WO2010041276A1 - Compositions pharmaceutiques comprenant de l’ésoméprazole amorphe, formes pharmaceutiques et procédé associés - Google Patents

Compositions pharmaceutiques comprenant de l’ésoméprazole amorphe, formes pharmaceutiques et procédé associés Download PDF

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Publication number
WO2010041276A1
WO2010041276A1 PCT/IN2009/000553 IN2009000553W WO2010041276A1 WO 2010041276 A1 WO2010041276 A1 WO 2010041276A1 IN 2009000553 W IN2009000553 W IN 2009000553W WO 2010041276 A1 WO2010041276 A1 WO 2010041276A1
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WIPO (PCT)
Prior art keywords
enteric
layer
pharmaceutical composition
drug
coating
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PCT/IN2009/000553
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English (en)
Inventor
Gopal Rajan
Pratik Kumar
Gour Mukherji
Pulak Kumar Metia
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Jubilant Organosys Limited
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Priority to EP09818889.9A priority Critical patent/EP2331084A4/fr
Priority to US13/121,281 priority patent/US20110177164A1/en
Publication of WO2010041276A1 publication Critical patent/WO2010041276A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/501—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—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
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention in general, relates to stabilized pharmaceutical compositions of benzimidazole compounds. More particularly, the present invention relates to stable pharmaceutical compositions of amorphous form of esomeprazole, suitable dosage forms comprising the same and a process for preparing the same.
  • Benzimidazole compounds such as Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole or single enantiomers thereof are strong inhibitors of proton pump and are widely used as therapeutic agents for stomach ulcer, duodenal ulcer, and gastroesophageal reflux disorders. Benzimidazole compounds effectively inhibit gastric acid secretion.
  • European Patent No. 723437 assigned to Astra discloses multiple unit tableted dosage forms comprising benzimidazole compound in the form of enteric-coated pellets, which are further overcoated with polymeric coating.
  • the use of overcoating ensures surface integrity of the enteric coating pellets and protects pellets from mechanical stress, thus, prevents cracking of the enteric layer.
  • each unit comprises inert core coated with first coating layer that includes one or more drugs and one or more rate controlling polymers and an outer layer comprising a material that is elastic and /or compressible waxy material such as PEG.
  • the rate controlling membrane controls release of the drug over a period of 24 hours.
  • the waxy outer layer protects the release control polymer layer from cracking during compression.
  • Nexium ® is a capsule dosage form for oral administration containing delayed release pellets of magnesium salts of esomeprazole.
  • Nexium is formulated in dosage form with most stable crystalline trihydrate form of esomeprazole magnesium.
  • amorphous form of an active pharmaceutical ingredient is thermodynamically less stable than any crystalline form and inadvertent crystallization from an amorphous drug substance may occur.
  • amorphous drug substances are also more likely to undergo solid-state reactions leading to degradation and subsequent loss of activity and purity.
  • amorphous forms exhibit better solubility and absorption characteristics.
  • US Patent No. 7482463 assigned to Ranbaxy, discloses a process for manufacturing amorphous form of esomeprazole.
  • a stabilized pharmaceutical composition comprising an inert core unit, a drug layer coated over the inert core unit, wherein the drug layer essentially consisting of amorphous esomeprazole, a binder and a disintegrant, one or more intermediate layer essentially consisting of basic metal compounds and icing sugar with starch having ratio from about 1 :5 to about 5:1, one or more subcoating layer essentially consisting of waxy material and one or more enteric layer comprising at least one enteric polymer, wherein the basic metal compounds are not in intimate contact with the drug in the pharmaceutical composition.
  • a solid dosage form of a stabilized pharmaceutical composition comprising an inert core unit, a drug layer coated over the inert core unit, wherein the drug layer essentially consisting of amorphous esomeprazole, a binder and a disintegrant, an intermediate layer essentially consisting of basic metal compounds and icing sugar with starch having ratio from about 1 :5 to about 5:1, a subcoating layer essentially consisting of waxy material, a second intermediate layer essentially consisting of basic metal compounds and icing sugar with starch having ratio from about 1 :5 to about 5:1, a second subcoating layer essentially consisting of waxy material, an enteric layer comprising at least one enteric polymer and a second enteric layer comprising at least one enteric polymer wherein the basic metal compound are not in intimate contact with the amorphous esomeprazole.
