Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-12-15
2001-08-14
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S468000, C424S475000, C424S482000, C424S494000, C424S495000, C424S497000, C514S772200, C514S772300, C514S781000
Reexamination Certificate
active
06274173
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to oral pharmaceutical compositions in pellet or tablet form for combined use of pantoprazole with an antimicrobially-active ingredient for the treatment of disorders caused by Helicobacter.
BACKGROUND
Pyridin-2-ylmethylsulfinyl-1H-benzimidazoles, as disclosed, for example, in EP-A 0005129, EP-A 0166287 and EP-A 0268956 are becoming increasingly important, because of their H
+
/K
+
ATPase-inhibiting action, for the therapy of diseases which originate from increased gastric acid secretion. Examples of active ingredients which are already commercially available from this group are omeprazole (INN), lansoprazole (INN) and pantoprazole (INN). These active ingredients are also called acid-labile irreversible proton pump inhibitors.
Control of the microbe, Helicobacter pylori, which is thought to be responsible for certain gastric disorders, by combined use of an antimicrobially-active ingredient which is active against Helicobacter pylori and of an agent which reduces gastric acid has been regarded as the method of choice for some time.
EP-A 0519365 proposes (for the active ingredient pantoprazole) a formulation based on the principle of an alkaline core coated with a water-soluble intermediate layer and with an enteric layer, where improved stability is achieved by using polyvinylpyrrolidone and/or hydroxypropylmethylcellulose as binder for the alkaline core.
EP-A 0342522 discloses a formulation for acid-sensitive benzimidazoles, in which an intermediate layer is located between the alkaline core and the enteric coating and is composed of a film-forming material which has only low solubility in water, such as ethylcellulose and polyvinyl acetate, and of a fine-particle inorganic or organic material which is suspended therein and has low solubility in water, such as magnesium oxide, silicon oxide or sucrose fatty acid esters.
JP-A 59020219 discloses an enteric composition for acid-labile active ingredients which comprises (under the enteric coating) an intermediate layer of a film-forming material, such as hydroxypropylmethylcellulose, hydroxypropylcellulose and hydroxypropylmethylcellulose phthalate with a content of higher fatty acids.
DE-A 3233764 proposes for enteric composition an intermediate layer which is formed from a water-soluble cellulose ether and a water-soluble mono- or polybasic organic acid, such as citric acid, tartaric acid, and the like.
Combined use of irreversible proton pump inhibitors with antimicrobially-active ingredients does indeed show a good effect against Helicobacter in vitro. However, the clinical effect achieved with this combined use is disappointing. Of practical inconvenience is the great delay in the onset of action.
SUMMARY OF THE INVENTION
The action of an antimicrobially-active ingredient on Helicobacter surprisingly is enhanced by administering pantoprazole in slow-release dosage form (extended release form). It must be regarded as particularly surprising that, in addition, administration of the slow-release pantoprazole results in the onset of action taking place significantly faster than on administration in a form without retarding such release. The duration of treatment until Helicobacter is eradicated is shortened, saving considerable amounts of antibiotic and acid inhibitor.
The invention thus relates to oral pharmaceutical compositions in pellet or tablet form for combined use of pantoprazole with an antimicrobially-active ingredient for treatment of disorders caused by Helicobacter, wherein pantoprazole is present at least partly in slow-release form.
The invention also relates to an oral pharmaceutical composition in pellet or tablet form for acid-labile irreversible proton pump inhibitors comprising an alkaline pellet or tablet core, at least one release-slowing, release-controlling intermediate layer and an outer enteric layer which is soluble in the small intestine, wherein the intermediate layer for the pharmaceutical composition is formed from a water-insoluble film former, the film former being applied from anhydrous solution or aqueous dispersion.
As noted in the Background, commercially available acid-labile irreversible proton pump inhibitors other than pantoprazole, such as omeprazole (INN) and lansoprazole (INN), are known.
DETAILS
In connection with the present invention, pantoprazole is the compound, 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole, its salts and solvates (e.g. hydrates), in particular the sodium salt with one and a half molecules of water of crystallization (pantoprazole Na×1.5 H
2
O).
Examples of suitable antimicrobially-active ingredients (active against Helicobacter and, in particular, against Helicobacter pylori) are enumerated in European Patent Application EP-A 0282131. These active ingredients include, for example, bismuth salts (such as bismuth subcitrate or bismuth subsalicylate), sulfonamides, nitrofurans (such as nitrofurazone, nitrofurantoin or furazolidone), metronidazole, tinidazole, nimorazole or antibiotics. Examples of antibiotics which may be mentioned in this connection are, arranged according to particular classes of active ingredient: aminoglycosides, such as gentamicin, neomycin, kanamycin, amikacin or streptomycin; macrolides, such as erythromycin, azithromycin, clarithromycin, clindamycin or rifampicin; penicillins, such as penicillin G, penicillin V, ampicillin, mezlocillin or amoxicillin; polypeptides, such as bacitracin or polymyxin; tetracyclines, such as tetracycline, chlorotetracycline, oxytetracycline, minocycline or doxycycline; carbapenems, such as imipenem, loracarbef, meropenem or panipenem; cephalosporins, such as cefalexin, cefoxitin, cefuroxime axetil, cefotaxime, cefpodoxim proxetil, cefaclor, cefadroxil or cephalothin; gyrase inhibitors, such as ciprofloxacin, norfloxacin, ofloxacin or pefloxacin, or other different antibiotics, such as chloramphenicol.
Particularly worth of mention in this connection is also the conjoint administration of pantoprazole with a plurality of antimicrobially-active ingredients, for example with a combination of bismuth salt and/or tetracycline with metronidazole, or with the combination of amoxicillin or clarithromycin with metronidazole.
Antimicrobially-active ingredients which may be emphasized are erythromycin, azithromycin, clarithromycin, clindamycin, rifampicin, ampicillin, mezlocillin, amoxicillin, tetracycline, minocycline, doxycycline, imipenem, meropenem, cefalexin, cefuroxime axetil, cefpodoxime proxetil, cefaclor, cefadroxil, ciprofloxacin, norfloxacin, ofloxacin and pefloxacin.
Clarithromycin and amoxicillin may be mentioned as antimicrobially-active ingredients which should be particularly emphasized.
Combined administration means, for the purpose of the present invention, fixed and, in particular, free combinations, i.e. either slow-release pantoprazole and the antimicrobially-active ingredient are present together in one dosage unit, or slow-release pantoprazole and antimicrobially-active ingredient, which are present in separate dosage units, are administered in direct succession or at a relatively large time interval; a relatively large time interval means a time span up to a maximum of 24 hours. For use as separate dosage units, these are preferably made available together in one pack. For example, the two dosage units are packed together in blister packs which are designed with regard to the relative arrangement of the two dosage units with respect to one another, the inscription and/or coloring in a manner known per se so that the time for taking the individual components (dosage regimen) of the two dosage units are evident to a patient.
A dosage unit means, in particular, a medicinal dosage form in which slowing of pantoprazole release is achieved with as few problems as possible. This includes, in particular, tablets, coated tablets or pellets, and microtablets in capsules, with the dosage form advantageously being designed so that the two active-ingredient components (pantoprazole on the one hand a
Dietrich Rango
Sachs George
ByK Gulden Lomberg Chemische Fabrik GmbH
Jacobson & Holman PLLC
Spear James M.
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