WO2005011691A1

WO2005011691A1 - Improved binding of pantoprazole to the proton pump

Info

Publication number: WO2005011691A1
Application number: PCT/US2004/024679
Authority: WO
Inventors: Richard J. Heaslip
Original assignee: Altana Pharma Ag
Priority date: 2003-07-31
Filing date: 2004-07-30
Publication date: 2005-02-10

Abstract

The present invention relates to a certain form of pantoprazole, which selectively binds to the proton pump, thus improving the degree and the duration of acid inhibition.

Description

Improved binding of pantoprazole to the proton pump

Subject-matter of the invention

The present invention relates to a certain form of pantoprazole, which selectively binds to the H⁺/K⁺- ATPase (proton pump), thus improving the degree and the duration of acid inhibition.

Background of the invention

Owing to their H⁺/K⁺-ATPase-iπhibitory action, pyridin-2-ylmethylsulphinyl-1 H-benzimidazoles, such as those known, for example, from EP-A-0005129, EP-A-0166287, EP-A-0174726 and EP-A-0268956 are of considerable importance in the therapy of disorders associated with an increased secretion of gastric acid.

Examples of active compounds from this group which are commercially available or in clinical development are 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole (INN: omeprazole), (S)-5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole (INN: esomeprazole), 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole (INN: pantoprazole), 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulphinyl]-1 H- benzimidazole (INN: lansoprazole), 2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulphinyl}-1 H- benzimidazole (INN: rabeprazole) and 5-methoxy-2-((4-methoxy-3,5-dimethyl-2- pyridylmethyl)sulphinyl)-1 H-imidazo[4,5-b]pyridine (INN: tenatoprazole).

Description of the related art

The abovementioned sulphinyl derivatives which, owing to their mechanism of action, are also referred to as proton pump inhibitors or, abbreviated, as PPIs, have revolutionized the management of acid- related disorders. The understanding of these agents has grown in recent years, so that the relationship between structure, binding, and functionality (i. e., suppression of acid secretion) is becoming clearer. PPIs are weak bases that undergo accumulation in the acidic space of the secreting parietal cell and are converted there to the active form of the drugs, which forms disulfide bonds with key cys- teines (cys) of the H⁺, K⁺-ATPase. Between the different PPIs exist differences with regard to the formation and with regard to the stability of these disulfide bonds. Experiments conducted by George Sachs et al. (e. g. Am J Gastroenterol. 2001 ; 96(9):S71 , Abstr 223; J Biol Chem. 1997; 272:22438- 22446) showed for pantoprazole a binding profile which is likely to be related to the unique binding of this compound compared with other PPIs. Whereas omeprazole and other PPI's bind only to cys 813 as well as cys 321 in the case of lansoprazole, pantoprazole binds to two cysteines in the proton transport pathway of the pump, cys 813 and cys 822. Cys 822 is a unique binding site, to which only panto- prazole binds, that is buried deep within the membrane domain of the pump, in contrast to the other cysteines that are exposed on the exoplasmic surface. In contrast to cys 321 or cys 813, cys 822 seems to be inaccessible to reducing agents, such as glutathioπe, in vitro and in vivo and this may explain the longer lasting inhibition of acid secretion by pantoprazole.

There have been attempts to obtain PPI forms with less side effects or with more uniform pharmaco- kinetic properties by separating the PPIs, which are chiral compounds, into their enantiomers. However, there have been no published attempts up to now to find PPI forms which favor one cys binding site compared to another cys binding site. In particular, there have been no attempts up to now to find forms of pantoprazole, which favor the cys 822 binding site compared to the cys 813 binding site, thus leading to an even longer lasting inhibition of acid secretion. .

Description of the invention

It has now been found, surprisingly, that a certain form of pantoprazole exists, which - as compared with the racemic pantoprazole currently used in therapy - binds more selectively and to a higher degree to cys 822 than to cys 813. The certain form of pantoprazole according to the invention is (-)- pantoprazole. The name (-)-pantoprazole is synonym for (S)-pantoprazole.

