Prior art W094/02141 describes an injection comprising a 2-[(2pyridyl) methylsulfinyl]-benzimidazole compound an aqueous solvent added with no nonaqueous solvent, wherein the pH of the injection is not less than 9.5 and not more than 11.5. It is mentioned that said injection does not cause hemolysis and causes less local irritation.

DE 43 24 014 describes the preparation of a lyophilisate of pantoprazole-sodium sesquihydrate in the presence of sucrose as an auxiliary at production temperatures of-25 to-30°C. ft is disclosed that the lyophilisate is of improved storage stability and can be stored at room temperature for at least 18 months and is easily reconstituted in liquid form in suitable doses for use.

CN 1235018 describes a freeze-dried injection powder of pantoprazole sodium containing no crystal- lised water with pH value of 9-12. 5, which is composed of pantoprazole sodium, freeze-dried powder supporting agent, metal ion complexing agent and pH regulator.

W099/18959 describes aqueous pharmaceutical compositions, which are chemically and physically stable for intravenous injection which comprise anti-ulcerative compound and glycine as stabilizer in carrier.

W002/41919 is related to lyophilized pantoprazole preparations which are obtainable by freeze-drying of an aqueous solution of pantoprazole, ethylenediamine tetraacetic acid and/or a suitable salt thereof, and sodium hydroxide and/or sodium carbonate. The preparations are said to have advantageous pro- perties when reconstituted for injection. Pantoprazole magnesium is mentioned as suitable pantoprazole salt.

Pantoprazole sodium for injection is commercially available in the U. S. A under the tradename ProtonixE l. V.

For the first time, the international patent application W092/08716 describes a chemical process which allows pyridin-2-ylmethylsulphinyl-1 H-benzimidazoles to be separated into their optical antipodes. The compounds mentioned as being prepared in an exemplary manner include inter alia the compounds <BR> <BR> <BR> (+) -and (-)-5-difluoromethoxy-2- [ (3, 4dimethoxy-2-pyridinyl) methylsulphinyl]-1 H-benzimidazole [= (+) - and (-)-pantoprazole]. The international patent application W092/08716 mentions that the optical an- tipodes of the pyridin-2-ylmethylsulphinyl-1 H-benzimidazoles, i. e. the (+)-and (-)-enantiomers or the (R) -and (S)-enantiomers, are used as active compounds in medicaments for the treatment of gastro- intestinal 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 W094/25028 claim the use of the compounds <BR> <BR> <BR> (-) -and (+)-pantoprazole for treating gastric disorders in humans. Each stereoisomer is said to have medical advantages compared to the respective other stereoisomers. The descriptions also mention a number of different possible salts of the stereoisomers, and particular preference is given to the sodium salt.

The International Patent Application W097/41114 describes a specific process for the preparation of magnesium salts of pyridin-2-ylmethylsulfinyl-1 H-benzimidazoles. Inter alia, the preparation of the mag- nesium salt of pantoprazole is also described by way of example. According to the analysis data indi- cated, the salt prepared is pantoprazole magnesium in anhydrous form.

International Patent Application WO 00/10995 describes the dihydrate of the magnesium salt of panto- prazole. It is disclosed that the dihydrate of the magnesium salt of pantoprazole has inter alia improved stability properties as in comparison to pantoprazole itself or to pantoprazole sodium sesquihydrate.

Description of invention Subject of the present invention is a stable lyophilized preparation for injection comprising magnesium <BR> <BR> <BR> (-)-bis {[5-(difluoromethoxy)]-2-[(3, 4-dimethoxy-2-pyridinyl) methylsulphi nyl]-1 H-benzimidazolide} and/or a solvate thereof. In one embodiment of the invention the lyophilized preparation essentially consists of magnesium (-)-bis {[5-(difl uoromethoxy)]-2-[(3, 4-dimethoxy-2-pyridin yl) methylsulphi nyl]-1 H-benzi mida- zolide} and/or a solvate thereof. In another embodiment according to the invention the lyophilized pre- paration for injection in addition to the active ingredient (magnesium (-)-bis{[5-(difluoromethoxy)]-2- [ (3, 4-dimethoxy-2-pyridinyl) methylsulphinyl]-1 H-benzimidazolide}) and/or a solvate thereof) comprises suitable pharmaceutical acceptable excipients. Suitable pharmaceutical acceptable excipients, which may be mentioned in connection with the preparations according to the invention are cheating agents, agents to control pH, stabilizers and suitable carriers.

The lyophilized preparations according to the invention are preferably in powder form and have im- proved stability.

