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US20060024362A1 - Composition comprising a benzimidazole and process for its manufacture - Google Patents

Composition comprising a benzimidazole and process for its manufacture Download PDF

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Publication number
US20060024362A1
US20060024362A1 US10/901,898 US90189804A US2006024362A1 US 20060024362 A1 US20060024362 A1 US 20060024362A1 US 90189804 A US90189804 A US 90189804A US 2006024362 A1 US2006024362 A1 US 2006024362A1
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Prior art keywords
composition
parts
active ingredient
core
disintegrant
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US10/901,898
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Pawan Seth
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Kremers Urban Pharmaceuticals Inc
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Individual
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Priority to US10/901,898 priority Critical patent/US20060024362A1/en
Assigned to PHARMAPASS II LLC reassignment PHARMAPASS II LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SETH, PAWAN
Publication of US20060024362A1 publication Critical patent/US20060024362A1/en
Assigned to PHARMAPASS II LLC reassignment PHARMAPASS II LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SCHMITT, BENOIT, SETH, PAWAN
Assigned to SCHWARZ PHARMA reassignment SCHWARZ PHARMA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PHARMAPASS II LLC
Assigned to UCB PHARMA GMBH reassignment UCB PHARMA GMBH CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: SCHWARZ PHARMA AG
Priority to US13/895,492 priority patent/US8968776B2/en
Priority to US14/633,766 priority patent/US20150164817A1/en
Assigned to KREMERS URBAN PHARMACEUTICALS INC. reassignment KREMERS URBAN PHARMACEUTICALS INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: UCB, INC.
Abandoned legal-status Critical Current

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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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer

Definitions

  • the invention relates to a novel composition comprising a benzimidazole, said composition being notably free of any binder.
  • the invention also relates to a very simple process for the manufacture of the present composition.
  • Benzimidazoles are known proton pump inhibitors. Representatives of this class of drugs are omeprazole, esomeprazole, pantoprazole, rabeprazole. Many formulation patents are known for this type of active pharmaceutical ingredient.
  • WO-A-9712581 discloses a composition exempt of alkaline-reacting compounds comprising:
  • U.S. Pat. No. 5,997,903 discloses a medicament in pellet or tablet form which contains the active compound pantoprazole, which is to be administered orally, is resistant to gastric juice and consists of a basic pellet core or tablet core, one or more inert, water-soluble intermediate layer(s) and an outer layer which is resistant to gastric juice, and which is characterized in that the core contains, in addition to pantoprazole or in addition to a pantoprazole salt, polyvinylpyrrolidone and/or hydroxypropylmethylcellulose as the binder, and if desired mannitol additionally as an inert filler.
  • U.S. 2003114494 discloses a stable oral pharmaceutical which comprises a benzimidazole, comprising:
  • the invention provides new benzimidazole compositions, especially the following compositions:
  • the invention also provides a process for manufacturing the compositions of the invention, said process comprising the steps of: (i) granulating said active ingredient with said diluents, said disintegrant and said lubricant if any; (ii) compressing the product of step (i) to form a tablet core containing an active ingredient; (iii) coating said core with said intermediate layer; and (iv) coating a product from step (iii) with said enteric layer.
  • the invention is designed for any benzimidazole, which is a class of compounds that is generally known.
  • the expression “benzimidazole active ingredient” should be taken to mean benzimidazole derivatives that are of therapeutic value.
  • the benzimidazole active ingredients as used in the instant application are notably, but not limitatively, disclosed in the following patents and patent applications: EP-A-0,005,129, EP-A-0,080,602, EP-A-0,127,763, EP-A-0,130,729, EP-A-0,134,400, EP-A-0,146,370, EP-A-0,150,586, EP-A-0,166,287, EP-A-0,173,664, EP-A-0,244,380, DE-3,415,971, GB-A-2,082,580, GB-A-2,141,429, GB-A-2163747, U.S.
  • the instant invention notably applies to omeprazole, esomeprazole, pantoprazole, lansoprazole, leminoprazole, pariprazole, rabeprazole, timoprazole, aripiprazole and diapiprazole.
  • alkaline salt form or derivative of the active ingredients cited above is also suitable in one embodiment.
  • Derivatives such as salts (hydrates such as sesquihydrates, etc.), alkaline salts (salts formed with lithium, sodium, magnesium, potassium, calcium etc. as well as any other base), esters and the like (including pro-drugs), are also contemplated. It is also possible to use an alkaline-reacting agent together with the benzimidazole active ingredient.
  • Such agents which may be mentioned here are the pharmacologically tolerated alkali metal, alkaline earth metal or earth metal salts of weak acids and the pharmacologically tolerated hydroxides and oxides of alkaline earth and earth metals, such as sodium carbonate, calcium carbonate, magnesium carbonate, magnesium oxide and magnesium hydroxide.
  • Acidic reacting-agent such as those disclosed in U.S. 2003114494, notably sodium dihydrogen phosphate (NaH 2 PO 4 ), can also be used.
  • the expression “exempt of alkaline-reacting compound” should be taken to mean a composition that substantially does not contain any alkaline-reacting compound, in other words a composition in which the amount of alkaline-reacting compound is not sufficient to set up an alkaline micro-environment around the active ingredient when it is in contact with an acid or neutral aqueous medium, for example a micro-environment having a pH above 7.
  • said benzimidazole active ingredient is not in the form of an alkaline salt, and said composition is exempt of alkaline-reacting compounds.
  • Mixtures of active ingredients are also envisaged, for example those comprising a benzimidazole in association with another active ingredient, or those containing two benzimidazoles.
  • the core contains the benzimidazole active ingredient together with various excipients, notably diluents (also known as fillers) and disintegrant, and optionally lubricant.
  • diluents also known as fillers
  • the diluents will generally comprise a first diluent which is water-soluble, and optionally a second diluent which is water-insoluble (or hydrodispersible). These types of diluents are known in the art. They are crystalline or amorphous, and are generally inert with respect to the benzimidazole active ingredient.
  • the first water-soluble diluent examples include lactose, mannitol, and mixtures thereof. Lactose is preferred.
  • the second water-insoluble diluent examples include cellulose acetate, microcrystalline cellulose, and mixtures thereof. Cellulose acetate is preferred.
  • the weight ratio first diluent to second diluent is preferably from about 1.5:1 to 1:1.5.
  • the particle size of the first (and optionally second diluent) is not critical.
  • the d 50 of the diluent particle is from about 50 ⁇ m to about 400 ⁇ m, preferably from about 75 ⁇ m to about 150 ⁇ m.
  • the disintegrant can be any compound known in the art to that effect.
  • examples of disintegrants are cross-linked polyvinylpyrrolidone (crospovidone), sodium croscarmellose, sodium carboxymethyl starch, modified starch or unmodified starch, colloidal silica and mixtures thereof.
  • the preferred disintegrant is cross-linked polyvinylpyrrolidone (crospovidone).
  • the lubricant can be selected from the group consisting of sodium stearylfumarate, magnesium stearate, talc, glyceryl behenate and mixtures thereof.
  • One exemplary core formulation is one where said core consists essentially of, by weight:
  • Another exemplary core formulation is one where said core consists essentially of, by weight:
  • the core consists essentially of the benzimidazole active ingredient, of the first, water-soluble diluent, optionally of the second, water-insoluble, diluent, of the disintegrant, and optionally of the lubricant.
  • the core consists essentially of the benzimidazole active ingredient, of the first, water-soluble diluent, the disintegrant, and the lubricant.
  • the term “consisting essentially of”, in one embodiment, is intended to mean that the listed compounds represent more than 90% by weight of the core, preferably more than 95% by weight of the core, most preferably more than 98% by weight of the core.
  • excipients such as fillers, plastifiers, surfactants, pigments, wetting agents, etc. may also be present in the core or the additional layers, if need be.
  • the excipients can be any one traditionally used in the art. For more details about these excipients, one can refer to the disclosure in “Handbook of pharmaceutical excipients”, American Pharmaceutical Association, 1994 ISBN 0 91730 66 8, by Wade A. and Weller P. Examples are polysorbate 80, sodium lauryl sulfate, colloidal silica, titanium dioxide, etc.
  • the intermediate layer comprises of at least one sub-layer. It corresponds to one or several inert water-soluble layers or layers which rapidly disintegrate in an aqueous medium, containing inert pharmaceutical excipients.
  • This layer comprises at least one polymer conventionally used in applications where a film is provided by coating such as: sugars, polyethyleneglycol, polyvinylpyrrolidone, poly(vinyl alcohol), hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, gelatine, etc.
  • This intermediate layer is applied to the core using any coating technique conventionally employed in a suitable coating tank or in a fluidized bed device, with the use of suitable aqueous and/or organic solvents, or by using latex suspensions of said excipients.
  • Water is the preferred solvent.
  • film-forming polymers generally water-soluble polymers albeit water-insoluble polymers may be used
  • plasticizers such as, for example, propylene glycol
  • auxiliaries e.g. buffers, bases, pigments, surfactants, etc.
  • these other additives and auxiliaries or excipients can be any one of the conventional pharmaceutical excipients cited in the section relating to the core, or a mixture thereof.
  • Talc is one preferred excipient used in the intermediate layer.
  • An exemplary composition for the intermediate layer comprises by weight, based on the weight of said layer:
  • the enteric layer according to this invention corresponds to at least one sub-layer that is entero-soluble and gastro-resistant. It is applied to the intermediate layer by conventional coating techniques such as coating in a tank or a fluidized bed employing polymer solutions in water or in suitable organic solvents or using latex suspensions of these polymers. Water is the preferred solvent.
  • the enteric coating can also be applied using aqueous dispersions of polymers. Water-soluble or water-insoluble polymers, or mixtures thereof can be used, according to methods known in the art. The expert knows, on the basis of his technical knowledge, what outer layers which are resistant to gastric juice can be used.
  • cellulose phthalates and derivatives thereof use can be made of: cellulose phthalates and derivatives thereof, cellulose acetyl phthalate, hydroxypropyl-methylcellulose phthalate, polyvinyl phthalate acetate, as well as (meth)acrylic (co)polymers.
  • acrylic copolymers one may cite especially the methacrylic acid/alkyl (meth)acrylate copolymers (sold as Eudragit®). A methyl radical and an ethyl radical are preferred as alkyl radical.
  • the methacrylic acid type C copolymer complying with the US pharmacopoeia is one polymer suited.
  • a preferred polymer is a copolymer based on methacrylic acid and ethyl acrylate, in which the ratio of free carboxyl groups to esters groups is about 1:1.
  • the average molecular weight is, for example, about 250,000.
  • Exemplary coating polymers are commercially available; they are those available as Aquateric® (FMC Corporation), CE5142 coating (BASF) and especially the Eudragit® products (Rohm Pharma), these latter being preferred.
  • the enteric layer can also contain a pharmaceutically-acceptable plastifying agent such as, for example, ketanol, triacetine, citric acid esters (e.g. triethyl citrate) such as those known under as Citroflex® (Pfizer), phthalic acid esters, dibutylsuccinate, polyethyleneglycol of varying molecular weights, or any other similar plastifying agent.
  • a pharmaceutically-acceptable plastifying agent such as, for example, ketanol, triacetine, citric acid esters (e.g. triethyl citrate) such as those known under as Citroflex® (Pfizer), phthalic acid esters, dibutylsuccinate, polyethyleneglycol of varying molecular weights, or any other similar plastifying agent.
  • the amount of plastifying agent is in general optimized for each polymer and the plastifying agent generally represents by weight 1 to 30% of the polymer, for example from 5 to 25%.
  • Supplementary agents such as talc, pigments, coloring agents, flavoring agents, as well as any other excipient that conventionally enters into the composition of enteric coatings can be employed; such other conventional excipients being e.g. those disclosed in connection with the core.
  • Talc is one preferred excipient.
  • An exemplary composition for the enteric layer comprises by weight, based on the weight of said layer:
  • composition according to the present invention generally comprises, based on the total weight of the composition:
  • the process used to manufacture the instant composition is very simple. First a core is manufactured, and then the intermediate and enteric layers are coated on said core using any classical method.
  • the present invention brings a novel manufacturing process as far as the core is concerned. It is important to note that the present process allows manufacturing the core without recourse to any binder.
  • the core is generally manufactured as follows. In a first step, the various ingredients are granulated together. In a second step, a tablet is obtained starting from the granulates obtained at the first step by compressing the product.
  • the first granulating step can be carried out by using any granulating method, such as dry granulation, sieving, fluidized bed granulation or wet granulation.
  • any granulating method such as dry granulation, sieving, fluidized bed granulation or wet granulation.
  • fluidized bed granulation and wet granulation one uses suitable aqueous and/or organic solvents, preferably an aqueous solvent.
  • Wet granulation is the preferred method.
  • the apparatus that can be used is for example a high shear mixer.
  • the disintegrant used in the composition can be partly into the granulate and partly in the outer phase.
  • the weight ratio distribution granulate:outer phase of the disintegrant can be from 100:0 to 0:100, especially 70:30 to 0:100.
  • the process for manufacturing the core comprises the following sub-steps:
  • the drying step can be carried out in any conventional apparatus known to that effect, for example a fluidized bed or a drying oven.
  • the drying step is considered as having been carried out when the residual water content is below 10%, for example below 3%, depending on the kind and amount of ingredients. Tableting then follows granulation.
  • the tableting step can be implemented using any conventional technique which is suitable, for example using alternating or rotating compressing equipment.
  • the core can be obtained by direct, dry, compression.
  • the water, if used, needed to produce the core is generally present in an amount of from 10% to 100% of the core weight.
  • the water needed to produce the intermediate layer and/or the enteric layer is generally present in an amount of from 100% to 1000% of the intermediate and/or enteric layer weight.
  • the composition according to the invention is provided in a single tablet form (which may be breakable, if need be).
  • the composition is in the form of micro-tablets enclosed inside a capsule, e.g. a gelatin capsule.
  • a gelatin capsule any gelatin capsule conventionally employed in the pharmaceutical formulation field can be used, such as the hard gelatin capsule known as Capsugel®, available from Eli Lilly.
  • the compositions of this invention are particularly suitable for oral administration of the active ingredients and are particularly suitable for treating gastrointestinal sicknesses.
  • Active ingredient, lactose and cellulose acetate are dry mixed. Water is added and granulation is carried out in a gravity funnel. Granulates are dried at 55° C. for 45 minutes. Crospovidone and glyceryl behenate are then added and mixed. The resulting mixture is then compressed into tablets (using a BetaPress® from Manesty with a punch having a curvature and a diameter of 7 mm—also known as 7R7).
  • HPMC HPMC is dissolved in the water, and talc and titanium dioxide are then added.
  • the suspension is homogenized and sprayed onto the tableted core in a coating pan (vector corporation perforated pan coater type LDCS).
  • enteric coating layer formulation is used.
  • Compound Amount (mg/unit) Eudragit ® L30D 11.10 Talc 2.23 Triethyl citrate 1.67 Water* 44 Total 15.00 *evaporates off during process
  • Triethyl citrate is dissolved in 60% of the water. The resulting solution is added to the Eudragit polymer and let in contact for 45 minutes under low stirring. Talc is added to the remaining 40% water, and the suspension is homogenized. Both compositions are then combined into one solution which is sprayed onto the intermediate coated core in a coating pan (identical to the one used for the intermediate layer) using a peristaltic pump and a spray nozzle (available from company spray systems).
  • the process is as in example 1.
  • the process differs in that half of crospovidone is mixed to form the granulates and half is mixed with the granulates as in example 1.
  • the intermediate and enteric layers are as in example 1 and the process for coating is the same.

