CA2025668C - Use of omeprazole as an antimicrobial agent - Google Patents

Abstract

Use of 5-methoxy-2-¢¢(4 methoxy-3,5-dimethyl-2-pyridinyl)methyl!-sulfinyl!-1H-be nzimidazole or a pharmaceutically acceptable salt thereof in the treatment of infectious diseases, especially such caused by Campylobacter plori.

Description

Wo90/Ogl75 PCT/SE90/04070 2025i668 use of omePrazole a5 an antimicrobial asent Field of the Invention The present invention relates to the new use of 5-metboxy-2-11~4-methoxy-3,5-dimethyl-2-pyridinyl)methyll-sulfinyll-10 lH-benzi i dazole ~generic name: omeprazole) or a salt thereof as an antimicrobial agent and more particularly as an antimicrobial agent, which is particularly active against qram-negative bacteria.

~acksround of the Invention In view of the abuse or uns~ lous use of antimicrobial drugs in the treatment of infectious diseases or for other purposes and the conse~u~t emergence of drug-resistant strains, increased incidence of microbial substitution due to disturbance of the bacterial flora, char3es in profile of infectious ~j~e~res, etc., there has been a constant de -nd for the development of new antimicrobial agents.

This application is e~p~cially directed to the treatment of infections caused by Campylobacter pylori.
Campylobacter pylori i~ a gram-negative spirilliform bacterium which co~oni~es deeply in the gastric mucosa.
Treatment with commonly u~ed antibiotics has given insufficient effect.

Prior ~rt ameprazole and its pharm~ceutic~lly acceptable ~alt~, which are used in ~ccc~dance with the invention, are known compound~, e.g. from EP 5129 and EP 124495 and can WO90/~l~5 PCT/SE90/~70 2 202~668 be produced by kr.own proceEses, for example by the process described in JAp-nese P~tent Application No. 34956/1985.

Outline of the invention The intensive research undertaken by the inventors of the present invention for accompli~ing the above-mentioned object revealed surprisingly that 5-methoxy-2-[1~4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]-sulfinyl]-lH-benzi idazole ~generic name: omeprazole) andpharmaceutically acceptable ~alts 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 ~ __ ' analogous thereto ha~ antimicrobial activity.

Predicated on the above finding, the present invention relates to an aneimicrobial agent cont~ning omeprazole or a salt thereof as an active ingredient.

The salt of omeprazole is virtually optional in kind but is preferably a ph~rmaceutically acceptable salt. Examples of such salts include inorganic salts, such as al~ali metal salts, e.g. sodium salt, potassium salt etc., ~l~al ir~ earth metai ~alts. e.g. calcium salt, ~ ium salt etc., ammonium salt, organic salts ~uch as organic amine salt~, e.g. trimetffl lamine salt, triethylamine salt, pyr~dine salt, proc~tn~ acid, picoline salt, dicyclohexylamine salt, N,N-dibenzylethyleneA~rmine salt, N-methylglucamine ~alt, diethanolamine salt, triet~ mine ~alt, tris~hydroxymethylamino)methane salt, phenylethylbonzylu~ine salt, dibenzylethylenediamine salt.

W090~0g17S PCT/SE90/ ~ 70 3 202~66~
The antimicrobial agent according to the present invention is particularly active against gram-negative bacteria, especially microaerophilic bacter$a, inter alia bacteria of the genus Campylobacter represented by C.
vvlori, and can be effectively utilized for the prevention and treatment of infectious diseases due to such bacteria in m~ -lian animals including man, cattle, horse, dog, mouse and rat, in the control and inhibition of envir. --tal pollution, or as a disinfectant.
The antimicrobial agent according to the present invention can be made available in a pha, --eu~ical formulation comprising one or more active ingredients selected from the group consisting of omeprazole and salts thereof or in lS a formulation contai n1 ng optional substances as additives (for example, a carrier).

For the treatment or p~vention of bacterial infections, for instance, the antimicrobial agent of the invention is generally administered in the form of a pha -ce~tical preparation conta~n~g omeprazole as such (i.e. the free base) or a salt thereof as an active ingredient in ~ tion with a ph- --eutically acceptable carrier by the oral, rectal or parenteral route. The carrier mentioned above may be a solid, semi-solid or liguid diluent or a caps~e. Compatible dos~s forms include various types of tablets, capsules, granules, powders, oral liguids, in~ections and so on. The pl OpG~ tions of the active ingredient in the total composition is generally O.l to lO0 weight percent and preferably O.l to 95 weight percent. In the case of an in~ectable preparation, the range of O.l to 20 weight percent is particularly pref-rr-d. In the case of a preparation for oral administration, the preferred y,o~r~ion i~ 2 to 50 w~ight ~e~nt.
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WO90/0917S PCT/SE90/~70 202~
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, _mylopectin, a cellulose derivative or gelatin, and a lubricating agent such as magnesium stearate, calcium stearate or polyethylene glycol wax may be further incGr~olated. The resulting composition i8 then compressed into tablets.
Coated tablets or dragees can be manufactured by coating the core tablets, thus prepared, with a thick sugar solution cont~ining gum arabic, gelatin, talc, titanium dioxide, etc. or a lacquor prepared using a volatile organic solvent or soIvent 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 conta;n;ng the active ingredient and a neutral oleaginous ba~e, 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 surpensions, typically a solution containing 0.2 to 20 weight percent of the active ingredient with th~e balAnce being a mixture of ~Cl~S~ witb ethanol, water, glycerol and/or propylene glycol. Opt~o~al~y, these preparations may additin~-11y contain colors, corrigents, s~cc~-rin and, a~ a t~ nor, carboxymethylcell~ se or the like.

