WO2008047320A2 - Multiple unit tablet compositions of benzimidazole compounds - Google Patents

Multiple unit tablet compositions of benzimidazole compounds Download PDF

Info

Publication number
WO2008047320A2
WO2008047320A2 PCT/IB2007/054233 IB2007054233W WO2008047320A2 WO 2008047320 A2 WO2008047320 A2 WO 2008047320A2 IB 2007054233 W IB2007054233 W IB 2007054233W WO 2008047320 A2 WO2008047320 A2 WO 2008047320A2
Authority
WO
WIPO (PCT)
Prior art keywords
enteric coating
coating layer
composition according
core
plasticizer
Prior art date
Application number
PCT/IB2007/054233
Other languages
French (fr)
Other versions
WO2008047320A3 (en
Inventor
Sachin Gahoi
Raveendra Pai M
Khalid Rafi
Ajay Kumar Singla
Original Assignee
Ranbaxy Laboratories Limited
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 Limited filed Critical Ranbaxy Laboratories Limited
Priority to AU2007311493A priority Critical patent/AU2007311493B2/en
Priority to EP07826778A priority patent/EP2081546A2/en
Priority to BRPI0717613-9A2A priority patent/BRPI0717613A2/en
Priority to CA002667039A priority patent/CA2667039A1/en
Publication of WO2008047320A2 publication Critical patent/WO2008047320A2/en
Publication of WO2008047320A3 publication Critical patent/WO2008047320A3/en

Links

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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

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. The multiple unit tablet composition comprises: a) tablet excipients, and b) multiple enteric coated 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.

