WO2006134611A1 - Compositions de benzimidazoles substitués anti-ulcérants - Google Patents

Compositions de benzimidazoles substitués anti-ulcérants Download PDF

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WO2006134611A1
WO2006134611A1 PCT/IN2005/000203 IN2005000203W WO2006134611A1 WO 2006134611 A1 WO2006134611 A1 WO 2006134611A1 IN 2005000203 W IN2005000203 W IN 2005000203W WO 2006134611 A1 WO2006134611 A1 WO 2006134611A1
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weight
range
formulation
capsule
sodium
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PCT/IN2005/000203
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Male Srinivas Reddy
Pothireddy Venkateswar Reddy
Muppidi Vanaja
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Hetero Drugs Limited
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Priority to PCT/IN2005/000203 priority Critical patent/WO2006134611A1/fr
Publication of WO2006134611A1 publication Critical patent/WO2006134611A1/fr

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    • 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
    • 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
    • A61K9/28—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
    • A61K9/48—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
    • 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
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular 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
    • A61K9/5021—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

Definitions

  • the present invention relates to a stable pharmaceutical formulation for hygroscopic antiulcerative substituted benzimidazoles, optionally in combination with other active pharmaceutical ingredients, in the form of pellets, capsules and tablets.
  • Rabeprazole chemically, 2-[[[4-(3-methoxypropoxy)-3-methyl-2- pyridinyl]methyl]sulfinyl]-1H-benzimidazole.
  • Rabeprazole is a proton pump inhibitor.
  • the therapeutic uses of rabeprazole sodium and related compounds, and their preparations were disclosed in U.S. patent No. 5,045,552.
  • Rabeprazole sodium is commercially available as 20 mg enteric-coated tablet. It is sold under the name ACIPHEX. Pantoprazole, chemically, 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2- pyridinyl)methyl]sulfinyl]-1H-benzimidazole. Pantoprazole is a proton pump inhibitor. The therapeutic uses of pantoprazole and related compounds, and their preparations were disclosed in U.S. patent No. 4,758,579.
  • Pantoprazole available as 20 mg and 40 mg enteric-coated tablets. Injection is available as freeze dried powder containing 40 mg of pantoprazole per vial. It is sold under the name PROTONIX.
  • Omeprazole chemically, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]sulfinyl]-1H-benzimidazole.
  • Omeprazole is a proton pump inhibitor.
  • the therapeutic uses of omeprazole and related compounds, and their preparations were disclosed in U.S. patent No. 4,255,431.
  • Omeprazole is commercially available as 10 mg, 20 mg and 40 mg enteric-coated capsules. It is sold under the name PRILOSEC.
  • Esomeprazole magnesium chemically, (T-4)-bis[5-methoxy-2-[(S)-[(4- methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazolato] magnesium.
  • Esomeprazole is a proton pump inhibitor. The therapeutic uses of esomeprazole and related compounds, and their preparations were disclosed in U.S. patent No. 4,255,431.
  • Esomeprazole magnesium trihydrate is commercially available as 20 mg and 40 mg enteric-coated capsules. It is sold under the name NEXIUM.
  • Lansoprazole chemically, 2-[[[3-methyI-4-(2,2,2-trifluoro-ethoxy)-2- pyridinyI]methyl]sulfinyl]-1 H-benzimidazole.
  • Lansoprazole is a proton pump inhibitor. The therapeutic uses of lansoprazole and related compounds, and their preparations were disclosed in U.S. patent No. 4,628,098.
  • Lansoprazole is commercially available as 15 mg and 30 mg enteric- coated capsules. It is sold under the name PREVACID.
  • Ondansetron chemically, 1 ,2,3,9-tetrahydro-9-methyI-3-[(2-methyl-1 H- imidazoI-1-yI)methyl]-4H-carbazol-4-one.
  • Ondansetron is a specific serotonin
  • Ondansetron hydrochloride is commercially available as 4 mg, 8 mg, and 24 mg tablets and 4 mg and 8 mg disintegrating tablets. It is sold under the name ZOFRAN.
  • Domperidone chemically, 5-chloro-1-[1-[3-(2,3-dihydro-2-oxo-1 H- benzimidazol-1-yl)propyl]-4-piperidinyl]-1 ,3-dihydro-2H-benzimidazol-2-one.
  • Domperidone is a dopamine antagonist with antinauseant properties. The therapeutic uses of domperidone and related compounds, and their preparations were disclosed in U.S. patent No. 4,066,772.
  • Itopride chemically, N-[[4-[2-dimethylamino)ethoxy]phenyl]methyl]-3,4- dimethoxybenzamide. Itopride is a dopamine D2 receptor antagonist.
  • the therapeutic uses of itopride and related compounds, and their preparations were disclosed in European Patent No. 306,827.
  • Mosapride chemically, ( ⁇ )-4-amino-5-chloro-2-ethoxy-N-[[4-(4- fluorobenzyl)-2-morpholinyl]methyl]benzamide.
  • Mosapride is a selective 5-HT 4 receptor agonist.
  • the therapeutic uses of mosapride and related compounds, and their preparations were disclosed in U.S. patent No. 4,870,074. All the above-mentioned patents are incorporated by reference.
  • the present invention relates to a stable pharmaceutical formulation for hygroscopic antiulcerative substituted benzimidazoles, optionally in combination with other active pharmaceutical ingredients.
  • a stable pharmaceutical formulations for hygroscopic antiulcerative substituted benzimidazoles optionally in combination with other active pharmaceutical ingredients, which comprises substituted benzimidazoles; other active pharmaceutical ingredients selected from domperidone, itopride hydrochloride, mosapride citrate and ondansetron; stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide, heavy sodium carbonate, light calcium carbonate, light magnesium carbonate, light magnesium oxide and light sodium carbonate; and mannitol.
  • Other additives conventionally used for pharmaceutical formulations may be included in.the present formulation.
  • the preferable substituted benzimidazoles are pantoprazole, rabeprazole, omeprazole, lansoprazole, tenatoprazole, esomeprazole, (S)- pantoprazole, (S)-rabeprazole and (S)-lansoprazole; other active pharmaceutical ingredients are domperidone, itopride hydrochloride, mosapride citrate and ondansetron or a salt thereof.
