Title of Invention	A PROCESS FOR THE PRODUCTION OF A FREEZE-DRIED PRE PARATION COMPRISING PANTOPRAZOLE & THE PRODUCT THE REOF
Abstract	Process for the production of a freeze-dried preparation comprlsing 5-difluoromethoxy-2-[(3,4-di-methoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (pantoprazole), a salt thereof, a solvate of pantoprazole or a salt thereof, a solvate of pantoprazole or a salt thereof, ethylenediamine tertraacetic acid and/or a suitable salt thereof,and sodium hydroxide and/or sodium carbonate.

Full Text

FORM 2 THE PATENTS ACT, 197 0 (39 of 1970) COMPLETE SPECIFICATION (See Section 10) EREEZE-DRIED PANTOPRAZOLE PREPARATION AND PANTOPRAZOLE. INJECTION ALTANA PHARMA AG of BYK-GULDEN-STRASSE 2, D-78467 KONSTANZ, DEUTSCHLAND, GERMANY, GERMAN Company The following specification particularly describes the nature of the invention and the manner in which it is to be performed : - GRANTED Technical Field The present invention relates to the field of pharmaceutical technology and describes freeze-dried 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole preparations and a 5-difluoromethoxy-2-[(3,4-djmethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole injection Further-more the invention also relates to a process for the production of freeze-dried 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsutfinyl]-1 H-benzlmldazole and a 5-difluoromethoxy-2-[(3,4-dlmeth-oxy-2-pyridinyl)methylsulfinyI]-1 H-benzimidazole injection. Prior art WO94/02141 describes an Injection comprising a 2-[(2-pyridyl)methylsulfinyl]-benzimidazole compound an aqueous solvent added with no nonagueous solvent, wherein the pH of the injection is not less than 9.5 and itot 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. It 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. DN 1235018 describes a freeze-dried Injection powder of pantoprazole sodium containing no crystallised 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. Description of Invention Reconstitution of lyophillsed pharmaceutical compounds with carrier solutions for application may lead to the formation of visible and/or subvlsible particles In the solution. Injectable solutions, including solu-tions constituted from sterile solids intended for parenteral use should be essentially free from particles that can be observed on visual inspection and for patient safety it is also desirable to have a low num¬ber of subvlsible particles. USP (United States Pharmacopeia) 24 describes physical tests performed for the purpose of enumerating subvisible extraneous particles within specific size ranges and also defines particulate matters limits set forth for the test being applied for large-volume injections for sin¬gle-dose infusion and small-volume injections (USP 24, Particulate Matter in Injections). : Surprisingly it has now been found that by freeze drying of an aqueous solution of pantoprazole, ethyl- enedtamine tetraacetic acid and/or a suitable salt thereof, and sodium hydroxide and/or sodium carbo-nate a lyophilisati is obtained having significantly lower number of subvisible particles after reconsti-tuion with a solvent compared to lyophjlisates of the state of the art. The lyophilisats according to the invention is very stabile and is easily reconstituted with suitable solvents. In particular the pantoprazoie Injection according to the Invention has less than 130, preferably less than 120 subvisible particles/per vial, the particles having a size equal to or greated as 10pm, the number of particles determined ac cording to USP 24 ( particle Matter in Injections) by light obscuration particle test count. 5-Difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole (INN: pantoprazoie, in connection with the invention also referred to as pantoprazoie) is known from EP-A-0 186 287. Pan-toprazole Is a,chiral compound. In connection with the invention the term pantoprazoie also includes the pure ©nantiomers of pantoprazoie and their mixtures in any mixing ratio, (S)-pantoprazoie [{-)-pantoprazote] may be mentioned by way of example. Pantoprazoie is present here as such or pref¬erably in the form of it"s salt with a base. Examples of salts with a base which may be mentioned are sodium, potassium, magnesium and calcium salts. Pantoprazoie and/or a salt thereof may contain, various amounts of solvent when isolated in crystalline form. In connection with the invention pantopra¬zoie also refers to all solvates and in particular to hydrates of 5-difluoromethoxy-2-[(3,4-dirnethoxy-2-pyridinyl)methylsulflnyl]-1H-benzlmidazoIe and salts thereof. Such a hydrate of the salt of pantoprazoie with a base is disclossed, for exemple, in WO91/19710. Expediently pantoprazoie refers to pantoprazoie sodium sesquihydrate (= pentoprazole sodium x 1.5 H20) and pantoprazoie magnesium dihydrate. According to the invention the pantoprazoie 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 trisodlum aalt and elhylonodlomlno totraacot!c acid totraaodlum salt. Th© proportion by weight of ethylenediamine tetraacetic acid and/or a suitable salt thereof, based on the amount of pan-toprazole 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 injection. Subsequently pantoprazole 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 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 is in the range from 10 to 13. 