WO1996001622A1 - New oral pharmaceutical formulation containing magnesium salt of omeprazole - Google Patents

New oral pharmaceutical formulation containing magnesium salt of omeprazole Download PDF

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Publication number
WO1996001622A1
WO1996001622A1 PCT/SE1995/000816 SE9500816W WO9601622A1 WO 1996001622 A1 WO1996001622 A1 WO 1996001622A1 SE 9500816 W SE9500816 W SE 9500816W WO 9601622 A1 WO9601622 A1 WO 9601622A1
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WO
WIPO (PCT)
Prior art keywords
formulation according
omeprazole
formulation
enteric
enteric coating
Prior art date
Application number
PCT/SE1995/000816
Other languages
French (fr)
Other versions
WO1996001622A8 (en
Inventor
Siv Inga Bengtsson
Kurt Ingmar LÖVGREN
Original Assignee
Astra Aktiebolag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astra Aktiebolag filed Critical Astra Aktiebolag
Priority to BR9508261A priority Critical patent/BR9508261A/en
Priority to HU9700039A priority patent/HUT78132A/en
Priority to MX9700152A priority patent/MX9700152A/en
Priority to AU29947/95A priority patent/AU695723C/en
Priority to EE9700014A priority patent/EE03378B1/en
Priority to SK1660-96A priority patent/SK166096A3/en
Priority to PL95318464A priority patent/PL181265B1/en
Priority to NZ289958A priority patent/NZ289958A/en
Priority to JP8504257A priority patent/JPH10504288A/en
Priority to EP95926067A priority patent/EP0768872A1/en
Priority to CZ963795A priority patent/CZ379596A3/en
Priority to KR1019970700059A priority patent/KR970704426A/en
Publication of WO1996001622A1 publication Critical patent/WO1996001622A1/en
Priority to IS4398A priority patent/IS4398A/en
Priority to NO970036A priority patent/NO970036D0/en
Priority to FI970058A priority patent/FI970058A0/en
Publication of WO1996001622A8 publication Critical patent/WO1996001622A8/en