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Abstract

The invention provides new benzimidazole compositions, comprising: (a) a core containing said benzimidazole active ingredient; (b) an intermediate layer; and (c) an enteric layer; said core being substantially free of binder. The invention also provides a process for manufacturing the composition of the invention.

Description

    FIELD OF THE INVENTION
  • The invention relates to a novel composition comprising a benzimidazole, said composition being notably free of any binder. The invention also relates to a very simple process for the manufacture of the present composition.
    • BACKGROUND OF THE INVENTION
  • Benzimidazoles are known proton pump inhibitors. Representatives of this class of drugs are omeprazole, esomeprazole, pantoprazole, rabeprazole. Many formulation patents are known for this type of active pharmaceutical ingredient. WO-A-9712581 discloses a composition exempt of alkaline-reacting compounds comprising:
      • (a) a core containing a benzimidazole active ingredient, said core being constituted of nuclei and said active ingredient mixed together and then compressed together, and said active ingredient not being in the form of an alkaline salt, and where a polymer acting as a binder is generally used in the core manufacture;
      • (b) an intermediate layer; and
      • (c) an enteric layer applied onto the intermediate layer.
  • U.S. Pat. No. 5,997,903 discloses a medicament in pellet or tablet form which contains the active compound pantoprazole, which is to be administered orally, is resistant to gastric juice and consists of a basic pellet core or tablet core, one or more inert, water-soluble intermediate layer(s) and an outer layer which is resistant to gastric juice, and which is characterized in that the core contains, in addition to pantoprazole or in addition to a pantoprazole salt, polyvinylpyrrolidone and/or hydroxypropylmethylcellulose as the binder, and if desired mannitol additionally as an inert filler. U.S. 2003114494 discloses a stable oral pharmaceutical which comprises a benzimidazole, comprising:
      • (a) an inert core;
      • (b) thereon an active ingredient layer which comprises the benzimidazole mixed with an acidic reacting compound and, where appropriate, pharmaceutically acceptable adjuvants among which binders (water-soluble polymers) which are always used in this document;
      • (c) at least one inert layer; and
      • (d) an enteric layer applied onto said at least one inert layer.
        Albeit “tablet” is mentioned in this latter document, the tablet form is only mentioned and is not exemplified; this document is in fact essentially towards the pellet form.
  • There is still a need for a composition which can be either alkaline free or not, or even can contain an acidic compound, and which would be easy to manufacture, notably without having to revert to any binder. None of the above documents teaches or suggests the instant invention.
    • SUMMARY OF THE INVENTION
  • The invention provides new benzimidazole compositions, especially the following compositions:
      • A composition comprising a benzimidazole active ingredient, said composition comprising:
      • (a) a core containing said benzimidazole active ingredient;
      • (b) an intermediate layer; and
      • (c) an enteric layer;
      • said core being substantially free of binder; or said core being substantially free of PVP and of HPMC.
      • A composition comprising a benzimidazole active ingredient, said composition comprising:
      • (a) a core containing said benzimidazole active ingredient, where said core consists essentially of, by weight:
        • about 10 to about 80 parts of said benzimidazole active ingredient,
        • about 20 to about 85 parts of a first, water-soluble, diluent,
        • about 0 to about 80 parts of a second, water-insoluble, diluent,
        • about 10 to about 40 parts of a disintegrant; and
        • 0 to about 5 parts of a lubricant;
      • (b) an intermediate layer; and
      • (c) an enteric layer.
      • A composition comprising a benzimidazole active ingredient, said composition comprising:
      • (a) a core containing said benzimidazole active ingredient, where said core consists essentially of, by weight:
        • about 15 to about 60 parts of said benzimidazole active ingredient,
        • about 40 to about 75 parts of lactose,
        • about 15 to about 30 parts of a disintegrant, and
        • about 0.5 to about 5 parts of a lubricant;
      • (b) an intermediate layer; and
      • (c) an enteric layer.
      • A composition comprising a benzimidazole active ingredient not being in the form of an alkaline salt, said composition being exempt of alkaline-reacting compounds, said composition comprising:
      • (a) a core containing said benzimidazole active ingredient, where said core consists essentially of, by weight:
        • about 15 to about 60 parts of said benzimidazole active ingredient,
        • about 40 to about 75 parts of a first, water-soluble, diluent,
        • about 0 to about 40 parts of a second, water-insoluble, diluent,
        • about 15 to about 30 parts of a disintegrant, and
        • about 0.5 to about 5 parts of a lubricant;
      • (b) an intermediate layer; and
      • (c) an enteric layer.
      • A composition comprising omeprazole or esomeprazole or pantoprazole or lansoprazole or rabeprazole, said composition comprising:
      • (a) a core containing said omeprazole or esomeprazole or pantoprazole or lansoprazole or rabeprazole, where said core consists essentially of, by weight:
        • about 15 to about 60 parts of said omeprazole or esomeprazole or pantoprazole or lansoprazole or rabeprazole,
        • about 40 to about 75 parts of lactose,
        • about 15 to about 30 parts of a disintegrant, and
        • about 0.5 to about 5 parts of a lubricant;
      • (b) an intermediate layer; and
      • (c) an enteric layer.
  • The invention also provides a process for manufacturing the compositions of the invention, said process comprising the steps of: (i) granulating said active ingredient with said diluents, said disintegrant and said lubricant if any; (ii) compressing the product of step (i) to form a tablet core containing an active ingredient; (iii) coating said core with said intermediate layer; and (iv) coating a product from step (iii) with said enteric layer.
    • DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
  • The invention is designed for any benzimidazole, which is a class of compounds that is generally known. Here, the expression “benzimidazole active ingredient” should be taken to mean benzimidazole derivatives that are of therapeutic value. The benzimidazole active ingredients as used in the instant application are notably, but not limitatively, disclosed in the following patents and patent applications: EP-A-0,005,129, EP-A-0,080,602, EP-A-0,127,763, EP-A-0,130,729, EP-A-0,134,400, EP-A-0,146,370, EP-A-0,150,586, EP-A-0,166,287, EP-A-0,173,664, EP-A-0,244,380, DE-3,415,971, GB-A-2,082,580, GB-A-2,141,429, GB-A-2163747, U.S. Pat. No. 4,045,563, U.S. Pat. No. 4,182,766, U.S. Pat. No. 4,255,431, U.S. Pat. No. 4,337,257, U.S. Pat. No. 4,508,905, U.S. Pat. No. 4,628,098, U.S. Pat. No. 4,689,333, U.S. Pat. No. 4,734,416, U.S. Pat. No. 4,738,974, U.S. Pat. No. 4,758,579, U.S. Pat. No. 4,786,505, U.S. Pat. No. 4,853,230, U.S. Pat. No. 5,006,528, U.S. Pat. No. 5,013,743, U.S. Pat. No. 5,026,560, U.S. Pat. No. 5,035,899, U.S. Pat. No. 5,039,806, U.S. Pat. No. 5,045,321, U.S. Pat. No. 5,045,552, U.S. Pat. No. 5,093,132, U.S. Pat. No. 5,433,959, U.S. Pat. No. 5,690,960, U.S. Pat. No. 5,714,504, U.S. Pat. No. 5,877,192, U.S. Pat. No. 5,900,424, U.S. Pat. No. 5,997,903, U.S. Pat. No. 6,147,103, U.S. Pat. No. 6,150,380, U.S. Pat. No. 6,166,213, U.S. Pat. No. 6,191,148, U.S. Pat. No. 6,369,085, and U.S. Pat. No. 6,428,810. The instant invention notably applies to omeprazole, esomeprazole, pantoprazole, lansoprazole, leminoprazole, pariprazole, rabeprazole, timoprazole, aripiprazole and diapiprazole.
  • The alkaline salt form or derivative of the active ingredients cited above is also suitable in one embodiment. Derivatives, such as salts (hydrates such as sesquihydrates, etc.), alkaline salts (salts formed with lithium, sodium, magnesium, potassium, calcium etc. as well as any other base), esters and the like (including pro-drugs), are also contemplated. It is also possible to use an alkaline-reacting agent together with the benzimidazole active ingredient. Examples of such agents which may be mentioned here are the pharmacologically tolerated alkali metal, alkaline earth metal or earth metal salts of weak acids and the pharmacologically tolerated hydroxides and oxides of alkaline earth and earth metals, such as sodium carbonate, calcium carbonate, magnesium carbonate, magnesium oxide and magnesium hydroxide. Acidic reacting-agent such as those disclosed in U.S. 2003114494, notably sodium dihydrogen phosphate (NaH2PO4), can also be used.
  • Here, the expression “exempt of alkaline-reacting compound” should be taken to mean a composition that substantially does not contain any alkaline-reacting compound, in other words a composition in which the amount of alkaline-reacting compound is not sufficient to set up an alkaline micro-environment around the active ingredient when it is in contact with an acid or neutral aqueous medium, for example a micro-environment having a pH above 7. In one embodiment, said benzimidazole active ingredient is not in the form of an alkaline salt, and said composition is exempt of alkaline-reacting compounds. Mixtures of active ingredients are also envisaged, for example those comprising a benzimidazole in association with another active ingredient, or those containing two benzimidazoles.
  • The core contains the benzimidazole active ingredient together with various excipients, notably diluents (also known as fillers) and disintegrant, and optionally lubricant. The diluents will generally comprise a first diluent which is water-soluble, and optionally a second diluent which is water-insoluble (or hydrodispersible). These types of diluents are known in the art. They are crystalline or amorphous, and are generally inert with respect to the benzimidazole active ingredient.
  • Examples of the first water-soluble diluent are lactose, mannitol, and mixtures thereof. Lactose is preferred. Examples of the second water-insoluble diluent, if used, are cellulose acetate, microcrystalline cellulose, and mixtures thereof. Cellulose acetate is preferred. When the composition comprises a first diluent and a second diluent, the weight ratio first diluent to second diluent is preferably from about 1.5:1 to 1:1.5. The particle size of the first (and optionally second diluent) is not critical. In general, the d50 of the diluent particle is from about 50 μm to about 400 μm, preferably from about 75 μm to about 150 μm.
  • The disintegrant can be any compound known in the art to that effect. Examples of disintegrants are cross-linked polyvinylpyrrolidone (crospovidone), sodium croscarmellose, sodium carboxymethyl starch, modified starch or unmodified starch, colloidal silica and mixtures thereof. The preferred disintegrant is cross-linked polyvinylpyrrolidone (crospovidone). The lubricant can be selected from the group consisting of sodium stearylfumarate, magnesium stearate, talc, glyceryl behenate and mixtures thereof.
  • These compounds are used in varying amounts. Exemplary amounts are:
      • about 10 to about 80 parts, preferably about 15 to about 60 parts of said benzimidazole active ingredient;