Accordingly, the invention provides a method of inhibiting gastric acid secretion in a human by selectively blocking cysteine 822 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid, which comprises administering (-)-pantoprazole, substantially free of the (+)-enantiomer, or a pharmaceutically acceptable salt thereof to the human in need of such therapy.

The invention likewise provides a method of inhibiting gastric acid secretion in a human by primarily blocking cysteine 822 instead of cysteine 813 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid, which comprises administering (- )-paπtoprazole, substantially free of the (+)-enantiomer, or a pharmaceutically acceptable salt thereof to the human in need of such therapy.

The invention further provides a method of inhibiting gastric acid secretion in a human for an extended period of time by selectively blocking cysteine 822 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid, which comprises administering (-)-pantoprazole, substantially free of the (+)-enantiomer, or a pharmaceutically acceptable salt thereof to the human in need of such therapy.

The invention additionally provides a method of inhibiting gastric acid secretion in a human for an extended period of time by primarily blocking cysteine 822 instead of cysteine 813 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid, which comprises administering (-)-pantoprazole, substantially free of the (-t-)-enaπtiomer, or a pharmaceutically acceptable salt thereof to the human in need of such therapy.

A further aspect of the present invention is a pharmaceutical composition intended for inhibiting gastric acid secretion in a human by selectively blocking cysteine 822 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid, which comprises (-)-pantoprazole, substantially free of the (+)-enantiomer, or a pharmaceutically acceptable salt thereof together with a carrier.

The invention further encompasses a pharmaceutical composition intended for inhibiting gastric acid secretion in a human by primarily blocking cysteine 822 instead of cysteine ^'813 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid, which comprises (-)-pantoprazole, substantially free of the (+)-enantiomer, or a pharmaceutically acceptable salt thereof together with a carrier.

In addition, the invention encompasses a pharmaceutical composition intended for inhibiting gastric acid secretion in a human for an extended period of time by selectively blocking cysteine 822 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid, which comprises (-)-pantoprazole, substantially free of the (+)-enantiomer, or a pharmaceutically acceptable salt thereof together with a carrier.

In addition, the invention encompasses a pharmaceutical composition intended for inhibiting gastric acid secretion in a human for an extended period of time by primarily blocking cysteine 822 instead of cysteine 813 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid, which comprises (-)-pantoprazole, substantially free of the (+)- enantiomer, or a pharmaceutically acceptable salt thereof together with a carrier.

A further aspect of the present invention is the use of (-)-pantoprazole, substantially free of the (+)- enantiomer, or a pharmaceutically acceptable salt thereof for the production of a medicament intended for inhibiting gastric acid secretion in a human by selectively blocking cysteine 822 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid.

The invention further encompasses the use of (-)-pantoprazole, substantially free of the (+)- enantiomer, or a pharmaceutically acceptable salt thereof for the production of a medicament intended for inhibiting gastric acid secretion in a human by primarily blocking cysteine 822 instead of cysteine 813 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid.

In addition, the invention encompasses the use of (-)-pantoprazole, substantially free of the (+)- enantiomer, or a pharmaceutically acceptable salt thereof for the production of a medicament intended for inhibiting gastric acid secretion in a human for an extended period of time by selectively blocking cysteine 822 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid.

In addition, the invention encompasses the use of (-)-pantoprazole, substantially free of the (+)- enantiomer, or a pharmaceutically acceptable salt thereof for the production of a medicament intended for inhibiting gastric acid secretion in a human for an extended period of time by primarily blocking cysteine 822 instead of cysteine 813 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid.

In the context of the invention, it is necessary to provide (-)-pantoprazole, substantially free of the (+)- enantiomer, in a form, which is suited to be incorporated in a pharmaceutical formulation, which meets the requirements of the health authorities with regard to stability, bio-availability, safety etc..