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Classifications

    • 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
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention is related to a new pharmaceutical formulation containing a novel physical form of a magnesium salt of omeprazole, to a method for the manufacture of such a formulation, and to the use of such a formulation in medicine.
  • Omeprazole is useful for inhibiting gastric acid secretion in mammals and man.
  • said substances may be used for prevention and treatment of gastric acid related diseases in mammals and man, including e.g. reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer.
  • omeprazole may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable e.g. in patients on NSATD therapy, in patients with Non Ulcer Dyspepsia, in patients with symptomatic gastro-esophageal reflux disease, and in patients with gastrinomas.
  • Omeprazole may also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre- and postoperatively to prevent acid aspiration of gastric acid and to prevent and treat stress ulceration. Further, omeprazole may be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections and diseases related to these. Omeprazole is susceptible to degradation/transformation in acidic and neutral media. The half-life of degradation of omeprazole in water solutions at pH-values less than three is shorter than ten minutes. Omeprazole may be stabilized in mixtures with alkaline compounds. The stability of omeprazole is also affected by moisture, heat, organic solvents and to some degree by light.
  • omeprazole From what is said about the stability properties of omeprazole, it is obvious that an oral dosage form of omeprazole must be protected from contact with the acid gastric juice and the active substance must be transferred in intact form to that part of the gastrointestinal tract where pH is near neutral and where rapid absorption of omeprazole can occur.
  • a pharmaceutical oral dosage form of omeprazole may well be protected from contact with acidic gastric juice by an enteric coating.
  • an enteric coated omeprazole preparation is described.
  • Said omeprazole preparation contains an alkaline core comprising omeprazole, a subcoating and an enteric coating.
  • magnesium omeprazole in this specification denoted magnesium omeprazole, in full manufacturing scale in preparing pharmaceutical formulations primarily for oral administration, such as tablets, it is necessary that said magnesium omeprazole possesses a combination of properties which makes such full scale manufacturing feasible.
  • novel form of magnesium omeprazole can be formulated into different dosage forms for oral and rectal administration.
  • examples of such formulations are tablets, granules, pellets, capsules, suppositories and suspensions. Description of the invention
  • One object of the present invention is to provide a pharmaceutical formulation of magnesium omeprazole.
  • Another object of the present invention is to provide a process for full scale production of pharmaceutical formulations of omeprazole, especially an enteric coated dosage form of omeprazole, which is resistant to dissolution in acid media and which dissolves rapidly in neutral to alkaline media and which has a good stability even against discoloration.
  • Yet another object of the invention is to provide an environmental friendly completely water-based process for the manufacture of pharmaceutical formulations of omeprazole.
  • a further object of the present invention is to provide a dosage form comprising omeprazole which is suitable for press-through blister packages and which also has an improved patient acceptance.
  • the new dosage form is characterized in the following way.
  • Core material in the form of pellets, granules, beads or tablets containing the novel form of a magnesium salt of omeprazole and on said core material one or more enteric coating layers.
  • the process of forming the enteric coated dosage form is preferably water-based.
  • the enteric coating process step can be carried out using a water-based process which is desirable both for the working environment inside the pharmaceutical plant and for global environmental reasons. It has been found that a magnesium omeprazole having a degree of crystallinity which is higher than 70% is advantageous in the manufacture of pharmaceutical formulations of omeprazole according to the present invention.
  • the new pharmaceutical formulation is defined in claims 1-9, a process for the manufacture of the pharmaceutical formulation according to the present invention is defined in claims 10-11, the use of the formulation in medicine is defined in claims 12-18 and a press- through blister package is stated in claim 19.
  • a magnesium omeprazole advantageous for the manufacturing of the claimed formulation is described in WO95/01977 hereby incorporated in a whole by reference.
  • Said magnesium omeprazole has a degree of crystallinity of not less than 70%, preferably higher than 75% as determined by X-ray powder diffraction
  • the novel magnesium salt of omeprazole herein referred to as magnesium omeprazole, is mixed with pharmaceutical constituents to obtain preferred handling and processing properties and a suitable concentration of the active substance in the final mixture.
  • Pharmaceutical constituents such as fillers, binders, lubricants, disintegrating agents, surfactants and other pharmaceutically acceptable additives, can be used.
  • the core may also contain an alkaline pharmaceutically acceptable substance (or substances).
  • the optionally added alkaline substance(s) is not essential for the invention. However, it may further improve the chemical stability of the formulations.
  • Such pharmaceutically acceptable substances can be chosen among, but are not restricted to substances such as the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; aluminium hydroxide/sodium bicarbonate coprecipitate; substances normally used in antacid preparations such as aluminium, calcium and magnesium hydroxides; magnesium oxide or composite substances, such as Al 2 ⁇ 3.6MgO.C ⁇ 2.12H2 ⁇ ,(Mg 6 Al2(OH) 16 CO 3 .4H 2 O), MgO.AUOo. 2S.O2.nH2O or similar compounds; organic pH-buffering substances such as trihydroxymethylaminomethane, basic amino acids and their salts or other similar, pharmaceutically acceptable pH-buffering substances.