Cheating agents which may be mentioned are ethylenediamine tetraacetic acid and/or a suitable salt thereof. Suitable salts of ethylenediamine tetraacetic acid which may be mentioned in connection with the invention by way of example are ethylenediamine tetraacetic acid disodium salt, ethylenediamine tetraacetic acid calcium disodium salt ethylenediamine tetraacetic acid trisodium salt and ethylenedia- mine tetraacetic acid tetrasodium salt.

Agents to control pH which may be mentioned are preferable basic agents to increase pH such as sodium hydroxide and/or sodium carbonate.

In one embodiment of the invention the lyophilized preparation for injection according to the invention comprises magnesium (-)-bis { [- (difl uoromethoxy)]-2- [ (3, 4-dimethoxy-2-pyridinyl) methylsulphinyl]-iH- benzimidazolide} and or a solvate thereof, ethylenediamine tetraacetic acid and/or a suitable salt thereof and sodium hydroxide and/or sodium carbonate. In another embodiment according to the in- vention the lyophilized preparation for injection according to the invention essentially consists of mag- nesium (-)-bis {[5-(difluoromethoxy)]-2-[(3, 4-dimethoxy-2-pyridinyl) methylsulphinyl]-1 H-benzimidazolide} and or a solvate thereof, ethylenediamine tetraacetic acid and/or a suitable salt thereof and sodium hydroxide and/or sodium carbonat.

Pantoprazole is the INN (International Nonproprietary Name) for the compound 5-difluoromethoxy- 2- [ (3, 4dimethoxy-2-pyridinyl) methylsulfinyl]-1 H-benzimidazole. The magnesium salt of pantoprazole is the chemical compound magnesium bis [5- [difluoromethoxy]-2- [ [3, 4-dimethoxy-2-pyridinyl] methyl] sulfin- yl]-1H-benzimidazolide]. The magnesium salt of (-)-pantoprazole and its hydrates (hereinafter also referred to as (-)-pantoprazole magnesium) in connection with the invention refers to the compound magnesium (-)-bis{[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl) methylsulphinyl]-1 H-benzimi- dazolide} including hydrates thereof. Here, particular emphasis is given to hydrates, which, after drying under reduced pressure at 50°C, have a water content of from 4.0 to 6.7% (by weight), in particular from 4.0 to 5.5%. Particular preference is given to the hydrate form which has a water content of from 4.0 to 5.0%, in particular from 4.2 to 4.4%, which corresponds to a dihydrate. The magnesium salt and its hydrates have highly surprising stability properties, making it a particularly suitable candidate for use in solid dosage forms (e. g. as lyophilized preparation). Compared to the sodium salt of (-)-pantopra- zole, it has considerably improved stability properties. Thus, for example, (-)-pantoprazole magnesium dihydrate is, at 70°C, completely stable for one week and shows virtually no discolouration or decom- position, whereas over the same period of time and under identical conditions, the colour of the hydrate of (-)-pantoprazole sodium changes to brown, with formation of considerable amounts of decompos- ition products. Furthermore, the (-)-pantoprazole magnesium dihydrate is a non-hygroscopic salt hav- ing a defined water content, which corresponds to that of the dihydrate, this (-)-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. Compared to the racemic pantoprazole magnesium dihydrate, the ()-pant- prazole magnesium dihydrate has, surprisingly, better wettability, a considerably higher dissolution rate and, at pH 7.4, better solubility.

The hydrates of ()-pantoprazole 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 mix- tures of water with polar organic solvents (for example alcohols, preferably methanol, ethanol or isopro- panol, 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, magne- sium propionate, magnesium gluconate or magnesium carbonate, It is also possible to react magne- sium alkoxide (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 lyophilized preparation according to the invention can be produced according to methods known in the art. In one embodiment according to invention lyophilized preparations are produced according to the process disclosed in W002/41919. To this end a (-)-pantoprazole magnesium solution used in the freeze drying process can be obtained by addition of ethylenediamine tetraacetic acid and/or a suitable salt thereof, and sodium hydroxide and/or sodium carbonate to an aqueous solvent. Suitable salts of ethylenediamine tetraacetic acid which may be mentioned in connection with the invention by way of example are ethylenediamine tetraacetic acid disodium salt, ethylenediamine tetraacetic acid calcium disodium salt ethylenediamine tetraacetic acid trisodium salt and ethylenediamine tetraacetic acid tet- rasodium salt. The proportion by weight of ethylenediamine tetraacetic acid and/or a suitable salt thereof, based on the amount of (-)-pantoprazole magnesium used is from 0.05 to 25 % preferably from 0.25 to 12.5 % or particular preferred from 1 to 5 %. The aqueous solvent preferentially is water for in- jection. Subsequently ()-pantoprazole magnesium is added to the solution and dissolved by stirring. It is preferred to have a solution wherein the proportion of weight (m/m) of (-)-pantoprazole magnesium is 0.5 to 10 %, particularly preferred 1 to 6 %. In a further preferred embodiment of the invention the pH of the solution used in the freeze-drying process is 8 or above 8. Particularly preferred the pH of said solution is in the range from 10 to 13, more preferred the pH of the solution is in the range from 10.5 to 11.5 and particularly more preferred the pH is in the range from 10.75 to 11.25. Exemplary pH values of said solution, which are to be emphasized are 10.75, 10.8, 10.85, 10.9, 10.95, 11,11. 05, 11. 1, 11.15, 11.2 and 11.25. Then this solution is filtered for sterilization and charged in vials. The solution is then freeze dried by a method known per se.

