WO1990009175A1 - Use of omeprazole as an antimicrobial agent - Google Patents

Use of omeprazole as an antimicrobial agent Download PDF

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Publication number
WO1990009175A1
WO1990009175A1 PCT/SE1990/000070 SE9000070W WO9009175A1 WO 1990009175 A1 WO1990009175 A1 WO 1990009175A1 SE 9000070 W SE9000070 W SE 9000070W WO 9009175 A1 WO9009175 A1 WO 9009175A1
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WO
WIPO (PCT)
Prior art keywords
omeprazole
salt
methoxy
treatment
antimicrobial agent
Prior art date
Application number
PCT/SE1990/000070
Other languages
French (fr)
Inventor
Masaaki Tomoi
Yoshifumi Ikeda
Yoshiko Yokota
Original Assignee
Aktiebolaget Hässle
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
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Application filed by Aktiebolaget Hässle filed Critical Aktiebolaget Hässle
Priority to AT90902854T priority Critical patent/ATE94063T1/en
Priority to EP90902854A priority patent/EP0414847B1/en
Priority to KR1019900702221A priority patent/KR0140236B1/en
Priority to CY190990A priority patent/CY1909A/en
Publication of WO1990009175A1 publication Critical patent/WO1990009175A1/en
Priority to LVP-94-169A priority patent/LV10577B/en
Priority to HK52196A priority patent/HK52196A/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • omeprazole as an antimicrobial agent
  • the present invention relates to the new use of 5-methoxy- 2-[ t (4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]- lH-benzimidazole (generic name: omeprazole) or a salt thereof as an antimicrobial agent and more particularly as an antimicrobial agent, which is particularly active against gram-negative bacteria.
  • Campylobacter pylori is a gram-negative spirilliform bacterium which colonises deeply in the gastric mucosa. Treatment with commonly used antibiotics has given insufficient effect.
  • Omeprazole and its pharmaceutically acceptable salts which are used in accordance with the invention, are known compounds, e.g. from EP 5129 and EP 124495 and can be produced by known processes, for example by the process described in Japanese Patent Application No. 34956/1985.
  • the present invention relates to an antimicrobial agent containing omeprazole or a salt thereof as an active ingredient.
  • the salt of omeprazole is virtually optional in kind but is preferably a pharmaceutically acceptable salt.
  • examples of such salts include inorganic salts, such as alkali metal salts, e.g. sodium salt, potassium salt etc., alkaline earth metal salts, e.g. calcium salt, magnesium salt etc., ammonium salt, organic salts such as organic amine salts, e.g.
  • the antimicrobial agent according to the present invention is particularly active against gram-negative bacteria, especially microaerophilic bacteria, inter alia bacteria of the genus Campylobacter represented by C. pylori, and can be effectively utilized for the prevention and treatment of infectious diseases due to such bacteria in mammalian animals including man, cattle, horse, dog, mouse and rat, in the control and inhibition of environmental pollution, or as a disinfectant.
  • the antimicrobial agent according to the present invention can be made available in a pharmaceutical formulation comprising one or more active ingredients selected from the group consisting of omeprazole and salts thereof or in a formulation containing optional substances as additives (for example, a carrier).
  • the antimicrobial agent of the invention is generally administered in the form of a pharmaceutical preparation containing omeprazole as such (i.e. the free base) or a salt thereof as an active ingredient in combination with a pharmaceutically acceptable carrier by the oral, rectal or parenteral route.
  • a pharmaceutical preparation containing omeprazole as such (i.e. the free base) or a salt thereof as an active ingredient in combination with a pharmaceutically acceptable carrier by the oral, rectal or parenteral route.
  • the carrier mentioned above may be a solid, semi-solid or liquid diluent or a capsule.
  • Compatible dosage forms include various types of tablets, capsules, granules, powders, oral liquids, injections and so on.
  • the proportions of the active ingredient in the total composition is generally 0.1 to 100 weight percent and preferably 0.1 to 95 weight percent. In the case of an injectable preparation, the range of 0.1 to 20 weight percent is particularly preferred.
  • the preferred proportion is 2 to 50 weight percent.
  • the active ingredient can be formulated with a solid particulate carrier such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, a cellulose derivative or gelatin, and a lubricating agent such as magnesium stearate, calcium stearate or polyethylene glycol wax may be further incorporated.
  • a lubricating agent such as magnesium stearate, calcium stearate or polyethylene glycol wax may be further incorporated.
  • the resulting composition is then compressed into tablets.
  • Coated tablets or dragees can be manufactured by coating the core tablets, thus prepared, with a thick sugar solution containing gum arabic, gelatin, talc, titanium dioxide, etc. or a lacquor prepared using a volatile organic solvent or solvent mixture.
  • Soft gelatin capsules can be manufactured by filling a composition comprising the active ingredient and a known vegetable oil into capsules.
  • Hard gelatin capsules can be manufactured by filling into capsules the granules or pellets each comprising the active ingredient and a solid particulate carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, a cellulose derivative or gelatin.
  • Preparations for rectal administration are preferably suppositories containing the active ingredient and a neutral oleaginous base, gelatin capsules for rectal administration which contain the active ingredient and a vegetal oil or paraffin oil, and rectal ointments.
  • Liquid preparations for oral administration can be syrups or suspensions, typically a solution containing 0.2 to 20 weight percent of the active ingredient with the balance being a mixture of sucrose with ethanol, water, glycerol and/or propylene glycol.
  • these preparations may additionally contain colors, corrigents, saccharin and, as a thickener, carboxymethylcellulose or the like.
  • Injections can be manufactured in the form of aqueous solutions, typically an aqueous solution containing a pharmaceutically acceptable water-soluble salt of the active ingredient preferably in a concentration of 0.1 to 10 weight percent.
  • These preparations may further contain a stabilizer and/or a buffer and may be provided in ampules containing various unit doses.
  • omeprazole or a salt thereof depends on individual needs (for example, the patient's condition, body weight, age, sex, etc.) as well as on the method of •administration.
  • the oral dosage may range from 1 to 400 mg as active ingredient per day per adult human and the intravenous dosage may range from 1 to 200 mg per day per adult human, and each may be administered in one to a few divided doses.
  • the in vitro antimicrobial activity of the active ingredient of the present invention was assayed by the following agar plate dilution method.
  • Test organism MIC ( ⁇ g/ l)
  • Example 2 (capsules) Omeprazole 93.5 weight % Carboxymethylcellulose calcium 3.7 weight % Magnesium stearate 1.9 weight % Light silicic anhydride 0.9 weight %
  • Example 3 capsules
  • the above ingredients are mixed thoroughly and filled into capsules in the conventional manner.
  • the above ingredients are aseptically filled into separate vials to provide an injectable preparation.
  • the dry ingredients (I) are mechanically pre-mixed and, then, a granulated liquid component (II) containing omeprazole is added.
  • the resulting mass is kneaded and moistened to a suitable viscosity.
  • the wet mass is processed by means of an extruder to give spherical pellets which are then dried and screened for size selection.
  • the polymer solution (III) is sprayed over the pellets without an intermediate layer.
  • the spray gun is positioned over the fluidized bed.
  • the polymer solution (IV) is sprayed over the intermediate-coated pellets using a spray gun positioned over the bed. After drying to a moisture content of 0.5%, the enteric-coated pellets are screened for size selection and filled in 225 mg portions into hard gelatin capsules. (The above amount corresponds to 20 mg of omeprazole). Thirty capsules thus manufactured are packed into a tight container together with a desiccant.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Use of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-1H-benzimidazole or a pharmaceutically acceptable salt thereof in the treatment of infectious diseases, especially such caused by Campylobacter pylori.