WO90/0917S PCT/SE90/ ~ 70 202~
Injections can be manufactured in the form of aqueous solutions, typically an agueous solutlon cont~ining a pharmaceutically acceptable water-soluble salt of the active ingredient preferably in ~ c~ncentration of 0.1 to 10 weight percent. ~hese preparations may further contain a stabiliser and/or a buffer and may be provided in ampules conta~ning various unit doses.

The dosage of omeprazole or a salt thereof ~?~ on individual needs (for example, the patient's condition, body weight, age, sex, etc.) as well as on the method of - ;n~stration. 6enerally 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.

Pharmacolosical data Experiment 1 The in vitro antimicrobial activity of the active ingredient of the ~ t t invention was assayed by the following agar plate dilution method.
A loopful ~107 cells/ml) of the test s~rain cultured in ~rucella Broth cont~inin9 5~ of horse serum under 10~
carbon dioxide gas for 2 days was inoculated onto Brucella Agar cont~in~ng 5% horse lysed blood. Thi~ medium contained a varying con~ntration of omeprazole. The inoculated media were incubated at 37-C under 10~ carbon ~i~r~e gas for 2 days and the minimal inhibitory c~ ntration (MIC) wa~ determined. The result is ~et forth in Table 1. -WO90/0917S PCT/SE90/~70 202~
Table 1 Te~t organlsm MIC ~g/ml) 5 Campylobacter pylori 8005 0.39 EXAMPLES
10The 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 q 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 -g~sium stearate is added. This mixture is then compressed into tablets each cont?in;ng 25 mg ~f omeprazole. --Example 2 (capsules) omeprazole , - 9~.5 weight %
CarbG~ .thylcellulose calcium 3.7 we~ght ~
Magnesium ~tearate 1.9 wei~ht %
Llght silic~c ~ d~ide 0.9 weight %

The above ir.~,e~ent~ are mixed thoroughly and f~lled into ~n~ 6.

WO90/09195 PCT/SE90/ ~ 70 7 202~668 Ex_mple 3 (cApsules) Omeprazole sodium 93.5 weight ~
Carboxymethylcellulose ealcium 3.7 weight %
Magnesium stearate1.9 weight %
Light silicic anhydride0.9 weight %

The above ingredients are mixed thoroughly and filled into capsules in the con~entional manner.

Ex_mple 4 ~injection) Omeprazole sodium 40 mg Sterile water to a final volume of 10 ml The above ingred~ents are aseptically filled into separate vials to provide an injectable preparation.

Example 5 ~capsules) Pellets without an intermediate laYer I - Pulverized mannitol16150 9 ~ehydrated lactose 800 g ~ydIo~y~lo~,lcellulose600 g - Miolo~ e cellulose 400 g II - Omeprazole 2000 g Sodium lauryl~ulfate40 9 Disodium hydrogen ~Gs~h-t~ 80 g - ~istilled water for in~ection 4400 9 The dry ingredientc (I) are m~hanically pre-mixed and, then, a grhnulated liguid c ~ t ~ cont~in1ng omepraz~le is added. The resulting mass is kne~ed and moistened t~ a suitable viscosity. The wet mas~ is ~ esEE~ ~q means of an extruder to give spherical pellet~ whicS~ are then dried and ~.eaned for size ~election.

WO90/0917S PCT/SE90/ ~ 70 2 ~ 8 Intermediate-coated Pellets Omeprazole pellets without an intermediate layer 6000 g III - Hydroxypropylmethylcellulo~e 240 g s - Distilled water 4800 g Using a fluidized-bed eguipment, the polymer 601ution ~III) is sprayed over the pellets without an intermediate layer. In this operation, the spray gun i~ positioned over the fluidized bed.

Enteric-coated Pellets Intermediate-coated pellet6500 g IV - Hydroxypropylmethylcellulose phtbalate 57 g Cetyl alcohol 3 g Acetone 540 9 Ethanol 231 g Using a fluidized-bed e~i - t, the polymer solution (IV) is sprayed over the inte~ te-coated pellets using a spray gun positioned over the bed. After drying to a moisture content of 0.5%, the enteric-coated pellets are scleened for size selection and filled in 225 mg portions into hard gelatin c~ les. (The above amcunt cor-~s~o~e to 20 mg of omeprazole). Thirty cap-ules thus manufactured are packed into a tight container together with a des~ccant.

Claims (3)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Use of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl -2-pyridinyl)methyl)-sulflnyl-1H-benzimidazole or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of Campylobacter infections.

2. Use of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl -2-pyridinyl)methyl]-sulfinyl]-1H-benzimidazole or a pharmaceutically acceptable salt thereof for the treatment of Campylobacter infections.

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]-1H-benzimidazole or a pharmaceutically acceptable salt thereof.