EP2081546A2 - Composition de comprimés à multiples unités de composés de benzimidazole - Google Patents

Composition de comprimés à multiples unités de composés de benzimidazole

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Publication number
EP2081546A2
EP2081546A2 EP07826778A EP07826778A EP2081546A2 EP 2081546 A2 EP2081546 A2 EP 2081546A2 EP 07826778 A EP07826778 A EP 07826778A EP 07826778 A EP07826778 A EP 07826778A EP 2081546 A2 EP2081546 A2 EP 2081546A2
Authority
EP
European Patent Office
Prior art keywords
enteric coating
coating layer
composition according
core
plasticizer
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP07826778A
Other languages
German (de)
English (en)
Inventor
Sachin Gahoi
Raveendra Pai M
Khalid Rafi
Ajay Kumar Singla
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
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 Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of EP2081546A2 publication Critical patent/EP2081546A2/fr
Withdrawn legal-status Critical Current

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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
    • 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
    • A61K9/20—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
    • A61K9/48—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
    • 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
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

Definitions

  • the present invention relates to multiple unit tablet compositions of benzimidazole compounds and process of preparation thereof.
  • the compositions are useful against various gastrointestinal disorders.
  • Benzimidazole compounds such as omeprazole, lansoprazole, pantoprazole, rabeprazole or single enantiomers thereof are strong inhibitors of proton pump and thus are widely used as therapeutic agents for stomach ulcer, duodenal ulcer, gastro esophageal reflux disorders etc. by inhibiting gastric acid secretion.
  • benzimidazole preparations are enteric-coated, due to the rapid degradation of the drug in the acidic conditions of the stomach. This is most commonly achieved by formulating multiple unit formulations i.e. enteric-coated granules within capsules, enteric-coated granules compressed into tablets etc., and single unit enteric-coated tablets.
  • the pharmacokinetics of the two formulations differ considerably.
  • the multiple unit formulation capsules or tablets
  • the multiple unit formulation is usually emptied gradually from the stomach into the intestine.
  • the single unit tablet will enter the intestine and dissolve as one unit.
  • the enteric- coated pellets of the multiple unit formulations disperse readily in contact with fluid, and are therefore suitable for patients with swallowing difficulties (can be dispersed in water or juice and the contents taken orally by the patient) or for patients with feeding tubes.
  • tablets offer the advantage of good mechanical stability and being more tamper-resistant than capsules, which is an important consideration in OTC settings.
  • U.S. Patent Nos. 4,786,505 and 4,853,230 teach compositions of benzimidazole compounds having an alkaline core, separating layer and enteric coating.
  • the application of compression forces to the tablet mixture comprising enteric-coated particles present a problem with respect to the strength of the coating and specifically the requirement to maintain the gastro-resistance and the integrity of the tablet and of the enteric- coated units after tableting.
  • the enteric coating layer contains pharmaceutically acceptable plasticizers to obtain the desired mechanical properties, such as flexibility and hardness of the enteric coating layers.
  • the amount of the plasticizer is optimized for each enteric coating layer formula, in relation to selected enteric coating layer polymer, selected plasticizer and the applied amount of said polymer, in such a way that the mechanical properties, i.e. flexibility and hardness of the enteric coating layer are adjusted so that the acid resistance of the pellets covered with enteric coating layer does not decrease significantly during the compression of pellets into tablets.
  • European Patent No. 0 723 437 Bl teaches an oral pharmaceutical multiple unit tableted dosage form of an acid labile H + K + - ATPase inhibitor or one of its single enantiomers, the core material being covered with one or more layer(s) of which at least one is an enteric coating layer, characterized in that the enteric coating layer has a thickness of at least 10 ⁇ m and said layer comprises a plasticizer in an amount of 15 - 50 % by weight of the enteric coating layer polymer.
  • enteric granules prepared by tabletting a mixture of enteric granules with at least one member selected from the group consisting of synthetic hydrotalcite, dried aluminium hydroxide gel, a coprecipitate of aluminium hydroxide with sodium hydrogencarbonate, aluminium magnesium hydroxide, synthetic aluminium silicate and dihydroxyaluminium aminoacetate.