Description

Use of omeprazole as an antimicrobial agent
Field of the Invention
The present invention relates to the new use of 5-methoxy- 2-[ t (4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]- lH-benzimidazole (generic name: omeprazole) or a salt thereof as an antimicrobial agent and more particularly as an antimicrobial agent, which is particularly active against gram-negative bacteria.
Background of the Invention
In view of the abuse or unscrupulous use of antimicrobial drugs in the treatment of infectious diseases or for other purposes and the consequent emergence of drug-resistant strains, increased incidence of microbial substitution due to disturbance of the bacterial flora, changes in profile of infectious diseases, etc., there has been a constant demand for the development of new antimicrobial agents.
This application is especially directed to the treatment of infections caused by Campylobacter pylori. Campylobacter pylori is a gram-negative spirilliform bacterium which colonises deeply in the gastric mucosa. Treatment with commonly used antibiotics has given insufficient effect.
Prior art
Omeprazole and its pharmaceutically acceptable salts, which are used in accordance with the invention, are known compounds, e.g. from EP 5129 and EP 124495 and can be produced by known processes, for example by the process described in Japanese Patent Application No. 34956/1985.
Outline of the invention
The intensive research undertaken by the inventors of the present invention for accomplishing the above-mentioned object revealed surprisingly that 5-methoxy-2-[ [ (4- methoxy-3,5-dimethyl-2-pyridinyl)methyl]-s lfinyl]-lH- benzimidazole (generic name: omeprazole) and pharmaceutically acceptable salts thereof, which are known to have gastric antisecretory activity known to be an antiulcer drug have excellent antimicrobial activity as well.
Heretofore, it has never been known that omeprazole or any compound analogous thereto has antimicrobial activity.
Predicated on the above finding, the present invention relates to an antimicrobial agent containing omeprazole or a salt thereof as an active ingredient.
The salt of omeprazole is virtually optional in kind but is preferably a pharmaceutically acceptable salt. Examples of such salts include inorganic salts, such as alkali metal salts, e.g. sodium salt, potassium salt etc., alkaline earth metal salts, e.g. calcium salt, magnesium salt etc., ammonium salt, organic salts such as organic amine salts, e.g. trimethylamine salt, triethylamine salt, pyridine salt, procaine acid, picoline salt, dicyclohexylamine salt, N,N-dibenzylethylenediamine salt, N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino)methane salt, phenylethylbenzylamine salt, dibenzylethylenediamine salt. The antimicrobial agent according to the present invention is particularly active against gram-negative bacteria, especially microaerophilic bacteria, inter alia bacteria of the genus Campylobacter represented by C. pylori, and can be effectively utilized for the prevention and treatment of infectious diseases due to such bacteria in mammalian animals including man, cattle, horse, dog, mouse and rat, in the control and inhibition of environmental pollution, or as a disinfectant.
The antimicrobial agent according to the present invention can be made available in a pharmaceutical formulation comprising one or more active ingredients selected from the group consisting of omeprazole and salts thereof or in a formulation containing optional substances as additives (for example, a carrier).
For the treatment or prevention of bacterial infections, for instance, the antimicrobial agent of the invention is generally administered in the form of a pharmaceutical preparation containing omeprazole as such (i.e. the free base) or a salt thereof as an active ingredient in combination with a pharmaceutically acceptable carrier by the oral, rectal or parenteral route. The carrier mentioned above may be a solid, semi-solid or liquid diluent or a capsule. Compatible dosage forms include various types of tablets, capsules, granules, powders, oral liquids, injections and so on. The proportions of the active ingredient in the total composition is generally 0.1 to 100 weight percent and preferably 0.1 to 95 weight percent. In the case of an injectable preparation, the range of 0.1 to 20 weight percent is particularly preferred. In the case of a preparation for oral administration, the preferred proportion is 2 to 50 weight percent. In the manufacture of a pharmaceutical preparation for oral administration, the active ingredient can be formulated with a solid particulate carrier such as lactose, sucrose, sorbitol, mannitol, starch, amylopectin, a cellulose derivative or gelatin, and a lubricating agent such as magnesium stearate, calcium stearate or polyethylene glycol wax may be further incorporated. The resulting composition is then compressed into tablets. Coated tablets or dragees can be manufactured by coating the core tablets, thus prepared, with a thick sugar solution containing gum arabic, gelatin, talc, titanium dioxide, etc. or a lacquor prepared using a volatile organic solvent or solvent mixture.