  • a multiple unit tablet dosage form comprising a stabilized pharmaceutical composition, wherein the pharmaceutical composition comprising an inert core unit, a drug layer coated over the inert core unit, wherein the drug layer essentially consisting of amorphous esomeprazole, a binder and a disintegrant, an intermediate layer essentially consisting of basic metal compounds, and icing sugar with starch having ratio from about 1 :5 to about 5:1, a subcoating layer essentially consisting of waxy material, a second intermediate layer essentially consisting of basic metal compounds and icing sugar with starch having ratio from about 1 :5 to about 5:1, a second subcoating layer essentially consisting of waxy material, an enteric layer comprising at least one enteric polymer, a second enteric layer comprising at least one enteric polymer; and tablet excipients wherein the basic metal compound is not in intimate contact with the amorphous esomeprazole in the pharmaceutical composition, and the pharmaceutical
  • the ratio of basic metallic compound to icing sugar with starch in the intermediate layers of the pharmaceutical composition is preferably between 1 :3 to about 1 :5.
  • a process for preparing the pharmaceutical composition comprising coating the inert core with aqueous dispersion or suspension of the drug coating layer and optionally other pharmaceutical excipients, applying the intermediate coating as an aqueous dispersion or suspension on the drug coated core, applying the aqueous dispersion or suspension of the waxy material of the subcoating layer on the resultant product, followed by optionally repeating the step of applying the intermediate and the subcoating layer on the resultant product and subsequently coating the resultant with one or more enteric layers using an aqueous dispersion of at least one enteric polymer and drying the enteric coated product to obtain the pharmaceutical composition.
  • a process for preparing the solid dosage form containing the pharmaceutical composition comprising coating the inert core with aqueous dispersion or suspension of the drug coating layer and optionally other pharmaceutical excipients, applying the intermediate coating as an aqueous dispersion or suspension on the drug coated core, applying an aqueous dispersion or suspension of waxy material of the subcoating layer on the resultant product, repeatedly applying a second intermediate and subcoating layer on the subcoated product followed by coating the resultant with one or more enteric layer using an aqueous dispersion of at least one enteric polymer and drying the enteric coated product to obtain the pharmaceutical composition and further formulating into a suitable dosage form.
  • the dosage form so obtained is optionally packaged in deoxidant-encapsulated or oxygen and water vapor permeation inhibitory packaging.
  • a process for preparing the multiple unit tablet dosage form comprising the stabilized pharmaceutical composition, the process comprising coating the inert core with aqueous dispersion or suspension of the drug coating layer and optionally other pharmaceutical excipients, applying the intermediate coating as an aqueous dispersion or suspension on the drug coated core, applying the aqueous dispersion or suspension of waxy material of the subcoating layer, repeatedly applying a second intermediate and subcoating layer on the subcoated product followed by coating the resultant product with one or more enteric layer employing an aqueous dispersion of at least one enteric polymer, drying the enteric coated product followed by passing the same through suitable sized mesh, blending the dried product with one or more tablet excipients and compression to obtain tablets.
  • the multiple unit tablet dosage form is optionally packaged in a deoxidant-encapsul
  • the present invention discloses a stabilized pharmaceutical composition of benzimidazole compound, preferably amorphous form of esomeprazole and process for preparing the same thereof.
  • the present invention discloses a solid dosage form comprising the pharmaceutical composition, specifically a multiple unit tablet dosage form.
  • the present invention also discloses a process for producing the solid dosage form and the multiple unit tablet dosage form thereof.
  • Amorphous esomeprazole or drug as used herein includes all pharmaceutically or therapeutically acceptable salts, hydrates, solvates, and other forms of amorphous esomeprazole.
  • Amorphous esomeprazole magnesium is preferable form.
  • Coating as used herein also refers to layering and two terms can be used interchangeably. Coating composition for drug layering, intermediate layering, subcoating and enteric coating layering is distinct from each other functionally. "Stability” or stabilization or stabilized as used herein refers to preservation of the amorphous nature of esomeprazole active pharmaceutical ingredient, and prevention of its conversion into degradation variants, in the dosage forms of the invention.
  • Related substances as referred herein means any variant of active pharmaceutical ingredient (drug substance) resulting from a molecular or chemical or physical change in the drug substance brought about during manufacture and/or storage of the dosage form by the effect of light, temperature, pH, water, or by reaction with an excipient and/or the immediate container closure system, which may or may not have deleterious effect on the safety and efficacy of the drug product
  • Active Pharmaceutical Ingredient refers to the molecular/chemical moiety, including its salt forms, responsible for bringing about a therapeutic response in mammal.
  • core refers to the inert spherical or granular material used for coating of drug layer and subsequently intermediate, subcoating and enteric coating. Core is interchangeably used with beads, units and /or pellets. Core can be made up of material, which is water soluble, water swellable or water insoluble or any combination thereof.
