granules and the pellets contain a core with an inner phase and an outer phase Phase.
  • the additives present in the inner phase are selected from the group consisting of sugar alcohols, pregelatinized starch and sodium carbonate.
  • Sugar alcohols are, for example, mannitol (for example Pearlitol®, for example Pearlitol 400DC), xylitol, sorbitol and lactitol.
  • Pearlitol 400DC is mannitol with a molecular weight of 182.17 Da, a melting point of 166 ° C to 168 ° C and a true density of 1,514 g / cm 3 .
  • pregelatinized starch also referred to as “gelatinized” starch
  • gelatinized starch is to be understood as natural starch of vegetable origin, such as that obtained from potatoes, rice, wheat, corn, beans and other plants, for example, and which may be obtained by heating in water, if appropriate with the addition of a little acid or alkali.
  • These gelatinized starches have a reduced molecular weight and, due to the reduced viscosity, are very easy to process.
  • Gelatinized starch with a viscosity in the range from 5 mPa-s to 25 mPa-s is preferred, preferably in the range from 8 mPa-s to 13 mPa-s.
  • Pregelatinized maize starch is preferred.
  • the gelatinized starch preferably has an LOD value of up to 15% by weight (LOD ⁇ 15% by weight).
  • the LOD value (weight loss) is measured at an acid value (pH) of 4.5 - 8 and at a temperature of 100 to 130 ° C, the weight loss at this temperature not exceeding 15 wt. -% his should.
  • the LOD value essentially indicates the water loss or the moisture which is contained in the gelatinized starch.
  • the norm here is 120 ° C / 4 hours weight loss of 14% by weight (Ph.Eur.) Or at 130 ° C / 90 minutes a weight loss of 15% by weight (USP).
  • the sugar alcohol and the starch mentioned are preferably used in a weight ratio of 1:10 to 10: 1, preferably in a weight ratio of 1: 1 to 5: 1.
  • the sugar alcohols can be partially replaced by microcrystalline cellulose (eg Avicel®), the weight ratios given for the application.
  • Avicel PH 102 Ph.Eur / NF is microcrystalline cellulose with a molecular weight of approx. 36,000 Da, a rest angle of 49 ° to 34.4 °, a melting point of 260 ° C to 270 ° C and a true density of 1,512 g / cm 3 to 1,668 g / cm 3 .
  • the gelatinized starch can be partially replaced by sodium carboxymethyl starch (e.g. Pri ojel®) and / or sodium carboxymethyl cellulose (sodium croscarmellose, Ac-Di-Sol®).
  • sodium carboxymethyl starch e.g. Pri ojel®
  • sodium carboxymethyl cellulose sodium croscarmellose, Ac-Di-Sol®
  • the outer phase of the core consists of at least one additive selected from the group consisting of fillers, flow regulators, lubricants and mold release agents, and the inner phase of the tablet core and also the enteric coating can also contain such additives.
  • Preferred fillers are, for example, sugar alcohols, microcrystalline cellulose and starch. Preferred amounts are, for example, 0.5% to 90% by weight, preferably 1 to 50% by weight, based on the weight of the respective phase.
  • Preferred flow regulators are, for example, highly disperse silicon dioxide, highly disperse aluminum dioxide. Preferred amounts are, for example, 0.2% to 50% by weight, preferably 0.5% to 20% by weight, based on the total weight of the respective phase.
  • Preferred lubricants and mold release agents are calcium stearate, magnesium stearate, stearic acid or hydrogenated castor oil. Preferred amounts are, for example, 0.1 to 5% by weight, preferably 0.5 to 3% by weight, based on the weight of the respective phase.
  • the core contains an intermediate layer according to (A) (iii), it consists of at least one polymeric polyol and / or a polyalkylene oxide and possibly other substances such as preferably hydroxypropyl cellulose (HPC), methyl cellulose, lecithin and / or xanthan gum.
  • the polymeric polyols include, for example, polyvinyl alcohol (e.g. Airvol®, Elvanol®, Gohsenol®).
  • Polyalkylene oxides are e.g. Polyethylene oxides, polypropylene oxides, polyethylene / propylene oxides, preferred is polyethylene glycol (e.g. Macrogol®).
  • the polymeric polyols and / or polyalkylene oxides can be used alone or in combination. If polyols and polyalkylene oxides are used in a mixture, the ratio of the components is not critical.
  • the weight ratio of polyol to polyalkylene oxide can range from 1: 100 to 100: 1, preferably in the range from 1: 3 to 3: 1.
  • the total weight of this intermediate layer is preferably approximately 0.1 to 30% by weight, preferably approximately 0.2 to 20% by weight, based on the total weight of the core plus the intermediate layer.
  • Polyvinyl alcohol preferably has a molecular weight in the range of about 20 * 000 to 200 * 000, a melting point of preferably about 228 ° C, a refractive index preferably in the range of about 1.49 to 1.53 and a viscosity in the range of about 4 to 65 mPa-s.
  • Polyethylene glycol preferably has a molecular weight of about 190 to 25 * 000, a melting point in the range of about 37 ° C to 63 ° C, a refractive index in the range of about 1,459 to 1,467, a density in the range of about 1.11 to 1.21 g / cm 3 and a viscosity in the range of about 80 to 14,000 mPa-s.
  • the enteric film coating contains at least one compound from the group comprising methacrylic polymers, methacrylic acid / methyl methacrylate copolymers, and ethyl acrylate copolymer (Eudragit®, for example Eudragit L 30 D-55) and optionally other auxiliaries, preferably polyethylene glycol (Macrogol®, for example macrogol) 6000), possibly also a plasticizer, e.g. Triethyl citrate (TEC).
  • methacrylic polymers methacrylic acid / methyl methacrylate copolymers
  • ethyl acrylate copolymer ethyl acrylate copolymer
  • other auxiliaries preferably polyethylene glycol (Macrogol®, for example macrogol) 6000
  • TEC Triethyl citrate
  • Such enteric additives are state of the art and can also be used in this invention.
  • Methacrylic acid copolymers (Eudragit®, Kollicoat® MAE 30D) preferably have an acid value of 180-330, a true density of 0.811 g / cm 3 to 1.072 g / cm 3 , a refractive index from 1.38 to 1.393 and a viscosity of 3 mPa-s to 200 mPa-s.
  • the present invention also relates to a method for producing the film tablet according to the invention.
  • Preference is given to the process in which the inner phase of the granule cores and / or the pellet cores as defined under (A) (i) is first prepared, which is admixed with the outer phase as defined under (A) (ii) and the mixture obtained compressed into tablets.
  • An intermediate layer is then optionally applied to the tablet cores and then an enteric layer is applied.
  • the techniques known per se can be used for this.
  • the procedure is, for example, that the active ingredient is mixed with the additives of the inner phase, using purified water as the granulating liquid, and the inner phase is produced by means of granulation.
  • an extruder or another mixer and granulator known per se can be used for this purpose.
  • the additives of the outer phase are then added to the dried granules and the mixture obtained is compressed into tablets or tablet cores.
  • the intermediate layer which may be present and then the enteric layer from an aqueous dispersion of the corresponding additives are then applied to these tablet cores in a manner known per se.
  • the granulate cores (inner phase only) can also be processed into pellets together with the components of the outer phase, for example by means of a pelletizing machine or an extruder, and then coated with the intermediate layer which may be present and the enteric layer.
  • the granules obtained in this way can be used as such in a suitable Neten administration form, for example in hard gelatin capsules, used or processed into tablets.
  • the formulation according to the invention is preferably used as an enteric administration form, preferably in the form of pellets or tablets, preferably as a film-coated tablet.
  • the pellets can be provided with an enteric coating and in sachets or capsules such as Hard gelatin capsules are filled or pressed into tablets.
  • Example 1 Production of pellets
  • Pellets are produced from the following substances:
  • the procedure for producing the pellets is as follows: constituents a) to f) are mixed in a mixer, then granulating liquid g) qs (quantum satis) is added and the whole is mixed well. The wet mass is extruder and the granules are spheronized into pellets. The pellets are dried and classified according to particle size.
  • Granules or pellets are obtained which, after they have been coated with an intermediate layer and provided with an enteric coating, can be packaged and used as such or filled into hard gelatin capsules or compressed into tablets.
  • the spheronized pellets can also be provided with a coating, the intermediate layer according to (A) (iii). To do this, you spray the intermediate layer in liquid form. The coated pellets obtained are then coated with the enteric coating. Possible compositions for the intermediate layer are given in the following table.
  • Example 3 (Production of tablet cores by direct compression). The tablet cores are pressed directly from the following materials:
  • the components a), b), c) to g) or to h) are mixed in a mixer.
  • the mixture is pressed directly into tablets.
  • the intermediate layer according to (A) (iii) and the enteric coating are then applied.