Soft gelatin capsules can be manufactured by filling a composition comprising the active ingredient and a known vegetable oil into capsules. Hard gelatin capsules can be manufactured by filling into capsules the granules or pellets each comprising the active ingredient and a solid particulate carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, amylopectin, a cellulose derivative or gelatin.
Preparations for rectal administration are preferably suppositories containing the active ingredient and a neutral oleaginous base, gelatin capsules for rectal administration which contain the active ingredient and a vegetal oil or paraffin oil, and rectal ointments.
Liquid preparations for oral administration can be syrups or suspensions, typically a solution containing 0.2 to 20 weight percent of the active ingredient with the balance being a mixture of sucrose with ethanol, water, glycerol and/or propylene glycol. Optionally, these preparations may additionally contain colors, corrigents, saccharin and, as a thickener, carboxymethylcellulose or the like. Injections can be manufactured in the form of aqueous solutions, typically an aqueous solution containing a pharmaceutically acceptable water-soluble salt of the active ingredient preferably in a concentration of 0.1 to 10 weight percent. These preparations may further contain a stabilizer and/or a buffer and may be provided in ampules containing various unit doses.
The dosage of omeprazole or a salt thereof depends on individual needs (for example, the patient's condition, body weight, age, sex, etc.) as well as on the method of •administration. Generally speaking, the oral dosage may range from 1 to 400 mg as active ingredient per day per adult human and the intravenous dosage may range from 1 to 200 mg per day per adult human, and each may be administered in one to a few divided doses.
Pharmacological data
Experiment 1
The in vitro antimicrobial activity of the active ingredient of the present invention was assayed by the following agar plate dilution method.
7 A loopful (10 cells/ml) of the test strain cultured in
Brucella Broth containing 5% of horse serum under 10% carbon dioxide gas for 2 days was inoculated onto Brucella Agar containing 5% horse lysed blood. This medium contained a varying concentration of omeprazole. The inoculated media were incubated at 37°C under 10% carbon dioxide gas for 2 days and the minimal inhibitory concentration (MIC) was determined. The result is set forth in Table 1. Table 1
Test organism MIC (μg/ l)
Campylobacter pylori 8005 0.39
EXAMPLES
The following examples are intended to illustrate the antimicrobial agent of the invention in further detail and should by no means be constructed as limiting the scope of the invention.
Example 1 (25 mg tablets)
Omeprazole 250 g
Lactose 175.8 g
Corn starch 169.7 g
The above ingredients are mixed and wetted with 10% gelatin solution, and the wet mixture is sieved through a 12-mesh screen and pulverized. The resulting powder is dried and magnesium stearate is added. This mixture is then compressed into tablets each containing 25 mg of omeprazole.
Example 2 (capsules) Omeprazole 93.5 weight % Carboxymethylcellulose calcium 3.7 weight % Magnesium stearate 1.9 weight % Light silicic anhydride 0.9 weight %
The above ingredients are mixed thoroughly and filled into capsules. Example 3 (capsules)
Omeprazole sodium 93.5 weight %
Carboxymethylcellulose calcium 3.7 weight %
Magnesium stearate 1.9 weight % Light silicic anhydride 0.9 weight %
The above ingredients are mixed thoroughly and filled into capsules in the conventional manner.
Example 4 (injection)
Omeprazole sodium 40 mg
Sterile water to a final volume of 10 ml
The above ingredients are aseptically filled into separate vials to provide an injectable preparation.
Example 5 (capsules)
Pellets without an intermediate layer I - Pulverized mannitol 16150 g
Dehydrated lactose 800 g
Hydroxypropylcelluloεe 600 g
- Microcrystalline cellulose 400 g II - Omeprazole 2000 g Sodium laurylsulfate 40 g
Disodiu hydrogen phosphate 80 g
- Distilled water for injection 4400 g
The dry ingredients (I) are mechanically pre-mixed and, then, a granulated liquid component (II) containing omeprazole is added. The resulting mass is kneaded and moistened to a suitable viscosity. The wet mass is processed by means of an extruder to give spherical pellets which are then dried and screened for size selection. Intermediate-coated pellets
Omeprazole pellets without an intermediate layer 6000 g
III - Hydroxypropylmethylcellulose 240 g - Distilled water 4800 g
Using a fluidized-bed equipment, the polymer solution (III) is sprayed over the pellets without an intermediate layer. In this operation, the spray gun is positioned over the fluidized bed.
Enteric-coated pellets
Intermediate-coated pellets 500 g
IV - Hydroxypropylmethylcellulose phthalate 57 g
Cetyl alcohol 3 g
Acetone 540 g
Ethanol 231 g
Using a fluidized-bed equipment, the polymer solution (IV) is sprayed over the intermediate-coated pellets using a spray gun positioned over the bed. After drying to a moisture content of 0.5%, the enteric-coated pellets are screened for size selection and filled in 225 mg portions into hard gelatin capsules. (The above amount corresponds to 20 mg of omeprazole). Thirty capsules thus manufactured are packed into a tight container together with a desiccant.