For the first time, the international patent application WO92/08716 describes a chemical process which allows pyridiπ-2-ylmethylsulphinyl-1H-benzimidazoles to be separated into their optical antipodes. The compounds mentioned as being prepared in an exemplary manner include, inter alia, the compounds (+)- and (-)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole [= (+)- and (-)-pantoprazole]. The international patent application WO92/08716 mentions that the optical antipodes of the pyridin-2-ylmethylsulphinyl-1H-benzimidazoles, i.e. the (+)- and (-)-enantiomers or the (R)- and (S)-enantiomers, are useful as active compounds in medicaments for the treatment of gastrointestinal disorders. For the mode of application and the dosage of the active compounds, reference is made, inter alia, to the European patent 166 287.

The international patent applications W094/24867 and WO94/25028 claim the use of the compounds (-)- and (-t-)-pantoprazole for treating gastric disorders in humans. Each stereo isomer is said to have medical advantages compared to the respective other stereoisomer. The descriptions also mention a number of different possible salts of the stereo isomers, and particular preference is given to the sodium salt.

The international patent application WO00/10995 describes the dihydrate of the magnesium salt of racemic pantoprazole.

A common property of all of the abovementioned PPI is their sensitivity to acids (ultimately essential for effectiveness) which becomes apparent in their strong tendency to decompose in a neutral and in particular an acidic environment, giving rise to intensely colored decomposition products. In the past, there has been no lack of considerable efforts, in spite of the sensitivity of the PPI to acids, to obtain stable and storable oral dosage forms comprising these PPI. Such stable and storable oral dosage forms (for example tablets or capsules) are now obtainable. However, the preparation of these oral dosage forms is relatively complicated, and with respect to the packaging too, certain complicated precautions have to be taken so that the dosage forms are sufficiently stable on storage even under extreme storage conditions (for example in tropical regions at high temperatures and high atmospheric humidity). Furthermore, in the past, there has been no lack of efforts to tailor the release of the PPI in the human body in the best possible manner to the respective requirements.

It has now been found that the sodium salt of (-)- or (S)-pantoprazole, which is particularly preferred in the international patent application WO 94/24867, does not form a stable storage form. During attempts to obtain a stable oral dosage form for (-)-pantoprazole, it has now been found that the magnesium salt and its hydrates have highly surprising stability properties, making the magnesium salt a particularly suitable candidate for use in solid or oral dosage forms. Compared to the sodium salt, the magnesium salt of (-)-pantoprazole has considerably improved stability properties. Thus, for example, (-)- pantoprazole magnesium dihydrate is, at 70°C, completely stable for one week and shows virtually no discoloration or decomposition, whereas over the same period of time and under identical conditions, the color of the hydrate of (-)-pantoprazole sodium changes to brown, with formation of considerable amounts of decomposition products.

Furthermore, the (-)-pantoprazole magnesium dihydrate is a non-hygroscopic salt having a defined water content, whereas (-)-pantoprazole sodium absorbs water depending on drying conditions and atmospheric humidity, and, correspondingly, its water content varies from 2 to 12%. This absorption of water is reversible, so that it is difficult to adjust an exact water content in the sodium salt of (-)- pantoprazole.

Compared to the racemic pantoprazole magnesium dihydrate, the (-)-pantoprazole magnesium dihydrate has, surprisingly, better wettability, a considerably higher dissolution rate at pH 7-7.4 and, at pH 10, about tenfold better solubility.

Accordingly, in context of the invention, (-)-pantoprazole is used preferably in the form of its magnesium salt and the hydrates thereof, i.e. in the form of magnesium (-)-bis{[5-(difluoromethoxy)]-2-[(3,4- dimethoxy-2-pyridinyl)methylsulphinyl]-1H-benzimidazolide} and its hydrates. Here, particular emphasis is given to hydrates which, after drying under reduced pressure at 50°C, have a water content of from about 4.0 to about 6.7%, in particular from about 4.0 to about 5.5%. Particular preference is given to the hydrate form which has a water content of from about 4.0 to about 5.0%, in particular from about 4.2 to about 4.4%, which corresponds to a dihydrate.