  • Dosage form refers to suitable physical form like capsules, tablet, dry syrup, sachets and the like, which are convenient for administration of drug to patient in need of that drug. Term dosage form has been frequently interchanged with composition and/or formulation for the description of the present invention.
  • Tablet excipients refers to customary excipients employed in manufacturing of tablets either from granules or by direct compression technique.
  • Acid resistance refers to property of tablet/capsule to prevent release or minimize release of the drug from dosage form when tested as per following dissolution conditions
  • Dissolution Media 0.1N HCL medium, RPM: lOOrpm Time: 2 hours, and calculated as drug retained in the dosage form after designated exposure.
  • the stabilized pharmaceutical composition comprises (a) an inert core unit,
  • a drug layer coated over the inert core unit wherein the drug layer essentially consisting of amorphous esomeprazole, a binder and a disintegrant, (c) one or more intermediate layer essentially consisting of basic metal compounds and icing sugar with starch, having ratio from about 1 :5 to about 5:1,
  • one or more enteric layer comprising at least one enteric polymer, wherein the basic metal compounds are not in intimate contact with the drug in the pharmaceutical composition.
  • the solid dosage form of the stabilized pharmaceutical composition comprises:
  • a second enteric layer comprising at least one enteric polymer, wherein the basic metal compound are not in intimate contact with the amorphous esomeprazole.
  • the ratio of the basic metallic compound to icing sugar with starch in the intermediate layers varies from about 1 :5 to about 5:1, preferably about 1 :3 to about 1:5 and the pharmaceutical composition is formulated into solid dosage forms preferably tablets or capsules.
  • a multiple unit tablet dosage form comprising a stabilized pharmaceutical composition, wherein the pharmaceutical composition comprising:
  • the inert core can be water-soluble, water- swellable and water-insoluble.
  • NPS Non-pareil seeds
  • sugar spheres exemplifies inert core of water-soluble type.
  • NPS are white, spherical particles of 62-92% sucrose and rest starch. NPS are commercially available from JRS Pharma, USA in various sieve sizes. Suitable examples of water swellable cores are microcrystalline cellulose spheres, commercially available from FMC Corporation under the trade name
  • Exemplary water-insoluble inert cores are glass beads and coarse grade silicon beads.
  • the inert core must be of sufficient density and strength to withstand stress and strain of coating process.
  • the inert core unit is made up of inert non-pareil sugar spheres or microcrystalline cellulose.
  • size of NPS is selected from the following sieve sizes: 40-60 mesh sieve (250-425 ⁇ m), 40-50 mesh size (420-300 ⁇ m),
  • 35-40 mesh sieve (425-500 ⁇ m), 30-35-mesh sieve (500-600 ⁇ m), 25-30 mesh sieve (600-710 ⁇ m), 20-25 mesh sieve (710-850 ⁇ m), 18-20 mesh sieve (850-1000 ⁇ m), 16-
  • the inert cores have a diameter ranging from about 250 to 600 ⁇ m, preferably from 300 to 500 ⁇ m and most preferably 300 to 420 ⁇ m.
  • inert core constitute from about 5% to about 40% by weight of the enteric-coated beads, preferably from about 10% to about 30%, still more preferably from about 15% to about 25% by weight of enteric-coated beads.
  • the drug layer essentially consists of the amorphous esomeprazole, binder and disintegrants.
  • the inert core is coated with aqueous dispersion essentially consisting of the amorphous esomeprazole, binder, and disintegrants.
  • the amorphous esomeprazole constitutes from about 10% to about 30% by weight of enteric-coated pellets.
  • the binders employed include, but not limited to, starch, gelatin, acacia, sodium alginate, alginic acid, polyvinyl pyrrolidone (Povidone K-30), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyacrylate, ethylcellulose, glucose, sucrose, sorbitol, mannitol, dextrose, icing sugar with starch, sodium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, polyvinyl alcohol, polymethacrylates (Eudragit ® NE 30 D and Eudragit ® RS 30 D) and methyl cellulose, maltodextrins and chitosan derivatives.
  • the binder is hydroxypropyl cellulose (HPC).
  • HPC for binder use, is commercially available from Aqualon, USA under the brand name Klucel ® EF and EXF.
  • Binder constitute from about 0.5% to about 15%, preferably from about 1 to about 10% by weight of the enteric-coated beads,
  • disintegrants include, but not limited to, croscarmellose sodium, sodium starch glycolate, carboxymethylstarch, crosslinked polyvinyl pyrrolidone (Crospovidone XLlO), and low-substituted hydroxypropyl cellulose (L- HPC), alginic acid, maltose, polacrilin potassium, pullulan, pregelatinized starch.