A (-)-pantoprazole magnesium injection according to the invention can be produced by dissolving the lyophilized product thus obtained in a suitable solvent for example physiological saline, aqueous solu- tion of 5% glucose, or distilled water for injection. Preferably the (-)-pantoprazole magnesium injection according to the invention is used in the form of intravenous injection.

The lyophilised product and (-)-pantoprazole magnesium injection according to the invention preferably contain (-)-pantoprazole magnesium in the dose customary for the treatment of the respective disease.

The lyophilised product and (-)-pantoprazole magnesium injection according to the invention can be employed for the treatment and prevention of all the diseases, which are regarded as treatable or avoidable by the use of pyridin-2-ylmethylsulfinyl-1 H-benzimidazoles. In particular, the lyophilised product and (-) pantoprazole magnesium injection according to the invention can be employed in the treatment of stomach disorders. Examples which may be mentioned in connection with the invention are the treatment or prophylaxis of benign gastric ulcer, IBD, Crohn's disease, gastro-oesophageal reflux disease, Zollinger-Ellison syndrome, duodenal ulcer, duodenal ulcer associated with Helico- bacter pylori, prophylaxis of NSAID-associated gastric or duodenal ulcer in patients with an increased risk of gastroduodenal complication who require continued NSAID treatment or combination therapy with antibiotics in the eradication of Helicobacter pylori. The lyophilized products in particular contain between 5 and 150 mg, preferably between 5 and 60 mg, of (-)-pantoprazole magnesium. Examples, which may be mentioned are lyophilized products or injections which contain 10,20, 40,50 or 96 mg of (-)-pantoprazole magnesium. The administration of the daily dose (e. g. 40 mg of active compound) can be carried out, for example, in the form of an individual dose or by means of a number of doses of the administration forms according to the invention (e. g. 2 times 20 mg of active compound). The concen- tration of pantoprazole in the injection according to the invention may vary depending upon the admini- stration route and generally ranges in a proportion of 0.05-10 mg/ml, preferably 0.1 to 5 mg/ml on a free compound basis. For example for bolus administration 20 to 120 mg of lyophilized product accord- ing to the invention can be reconstituted with 10 ml physiological saline.

The production of the lyophilized product and pantoprazole injection is described by way of example below. The following examples illustrate the invention in greater detail, without restricting it.

Examples A. Synthesis of Magnesium (-)-bisfr5-(difluoromethoxv) 1-2-[(344imethoxv-2-pyridinvls methylsulphinyll-lH-benzimidazolide} dihydrate At 20-25°C, 20.2 g (52.7 mmol) of (-)-pantoprazole { (-)- [5- (difluoromethoxy)]-2- [ (3, 4-dimethoxy-2-py- ridinyl) 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 20-30C 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 mi 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: aD20'=-1140 (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.

B. Magnesium (-)-bis{[5-(difluoromethoxy)]-2-[(3,4-dimethoxy-2-pyridinyl) methylsulphinyl]-1H- benzimidazolidel dihydrate B. 1 (-pPantoprazole-Na 36 g of (-)-Pantoprazole are suspended in 180 ml of isobutyl methyl ketone (MIBK) and 18 ml of 2-pro- panol 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 dis- pense 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 anhy- drous product). Specific rotation: aD =-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. 2 (-pPantoprazole-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 mi 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 27.5g (90%) of the title compound of m. p. 160-163°C. Water content 4.3-4. 4%; specific rotation : aD =-129 (c= 0.5, measured in methanol).