      • about 20 to about 85 parts, preferably about 40 to about 75 parts, of said first, water-soluble, diluent;
      • about 0 to about 80 parts, preferably about 0 to about 40 parts, of said second, water-insoluble, diluent, and most preferably no second, water-insoluble, diluent is used;
      • about 10 to about 40 parts, preferably about 15 to about 30 parts, of said disintegrant;
      • 0 to about 5 parts, preferably about 0.5 to about 5 parts, of said lubricant.
  • One exemplary core formulation is one where said core consists essentially of, by weight:
      • about 15 to about 60 parts of said benzimidazole active ingredient,
      • about 40 to about 75 parts of lactose,
      • about 15 to about 30 parts of a disintegrant, and
      • about 0.5 to about 5 parts of a lubricant.
  • Another exemplary core formulation is one where said core consists essentially of, by weight:
      • about 15 to about 60 parts of said benzimidazole active ingredient,
      • about 30 to about 60 parts of lactose,
      • about 30 to about 60 parts of cellulose acetate,
      • about 15 to about 30 parts of a disintegrant, and
      • about 0.5 to about 5 parts of a lubricant.
  • In one embodiment, the core consists essentially of the benzimidazole active ingredient, of the first, water-soluble diluent, optionally of the second, water-insoluble, diluent, of the disintegrant, and optionally of the lubricant. In another, preferred embodiment, the core consists essentially of the benzimidazole active ingredient, of the first, water-soluble diluent, the disintegrant, and the lubricant. The term “consisting essentially of”, in one embodiment, is intended to mean that the listed compounds represent more than 90% by weight of the core, preferably more than 95% by weight of the core, most preferably more than 98% by weight of the core.
  • Other excipients such as fillers, plastifiers, surfactants, pigments, wetting agents, etc. may also be present in the core or the additional layers, if need be. The excipients can be any one traditionally used in the art. For more details about these excipients, one can refer to the disclosure in “Handbook of pharmaceutical excipients”, American Pharmaceutical Association, 1994 ISBN 0 91730 66 8, by Wade A. and Weller P. Examples are polysorbate 80, sodium lauryl sulfate, colloidal silica, titanium dioxide, etc.
  • The intermediate layer, according to the invention comprises of at least one sub-layer. It corresponds to one or several inert water-soluble layers or layers which rapidly disintegrate in an aqueous medium, containing inert pharmaceutical excipients. This layer comprises at least one polymer conventionally used in applications where a film is provided by coating such as: sugars, polyethyleneglycol, polyvinylpyrrolidone, poly(vinyl alcohol), hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, gelatine, etc. This intermediate layer is applied to the core using any coating technique conventionally employed in a suitable coating tank or in a fluidized bed device, with the use of suitable aqueous and/or organic solvents, or by using latex suspensions of said excipients. Water is the preferred solvent. Examples which may be mentioned of film-forming polymers (generally water-soluble polymers albeit water-insoluble polymers may be used) which can be used advantageously for the intermediate layer are given above, and especially hydroxypropylmethylcellulose and/or polyvinylpyrrolidone, to which plasticizers (such as, for example, propylene glycol) and/or other additives and auxiliaries (e.g. buffers, bases, pigments, surfactants, etc.) can also be added if desired. These other additives and auxiliaries or excipients can be any one of the conventional pharmaceutical excipients cited in the section relating to the core, or a mixture thereof. Talc is one preferred excipient used in the intermediate layer.
  • An exemplary composition for the intermediate layer comprises by weight, based on the weight of said layer:
      • about 30% to about 80%, preferably about 50% to about 70%, of hydroxypropylmethylcellulose (or another polymer such as PVP);
      • about 15% to about 50%, preferably about 20% to about 40%, of talc;
      • about 3% to about 25%, preferably about 5% to about 15%, of titanium dioxide.
  • The enteric layer according to this invention corresponds to at least one sub-layer that is entero-soluble and gastro-resistant. It is applied to the intermediate layer by conventional coating techniques such as coating in a tank or a fluidized bed employing polymer solutions in water or in suitable organic solvents or using latex suspensions of these polymers. Water is the preferred solvent. The enteric coating can also be applied using aqueous dispersions of polymers. Water-soluble or water-insoluble polymers, or mixtures thereof can be used, according to methods known in the art. The expert knows, on the basis of his technical knowledge, what outer layers which are resistant to gastric juice can be used.
  • As a polymer, use can be made of: cellulose phthalates and derivatives thereof, cellulose acetyl phthalate, hydroxypropyl-methylcellulose phthalate, polyvinyl phthalate acetate, as well as (meth)acrylic (co)polymers. As acrylic copolymers, one may cite especially the methacrylic acid/alkyl (meth)acrylate copolymers (sold as Eudragit®). A methyl radical and an ethyl radical are preferred as alkyl radical. The methacrylic acid type C copolymer complying with the US pharmacopoeia is one polymer suited. A preferred polymer is a copolymer based on methacrylic acid and ethyl acrylate, in which the ratio of free carboxyl groups to esters groups is about 1:1. The average molecular weight is, for example, about 250,000. Exemplary coating polymers are commercially available; they are those available as Aquateric® (FMC Corporation), CE5142 coating (BASF) and especially the Eudragit® products (Rohm Pharma), these latter being preferred.
  • The enteric layer can also contain a pharmaceutically-acceptable plastifying agent such as, for example, ketanol, triacetine, citric acid esters (e.g. triethyl citrate) such as those known under as Citroflex® (Pfizer), phthalic acid esters, dibutylsuccinate, polyethyleneglycol of varying molecular weights, or any other similar plastifying agent. The amount of plastifying agent is in general optimized for each polymer and the plastifying agent generally represents by weight 1 to 30% of the polymer, for example from 5 to 25%. Supplementary agents such as talc, pigments, coloring agents, flavoring agents, as well as any other excipient that conventionally enters into the composition of enteric coatings can be employed; such other conventional excipients being e.g. those disclosed in connection with the core. Talc is one preferred excipient.
  • An exemplary composition for the enteric layer comprises by weight, based on the weight of said layer:
      • about 50% to about 90%, preferably about 60% to about 85%, of methacrylic acid/alkyl (meth)acrylate copolymer (or another enteric polymer);
      • about 3% to about 25%, preferably about 5% to about 15%, of triethyl citrate (or another plastifying agent);
      • about 5% to about 30%, preferably about 10% to about 20%, of talc.
  • The composition according to the present invention generally comprises, based on the total weight of the composition:
      • a core representing about 70 to about 95% by weight, preferably about 70 to about 90% by weight;
      • an intermediate layer representing about 5 to about 30% by weight, preferably about 8 to about 15% by weight;
      • an enteric layer representing from about 3 to about 20% by weight, preferably about 5 to about 15% by weight.
        It should be noted that additional layers or sub-layers can be added, for the purposes of adding flavor and/or color, and/or improving acceptability of the medicament and/or allowing it to be marked.
  • The process used to manufacture the instant composition is very simple. First a core is manufactured, and then the intermediate and enteric layers are coated on said core using any classical method. The present invention brings a novel manufacturing process as far as the core is concerned. It is important to note that the present process allows manufacturing the core without recourse to any binder.
  • The core is generally manufactured as follows. In a first step, the various ingredients are granulated together. In a second step, a tablet is obtained starting from the granulates obtained at the first step by compressing the product.
  • The first granulating step can be carried out by using any granulating method, such as dry granulation, sieving, fluidized bed granulation or wet granulation. In the case of fluidized bed granulation and wet granulation, one uses suitable aqueous and/or organic solvents, preferably an aqueous solvent. Wet granulation is the preferred method. The apparatus that can be used is for example a high shear mixer. It should be noted that the disintegrant used in the composition can be partly into the granulate and partly in the outer phase. The weight ratio distribution granulate:outer phase of the disintegrant can be from 100:0 to 0:100, especially 70:30 to 0:100.
  • In one preferred embodiment, the process for manufacturing the core comprises the following sub-steps:
      • (a) dry mixing said benzimidazole active ingredient, said first diluent and optionally said second diluent and optionally part of said disintegrant;
      • (b) granulating the product of sub-step (a) with water;
      • (c) drying the granulates of sub-step (b); and
      • (d) dry mixing the dried granulates of sub-step (c) with said disintegrant or the remainder thereof and said lubricant.
  • The drying step can be carried out in any conventional apparatus known to that effect, for example a fluidized bed or a drying oven. The drying step is considered as having been carried out when the residual water content is below 10%, for example below 3%, depending on the kind and amount of ingredients. Tableting then follows granulation. The tableting step can be implemented using any conventional technique which is suitable, for example using alternating or rotating compressing equipment. In another, less preferred, embodiment, the core can be obtained by direct, dry, compression.
  • The water, if used, needed to produce the core is generally present in an amount of from 10% to 100% of the core weight. The water needed to produce the intermediate layer and/or the enteric layer is generally present in an amount of from 100% to 1000% of the intermediate and/or enteric layer weight.
  • In one preferred embodiment, the composition according to the invention is provided in a single tablet form (which may be breakable, if need be). In another embodiment, the composition is in the form of micro-tablets enclosed inside a capsule, e.g. a gelatin capsule. For this, any gelatin capsule conventionally employed in the pharmaceutical formulation field can be used, such as the hard gelatin capsule known as Capsugel®, available from Eli Lilly. The compositions of this invention are particularly suitable for oral administration of the active ingredients and are particularly suitable for treating gastrointestinal sicknesses.
    • EXAMPLES
  • The following examples illustrate the invention without limiting it.
    • Example 1
  • The following core formulations are prepared.
    Amount (mg/unit)
    Compound Ex. 1A Ex. 1B
    Rabeprazole Na 20.10 —
    Pantoprazole Na Sesquihydrate — 45.10
    Lactose 200 mesh 44.00 44.00
    Cellulose Acetate 44.00 44.00
    Glyceryl behenate 1.50 1.50
    Crospovidone 22.40 22.40
    Water* 40.00 40.00
    Total (dry) 131.90 157.00