  • Disintegrant constitute from about 1% to about 15%, preferably from about 2% to about 10% by weight of the enteric-coated beads. Crospovidone, commercially available from International Specialty Products, USA, is the preferred choice of disintegrant for drug layer.
  • the drug layer may further contain other pharmaceutically acceptable excipients such as solvents for dissolving the binders and/or the esomeprazole, anti- tacking agents and surfactants.
  • Suitable examples of surfactants include, but not limited to, polysorbate series such as, 80, 60, 40, 20; sorbitan monooleate, sodium lauryl sulphate, benzalkonium chloride, cetylpyridinium chloride.
  • Surfactants promote the dispersion of the drug and low aqueous-solubility excipients in aqueous medium.
  • Surfactant constitute preferably from about 0% to about 1% by weight of the enteric-coated beads.
  • the surfactants include sodium lauryl sulphate, polysorbate 80, and polysorbate 20.
  • Suitable antitacking agents according to the invention include but are not limited to talc, silicon dioxide and magnesium stearate. Antitacking agents constitute preferably from about 0% to about 1% by weight of the enteric-coated beads.
  • the drug layer is applied to the inert core by any conventional techniques known in the art, such as, pan coating, roto-granulation or fluidized bed coating. During such coating operations the drug is dispersed or dissolved or suspended in an organic or aqueous solvent, which can also contain above-mentioned excipients.
  • the solvent system used for processing the drug layer can be aqueous or non aqueous. Appropriate non-aqueous solvents can be alcoholic, such as, methanol, ethanol, isopropyl alcohol (IPA); hydro-alcoholic, such as, water-IP A; organic solvents, such as, acetone, methylene chloride or any combination of those mentioned above.
  • aqueous solvent, purified water is employed and drug layering is carried out in fluid bed processor fitted with wurster apparatus.
  • Drug layering constitutes from about 10% to about 25% by weight enteric- coated beads.
  • Intermediate layer Composition of the invention contains one or more intermediate layers, which may alternate with one or more subcoating layers.
  • the composition of the first and second intermediate layers according to the invention may be similar or different.
  • the intermediate layer is critical for the stabilized composition of the present invention as it is instrumental in securing the stability of the composition of the present invention.
  • Composition of the intermediate layer reduces the formation of related substances in dosage form and in concert with processing conditions preserves and conserves the amorphous nature of the esomeprazole in the dosage form.
  • the intermediate layer essentially consists of basic metallic compounds and icing sugar with starch.
  • the basic metallic compounds are selected from metal carbonates, and metal oxides.
  • Other suitable examples of the basic metallic compound include, but not limited to, magnesium carbonate, calcium carbonate, magnesium oxide, calcium oxide, magnesium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, magnesium metasilicate aluminate, magnesium silicate aluminate and magnesium aluminate.
  • magnesium oxide is the preferable basic metallic compound employed in the intermediate layer.
  • the coating suspension/dispersion containing the basic metallic compound in order to ensure uniform distribution of the basic metallic compound in the intermediate layer, it is essential to incorporate a carrier in the coating suspension/dispersion containing the basic metallic compound.
  • the most preferred carrier for the intermediate layer is icing sugar with starch.
  • the basic metallic compound, for each of the intermediate layers constitute from about 0.5% to about 7%, preferably from about 1% to about 3% by weight of the enteric-coated units.
  • carrier for the basic inorganic compound in the intermediate layer constitute from about 1% to about 12%, preferably from about 3 % to about 9% by weight of the enteric-coated beads.
  • the basic metallic compounds are not mixed with drugs nor are they in uniform contact with one another. Presence of the basic metallic compound, preferably, magnesium oxide in combination with icing sugar with starch stabilizes the composition of invention, as related substances are restricted to at a very low level.
  • the intermediate layer may further contain antitacking agents, suspending agents, and surfactants to facilitate the processing of layering or coating operation.
  • Antitacking agents such as talc constitute preferably from about 0.5% to about 5% by weight of the enteric-coated beads.
  • the ratio of basic metallic compounds, such as, magnesium oxide to icing sugar with starch, in the intermediate layers is also vital for the stability of the composition of the invention.
  • Preferable ratio of the basic metallic compound to icing sugar with starch varies from about 1 :5 to about 5:1, preferably from about 1 :3 to about 1 :5.
  • Fluid bed processor (FBP) fitted with necessary apparatus is used to carry out application of the intermediate layer on drug-coated beads. Operating parameters of the FBP are well known to the skilled artisan.
  • Each intermediate layer constitutes from about 2% to about 20% by weight of enteric-coated beads.
  • the pharmaceutical composition of the present invention further contains one or more layer of subcoating, which may alternate, with one or more intermediate layers.