Description

MULTIPLE UNIT TABLET COMPOSITIONS OF BENZIMIDAZOLE
COMPOUNDS
Field of the Invention
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.
Background of the Invention
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.
The single isomers of corresponding benzimidazole compounds are reported to be more useful in therapy compared to the racemic benzimidazole compounds. U.S. Patent No. 5,877,192 describes the use of the (-)-enantiomer of omeprazole (esomeprazole), or a pharmaceutically acceptable salt thereof, in the treatment of gastric acid related diseases.
Because of the instability of benzimidazole compounds under neutral and acidic environment, moisture, heat, organic solvents and to some degree by light, numerous approaches have been tried to form a stable pharmaceutical formulation comprising a benzimidazole compound. Most oral 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) is usually emptied gradually from the stomach into the intestine. In contrast to this, the single unit tablet will enter the intestine and dissolve as one unit. Further, 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. Among the multiple unit formulations, 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. When preparing multiple unit tablets, 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.
It is known that the film-forming agents generally used to coat particles cannot under normal conditions absorb the mechanical stresses applied during tableting. Films composed of only enteric polymers or copolymers have very mediocre mechanical properties, such that they do not withstand tableting. The application of these compression forces can result in the appearance of cracks in the enteric coating film or by the splitting thereof, resulting in the partial or complete loss of the properties of the film coating. The prior art provides solutions such as for example modifying the composition of the enteric coating films, so as to substantially improve its mechanical characteristics with regard to tableting properties, i.e. to withstand the application of compression forces. Improvements in gastro-resistance and less film damage can also be achieved by using excipients that deform plastically during tableting. Alternative solutions consist of diluting/mixing the enteric-coated particles with auxiliary substances, which substances can absorb the physical stresses during tableting.
The document "Drugs made in Germany", 37(2) p. 53 (1994) teaches combination of Eudragit®. L30D and Eudragit®. NE30D to produce multiparticulate tablets comprising the enteric coated particles. European Patent No. 0 723 436 Bl teaches an oral pharmaceutical multiple unit tableted dosage form comprising tablet excipients and individually enteric coating layered units of a core material containing active substance in the form of omeprazole 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 comprises a plasticizer in the amount of 20 - 50% by weight of the enteric coating layer polymer. This patent teaches that 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 μm and said layer comprises a plasticizer in an amount of 15 - 50 % by weight of the enteric coating layer polymer. European Patent Application No. 0 723 777 Al teaches a tablet containing 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. However, 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).
However, there is still a need for development of new enteric coating layered multiple unit preparations with good mechanical and chemical stability. We have surprisingly found that multiple unit tablets of benzimidazole compounds having desired mechanical properties and good acid resistance can be prepared by using a plasticizer in the enteric coating layer in an amount lower than that disclosed in the prior art.
Summary of the Invention Multiple unit tablet compositions of benzimidazole compounds are disclosed.
According to one embodiment 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.
According to another embodiment 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.
According to still another embodiment 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.
According to further embodiment 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. According to further embodiment the process of preparation of multiple unit tablet composition of the present invention is disclosed.
Detailed Description of the Invention
The term 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. For example, 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. Generally 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. Generally 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. Generally 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. An 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. For example, the amount of the plasticizer may range from 8% to 14% by weight of the enteric coating layer polymer. For example, 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. For example, 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.
Generally 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.
Generally 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.
Generally 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.
According to one embodiment 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.
According to another embodiment 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.
The following non-limiting examples describe the various embodiments:
Example 1
Figure imgf000010_0001
Figure imgf000011_0001
Process of preparation: Drug Layering
1. Sugar spheres were sifted through # 36 BSS and # 60 BSS and the fraction retained between # 36-60 BSS was collected.
2. Hydroxypropylcellulose and Crospovidone was sifted through # 30 BSS followed by dispersing in purified water under mechanical stirring to obtain a dispersion.
3. Esomeprazole Magnesium was sifted through # 30 BSS followed by dispersing in step 2 dispersion.
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 0C for 15- 30 minutes. Separating layer
6. 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.
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 were dried at product temperature of 35 ± 5 ° C for 15-30 minutes. Enteric Coating 10. Diethylpthalate was dissolved in acetone followed by hydroxypropylmethylcellulose phthalate under continuous stirring.
11. Purified water was added in the dispersion of step 10 under stirring.
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
12 hrs in vacuum tray drier.
Overcoating
14. 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.
15. The enteric-coated beads of step 13 were coated with the dispersion of step 14 to obtain overcoated coated beads.
16. The beads were dried at product temperature of 35 ± 5 0C for 15-30 minutes. Compression 17. The overcoated beads of step 16 were sifted through # 22 BSS.
18. Microcrystalline cellulose, polyvinylpyrrolidone/Hydroxypropylcellulose-L and crospovidone was sifted through # 30 BSS. 19. The material of step 17 & 18 were blended in a blender.
20. Sodium stearyl fumarate was sifted through # 30 BSS and added to the material of step 19 and blended further.
21. The material of step 20 was compressed using approved tooling. Film Coating