  • the enteric-coated granules include a plasticizer, preferably added during formulation of the coating to be coated on the granules, at 15-40% w/w, and preferably 30- 40 % w/w with respect to the total amount of the enteric coating.
  • PCT Application No. WO 02/19991 teaches a multiparticulate dosage form, produced from particles compressed with conventional binding agents. Said particles contain a pharmaceutical active ingredient and are covered with a gastric juice resistant coating consisting of a methacrylate copolymer and more than 15 and up to 50 wt % of the plasticizer propylene glycol in relation to the methacrylate copolymer.
  • U.S. Patent Application No. 2006/0018964 discloses a multiparticulate tablet comprising a pharmaceutically active substance in the form of enteric-coated particles, and a mixture of tableting excipients, wherein the mixture of excipients comprises: a first diluent selected from the group consisting of xylitol, maltitol, and mixtures thereof, wherein the first diluent is in a directly compressible form; a disintegrating agent; a lubricant; and at least one other diluent, and wherein the ratio of a) the first diluent to b) the other diluent(s) is less than 5/95 (weight/weight).
  • the enteric coating composition can also comprise a plasticizer.
  • the plasticizer is usually used in a total proportion of at most 40%, preferably between 10% and 30%, expressed by weight with respect to the dry weight of polymer.
  • the examples disclosed in this patent application state that the enteric coated microgranules are manufactured according to the teaching of the prior art WO 96/01623 (PCT application corresponding to EP 0 723 436 Bl).
  • the multiple unit tablet composition comprises: a) one or more tablet excipients, and b) a multiple of enteric coating layered core units containing a benzimidazole compound, wherein each core unit is covered with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer.
  • the multiple unit tablet composition comprises: a) one or more tablet excipients, and b) a multiple of enteric coating layered core units containing a benzimidazole compound, wherein each core unit is covered with an enteric coating layer comprising a plasticizer in an amount ranging from 8% to 14% by weight of the enteric coating layer polymer.
  • the multiple unit tablet composition comprises: a) one or more tablet excipients, and b) a multiple of enteric coating layered core units containing a benzimidazole compound, wherein each core unit is covered with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer and the enteric coating layer is further covered by an over-coating layer.
  • the multiple unit tablet composition comprises: a) one or more tablet excipients, and b) a multiple of enteric coating layered core units containing a benzimidazole compound, wherein each core unit is covered with an enteric coating layer comprising a plasticizer in an amount ranging from 8% to 14% by weight of the enteric coating layer polymer and the enteric coating layer is further covered by an over-coating layer comprising a plasticizer in an amount ranging from 0-30% by weight of the enteric coating layer polymer.
  • the process of preparation of multiple unit tablet composition of the present invention is disclosed.
  • benzimidazole compound used herein refers to any of the compounds belonging to the category of benzimidazole used for gastrointestinal disorders and may be selected from omeprazole, lansoprazole, rabeprazole, pantoprazole, leminoprazole and pariprazole, including their single enantiomers, pharmaceutically accepted salts, solvates and mixtures.
  • the benzimidazole compound may be esomeprazole in the form of a pharmaceutically acceptable alkaline salt such as esomeprazole calcium or esomeprazole magnesium.
  • the benzimidazole compound may be either in the crystalline or amorphous form.
  • the core may be in the form of pellets, granules or beads.
  • the core may be acidic, alkaline or neutral depending on the type of formulation.
  • the core may contain one or more pharmaceutically acceptable excipients selected from the group consisting of inert carriers, binders, diluents, disintegrants, lubricants/glidants, solubilizers/wetting agents and mixtures thereof.
  • the inert carrier may be coated with the benzimidazole compound and one or more of the binders, diluents, disintegrants, lubricants/glidants, solubilizers/wetting agents and mixtures thereof.
  • the inert carrier may comprise starch, microcrystalline cellulose or sugar sphere such as nonpareil sugar seeds.