    *evaporates off during process
  • Active ingredient, lactose and cellulose acetate are dry mixed. Water is added and granulation is carried out in a gravity funnel. Granulates are dried at 55° C. for 45 minutes. Crospovidone and glyceryl behenate are then added and mixed. The resulting mixture is then compressed into tablets (using a BetaPress® from Manesty with a punch having a curvature and a diameter of 7 mm—also known as 7R7).
  • The following intermediate layer formulation is used.
    Compound Amount (mg/unit)
    HPMC 3 cp 11.75
    Titanium dioxide 2.35
    Talc 5.90
    Water* 100
    Total 20.00

    *evaporates off during process
  • HPMC is dissolved in the water, and talc and titanium dioxide are then added. The suspension is homogenized and sprayed onto the tableted core in a coating pan (vector corporation perforated pan coater type LDCS).
  • The following enteric coating layer formulation is used.
    Compound Amount (mg/unit)
    Eudragit ® L30D 11.10
    Talc 2.23
    Triethyl citrate 1.67
    Water* 44
    Total 15.00

    *evaporates off during process
  • Triethyl citrate is dissolved in 60% of the water. The resulting solution is added to the Eudragit polymer and let in contact for 45 minutes under low stirring. Talc is added to the remaining 40% water, and the suspension is homogenized. Both compositions are then combined into one solution which is sprayed onto the intermediate coated core in a coating pan (identical to the one used for the intermediate layer) using a peristaltic pump and a spray nozzle (available from company spray systems).
    • Example 2
  • The following core formulations are prepared.
    Amount (mg/unit)
    Compound Ex. 2A Ex. 2B
    Rabeprazole Na 20.00 —
    Pantoprazole Na Sesquihydrate — 45.10
    Lactose 200 mesh 88.00 88.00
    Glyceryl behenate 1.50 3.00
    Crospovidone 22.00 22.90
    Water* 40.00 20.00
    Total (dry) 131.50 159.00

    *evaporates off during process
  • For example 2A, the process is as in example 1. For example 2B, the process differs in that half of crospovidone is mixed to form the granulates and half is mixed with the granulates as in example 1. The intermediate and enteric layers are as in example 1 and the process for coating is the same.