Abstract

The invention relates to an entericcoated form of administration in the form of granules, pellets or tablets, for oral administration. The inventive form of administration comprises at least one optionally substituted 2-[(2-pyridyl)methylsulfinyl]benzimidazole compound or a salt of said compound, wherein (A) the granules and the pellets are constituted of a core and a gastric juice-resistant film coating, the core has an inner and an outer phase and optionally an intermediate phase, and (i) the inner phase of the core comprises as the active substance at least one benzimidazole compound and/or a salt thereof, and optionally an organic, alkaline-reacting compound; and selected additives; (ii) the outer phase of the core is constituted of at least one additive selected from the group including fillers, flowing agents, lubricating agents and mold-release agents; (iii) the optionally present intermediate layer consists of at least one polymer polyol and/or a polyalkylene oxide; and (iv) the gastric juice-resistant film coating is constituted of selected enteric compounds. The invention also relates to tablets produced on the basis of the aforementioned granules, pellets, granule cores, pellet cores or the compounds used therefor.

Description

Magensaftresistente VerabreichungsformEnteric-coated form of administration
Die vorliegende Erfindung betrifft eine magensaftresistente Verabreichungsform, vorzugsweise in Form von Granulaten, Pellets oder Tabletten, vorzugsweise als Filmtablette, für die orale Verabreichung, enthaltend mindestens eine 2- [(2- pyridyl)methylsulfinyl]benzimidazolverbindung oder ein Salz dieser Verbindung, insbesondere 5- (Difluormethoxy) -2- [ (3, 4, -dimethoxy-2-pyridyl)methylsulfinyl] -lH-benzimidazol) (Pantoprazol) oder ein Salz davon.The present invention relates to an enteric administration form, preferably in the form of granules, pellets or tablets, preferably as a film tablet, for oral administration, containing at least one 2- [(2-pyridyl) methylsulfinyl] benzimidazole compound or a salt of this compound, in particular 5- (Difluoromethoxy) -2- [(3, 4, -dimethoxy-2-pyridyl) methylsulfinyl] -lH-benzimidazole) (pantoprazole) or a salt thereof.
2- [ (2-pyridyl)methylsulfinyl]benzimidazolverbindungen und deren Salze, deren Herstellung sowie deren pharmazeutische Wirkungen sind bekannt. Insbesondere ist es bekannt, diese Verbindungen in Gegenwart von anorganischen alkalischen2- [(2-pyridyl) methylsulfinyl] benzimidazole compounds and their salts, their preparation and their pharmaceutical effects are known. In particular, it is known to use these compounds in the presence of inorganic alkaline
Salzen, wie beispielsweise in Gegenwart von Natrium-, Ka- • lium-, Calcium- oder Magnesiumsalzen, zu verwenden, um die Stabilität und Lagerfähigkeit der genannten Benzimidazol- verbindungen zu erhöhen. Salze dieser 2- [ (2-pyridyl)methyl- sulfinyl]benzimidazolverbindungen sind beispielsweise die Natrium-, Kalium-, Calcium- oder Magnesiumsalze.Such as, connections to the stability and shelf life of said benzimidazole to increase in the presence of sodium salts, Ka • lium-, calcium or magnesium salts, to be used. Salts of these 2- [(2-pyridyl) methylsulfinyl] benzimidazole compounds are, for example, the sodium, potassium, calcium or magnesium salts.
Die genannten Benzimidazolverbindungen sind vergleichsweise instabil. In festem Zustand wird deren Stabilität insbeson- dere durch Hitze, Feuchtigkeit und Licht beeinflusst, so dass der Gehalt an Aktivstoff in der pharmazeutischen Verabreichungsform im Laufe der Zeit abnimmt. Zahlreiche Zusatzstoffe, welche üblicherweise für die Formulierung von pharmazeutischen Wirkstoffen verwendet werden, sind für die Formulierung der genannten Benzimidazolverbindungen, insbesondere für die Formulierung von Pantoprazol, aus Gründen der Stabilität und Kompatibilität unbrauchbar. Dies gilt gleichermassen für die Herstellung von magensaftresistenten (enterischen) Verabreichungsformen.The benzimidazole compounds mentioned are comparatively unstable. In the solid state, their stability is influenced in particular by heat, moisture and light, so that the content of active substance in the pharmaceutical administration form decreases over time. Numerous additives, which are usually used for the formulation of active pharmaceutical ingredients, are unusable for the formulation of the benzimidazole compounds mentioned, in particular for the formulation of pantoprazole, for reasons of stability and compatibility. this applies equally for the production of enteric forms of administration.
In EP-A-244 380 werden orale Verabreichungsformen für 2- [ (2-pyridyl)methylsulfinyl]benzimidazolverbindungen beschrieben, welche einen Kern, eine oder mehrere Zwischenschichten und eine magensaftresistente aussere Schicht aufweisen. Analoge Formulierungen sind aus EP 0 247 983 bekannt. Diese Formulierungen sind aufwändig in der Herstel- lung. Zudem soll der Wassergehalt der Pellets gemäss Angabe in EP 0 247 983 nicht über 1.5 Gew.-% liegen, was bedingt, dass auch das Herstellungsverfahren mit möglichst niedrigem Wassergehalt ausgeführt werden uss, was die Qualität des Endprodukts negativ beeinflusst.EP-A-244 380 describes oral administration forms for 2- [(2-pyridyl) methylsulfinyl] benzimidazole compounds which have a core, one or more intermediate layers and an enteric-resistant outer layer. Analogous formulations are known from EP 0 247 983. These formulations are complex to manufacture. In addition, the water content of the pellets should not exceed 1.5% by weight, as stated in EP 0 247 983, which means that the production process must also be carried out with the lowest possible water content, which has a negative effect on the quality of the end product.
Es wurde nun gefunden, dass es möglich ist, eine aus zwei Schichten bestehende magensaftresistente (enterische) Verabreichungsform mit hoher Stabilität für die orale Verabreichung herzustellen, welche eine 2- [ (2-pyridyl)methylsul- finyl]benzimidazolverbindung oder ein Salz dieser Verbindung, insbesondere 5- (Difluormethoxy) -2- [ (3, , -dimethoxy-2- pyridyl)methylsulfinyl]-lH-benzimidazol) (Pantoprazol) oder ein Salz davon, enthält. Insbesondere 5- (Difluormethoxy) -2- • [ (3, 4, -dimethoxy-2-pyridyl)methylsulfinyl] -lH-benzimidazol) (Pantoprazol) oder die Salze davon sind bekannt für die Verwendung als H+/K+-ATPase-Hemmer. Eine solche Verabreichungsform kann in der Form als Granulat oder als Pellets vorliegen. Diese können zu einer Tablette verpresst werden. Das Granulat und die Pellets bestehen aus einem Kern und einem magensaftresistenten Filmüberzug, wobei der Kern gegebenenfalls zusätzlich eine Zwischenschicht aufweisen kann. Für die Herstellung der erfindungsge ässen Verabrei- cmαngsform können genügend Wasser für die Feuchtgranulie- rung, unter Ausschluss von organischen Lösungsmitteln, ein als trockenes Pulver vorliegendes Bindemittel, sowie ausgewählte kostengünstige Zusatzstoffe verwendet werden. Die erfindungsgemässe magensaftresistente Verabreichungsform weist zudem eine überraschend hohe physikalische und chemische Stabilität auf.It has now been found that it is possible to produce a two-layer, enteric, enteric form of administration with high stability for oral administration, which is a 2- [(2-pyridyl) methylsulfinyl] benzimidazole compound or a salt of this compound, in particular 5- (difluoromethoxy) -2- [(3,, -dimethoxy-2-pyridyl) methylsulfinyl] -lH-benzimidazole) (pantoprazole) or a salt thereof. In particular, 5- (difluoromethoxy) -2- • [(3, 4, -dimethoxy-2-pyridyl) methylsulfinyl] -IH-benzimidazole) (pantoprazole) or the salts thereof are known for use as H + / K + -ATPase inhibitors. Such an administration form can be in the form of granules or pellets. These can be compressed into a tablet. The granules and the pellets consist of a core and an enteric film coating, the core optionally being able to additionally have an intermediate layer. For the preparation of the administration form according to the invention, sufficient water for the wet granules tion, with the exclusion of organic solvents, a binder present as a dry powder, as well as selected inexpensive additives. The gastric juice-resistant administration form according to the invention also has a surprisingly high physical and chemical stability.