In view of the capability of (-)-pantoprazole to primarily bind to cysteine 822 instead of cysteine 813 of the proton pump, thus leading to an even longer lasting inhibition of acid secretion, (-)-pantoprazole, in particular in the form of its magnesium salt and the hydrates thereof, is outstandingly suited for the treatment and prevention of all disorders which can be treated or prevented by using PPI. In particular, (-)-pantoprazole magnesium and its hydrates can be used for treating gastric disorders. In this context, particular mention should be made of the relatively high stability of (-)-pantoprazole magnesium in the form of its dihydrate. On storage under atmospheric conditions (at 60-70°C), the sum of byproducts in (-)-pantoprazole magnesium dihydrate remains virtually constant, whereas in the case of (-)- pantoprazole sodium, under identical conditions, the purity (according to HPLC) decreases from 99.5 to

96-97%. This relatively high storage stability makes (-)-pantoprazole magnesium dihydrate particularly suitable for use in medicaments.

The hydrates of (-)-paπtoprazole magnesium are prepared in a manner known per se by reacting (-)- pantoprazole with a magnesium base, for example a magnesium alkoxide, or from a readily soluble (-)- pantoprazole salt (for example (-)-pantoprazole sodium) using a magnesium salt in water or in mixtures of water with polar organic solvents (for example alcohols, preferably methanol, ethanol or isopropanol, or ketones, preferably acetone).

Magnesium salts suitable for use in the process are, for example, magnesium chloride, magnesium bromide, magnesium fluoride, magnesium iodide, magnesium formate, magnesium acetate, magnesium propionate, magnesium gluconate or magnesium carbonate. It is also possible to react magnesium alkoxides (for example magnesium methoxide, magnesium ethoxide, magnesium (iso)propoxide, magnesium butoxide, magnesium hexoxide or magnesium phenoxide) in aqueous medium with (-)- pantoprazole or (-)-pantoprazole sodium.

The examples below illustrate the synthesis of the (-)-pantoprazole magnesium salts in more .detail; m.p. denotes melting point, min. denotes minute(s), h denotes hour(s).

Examples

1. Magnesium (-)-bis(r5-(difluoromethoxy)1-2-r(3,4-dimethoxy-2-pyridinyl)methylsulphinvn-1H- benzimidazolide) dihydrate (method a)

At 20-25°C, 20.2 g (52.7 mmol) of (-)-pantoprazole {(-)-[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2- pyridinyl)methylsulphinyl]-1 H-benzimidazole} are suspended in 200 ml of purified water. A solution of (55.2 mmol) sodium hydroxide in 10 ml of water is added, and the mixture is stirred at 20-30°C for 30 min. With addition of a filter aid (1g Hyflo-Super-Cel), the turbid solution is filtered. 6.32 g (31.2 mmol) of magnesium dichloride hexahydrate in 150 ml of water are then added dropwise with stirring over a period of 30 min. After a further 30 min., the precipitated solid is filtered off with suction using a Nutsche filter, stirred with water (2 x 50 ml) and again filtered off with suction. Drying under reduced pressure at 50-60°C gives, in a yield of 17.36 g (80%), a hydrate of magnesium (-)-bis{[5- (difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1 H-benzimidazolide} having a water content of 4.5-4.7% as a colourless to beige powder (m.p. 158-161 °C, with decomposition).

Specific rotation: σ_D ^20" = -114° (c = 0.5, measured in methanol)

For recrystallization, 1.88 g of the hydrate are, at 55°C, dissolved in 6 ml of methanol, and 20 ml of water are added with stirring. A colourless to beige solid crystallizes out. This gives the title compound of m.p. 160-163°C (with decomposition) having a water content of 4.3-4.4%.