  • the diluents may be selected from one or more of sugars like dextrose, glucose, lactose; sugar alcohols like sorbitol, xylitol, mannitol; cellulose derivatives like powdered cellulose, microcrystalline cellulose; starches like corn starch, pregelatinized starch, maize starch and mixtures thereof.
  • the binders are selected from one or more of cellulose derivatives like hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylcellulose; gums like xanthan gum, gum acacia, tragacanth; water-soluble vinylpyrrolidone polymers like polyvinylpyrrolidone, copolymer of vinylpyrrolidone and vinyl acetate; sugars like sorbitol, mannitol and mixtures thereof.
  • the disintegrants are selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone, cornstarch and mixtures thereof.
  • the solubilizers/wetting agents may be selected from one or more of sodium lauryl sulphate, polysorbate 80 and mixtures thereof.
  • the lubricant/glidants may be selected from one or more of magnesium stearate, talc, sodium stearyl fumarate, colloidal silicon dioxide and mixtures thereof.
  • the core may be coated with a separating layer prior to the enteric coating layer.
  • the separating layer is made up of substantially water-soluble material, which is capable of dissolving or forming a gel in contact with water.
  • Such material may include substantially water-soluble polymer and/or substantially water-soluble excipients.
  • the substantially water-soluble excipients may be selected from glucose, lactose, mannitol, sorbitol, sucrose, dextrose and mixtures thereof.
  • the substantially water-soluble polymers may be selected from hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sodium alginate, sodium carboxymethyl cellulose, copolymer of vinylpyrrolidone and vinyl acetate.
  • the enteric coating layer is applied onto the core coated with the separating layer by using suitable coating techniques.
  • the enteric coating layer may include polymers such as cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, methacrylic acid copolymers, for example, compounds known under the trademarks of Eudragit NE30D, Eudragit L, Eudragit S, Eudragit L 100 55 or mixtures thereof.
  • the enteric coating layer contains plasticizers and may also include inert excipients such as talc, titanium dioxide, colloidal silicon dioxide, hydroxypropyl methylcellulose and crospovidone.
  • the plasticizer is used in an amount of less than 15% by weight of the enteric coating layer polymer.
  • the amount of the plasticizer may range from 8% to 14% by weight of the enteric coating layer polymer.
  • the amount of plasticizer is 13% by weight of the enteric coating layer polymer.
  • These amounts of the plasticizer in the enteric coating layer provide the desired mechanical properties, such as flexibility and hardness of the enteric coating layers.
  • the acid resistance of the core covered with enteric coating layer does not decrease significantly during the compression of core into tablets.
  • the plasticizers may be selected from one or more of triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates and mixtures thereof.
  • the core covered with enteric coating layer may further be covered with one or more over-coating layers.
  • the materials for over-coating layers are pharmaceutically acceptable compounds such as sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose and carboxymethylcellulose sodium, used alone or in mixtures.
  • Additives such as plasticizers, colorants, pigments, fillers, anti-tacking and antistatic agents, such as magnesium stearate, titanium dioxide and talc may also be included into the over-coating layer.
  • the over coating layer may contain plasticizers in an amount ranging from 0-30 % by weight of the enteric coating layer polymer.
  • the amount of the plasticizer may range from 5-20 % by weight of the enteric coating layer polymer.
  • Said over-coating layer may further prevent potential agglomeration of enteric coating layered core, protect the enteric coating layer towards cracking during the compaction process and enhance the tableting process.
  • the separating layer, enteric coating layer and the over-coating layer can be applied to the core 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 layering process.
  • the multiple enteric-coating layered core units are mixed with one or more tablet excipients and compressed into a multiple unit tablet dosage form.
  • the enteric coating layered core units, with or without an over-coating layer, are mixed with tablet excipients such as fillers, binders, disintegrants, lubricants and other pharmaceutically acceptable additives and compressed into tablets.
  • the fillers may be selected from one or more of sugars like dextrose, glucose, lactose; sugar alcohols like sorbitol, xylitol, mannitol; cellulose derivatives like powdered cellulose, microcrystalline cellulose; starches like corn starch, pregelatinized starch, maize starch and mixtures thereof.