Die vorliegende Erfindung ist in den Patentansprüchen definiert. Insbesondere betrifft die vorliegende Erfindung eine magensaftresistente Verabreichungsform, vorzugsweise in der Form als Granulat, als Pellets oder als Tablette, für die orale Verabreichung, enthaltend mindestens eine gegebenenfalls substituierte 2- [ (2-pyridyl)methylsulfinyl]benzimid- azolverbindung oder ein Salz dieser Verbindung, dadurch ge- kennzeichnet, dassThe present invention is defined in the claims. In particular, the present invention relates to an enteric administration form, preferably in the form of granules, as pellets or as a tablet, for oral administration, containing at least one optionally substituted 2- [(2-pyridyl) methylsulfinyl] benzimidazole compound or a salt of this compound , characterized in that
(A) das Granulat und die Pellets aus einem Kern und einem magensaftresistenten Filmüberzug bestehen, wobei der Kern eine innere und eine aussere Phase und gegebenen- falls eine Zwischenschicht aufweist; (i) die innere Phase des Kerns als Wirkstoff mindestens eine der genannten Benzimidazolverbindungen zusammen mit einer anorganischen, alkalisch wirkenden, Verbindung, vorzugsweise Natriumcarbonat, und/oder ein Salz einer der genannten Benzimidazolverbindungen; sowie eine Kombination von mindestens einem Zuckeralkohol mit prägelatinisierter Stärke, vorzugsweise im Gewichtsverhältnis von 1:10 bis 10:1, vorzugsweise im Gewichtsverhältnis von 1:1 bis 5:1; und gegebenenfalls weitere Zusatzstoffe, enthält; (ii) die aussere Phase des Kerns aus mindestens einem Zusatzstoff ausgewählt aus der Gruppe enthaltend Füll- Stoffe, Fliessregulier-, Schmier- und Form- rennmittel, gebildet ist; (iii) die gegebenenfalls anwesende Zwischenschicht aus mindestens einem polymeren Polyol und/oder einem Poly- alkylenoxid und gegebenenfalls weiteren Stoffen wie vorzugsweise Hydroxypropylcellulose (HPC) , Lecithin, Xanthan Gummi, Methylcellulose, Polyvinylalkohol und/oder Polyethylenglykol besteht; und (iv) der magensaftresistente Filmüberzug, aus mindestens einer Verbindung der Gruppe enthaltend Methacrylsäure- poly ere, Methacrylsäure/Methacrylsäuremethylester- Copolymere, und Ethylacrylat-Copolymer, gebildet ist; und (B) die Tablette (i) aus Granulat und/oder Pellets, welche mit einem magensaftresistenten Filmüberzug versehen sind, wie dies unter (A) (i) , (A) (ii) , (A) (iii) und A(iv) definiert ist, besteht und welche zu einer Tablette verpresst sind; oder (ii) aus Granulatkernen und/oder Pelletkernen (ohne deren magensaftresistenten Filmüberzug) wie dies unter (A) (i) , (A) (ii) und A(iii) definiert ist besteht, welche zu einem Tablettenkern verpresst sind, und dieser Tablettenkern mit einem magensaftresistenten Filmüberzug gemäss der Definition von (A) (iv) und gegebenenfalls einer Zwischenschicht gemäss (A) (iii) versehen ist.(A) the granules and the pellets consist of a core and an enteric film coating, the core having an inner and an outer phase and optionally an intermediate layer; (i) the inner phase of the core as active ingredient at least one of the benzimidazole compounds mentioned together with an inorganic, alkaline compound, preferably sodium carbonate, and / or a salt of one of the benzimidazole compounds mentioned; and a combination of at least one sugar alcohol with pregelatinized starch, preferably in a weight ratio of 1:10 to 10: 1, preferably in a weight ratio of 1: 1 to 5: 1; and optionally further additives; (ii) the outer phase of the core from at least one additive selected from the group comprising fillers Substances, flow regulators, lubricants and mold release agents is formed; (iii) the intermediate layer optionally present consists of at least one polymeric polyol and / or a polyalkylene oxide and optionally further substances such as preferably hydroxypropyl cellulose (HPC), lecithin, xanthan gum, methyl cellulose, polyvinyl alcohol and / or polyethylene glycol; and (iv) the enteric film coating is formed from at least one compound from the group containing methacrylic acid polymers, methacrylic acid / methacrylic acid methyl ester copolymers, and ethyl acrylate copolymer; and (B) the tablet (i) made of granules and / or pellets, which are provided with an enteric film coating, as described under (A) (i), (A) (ii), (A) (iii) and A ( iv) is defined, exists and which are compressed into a tablet; or (ii) granule cores and / or pellet cores (without their enteric film coating) as defined under (A) (i), (A) (ii) and A (iii), which are pressed into a tablet core, and the latter Tablet core is provided with an enteric film coating according to the definition of (A) (iv) and optionally an intermediate layer according to (A) (iii).
Dabei können sowohl die innere und/oder die aussere Phase der Granulatkerne und/oder der Pelletkerne, die gegebenenfalls anwesende Zwischenschicht, sowie der magensaftresis- tente Filmüberzug, gegebenenfalls weitere Zusatzstoffe enthalten. Die Granulate und Pellets sind vorzugsweise in Sachets oder Hartgelatinekapseln abgefüllt oder zu Tabletten verpresst. Bevorzugt sind Tabletten, insbesondere Filmtabletten.Both the inner and / or the outer phase of the granule cores and / or the pellet cores, the intermediate layer which may be present, and the enteric coating film may optionally contain further additives. The granules and pellets are preferably filled in sachets or hard gelatin capsules or compressed into tablets. Tablets, in particular film-coated tablets, are preferred.
Die Erfindung betrifft im Weiteren ein Verfahren zur Herstellung der erfindungsgemässen [vorgehend unter (A) definierten] Granulate oder Pellets bestehend aus einem Kern und einem magensaftresistenten Filmüberzug, wobei deren Kern eine innere und eine aussere Phase aufweist, welches dadurch gekennzeichnet ist, dass man, vorzugsweise im Gra- nulierungsverfahren, zuerst die innere Phase des Kerns, herstellt, anschliessend die Verbindungen der äusseren Phase, gegebenenfalls die Verbindungen der Zwischenschicht und anschliessend die Verbindungen für den Aufbau der magen- saftresistenten Schicht, aufträgt.The invention further relates to a method for producing the granules or pellets according to the invention [previously defined under (A)] consisting of a core and an enteric film coating, the core of which has an inner and an outer phase, which is characterized in that preferably in the granulation process, first of all the inner phase of the core, then the connections of the outer phase, optionally the connections of the intermediate layer and then the connections for the build-up of the gastric juice-resistant layer.
Die Erfindung betrifft im Weiteren ein Verfahren zur Herstellung der erfindungsgemässen [vorgehend unter (B) definierten] Tablette, welches dadurch gekennzeichnet ist, dass man (i) Granulate und/oder Pellets, welche mit einem magensaftresistenten Filmüberzug versehen sind, wie dies unter (A) (i) , (A)(ii), (A) (iii) und (A) (iv) definiert ist, verpresst; oder (ii) Granulatkerne und/oder Pelletkerne (ohne deren magensaftresistenten Filmüberzug) gemäss der Defini- tion unter (A) (i), (A) (ii) und (A) (iii) zu einem Tablettenkern verpresst und auf diesen einen magensaftresistenten Filmüberzug gemäss der Definition von (A) (iv) aufträgt. Hierzu können an sich bekannte Techniken verwendet werden.The invention further relates to a method for producing the tablet according to the invention [previously defined under (B)], which is characterized in that (i) granules and / or pellets which are provided with an enteric film coating, as described under (A ) (i), (A) (ii), (A) (iii) and (A) (iv) is defined, pressed; or (ii) granule cores and / or pellet cores (without their enteric film coating) according to the definition under (A) (i), (A) (ii) and (A) (iii) pressed into a tablet core and an enteric-resistant material thereon Apply film coating as defined in (A) (iv). Techniques known per se can be used for this.
Die vorliegende Erfindung betrifft auch Granulatkerne und/- oder Pelletkerne (ohne deren magensaftresistenten Filmüberzug) gemäss der Definition unter (A) (i) , (A) (ii) und (Ä) (iii) als Ausgangsmaterialien für die Herstellung der erfindungsgemässen Granulate, Pellets [gemäss der Definition unter (A) ] und Tabletten [gemäss der Definition unter (B) ] sowie die Verwendung dieser Granulatkerne und/oder Pelletkerne (ohne deren magensaftresistenten Filmüberzug) gemäss der Definition unter (A) (i) , (A) (ii) und (A) (iii) für die Herstellung von Tablettenkernen.The present invention also relates to granule cores and / or pellet cores (without their enteric film coating) as defined under (A) (i), (A) (ii) and (Ä) (iii) as starting materials for the production of the granules according to the invention, pellets [as defined under (A)] and tablets [as defined under (B)] and the use of these granule cores and / or pellet cores (without their enteric film coating) as defined under (A) (i), (A) (ii) and (A) (iii) for the manufacture of tablet cores.
Die vorliegende Erfindung betrifft im Weiteren auch die Verwendung der erfindungsgemässen Verabreichungsformen als H+/K+-ATPase-Hemmer.The present invention also relates to the use of the administration forms according to the invention as H + / K + -ATPase inhibitors.