  • the composition forming the first and second subcoating layers according to the invention may be similar or different.
  • the subcoating layer of the pharmaceutical composition of the present invention essentially consists of waxy substances.
  • suitable examples of the waxy substances include, but are not limited to, compounds of PEG seriessuch as polyethylene glycol 4000, 6000; glyceryl behenate, stearic acid and Gelucire ® or combinations thereof.
  • the waxy material for the subcoating layer is polyethylene glycol 6000.
  • the subcoating layer is applied to the intermediate layered units by coating in suitable equipment like coating pan, coating granulator and fluid bed processor using water or organic solvents like isopropyl alcohol.
  • suitable equipment like coating pan, coating granulator and fluid bed processor using water or organic solvents like isopropyl alcohol.
  • other additives such as, plasticizer, anti-tacking and anti-static agents may be used along with waxy substances.
  • the waxy substance constitutes 90% to 100% of waxy layer and 0.5% to 10% by weight of the enteric-coated beads/units.
  • Each subcoating layer constitutes from about 1% to about 15% by weight of the enteric-coated beads.
  • the pharmaceutical composition contains one or more enteric layers, of same or different enteric polymers, disposed on subcoated beads.
  • the enteric layer essentially consists of enteric polymers.
  • enteric layer may also contain plasticizers, opacifying agents, antitacking agents, stabilizers, antifoaming agents, surfactants, antistatic agent, colorants, and pigments to enhance the processability, functionality and elegance of the said layers.
  • the polymers useful in the enteric layer include, but not limited to, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), shellac, polyvinylacetate phthalate, acrylic acid polymers & copolymers, and methacrylic acid polymers & co-polymers or any combinations thereof.
  • the enteric polymers are methacrylic acid copolymers or HPMCP or combination thereof.
  • Methacrylic acid copolymer is commercially available under the brand name Eudragit ® L30 D55.
  • the enteric polymers constitute from about 10% to about 50% by weight of enteric-coated beads, preferably, from about 20% to about 30%.
  • the plasticizers, which impart flexibility to the enteric layer constitute from about 1% to about 15%, preferably from about 3% to about 9% by weight of the enteric-coated beads, all percentages based on weight-by-weight basis.
  • Exemplary, plasticizers are triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, polyethylene glycol and cetyl alcohol.
  • antitacking and antistatic agents include, but are not limited to, talc, silicon dioxide, metallic salts of stearic acid and glyceryl monostearate. Optimum concentration of these agents in the enteric layer is well known to the skilled artisan.
  • the enteric layer may also include 0.1% to about 2% of surfactant.
  • the enteric layers are deposited on the subcoated beads in suitable equipment like fluid bed processor using aqueous or non-aqueous solvents.
  • the solvent system employed for processing of enteric layer and is preferably aqueous, but it can be a combination of aqueous and organic solvent.
  • the enteric layer is essential to prevent degradation of the acid-susceptible esomeprazole drug during its transit from the acidic environment of stomach.
  • each enteric- coated layer constitutes from about 15% to about 40% by weight of enteric-coated beads.
  • the waxy and enteric coating can be carried out using fluid bed processor.
  • Enteric-coated units are either filled into suitable size capsules or formulated into suitable size tablets.
  • suitable size capsules for formulation of enteric-coated units into tablets, said units are combined with necessary tableting excipients, which afford essential attributes, to enteric-coated beads/pellets, for compression into tablets.
  • various tableting excipients include but are not limited to, diluents, binders, cushioning agents, surfactants, disintegrants, lubricants, sweeteners, anti-tacking agents, flavoring agents antiadherants and glidants.
  • the tablet excipients are added before compressing into tablets.
  • Diluents employed are preferably directly compressible diluents, which impart necessary flow and compressibility property to the tablet mix to facilitate the process of tablet manufacturing.
  • the enteric-coated beads are transformed into tablets after combining with necessary tableting excipients.
  • the enteric-coated beads constitute from about 25% to about 60% by weight of tablet weight. Ratio of enteric-coated beads to tableting excipients preferably varies from 2:3 to 3 :2.
  • Various tableting excipients are directly compressible diluent or simple diluents, binders, disintegrants, cushioning agents, surfactants, anti-adherents, glidants and lubricants.
  • the directly compressible diluents employed include microcrystalline cellulose (Avicel PH 102 from Signet), Cellactose (a combination of MCC and lactose from Meggle, Germany), Pharmatose DCL-40 (combination of anhydrous lactose and lactitol from DMV, Netherlands), Di-pac (sucrose and dextrin from
  • the diluent for the present invention is Avicel ® PH 102.