  • the binders are selected from one or more of cellulose derivatives like hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylcellulose; gums like xanthan gum, gum acacia, tragacanth; water-soluble vinylpyrrolidone polymers like polyvinylpyrrolidone, copolymer of vinylpyrrolidone and vinyl acetate; sugars like sorbitol, mannitol and mixtures thereof.
  • the disintegrants are selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone, cornstarch and mixtures thereof.
  • the lubricant/glidants may be selected from one or more of magnesium stearate, talc, sodium stearyl fumarate, colloidal silicon dioxide and mixtures thereof.
  • the process for the preparation of the multiple unit tablet composition comprises the steps of: a) preparing a multiple of core units comprising the benzimidazole compound and one or more pharmaceutically acceptable excipients. b) coating the core of step (a) with a separating layer, c) covering the core of step (b) with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer, d) mixing the multiple of enteric coating layered core units of step (c) with one or more tablet excipients, and e) compressing the mixture of step (d) into tablets.
  • the process for the preparation of the multiple unit tablet composition comprises the steps of: a) preparing a multiple of core units comprising the benzimidazole compound and one or more pharmaceutically acceptable excipients. b) coating the core of step (a) with a separating layer, c) covering the core of step (b) with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer, d) covering the enteric coating layered core units of step (c) with an over-coating layer, e) mixing the multiple of over coating layered core units of step (d) with one or more tablet excipients, and f) compressing the mixture of step (e) into tablets.
  • the compressed tablet is optionally coated with a non-functional film coating to obtain a smooth surface of the tablet and further enhance the stability of the tablet during packaging and transport.
  • Hydroxypropylcellulose and Crospovidone was sifted through # 30 BSS followed by dispersing in purified water under mechanical stirring to obtain a dispersion.
  • step 4 The sugar spheres of step 1 were loaded into Wurster coater and coated with the dispersion of step 3 to obtain drug layered beads.
  • step 4 The beads obtained in step 4 were dried at product temperature of 35 ⁇ 5 0 C for 15- 30 minutes. Separating layer
  • Polyvinylpyrrolidone was sifted through # 30 BSS and dissolved in purified water/Isopropyl alcohol followed by addition of polyethylene glycol (PEG 400) in the solution. 7.
  • Talc was sifted through # 30 BSS and dispersed in solution of step 6.
  • step 8 The drug-layered beads of step 5 were coated with the dispersion of step 7 to obtain separating layer coated beads.
  • step 12 The separating layer coated beads of step 9 was coated with dispersion of step 11 to obtain enteric-coated beads. 13. The beads obtained in step 12 were dried at product temperature of 35 ⁇ 5 ° C for
  • Hydroxypropylcellulose was sifted through # 30 BSS and dissolved in Isopropyl alcohol/Dichloromethane followed by addition of Polyethylene glycol (PEG 400) in the solution to obtain a dispersion.
  • PEG 400 Polyethylene glycol
  • step 13 The enteric-coated beads of step 13 were coated with the dispersion of step 14 to obtain overcoated coated beads.
  • step 16 The beads were dried at product temperature of 35 ⁇ 5 0 C for 15-30 minutes. Compression 17. The overcoated beads of step 16 were sifted through # 22 BSS.
  • Microcrystalline cellulose, polyvinylpyrrolidone/Hydroxypropylcellulose-L and crospovidone was sifted through # 30 BSS. 19. The material of step 17 & 18 were blended in a blender.
  • step 21 The material of step 20 was compressed using approved tooling. Film Coating
  • step 21 The tablets of step 21 were coated with the dispersion of step 22.
  • Hydroxypropylcellulose and Crospovidone was sifted through # 30 BSS followed by dispersing in purified water under mechanical stirring to obtain a dispersion.
  • step 4 The sugar spheres of step 1 were loaded into Wurster coater and coated with the dispersion of step 3 to obtain drug-layered beads. 5. The beads obtained in step 4 were dried at product temperature of 35 ⁇ 5 ° C for
  • Polyvinylpyrrolidone was sifted through # 30 BSS and dissolved in purified water/Isopropyl alcohol followed by addition of Polyethylene glycol (PEG 400) in the solution.
  • step 8 The drug-layered beads of step 5 were coated with the dispersion of step 7 to obtain separating layer coated beads. 9. The beads obtained in step 8 were dried at product temperature of 35 ⁇ 5 ° C for 15-30 minutes.
  • Triethylcitrate was dissolved in acetone followed by hydroxypropylmethylcellulose phthalate and Eudragit L IOOD 55 under continuous stirring.
  • step 9 The separating layer coated beads of step 9 were coated with dispersion of step 11 to obtain enteric-coated beads.