2- [ (2-pyridyl)methylsulfinyl] benzimidazolverbindungen und deren Salze sind beispielsweise aus EP 0 166 283 bekannt. Die dort genannten Verbindungen sind auch Teil der vorlie- genden Erfindung (incorporated herein by reference) . Bevorzugt enthalten die erfindungsgemässen Verabreichungsformen die Verbindung in Salzform, vorzugsweise als Alkali- oder Erdalkalisalz, z.B. als Natrium-, Kalium-, Calcium- oder Magnesiumsalz, vorzugsweise als Natriumsalz. Vorzugsweise enthält die erfindungsgemässe Verabreichungsform 5- (Di- fluormethoxy) -2- [ (3, , -dimethoxy-2-pyridyl)methylsulfinyl] - lH-benzimidazol) (Pantoprazol) oder ein Salz davon, vorzugsweise Pantoprazol-Natrium, vorzugsweise Pantoprazol- Natrium Sesquihydrat . Analoges gilt jeweils für andere 2- [ (2-pyridyl)methylsulfinyl]benzimidazol-Verbindungen.2- [(2-pyridyl) methylsulfinyl] benzimidazole compounds and their salts are known for example from EP 0 166 283. The compounds mentioned there are also part of the present invention (incorporated in by reference). The administration forms according to the invention preferably contain the compound in salt form, preferably as an alkali or alkaline earth salt, e.g. as the sodium, potassium, calcium or magnesium salt, preferably as the sodium salt. The administration form according to the invention preferably contains 5- (difluoromethoxy) -2- [(3,, -dimethoxy-2-pyridyl) methylsulfinyl] - 1H-benzimidazole) (pantoprazole) or a salt thereof, preferably pantoprazole sodium, preferably pantoprazole Sodium sesquihydrate. The same applies in each case to other 2- [(2-pyridyl) methylsulfinyl] benzimidazole compounds.
Neben der freien Base der 2- [ (2-pyridyl)methylsulfinyl] - benzimidazolverbindung (d.h. die Verbindung wurde nicht vorgängig in ein Salz umgewandelt) enthält die erfindungs- gemässe Verabreichungsform, bzw. enthalten die Kerne, d.h. die Granulatkerne, Pelletkerne und Tablettenkerne, vorzugsweise als Beimischung, eine anorganische pharmazeutisch annehmbare basisch reagierende Verbindung, vorzugsweise ein Salz eines Kations mit einem Anion einer schwachen Säure oder ein Hydroxid, beispielsweise Salze von Natrium, Kalium, Calcium oder Magnesium, jeweils als Carbonat oder als Hydroxyd, vorzugsweise Natriumcarbonat, Natriumhydrogencar- bonat oder Natriumhydroxid. Das Molverhältnis der freien Base zur basisch reagierenden Verbindung ist vorzugsweise im Bereich von 1 : 0.5 bis 1 : 3.5, vorzugsweise im Bereich von 1 : 1.5 bis 1 : 3.In addition to the free base of the 2- [(2-pyridyl) methylsulfinyl] benzimidazole compound (ie the compound was not previously converted into a salt), the administration form according to the invention contains or contains the cores, ie the granule cores, pellet cores and tablet cores, preferably as an admixture, an inorganic pharmaceutically acceptable basic reacting compound, preferably a Salt of a cation with an anion of a weak acid or a hydroxide, for example salts of sodium, potassium, calcium or magnesium, in each case as carbonate or as hydroxide, preferably sodium carbonate, sodium hydrogen carbonate or sodium hydroxide. The molar ratio of the free base to the basic compound is preferably in the range from 1: 0.5 to 1: 3.5, preferably in the range from 1: 1.5 to 1: 3.
Bevorzugt enthält die Verabreichungsform, bzw. enthalten die genannten Kerne, sowohl die 2- [ (2-pyridyl)methylsulfi- nyl]benzimidazolverbindung in Salzform als auch ein anorganisches pharmazeutisch annehmbares basisches Salz. Vorzugsweise enthält die Verabreichungsform, bzw. enthalten die genannten Kerne, die Benzimidazolverbindung zusammen mit dem basischen Salz, vorzugsweise Pantoprazol-Natriumsalz Sesquihydrat (Pantoprazol-Natrium Sesquihydrat) zusammen mit einem Alkalisalz oder Erdalkalisalz, im Gewichtsverhältnis der Benzimidazolverbindung zur basisch reagierenden Verbindung von 1:1 bis 10:1, vorzugsweise von 3:1 bis 10:1.The administration form or the cores mentioned preferably contain both the 2- [(2-pyridyl) methylsulfinyl] benzimidazole compound in salt form and also an inorganic pharmaceutically acceptable basic salt. The administration form or the named cores preferably contain the benzimidazole compound together with the basic salt, preferably pantoprazole sodium salt sesquihydrate (pantoprazole sodium sesquihydrate) together with an alkali salt or alkaline earth salt, in the weight ratio of the benzimidazole compound to the basic reacting compound of 1: 1 to 10: 1, preferably from 3: 1 to 10: 1.
Dabei beträgt die Menge an 2- [ (2-pyridyl)methylsulfinyl] - benzimidazolverbindung und/oder eines Salzes davon, welche pro Verabreichungsform, z.B. in einer Tablette, anwesend ist, jeweils etwa 5 mg bis 60 mg, vorzugsweise 10 mg, 20 mg oder 40 mg pro Tablette. Die Menge an 2- [ (2-pyridyl)methyl- sulfinyl] benzimidazolverbindung und/oder eines Salzes davon, bezogen z.B. auf den Tablettenkern, ist im Bereich von etwa 1% bis 50%, vorzugsweise von 5% bis 30%, bezogen auf das Gesamtgewicht des Tablettenkerns.The amount of 2- [(2-pyridyl) methylsulfinyl] benzimidazole compound and / or a salt thereof, which per administration form, e.g. in a tablet, is present, about 5 mg to 60 mg, preferably 10 mg, 20 mg or 40 mg per tablet. The amount of 2- [(2-pyridyl) methylsulfinyl] benzimidazole compound and / or a salt thereof, e.g. on the tablet core is in the range of about 1% to 50%, preferably from 5% to 30%, based on the total weight of the tablet core.
Das Granulat und die Pellets enthalten wie vorgehend erwähnt einen Kern mit einer inneren Phase und einer äusseren Phase. Die in der inneren Phase anwesenden Zusatzstoffe sind ausgewählt aus der Gruppe enthaltend Zuckeralkohole, prägelatinisierte Stärke und Natriumcarbonat . Zuckeralkohole sind beispielsweise Mannitol (z.B. Pearlitol®, z.B. Pearlitol 400DC) , Xylitol, Sorbitol und Lactitol. Pearlitol 400DC ist Mannitol mit einem Molekulargewicht von 182.17 Da, einem Schmelzpunkt von 166°C bis 168°C und einer wahren Dichte von 1.514 g/cm3.As mentioned above, the granules and the pellets contain a core with an inner phase and an outer phase Phase. The additives present in the inner phase are selected from the group consisting of sugar alcohols, pregelatinized starch and sodium carbonate. Sugar alcohols are, for example, mannitol (for example Pearlitol®, for example Pearlitol 400DC), xylitol, sorbitol and lactitol. Pearlitol 400DC is mannitol with a molecular weight of 182.17 Da, a melting point of 166 ° C to 168 ° C and a true density of 1,514 g / cm 3 .
Die Verwendung der Kombination eines Zuckeralkohols und gelatinisierter Stärke, wie z.B. von Mannitol und gelatinisierter Stärke in der inneren Phase und die damit erreichte Stabilität der erfindungsgemässen Filmtablette ist überraschend.The use of the combination of a sugar alcohol and gelatinized starch, e.g. of mannitol and gelatinized starch in the inner phase and the stability of the film tablet according to the invention thus achieved is surprising.
Unter dem Begriff "prägelatinisierte" Stärke, auch als "gelatinisierte" Stärke bezeichnet, ist natürliche Stärke pflanzlichen Ursprungs zu verstehen, wie solche beispielsweise aus Kartoffeln, Reis, Weizen, Mais, Bohnen und andern Pflanzen gewonnen wird und welche durch Erhitzen in Wasser, gegebenenfalls unter Zugabe von wenig Säure oder Alkali, behandelt wurde. Diese gelatinisierten Stärken besitzen ein reduziertes Molekulargewicht und sind, infolge der verringerten Viskosität, sehr gut verarbeitbar. Bevorzugt ist ge- latinisierte Stärke mit einer Viskosität im Bereich von 5 mPa-s bis 25 mPa-s, vorzugsweise im Bereich von 8 mPa-s bis 13 mPa-s. Bevorzugt ist prägelatinisierte Maisstärke. Die gelatinisierte Stärke hat vorzugsweise einen LOD-Wert von bis zu 15 Gew.-% (LOD <15 Gew.-%) . Der LOD-Wert (Ge- wichtsverlust) wird bei einem Säurewert (pH) von 4.5 - 8 und bei einer Temperatur von 100 bis 130°C gemessen, wobei der Gewichtsverlust bei dieser Temperatur bei einer Erhitzungsdauer von 4 Stunden nicht höher als 15 Gew.-% sein soll. Dabei gibt im vorliegenden Fall der LOD-Wert im wesentlichen den Wasserverlust an bzw. die Feuchtigkeit, welche in der gelatinisierten Stärke enthalten ist. Als Norm gilt hier 120°C/4 Stunden ein Gewichtsverlust von 14 Gew.-% (Ph.Eur.) oder bei 130°C/90 Minuten ein Gewichtsverlust von 15 Gew.-% (USP) .The term "pregelatinized" starch, also referred to as "gelatinized" starch, is to be understood as natural starch of vegetable origin, such as that obtained from potatoes, rice, wheat, corn, beans and other plants, for example, and which may be obtained by heating in water, if appropriate with the addition of a little acid or alkali. These gelatinized starches have a reduced molecular weight and, due to the reduced viscosity, are very easy to process. Gelatinized starch with a viscosity in the range from 5 mPa-s to 25 mPa-s is preferred, preferably in the range from 8 mPa-s to 13 mPa-s. Pregelatinized maize starch is preferred. The gelatinized starch preferably has an LOD value of up to 15% by weight (LOD <15% by weight). The LOD value (weight loss) is measured at an acid value (pH) of 4.5 - 8 and at a temperature of 100 to 130 ° C, the weight loss at this temperature not exceeding 15 wt. -% his should. In this case, the LOD value essentially indicates the water loss or the moisture which is contained in the gelatinized starch. The norm here is 120 ° C / 4 hours weight loss of 14% by weight (Ph.Eur.) Or at 130 ° C / 90 minutes a weight loss of 15% by weight (USP).