Alternatively, the title compound can also be prepared from organic-aqueous solvent mixtures. To this end, (-)-pantoprazole sodium, or (-)-pantoprazole together with one equivalent of aqueous, for example 2N, sodium hydroxide solution, is dissolved in an organic solvent, for example warm acetone. 0.5 to 0.55 equivalents of a magnesium salt (for example magnesium chloride hexahydrate), dissolved in water, are added dropwise, and the mixture is cooled with stirring. The precipitated solid is filtered off, washed with the solvent mixture in question and dried at 50°C under reduced pressure until the weight remains constant. This gives the title compound as a colourless to beige powder.

2. Magnesium (-)-bis(r5-(difluoromethoxy)l-2-r(3,4-dimethoxy-2-pyridinyl)methylsulphinvπ-1H- benzimidazolide) dihydrate (method b)

A. (-)-Pantoprazole-Na

36 g of (-)-Pantoprazole are suspended in 180 ml of isobutyl methyl ketone (MIBK) and 18 ml of 2-propanol and heated to an internal temperature of 45°C. The suspension is stirred at this temperature for 15 min. At 50°C, 11 g of 30% (w/w) aqueous sodium hydroxide solution are slowly added dropwise to this suspension. A clear to slightly turbid solution results. This solution is stirred for a bit longer and then filtered to give a clear solution. The clear filtrate is slowly cooled to room temperature. Between 45 and 30°C crystallization, which can be accelerated by seeding with (-)-pantoprazole sodium, sets in. The resulting suspension is stirred at an internal temperature of < 20°C for another 2 h. The suspension is then filtered, and the crystals are washed with 40 ml of MIBK.

Drying is carried out in a vacuum drying cabinet at < 50 mbar and 40-45°C. [It is also possible to dispense with drying and to use the moist product (having an MIBK content of 10-20%) directly for step B]. The white-beige crystalline product obtained after drying is hygroscopic. The water content is from 2 to 12%. The absorption and release of water are reversible. Yield: 34 g = 90% of theory (based on anhydrous product). Specific rotation: α₀ ^20' = - 95 (c = 0.5, measured in methanol, sodium salt having a water content of 12%) m.p.: 145-165°C (decomposition, sodium salt having a water content of 2%); 102-109°C (decomposition, sodium salt having a water content of 12%).

B. (-)-Pantoprazole-Mg

30 g of (-)-pantoprazole sodium salt (calculated anhydrous substance) are suspended in 260 ml of water. The suspension is heated to 35-40°C and stirred at 35-40°C for another 10 min. This gives a clear solution. The clear solution is cooled to 22-27°C. 14.3 g of magnesium chloride hexahydrate are dissolved in 100 ml of water, and at room temperature and with stirring, the solution is slowly added dropwise to the (-)-pantoprazole sodium salt solution. The resulting suspension is then stirred at room temperature for another 4 h. The suspension is, under pressure, filtered through a Nutsche filter, and the product is, a little at a time, washed twice with 300 ml of water. Drying in a vacuum drying cabinet at < 50 mbar and 40-45°C gives 27.5 g (90%) of the title compound of m.p. 160-163°C. Water content 4.3-4.4%; specific rotation: α_D ^20" = -129 (c= 0.5, measured in methanol).

3. Tablets containing 40 mq of (-)-pantoprazole as (-)-pantoprazole magnesium dihydrate

I. Tablet core a) (-)-pantoprazole-Mg dihydrate 43.08 mg b) Sodium carbonate 10.0 mg c) Mannitol 42.7 mg d) Crospovidone 50.0 mg e) PVP 90 (povidone) 4.0 mg f) Calcium stearate 3.2 mg Total weight per core ca. 153 mg

a) is mixed with some of b), c) and d). The remainders of b) and c) are added to a clear aqueous solu- tion of e) and the pH is brought to >10 with b). Granules are obtained with this solution in a fluidized bed. The remainder of d), and f) are added to the dry granules and the granules are pressed on a suitable tablet-making machine.