  • step 13 The beads obtained in step 12 were dried at product temperature of 35 ⁇ 5 ° C for 12 hrs in vacuum tray drier.
  • Hydroxypropylcellulose was sifted through # 30 BSS and dissolved in Isopropyl alcohol/Dichloromethane followed by addition of Polyethylene glycol (PEG 400) in the solution.
  • step 13 The enteric-coated beads of step 13 were coated with the dispersion of step 14 to obtain overcoated coated beads.
  • step 15 The beads obtained in step 15 were dried at product temperature of 35 ⁇ 5 0 C for 15-30 minutes.
  • step 16 The overcoated beads of step 16 were sifted through # 18 BSS.
  • Microcrystalline cellulose, L- Hydroxypropylcellulose and crospovidone was sifted through # 30 BSS. 19. The material of step 17 & 18 were blended in a blender.
  • step 21 The material of step 20 was compressed using approved tooling. Film Coating
  • step 21 The tablets of step 21 were coated with the dispersion of step 22.
  • composition of the present invention is stable even after storage for 3 months at 40° C and 75% RH.
  • Hydroxypropylcellulose (HPC-L) and Crospovidone was sifted through # 30 BSS followed by dispersing in purified water under mechanical stirring.
  • Esomeprazole calcium was sifted through # 30 BSS followed by dispersing in step 2 dispersion.
  • step 4 The sugar spheres of step 1 were loaded into Wurster coater and coated with the dispersion of step 3 to obtain drug-layered beads.
  • step 4 The beads obtained in step 4 were dried at product temperature of 35 ⁇ 5 ° C for 15-30 minutes.
  • Polyvinylpyrrolidone was sifted through # 30 BSS and dissolved in purified water/Isopropyl alcohol followed by addition of Polyethylene glycol (PEG 400) in the solution.
  • step 7 Talc was sifted through # 30 BSS and dispersed in solution of step 6 to obtain a dispersion. 8. The drug-layered beads of step 5 were coated with the dispersion of step 7 to obtain separating layer coated beads.
  • step 9 The separating layer coated beads of step 9 was coated with dispersion of step 11 to obtain enteric-coated beads.
  • the beads were dried at product temperature of 35 ⁇ 5 ° C for 12 hrs in vacuum tray drier.
  • Hydroxypropylcellulose was sifted through # 30 BSS and dissolved in Isopropyl alcohol/Dichloromethane followed by addition of Polyethylene glycol (PEG 400) in the solution to obtain a dispersion.
  • PEG 400 Polyethylene glycol
  • step 13 The enteric-coated beads of step 13 were coated with the dispersion of step 14 to obtain overcoated coated beads.
  • step 16 The overcoated beads of step 16 were sifted through # 18 BSS.
  • Microcrystalline cellulose, L- hydroxypropylcellulose and crospovidone was sifted through # 30 BSS.
  • step 17 & 18 were blended in a blender.
  • Sodium stearyl fumarate was sifted through # 30 BSS and added to the material of step 19 and blended further.
  • step 21 The material of step 20 was compressed using approved tooling. Film Coating
  • step 21 The tablets of step 21 were coated with the dispersion of step 22.
  • Esomeprazole magnesium was sifted through # 30 BSS followed by dispersing in step 2 dispersion.
  • step 4 The sugar spheres of step 1 were loaded into Wurster coater and coated with the dispersion of step 3 to obtain drug-layered beads.
  • step 4 The beads obtained in step 4 were dried at product temperature of 35 ⁇ 5 ° C for 15-30 minutes.
  • Polyvinylpyrrolidone was sifted through # 30 BSS and dissolved in purified water/Isopropyl alcohol followed by addition of Polyethylene glycol (PEG 400) in the solution.
  • step 8 The drug-layered beads of step 5 were coated with the dispersion of step 7 to obtain separating layer coated beads.
  • the beads were dried at product temperature of 35 ⁇ 5 ° C for 15-30 minutes.
  • Triethylcitrate was dissolved in purified water followed by addition of talc under continuous stirring. 11. Eudragit dispersion was added to step 10 under continuous stirring.
  • step 9 The separating layer coated beads of step 9 were coated with dispersion of step 11 to obtain enteric-coated beads.
  • step 13 The beads obtained in step 12 were dried at product temperature of 35 ⁇ 5 ° C for 12 hrs in vacuum tray drier.
  • step 15 The beads obtained in step 15 were dried at product temperature of 35 ⁇ 5 0 C for 15-30 minutes.
  • Microcrystalline cellulose, Polyvinylpyrrolidone /Hydroxypropylcellulose / low substituted hydroxypropylcellulose (L-HPC) and crospovidone were sifted through
  • step 17 & 18 were blended in a blender.
  • Sodium stearyl fumarate was sifted through # 30 BSS and added to the material of step 19 and blended further.
  • step 21 The material of step 20 was compressed using approved tooling. Film Coating
  • step 22 Opadry pink was dispersed in isopropyl alcohol/dichloromethane.
  • step 21 The tablets of step 21 were coated with the dispersion of step 22.