Claims (44)

1. A composition comprising a benzimidazole active ingredient, said composition comprising:
(a) a core containing said benzimidazole active ingredient;
(b) an intermediate layer; and
(c) an enteric layer;
said core being substantially free of binder.
2. A composition comprising a benzimidazole active ingredient, said composition comprising:
(a) a core containing said benzimidazole active ingredient;
(b) an intermediate layer; and
(c) an enteric layer;
said core being substantially free of PVP and of HPMC.
3. A composition comprising a benzimidazole active ingredient, said composition comprising:
(a) a core containing said benzimidazole active ingredient, where said core consists essentially of, by weight:
about 10 to about 80 parts of said benzimidazole active ingredient,
about 20 to about 85 parts of a first, water-soluble, diluent,
about 0 to about 80 parts of a second, water-insoluble, diluent,
about 10 to about 40 parts of a disintegrant; and
0 to about 5 parts of a lubricant;
(b) an intermediate layer; and
(c) an enteric layer.
4. The composition of claim 3, in which said core consists essentially of, by weight:
(a) a core containing said benzimidazole active ingredient, where said core consists essentially of, by weight:
about 15 to about 60 parts of said benzimidazole active ingredient,
about 40 to about 75 parts of a first, water-soluble, diluent,
about 0 to about 40 parts of a second, water-insoluble, diluent,
about 15 to about 30 parts of a disintegrant; and
about 0.5 to about 5 parts of a lubricant;
(b) an intermediate layer; and
(c) an enteric layer.
5. The composition of claim 3, comprising a first diluent and a second diluent and in which the weight ratio first diluent to second diluent is from about 1.5:1 to 1:1.5.
6. The composition of claim 3, in which said first, water-soluble, diluent is lactose and said second, water-insoluble, diluent if present is cellulose acetate.
7. The composition of claim 3, in which said disintegrant is cross-linked polyvinylpyrrolidone.
8. The composition of claim 3, in which said lubricant is selected from the group consisting of sodium stearylfumarate, magnesium stearate, talc, glyceryl behenate and their mixtures.
9. A composition comprising a benzimidazole active ingredient, said composition comprising:
(a) a core containing said benzimidazole active ingredient, where said core consists essentially of, by weight:
about 15 to about 60 parts of said benzimidazole active ingredient,
about 40 to about 75 parts of lactose,
about 15 to about 30 parts of a disintegrant, and
about 0.5 to about 5 parts of a lubricant;
(b) an intermediate layer; and
(c) an enteric layer.
10. The composition of claim 9, in which said disintegrant is cross-linked polyvinylpyrrolidone.
11. The composition of claim 9, in which said lubricant is selected from the group consisting of sodium stearylfumarate, magnesium stearate, talc, glyceryl behenate and their mixtures.
12. The composition of claim 3, in which said core is substantially free of PVP and of HPMC.
13. The composition of claim 9, in which said core is substantially free of PVP and of HPMC.
14. The composition of claim 1, in which said benzimidazole active ingredient is selected from the group consisting of omeprazole, esomeprazole, pantoprazole, lansoprazole, leminoprazole, pariprazole, rabeprazole, timoprazole, aripiprazole and diapiprazole.
15. The composition of claim 2, in which said benzimidazole active ingredient is selected from the group consisting of omeprazole, esomeprazole, pantoprazole, lansoprazole, leminoprazole, pariprazole, rabeprazole, timoprazole, aripiprazole and diapiprazole.
16. The composition of claim 3, in which said benzimidazole active ingredient is selected from the group consisting of omeprazole, esomeprazole, pantoprazole, lansoprazole, leminoprazole, pariprazole, rabeprazole, timoprazole, aripiprazole and diapiprazole.
17. The composition of claim 9, in which said benzimidazole active ingredient is selected from the group consisting of omeprazole, esomeprazole, pantoprazole, lansoprazole, leminoprazole, pariprazole, rabeprazole, timoprazole, aripiprazole and diapiprazole.
18. The composition of claim 1, in which said benzimidazole active ingredient is not in the form of an alkaline salt, and said composition being exempt of alkaline-reacting compounds.
19. The composition of claim 2, in which said benzimidazole active ingredient is not in the form of an alkaline salt, and said composition being exempt of alkaline-reacting compounds.
20. The composition of claim 3, in which said benzimidazole active ingredient is not in the form of an alkaline salt, and said composition being exempt of alkaline-reacting compounds.
21. The composition of claim 9, in which said benzimidazole active ingredient is not in the form of an alkaline salt, and said composition being exempt of alkaline-reacting compounds.
22. A composition comprising a benzimidazole active ingredient not being in the form of an alkaline salt, said composition being exempt of alkaline-reacting compounds, said composition comprising:
(a) a core containing said benzimidazole active ingredient, where said core consists essentially of, by weight:
about 15 to about 60 parts of said benzimidazole active ingredient,
about 40 to about 75 parts of a first, water-soluble, diluent,
about 0 to about 40 parts of a second, water-insoluble, diluent,
about 15 to about 30 parts of a disintegrant, and
about 0.5 to about 5 parts of a lubricant;
(b) an intermediate layer; and
(c) an enteric layer.
23. The composition of claim 22, in which said benzimidazole active ingredient is selected from the group consisting of omeprazole, esomeprazole, pantoprazole, lansoprazole, leminoprazole, pariprazole, rabeprazole, timoprazole, aripiprazole and diapiprazole.
24. A composition comprising omeprazole, said composition comprising:
(a) a core containing said omeprazole, where said core consists essentially of, by weight:
about 15 to about 60 parts of said omeprazole,
about 40 to about 75 parts of lactose,
about 15 to about 30 parts of a disintegrant, and
about 0.5 to about 5 parts of a lubricant;
(b) an intermediate layer; and
(c) an enteric layer.
25. A composition comprising esomeprazole, said composition comprising:
(a) a core containing said esomeprazole, where said core consists essentially of, by weight:
about 15 to about 60 parts of said esomeprazole,
about 40 to about 75 parts of lactose,
about 15 to about 30 parts of a disintegrant, and
about 0.5 to about 5 parts of a lubricant;
(b) an intermediate layer; and
(c) an enteric layer.
26. A composition comprising pantoprazole, said composition comprising:
(a) a core containing said pantoprazole, where said core consists essentially of, by weight:
about 15 to about 60 parts of said pantoprazole,
about 40 to about 75 parts of lactose,
about 15 to about 30 parts of a disintegrant, and
about 0.5 to about 5 parts of a lubricant;
(b) an intermediate layer; and
(c) an enteric layer.
27. A composition comprising lansoprazole, said composition comprising:
(a) a core containing said lansoprazole, where said core consists essentially of, by weight:
about 15 to about 60 parts of said lansoprazole,
about 40 to about 75 parts of lactose,
about 15 to about 30 parts of a disintegrant, and
about 0.5 to about 5 parts of a lubricant;
(b) an intermediate layer; and
(c) an enteric layer.
28. A composition comprising rabeprazole, said composition comprising:
(a) a core containing said rabeprazole, where said core consists essentially of, by weight:
about 15 to about 60 parts of said rabeprazole,
about 40 to about 75 parts of lactose,
about 15 to about 30 parts of a disintegrant, and
about 0.5 to about 5 parts of a lubricant;
(b) an intermediate layer; and
(c) an enteric layer.
29. The composition according to claim 1, provided either in a single tablet form or in the form of micro-tablets enclosed inside a capsule.
30. The composition according to claim 2, provided either in a single tablet form or in the form of micro-tablets enclosed inside a capsule.
31. The composition according to claim 3, provided either in a single tablet form or in the form of micro-tablets enclosed inside a capsule.
32. The composition according to claim 9, provided either in a single tablet form or in the form of micro-tablets enclosed inside a capsule.
33. The composition according to claim 22, provided either in a single tablet form or in the form of micro-tablets enclosed inside a capsule.
34. The composition according to claim 24, provided either in a single tablet form or in the form of micro-tablets enclosed inside a capsule.
35. The composition according to claim 25, provided either in a single tablet form or in the form of micro-tablets enclosed inside a capsule.
36. The composition according to claim 26, provided either in a single tablet form or in the form of micro-tablets enclosed inside a capsule.
37. The composition according to claim 27, provided either in a single tablet form or in the form of micro-tablets enclosed inside a capsule.
38. The composition according to claim 28, provided either in a single tablet form or in the form of micro-tablets enclosed inside a capsule.
39. A process for preparing a composition comprising a benzimidazole active ingredient, said composition comprising:
(a) a core containing said benzimidazole active ingredient, where said core consists essentially of, by weight:
about 10 to about 80 parts of said benzimidazole active ingredient,
about 20 to about 85 parts of a first, water-soluble, diluent,
about 0 to about 80 parts of a second, water-insoluble, diluent,
about 10 to about 40 parts of a disintegrant; and
0 to about 5 parts of a lubricant;
(b) an intermediate layer; and
(c) an enteric layer;
said process comprising the steps of
(i) granulating said active ingredient with said diluents, said disintegrant and said lubricant if any;
(ii) compressing the product of step (i) to form a tablet core containing an active ingredient;
(iii) coating said core with said intermediate layer; and
(iv) coating a product from step (iii) with said enteric layer.
40. The process according to claim 39, in which step (i) is wet granulation.
41. The process according to claim 39, in which step (i) comprises the following sub-steps:
(a) dry mixing said benzimidazole active ingredient, said first diluent and optionally said second diluent and optionally part of said disintegrant;
(b) granulating the product of sub-step (a) with water;
(c) drying the granulates of sub-step (b);
(d) dry mixing the dried granulates of sub-step (c) with said disintegrant or the remainder thereof and said lubricant, if any.
42. A process for preparing a composition comprising a benzimidazole active ingredient, said composition comprising:
(a) a core containing said benzimidazole active ingredient, where said core consists essentially of, by weight:
about 15 to about 60 parts of said benzimidazole active ingredient,
about 40 to about 75 parts of lactose,
about 15 to about 30 parts of a disintegrant, and
about 0.5 to about 5 parts of a lubricant;
(b) an intermediate layer; and
(c) an enteric layer;
said process comprising the steps of
(i) granulating said active ingredient with said lactose, said cellulose acetate, said disintegrant and said lubricant;
(ii) compressing the product of step (i) to form a tablet core containing an active ingredient;
(iii) coating said core with said intermediate layer; and
(iv) coating a product from step (iii) with said enteric layer.
43. The process according to claim 42, in which step (i) is wet granulation.
44. The process according to claim 42, in which step (i) comprises the following sub-steps:
(a) dry mixing said benzimidazole active ingredient, said lactose and optionally part of said disintegrant;
(b) granulating the product of sub-step (a) with water;
(c) drying the granulates of sub-step (b);
(d) dry mixing the dried granulates of sub-step (c) with said disintegrant or the remainder thereof and said lubricant.
US10/901,898 2004-07-29 2004-07-29 Composition comprising a benzimidazole and process for its manufacture Abandoned US20060024362A1 (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008065107A1 (en) * 2006-11-28 2008-06-05 Monteresearch S.R.L. Storage stable tablets based on benzimidazole derivatives coated with a gastro-resistant film
US20090022795A1 (en) * 2006-01-16 2009-01-22 Pradip Ghosh Stable Pharmaceutical Formulation of an Acid Labile Compound and Process for Preparing the Same
US20090098199A1 (en) * 2007-10-12 2009-04-16 Lee Ronald D Methods of treating gastrointestinal disorders independent of the intake of food
US20100021825A1 (en) * 2008-06-06 2010-01-28 Chikaaki Kodama Mask pattern data creation method and mask
WO2011140446A3 (en) * 2010-05-06 2012-03-15 Dr. Reddy's Laboratories Ltd. Pharmaceutical formulations
US8461187B2 (en) 2004-06-16 2013-06-11 Takeda Pharmaceuticals U.S.A., Inc. Multiple PPI dosage form
JP2015504083A (en) * 2012-01-23 2015-02-05 バイエル・オーイュー Drug delivery system
US8968776B2 (en) 2004-07-29 2015-03-03 Ucb, Inc. Composition comprising a benzimidazole and process for its manufacture