22. Opadry pink was dispersed in isopropyl alcohol/dichloromethane.
23. The tablets of step 21 were coated with the dispersion of step 22.
Example 2
Figure imgf000013_0001
Figure imgf000014_0001
Drug Layering
1. Sugar spheres were sifted through # 36 BSS and # 60 BSS and the fraction retained between # 36-60 BSS was collected.
2. Hydroxypropylcellulose and Crospovidone was sifted through # 30 BSS followed by dispersing in purified water under mechanical stirring to obtain a dispersion.
3. Esomeprazole Magnesium was sifted through # 30 BSS followed by dispersing in step 2 dispersion.
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
15-30 minutes.
Separating layer
6. 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.
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.
Enteric Coating
10. Triethylcitrate was dissolved in acetone followed by hydroxypropylmethylcellulose phthalate and Eudragit L IOOD 55 under continuous stirring.
11. Purified water was added in the dispersion of step 10 under stirring to obtain a dispersion.
12. The separating layer coated beads of step 9 were 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 12 hrs in vacuum tray drier.
Overcoating
14. Hydroxypropylcellulose was sifted through # 30 BSS and dissolved in Isopropyl alcohol/Dichloromethane followed by addition of Polyethylene glycol (PEG 400) in the solution.
15. The enteric-coated beads of step 13 were coated with the dispersion of step 14 to obtain overcoated coated beads.
16. The beads obtained in step 15 were dried at product temperature of 35 ± 5 0C for 15-30 minutes.
Compression
17. The overcoated beads of step 16 were sifted through # 18 BSS.
18. Microcrystalline cellulose, L- Hydroxypropylcellulose and crospovidone was sifted through # 30 BSS. 19. The material of step 17 & 18 were blended in a blender.
20. Sodium stearyl fumarate was sifted through # 30 BSS and added to the material of step 19 and blended further.
21. The material of step 20 was compressed using approved tooling. Film Coating
22. Opadry pink was dispersed in isopropyl alcohol/dichloromethane.
23. The tablets of step 21 were coated with the dispersion of step 22.
Acid resistance test of the multiple unit tablet was performed in 0. IN HCl at 75 rpm paddle for 120min (at initial time point and after 3 months storage at accelerated conditions). The result is given in the following table 1 below:
Table 1: Acid resistance test of Example 2
Figure imgf000016_0001
Dissolution of the multiple unit tablet was carried out in 0.1N HCl (300ml) at 75rpm paddle for 2hrs followed by pH 6.8 (700ml) at 75rpm paddle for 45 minutes (at initial time point and after 3 months storage at accelerated conditions). The result for Example 2 is given in Table 2 given below:
Table 2: Dissolution test of Example 2
Figure imgf000016_0002
Further, it was observed that the multiple unit tablet dosage form according to the present invention has good stability. The assay values and the amount of impurities (at initial time point and after 3 months storage at accelerated conditions) for Example 2 is provided in Table 3 below: Table 3: Stability data for Example 2
Figure imgf000017_0001
The above results show that composition of the present invention is stable even after storage for 3 months at 40° C and 75% RH.
Example 3
Figure imgf000017_0002
Figure imgf000018_0001
Process of preparation: Drug Layering
1. Sugar spheres were sifted through # 36 BSS and # 60 BSS and the fraction retained between # 36-60 BSS was collected.
2. Hydroxypropylcellulose (HPC-L) and Crospovidone was sifted through # 30 BSS followed by dispersing in purified water under mechanical stirring.
3. Esomeprazole calcium was sifted through # 30 BSS followed by dispersing in step 2 dispersion.
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 15-30 minutes.
Separating layer
6. 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 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.
9. The beads were dried at product temperature of 35 ± 5 ° C for 15-30 minutes. Enteric Coating 10. Diethyl phthalate was dissolved in acetone followed by hydroxypropylmethylcellulose phthalate under continuous stirring.
11. Purified water was added in the dispersion of step 10 under stirring to obtain a dispersion.
12. The separating layer coated beads of step 9 was coated with dispersion of step 11 to obtain enteric-coated beads.
13. The beads were dried at product temperature of 35 ± 5 ° C for 12 hrs in vacuum tray drier.
Over coating
14. 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.
15. The enteric-coated beads of step 13 were coated with the dispersion of step 14 to obtain overcoated coated beads.
16. The beads were dried at product temperature of 35 ± 5 0C for 15-30 minutes. Compression
17. The overcoated beads of step 16 were sifted through # 18 BSS.
18. Microcrystalline cellulose, L- hydroxypropylcellulose and crospovidone was sifted through # 30 BSS.
19. The material of step 17 & 18 were blended in a blender. 20. Sodium stearyl fumarate was sifted through # 30 BSS and added to the material of step 19 and blended further.
21. The material of step 20 was compressed using approved tooling. Film Coating
22. Opadry pink was dispersed in isopropyl alcohol/dichloromethane.
23. The tablets of step 21 were coated with the dispersion of step 22.
Example 4
Figure imgf000020_0001
Figure imgf000021_0001
Process of preparation: Drug Layering
1. Sugar spheres were sifted through # 36 BSS and # 60 BSS and the fraction retained between # 36-60 BSS was collected. 2. Hydroxypropylcellulose and Crospovidone was sifted through # 30 BSS followed by dispersing in purified water under mechanical stirring.
3. Esomeprazole magnesium was sifted through # 30 BSS followed by dispersing in step 2 dispersion.
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 15-30 minutes.
Separating layer
6. 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 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.
9. The beads were dried at product temperature of 35 ± 5 ° C for 15-30 minutes.
Enteric Coating
10. 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.
12. The separating layer coated beads of step 9 were 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 12 hrs in vacuum tray drier.
Overcoating
14. Hydroxypropylmethylcellulose (HPMC-E5) was sifted through # 30 BSS and dissolved in Isopropyl alcohol/Dichloromethane followed by addition of Polyethylene glycol (PEG 400) in the solution. 15. The enteric-coated beads of step 13 were coated with the dispersion of step 14 to obtain overcoated coated beads.
16. The beads obtained in step 15 were dried at product temperature of 35 ± 5 0C for 15-30 minutes.
Compression 17. The overcoated beads of step 16 were sifted through # 18 BSS.
18. Microcrystalline cellulose, Polyvinylpyrrolidone /Hydroxypropylcellulose / low substituted hydroxypropylcellulose (L-HPC) and crospovidone were sifted through
# 30 BSS.
19. The material of step 17 & 18 were blended in a blender. 20. Sodium stearyl fumarate was sifted through # 30 BSS and added to the material of step 19 and blended further.
21. The material of step 20 was compressed using approved tooling. Film Coating
22. Opadry pink was dispersed in isopropyl alcohol/dichloromethane. 23. The tablets of step 21 were coated with the dispersion of step 22.