Claims

1. Use of 5-methoxy-2-[[ (4-methoxy-3,5-dimethγl-2- . pyridinyl)methyl]-sulfinyl]-lH-benzimidazole or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of Campylobacter infections.
2. A method for the treatment of Campylobacter in ections comprising administering to a patient suffering therefrom an amount of 5-methoxy-2-[ [(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]-sulfinyl]-lH-benzimidazole or a pharmaceutically acceptable salt thereof sufficient for the treatment of said infection.
3. A pharmaceutical preparation for use in the treatment of Campylobacter infections wherein the active ingredient is 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]-sulfinyl]-lH-benzimidazole or a pharmaceutically acceptable salt thereof.
PCT/SE1990/000070 1989-02-09 1990-02-02 Use of omeprazole as an antimicrobial agent WO1990009175A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AT90902854T ATE94063T1 (en) 1989-02-09 1990-02-02 USE OF OMEPRAZOLE AS AN ANTMICROBIAL AGENT.
EP90902854A EP0414847B1 (en) 1989-02-09 1990-02-02 Use of omeprazole as an antimicrobial agent
KR1019900702221A KR0140236B1 (en) 1989-02-09 1990-02-02 Use of omeprazole as an antimicrobial agent
CY190990A CY1909A (en) 1989-02-09 1990-02-02 Use of omeprazole as an antimicrobial agent
LVP-94-169A LV10577B (en) 1989-02-09 1994-08-30 Use of omeprazole as an antimicrobal agent
HK52196A HK52196A (en) 1989-02-09 1996-03-21 Use of omeprazole as an antimicrobial agent