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19814084B4 (en) 1998-03-30 2005-12-22 Lts Lohmann Therapie-Systeme Ag D2 agonist-containing transdermal therapeutic system for the treatment of Parkinson's syndrome and process for its preparation
DE10359528A1 (en) 2003-12-18 2005-07-28 Schwarz Pharma Ag (S) -2-N-propylamino-5-hydroxytetralin as a D3 agonist therapeutic
EP2281559A1 (en) 2009-06-26 2011-02-09 UCB Pharma GmbH Pharmaceutical composition comprising rotigotine salts (acid or Na), especially for iontophoresis
HUE039447T2 (en) 2009-12-22 2018-12-28 Ucb Biopharma Sprl Polyvinylpyrrolidone for the stabilization of a solid dispersion of the non-crystalline form of rotigotine
US20170042806A1 (en) 2015-04-29 2017-02-16 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions
WO2017145146A1 (en) 2016-02-25 2017-08-31 Dexcel Pharma Technologies Ltd. Compositions comprising proton pump inhibitors
US10076494B2 (en) 2016-06-16 2018-09-18 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions

Citations (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9496A (en) * 1852-12-21 Method of measuring cloth on the cloth-beam
US35834A (en) * 1862-07-08 Improvement in counterfelt-cqin detectors
US58005A (en) * 1866-09-11 Improvement in distilling petroleum and other liquids
US57998A (en) * 1866-09-11 Improvement in broom-heads
US57999A (en) * 1866-09-11 Improved composition for roofing
US57997A (en) * 1866-09-11 Improvement in malt-ksln floors
US59466A (en) * 1866-11-06 Improved school desk and seat
US86567A (en) * 1869-02-02 Improved brick-machine
US91634A (en) * 1869-06-22 Improvement in screw-driver
US92597A (en) * 1869-07-13 Improved counterpoise gun-carriage
US104060A (en) * 1870-06-07 Improvement in organ-bellows
US118647A (en) * 1871-08-29 Improvement in journal-boxes
US161461A (en) * 1875-03-30 Improvement in apparatus for breaking horses
US162320A (en) * 1875-04-20 Improvement in automatic fans
US170302A (en) * 1875-11-23 Improvement in iron fences
US176465A (en) * 1876-04-25 Improvement in plows
US224949A (en) * 1880-02-24 Method of printing on textile fabrics
US4045563A (en) * 1974-05-16 1977-08-30 Ab Hassle Substituted 2-[pyridylalkylenesulfinyl]-benzimidazoles with gastric acid secretion inhibiting effects
US4182766A (en) * 1977-09-19 1980-01-08 Hoffmann-La Roche Inc. Naphth[2,3-d]imidazoles
US4255431A (en) * 1978-04-14 1981-03-10 Aktiebolaget Hassle Gastric acid secretion inhibiting substituted 2-(2-benzimidazolyl)-pyridines, pharmaceutical preparations containing same, and method for inhibiting gastric acid secretion
US4472409A (en) * 1981-11-05 1984-09-18 Byk Gulden Lomberg Chemische Fabrik Gesellschaft Mit Beschrankter Haftung 2-Pyridylmethyl thio(sulfinyl)benzimidazoles with gastric acid secretion inhibiting effects
US4560693A (en) * 1983-05-03 1985-12-24 Byk Gulden Lomberg Chemische Fabrik Gmbh [1,3]-Dioxolo[4,5-f]benzimidazoles and [1,4]-dioxino[2,3-f]benzimidazoles
US4628098A (en) * 1984-08-16 1986-12-09 Takeda Chemical Industries, Ltd. 2-[2-pyridylmethylthio-(sulfinyl)]benzimidazoles
US4721709A (en) * 1984-07-26 1988-01-26 Pyare Seth Novel pharmaceutical compositions containing hydrophobic practically water-insoluble drugs adsorbed on pharmaceutical excipients as carrier; process for their preparation and the use of said compositions
US4734416A (en) * 1978-03-30 1988-03-29 Otsuka Pharmaceutical Co., Ltd. Pharmaceutically useful carbostyril derivatives
US4738974A (en) * 1983-03-04 1988-04-19 Aktiebolaget Hassle Base addition salts of omeprazole
US4758579A (en) * 1984-06-16 1988-07-19 Byk Gulden Lomberg Chemische Fabrik Gmbh Fluoroalkoxy substituted benzimidazoles useful as gastric acid secretion inhibitors
US4786505A (en) * 1986-04-30 1988-11-22 Aktiebolaget Hassle Pharmaceutical preparation for oral use
US4795643A (en) * 1987-02-02 1989-01-03 Mepha Ag Dornacherstrasse 114 Medicament with a delayed release of active ingredient
US4844903A (en) * 1986-11-07 1989-07-04 Mepha Ag Process for the production of an adhesive plaster
US4853230A (en) * 1986-04-30 1989-08-01 Aktiebolaget Hassle Pharmaceutical formulations of acid labile substances for oral use
US5006528A (en) * 1988-10-31 1991-04-09 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives
US5013743A (en) * 1989-02-10 1991-05-07 Takeda Chemical Industries, Ltd. Selective antibacterial agent against campytobacter
US5026560A (en) * 1987-01-29 1991-06-25 Takeda Chemical Industries, Ltd. Spherical granules having core and their production
US5035899A (en) * 1988-05-18 1991-07-30 Eisai Co., Ltd. Peroral preparation of acid-unstable compound
US5039806A (en) * 1983-02-11 1991-08-13 Ab Hassle Novel pharmacologically active compound pyridyl methylsulfinyl benzimidazole
US5045321A (en) * 1986-02-13 1991-09-03 Takeda Chemical Industries, Ltd. Stabilized pharmaceutical composition and its production
US5045552A (en) * 1986-11-13 1991-09-03 Eisai Co., Ltd. Pyridine derivatives having anti-ulcerative activity
US5150380A (en) * 1989-10-18 1992-09-22 Nec Corporation Receiver capable of removing both intersymbol interference and frequency offset
US5433959A (en) * 1986-02-13 1995-07-18 Takeda Chemical Industries, Ltd. Stabilized pharmaceutical composition
US5690960A (en) * 1993-07-09 1997-11-25 Astra Aktiebolag Pharmaceutical formulation of omeprazole
US5693818A (en) * 1993-05-28 1997-12-02 Astra Aktiebolag Process for preparing pure salts of pyridinylmethyl-sulfinyl-1H-benzimidazole
US5817338A (en) * 1994-07-08 1998-10-06 Astra Aktiebolag Multiple unit tableted dosage form of omeprazole
US5824341A (en) * 1994-08-11 1998-10-20 Pharma Pass Composition providing selective release of an active ingredient
US5877192A (en) * 1993-05-28 1999-03-02 Astra Aktiebolag Method for the treatment of gastric acid-related diseases and production of medication using (-) enantiomer of omeprazole
US5900424A (en) * 1993-07-09 1999-05-04 Astra Aktiebolag Omeprazole magnesium salt form
US5997903A (en) * 1991-06-17 1999-12-07 Byk Gulden Lomberg Chemische Fabrik Gmbh Oral-administration forms of a medicament containing pantoprazol
US6033686A (en) * 1998-10-30 2000-03-07 Pharma Pass Llc Controlled release tablet of bupropion hydrochloride
US6048547A (en) * 1996-04-15 2000-04-11 Seth; Pawan Process for manufacturing solid compositions containing polyethylene oxide and an active ingredient
US6074670A (en) * 1997-01-17 2000-06-13 Laboratoires Fournier, S.A. Fenofibrate pharmaceutical composition having high bioavailability and method for preparing it
US6096341A (en) * 1998-10-30 2000-08-01 Pharma Pass Llc Delayed release tablet of bupropion hydrochloride
US6117453A (en) * 1995-04-14 2000-09-12 Pharma Pass Solid compositions containing polyethylene oxide and an active ingredient
US6147103A (en) * 1998-08-11 2000-11-14 Merck & Co., Inc. Omeprazole process and compositions thereof
US6159499A (en) * 1995-09-21 2000-12-12 Pharma Pass Llc Composition containing an acid-labile benzimidazole and process for its preparation
US6191148B1 (en) * 1998-08-11 2001-02-20 Merck & Co., Inc. Omerazole process and compositions thereof
US6338857B1 (en) * 2000-05-26 2002-01-15 Pharma Pass Llc Sustained release carbamazepine pharmaceutical composition free of food effect and a method for alleviating food effect in drug release
US6348469B1 (en) * 1995-04-14 2002-02-19 Pharma Pass Llc Solid compositions containing glipizide and polyethylene oxide
US6350471B1 (en) * 2000-05-31 2002-02-26 Pharma Pass Llc Tablet comprising a delayed release coating
US6368628B1 (en) * 2000-05-26 2002-04-09 Pharma Pass Llc Sustained release pharmaceutical composition free of food effect
US6369085B1 (en) * 1997-05-30 2002-04-09 Astrazeneca Ab Form of S-omeprazole
US6428810B1 (en) * 1998-11-05 2002-08-06 Astrazeneca Ab Pharmaceutical formulation comprising omeprazole
US20030003151A1 (en) * 2001-05-25 2003-01-02 Sham Chopra Chemical delivery device
US6531153B2 (en) * 2001-05-29 2003-03-11 Drugtech Corporation Composition with sustained release of levodopa and carbidopa
US20030114494A1 (en) * 1999-12-09 2003-06-19 Benoit Schmitt Stable galenic preparations comprising a benzimidazol and method for the production thereof
US20050214372A1 (en) * 2004-03-03 2005-09-29 Simona Di Capua Stable pharmaceutical composition comprising an acid labile drug