Claims

We claim: 1. A multiple unit tablet composition comprising: 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.
2. The composition according to claim 1, wherein the enteric coating layered core units comprise: a) a core comprising the benzimidazole compound and one or more pharmaceutically acceptable excipients, and b) a separating layer surrounding the core, and c) an enteric coating layer surrounding the separating layer.
3. The composition according to claim 1, wherein the benzimidazole compound is selected from one or more of omeprazole, lansoprazole, rabeprazole, pantoprazole, leminoprazole, pariprazole and their single enantiomers, pharmaceutically accepted salts, solvates and their mixtures.
4. The composition according to claim 3, wherein the benzimidazole compound is in the form of a pharmaceutically acceptable alkaline salt.
5. The composition according to claim 1, wherein the enteric coating layer polymer is selected from one or more of cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose and methacrylic acid copolymers.
6. The composition according to claim 1, wherein the plasticizer is selected from one or more of triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols and polysorbates.
7. The composition according to claim 1, wherein the amount of the plasticizer ranges from 8% to 14% by weight of the enteric coating layer polymer.
8. The composition according to claim 1, wherein the tablet excipients are selected from one or more of binders, fillers, disintegrants and lubricants.
9. The composition according to claim 8, wherein the binders are selected from one or more of cellulose derivatives selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose and methylcellulose; gums selected from xanthan gum, gum acacia and tragacanth; water-soluble vinylpyrrolidone polymers selected from polyvinylpyrrolidone and copolymer of vinylpyrrolidone vinyl acetate; and sugars selected from sorbitol and mannitol.
10. The composition according to claim 8, wherein the fillers are selected from one or more of sugars selected from dextrose, glucose and lactose; sugar alcohols selected from sorbitol, xylitol and mannitol; cellulose derivatives selected from powdered cellulose and microcrystalline cellulose and starches selected from corn starch, pregelatinized starch and maize starch.
11. The composition according to claim 8, wherein the disintegrants are selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone and corn starch.
12. The composition according to claim 8, wherein the lubricants are selected from one or more of magnesium stearate, talc, sodium stearyl fumarate and colloidal silicon dioxide.
13. The composition according to claim 2, wherein the enteric coating layer is further covered by an over-coating layer.
14. The composition according to claim 13, wherein the over-coating layer comprises a plasticizer in an amount ranging from 0-30% by weight of the enteric coating layer polymer.
15. The process for the preparation of composition of any of claims 2-12, wherein the process 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.
16. The process for the preparation of composition of any of claims 13 or 14, wherein the process 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.
17. A method of inhibiting gastric acid secretion, the method comprising administering to a patient in need thereof a multiple unit tablet composition according to claim 1.
PCT/IB2007/054233 2006-10-17 2007-10-17 Multiple unit tablet compositions of benzimidazole compounds WO2008047320A2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU2007311493A AU2007311493B2 (en) 2006-10-17 2007-10-17 Multiple unit tablet compositions of benzimidazole compounds
EP07826778A EP2081546A2 (en) 2006-10-17 2007-10-17 Multiple unit tablet compositions of benzimidazole compounds
BRPI0717613-9A2A BRPI0717613A2 (en) 2006-10-17 2007-10-17 COMPOSITION ON TABLE OF MULTIPLE UNITS, PROCESS FOR PREPARING THE SAME AND METHOD FOR INHIBITING GASTRIC ACID SECRETION
CA002667039A CA2667039A1 (en) 2006-10-17 2007-10-17 Multiple unit tablet compositions of benzimidazole compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2279DE2006 2006-10-17
IN2279/DEL/2006 2006-10-17