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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention porte sur des compositions de comprimés à multiples unités composés de benzimidazole et sur un procédé de préparation de celle-ci. Les compositions sont utiles contre divers troubles gastro-intestinaux. La composition de comprimés à multiples unités comprend : a) des excipients de comprimés, et b) de multiples unités de cœur à enrobage entérique qui contiennent un composé de benzimidazole, chaque unité de cœur étant enrobée d'une couche d'enrobage entérique contenant un plastifiant dans une quantité inférieure à 15 % en poids du polymère de couche d'enrobage entérique.
EP07826778A 2006-10-17 2007-10-17 Composition de comprimés à multiples unités de composés de benzimidazole Withdrawn EP2081546A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2279DE2006 2006-10-17
PCT/IB2007/054233 WO2008047320A2 (fr) 2006-10-17 2007-10-17 Composition de comprimés à multiples unités de composés de benzimidazole

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EP2081546A2 true EP2081546A2 (fr) 2009-07-29

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EP (1) EP2081546A2 (fr)
AU (1) AU2007311493B2 (fr)
BR (1) BRPI0717613A2 (fr)
CA (1) CA2667039A1 (fr)
WO (1) WO2008047320A2 (fr)

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Publication number Priority date Publication date Assignee Title
US20130122090A1 (en) 2010-07-22 2013-05-16 Lupin Limited Multiple Unit Tablet Composition
US20170042806A1 (en) 2015-04-29 2017-02-16 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions
US10076494B2 (en) 2016-06-16 2018-09-18 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0723436B1 (fr) * 1994-07-08 2001-09-26 AstraZeneca AB Forme posologique sous forme de comprime composite (i)

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2189698A (en) * 1986-04-30 1987-11-04 Haessle Ab Coated omeprazole tablets
WO1996007421A2 (fr) * 1994-09-09 1996-03-14 Takeda Chemical Industries, Ltd. Medicament anti-ulcereux comprenant une proteine ayant une activite de facteur de croissance cellulaire et un inhibiteur de la pompe a protons
FR2774288B1 (fr) * 1998-01-30 2001-09-07 Ethypharm Sa Microgranules d'omeprazole gastroproteges, procede d'obtention et preparations pharmaceutiques
US6228400B1 (en) * 1999-09-28 2001-05-08 Carlsbad Technology, Inc. Orally administered pharmaceutical formulations of benzimidazole derivatives and the method of preparing the same
PE20050150A1 (es) * 2003-05-08 2005-03-22 Altana Pharma Ag Una forma de dosificacion que contiene (s)-pantoprazol como ingrediente activo

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0723436B1 (fr) * 1994-07-08 2001-09-26 AstraZeneca AB Forme posologique sous forme de comprime composite (i)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LEHMANN K ET AL: "FAST DISINTEGRATING CONTROLLED RELEASE TABLETS FORM COATED PARTICLES", DRUGS MADE IN GERMANY, AULENDORF, DE, vol. 37, no. 2, 1 January 1994 (1994-01-01), pages 53 - 60, XP001016125, ISSN: 0012-6682 *

Also Published As

Publication number Publication date
WO2008047320A3 (fr) 2008-06-19
BRPI0717613A2 (pt) 2013-10-22
WO2008047320A2 (fr) 2008-04-24
CA2667039A1 (fr) 2008-04-24
AU2007311493B2 (en) 2013-01-31
AU2007311493A1 (en) 2008-04-24

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