II. Preliminary isolation (intermediate layer) g) HPMC 2910, 3 cps 15.83 mg h) PVP 25 0.32 mg i) Titanium dioxide 0.28 mg j) LB Iron oxide yellow 100 E 172 0.025 mg k) Propylene glycol 3.54 mg Total weight of pre-isolation 20.00 mg Total weight per pre-isolated core ca. 173 mg

g) is dissolved in water and h) is added and also dissolved (A), i) and j) are suspended in water using a suitable stirrer (B). A and B are combined. After addition of k), the suspension is sieved immediately before further processing, during which the tablet cores obtained under I. are coated with an adequate layer thickness of the suspension in a suitable apparatus.

III. Coating with a layer which is resistant to gastric juice

I) Eudragit .RTM. L 30 D 13.64 mg m) Triethyl citrate 1.36 mg Total weight of enteric coating 15.00 mg Total weight per film-coated tablet ca. 188 mg

I) is diluted with water and m) is added. The dispersion is sieved before processing.

III. is sprayed, in suitable apparatuses, onto the pre-isolated cores obtained under II Commercial utility

In view of the capability of (-)-pantoprazole to primarily block cysteine 822 instead of cysteine 813, (-)- pantoprazole can be used to more selectively and irreversibly block the proton pump, thus leading to a longer lasting inhibition of acid secretion than it is known for the racemic pantoprazole form currently used in therapy. In particular in the form of its magnesium salt and the hydrates thereof, (-)- pantoprazole has a pronounced inhibitory effect on the secretion of gastric acid and excellent gastrointestinal protective action in warm-blooded animals, in particular humans. Here, (-)-pantoprazole is distinguished by a highly selective action, an advantageous long duration of action, a particularly high bioavailability, an advantageous metabolization profile which - in addition - is uniform among different individuals, the lack of significant side-effects and a wide therapeutic spectrum.

In this context, "gastrointestinal protection" is to be understood as the prevention and treatment of gastrointestinal disorders, in particular gastrointestinal inflammatory disorders and lesions (such as, for example, Ulcus ventriculi, Ulcus duodeni, gastritis, irritable bowel owing to an increased production of acid or as a result of medicaments, GERD, Crohn's disease, IBD) which may be caused, for example, by microorganisms (for example Helicobacter pylori), bacterial toxins, medicaments (for example certain antiphlogistics and antirheumatic drugs), chemicals (for example ethanol), gastric acid or. stress.

With its excellent properties, due to the higher binding quotient cystein 822/cystein 813, as compared with racemic pantoprazole, (-)-pantoprazole, in particular in the form of its magnesium salt and the hydrates thereof, in various models for the determination of antiulcerogenic and antisecretory properties, is surprisingly clearly superior to the prior-art compounds, in particular with respect to its selectivity, its duration of action and its metabolization properties. Owing to these properties, (-)-pantoprazole, in particular in the form of its magnesium salt and the hydrates thereof, is highly suitable for use in human and veterinary medicine, where it is used, in particular, for the treatment and/or prophylaxis of gastrointestinal disorders.

For the use according to the invention, (-)-pantoprazole, in particular in the form of its magnesium salt and the hydrates thereof, has to be administered in the form of a pharmaceutical composition (medicament). Medicaments are prepared by processes known per se which are familiar to the person skilled in the art. In medicaments, (-)-pantoprazole, in particular in the form of its magnesium salt and the hydrates thereof, is employed preferably in combination with suitable pharmaceutical auxiliaries or carriers in the form of tablets, coated tablets, capsules, suppositories, plasters (for example as TTS), emulsions, suspensions or solutions, where the content of active compound is advantageously from 0.1 to 95% and where it is possible to produce pharmaceutical dosage forms (for example flow-release forms or enteric forms) which, by the appropriate choice of auxiliaries and carriers, are tailored for the active compound and/or the desired onset of action and/or the duration of action.