C. Production of a Iyophilized pantoprazole preparation Example C. 1 Under nitrogen atmosphere, 0.276 g Ethylenediamine tetraacetic acid disodium salt and 6.7 g sodium hydroxide (1N aqueous solution) are added to 480 g water for injection of 4°C to 8°C. 12.47 g (-)- pantoprazole magnesium dihydrate is added while stirring to give a clear solution. The weight of the solution is adjusted to 500 g by addition of water for injection. The pH of the solution is 11.76. The solution is filtered through a 0.2 urn membrane filter and filled in glass vials (1.81 g by vial). Filled vials are semi-stoppered and put into a freeze-dryer (GT4 Edwards/Kniese or GT8 Amsco) for lyophilisation.

The vials are cooled to-45°C, then the temperature is raised to-20 to-5°C under vacuum (0.1 to 0.5 mbar) for drying. After finishing main drying the temperature is raised to 30°C, the vacuum is adjusted to 0.01 mbar and drying is continued for an additional 3 hours. An off-white tyophitized product is ob- tained which is easily reconstituted with physiological saline to give a clear solution.

Example C. 2 Under nitrogen atmosphere, 0.276 g Ethylenediamine tetraacetic acid disodium salt and 1.66 ml so- dium hydroxide solution (1 N aqueous solution) are added to 480 g water for injection of 4°C to 8°C.

12.47 g ()-pantoprazole magnesium dihydrate is added while stirring to give a clear solution. The weight of the solution is adjusted to 500 g by addition of water for injection. The pH of the solution is 11.76. The solution is filtered through a 0.2 urn membrane filter and filled in glass vials (1.81 g by vial) Filled vials are semi-stoppered and put into a freeze-dryer (GT4 Edwards/Kniese or GT8 Amsco) for lyophilisation. The vials are cooled to-45°C, then the temperature is raised to-20 to-5°C under vac- uum (0.1 to 0.5 mbar) for drying. After finishing main drying the temperature is raised to 30°C, the vac- uum is adjusted to 0.01 mbar and drying is continued for an additional 3 hours. An off-white lyophilized product is obtained which is easily reconstituted with physiological saline to give a clear solution.

Example C. 3 Under nitrogen atmosphere, 12.47 g (-)-pantoprazole magnesium dihydrate is added to 480 g water for injection of 4°C to 8°C while stirring to give a clear solution. The volume of the solution is adjusted to 500 g by addition of water for injection. The pH of the solution is 10.85. The solution is filtered through a 0. 2 um membrane filter and filled in glass vials (1.81 g by vial). Filled vials are semi-stoppered and put into a freeze-dryer (GT4 Edwards/Kniese or GT8 Amsco) for lyophilisation. The vials are cooled to -45°C, then the temperature is raised to-20 to-5°C under vacuum (0.1 to 0.5 mbar) for drying. After finishing main drying the temperature is raised to 30°C, the vacuum is adjusted to 0.01 mbar and dry- ing is continued for an additional 3 hours. An off-white lyophilized product is obtained.

Example C4 Under nitrogen atmosphere, 2.45 g sodium hydroxide (1 N aqueous solution) is added to 480 g water for injection of 4°C to 8°C. 12.47 g (-)-pantoprazole magnesium dihydrate is added while stirring to give a clear solution. The weight of the solution is adjusted to 500 g by addition of water for injection. The pH of the solution is 12.02. The solution is filtered through a 0.2 lim membrane filter and filled in glass vials (1.81 g by vial). Filled vials are semi-stoppered and put into a freeze-dryer (GT4 Edwards/Kniese or GT8 Amsco) for lyophilisation. The vials are cooled to-45°C, then the temperature is raised to-20 to-5°C under vacuum (0. 1 to 0.5 mbar) for drying. After finishing main drying the temperature is raised to 30°C, the vacuum is adjusted to 0.01 mbar and drying is continued for an additional 3 hours. An off- white lyophilized product is obtained.

Example C. 5 Under nitrogen atmosphere, 0.05 g Ethylenediamine tetraacetic acid disodium salt is added to 480 g water for injection of 4°C to 8°C. The pH is adjusted with sodium hydroxide to 10-11.5. 12.47 g (-)- pantoprazole magnesium dihydrate is added while stirring to give a clear solution. The weight of the solution is adjusted to 500 g by addition of water for injection. The pH of the solution is 10.2. The solu- tion is filtered through a 0.2 um membrane filter and filled in glass vials (1.81 g by vial). Filled vials are semi-stoppered and put into a freeze-dryer (GT4 Edwards/Kniese or GT8 Amsco) for lyophilisation.

The vials are cooled to-45°C, then the temperature is raised to-20 to-5°C under vacuum (0.1 to 0.5 mbar) for drying. After finishing main drying the temperature is raised to 30°C, the vacuum is adjusted to 0.01 mbar and drying is continued for an additional 3 hours. An off-white lyophilized product is ob- tained.

The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.