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH644116A5 (en) 1980-08-21 1984-07-13 Hoffmann La Roche IMIDAZOLE DERIVATIVES.
IL71664A (en) 1983-05-03 1987-11-30 Byk Gulden Lomberg Chem Fab Fluoroalkoxy compounds,process for their preparation and pharmaceutical compositions containing the same
DE3415971A1 (en) 1983-05-03 1984-11-08 Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz Acylated benzimidazoles, processes for their preparation, their use and medicaments containing them
GR81595B (en) 1983-06-18 1984-12-11 Wyeth John & Brother Ltd
CA1259070A (en) 1983-07-01 1989-09-05 Upjohn Company (The) Substituted 2-¬monoannelated(3,4-,4,5-, and 5,6-)- pyridylalkylenesulfinyl|-benzimidazoles
US4575554A (en) 1983-12-05 1986-03-11 The Upjohn Company Substituted 2-pyridylmethylthio- and sulfinyl-benzimidazoles as gastric antisecretory agents
IE57646B1 (en) 1983-12-16 1993-02-10 Wyeth John & Brother Ltd Derivatives of imidazoquinolines and analogues thereof
EP0159144B1 (en) 1984-02-27 1989-06-07 Niigata Engineering Co., Ltd. Azimuth thruster for use in ships
SE8404065D0 (en) 1984-08-10 1984-08-10 Haessle Ab NOVEL BIOLOGICALLY ACTIVE COMPOUNDS
AU4640985A (en) 1984-08-31 1986-03-06 Nippon Chemiphar Co. Ltd. Benzimidazole derivatives
UA72748C2 (en) 1998-11-10 2005-04-15 Astrazeneca Ab A novel crystalline form of omeprazole
US20030035834A1 (en) 2000-05-26 2003-02-20 Pawan Seth Sustained release verapamil pharmaceutical composition free of food effect and a method for alleviating food effect in drug release
KR20030072555A (en) 2000-12-07 2003-09-15 알타나 파마 아게 Rapidly disintegrating tablet comprising an acid-labile active ingredient
US20030059466A1 (en) 2001-09-14 2003-03-27 Pawan Seth Delayed release tablet of venlafaxin
US20030091634A1 (en) 2001-09-14 2003-05-15 Pawan Seth Delayed release tablet of venlafaxin
US20030118647A1 (en) 2001-12-04 2003-06-26 Pawan Seth Extended release tablet of metformin
US20050182056A9 (en) 2002-02-21 2005-08-18 Seth Pawan Modified release formulations of at least one form of tramadol
US20040086567A1 (en) 2002-10-30 2004-05-06 Pawan Seth Bioequivalent composition of itraconazole and a hydrophilic polymer
US20040162320A1 (en) 2003-02-14 2004-08-19 Pawan Seth Solid composition containing nisoldipine a mixture of polyethylene oxides and an antioxidant
US20040176465A1 (en) 2003-03-07 2004-09-09 Pawan Seth Solid compositions containing fluoxetine and a coating
US20060024362A1 (en) 2004-07-29 2006-02-02 Pawan Seth Composition comprising a benzimidazole and process for its manufacture