Bevorzugt verwendet man den Zuckeralkohol und die genannte Stärke im Gewichtsverhältnis von 1:10 bis 10:1, vorzugs- weise im Gewichtsverhältnis von 1:1 bis 5:1.The sugar alcohol and the starch mentioned are preferably used in a weight ratio of 1:10 to 10: 1, preferably in a weight ratio of 1: 1 to 5: 1.
Die Zuckeralkohole können teilweise ersetzt werden durch mikrokristalline Cellulose (z.B. Avicel®) , wobei die angegebenen Gewichtsverhältnisse für die Anwendung gelten. Avi- cel PH 102 Ph.Eur/NF ist mikrokristalline Cellulose mit einem Molekulargewicht von ca. 36 '000 Da, einem Ruhewinkel von 49° bis 34.4°, einem Schmelzpunkt von 260°C bis 270°C und einer wahren Dichte von 1.512 g/cm3 bis 1.668 g/cm3.The sugar alcohols can be partially replaced by microcrystalline cellulose (eg Avicel®), the weight ratios given for the application. Avicel PH 102 Ph.Eur / NF is microcrystalline cellulose with a molecular weight of approx. 36,000 Da, a rest angle of 49 ° to 34.4 °, a melting point of 260 ° C to 270 ° C and a true density of 1,512 g / cm 3 to 1,668 g / cm 3 .
Die gelatinisierte Stärke kann teilweise ersetzt werden durch Natriumcarboxymethylstärke (z.B. Pri ojel®) und/oder Natriumcarboxymethylcellulose (Natriumcroscarmellose, Ac- Di-Sol®) .The gelatinized starch can be partially replaced by sodium carboxymethyl starch (e.g. Pri ojel®) and / or sodium carboxymethyl cellulose (sodium croscarmellose, Ac-Di-Sol®).
Die aussere Phase des Kerns besteht aus mindestens einem Zusatzstoff ausgewählt aus der Gruppe enthaltend Füllstoffe, Fliessregulier-, Schmier- und Form-Trennmittel, wobei auch die innere Phase des Tablettenkerns sowie auch der magensaftresistente Überzug solche Zusatzstoffe enthalten können.The outer phase of the core consists of at least one additive selected from the group consisting of fillers, flow regulators, lubricants and mold release agents, and the inner phase of the tablet core and also the enteric coating can also contain such additives.
Bevorzugte Füllstoffe sind beispielsweise Zuckeralkohole, mikrokristalline Cellulose und Stärke. Bevorzugte Mengen sind beispielsweise 0.5% bis 90 Gew.-%, vorzugsweise 1 bis 50 Gew.-%, bezogen auf das Gewicht der jeweiligen Phase.Preferred fillers are, for example, sugar alcohols, microcrystalline cellulose and starch. Preferred amounts are, for example, 0.5% to 90% by weight, preferably 1 to 50% by weight, based on the weight of the respective phase.
Bevorzugte Fliessreguliermittel sind beispielsweise hoch- disperses Siliziumdioxid, hochdisperses Aluminiumdioxid. Bevorzugte Mengen sind beispielsweise 0.2% bis 50 Gew.-%, vorzugsweise 0.5% bis 20 Gew.-%, bezogen auf das Gesamtgewicht der jeweiligen Phase.Preferred flow regulators are, for example, highly disperse silicon dioxide, highly disperse aluminum dioxide. Preferred amounts are, for example, 0.2% to 50% by weight, preferably 0.5% to 20% by weight, based on the total weight of the respective phase.
Bevorzugte Schmier- und Form-Trennmittel sind Calciumstea- rat, Magnesiumstearat, Stearinsäure oder hydriertes Rizinusöl. Bevorzugte Mengen sind beispielsweise 0.1 bis 5 Gew.-%, vorzugsweise 0.5 bis 3 Gew.-%, bezogen auf das Gewicht der jeweiligen Phase.Preferred lubricants and mold release agents are calcium stearate, magnesium stearate, stearic acid or hydrogenated castor oil. Preferred amounts are, for example, 0.1 to 5% by weight, preferably 0.5 to 3% by weight, based on the weight of the respective phase.
Enthält der Kern eine Zwischenschicht gemäss (A) (iii) , so besteht diese aus mindestens einem polymeren Polyol und/- oder einem Polyalkylenoxid und allenfalls weiteren Stoffen wie vorzugsweise Hydroxypropylcellulose (HPC) , Methylcellu- lose, Lecithin und/oder Xanthan Gummi. Zu den polymeren Po- lyolen gehört beispielsweise Polyvinylalkohol (z.B. Air- vol®, Elvanol®, Gohsenol®) .If the core contains an intermediate layer according to (A) (iii), it consists of at least one polymeric polyol and / or a polyalkylene oxide and possibly other substances such as preferably hydroxypropyl cellulose (HPC), methyl cellulose, lecithin and / or xanthan gum. The polymeric polyols include, for example, polyvinyl alcohol (e.g. Airvol®, Elvanol®, Gohsenol®).
Polyalkylenoxide sind z.B. Polyethylenoxide, Polypropyleno- xide, Polyethylen-/propylenoxide, bevorzugt ist Polyethy- lenglykol (z.B. Macrogol®) .Polyalkylene oxides are e.g. Polyethylene oxides, polypropylene oxides, polyethylene / propylene oxides, preferred is polyethylene glycol (e.g. Macrogol®).
Die polymeren Polyole und/oder Polyalkylenoxide können alleine oder in Kombination verwendet werden. Verwendet man Polyole und Polyalkylenoxide im Gemisch, so ist das Verhältnis der Komponenten nicht kritisch. Das Gewichtsverhältnis von Polyol zu Polyalkylenoxid kann im Bereich von 1:100 bis 100:1 liegen, vorzugsweise im Bereich von 1:3 bis 3:1.The polymeric polyols and / or polyalkylene oxides can be used alone or in combination. If polyols and polyalkylene oxides are used in a mixture, the ratio of the components is not critical. The weight ratio of polyol to polyalkylene oxide can range from 1: 100 to 100: 1, preferably in the range from 1: 3 to 3: 1.
Das Gesamtgewicht dieser Zwischenschicht beträgt vorzugs- weise etwa 0.1 bis 30 Gew.-%, vorzugsweise etwa 0.2 bis 20 Gew.-%, bezogen auf das Gesamtgewicht von Kern plus Zwischenschicht .The total weight of this intermediate layer is preferably approximately 0.1 to 30% by weight, preferably approximately 0.2 to 20% by weight, based on the total weight of the core plus the intermediate layer.
Polyvinylalkohol hat vorzugsweise ein Molekulargewicht im Bereich von etwa 20*000 bis 200*000, einen Schmelzpunkt von vorzugsweise etwa 228 °C, einen Brechindex vorzugsweise im Bereich von etwa 1.49 bis 1.53 und eine Viskosität im Bereich von etwa 4 bis 65 mPa-s . Polyehtylenglykol hat ein Molekulargewicht vorzugsweise von etwa 190 bis 25*000, ei- nen Schmelzpunkt im Bereich von etwa 37 °C bis 63 °C, einen Brechindex im Bereich von etwa 1.459 bis 1.467, eine Dichte im Bereich von etwa 1.11 bis 1.21 g/cm3 und eine Viskosität im Bereich von etwa 80 bis 14 '000 mPa-s.Polyvinyl alcohol preferably has a molecular weight in the range of about 20 * 000 to 200 * 000, a melting point of preferably about 228 ° C, a refractive index preferably in the range of about 1.49 to 1.53 and a viscosity in the range of about 4 to 65 mPa-s. Polyethylene glycol preferably has a molecular weight of about 190 to 25 * 000, a melting point in the range of about 37 ° C to 63 ° C, a refractive index in the range of about 1,459 to 1,467, a density in the range of about 1.11 to 1.21 g / cm 3 and a viscosity in the range of about 80 to 14,000 mPa-s.