  • the particularly preferable stable pharmaceutical formulations for antiulcerative substituted benzimidazoles optionally in combination with other active pharmaceutical ingredients, which comprises substituted benzimidazoles selected from pantoprazole, rabeprazole, omeprazole, lansoprazole, tenatoprazole, esomeprazole, (S)-pantoprazole, (S)-rabeprazole and (S)- Iansoprazole or a salt thereof in the range of 3 to 70% by weight, more preferably 8 to 65% by weight; other active pharmaceutical ingredients selected from domperidone, itopride hydrochloride, mosapride citrate and ondansetron in the range of 10 to 90% by weight, more preferably 20 to 70% by weight; stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide, heavy sodium carbonate, light calcium carbonate, light magnesium carbonate, light magnesium oxide and light sodium carbonate in the range of 0.5 to 90% by weight, more preferably 5 to 60% by weight
  • a pharmaceutical formulation for antiulcerative substituted benzimidazoles according to the invention comprises additives, which are conventionally used in dosage forms. These include but are not limited to disintegrants, binders, lubricants, glidants, fillers or diluents, stabilizing agents, seal coating materials, enteric coating materials, plasticizers, anti-adherents, colorants and the. like.
  • disintegrants one can particularly mention sodium starch glycolate, starch, croscarmellose sodium, crospovidone, carboxymethylcellulose calcium, carboxymethylcellulose sodium, magnesium aluminum silicate; or a mixture thereof.
  • binder one can particularly mention hydroxypropylcellulose, polyvinylpyrrolidone k-30, hydroxypropylcellulose (low-substituted), starch, or a mixture thereof.
  • lubricants one can particularly mention stearic acid; or a salt of stearic acid, talc, sodium stearyl fumarate, glyceryl behenate, magnesium silicate, magnesium trisilicate, hydrogenated castor oil; or a mixture thereof.
  • glidants one can particularly mention colloidal anhydrous silica, talc; or a mixture thereof.
  • fillers one can particularly mention calcium carbonate, dibasic calcium phosphate, lactose, magnesium carbonate, sucrose, starch, magnesium oxide, lactose anhydrous, microcrystalline cellulose, mannitol; or a mixture thereof.
  • stabilizing agents one can particularly mention heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide, heavy sodium carbonate, light calcium carbonate, light magnesium carbonate, light magnesium oxide, light sodium carbonate; or a mixtures thereof.
  • seal coating materials one can particularly mention hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone derivatives, alginate derivatives, opadry organic; or a mixture thereof.
  • enteric coating materials one can particularly mention cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate and methacrylic acid derivatives such as eudragit L 100-55, eudragit L30 D-55, opadry enteric; or a mixture thereof.
  • the enteric polymeric composition also contains plasticizer and anti-adherents. Further it may also optionally contain colorants and opacifiers.
  • plasticizers one can particularly mention cetyl alcohol, stearyl alcohol or phthalate derivatives such as diethyl phthalate, dipropyl phthalate, dibutyl phthalate, dioctyl phthalate or polyethleneglycol derivatives; or a mixture thereof.
  • anti-adherents one can particularly mention talc, starch, stearic acid, hydrogenated castor oil; or a mixture thereof.
  • colorants and opacifiers one can particularly mention iron oxides, titanium dioxide; or a mixture thereof.
  • Other ingredients antioxidants and solvents conventionally used for pharmaceutical formulations may be included in the present invention.
  • a stable pharmaceutical formulations for antiulcerative substituted benzimidazoles optionally in combination with other active pharmaceutical ingredients, which comprises antiulcerative substituted benzimidazoles selected from pantoprazole, rabeprazole, omeprazole, lansoprazole, esomeprazole, tenatoprazole, (S)-pantoprazoIe, (S)-rabeprazole and (S)- lansoprazole or a salt thereof are enteric coated (EC) pellets or tablets; other active pharmaceutical ingredients selected from domperidone, itopride hydrochloride, mosapride citrate and ondansetron are sustained release (SR) pellets or pellets.
  • SR sustained release
  • a stable pharmaceutical formulations for antiulcerative substituted benzimidazoles which comprises rabeprazole sodium or (S)-rabeprazoIe sodium; stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide, heavy sodium carbonate, light magnesium oxide, light calcium carbonate, light magnesium carbonate and light sodium carbonate; mannitol, starch, polyvinylpyrrolidone s-630, hydroxypropylcellulose or hydroxypropylcellulose (low-substituted); ethanol, mannitol, sodium stearyl fumarate, hydroxypropylmethylcellulose-i ⁇ cps, acryl EZE, opadry organic and opadry enteric.
  • the present invention provides a formulation suitable for rabeprazole sodium having therapeutically active strengths: which comprises rabeprazole sodium in the range of 3 to 23% by weight, light magnesium oxide in the range of 0.5 to 2.5% by weight, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate in the range of 25 to 78% by weight, mannitol in the range of 9 to 80% by weight, polyvinylpyrrolidone s-630 in the range of 0.5 to 4% by weight, starch in the range of 0.5 to 2.5% by weight, hydroxypropylcellulose (low- substituted) or hydroxypropylcellulose in the range of 0.5 to 23% by weight, sodium stearyl fumarate in the range of 0.5 to 2.5% by weight, hydroxypropylmethylcellulose-15cps in the range of 2.5 to 15% by weight, acryl EZE in the range of 7 to 28% by weight, opadry organic white in the range of 3 to 10% by weight and opadry enter
  • rabeprazole sodium enteric coated tablets comprising rabeprazole sodium in the range of 6 to 14% by weight, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate in the range of 43 to 60% by weight; mannitol in the range of 16 to 21% by weight, polyvinylpyrrolidone s- 630 in the range of 1.5 to 2.5% by weight, starch in the range of 1 to 2% by weight, hydroxypropylcellulose (low-substituted) or hydroxypropylcellulose in the range of 13 to 17% by weight, sodium stearyl fumarate in the range of 1 to 2% by weight, hydroxypropylmethylcellulose-15cps in the range of 4.5 to 5.5% by weight and acryl EZE in the range
  • Rabeprazole sodium enteric coated tablets (10 mg): which comprises rabeprazole sodium is 7.69% by weight, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate is 53.8% by weight; mannitol is 18.5% by weight, polyvinylpyrrolidone s-630 is 1.92% by weight, starch is 1.15% by weight, hydroxypropylcellulose (low-substituted) or hydroxypropylcellulose is 15.4% by weight, sodium stearyl fumarate is 1.54% by weight, hydroxypropylmethylcellulose-15cps is 5% by weight and acryl EZE is 14.7% by weight, based on the total weight of enteric coated tablets.