The auxiliaries or carriers suitable for the desired pharmaceutical formulations are known to the person skilled in the art owing to his expert knowledge. In addition to solvents, gel formers, suppository bases, tabletting auxiliaries and other carriers for active compounds, it is possible to use, for example, antioxi- dants, dispersants, emulsifiers, antifoams, flavor-masking agents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complex formers (for example cyclodextrins).

(-)-Pantoprazole, in particular in the form of its magnesium salt and the hydrates thereof, can be administered orally, pareπterally or percutaneously.

In human medicine, it has generally been found to be advantageous to administer (-)-pantoprazole, in particular in the form of its magnesium salt and the hydrates thereof, when given orally, in a daily dose of from about 0.1 to 2, preferably 0.2 to 1.5 and in particular 0.3 to 1.1 , mg/kg of body weight [based on (-)-pantoprazole], if appropriate in the form of a plurality of, preferably 1 to 4, individual doses, to obtain the desired result. For parenteral treatment, it is possible to use similar or (in particular when the active compounds are administered intravenously) generally lower dosages. The person skilled in the art, owing to his expert knowledge, can easily determine the optimum dosage and the type of administration of the active compounds required in each case.

If (-)-pantoprazole, in particular in the form of its magnesium salt and the hydrates thereof, is to be used for treating the abovementioned diseases, the pharmaceutical preparations may also comprise one or more pharmacologically active ingredients from other groups of medicaments. Examples which may be mentioned are: tranquilizers (for example from the group of the benzodiazepines, e.g. diaze- pam), spasmolytic drugs (e.g. bietamiverine or camylofine), anticholinergic drugs (e.g. oxypheπ- cyclimine or phencarbamide), local anesthetics (e.g. tetracaine or procaine), optionally also enzymes, vitamins or amino acids.

In this context, particular emphasis is given to the combination of (-)-pantoprazole, in particular in the form of its magnesium salt and the hydrates thereof, with other pharmaceuticals which buffer or neutralize gastric acid or which inhibit the secretion of acid, such as, for example, antacids (such as, for example, magaldrate) or H₂ blockers (e.g. cimetidine, ranitidine), and with gastrin antagonists with the aim to enhance the main action in an additive or superadditive sense and/or to eliminate or reduce side-effects or to obtain a more rapid onset of action. Mention may also be made of the fixed or free combination with NSAIDs (such as, for example, etofenamate, diclofenac, indometacin, ibuprofen or piroxicam) for preventing the gastrointestinal damage caused by the NSAIDs, or with antibacterial substances (such as, for example, cephalosporins, tetracyclins, penicillins, macrolides, nitroimidazoles or else bismuth salt) for controlling Helicobacter pylori. Antibacterial combination partners which may be mentioned are, for example, mezlocillin, ampicillin, amoxicillin, cefalothin, cefoxitin, cefotaxim, imipene , gentamycin, amicacin, erythromycin, ciprofloxacin, metronidazole, clarithromycin, azithro- mycin and combinations thereof (e.g. clarithromycin + metronidazole or amoxicillin + clarithromycin).

Claims

1. A method of inhibiting gastric acid secretion in a human by selectively blocking cysteine 822 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid, which comprises administering (-)-pantoprazole, substantially free of the (+)- enantiomer, or a pharmaceutically acceptable salt thereof to the human in need of such therapy.

2. A method of inhibiting gastric acid secretion in a human by primarily blocking cysteine 822 instead of cysteine 813 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid, which comprises administering ^'(-)-pantoprazole, substantially free of the (+)-enantiomer, or a pharmaceutically acceptable salt thereof to the human in need of such therapy.