Der magensaftresistente Filmüberzug enthält mindestens eine Verbindung aus der Gruppe enthaltend Methacrylsäurepolyme- re, Methacrylsäure/Methacrylsäuremethylester-Copolymere, und Ethylacrylat-Copolymer (Eudragit®, z.B. Eudragit L 30 D-55) und gegebenenfalls weitere Hilfsstoffe, vorzugsweise Polyethylenglykol (Macrogol®, z.B. Macrogol 6000), allenfalls noch einen Weichmacher, z.B. Triethylcitrat (TEC) . Solche magensaftresistente Zusatzstoffe entsprechen dem Stand der Technik und können auch in dieser Erfindung verwendet werden.The enteric film coating contains at least one compound from the group comprising methacrylic polymers, methacrylic acid / methyl methacrylate copolymers, and ethyl acrylate copolymer (Eudragit®, for example Eudragit L 30 D-55) and optionally other auxiliaries, preferably polyethylene glycol (Macrogol®, for example macrogol) 6000), possibly also a plasticizer, e.g. Triethyl citrate (TEC). Such enteric additives are state of the art and can also be used in this invention.
Methacrylsäure-Copolymere (Eudragit®, Kollicoat® MAE 30D) haben vorzugsweise einen Säurewert von 180-330, eine wahre Dichte von 0.811 g/cm3 bis 1.072 g/cm3, einen Brechindex von 1.38 bis 1.393 und einer Viskosität von 3 mPa-s bis 200 mPa-s.Methacrylic acid copolymers (Eudragit®, Kollicoat® MAE 30D) preferably have an acid value of 180-330, a true density of 0.811 g / cm 3 to 1.072 g / cm 3 , a refractive index from 1.38 to 1.393 and a viscosity of 3 mPa-s to 200 mPa-s.
Die vorliegende Erfindung betrifft, wie eingangs erwähnt, auch ein Verfahren zur Herstellung der erfindungsgemässen Filmtablette. Bevorzugt ist das Verfahren worin man zuerst die innere Phase der Granulatkerne und/oder der Pelletkerne wie dies unter (A) (i) definiert ist, herstellt, dieser die aussere Phase gemäss der Definition unter (A) (ii) beimischt und das erhaltene Gemisch zu Tabletten verpresst. Anschliessend wird auf die Tablettenkerne gegebenenfalls eine Zwischenschicht und anschliessend eine magensaftresistente Schicht aufgebracht. Hierzu können die an sich bekannten Techniken verwendet werden. Dabei geht man beispielsweise so vor, dass man den Wirkstoff mit den Zusatzstoffen der inneren Phase mischt, wobei gereinigtes Wasser als Granulierflüssigkeit verwendet wird, und die innere Phase mittels Granulierung herstellt. Hierzu kann beispielsweise ein Extruder oder ein anderer an sich bekannter Mischer und Granulator verwendet werden. Den getrockneten Granulaten werden anschliessend die Zusatzstoffe der äusseren Phase beigemischt und das erhaltene Gemisch zu Tabletten bzw. Tablettenkernen verpresst. Auf diese Tablettenkerne werden dann die gegebenenfalls anwesende Zwischenschicht und an- schliessend die magensaftresistente Schicht aus einer wässerigen Dispersion der entsprechenden Zusatzstoffe in an sich bekannter Weise aufgebracht. Die Granulatkerne (nur innere Phase) können aber auch, z.B. mittels einer Pelletiermaschine oder eines Extruders, zusammen mit den Ko po- nenten der äusseren Phase zu Pellets verarbeitet und anschliessend mit der gegebenenfalls anwesenden Zwischenschicht und der enterischen Schicht beschichtet werden. Das derart erhaltene Granulat kann als solches in einer geeig- neten Verabreichungsform, z.B. in Hartgelatinekapseln, verwendet oder zu Tabletten verarbeitet werden.As mentioned at the beginning, the present invention also relates to a method for producing the film tablet according to the invention. Preference is given to the process in which the inner phase of the granule cores and / or the pellet cores as defined under (A) (i) is first prepared, which is admixed with the outer phase as defined under (A) (ii) and the mixture obtained compressed into tablets. An intermediate layer is then optionally applied to the tablet cores and then an enteric layer is applied. The techniques known per se can be used for this. The procedure is, for example, that the active ingredient is mixed with the additives of the inner phase, using purified water as the granulating liquid, and the inner phase is produced by means of granulation. For example, an extruder or another mixer and granulator known per se can be used for this purpose. The additives of the outer phase are then added to the dried granules and the mixture obtained is compressed into tablets or tablet cores. The intermediate layer which may be present and then the enteric layer from an aqueous dispersion of the corresponding additives are then applied to these tablet cores in a manner known per se. The granulate cores (inner phase only) can also be processed into pellets together with the components of the outer phase, for example by means of a pelletizing machine or an extruder, and then coated with the intermediate layer which may be present and the enteric layer. The granules obtained in this way can be used as such in a suitable Neten administration form, for example in hard gelatin capsules, used or processed into tablets.
Die erfindungsgemasse Formulierung wird vorzugsweise als magensaftresistente Verabreichungsform, vorzugsweise in Form von Pellets oder Tabletten, vorzugsweise als Filmtablette, verwendet. Die Pellets können mit einem magensaftresistenten Überzug versehen und in Sachets oder Kapseln wie z.B. Hartgelatinekapseln abgefüllt oder zu Tabletten verpresst werden.The formulation according to the invention is preferably used as an enteric administration form, preferably in the form of pellets or tablets, preferably as a film-coated tablet. The pellets can be provided with an enteric coating and in sachets or capsules such as Hard gelatin capsules are filled or pressed into tablets.
Die folgenden Beispiele erläutern die Erfindung.The following examples illustrate the invention.
Beispiel 1 (Herstellung von Pellets) Pellets werden aus den folgenden Stoffen hergestellt:Example 1 (production of pellets) Pellets are produced from the following substances:
Figure imgf000014_0001
Figure imgf000014_0001
Für die Herstellung der Pellets geht man wie folgt vor: Bestandteile a) bis f) werden in einem Mixer vermischt, dann wird Granulierflüssigkeit g) q.s. (quantum satis) zugegeben und das Ganze gut gemischt. Die nasse Masse wird durch ei- nen Extruder gepresst und das Granulat zu Pellets sphäroni- siert. Die Pellets werden getrocknet und nach Partikelgrös- se klassifiziert.The procedure for producing the pellets is as follows: constituents a) to f) are mixed in a mixer, then granulating liquid g) qs (quantum satis) is added and the whole is mixed well. The wet mass is extruder and the granules are spheronized into pellets. The pellets are dried and classified according to particle size.
Man erhält Granulat oder Pellets, welche - nachdem sie mit einer Zwischenschicht überzogen und einem magensaftresistenten Überzug versehen worden sind - als solche abgepackt und verwendet oder in Hartgelatinekapseln abgefüllt oder zu Tabletten verpresst werden können.Granules or pellets are obtained which, after they have been coated with an intermediate layer and provided with an enteric coating, can be packaged and used as such or filled into hard gelatin capsules or compressed into tablets.
Ebenso kann man die sphäronisierten Pellets mit einem Überzug, der Zwischenschicht gemäss (A) (iii) , versehen. Hiezu geht man so vor, dass man die Zwischenschicht in flüssiger Form aufsprüht. Anschliessend werden die erhaltenen beschichteten Pellets mit dem magensaftresistenten Überzug versehen. Mögliche Zusammensetzungen für die Zwischenschicht sind in der folgenden Tabelle angegeben.The spheronized pellets can also be provided with a coating, the intermediate layer according to (A) (iii). To do this, you spray the intermediate layer in liquid form. The coated pellets obtained are then coated with the enteric coating. Possible compositions for the intermediate layer are given in the following table.
Figure imgf000015_0001
1) HPC (Klucel®) 2) Metolose® 3) Airvol®, Elvanol®, Gohsenol® 4) Macrogol® Beispiel 2 (Herstellung von Tablettenkernen aus Granulat) Die Tablettenkerne werden aus den folgenden Stoffen hergestellt:
Figure imgf000015_0001
1) HPC (Klucel®) 2) Metolose® 3) Airvol®, Elvanol®, Gohsenol® 4) Macrogol® Example 2 (Production of tablet cores from granulate) The tablet cores are produced from the following substances:
Figure imgf000016_0001
Figure imgf000016_0001
Die Bestandteile a) , b) , c) d ) und e) werden in einem Mixer vermischt, dann wird Granulierflüssigkeit f) q.s. zugegeben. Das getrocknete Granulat wird mit den Bestandteilen g) bis k) vermischt und das Gemisch zu Tabletten verpresst. Anschliessend werden die Zwischenschicht gemäss (A) (iii) und der magensaftresistente Überzug aufgebracht, wie dies bereits vorgehend beschrieben ist. Beispiel 3: (Herstellung von Tablettenkernen durch Direktverpressung) . Die Tablettenkerne werden aus folgenden Stoffen direkt verpresst:The components a), b), c) d) and e) are mixed in a mixer, then granulating liquid f) qs is added. The dried granules are mixed with the components g) to k) and the mixture is compressed into tablets. The intermediate layer according to (A) (iii) and the enteric coating are then applied, as has already been described above. Example 3: (Production of tablet cores by direct compression). The tablet cores are pressed directly from the following materials:
Beispiel 3aExample 3a
Figure imgf000017_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000018_0001
Die Bestandteile a) , b) , c) bis g) oder bis h) werden in einem Mixer vermischt. Das Gemisch wird direkt zu Tabletten verpresst. Anschliessend werden die Zwischenschicht gemäss (A) (iii) und der magensaftresistente Überzug aufgebracht. The components a), b), c) to g) or to h) are mixed in a mixer. The mixture is pressed directly into tablets. The intermediate layer according to (A) (iii) and the enteric coating are then applied.