  • Rabeprazole sodium enteric coated tablets (20 mg): which comprises rabeprazole sodium is 12.5% by weight, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate is 48.8% by weight; mannitol is 18.8% by weight, polyvinylpyrrolidone s-630 is 2.19% by weight, starch is 1.25% by weight, hydroxypropylcellulose (low-substituted) or hydroxypropylcellulose is 15% by weight, sodium stearyl fumarate is 1.56% by weight, hydroxypropylmethylcellulose-15cps is 5% by weight and acryl EZE is 14.7% by weight, based on the total weight of enteric coated tablets.
  • rabeprazole sodium enteric coated pellets which comprises rabeprazole sodium in the range of 6 to 9% by weight, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate in the range of 46 to 58% by weight, light magnesium oxide in the range of 1 to 2% by weight; mannitol in the range of 16 to 77% by weight, polyvinylpyrrolidone s-630 in the. range of 1.5 to 2.5% by weight, starch in the range of 1 to 1.5% by weight, hydroxypropylmethylcellulose-15cps in the range of 6 to 8% by weight, acryl
  • rabeprazole sodium enteric coated pellets which comprises rabeprazole sodium enteric coated pellets in the range of 6 to 20% by weight, based on the total weight of pellets that are filled in hard gelatin capsules.
  • the present invention provides a formulation suitable for (S)- rabeprazole sodium having therapeutically active strengths: which comprises (S)-rabeprazole sodium in the range of 3 to 23% by weight, light magnesium oxide in the range of 0.5 to 2.5% by weight, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate in the range of 25 to 78% by weight, mannitol in the range of 9 to 80% by weight, polyvinylpyrrolidone s-630 in the range of 0.5 to 4% by weight, starch in the range of 0.5 to 2.5% by weight, hydroxypropylcellulose (low-substituted) or hydroxypropylcellulose in the range of 0.5 to 23% by weight, sodium stearyl fumarate in the range of 0.5 to 2.5% by weight, hydroxypropylmethylcellulose-15cps in the range of 2.5 to 15%.
  • acryl EZE in the range of 7 to 28% by weight
  • opadry organic white in the range of 3 to 10% by weight
  • opadry enteric pink in the range of 7 to 17% by weight,based on the total weight of pharmaceutical dosage form.
  • additional excipients may be used.
  • Particularly preferred additives heavy magnesium oxide, heavy calcium carbonate, heavy magnesium carbonate, heavy sodium carbonate and mannitol.
  • the preferable (S)-rabeprazole sodium enteric coated tablets comprising (S)-rabeprazole sodium in the range of 6 to 14% by weight, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate in the range of 43 to 60% by weight; mannitol in the range of 16 to 21% by weight, polyvinylpyrrolidone s-630 in the range of 1.5 to 2.5% by weight, starch in the range of 1 to 2% by weight, hydroxypropylcellulose (low-substituted) or hydroxypropylcellulose in the range of 13 to 17% by weight, sodium stearyl fumarate in the range of 1 to 2% by weight, hydroxypropylmethylcellulose- 15cps in the range of 4.5 to 5.5% by weight and acryl EZE in the range of 13 to 17 % by weight, based on the total weight of enteric coated tablets. More preferable enteric-coated tablets formulations are:
  • (S)-rabeprazole sodium enteric coated tablets (10 mg): which comprises (S)- rabeprazole sodium is 7.69% by weight, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate is 53.8% by weight; mannitol is 18.5% by weight, polyvinylpyrrolidone s-630 is 1.92% by weight, starch is 1.15% by weight, hydroxypropylcellulose (low-substituted) or hydroxypropylcellulose is 15.4% by weight, sodium stearyl fumarate is 1.54% by weight, hydroxypropyl methylcellulose-15cps is 5% by weight and acryl EZE is 14.7% by weight, based on the total weight of enteric coated tablets.
  • (S)-rabeprazole sodium enteric coated tablets (20mg): which comprises (S)- rabeprazole sodium is 12.5% by weight, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate is 48.8% by weight; mannitol is 18.8% by weight, polyvinylpyrrolidone s-630 is 2.19% by weight, starch is 1.25% by weight, hydroxypropylcellulose (low-substituted) or hydroxypropylcellulose is 15% by weight, sodium stearyl fumarate is 1.56% by weight, hydroxypropyl methylcellulose-15cps is 5% by weight and acryl EZE is 14.7% by weight, based on the total weight of enteric coated tablets.
  • the preferable (S)-rabeprazole sodium enteric coated pellets which comprises (S)-rabeprazoIe sodium in the range of 6 to 9% by weight, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate in the range of .46 to 58% by weight, light magnesium oxide in the range of 1 to 2% by weight; mannitol in the range of 16 to 77% by weight, polyvinylpyrrolidone s-630 in the range of 1.5 to 2.5% by weight, starch in the range of 1 to 1.5% by weight, hydroxypropylmethylcellulose-i ⁇ cps in the range of 6 to 8% by weight, acryl EZE in the range of 10 to 14% by weight, opadry organic white in the range of
  • the preferable (S)-rabeprazole sodium enteric coated pellets which comprises (S)-rabeprazole sodium enteric coated pellets in the range of 6 to 20% by weight, based on the total weight of pellets that are filled in hard gelatin capsules.
  • a stable pharmaceutical formulations for antiulcerative substituted benzimidazoles which comprises antiulcerative substituted benzimidazoles selected from pantoprazole and (S)-pantoprazole or a salt thereof; stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate; mannitol, starch, polyvinylpyrrolidone-630 or polyvinylpyrrolidone k-30; hydroxypropylcellulose or hydroxypropylcellulose (low-substituted); sodium stearyl fumarate, hydroxypropylmethylcellulose-15cps, acryl EZE, light calcium carbonate, crospovidone, propylene glycol, croscarmellose sodium, sodium Iauryl sulfate, hydroxypropylmethylcellulose E5 and opadry enteric pink.