Publications (2)

Publication Number Publication Date
WO2008047320A2 true WO2008047320A2 (en) 2008-04-24
WO2008047320A3 WO2008047320A3 (en) 2008-06-19

Family

ID=39271195

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2007/054233 WO2008047320A2 (en) 2006-10-17 2007-10-17 Multiple unit tablet compositions of benzimidazole compounds

Country Status (5)

Country Link
EP (1) EP2081546A2 (en)
AU (1) AU2007311493B2 (en)
BR (1) BRPI0717613A2 (en)
CA (1) CA2667039A1 (en)
WO (1) WO2008047320A2 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012010944A2 (en) 2010-07-22 2012-01-26 Lupin Limited Multiple unit tablet composition
US10076494B2 (en) 2016-06-16 2018-09-18 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions
US11077055B2 (en) 2015-04-29 2021-08-03 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0496437A2 (en) * 1986-04-30 1992-07-29 Aktiebolaget Hässle Use of specific core material and layers to obtain pharmaceutical formulations stable to discolouration of omeprazole
WO1996007421A2 (en) * 1994-09-09 1996-03-14 Takeda Chemical Industries, Ltd. An antiulcer medicine comprising a protein possessing all growth factor activity and a proton pump inhibitor
FR2774288A1 (en) * 1998-01-30 1999-08-06 Ethypharm Sa GASTROPROTECTED OMEPRAZOLE MICROGRANULES, PROCESS FOR OBTAINING THEM AND PHARMACEUTICAL PREPARATIONS
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
WO2004098577A2 (en) * 2003-05-08 2004-11-18 Altana Pharma Ag Dosage form containing (s)-pantoprazole as active ingredient

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EE03305B1 (en) * 1994-07-08 2000-12-15 Astra Aktiebolag Multiparticulate tableted dosage form I

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0496437A2 (en) * 1986-04-30 1992-07-29 Aktiebolaget Hässle Use of specific core material and layers to obtain pharmaceutical formulations stable to discolouration of omeprazole
EP0567201A2 (en) * 1986-04-30 1993-10-27 Aktiebolaget Hässle Vehicles for oral administration of a specific pharmaceutically active acid labile substance
WO1996007421A2 (en) * 1994-09-09 1996-03-14 Takeda Chemical Industries, Ltd. An antiulcer medicine comprising a protein possessing all growth factor activity and a proton pump inhibitor
FR2774288A1 (en) * 1998-01-30 1999-08-06 Ethypharm Sa GASTROPROTECTED OMEPRAZOLE MICROGRANULES, PROCESS FOR OBTAINING THEM AND PHARMACEUTICAL PREPARATIONS
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
WO2004098577A2 (en) * 2003-05-08 2004-11-18 Altana Pharma Ag Dosage form containing (s)-pantoprazole as active ingredient