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP1/30311 1989-02-09
JP1030311A JP2694361B2 (en) 1989-02-09 1989-02-09 Antibacterial agent

Publications (1)

Publication Number Publication Date
WO1990009175A1 true WO1990009175A1 (en) 1990-08-23

Family

ID=12300238

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE1990/000070 WO1990009175A1 (en) 1989-02-09 1990-02-02 Use of omeprazole as an antimicrobial agent

Country Status (19)

Country Link
US (1) US5093342A (en)
EP (1) EP0414847B1 (en)
JP (1) JP2694361B2 (en)
KR (1) KR0140236B1 (en)
AT (1) ATE94063T1 (en)
AU (1) AU626641B2 (en)
CA (1) CA2025668C (en)
CY (1) CY1909A (en)
DE (1) DE69003207T2 (en)
DK (1) DK0414847T3 (en)
ES (1) ES2058892T3 (en)
HK (1) HK52196A (en)
HU (1) HU205253B (en)
IE (1) IE65814B1 (en)
IL (1) IL93263A0 (en)
LV (1) LV10577B (en)
MY (1) MY111737A (en)
PH (1) PH26787A (en)
WO (1) WO1990009175A1 (en)

Cited By (9)

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EP0382489A2 (en) * 1989-02-10 1990-08-16 Takeda Chemical Industries, Ltd. Use of benzimidazole derivatives as antibacterial agents
WO1992003135A1 (en) * 1990-08-24 1992-03-05 Byk Gulden Lomberg Chemische Fabrik Gmbh Pharmaceutical compositions containing 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl) methylsulfinyl] benzimidazole and an anti-helicobacter agent for the treatment of gastrointestinal disorders
WO1992004898A1 (en) * 1990-09-14 1992-04-02 Byk Gulden Lomberg Chemische Fabrik Gmbh Use of pyridylmethylsulphinyl-1h-benzimidazole derivates in the treatment of illnesses caused by helicobacter bacteria
WO1993021920A1 (en) * 1992-04-24 1993-11-11 Astra Aktiebolag Synergistic combination of a substance with gastric acid secretion inhibiting effect and an acid degradable antibiotic
WO1994013290A1 (en) * 1992-12-10 1994-06-23 Byk Gulden Lomberg Chemische Fabrik Gmbh Use of alkylthiopyridines for controlling helicobacter bacteria
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US6673819B2 (en) 2000-06-30 2004-01-06 Astrazeneca Ab Compounds useful as antibacterial agents
US7399772B2 (en) 1996-01-04 2008-07-15 Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same

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US6268385B1 (en) 1999-08-26 2001-07-31 Robert R. Whittle Dry blend pharmaceutical formulations
US6369087B1 (en) 1999-08-26 2002-04-09 Robert R. Whittle Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
US6262085B1 (en) 1999-08-26 2001-07-17 Robert R. Whittle Alkoxy substituted Benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
US6780880B1 (en) * 1999-08-26 2004-08-24 Robert R. Whittle FT-Raman spectroscopic measurement
US6312723B1 (en) 1999-08-26 2001-11-06 Robert R. Whittle Pharmaceutical unit dosage form
US6262086B1 (en) 1999-08-26 2001-07-17 Robert R. Whittle Pharmaceutical unit dosage form
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AU626641B2 (en) 1992-08-06
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LV10577B (en) 1995-10-20
EP0414847A1 (en) 1991-03-06
CY1909A (en) 1990-02-02
ATE94063T1 (en) 1993-09-15
CA2025668C (en) 1998-09-15
DE69003207T2 (en) 1994-02-03
EP0414847B1 (en) 1993-09-08
AU5038190A (en) 1990-09-05
HK52196A (en) 1996-03-29
HU901539D0 (en) 1991-02-28
LV10577A (en) 1995-04-20
KR910700048A (en) 1991-03-13
IE900418L (en) 1990-08-09
IL93263A0 (en) 1990-11-29
DE69003207D1 (en) 1993-10-14
CA2025668A1 (en) 1990-08-10
PH26787A (en) 1992-10-13
MY111737A (en) 2000-12-30
HU205253B (en) 1992-04-28
US5093342A (en) 1992-03-03
JP2694361B2 (en) 1997-12-24
DK0414847T3 (en) 1993-12-13
ES2058892T3 (en) 1994-11-01

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