  • PH 102 is favorable because it possesses binder property also.
  • the diluent constitutes from about 30 to about 60% by weight of tablet weight.
  • Suitable examples of binders in the present invention include methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, microcrystalline cellulose and hydroxypropyl methylcellulose and low substituted hydroxypropyl cellulose. Binders constitute from about 1% to about 10%, by weight of tablet weight.
  • Useful examples of disintegrants including superdisintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, crosslinked polyvinyl pyrrolidone (crospovidone), and low-substituted hydroxypropyl cellulose (L-HPC), alginic acid, maltose, polacrilin potassium, pullulan, pregelatinized starch.
  • Preferred disintegrant is crosslinked polyvinyl pyrrolidone (crospovidone).
  • Disintegrant constitute from about 1% to about 20%, preferably from about 5% to about 15% by weight of tablet weight.
  • a cushioning agent preferably polyethylene glycol is employed in concentration of about 5% to about 30% by weight of tablet weight.
  • Suitable examples of lubricants include calcium and magnesium salts of stearic acid, glyceryl behenate and sodium stearyl fumarate. Preferred lubricant is sodium stearyl fumarate.
  • the lubricant is used in an amount of about 0.1% to about 5% by weight of tablet weight.
  • the tablet composition may also contain suitable glidants and antiadherants, as known to skilled artisan, in customary concentration.
  • the tableting excipients are blended homogeneously with enteric- coated pellets in a suitable blender, like twinshell blender, before being compressed in rotary tableting machine equipped with appropriate punches.
  • the pharmaceutical composition of the invention in tablet form may optionally be film coated to improve its elegance.
  • Film coating materials usually include water-soluble polymers like hydroxypropyl methylcellulose, polyethylene glycol; coloring agents, and pigments.
  • Opadry ® pink is the commercially available film coating material from Colorcon, USA. Opadry ® pink constitute of polyethylene glycol, hypromellose, iron oxide red, and titanium dioxide.
  • a solvent system is used for processing the drug layer or other coatings/layers wherein the system can be aqueous or non aqueous.
  • non-aqueous solvents can be alcoholic, such as, methanol, ethanol, isopropyl alcohol (IPA): hydro- alcoholic, such as, water-IP A; organic solvents, such as, acetone, methylene chloride or any combination of those mentioned above.
  • IPA isopropyl alcohol
  • hydro- alcoholic such as, water-IP A
  • organic solvents such as, acetone, methylene chloride or any combination of those mentioned above.
  • step (c) applying aqueous dispersion or suspension of the waxy material of the subcoating layer on the resultant product; (d) optionally repeating step (b) and (c) on the subcoated product obtained in step (c);
  • the process for preparing the pharmaceutical composition in a suitable dosage form comprises:
  • step (c) applying an aqueous dispersion or suspension of the waxy material of the subcoating layer on the resultant product; (d) repeating step (b) and (c) on the subcoated product obtained in step (c);
  • the process for preparing the multiple unit tablet dosage form containing the stabilized pharmaceutical composition comprises:
  • step b applying an aqueous dispersion or suspension of the waxy material of the subcoating layer on the resultant product of step b;, (d) repeating the step (b) and (c) on the subcoated product obtained in step
  • step f blending the dried product of step f with one or more tablet excipients; and (h) compressing the blend obtained in step g to obtain tablets and optionally packaging the same in deoxidant-encapsulated or oxygen and water vapor permeation inhibitory packaging.
  • the dried enteric coated units are passed through a suitable size mesh and the enteric coated units are filled in suitable size capsules.
  • the enteric coated beads of step (g) are blended with tablet excipients including diluents, disintegrant, binders, surfactants, cushioning agent, lubricant, anti-adherants and glidants, followed by compressing the blend on a tableting machine using suitable tooling to obtain tablets of suitable size.
  • the dosage form is packed in the package, which prevents the permeation of oxygen and water vapor, package wherein reactive oxygen is replaced with non- reactive gases, and package encapsulated with deoxidizer.
  • the tablets or capsules thus obtained are packaged in deoxidant-encapsulated or oxygen and water vapor permeation inhibitory packaging.
  • the stable pharmaceutical composition comprising amorphous esomeprazole and said composition, either in capsule or compressed tablet form, is resistant to dissolution in acidic dissolution media.
  • dissolution profile of composition of invention is in absolute conformity with the established standards of USP and EP.
  • the tablets of present invention exhibit outstanding acid resistance property.
  • Composition of the invention is useful and recommended in the treatment of gastro-esophageal reflux disease, duodenal ulcer and Zollinger-EUison syndrome.