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2081546A2 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012010944A2 (en) 2010-07-22 2012-01-26 Lupin Limited Multiple unit tablet composition
US11077055B2 (en) 2015-04-29 2021-08-03 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions
US10076494B2 (en) 2016-06-16 2018-09-18 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions
US10835488B2 (en) 2016-06-16 2020-11-17 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions

Also Published As

Publication number Publication date
AU2007311493B2 (en) 2013-01-31
CA2667039A1 (en) 2008-04-24
AU2007311493A1 (en) 2008-04-24
BRPI0717613A2 (en) 2013-10-22
EP2081546A2 (en) 2009-07-29
WO2008047320A3 (en) 2008-06-19

Similar Documents

Publication Publication Date Title
US6610323B1 (en) Oral pharmaceutical pulsed release dosage form
JP3878669B2 (en) Multi-unit formulations containing proton pump inhibitors
US20100178334A1 (en) Oral Pharmaceutical Dosage Form Comprising as Active Ingredients a Proton Pump Inhibitor together with Acetyl Salicyclic Acid
US20080003281A1 (en) Modified Release Tablet Formulations for Proton Pump Inhibitors
EP1596838A2 (en) Once a day orally administered pharmaceutical compositions comprising a proton pump inhibitor and a prokinetic agent
US20150209432A1 (en) Pharmaceutical compositions of proton pump inhibitor
WO2011140446A2 (en) Pharmaceutical formulations
EP2331084A1 (en) Pharmaceutical compositions comprising amorphous esomeprazole, dosage forms and process thereof
WO2011144975A1 (en) Multi-unit compositions
US20110177164A1 (en) Pharmaceutical Compositions Comprising Amorphous Esomeprazole, Dosage Forms And Process Thereof
US8658216B2 (en) Stable oral benzimidazole compositions and process of preparation thereof
US20130122090A1 (en) Multiple Unit Tablet Composition
AU2007311493B2 (en) Multiple unit tablet compositions of benzimidazole compounds
US20120164233A1 (en) Pulsatile release pharmaceutical formulation of dexlansoprazole
WO2004066982A1 (en) Stable oral benzimidazole compositions and processes for their preparation
US8911787B2 (en) Stable oral benzimidazole compositions and process of preparation thereof
US20120321702A1 (en) Pharmaceutical composition of lansoprazole
US20080279951A1 (en) Stable Oral Benzimidazole Compositions Prepared by Non-Aqueous Layering Process
CA2547398A1 (en) Oral benzimidazole compositions comprising an active core, an optional separating layer and an enteric coating
WO2010018593A2 (en) Gastric acid resistant benzimidazole multiple unit tablet composition
WO2006111853A2 (en) Stable solid dosage forms of acid labile drug
WO2011138797A2 (en) Delayed release oral disintegrating pharmaceutical compositions of lansoprazole
US20240033224A1 (en) Enteric-coated pellet, method for preparing same and formulation comprising same
CA2623560A1 (en) A process for preparing stable amorphous benzimidazole composition

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07826778

Country of ref document: EP

Kind code of ref document: A2

REEP Request for entry into the european phase

Ref document number: 2007826778

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2007826778

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2667039

Country of ref document: CA

NENP Non-entry into the national phase in:

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2007311493

Country of ref document: AU

ENP Entry into the national phase in:

Ref document number: 2007311493

Country of ref document: AU

Date of ref document: 20071017

Kind code of ref document: A

ENP Entry into the national phase in:

Ref document number: PI0717613

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20090416