Patent Citations (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US170302A (en) * 1875-11-23 Improvement in iron fences
US224949A (en) * 1880-02-24 Method of printing on textile fabrics
US58005A (en) * 1866-09-11 Improvement in distilling petroleum and other liquids
US57998A (en) * 1866-09-11 Improvement in broom-heads
US57999A (en) * 1866-09-11 Improved composition for roofing
US57997A (en) * 1866-09-11 Improvement in malt-ksln floors
US59466A (en) * 1866-11-06 Improved school desk and seat
US86567A (en) * 1869-02-02 Improved brick-machine
US91634A (en) * 1869-06-22 Improvement in screw-driver
US92597A (en) * 1869-07-13 Improved counterpoise gun-carriage
US104060A (en) * 1870-06-07 Improvement in organ-bellows
US118647A (en) * 1871-08-29 Improvement in journal-boxes
US161461A (en) * 1875-03-30 Improvement in apparatus for breaking horses
US162320A (en) * 1875-04-20 Improvement in automatic fans
US35834A (en) * 1862-07-08 Improvement in counterfelt-cqin detectors
US9496A (en) * 1852-12-21 Method of measuring cloth on the cloth-beam
US176465A (en) * 1876-04-25 Improvement in plows
US4045563A (en) * 1974-05-16 1977-08-30 Ab Hassle Substituted 2-[pyridylalkylenesulfinyl]-benzimidazoles with gastric acid secretion inhibiting effects
US4182766A (en) * 1977-09-19 1980-01-08 Hoffmann-La Roche Inc. Naphth[2,3-d]imidazoles
US4734416A (en) * 1978-03-30 1988-03-29 Otsuka Pharmaceutical Co., Ltd. Pharmaceutically useful carbostyril derivatives
US4255431A (en) * 1978-04-14 1981-03-10 Aktiebolaget Hassle Gastric acid secretion inhibiting substituted 2-(2-benzimidazolyl)-pyridines, pharmaceutical preparations containing same, and method for inhibiting gastric acid secretion
US4337257A (en) * 1978-04-14 1982-06-29 Aktiebolaget Hassle Gastric acid secretion inhibiting substituted 2-(2-benzimidazolyl)-pyridines, their preparation, pharmaceutical preparations containing same, and method for inhibiting gastric acid secretion
US4508905A (en) * 1978-04-14 1985-04-02 Aktiebolaget Hassle Substituted 2-(-benzimidazolyl)pyridines
US4472409A (en) * 1981-11-05 1984-09-18 Byk Gulden Lomberg Chemische Fabrik Gesellschaft Mit Beschrankter Haftung 2-Pyridylmethyl thio(sulfinyl)benzimidazoles with gastric acid secretion inhibiting effects
US5039806A (en) * 1983-02-11 1991-08-13 Ab Hassle Novel pharmacologically active compound pyridyl methylsulfinyl benzimidazole
US4738974A (en) * 1983-03-04 1988-04-19 Aktiebolaget Hassle Base addition salts of omeprazole
US4560693A (en) * 1983-05-03 1985-12-24 Byk Gulden Lomberg Chemische Fabrik Gmbh [1,3]-Dioxolo[4,5-f]benzimidazoles and [1,4]-dioxino[2,3-f]benzimidazoles
US4758579A (en) * 1984-06-16 1988-07-19 Byk Gulden Lomberg Chemische Fabrik Gmbh Fluoroalkoxy substituted benzimidazoles useful as gastric acid secretion inhibitors
US4721709A (en) * 1984-07-26 1988-01-26 Pyare Seth Novel pharmaceutical compositions containing hydrophobic practically water-insoluble drugs adsorbed on pharmaceutical excipients as carrier; process for their preparation and the use of said compositions
US4628098A (en) * 1984-08-16 1986-12-09 Takeda Chemical Industries, Ltd. 2-[2-pyridylmethylthio-(sulfinyl)]benzimidazoles
US4689333A (en) * 1984-08-16 1987-08-25 Takeda Chemical Industries, Ltd. 2-(2-pyridylmethylthio (sulfinyl)) benzimidazoles
US5045321A (en) * 1986-02-13 1991-09-03 Takeda Chemical Industries, Ltd. Stabilized pharmaceutical composition and its production
US5433959A (en) * 1986-02-13 1995-07-18 Takeda Chemical Industries, Ltd. Stabilized pharmaceutical composition
US5093132A (en) * 1986-02-13 1992-03-03 Takeda Chemical Industries, Ltd. Stabilized pharmaceutical composition and its production
US4786505A (en) * 1986-04-30 1988-11-22 Aktiebolaget Hassle Pharmaceutical preparation for oral use
US4853230A (en) * 1986-04-30 1989-08-01 Aktiebolaget Hassle Pharmaceutical formulations of acid labile substances for oral use
US4844903A (en) * 1986-11-07 1989-07-04 Mepha Ag Process for the production of an adhesive plaster
US5045552A (en) * 1986-11-13 1991-09-03 Eisai Co., Ltd. Pyridine derivatives having anti-ulcerative activity
US5026560A (en) * 1987-01-29 1991-06-25 Takeda Chemical Industries, Ltd. Spherical granules having core and their production
US4795643A (en) * 1987-02-02 1989-01-03 Mepha Ag Dornacherstrasse 114 Medicament with a delayed release of active ingredient
US5035899A (en) * 1988-05-18 1991-07-30 Eisai Co., Ltd. Peroral preparation of acid-unstable compound
US5006528A (en) * 1988-10-31 1991-04-09 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives
US5013743A (en) * 1989-02-10 1991-05-07 Takeda Chemical Industries, Ltd. Selective antibacterial agent against campytobacter
US5150380A (en) * 1989-10-18 1992-09-22 Nec Corporation Receiver capable of removing both intersymbol interference and frequency offset
US5997903A (en) * 1991-06-17 1999-12-07 Byk Gulden Lomberg Chemische Fabrik Gmbh Oral-administration forms of a medicament containing pantoprazol
US5877192A (en) * 1993-05-28 1999-03-02 Astra Aktiebolag Method for the treatment of gastric acid-related diseases and production of medication using (-) enantiomer of omeprazole
US5693818A (en) * 1993-05-28 1997-12-02 Astra Aktiebolag Process for preparing pure salts of pyridinylmethyl-sulfinyl-1H-benzimidazole
US5714504A (en) * 1993-05-28 1998-02-03 Astra Aktiebolag Compositions
US5690960A (en) * 1993-07-09 1997-11-25 Astra Aktiebolag Pharmaceutical formulation of omeprazole
US5900424A (en) * 1993-07-09 1999-05-04 Astra Aktiebolag Omeprazole magnesium salt form
US5817338A (en) * 1994-07-08 1998-10-06 Astra Aktiebolag Multiple unit tableted dosage form of omeprazole
US5824341A (en) * 1994-08-11 1998-10-20 Pharma Pass Composition providing selective release of an active ingredient
US6348469B1 (en) * 1995-04-14 2002-02-19 Pharma Pass Llc Solid compositions containing glipizide and polyethylene oxide
US6117453A (en) * 1995-04-14 2000-09-12 Pharma Pass Solid compositions containing polyethylene oxide and an active ingredient
US6159499A (en) * 1995-09-21 2000-12-12 Pharma Pass Llc Composition containing an acid-labile benzimidazole and process for its preparation
US6248355B1 (en) * 1995-09-21 2001-06-19 Schwarz Pharma Ag Pharmaceutical composition containing an acid-labile omeprazole and process for its preparation
US6207198B1 (en) * 1995-09-21 2001-03-27 Schwarz Pharma Ag Composition containing an acid-labile omeprazole and process for its preparation
US6048547A (en) * 1996-04-15 2000-04-11 Seth; Pawan Process for manufacturing solid compositions containing polyethylene oxide and an active ingredient
US6074670A (en) * 1997-01-17 2000-06-13 Laboratoires Fournier, S.A. Fenofibrate pharmaceutical composition having high bioavailability and method for preparing it
US6596317B2 (en) * 1997-01-17 2003-07-22 Laboratoires Fournier, Sa Fenofibrate pharmaceutical composition having high bioavailability and method for preparing it
US6652881B2 (en) * 1997-01-17 2003-11-25 Laboratories Fournier, S.A. Fenofibrate pharmaceutical composition having high bioavailability
US6277405B1 (en) * 1997-01-17 2001-08-21 Labaratoires Fournier, S.A. Fenofibrate pharmaceutical composition having high bioavailability and method for preparing it
US6589552B2 (en) * 1997-01-17 2003-07-08 Laboratoires Fournier, S.A. Fenofibrate pharmaceutical composition having high bioavailability and method for preparing it
US6369085B1 (en) * 1997-05-30 2002-04-09 Astrazeneca Ab Form of S-omeprazole
US6147103A (en) * 1998-08-11 2000-11-14 Merck & Co., Inc. Omeprazole process and compositions thereof
US6166213A (en) * 1998-08-11 2000-12-26 Merck & Co., Inc. Omeprazole process and compositions thereof
US6191148B1 (en) * 1998-08-11 2001-02-20 Merck & Co., Inc. Omerazole process and compositions thereof
US6143327A (en) * 1998-10-30 2000-11-07 Pharma Pass Llc Delayed release coated tablet of bupropion hydrochloride
US6033686A (en) * 1998-10-30 2000-03-07 Pharma Pass Llc Controlled release tablet of bupropion hydrochloride
US6096341A (en) * 1998-10-30 2000-08-01 Pharma Pass Llc Delayed release tablet of bupropion hydrochloride
US6428810B1 (en) * 1998-11-05 2002-08-06 Astrazeneca Ab Pharmaceutical formulation comprising omeprazole
US20030114494A1 (en) * 1999-12-09 2003-06-19 Benoit Schmitt Stable galenic preparations comprising a benzimidazol and method for the production thereof
US6338857B1 (en) * 2000-05-26 2002-01-15 Pharma Pass Llc Sustained release carbamazepine pharmaceutical composition free of food effect and a method for alleviating food effect in drug release
US6368628B1 (en) * 2000-05-26 2002-04-09 Pharma Pass Llc Sustained release pharmaceutical composition free of food effect
US6350471B1 (en) * 2000-05-31 2002-02-26 Pharma Pass Llc Tablet comprising a delayed release coating
US20030003151A1 (en) * 2001-05-25 2003-01-02 Sham Chopra Chemical delivery device
US6531153B2 (en) * 2001-05-29 2003-03-11 Drugtech Corporation Composition with sustained release of levodopa and carbidopa
US20050214372A1 (en) * 2004-03-03 2005-09-29 Simona Di Capua Stable pharmaceutical composition comprising an acid labile drug

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8461187B2 (en) 2004-06-16 2013-06-11 Takeda Pharmaceuticals U.S.A., Inc. Multiple PPI dosage form
US9889152B2 (en) 2004-06-16 2018-02-13 Takeda Pharmaceuticals U.S.A., Inc. Multiple PPI dosage form
US9238029B2 (en) 2004-06-16 2016-01-19 Takeda Pharmaceuticals U.S.A., Inc. Multiple PPI dosage form
US8968776B2 (en) 2004-07-29 2015-03-03 Ucb, Inc. Composition comprising a benzimidazole and process for its manufacture
US8865212B2 (en) 2006-01-16 2014-10-21 Jubilant Generics Limited Stable pharmaceutical formulation of an acid labile compound and process for preparing the same
US20090022795A1 (en) * 2006-01-16 2009-01-22 Pradip Ghosh Stable Pharmaceutical Formulation of an Acid Labile Compound and Process for Preparing the Same
WO2008065107A1 (en) * 2006-11-28 2008-06-05 Monteresearch S.R.L. Storage stable tablets based on benzimidazole derivatives coated with a gastro-resistant film
US8173158B2 (en) 2007-10-12 2012-05-08 Takeda Pharmaceuticals U.S.A., Inc. Methods of treating gastrointestinal disorders independent of the intake of food
US20090098199A1 (en) * 2007-10-12 2009-04-16 Lee Ronald D Methods of treating gastrointestinal disorders independent of the intake of food
US20100021825A1 (en) * 2008-06-06 2010-01-28 Chikaaki Kodama Mask pattern data creation method and mask
WO2011140446A3 (en) * 2010-05-06 2012-03-15 Dr. Reddy's Laboratories Ltd. Pharmaceutical formulations
JP2015504083A (en) * 2012-01-23 2015-02-05 バイエル・オーイュー Drug delivery system
US10500381B2 (en) 2012-01-23 2019-12-10 Bayer Oy Drug delivery system

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