  • substances such as the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; aluminium hydroxide/sodium bicarbonate copre
  • the powder mixture is then formulated into pellets, granules, beads or tablets by pharmaceutical procedures.
  • the pellets, granules, beads or tablets are used as core material for further processing.
  • the enteric coating layer is applied in one or more layers onto the formulated core material by coating procedures in suitable equipments such as pan coating, coating granulator or fluidized bed apparatus using solutions of polymers in water, or by using latex suspensions of said polymers or optionally using polymer solutions in suitable organic solvents.
  • suitable equipments such as pan coating, coating granulator or fluidized bed apparatus using solutions of polymers in water, or by using latex suspensions of said polymers or optionally using polymer solutions in suitable organic solvents.
  • enteric coating polymers can be used one or more of the following, for example solutions or dispersions of acrylates (methacrylic acid/methacrylic acid methylester copolymer), cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac or other suitable enteric coating polymer(s).
  • acrylates methacrylic acid/methacrylic acid methylester copolymer
  • cellulose acetate phthalate hydroxypropyl methylcellulose phthalate
  • hydroxypropyl methylcellulose acetate succinate polyvinyl acetate phthalate
  • cellulose acetate trimellitate carboxymethylethylcellulose
  • shellac or other suitable enteric coating polymer(s).
  • enteric coating layer can optionally contain a pharmaceutically acceptable plasticizer for example cetanol, triacetin, citric acid es- ters such as, those known under the trade name Citroflex® (Pfizer), phthalic acid esters, dibutyl succinate, polyethylene glycol (PEG) or similar plasticizers.
  • a pharmaceutically acceptable plasticizer for example cetanol, triacetin, citric acid es- ters such as, those known under the trade name Citroflex® (Pfizer), phthalic acid esters, dibutyl succinate, polyethylene glycol (PEG) or similar plasticizers.
  • the amount of plasticizer is usually optimized for each enteric coating polymer(s) and is usually in the range of 1-50 % of the enteric coating polymer(s).
  • Additives such as talc, colorants and pigments may also be included into the enteric coating layer or sprayed onto the enteric coated material as an overcoat.
  • the thickness of the enteric coating may vary widely without influencing the release rate of omeprazole.
  • the enteric coating constitutes at least an amount of 1.0 % by weight of the core weight, preferably at least 3.0 % and more preferably more than 8.0 %.
  • the upper amount of the applied enteric coating is normally only limited by processing conditions. This possibility to increase the thickness of the enteric coating without deleterious influence on the release rate of omeprazole is especially desirable in large scale processes.
  • the enteric coating layer(s) may be applied on the pre-processed formulation without exactly controlling the thickness of the applied coating layer(s).
  • the formulation according to the invention consists of core material containing magnesium omeprazole.
  • the core material is coated with enteric coating(s) rendering the dosage form insoluble in acid media, but disintegrating/dissolving in neutral to alkaline media such as, for instance the liquids present in the proximal part of the small intestine, the site where dissolution is wanted.
  • Final dosage form
  • the final dosage form is either an enteric coated tablet or capsule or in the case of enteric coated pellets, beads or granules, these pellets, beads or granules are dispensed in hard gelatin capsules or sachets.
  • the final dosage form may further be coated with an additional layer containing pigment(s) and/or colourant(s). It is essential for the long term stability during storage that the water content of the final dosage form containing magnesium omeprazole (enteric coated tablets, capsules, granules, beads or pellets) is kept low.
  • a process for the manufacture of a dosage form according to the present invention represents a further aspect of the invention. After the fo ⁇ ning of the core material, said material is coated with enteric coating layer(s). The coating(s) are carried out as described above. Further another aspect of the invention is that the pharmaceutical processes can be completely water-based.
  • the preparation according to the invention is especially advantageous in reducing gastric acid secretion. It is administered one to several times a day.
  • the typical daily dose of the active substance varies and will depend on various factors such as the individual requirements of the patients, the mode of administration and the disease. In general the daily dose will be in the range of 1-400 mg of omeprazole.
  • Examples 1-2 disclose compositions of different enteric coated tablets containing magnesium omeprazole. Said examples also show the result of a gastric acid resistance test in vitro.
  • Example 3 discloses an enteric coated pellet formulation. Said example also shows the result of a gastric acid resistance test in vitro.
  • Paraffin powder 0.05 Tablets with the composition described above have been manufactured in a laboratory scale of about 20 000 tablets.
  • Magnesium omeprazole, mannitol, hydroxypropyl methylcellulose, microcrystalline cellulose and sodium starch glycolate are dry-mixed, moistened with water and wet mixed.
  • the wet mass is dried and milled and finally mixed with anti-adherent and lubricant substances.
  • the milled granulate is compressed to tablets with a diameter of 7 mm.
  • the tablets are enteric coated with a methacrylic acid copolymer film. Water used in the manufacture of the tablets is removed during subsequent processing.
  • Amount omeprazole 40 Ingredient (mg/tabl.) ⁇
  • Magnesium omeprazole, mannitol, hydroxypropyl methylcellulose, microcrystalline cellulose and sodium starch glycolate are dry-mixed, moistened with water and wet mixed. The wet mass is dried and milled and finally mixed with anti-adherent and lubricant substances. T e milled granulate is compressed to tablets with a diameter of 7 mm. The tablets are enteric coated with a methacrylic acid copolymer film.
  • Enteric coated pellet formulation containing magnesium omeprazole being produced as described in WO95/01977.
  • Non-pareil pellets 1.5 kg Hydroxypropyl methylcellulose 0.23 kg