  • Dose-requirement of the drug is worked out on the basis of severity of disease and other factors. Typical dose varies from 20 mg to 40 mg once daily for 4 to 8 weeks only.
  • Example 1 illustrate specific embodiments of the present invention. They are, however, not intended to be limiting the scope of the present invention in any way.
  • Example 1 illustrate specific embodiments of the present invention. They are, however, not intended to be limiting the scope of the present invention in any way.
  • composition/Formulation (For example IT to 4T) Manufacturing Procedure:
  • Enteric coating-I a) Emulsion of glycerol monostearate was prepared in warm purified water with the help of polysorbate 80. b) Polyethylene glycol was dispersed in suitable quantity of purified water and added to emulsion of IV (a). c) Dispersion of IV (b) was added to dispersion of Eudragit L30 D55 under constant stirring. d) Subcoated pellets of III (b) were loaded into fluid bed processor and coated with dispersion of IV (c). e) Enteric-coated pellets were dried and passed through suitable size mesh.
  • Enteric coating -II a) Polyethylene glycol 400 was dispersed in the mixture of acetone and water. b) Hydroxypropyl methylcellulose phthalate 55 was added to dispersion of V (a). c) Enteric-coated pellets of IV (e) were loaded in fluid bed processor and coated with dispersion of V (b), subsequently, pellets were dried and passed through suitable size mesh. Stage VI:
  • Tablet formation a) Microcrystalline cellulose, sodium stearyl fumarate, polyethylene glycol 6000 and crospovidone XL were passed through suitable size mesh and mixed with enteric-coated pellets of V(c) in a conta blender for 15 minutes. b) Blend of VI (a) was compressed into tablets of suitable dimensions using tableting machine.
  • Stage VII Film coating a) Opadry pink was dispersed in purified water under stirring to get a homogenous dispersion. b) Compressed tablets of VI (b) were film coated in coating pan.
  • Drug layering a) Hydroxypropyl cellulose, Povidone K30 and the amorphous esomepraozle magnesium were dispersed in sufficient quantity of water and isopropyl alcohol. b) Sugar spheres (NPS) (inert core) were loaded in fluid bed processor and coated with dispersion of stage I (a). c) Drug layered pellets were dried and passed through suitable size mesh.
  • NPS Sugar spheres
  • Stage II Intermediate coating: a) Hydroxyethyl cellulose and talc were suspended in sufficient quantity of purified water, and passed through suitable size mesh. b) Drug coated pellets of I (c) were coated with suspension of II (a) in fluid bed processor. c) Intermediate-coated pellets were dried and passed through suitable size mesh.
  • Stage III Enteric coating-I: a) Triethyl citrate, and talc were dispersed in suitable quantity of purified water. b) Dispersion of HI (a) was added to dispersion of Eudragit L30 D55 under constant stirring. c) Subcoated pellets of II (c) were loaded into fluid bed processor and coated with dispersion of III (b). d) Enteric-coated pellets were dried and passed through suitable size mesh.
  • Stage IV Enteric coating -II: a) Triethyl citrate and talc was dispersed in the mixture of acetone and water. b) Hydroxypropyl methylcellulose phthalate 55 was added to dispersion of IV
  • Tablet formation a) Microcrystalline cellulose, sodium stearyl fumarate and crospovidone XL were passed through suitable size mesh and mixed with enteric-coated pellets of IV(c) in a conta blender for 15 minutes. b) Blend of V (a) was compressed into tablets of suitable dimensions using tableting machine.
  • compositions of the invention and reference example 1 were subjected to accelerated stability testing at 40°C ⁇ 2°C, 75% ⁇ 5%RH in closed containers (HDPE Bottles) for 1 to 3 months, and in open petridishes for 7 to 14 days. The results were analyzed for the total Related Substances. Results are set out in table 5 below: (a) Stability Testing in closed container (HDPE Bottles)
  • composition of invention has unexpectedly reduced the formation of total related substances as compared with composition of reference.
  • Experimental data profoundly testify to the fact that magnesium oxide in intermediate layer along with icing sugar with starch is critical for stabilizing the composition of the invention.
  • composition of the invention retains the amorphous nature of the esomeprazole after exposure to stringent stability testing conditions.
  • Acid resistance test for the multiple unit tablets and enteric coated of the composition of the present invention was carried out and the results were compared with data of omeprazole magnesium multiple unit tablet as reported in Ex. 3 of EP 1078628 assigned to Astra Zeneca UK.