Claims

Patentansprüche claims
1. Magensaftresistente Verabreichungsform, vorzugsweise in der Form als Granulat, als Pellets oder als Tablette, für die orale Verabreichung, enthaltend mindestens eine gegebenenfalls substituierte 2- [ (2-pyridyl)methylsulfi- nyl] benzimidazolverbindung oder ein Salz dieser Verbindung, dadurch gekennzeichnet, dass1. enteric administration form, preferably in the form of granules, as pellets or as a tablet, for oral administration, containing at least one optionally substituted 2- [(2-pyridyl) methylsulfinyl] benzimidazole compound or a salt of this compound, characterized in that that
(A) das Granulat und die Pellets aus einem Kern und einem magensaftresistenten Filmüberzug bestehen, wobei der Kern eine innere und eine aussere Phase und gegebenenfalls eine Zwischenschicht aufweist; (i) die innere Phase des Kerns als Wirkstoff mindestens eine der genannten Benzimidazolverbindungen zusammen mit einer anorganischen, alkalisch wirkenden, Verbindung, vorzugsweise Natriumcarbonat, und/oder ein Salz einer der genannten Benzimidazolverbindungen; sowie eine Kombination von mindestens einem Zuckeralkohol mit prägelatinisierter Stärke, vorzugsweise im Gewichtsverhältnis von 1:10 bis 10:1, und gegebenenfalls weitere Zusatzstoffe, enthält; (ii) die aussere Phase des Kerns aus mindestens einem Zusatzstoff ausgewählt aus der Gruppe enthaltend Füll- Stoffe, Fliessregulier-, Schmier- und Form-Trennmittel,, gebildet ist; (iii) die gegebenenfalls anwesende Zwischenschicht aus mindestens einem polymeren Polyol und/oder einem Polyalkylenoxid und gegebenenfalls weiteren Stoffen, vor- zugsweise Hydroxypropylcellulose, Lecithin, Xanthan Gummi, Methylcellulose, Polyvinylalkohol und/oder Po- lyethylenglykol, besteht; und (iv) der magensaftresistente Filmüberzug, aus mindestens einer Verbindung der Gruppe enthaltend Methacrylsäure- polymere, Methacrylsäure/Methacrylsäuremethylester- Copolymere, und Ethylacrylat-Copolymer, gebildet ist; und(A) the granules and the pellets consist of a core and an enteric film coating, the core having an inner and an outer phase and optionally an intermediate layer; (i) the inner phase of the core as active ingredient at least one of the benzimidazole compounds mentioned together with an inorganic, alkaline compound, preferably sodium carbonate, and / or a salt of one of the benzimidazole compounds mentioned; and also a combination of at least one sugar alcohol with pregelatinized starch, preferably in a weight ratio of 1:10 to 10: 1, and optionally further additives; (ii) the outer phase of the core is formed from at least one additive selected from the group comprising fillers, flow regulators, lubricants and mold release agents; (iii) the intermediate layer which may be present consists of at least one polymeric polyol and / or a polyalkylene oxide and optionally further substances, preferably hydroxypropyl cellulose, lecithin, xanthan gum, methyl cellulose, polyvinyl alcohol and / or polyethylene glycol; and (iv) the enteric film coating is formed from at least one compound from the group comprising methacrylic acid polymers, methacrylic acid / methacrylic acid methyl ester copolymers, and ethyl acrylate copolymer; and
(B) die Tablette (i) aus Granulat und/oder Pellets, welche mit einem magensaftresistenten Filmüberzug versehen sind, wie dies unter (A) (i) , (A) (ii) , (A) (iii) und A(iv) definiert ist, besteht und welche zu einer Tab- lette verpresst sind; oder (ii) aus Granulatkernen und/oder Pelletkernen (ohne deren magensaftresistenten Filmüberzug) wie dies unter (A) (i) , (A) (ii) und A(iii) definiert ist besteht, welche zu einem Tablettenkern verpresst sind, und dieser Tablettenkern mit einem a- gensaftresistenten Filmüberzug gemäss der Definition von (A) (iv) versehen ist.(B) the tablet (i) made of granules and / or pellets, which are provided with an enteric film coating, as described under (A) (i), (A) (ii), (A) (iii) and A (iv ) is defined, exists and which are pressed into a tablet; or (ii) granule cores and / or pellet cores (without their enteric film coating) as defined under (A) (i), (A) (ii) and A (iii), which are pressed into a tablet core, and the latter Tablet core is provided with an eye-resistant film coating according to the definition of (A) (iv).
2. Verabreichungsform nach Anspruch 1, dadurch gekennzeichnet, dass die innere und/oder die aussere Phase der Granulatkerne und/oder der Pelletkerne, die gegebenenfalls anwesende Zwischenschicht, als auch der magensaftresistente Filmüberzug weitere Zusatzstoffe enthalten.2. Administration form according to claim 1, characterized in that the inner and / or the outer phase of the granule cores and / or the pellet cores, the intermediate layer which may be present, and also the enteric film coating contain further additives.
3. Verabreichungsform nach Anspruch 1 oder 2, dadurch ge- kennzeichnet, dass diese die Benzimidazolverbindung als Alkali- oder Erdalkalisalz, vorzugsweise als Natrium-, Kalium-, Calcium- oder Magnesiumsalz, vorzugsweise als Natriumsalz enthält.3. Administration form according to claim 1 or 2, characterized in that it contains the benzimidazole compound as an alkali or alkaline earth metal salt, preferably as a sodium, potassium, calcium or magnesium salt, preferably as a sodium salt.
4. Verabreichungsform nach einem der Ansprüche 1-3, dadurch gekennzeichnet, dass diese als Benzimidazolverbindung 5- (Difluormethoxy) -2- [ (3, 4, -dimethoxy-2-pyridyl)methyl- su-lfinyl] -lH-benzimidazol) (Pantoprazol) oder ein Salz da- von, vorzugsweise Pantoprazol-Natrium, vorzugsweise Pan- toprazol-Natrium Sesquihydrat, enthält.4. Dosage form according to one of claims 1-3, characterized in that it is a benzimidazole compound 5- (difluoromethoxy) -2- [(3, 4, -dimethoxy-2-pyridyl) methyl-su-lfinyl] -lH-benzimidazole) (Pantoprazole) or a salt there- of, preferably pantoprazole sodium, preferably pantoprazole sodium, contains sesquihydrate.
5. Verabreichungsform nach einem der Ansprüche 1-4, da- durch gekennzeichnet, dass diese neben der freien Base der Benzimidazolverbindung, als Beimischung in den Kernen (Granulatkerne, Pelletkerne und Tablettenkerne) eine anorganische pharmazeutisch annehmbare basisch reagierende Verbindung, vorzugsweise ein Salz eines Kations mit einem Anion einer schwachen Säure oder ein Hydroxid, vorzugsweise ein Salz von Natrium, Kalium, Calcium oder Magnesium, jeweils als Carbonat oder als Hydroxyd, vorzugsweise Natriumcarbonat oder Natriumhydroxid, enthält.5. Administration form according to any one of claims 1-4, characterized in that, in addition to the free base of the benzimidazole compound, as an admixture in the cores (granule cores, pellet cores and tablet cores), an inorganic pharmaceutically acceptable basic reaction compound, preferably a salt of a cation with an anion of a weak acid or a hydroxide, preferably a salt of sodium, potassium, calcium or magnesium, in each case as carbonate or as hydroxide, preferably sodium carbonate or sodium hydroxide.
6. Verabreichungsform nach einem der Ansprüche 1-4, dadurch gekennzeichnet, dass diese sowohl die Benzimidazolverbindung in Salzform als auch als Beimischung in den Kernen eine anorganische pharmazeutisch annehmbare basisch reagierende Verbindung, vorzugsweise ein Salz eines Kations mit einem Anion einer schwachen Säure oder ein Hydroxid, beispielsweise Salze von Natrium, Kalium, Calcium oder Magnesium, jeweils als Carbonat oder als Hydroxyd, vorzugsweise Natriumcarbonat oder Natriumhydroxid, enthält, vorzugsweise im Gewichtsverhältnis der Benzimidazolverbindung zur basisch reagierenden Verbindung von 1:1 bis 10:1, vorzugsweise, von 3:1 bis 10:1.6. Administration form according to any one of claims 1-4, characterized in that it contains both the benzimidazole compound in salt form and as an admixture in the kernels an inorganic pharmaceutically acceptable basic reaction compound, preferably a salt of a cation with an anion of a weak acid or a hydroxide , for example salts of sodium, potassium, calcium or magnesium, in each case as carbonate or as hydroxide, preferably sodium carbonate or sodium hydroxide, preferably in the weight ratio of the benzimidazole compound to the basic compound of 1: 1 to 10: 1, preferably 3: 1 to 10: 1.