  • the present invention provides a formulation suitable for forming enteric coated tablets or pellets comprising pantoprazole or a salt thereof in the range of 7 to 40% by weight equivalent to pantoprazole, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate in the range of 19 to 62% by weight, light calcium carbonate in the range of 4 to 11 % by weight; mannitol in the range of
  • croscarmellose sodium in the range of 1.5 to 5% by weight
  • crospovidone in the range of 1.5 to 5% by weight
  • sodium Iauryl sulfate in the range of 0.25 to 1.25% by weight
  • polyvinylpyrrolidone s-630 or polyvinylpyrrolidone k-30 in the range of 0.5 to 4% by weight
  • starch in the range of 0.5 to 2.5% by weight, hydroxypropylcellulose (low-substituted) or hydroxypropylcellulose in the range of 7 to 24% by weight
  • hydroxypropyl methylcellulose E5 in the range of 4 to 12% by weight
  • sodium stearyl fumarate in the range of 0.5 to 2.5% by weight
  • propylene glycol in the range of 0.1 to 1.5% by weight
  • hydroxypropylmethylcellulose-15cps in the range of 2.5 to 15% by weight
  • acryl EZE in the range of 8 to 21% by weight
  • opadry enteric pink in the
  • pantoprazole enteric coated tablets comprising pantoprazole or a salt thereof in the range of 15 to 32% by weight equivalent to pantoprazole, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate in the range of 29 to 49% by weight; mannitol in the range of 16 to 21% by weight, polyvinylpyrrolidone s-630 in the range of 1 to 2.5% by weight, starch in the range of 1 to 2% by weight, hydroxypropylcellulose (low-substituted) or hydroxypropylcellulose in the range of 13 to 17% by weight; sodium stearyl fumarate in the range of 1 to 2% by weight, hydroxypropylmethylcellulose-5cps in the range of 3 to 7% by weight and acryl EZE in the range of 12 to 16% by weight, based on the total weight of enteric coated tablets. More preferable enteric-coated tablets formulations are:
  • Pantoprazole enteric coated tablets (20 mg): which comprises pantoprazole or a salt thereof is 17.4% by weight equivalent to pantoprazole, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate is 44.2% by weight; mannitol is 18.5% by weight, polyvinylpyrrolidone s-630 is 1.92% by weight, starch is 1.15% by weight, hydroxypropylcellulose (low-substituted) or hydroxypropyl cellulose is 15.4% by weight; sodium stearyl fumarate is 1.54% by weight, propylene glycol in the range of 0.5 to 1% by weight, hydroxypropyl methylcellulose-15cps is 5% by weight and acryl EZE is 14% by weight, based on the total weight of enteric coated tablets.
  • Pantoprazole enteric coated tablets 40 mg; which comprises pantoprazole or a salt thereof is 28.3% by weight equivalent to pantoprazole, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate is 33% by weight; mannitol is 18.8% by weight, polyvinylpyrrolidone s-630 is 2.19% by weight, starch is 1.25% by weight, hydroxypropylcellulose (low-substituted) or hydroxypropylcellulose is 15% by weight; sodium stearyl fumarate is 1.56% by weight, hydroxypropyImethylcellulose-15cps is 5% by weight and acryl EZE is 14% by weight, based on the total weight of enteric coated tablets.
  • pantoprazole enteric coated pellets which comprises pantoprazole or a salt thereof in the range of 11 to 15% by weight equivalent to pantoprazole, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide, and heavy sodium carbonate in the range of 33 to 41 % by weight, light calcium carbonate in the range of 6.5 to 8.5% by weight; mannitol in the range of 11 to 52% by weight, polyvinylpyrrolidone s-630 in the range of 1 to 2% by weight or polyvinylpyrrolidone k-30 in the range of 1.5 to 2.5% by weight, starch in the range of 0.5 to 2.5% by weight, croscarmellose sodium in the range of 2.5 to 3.5% by weight, crospovidone in the range of 2.5 to 3.5% by weight, sodium lauryl sulfate in the range of 0.2 to 1 % by weight, hydroxypropylmethylcellulose E5 in the range of 7 to 9% by weight, propylene glycol in the
  • pantoprazole enteric coated pellets which comprises pantoprazole enteric-coated pellets are in the range of 10 to 22% by weight, based on the total weight of pellets that are filled in hard gelatin capsules.
  • the present invention provides a formulation suitable for forming enteric coated tablets or pellets comprising (S)-pantoprazole or a salt thereof in the range of 7 to 40% by weight equivalent to (S)-pantoprazole, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate in the range of 19 to 62% by weight, light calcium carbonate in the range of 4 to 11% by weight; mannitol in the range of 7 to 70% by weight, croscarmellose sodium in the range of 1.5 to 5% by weight, crospovidone in the range of 1.5 to 5% by weight, sodium lauryl sulfate in the range of 0.25 to 1.25% by weight, polyvinylpyrrolidone s-630 or polyvinylpyrroli
  • pantoprazole enteric coated tablets comprising (S)- pantoprazole or a salt thereof in the range of 15 to 32% by weight equivalent to (S)-pantoprazole, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate in the range of 29 to 49% by weight; mannitol in the range of 16 to 21% by weight, polyvinylpyrrolidone s-630 in the range of 1 to 2.5% by weight, starch in the range of 1 to 2% by weight, hydroxypropylcellulose (low-substituted) or hydroxypropylcellulose in the range of 13 to 17% by weight; sodium stearyl fumarate in the range of 1 to 2% by weight, hydroxypropylmethylcellulose-5cps in the range of 3 to 7% by weight and acryl EZE in the range of 12 to 16% by weight, based on the total weight of enteric coated tablets. More preferable enteric-coated tablets formulations are:
  • (S)-pantoprazole enteric coated tablets (20 mg): which comprises (S)- pantoprazole or a salt thereof is 17.4% by weight equivalent to (S)- pantoprazole, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate is 44.2% by weight; mannitol is 18.5% by weight, polyvinylpyrrolidone s-630 is 1.92% by weight, starch is 1.15% by weight, hydroxypropylcellulose (low- substituted) or hydroxypropylcellulose is 15.4% by weight; sodium stearyl fumarate is 1.54% by weight, propylene glycol in the range of 0.5 to 1% by weight, hydroxypropylmethylcellulose-15cps is 5% by weight and acryl EZE is 14% by weight, based on the total weight of enteric coated tablets.