Abstract

A new oral pharmaceutical formulation containing a novel physical form of a magnesium salt of omeprazole coated with one or more enteric coating layers, a method for the manufacture of such a formulation, the use of such a formulation in medicine and a blister package containing the new formulation.

Description

NEW ORAL PHARMACEUTICAL FORMULATION CONTAINING MAGNESIUM
SALT OF OMEPRAZOLE
Field of the invention.
The present invention is related to a new pharmaceutical formulation containing a novel physical form of a magnesium salt of omeprazole, to a method for the manufacture of such a formulation, and to the use of such a formulation in medicine.
Background of the invention.
The compound known under the generic name omeprazole, 5-methoxy-2(((4- methoxy-3,5-dimethyl-2-pyridinyl)methyl)sulfιnyl)- 1 H-benzimidazole, is described i.a. in EP-A 0 005 129.
Omeprazole is useful for inhibiting gastric acid secretion in mammals and man. In a more general sense, said substances may be used for prevention and treatment of gastric acid related diseases in mammals and man, including e.g. reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. Furthermore, omeprazole may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable e.g. in patients on NSATD therapy, in patients with Non Ulcer Dyspepsia, in patients with symptomatic gastro-esophageal reflux disease, and in patients with gastrinomas. Omeprazole may also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre- and postoperatively to prevent acid aspiration of gastric acid and to prevent and treat stress ulceration. Further, omeprazole may be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections and diseases related to these. Omeprazole is susceptible to degradation/transformation in acidic and neutral media. The half-life of degradation of omeprazole in water solutions at pH-values less than three is shorter than ten minutes. Omeprazole may be stabilized in mixtures with alkaline compounds. The stability of omeprazole is also affected by moisture, heat, organic solvents and to some degree by light.
From what is said about the stability properties of omeprazole, it is obvious that an oral dosage form of omeprazole must be protected from contact with the acid gastric juice and the active substance must be transferred in intact form to that part of the gastrointestinal tract where pH is near neutral and where rapid absorption of omeprazole can occur.
A pharmaceutical oral dosage form of omeprazole may well be protected from contact with acidic gastric juice by an enteric coating. In US-A 4,786,505 an enteric coated omeprazole preparation is described. Said omeprazole preparation contains an alkaline core comprising omeprazole, a subcoating and an enteric coating.
The hard gelatine capsules containing an enteric coated pellet formulation of omeprazole marketed by the Applicant today, are not suitable for press-through blister packages. Thus, there has been a demand for development of new enteric coated preparations of omeprazole with good chemical stability as well as improved mechanical stability making it possible to produce well functioning and patient-friendly packages.
Certain salts of omeprazole including alkaline salts of omeprazole are described in EP-A 0 124 495. In said patent specification the requirements and importance regarding storage stability of omeprazole for incorporation in pharmaceutical preparations are emphasized. There is however, a demand for the development of new enteric preparations of omeprazole with enhanced stability and for environmental aspects there is also a strong desire for the use of water based processes in production of pharmaceutical products.
The isolation and purification in full manufacturing scale of the magnesium omeprazole salts described in EP-A 0 124 495 presents one major problem in that the magnesium omeprazole salt particles are very fragile making pharmaceutical manufacturing processes utilising this product less attractive in full scale production. Manufactirring of magnesium omeprazole without a separate crystallisation step gives a product which is less suitable as a pharmaceutical substance.
In order to use the magnesium salt of omeprazole, in this specification denoted magnesium omeprazole, in full manufacturing scale in preparing pharmaceutical formulations primarily for oral administration, such as tablets, it is necessary that said magnesium omeprazole possesses a combination of properties which makes such full scale manufacturing feasible.
The combination of physical properties of the novel magnesium omeprazole product described in WO95/01977 with respect to the degree of crystallinity, particle diameter, density, hygroscopicity, low water content and low content of other solvents is favorable and permits the manufacture of magnesium omeprazole in a form which is advantageous for the manufacture of the new pharmaceutical formulations.
The novel form of magnesium omeprazole can be formulated into different dosage forms for oral and rectal administration. Examples of such formulations are tablets, granules, pellets, capsules, suppositories and suspensions. Description of the invention
One object of the present invention is to provide a pharmaceutical formulation of magnesium omeprazole.
Another object of the present invention is to provide a process for full scale production of pharmaceutical formulations of omeprazole, especially an enteric coated dosage form of omeprazole, which is resistant to dissolution in acid media and which dissolves rapidly in neutral to alkaline media and which has a good stability even against discoloration.
Yet another object of the invention is to provide an environmental friendly completely water-based process for the manufacture of pharmaceutical formulations of omeprazole.
A further object of the present invention is to provide a dosage form comprising omeprazole which is suitable for press-through blister packages and which also has an improved patient acceptance.
The new dosage form is characterized in the following way. Core material in the form of pellets, granules, beads or tablets containing the novel form of a magnesium salt of omeprazole and on said core material one or more enteric coating layers.
The process of forming the enteric coated dosage form is preferably water-based.
Also the enteric coating process step can be carried out using a water-based process which is desirable both for the working environment inside the pharmaceutical plant and for global environmental reasons. It has been found that a magnesium omeprazole having a degree of crystallinity which is higher than 70% is advantageous in the manufacture of pharmaceutical formulations of omeprazole according to the present invention.
Detailed description of the invention
The new pharmaceutical formulation is defined in claims 1-9, a process for the manufacture of the pharmaceutical formulation according to the present invention is defined in claims 10-11, the use of the formulation in medicine is defined in claims 12-18 and a press- through blister package is stated in claim 19.
Magnesium omeprazole
A magnesium omeprazole advantageous for the manufacturing of the claimed formulation is described in WO95/01977 hereby incorporated in a whole by reference. Said magnesium omeprazole has a degree of crystallinity of not less than 70%, preferably higher than 75% as determined by X-ray powder diffraction
Pharmaceutical formulations containing the magnesium omeprazole are manufactured as described herein below.
Core material
The novel magnesium salt of omeprazole, herein referred to as magnesium omeprazole, is mixed with pharmaceutical constituents to obtain preferred handling and processing properties and a suitable concentration of the active substance in the final mixture. Pharmaceutical constituents such as fillers, binders, lubricants, disintegrating agents, surfactants and other pharmaceutically acceptable additives, can be used. The core may also contain an alkaline pharmaceutically acceptable substance (or substances). The optionally added alkaline substance(s) is not essential for the invention. However, it may further improve the chemical stability of the formulations. Such pharmaceutically acceptable substances can be chosen among, but are not restricted to substances such as the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; aluminium hydroxide/sodium bicarbonate coprecipitate; substances normally used in antacid preparations such as aluminium, calcium and magnesium hydroxides; magnesium oxide or composite substances, such as Al2θ3.6MgO.Cθ2.12H2θ,(Mg6Al2(OH)16CO3.4H2O), MgO.AUOo. 2S.O2.nH2O or similar compounds; organic pH-buffering substances such as trihydroxymethylaminomethane, basic amino acids and their salts or other similar, pharmaceutically acceptable pH-buffering substances.