7. Verabreichungsform nach einem der Ansprüche 1-6, dadurch gekennzeichnet, dass diese die Benzimidazolverbindung und/oder ein Salz davon jeweils in einer Menge von etwa 5 mg bis 60 mg, vorzugsweise 10 mg, 20 mg oder 40 mg pro Verabreichungsform enthält. 7. Administration form according to one of claims 1-6, characterized in that it contains the benzimidazole compound and / or a salt thereof in an amount of about 5 mg to 60 mg, preferably 10 mg, 20 mg or 40 mg per administration form.
8. Verabreichungsform nach einem der Ansprüche 1-7, dadurch gekennzeichnet, dass die Zuckeralkohole ausgewählt sind aus der Gruppe enthaltend Mannitol, Xylitol, Sorbitol und Lactitol.8. Administration form according to one of claims 1-7, characterized in that the sugar alcohols are selected from the group comprising mannitol, xylitol, sorbitol and lactitol.
9. Verabreichungsform nach einem der Ansprüche 1-8, dadurch gekennzeichnet, dass die gelatinisierte Stärke, vorzugsweise Maisstärke, einen LOD-Wert von bis zu 15 Gew.-% (< 15 Gew.-%) und eine Viskosität im Bereich von 5 mPa-s bis 25 mPa-s, vorzugsweise im Bereich von 8 mPa-s bis 13 mPa-s, aufweist.9. Dosage form according to one of claims 1-8, characterized in that the gelatinized starch, preferably corn starch, has an LOD value of up to 15% by weight (<15% by weight) and a viscosity in the range of 5 mPa -s to 25 mPa-s, preferably in the range from 8 mPa-s to 13 mPa-s.
10. Verabreichungsform nach einem der Ansprüche 1-9, dadurch gekennzeichnet, dass den Zuckeralkohol und die gela- tinisierte Stärke im Gewichtsverhältnis von 1:1 bis 5:1, verwendet .10. The dosage form according to any one of claims 1-9, characterized in that the sugar alcohol and the gelatinized starch are used in a weight ratio of 1: 1 to 5: 1.
11. Verabreichungsform nach einem der Ansprüche 1-10, dadurch gekennzeichnet, dass der Zuckeralkohol teilweise er- setzt ist durch mikrokristalline Cellulose.11. Administration form according to one of claims 1-10, characterized in that the sugar alcohol is partially replaced by microcrystalline cellulose.
12. Verabreichungsform nach einem der Ansprüche 1-11, dadurch gekennzeichnet, dass die gelatinisierte Stärke teilweise ersetzt ist durch Natriumcarboxymethylstärke und/oder Natriumcarboxymethylcellulose.12. Administration form according to one of claims 1-11, characterized in that the gelatinized starch is partially replaced by sodium carboxymethyl starch and / or sodium carboxymethyl cellulose.
13. Verabreichungsform nach einem der Ansprüche 1-12, dadurch gekennzeichnet, dass als Füllstoff Zuckeralkohol, mikrokristalline Cellulose und/oder Stärke verwendet wird, vorzugsweise in einer Menge von 0.5% bis 90 Gew.-%, vorzugsweise 1 bis 50 Gew.-%, bezogen auf das Gewicht der jeweiligen Phase. 13. Administration form according to one of claims 1-12, characterized in that sugar alcohol, microcrystalline cellulose and / or starch is used as filler, preferably in an amount of 0.5% to 90% by weight, preferably 1 to 50% by weight. , based on the weight of the respective phase.
14. Verabreichungsform nach einem der Ansprüche 1-13, dadurch gekennzeichnet, dass als Fliessreguliermittel hochdisperses Siliziumdioxid und/oder hochdisperses Aluminium- dioxid verwendet wird.14. Dosage form according to one of claims 1-13, characterized in that highly disperse silicon dioxide and / or highly disperse aluminum dioxide is used as the flow regulating agent.
15. Verabreichungsform nach einem der Ansprüche 1-14, dadurch gekennzeichnet, dass als Schmier- und Form-Trennmittel Calciumstearat, Magnesiumstearat, Stearinsäure und/oder hydriertes Rizinusöl, verwendet werden, vorzugsweise in15. Administration form according to one of claims 1-14, characterized in that calcium stearate, magnesium stearate, stearic acid and / or hydrogenated castor oil are used as lubricants and mold release agents, preferably in
Mengen von 0.1 bis 5 Gew.-%, vorzugsweise 0.5 bis 3 Gew.-%, bezogen auf das Gewicht der jeweiligen Phase.Quantities of 0.1 to 5% by weight, preferably 0.5 to 3% by weight, based on the weight of the respective phase.
16. Verabreichungsform nach einem der Ansprüche 1-15, da- durch gekennzeichnet, dass der magensaftresistente Filmüberzug mindestens eine Verbindung aus der Gruppe enthaltend Methacrylsäurepolymere, Methacrylsäure/Methacrylsäure- methylester-Copolymere und Ethylacrylat-Copolymer und gegebenenfalls weitere Hilfsstoffe, vorzugsweise Polyethylen- glykol, enthält.16. Dosage form according to one of claims 1-15, characterized in that the enteric film coating comprises at least one compound from the group comprising methacrylic acid polymers, methacrylic acid / methacrylic acid-methyl ester copolymers and ethyl acrylate copolymer and optionally further auxiliaries, preferably polyethylene glycol, contains.
17. Granulate und Pellets nach einem der Ansprüche 1-16, zu Tabletten verarbeitet oder abgefüllt in Sachets oder Hartgelatinekapseln, vorzugsweise zu Filmtabletten verar- beitet.17. Granules and pellets according to one of claims 1-16, processed into tablets or filled into sachets or hard gelatin capsules, preferably processed into film tablets.
18. Verfahren zur Herstellung von Granulaten oder Pellets nach einem der Patentansprüche 1-16 bestehend aus einem Kern und einem magensaftresistenten Filmüberzug, wobei de- ren Kern eine innere und eine aussere Phase aufweist, dadurch gekennzeichnet, dass man, im Granulierungsverfahren, zuerst die innere Phase des Kerns, herstellt, die Verbindungen der äusseren Phase und gegebenenfalls die Verbindun- gen der Zwischenschicht, und anschliessend die Verbindungen für den Aufbau der magensaftresistenten Schicht aufträgt.18. A process for the production of granules or pellets according to any one of claims 1-16 consisting of a core and an enteric film coating, the core of which has an inner and an outer phase, characterized in that, in the granulation process, first the inner Phase of the core, establishes the connections of the outer phase and, if necessary, the connections towards the intermediate layer, and then applying the connections for the construction of the enteric layer.
19. Verfahren zur Herstellung einer Tablette nach einem der Ansprüche 1-16, dadurch gekennzeichnet, dass man (i)19. A method for producing a tablet according to any one of claims 1-16, characterized in that (i)
Granulate und/oder Pellets, welche mit einem magensaftresistenten Filmüberzug versehen sind, wie dies in Anspruch 1 unter (A) (i) , (A) (ii) , (A) (iii) und (A) (iv) definiert ist, verpresst; oder (ii) Granulatkerne und/oder Pelletkerne (ohne deren magensaftresistenten Filmüberzug) gemäss derGranules and / or pellets which are provided with an enteric film coating as defined in claim 1 under (A) (i), (A) (ii), (A) (iii) and (A) (iv), pressed; or (ii) granule cores and / or pellet cores (without their enteric film coating) according to the
Definition in Anspruch 1 unter (A) (i) , (A) (ii) und (A) (iii) zu einem Tablettenkern verpresst und auf diesen einen magensaftresistenten Filmüberzug gemäss der Definition von Anspruch 1, (A) (iv) , aufträgt.Definition in claim 1 under (A) (i), (A) (ii) and (A) (iii) pressed into a tablet core and applied to this an enteric film coating according to the definition of claim 1, (A) (iv) ,
20. Granulatkerne und/oder Pelletkerne nach Anspruch 1 gemäss der Definition unter (A) (i) , (A) (ii) und (A) (iii) als Ausgangsmaterialien für die Herstellung der Granulate, Pellets [gemäss der Definition in Anspruch 1 unter (A) ] und Tabletten [gemäss der Definition in Anspruch 1 unter (B) ] .20. Granule cores and / or pellet cores according to claim 1 as defined under (A) (i), (A) (ii) and (A) (iii) as starting materials for the production of the granules, pellets [as defined in claim 1 under (A)] and tablets [as defined in claim 1 under (B)].
21. Verwendung der Granulatkerne und/oder Pelletkerne (ohne deren magensaftresistenten Filmüberzug) gemäss der Definition in Anspruchl unter (A) (i) , (A) (ii) und (A) (iii) für die Herstellung von Tablettenkernen.21. Use of the granule cores and / or pellet cores (without their enteric film coating) as defined in claim 1 under (A) (i), (A) (ii) and (A) (iii) for the production of tablet cores.
22. Verwendung der Verabreichungsformen nach einem der Ansprüche 1-16 als H+/K+-ATPase-Hemmer. 22. Use of the administration forms according to one of claims 1-16 as H + / K + -ATPase inhibitors.
PCT/CH2004/000677 2003-11-14 2004-11-08 Gastric juice-resistant form of administration WO2005046634A2 (en)

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