  • (S)-pantoprazole enteric coated tablets (40mg); which comprises (S)- pantoprazole or a salt thereof is 28.3% by weight equivalent to (S)- pantoprazole, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate is 33% by weight; mannitol is 18.8% by weight, polyvinylpyrrolidone s-630 is 2.19% by weight, starch is 1.25% by weight, hydroxypropylcellulose (low- substituted) or hydroxypropylcellulose is 15% by weight; sodium stearyl fumarate is 1.56% by weight, hydroxypropylmethylcellulose-15cps is 5% by weight and acryl EZE is 14% by weight, based on the total weight of enteric coated tablets.
  • the preferable (S)-pantoprazole enteric coated pellets which comprises (S)-pantoprazole or a salt thereof in the range of 11 to 15% by weight equivalent to (S)-pantoprazole, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide, and heavy sodium carbonate in the range of 33 to 41% by weight, light calcium carbonate in the range of 6.5 to 8.5% by weight; mannitol in the range of 11 to 52% by weight, polyvinylpyrrolidone s-630 in the range of 1 to 2% by weight or polyvinylpyrrolidone k-30 in the range of 1.5 to 2.5% by weight, starch in the range of 0.5 to 2.5% by weight, croscarmellose sodium in the range of 2.5 to 3.5% by weight, crospovidone in the range of 2.5 to 3.5% by weight, sodium lauryl sulfate in the range of 0.2 to 1% by weight, hydroxypropylmethylcellulose E5 in the range of 7 to 9%
  • the preferable (S)-pantoprazole enteric coated pellets which comprises (S)-pantoprazole enteric-coated pellets are in the range of 10 to 22% by weight, based on the total weight of pellets that are filled in hard gelatin capsules.
  • a stable pharmaceutical formulations for antiulcerative substituted benzimidazoles which comprises omeprazole or a salt thereof, disodium hydrogen phosphate, calcium carbonate, lactose, sucrose, methacrylic acid L- 3OD, tween 80, mannitol, polyvinylpyrrolidone k-30 hydroxypropyl methylcellulose E5, propylene glycol, sodium hydroxide, diethyl phthalate, titanium dioxide, cetyl alcohol and purified talc.
  • omeprazole enteric coated pellets which comprises omeprazole or a salt thereof in the range of 5 to 15% by weight, more preferably 7 to 10% by weight, e.g.8.47%, disodium hydrogen phosphate in the range of 0.5 to 2% by weight, more preferably 1 to 1.5% by weight, e.g. 1.27%, light calcium carbonate in the range of 2 to 5% by weight, more preferably 3 to 4% by weight, e.g.
  • omeprazole enteric coated pellets which comprises omeprazole enteric-coated pellets are in the range of 5 to 15% by weight, based on the total weight of pellets that are filled in hard gelatin capsules.
  • a stable pharmaceutical formulations for antiulcerative substituted benzimidazoles which comprises esomeprazole or a salt thereof; stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate; mannitol, starch, crospovidone, polyvinylpyr r olidone s-630; or polyvinylpyrrolidone k-30, hydroxypropylcellulose or hydroxypropylcellulose (low-substituted); acryl EZE, croscarmellose sodium, light calcium carbonate, sodium stearyl fumarate, hydroxypropylmethylcellulose-15cps, sodium lauryl sulfate, propylene glycol, hydroxypropylmethylcellulose E5 and opadry enteric pink.
  • the present invention provides a formulation suitable for esomeprazole enteric coated tablets or pellets comprising esomeprazole or a salt thereof in the range of 7 to 40% by weight equivalent to esomeprazole, croscarmellose sodium in the range of 1.5 to 4.5% by weight, crospovidone in the range of 1.5 to 4.5% by weight, sodium lauryl sulfate in the range of 0.1 to 1.0% by weight, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate in the range of 20 to 63% by weight, light calcium carbonate in the range of 4 to 11 % by weight; polyvinylpyrrolidone k-30 or polyvinylpyrrolidone s-630 in the range of 0.5 to 4% by weight; hydroxypropylcellulose (low-substituted) or hydroxypropylcellulose in the range of 7 to 24% by weight; mannitol in the range of 9 to 67% by weight, hydroxypropylmethylcellulose E5
  • the preferable esomeprazole enteric coated tablets comprising esomeprazole or a salt thereof in the range of 15 to 31% by weight equivalent to esomeprazole, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate in the range of 30 to 49% by weight; hydroxypropylcellulose (low-substituted) or hydroxypropylcellulose in the range of 14 to 17% by weight; mannitol in the range of 17 to 21% by weight, polyvinylpyrrolidone s-630 in the range of 1.5 to 2.5% by weight, starch in the range of 1 to 1.5% by weight, sodium stearyl fumarate in the range of 1 to 2% by weight, hydroxypropylmethylcellulose- 15cps in the range of 4.5 to 5.5% by weight and acryl EZE in the range of 13 to 16% by weight, based on the total weight of enteric-coated tablets.
  • stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate,
  • enteric-coated tablet formulations are: i) Esomeprazole enteric coated tablets (20mg): which comprises esomeprazole or a salt thereof is 17.2% by weight equivalent to esomeprazole, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate is 44.4% by weight; mannitol is 18.5% by weight, polyvinylpyrrolidone s-630 is 1.92% by weight, sodium stearyl fumarate is 1.54% by weight, starch is 1.15% by weight, hydroxypropylcellulose (low-substituted) or hydroxypropylcellulose is 15.4% by weight; hydroxypropylmethylcellulose-15cps is 5% by weight and acryl EZE is 14% by weight, based on the total weight of enteric coated tablets, ii) Esomeprazole enteric coated tablets (40 mg): which comprises esomeprazole or a salt thereof is 27.9% by weight equivalent to esomeprazole, stabilizers
  • the preferable esomeprazole enteric coated pellets which comprises esomeprazole or a salt thereof in the range of 12 to 15% by weight equivalent to esomeprazole, light calcium carbonate in the range of 6.5 to 8.5% by weight, croscarmellose sodium in the range of 2.5 to 3% by weight, crospovidone in the range of 2.5 to 3% by weight, sodium lauryl sulfate in the range of 0.3 to 0.8% by weight, stabilizers selected from heavy calcium carbonate, heavy magnesium carbonate, heavy magnesium oxide and heavy sodium carbonate in the range of 33 to 41% by weight; mannitol in the range of 20 to 52% by weight, polyvinylpyrrolidone s-630 or polyvinylpyrrolidone k-30 in the range of 1 to 2.5% by weight; starch in the range of 0.5 to 1.5% by weight, hydroxypropylmethylcellulose E5 in the range of 7 to 9% by weight, hydroxypropylmethylcellulose-15cps in the range of 9 to
  • a stable pharmaceutical formulations for antiulcerative substituted benzimidazoles which comprises lansoprazole or (S)-Iansoprazole; calcium carboxymethylcellulose, light magnesium carbonate, lactose, sucrose, methacrylic acid L-30D, mannitol, polyvinylpyrrolidone k-30 hydroxypropylmethylcellulose E5, starch, propylene glycol, sodium hydroxide tween 80, diethyl phthalate, titanium dioxide and cetyl alcohol.
  • the preferable lansoprazole enteric coated pellets which comprises lansoprazole in the range of 5 to 12% by weight, more preferably 7 to 10% by weight, e.g. 8.47%, light magnesium carbonate in the range of 3 to 10% by weight, more preferably 5.5 to 7.5% by weight, e.g. 6.58%, lactose in the range of 3 to 10% by weight, more preferably 5.5 to 7.5 % by weight, e.g. 6.58%, sucrose in the range of 10 to 24% by weight, more preferably 15 to 19% by weight, e.g. 16.8%, calcium carboxymethylcellulose in the range of 2 to 7% by weight, more preferably 4 to 6 % by weight, e.g.
  • mannitol in the range of 5 to 14% by weight, more preferably 8 to 11% by weight, e.g. 9.97%, tween 80. in the range of 0.1 to 0.5% by weight, more preferably 0.1 to 0.4% by weight, e.g. 0.35%, polyvinylpyrrolidone k-30 in the range of 0.1 to 0.5% by weight, more preferably 0.1 to 0.3% by weight, e.g. 0.2%, starch in the range of 4 to 11%by weight, more preferably 6 to 8% by weight, e.g. 7.21%, methacrylic acid L-30D in the range of 14.5 to 35% by weight, more preferably 22 to 28% by weight, e.g.
  • hydroxypropylmethylcellulose E5 in the range of 5 to 13% by weight, more preferably 7.5 to 10% by weight, e.g. 8.72%, propylene glycol in the range of 0.2 to 1.5% by weight, more preferably 0.5 to 1% by weight.e.g. 0.81%, sodium hydroxide in the range of 0.05 to 0.25% by weight, more preferably 0.1 to 0.2% by weight,e.g.0.14%, diethyl phthalate in the range of 1 to 3.5% by weight, more preferably 2 to 3% by weight, e.g. 2.49%, titanium dioxide in the range of 0.5 to 2% by weight, more preferably 0.5 to 1.5% by weight, e.g. 0.4% and cetyl alcohol in the range of 0.1 to 1.5% by weight, more preferably 0.5 to 1 % by weight, e.g. 0.75%, based on the total weight of pellets that are filled in hard gelatin capsules.
  • the preferable lansoprazole enteric coated pellets which comprises lansoprazole enteric-coated pellets are in the range of 5 to 15% by weight, based on the total weight of pellets that are filled in hard gelatin capsules.
  • the preferable (S)-Iansoprazole enteric coated pellets which comprises (S)-Iansoprazole in the range of 5 to 12% by weight, more preferably 7 to 10% by weight, e.g. 8.47%, light magnesium carbonate in the range of 3 to 10% by weight, more preferably 5.5. to 7.5% by weight, e.g. 6.58%, lactose in the range of 3 to 10% by weight, more preferably 5.5 to 7.5 % by weight, e.g. 6.58%, sucrose in the range of 10 to 24% by weight, more preferably 15 to 19% by weight, e.g.
  • calcium carboxymethylcellulose in the range of 2 to 7% by weight, more preferably 4 to 6 % by weight,e.g. 4.98%, mannitol in the range of 5 to 14% by weight, more preferably 8 to 11% by weight,e.g. 9.97%, tween 80 in the range of 0.1 to 0.5% by weight, more preferably 0.1 to 0.4% by weight,e.g.0.35%, polyvinylpyrrolidone k-30 in the range of 0.1 to 0.5% by weight, more preferably 0.1 to 0.3% by weight.e.g. 0.2%, starch in the range of 4 to 11%by weight, more preferably 6 to 8% by weight, e.g.
  • methacrylic acid L-30D in the range of 14.5 to 35% by weight, more preferably 22 to 28% by weight, e.g. 24.9%, hydroxypropylmethylcellulose E5 in the range of 5 to 13% by weight, more preferably 7.5 to 10% by weight, e.g. 8.72%, propylene glycol in the range of 0.2 to 1.5% by weight, more preferably 0.5 to 1% by weight, e.g. 0.81%, sodium hydroxide in the range of 0.05 to 0.25% by weight, more preferably 0.1 to 0.2% by weight, e.g. 0.14%, diethyl phthalate in the range of 1 to 3.5% by weight, more preferably 2 to 3% by weight, e.g.
  • titanium dioxide in the range of 0.5 to 2% by weight, more preferably 0.5 to 1.5% by weight, e.g. 0.4% and cetyl alcohol in the range of 0.1 to 1.5% by weight, more preferably 0.5 to 1 % by weight, e.g. 0.75%, based on the total weight of pellets that are filled in hard gelatin capsules.
  • the preferable (S)-lansoprazole enteric coated pellets which comprises (S)-lansoprazole enteric-coated pellets are in the range of 5 to 15% by weight, based on the total weight of pellets that are filled in hard gelatin capsules.