The powder mixture is then formulated into pellets, granules, beads or tablets by pharmaceutical procedures. The pellets, granules, beads or tablets are used as core material for further processing.
Enteric coating layer
The enteric coating layer is applied in one or more layers onto the formulated core material by coating procedures in suitable equipments such as pan coating, coating granulator or fluidized bed apparatus using solutions of polymers in water, or by using latex suspensions of said polymers or optionally using polymer solutions in suitable organic solvents. As enteric coating polymers can be used one or more of the following, for example solutions or dispersions of acrylates (methacrylic acid/methacrylic acid methylester copolymer), cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac or other suitable enteric coating polymer(s). Preferably water-based polymer dispersions such as for example compounds known under the trade names Aquateric® (FMC Corporation) Eudragit® (Rohm Pharma), Aqoat™ (Shin-Etsu Chemical), Opadry™ (Colorcon) or similar compounds are used to obtain enteric coatings. The enteric coating layer can optionally contain a pharmaceutically acceptable plasticizer for example cetanol, triacetin, citric acid es- ters such as, those known under the trade name Citroflex® (Pfizer), phthalic acid esters, dibutyl succinate, polyethylene glycol (PEG) or similar plasticizers. The amount of plasticizer is usually optimized for each enteric coating polymer(s) and is usually in the range of 1-50 % of the enteric coating polymer(s). Additives such as talc, colorants and pigments may also be included into the enteric coating layer or sprayed onto the enteric coated material as an overcoat.
The thickness of the enteric coating may vary widely without influencing the release rate of omeprazole. To protect the acid susceptible omeprazole compound and to obtain an acceptable acid resistance, the enteric coating constitutes at least an amount of 1.0 % by weight of the core weight, preferably at least 3.0 % and more preferably more than 8.0 %. The upper amount of the applied enteric coating is normally only limited by processing conditions. This possibility to increase the thickness of the enteric coating without deleterious influence on the release rate of omeprazole is especially desirable in large scale processes. The enteric coating layer(s) may be applied on the pre-processed formulation without exactly controlling the thickness of the applied coating layer(s).
Thus, the formulation according to the invention consists of core material containing magnesium omeprazole. The core material is coated with enteric coating(s) rendering the dosage form insoluble in acid media, but disintegrating/dissolving in neutral to alkaline media such as, for instance the liquids present in the proximal part of the small intestine, the site where dissolution is wanted. Final dosage form
The final dosage form is either an enteric coated tablet or capsule or in the case of enteric coated pellets, beads or granules, these pellets, beads or granules are dispensed in hard gelatin capsules or sachets. The final dosage form may further be coated with an additional layer containing pigment(s) and/or colourant(s). It is essential for the long term stability during storage that the water content of the final dosage form containing magnesium omeprazole (enteric coated tablets, capsules, granules, beads or pellets) is kept low.
Process
A process for the manufacture of a dosage form according to the present invention represents a further aspect of the invention. After the foπning of the core material, said material is coated with enteric coating layer(s). The coating(s) are carried out as described above. Further another aspect of the invention is that the pharmaceutical processes can be completely water-based.
The preparation according to the invention is especially advantageous in reducing gastric acid secretion. It is administered one to several times a day. The typical daily dose of the active substance varies and will depend on various factors such as the individual requirements of the patients, the mode of administration and the disease. In general the daily dose will be in the range of 1-400 mg of omeprazole.
The invention is illustrated in detail by the following examples. Examples 1-2 disclose compositions of different enteric coated tablets containing magnesium omeprazole. Said examples also show the result of a gastric acid resistance test in vitro. Example 3 discloses an enteric coated pellet formulation. Said example also shows the result of a gastric acid resistance test in vitro. EXAMPLES
Example 1
Tablet formulation containing magnesium omeprazole being produced as described in WO95/01977.
Amount omeprazole 10
Ingredient (mg/tabl)
Tablet core
Magnesium omeprazole 11.2
Mannitol 68.7
Microcrystalline cellulose 25.0
Sodium starch glycolate 6.0
Hydroxypropyl methylcellulose 6.0
Talc 5.0
Sodium stearyl fumarate 2.5
Water purified 50.0
Enteric coating layer
Methacrylic acid copolymer 9.1
Polyethylene glycol 1.0
Titanium dioxide 0.82
Colour iron oxide, red-brown 0.04 Colour iron oxide, yellow 0.02
Water purified 45.0
Polish
Paraffin powder 0.05 Tablets with the composition described above have been manufactured in a laboratory scale of about 20 000 tablets.
Description of manufacturing Magnesium omeprazole, mannitol, hydroxypropyl methylcellulose, microcrystalline cellulose and sodium starch glycolate are dry-mixed, moistened with water and wet mixed. The wet mass is dried and milled and finally mixed with anti-adherent and lubricant substances. The milled granulate is compressed to tablets with a diameter of 7 mm. The tablets are enteric coated with a methacrylic acid copolymer film. Water used in the manufacture of the tablets is removed during subsequent processing.
Investigation of acid-resistance
Six individual tablets were exposed to artificial gastric fluid without enzymes, pH 1.2. After six hours the tablets were removed, washed and analysed for omeprazole content using HPLC. The amount of omeprazole is taken as acid resistance.
Tablet Acid resistance
Strength
(mg) (%)
10 101 (98 - 103)
Example 2
Tablet formulation containing magnesium omeprazole being produced as described in WO95/01977.
Amount omeprazole 40 Ingredient (mg/tabl.) π
Table core
Magnesium omeprazole 45.0
Mannitol 34.9 Microcrystalline cellulose 25.0
Sodium starch glycolate 6.0
Hydroxypropyl methylcellulose 6.0
Talc 5.0
Sodium stearyl fumarate 2.5 Water purified 50.0
Enteric coating layer
Metacrylic acid copolymer 9.1
Polyethylene glycol 1.0 Titanium dioxide 0.51
Colour iron oxide red-brown 0.43
Water purified 45.0
Polish Paraffin 0.05
Description of manufacturing
Magnesium omeprazole, mannitol, hydroxypropyl methylcellulose, microcrystalline cellulose and sodium starch glycolate are dry-mixed, moistened with water and wet mixed. The wet mass is dried and milled and finally mixed with anti-adherent and lubricant substances. T e milled granulate is compressed to tablets with a diameter of 7 mm. The tablets are enteric coated with a methacrylic acid copolymer film.
Water used in the manufacture of the tablets is removed during subsequent processing. Investigation of acid-resistance
Six individual tablets were exposed to artificial gastric fluid without enzymes, pH 1.2. After six hours the tablets were removed, washed and analysed for omeprazole content using HPLC. The amount of omeprazole is taken as acid resistance.
Tablet Acid resistance
Strength
(mg) (%)
40 95 (92-101)
Example 3
Enteric coated pellet formulation containing magnesium omeprazole being produced as described in WO95/01977.
Pellet Core
Magnesium omeprazole 1.5 kg
Non-pareil pellets 1.5 kg Hydroxypropyl methylcellulose 0.23 kg
Water purified 4.0 kg
Enteric -coating layer
Uncoated pellets 500 g Methacrylic acid copolymer 300 g
Triethyl citrate 90 g
Mono- and diglycerides (NF) 15 g
Polysorbate 80 1.5 g
Water purified 1290 g Description of manufacturing.
Suspension layering was performed in a fluid bed apparatus. Magnesium omeprazole was sprayed onto inert non-pareil cores from a water suspension containing the dissolved binder. The prepared pellets were enteric-coated in a fluid bed apparatus.
Investigation of acid resistance.
Pellets were added to gastric fluid USP (without enzyme), 37°C (paddle) 100 r/min. After 2 hours the actual amount of omeprazole remaining intact in the formulation was determined.
Acid resistance (n=6) Pellets % omeprazole 20 mg 94 ( 93 - 95 )