Abstract

Cette invention concerne une composition pharmaceutique stabilisée de composés de benzimidazole, de préférence la forme amorphe d’ésoméprazole, et son procédé de préparation. L’invention concerne par ailleurs les compositions pharmaceutiques préparées sous formes pharmaceutiques solides, de préférence des comprimés et des capsules sous forme unitaire, et leur procédé de préparation.
PCT/IN2009/000553 2008-10-06 2009-10-06 Compositions pharmaceutiques comprenant de l’ésoméprazole amorphe, formes pharmaceutiques et procédé associés WO2010041276A1 (fr)

Priority Applications (2)

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EP09818889.9A EP2331084A4 (fr) 2008-10-06 2009-10-06 Compositions pharmaceutiques comprenant de l ésoméprazole amorphe, formes pharmaceutiques et procédé associés
US13/121,281 US20110177164A1 (en) 2008-10-06 2009-10-06 Pharmaceutical Compositions Comprising Amorphous Esomeprazole, Dosage Forms And Process Thereof

Applications Claiming Priority (2)

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IN2315DE2008 2008-10-06
IN2315/DEL/2008 2008-10-06

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WO2011140446A2 (fr) * 2010-05-06 2011-11-10 Dr. Reddy's Laboratories Ltd. Formulations pharmaceutiques
WO2011154009A1 (fr) * 2010-06-10 2011-12-15 Lifecycle Pharma A/S Composition comprenant un principe actif sous une forme amorphe et une substance poreuse adsorbante
ITFI20100175A1 (it) * 2010-08-06 2012-02-07 Valpharma Sa Nuove formulazioni farmaceutiche idonee per la somministrazione orale di esomeprazolo magnesio diidrato, in forma di compresse mups (multi unit pellets system).
EP2604256A1 (fr) * 2011-12-14 2013-06-19 Hexal AG Revêtements multicouches
CN103462924A (zh) * 2012-06-06 2013-12-25 南京亿华药业有限公司 一种埃索美拉唑缓释片的处方和制备方法
CN103520226A (zh) * 2013-10-11 2014-01-22 惠州市九惠制药股份有限公司 一种pH依赖型结肠定位硬胶囊
EP3292862A1 (fr) * 2016-09-07 2018-03-14 Sandoz Ag Formulations d'oméprazole

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US20070122470A1 (en) * 2005-11-30 2007-05-31 Dick Johansson New Combination Dosage Form
EP1813275A1 (fr) * 2005-12-20 2007-08-01 Teva Pharmaceutical Industries Ltd Comprime oral desintegrable de lansoprazole
WO2007115305A2 (fr) * 2006-04-04 2007-10-11 Cogentus Pharmaceuticals, Inc. Formes de dosage orales incluant un inhibiteur de l'agrégation plaquettaire et un inhibiteur acide
WO2008018825A1 (fr) * 2006-08-10 2008-02-14 Astrazeneca Ab Capsules orales d'alcool polyvinylique comprenant des inhibiteurs de la pompe à protons

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011140446A2 (fr) * 2010-05-06 2011-11-10 Dr. Reddy's Laboratories Ltd. Formulations pharmaceutiques
WO2011140446A3 (fr) * 2010-05-06 2012-03-15 Dr. Reddy's Laboratories Ltd. Formulations pharmaceutiques
WO2011154009A1 (fr) * 2010-06-10 2011-12-15 Lifecycle Pharma A/S Composition comprenant un principe actif sous une forme amorphe et une substance poreuse adsorbante
ITFI20100175A1 (it) * 2010-08-06 2012-02-07 Valpharma Sa Nuove formulazioni farmaceutiche idonee per la somministrazione orale di esomeprazolo magnesio diidrato, in forma di compresse mups (multi unit pellets system).
WO2012017074A1 (fr) * 2010-08-06 2012-02-09 Valpharma S.P.A. Formulations pharmaceutiques orales d'ésoméprazole sous la forme de comprimés mups (multi unit pellets system)
EP2604256A1 (fr) * 2011-12-14 2013-06-19 Hexal AG Revêtements multicouches
CN103462924A (zh) * 2012-06-06 2013-12-25 南京亿华药业有限公司 一种埃索美拉唑缓释片的处方和制备方法
CN103520226A (zh) * 2013-10-11 2014-01-22 惠州市九惠制药股份有限公司 一种pH依赖型结肠定位硬胶囊
CN103520226B (zh) * 2013-10-11 2015-09-02 惠州市九惠制药股份有限公司 一种pH依赖型结肠定位硬胶囊
EP3292862A1 (fr) * 2016-09-07 2018-03-14 Sandoz Ag Formulations d'oméprazole
WO2018046498A1 (fr) * 2016-09-07 2018-03-15 Sandoz Ag Formulations d'oméprazole

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