  • the pharmaceutical composition may be for example, in the form of a tablet, a caplet, pellets, a capsule, granules, a pill, powder or a sachet.
  • the pharmaceutical composition is in the form of pellets, tablets and capsules.
  • the capsule may contain powder, compressed powder, pellets or granules.
  • EXAMPLES In the following embodiments of the invention, the below listed quantities of drug substance and additional components are combined using standard pharmaceutical manufacturing techniques. The resulting formulations are used to fill gelatin capsule shells or compressed into tablets.
  • Enteric-coated tablet formulation Method of manufacture: The antiulcerative substituted benzimidazole, stabilizer and mannitol are granulated using binder solution of polyvinylpyrrolidone s-630 and starch in planetary mixer, rapid mixer granulator; or other suitable granulator. This wet mass may be then dried in a fluid bed dryer, tray dryer; or other suitable dryer. The dried granulation may be then milled to acheive the desired particle size distribution and then blended with the other ingredients. This blend is compressed into tablets.
  • These compressed tablets are seal coated using an aqueous solution of hydroxypropylmethylcellulose-15cps and seal coated tablets are enteric coated using an aqueous dispersion of acryl EZE by using autocota, neocota; or other suitable coating pan.
  • Pantoprazole enteric coated (20mg) tablets The components and their amounts were as follows: Pantoprazole enteric coated (20mg) tablets:
  • Pantoprazole enteric coated (40mg) tablets The components and their amounts were as follows: Pantoprazole enteric coated (40mg) tablets:
  • L-hydroxypropylcellulose (LH-11) 24 15 S Sooddiiuumm sstteeaarryyll ffuummaarraattee 2 2..55 1.56
  • the antiulcerative substituted benzimidazole; stabilizer and mannitol are granulated using binder having polyvinylpyrrolidone s-630 and starch in planetary mixer, rapid mixer granulator; or other suitable granulator.
  • This wet mass then may be thread like pieces in extruder. Thread like pieces then may be spherical wet pellets in spherodizer. This spherical wet pellets then may be dried in a fluid bed dryer, tray dryer; or other suitable dryer.
  • the spherical wet pellets are coated using an aqueous solution of hydroxypropylmethylcellulose in fluid bed coater or other suitable coater.
  • the intermediate coated pellets are coated using an aqueous dispersion of acryl EZE in fluid bed coater or other suitable coater.
  • the enteric-coated pellets are filled into hard gelatin capsules.
  • Rabeprazole sodium enteric-coated pellets The components and their amounts were as follows: Rabeprazole sodium enteric-coated pellets:
  • Example 8 The components and their amounts were as follows: Pantoprazole sodium enteric-coated pellets:
  • the rabeprazole sodium or (S)- rabeprazole sodium, stabilizer and hydroxypropyl cellulose LF are dissolved in non-aqueous solution.
  • the drug solution is loaded on mannitol to get the drug pellets. This drug pellets may be then dried in a fluid bed dryer, tray dryer; or other suitable dryer. B.lntermed ⁇ ate coating
  • the drug pellets are coated using non-aqueous solution of opadry oraganic in fluid bed coater; or other suitable coater.
  • the intermediate coated pellets are coated using non-aqueous solution of opadry enteric in fluid bed coater; or other suitable coater.
  • the enteric-coated pellets are filled into hard gelatin capsules.
  • Rabeprazole sodium enteric-coated pellets The components and their amounts were as follows: Rabeprazole sodium enteric-coated pellets:
  • pantoprazole (S)- pantoprazole and esomeprazole or a salt thereof:
  • pantoprazole, (S)-pantoprazoIe and esomeprazole or a salt thereof, stabilizer, crospovidone, croscarmellose sodium, sodium lauryl sulfate and mannitol are blended.
  • Mannitol is wetted using binder having polyvinylpyrrolidone k-30.
  • binder having polyvinylpyrrolidone k-30 The above blend is loaded on wet mannitol.
  • These drug pellets may be then dried in a fluid bed dryer, tray dryer; or other suitable dryer. B.lntermediate coating
  • the drug pellets are coated using non-aqueous solution of hydroxypropylmethyl cellulose E5 and propylene glycol in fluid bed coater; or other suitable coater.
  • the intermediate coated pellets are coated using non-aqueous solution of opadry enteric in fluid bed coater; or other suitable coater.
  • the enteric-coated pellets are filled into hard gelatin capsules.
  • Pantoprazole enteric-coated pellets are Pantoprazole enteric-coated pellets:
  • Esomeprazole enteric-coated pellets Ingredients Quantity (mg) %(W/W)
  • Enteric-coated pellets formulation Manufacture of omeprazole; or a salt thereof:
  • omeprazole or a salt thereof, calcium carbonate, mannitol, sodium lauryl sulfate, lactose, disodium hydrogen phosphate and sucrose are blended.
  • Sucrose is wetted using binder having sucrose syrup.
  • the above blend is loaded on wet sucrose.
  • These drug pellets may be then dried in a fluid bed dryer; tray dryer; or other suitable dryer.
  • the drug pellets are coated using aqueous solution of hydroxypropylmethyl cellulose E5, polyvinylpyrrolidone k-30 and propylene glycol in fluid bed coater; or other suitable coater.
  • the intermediate coated pellets are coated using aqueous solution of methacrylic acid L-30D, sodium hydroxide, tween 80, diethyl phthalate, titanium dioxide, cetyl alcohol and purified talc in fluid bed coater; or other suitable coater.
  • the enteric-coated pellets are filled into hard gelatin capsules.
  • Omeprazole enteric-coated pellets are Omeprazole enteric-coated pellets:
  • Enteric-coated pellets formulation Manufacture of lansoprazole or (S)-lansoprazole:
  • the lansoprazole or (S)-lansoprazole, magnesium carbonate, mannitol, calcium carboxymethylcellulose, lactose, starch and sucrose are blended. Sucrose is wetted using binder. The above blend is loaded on wet sucrose. These drug pellets may be then dried in a fluid bed dryer, tray dryer; or other suitable dryer. B.lntermediate coating
  • the drug pellets are coated using aqueous solution of hydroxypropyl methyl cellulose E5, polyvinylpyrrolidone k-30, acetone and propylene glycol in fluid bed coater; or other suitable coater.