Claims

1. An oral enteric coated formulation containing a core material of an active substance coated with one or more enteric coating layers characterized in that the core material as active substance contains a magnesium salt of omeprazole having a degree of crystallinity which is higher than 70 % as determined by X-ray powder diffraction and on the core material enteric coating layer(s), whereby the thickness of the enteric coating does not essentially influence the release of omeprazole into aqueous solutions at pH values predominantly present in the small intestine.
2. A formulation according to claim 1, wherein the formulation is a tablet formulation.
3. A formulation according to claim 1, wherein the formulation is a pellet formulation.
4. A formulation according to claim 1, wherein the enteric coating comprising an enteric coating material, optionally containing one or more pharmaceutically acceptable plasticizers, dispersants, colorants and pigments.
5. A formulation according to claim 4, wherein the enteric coating comprises water-based polymer solutions or dispersions of acrylates, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate and/or cellulose acetate phthalate.
6. A formulation according to claim 1 , wherein the enteric coating constitutes from 1.0 % by weight of the weight of the core material.
7. A formulation according to claim 6, wherein the enteric coating constitutes at least 3.0 % by weight of the weight of the core material.
8. A formulation according to claim 6, wherein the enteric coating constitutes at least 8.0 % by weight of the weight of the core material.
9. A formulation according to claim 1 , wherein one of the coating layers is an overcoat applied on the enteric coated formulation, which overcoat optionally comprises one or more pharmaceutically acceptable plasticizers, dispersants, colorants and pigments.
10. A process for the manufacture of a formulation according to claim 1 in which core material containing magnesium omeprazole is coated with one or more enteric coating layer(s), having a thickness which does not essentially influence the release rate of omeprazole into aqueous solutions at pH values predominantly present in the small intestinate.
11. A process according to claim 10 in which the enteric coated formulation is further coated with an overcoat
12. An oral enteric coated formulation according to any of claims 1 to 9 for use in therapy.
13. An oral enteric coated formulation according to any of claims 1 to 9 for use in inhibiting gastric acid secretion in mammals and man.
14. An oral enteric coated formulation according to any of claims 1 to 9 for use in the treatment of gastric acid related diseases in mammals and man.
15. The use of an oral enteric coated formulation according to any of claims 1 to 9 in the manufacture of a medicament for inhibiting gastric acid secretion in mammals and man.
16. The use of an oral enteric coated formulation according to any of claims 1 to 9 in the manufacture of a medicament for treatment of gastric acid related diseases in mammals and man.
17. A method for inhibiting gastric acid secretion in mammals and man by administring to a host in need thereof a therapeutically effective dose of an enteric coated formulation according to any of claims 1 to 9.
18. A method for the treatment of gastric acid related diseases in mammals and man by administring to a host in need thereof a therapeutically effective dose of an enteric coated formulation according to any of claims 1 to 9.
19. A press-through blister package comprising a formulation according to any of claims 1-9.
PCT/SE1995/000816 1994-07-08 1995-07-03 New oral pharmaceutical formulation containing magnesium salt of omeprazole WO1996001622A1 (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
BR9508261A BR9508261A (en) 1994-07-08 1995-07-03 Enterically coated oral formulation using the same process to prepare the formulation to inhibit gastric acid secretion in mammals and humans and to treat gastric acid-related diseases in humans and humans and cross-pressure blister pack
HU9700039A HUT78132A (en) 1994-07-08 1995-07-03 New oral pharmaceutical formulation containing magnesium salt of omeprazole
MX9700152A MX9700152A (en) 1994-07-08 1995-07-03 New oral pharmaceutical formulation containing magnesium salt of omeprazole.
AU29947/95A AU695723C (en) 1994-07-08 1995-07-03 New oral pharmaceutical formulation containing magnesium salt of omeprazole
EE9700014A EE03378B1 (en) 1994-07-08 1995-07-03 Oral dosage form containing magnesium salt of omeprazole
NZ289958A NZ289958A (en) 1994-07-08 1995-07-05 Oral enteric coated medicament containing a magnesium salt of omeprazole having a degree of crystallinity which is higher than 70%, used to inhibit gastric acid secretion
PL95318464A PL181265B1 (en) 1994-07-08 1995-07-05 Novel pharmaceutic preparation for oral administration containing a magnesium salt of omeprasole
SK1660-96A SK166096A3 (en) 1994-07-08 1995-07-05 New oral pharmaceutical formulation containing magnesium salt of omeprazole
JP8504257A JPH10504288A (en) 1994-07-08 1995-07-05 Novel oral pharmaceutical formulations containing magnesium salt of omeprazole
EP95926067A EP0768872A1 (en) 1994-07-08 1995-07-05 New oral pharmaceutical formulation containing magnesium salt of omeprazole
CZ963795A CZ379596A3 (en) 1994-07-08 1995-07-05 Novel oral pharmaceutical preparation containing omeprazol magnesium salt
KR1019970700059A KR970704426A (en) 1994-07-08 1995-07-05 A New Oral Pharmaceutical Formulation Containing Magnesium Salt of Omeprazole Containing Magnesium Salt of Omeprazole
IS4398A IS4398A (en) 1994-07-08 1996-12-17 New oral oral formulations containing magnesium salt of omeprazole
NO970036A NO970036D0 (en) 1994-07-08 1997-01-06 New oral pharmaceutical preparation containing magnesium salt of omeprazole
FI970058A FI970058A0 (en) 1994-07-08 1997-01-07 A new oral pharmaceutical preparation containing the magnesium salt of omeprazole