3. A method of inhibiting gastric acid secretion in a human for an extended period of time by selectively blocking cysteine 822 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid, which comprises administering (-)-pantoprazole, substantially free of the (+)-enantiomer, or a pharmaceutically acceptable salt thereof to the human in need of such therapy.

4. A method of inhibiting gastric acid secretion in a human for an extended period of time by primarily blocking cysteine 822 instead of cysteine 813 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid, which comprises administering (- )-pantoprazole, substantially free of the (+)-enantiomer, or a pharmaceutically acceptable salt thereof to the human in need of such therapy.

5. A pharmaceutical composition intended for inhibiting gastric acid secretion in a human by selectively blocking cysteine 822 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid, which comprises (-)-pantoprazole, substantially free of the (+)-enantiomer, or a pharmaceutically acceptable salt thereof together with a carrier.

6. A pharmaceutical composition intended for inhibiting gastric acid secretion in a human by primarily blocking cysteine 822 instead of cysteine 813 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid, which comprises (-)- pantoprazole, substantially free of the (-t-)-enantiomer, or a pharmaceutically acceptable salt thereof together with a carrier.

7. A pharmaceutical composition intended for inhibiting gastric acid secretion in a human for an extended period of time by selectively blocking cysteine 822 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid, which comprises (-)- pantoprazole, substantially free of the (+)-enantiomer, or a pharmaceutically acceptable salt thereof together with a carrier.

8. A pharmaceutical composition intended for inhibiting gastric acid secretion in a human for an extended period of time by primarily blocking cysteine 822 instead of cysteine 813 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid, which comprises (-)-pantoprazole, substantially free of the (+)-enantiomer, or a pharmaceutically acceptable salt thereof together with a carrier.

9. Use of (-)-pantoprazole, substantially free of the (+)-enantiomer, or a pharmaceutically acceptable salt thereof for the production of a medicament intended for inhibiting gastric acid secretion in a human by selectively blocking cysteine 822 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid.

10. Use of (-)-pantoprazole, substantially free of the (+)-enantiomer, or a pharmaceutically acceptable salt thereof for the production of a medicament intended for inhibiting gastric acid secretion in a human by primarily blocking cysteine 822 instead of cysteine 813 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid.

11. Use of (-)-pantoprazole, substantially free of the (+)-enantiomer, or a pharmaceutically acceptable salt thereof for the production of a medicament intended for inhibiting gastric acid secretion in a human for an extended period of time by selectively blocking cysteine 822 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid.

12. Use of (-)-pantoprazole, substantially free of the (+)-enantiomer, or a pharmaceutically acceptable salt thereof for the production of a medicament intended for inhibiting gastric acid secretion in a human for an extended period of time by primarily blocking cysteine 822 instead of cysteine 813 of the proton pump in the canaliculus of the parietal cell, thus rendering the acid pump irreversibly incapable of secreting acid.

13. A method according to claims 1 to 4, which comprises administering (-)-pantoprazole, substantially free of the (+)-enantiomer, in the form of its magnesium salt.

14. A method according to claims 1 to 4, which comprises administering (-)-pantoprazole, substantially free of the (+)-enantiomer, as (-)-pantoprazole magnesium dihydrate.

15. A composition according to claims 5 to 8, which comprises (-)-pantoprazole, substantially free of the (+)-enantiomer, in the form of its magnesium salt.

16. A composition according to claims 5 to 8, which comprises (-)-pantoprazole, substantially free of the (+)-enantiomer, as (-)-pantoprazole magnesium dihydrate.

17. Use according to claims 9 to 12, in which (-)-pantoprazole, substantially free of the (+)-enantiomer, is used in the form of its magnesium salt.

18. Use according to claims 9 to 12, in which (-)-pantoprazole, substantially free of the (+)-enantiomer, is used as (-)-pantoprazole magnesium dihydrate.