  • the intermediate coated pellets are coated using aqueous solution of methacrylic acid L-30D, sodium hydroxide, tween 80, diethyl phthalate, titanium dioxide and cetyl alcohol in fluid bed coater; or other suitable coater.
  • the enteric-coated pellets are filled into hard gelatin capsules.
  • a single dosage unit capsule formulations :
  • the antiulcerative substituted benzimidazoles are rabeprazole, pantoprazole, omeprazole, lansoprazole, tenatoprazole, esomeprazole, (S)- pantoprazole, (S)-rabeprazole and (S)-lansoprazole or a salt thereof as enteric coated pellets or tablets and optionally in combination with other active pharmaceutical ingredients are domperidone, itopride hydrochloride, mosapride citrate and ondansetron as sutained release pellets or pellets are filled in required size hard gelatin capsules in various combination of single dosage units.
  • Ondansetron (As sustained release pellets) (12%) 100 24.4 Dummy pellets 50 12.2
  • Domperidone As sustained release pellets (24%) 125 ' 35.7 Dummy pellets 70 20
  • Pantoprazole (20mg)(EC) and ondansetron (4mg) capsules Ingredients Quantity (mg) %(W/W)
  • Example 53 Lansoprazole (15mg)(EC) and itopride hydrochloride (50mg) capsules: Ingredients Quantity (mg) %(W/
  • Omeprazole (As enteric coated pellets) (8.5%) 236 65.4
  • Example 65 Omeprazole (10mg)(EC) and domperidone (10mg) capsules:
  • Example 67 Omeprazole (10mg)(EC) and itopride hydrochloride (150mg)(SR) capsules: Ingredients Quantity (mg) %(W/W)
  • Omeprazole (As enteric coated pellets) (8.5%) 236 47.1
  • Example 71 Omeprazole (10mg)(EC) and mosapride citrate (15mg)(SR) capsules:
  • Example 72 Omeprazole (20mg)(EC) and mosapride citrate (15mg)(SR) capsules:
  • Example 80 Esomeprazole (40mg)(EC) and domperidone (30mg)(SR) capsules:
  • Esomeprazole (40mg)(EC) and domperidone (10mg) capsules Ingredients Quantity (mg) %(W/W)
  • Esomeprazole magnesium trihydrate Eq .to esomeprazole (As enteric coated pellets) (13%) 310 68.9

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Abstract

La présente invention concerne particulièrement des compositions pharmaceutiques stables améliorées pour benzimidazoles substitués hygroscopiques anti-ulcérant, éventuellement combinées avec d’autres principes actifs sous la forme de pastilles, de gélules et de comprimés. Par exemple, des compositions pharmaceutiques stables de rabéprazole sodique, comprenant du rabéprazole sodique, du carbonate de calcium lourd, du mannitol, de la polyvinylpyrrolidone s-630, de l’amidon, de l’hydroxypropylcellulose (faiblement substituée), du fumarate de stéaryle sodique, de l’hydroxypropylméthylcellulose de 15 cps et de l’Acryl-EZE.
PCT/IN2005/000203 2005-06-16 2005-06-16 Compositions de benzimidazoles substitués anti-ulcérants WO2006134611A1 (fr)

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CN101756945B (zh) * 2008-12-24 2012-06-27 鲁南制药集团股份有限公司 一种枸橼酸莫沙必利滴丸
WO2013081566A1 (fr) * 2011-11-25 2013-06-06 Mahmut Bilgic Formulation comprenant du benzimidazole
CN103599087A (zh) * 2013-05-21 2014-02-26 海南海力制药有限公司 雷贝拉唑钠肠溶微丸及其制备方法
WO2016155786A1 (fr) * 2015-03-31 2016-10-06 Laboratorios Bagó S.A. Granules gastro-résistants contenant un inhibiteur de la pompe à protons
US20160331688A1 (en) * 2014-01-31 2016-11-17 Shionogi & Co., Ltd. Sustained release formulation
WO2017185123A1 (fr) * 2016-04-29 2017-11-02 Alan Thompson Composition vétérinaire
EP3354262A1 (fr) * 2017-01-31 2018-08-01 Sanovel Ilac Sanayi ve Ticaret A.S. Compositions pharmaceutiques de dexlansoprazole à enrobage entérique
CN109125282A (zh) * 2018-09-05 2019-01-04 珠海润都制药股份有限公司 一种奥美拉唑肠溶胶囊及其制备方法
JP2021107333A (ja) * 2019-12-27 2021-07-29 小林製薬株式会社 内服用医薬組成物

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US20040092511A1 (en) * 1999-12-10 2004-05-13 Billstein Stephan Anthony Pharmaceutical combinations and their use in treating gastrointestinal and abdominal viscera disorders
WO2005051384A1 (fr) * 2003-11-25 2005-06-09 Pfizer Limited Compositions pharmaceutiques stabilisees

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040092511A1 (en) * 1999-12-10 2004-05-13 Billstein Stephan Anthony Pharmaceutical combinations and their use in treating gastrointestinal and abdominal viscera disorders
WO2005051384A1 (fr) * 2003-11-25 2005-06-09 Pfizer Limited Compositions pharmaceutiques stabilisees

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101756945B (zh) * 2008-12-24 2012-06-27 鲁南制药集团股份有限公司 一种枸橼酸莫沙必利滴丸
WO2013081566A1 (fr) * 2011-11-25 2013-06-06 Mahmut Bilgic Formulation comprenant du benzimidazole
CN103599087A (zh) * 2013-05-21 2014-02-26 海南海力制药有限公司 雷贝拉唑钠肠溶微丸及其制备方法
US20160331688A1 (en) * 2014-01-31 2016-11-17 Shionogi & Co., Ltd. Sustained release formulation
RU2679652C1 (ru) * 2015-03-31 2019-02-12 Лабораториос Баго С. А. Способ получения гранул с энтеросолюбильным покрытием, содержащих ингибитор протонного насоса, и фармацевтических композиций, состоящих из множества частиц и содержащих эти гранулы
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JP7499028B2 (ja) 2019-12-27 2024-06-13 小林製薬株式会社 内服用医薬組成物

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