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US31320894A 1994-07-08 1994-07-08
SEPCT/SE94/00679 1994-07-08
SE9400679 1994-07-08

Publications (2)

Publication Number Publication Date
WO1996001622A1 true WO1996001622A1 (en) 1996-01-25
WO1996001622A8 WO1996001622A8 (en) 1999-12-23

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PCT/SE1995/000816 WO1996001622A1 (en) 1994-07-08 1995-07-03 New oral pharmaceutical formulation containing magnesium salt of omeprazole

Country Status (15)

Country Link
EP (1) EP0768872A1 (en)
KR (1) KR970704426A (en)
BR (1) BR9508261A (en)
CA (1) CA2193681A1 (en)
CZ (1) CZ379596A3 (en)
EE (1) EE03378B1 (en)
FI (1) FI970058A0 (en)
HU (1) HUT78132A (en)
IS (1) IS4398A (en)
MX (1) MX9700152A (en)
NO (1) NO970036D0 (en)
NZ (1) NZ289958A (en)
PL (1) PL181265B1 (en)
SK (1) SK166096A3 (en)
WO (1) WO1996001622A1 (en)

Cited By (19)

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US5900258A (en) * 1996-02-01 1999-05-04 Zeolitics Inc. Anti-bacterial compositions
US6013281A (en) * 1995-02-09 2000-01-11 Astra Aktiebolag Method of making a pharmaceutical dosage form comprising a proton pump inhibitor
US6077541A (en) * 1997-11-14 2000-06-20 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6174548B1 (en) 1998-08-28 2001-01-16 Andrx Pharmaceuticals, Inc. Omeprazole formulation
WO2001066117A1 (en) * 2000-03-09 2001-09-13 Ian Andrew Whitcroft Treatment of inflammatory dermatoses comprising erythromycin or clarythromycin metronidazole and a gastrointestinal hydrogen pump inhibitor
EP1133987A1 (en) * 2000-03-09 2001-09-19 Ian Whitcroft Treatment of inflammatory dermatoses with combinations of erythromycin or clarythromycin, metronidazole and a hydrogen pump inhibitor
US6316020B1 (en) * 1999-08-26 2001-11-13 Robert R. Whittle Pharmaceutical formulations
JP2001526211A (en) * 1997-12-22 2001-12-18 アストラゼネカ・アクチエボラーグ Oral extended release pharmaceutical dosage form
JP2001526213A (en) * 1997-12-22 2001-12-18 アストラゼネカ・アクチエボラーグ Oral drug pulse release dosage form
US6521253B1 (en) 1998-09-03 2003-02-18 Astrazeneca Ab Immediate release tablet
US6576258B1 (en) 1997-07-14 2003-06-10 Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D. Pharmaceutical formulation with controlled release of active substances
US6733778B1 (en) 1999-08-27 2004-05-11 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
WO2006002077A2 (en) * 2004-06-15 2006-01-05 Teva Pharmaceutical Industries Ltd. Stable pharmaceutical formulations of benzimidazole compounds
EP2596792A1 (en) * 2002-10-16 2013-05-29 Takeda Pharmaceutical Company Limited Stable solid preparations
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
CN105106168A (en) * 2015-08-19 2015-12-02 德州德药制药有限公司 Esomeprazole magnesium enteric capsules and preparation method thereof

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EP0342522A1 (en) * 1988-05-18 1989-11-23 Eisai Co., Ltd. Peroral preparation of an acid-unstable compound
WO1995001977A1 (en) * 1993-07-09 1995-01-19 Astra Aktiebolag Magnesium omeprazole
WO1995001783A1 (en) * 1993-07-09 1995-01-19 Astra Aktiebolag New pharmaceutical formulation

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EP0247983A2 (en) * 1986-04-30 1987-12-02 Aktiebolaget Hässle New pharmaceutical preparation for oral use
EP0342522A1 (en) * 1988-05-18 1989-11-23 Eisai Co., Ltd. Peroral preparation of an acid-unstable compound
WO1995001977A1 (en) * 1993-07-09 1995-01-19 Astra Aktiebolag Magnesium omeprazole
WO1995001783A1 (en) * 1993-07-09 1995-01-19 Astra Aktiebolag New pharmaceutical formulation

Cited By (30)

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US6013281A (en) * 1995-02-09 2000-01-11 Astra Aktiebolag Method of making a pharmaceutical dosage form comprising a proton pump inhibitor
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US7399772B2 (en) 1996-01-04 2008-07-15 Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US5900258A (en) * 1996-02-01 1999-05-04 Zeolitics Inc. Anti-bacterial compositions
US6576258B1 (en) 1997-07-14 2003-06-10 Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D. Pharmaceutical formulation with controlled release of active substances
US6077541A (en) * 1997-11-14 2000-06-20 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6096340A (en) * 1997-11-14 2000-08-01 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6780435B2 (en) 1997-11-14 2004-08-24 Andrx Pharmaceuticals, Inc. Omeprazole formulation
JP4907765B2 (en) * 1997-12-22 2012-04-04 アストラゼネカ・アクチエボラーグ Oral pharmaceutical pulse release dosage form
JP2001526211A (en) * 1997-12-22 2001-12-18 アストラゼネカ・アクチエボラーグ Oral extended release pharmaceutical dosage form
JP2001526213A (en) * 1997-12-22 2001-12-18 アストラゼネカ・アクチエボラーグ Oral drug pulse release dosage form
JP4865945B2 (en) * 1997-12-22 2012-02-01 アストラゼネカ・アクチエボラーグ Oral extended release pharmaceutical dosage form
US6855336B2 (en) 1998-08-28 2005-02-15 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6174548B1 (en) 1998-08-28 2001-01-16 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6521253B1 (en) 1998-09-03 2003-02-18 Astrazeneca Ab Immediate release tablet
US6875446B2 (en) 1998-09-03 2005-04-05 Astrazeneca Ab Method for prophylaxis and/or treatment of thromboembolism
US6316020B1 (en) * 1999-08-26 2001-11-13 Robert R. Whittle Pharmaceutical formulations
US6733778B1 (en) 1999-08-27 2004-05-11 Andrx Pharmaceuticals, Inc. Omeprazole formulation
EP1133987A1 (en) * 2000-03-09 2001-09-19 Ian Whitcroft Treatment of inflammatory dermatoses with combinations of erythromycin or clarythromycin, metronidazole and a hydrogen pump inhibitor
WO2001066117A1 (en) * 2000-03-09 2001-09-13 Ian Andrew Whitcroft Treatment of inflammatory dermatoses comprising erythromycin or clarythromycin metronidazole and a gastrointestinal hydrogen pump inhibitor
US9265730B2 (en) 2002-10-16 2016-02-23 Takeda Pharmaceutical Company Limited Stable solid preparations
EP2596792A1 (en) * 2002-10-16 2013-05-29 Takeda Pharmaceutical Company Limited Stable solid preparations
US8697094B2 (en) 2002-10-16 2014-04-15 Takeda Pharmaceutical Company Limited Stable solid preparations
US8697097B2 (en) 2002-10-16 2014-04-15 Takeda Pharmaceutical Company Limited Stable solid preparations
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
WO2006002077A3 (en) * 2004-06-15 2006-11-16 Teva Pharma Stable pharmaceutical formulations of benzimidazole compounds
WO2006002077A2 (en) * 2004-06-15 2006-01-05 Teva Pharmaceutical Industries Ltd. Stable pharmaceutical formulations of benzimidazole compounds
CN105106168A (en) * 2015-08-19 2015-12-02 德州德药制药有限公司 Esomeprazole magnesium enteric capsules and preparation method thereof

Also Published As

Publication number Publication date
KR970704426A (en) 1997-09-06
PL181265B1 (en) 2001-06-29
AU695723B2 (en) 1998-08-20
EP0768872A1 (en) 1997-04-23
NO970036L (en) 1997-01-06
EE03378B1 (en) 2001-04-16
HU9700039D0 (en) 1997-02-28
BR9508261A (en) 1997-12-23
AU2994795A (en) 1996-02-09
MX9700152A (en) 1997-04-30
PL318464A1 (en) 1997-06-09
FI970058A (en) 1997-01-07
WO1996001622A8 (en) 1999-12-23
CZ379596A3 (en) 1997-08-13
NZ289958A (en) 1998-09-24
FI970058A0 (en) 1997-01-07
SK166096A3 (en) 1997-09-10
HUT78132A (en) 2000-06-28
NO970036D0 (en) 1997-01-06
EE9700014A (en) 1997-06-16
IS4398A (en) 1996-12-17
CA2193681A1 (en) 1996-01-25

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