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 injection according to the invention can be produced by dissolving the lyophilized prod¬uct thus obtained in a suitable solvent for example physiological saline, aqueous solution of 5% glu¬cose, or distilled water for injection. Preferably the pantoprazole injection according to the invention is used In the form of intravenous Injection. The lyophilised product and pantoprazole injection according to the Invention preferably contain panto¬prazole fn the dose customary for the treatment of the respective disease. The lyophilised product and pantoprazole injection according to the invention can be employed for the treetment and prevention of all the diseases which are regarded as treatable or avoidable by the use of pyridin-2-ylmethylsulfinyl-1H-benzimidazoles, In "particular, the lyophilised product and pantoprazole Injection according to the Invention can be employed in the treatment of stomach disorders. The lyobhillzed products in particular contain between 5 and 150 mg, preferably between 5 and 60 mg, of pantoprazole. Examples which may be mentioned am lyophilized products or injections which contain 10, 20, 40, 50 or. 96 mg of pan¬toprazole. 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 concentration of panto¬prazole in the injection according to the invention may vary depending upon the administration 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 according to the Inven¬tion 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 Production of a lyophilized pantoprazole preparation Example 1 Under nitrogen atmosphere, 0.276 g Ethylenedlamine tetraacetlc acid disodium salt and_6.7.g sodium hydroxide (1N aqueous solution) are added to 480 g water for injection of 4fC to 8°C. 12.47 g panto- prazole sodium sesquihydrate 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 afreeze-dryer (GT4 Edwards/Kniese or GT8 Amsco) for lyophiiisation. The vials are cooled to -45*C, then tfte 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 adiusted 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, Comparative Examples Example 2 Under nitrogen atmosphere, 12.47 g pantoprazole sodium sesquihydrate is added to 480 g water for Injection of 4°C to 8oG 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 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 lyophiiisation. The vials are cooled to -45°C, then the temperature is raised to -20 to -5oC 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 3 Under nitrogen atmosphere, 2.45 g sodium hydroxide (1N aqueous solution) is added to 480 g water for injection of 4°C to 8oC. 12.47 g pantoprazole sodium sesquihydrate 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 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 lyophiiisation, 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 30eC, the vacuum Is adjusted to 0.01 mbar and drying is continued for an additional 3 hours. An off-white fyophilized product (s obtained. Example 4 Under nitrogen atmosphere, 0.05 g Ethylenediamine tetraacetic acid disodium salt Is added to 480 g water for Injection of 4oC to 8°C. 12.47 g pantoprazole sodium sesquihydrate 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 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/-Knlese 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. Light obscuration particle test count Particulate matter/per vial in solutions constituted from the lyophilized products obtained according to Examples 1 to 4 were determined according to USP 24 ( Particulate Matter in Injections) by light obscuration particle test count. The number of extraneous particles per vial having a size equal to or greater as 10 um detected, are summarized in Table 1. As may be evident from table 1, the number of subvisible particles per vial (equal to or greater as 10pm) in solutions constituted from products obtained according to the invention (EXAMPLE 1) is lower than for products obtained by methods which differ from the present Invention (EXAMPLES 2 to 4). Table 1: EXAMPLE 1 (Product obtained by freeze drying of Pan-toprazole sodium sesquihydrate, so¬dium hydroxide and ethylenediamine tetraacetfc acfd dfso- dium salt) particles/per vial >=10um EXAMPLE 2 (Product obtained by freeze drying of Pan- toprazole sodium sesquihydrate) particles/per vial >= 10pm EXAMPLE 3 (Product obtained by freeze drying of Pan- toprazole sodium sesquihydrate and sodium hydroxide) particles/per vial >= 10pm EXAMPLE 4 (Product obtained by freeze drying of Pan- toprazole sodium sesquihydrate and ethylenediamine tetraacetic acid diso- dium salt) particles/per vial >= 10um 109 458 144 211 We Claim: 1. Process for the production of a freeze-dried preparation comprising 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-lH-benzimidazole (pantoprazole), a salt thereof, a solvate of pantoprazole or a salt thereof, comprising freeze-drying of an aqueous solution consisting of pantoprazole, a salt thereof, a solvate of pantoprazole or a salt thereof, ethylenediamine tetraacetic acid and/or a suitable salt thereof, and sodium hydroxide and/or sodium carbonate, wherein upon dissolution in an aqueous solvent, the preparation has less than 130 subvisible particles per vial, the particles having a size equal to or greater than 10pm, wherein the number of particles is determined according to USP 24 by light obscuration particle test count. 2. Process as claimed in claim 1, comprising dissolution of ethylenediamine tetraacetic acid and/or a suitable salt thereof in water, adjusting pH of the solution to 8 or above 8 by addition of sodium hydroxide and/or sodium carbonate and addition of pantoprazole, a salt thereof, a solvate of pantoprazole or a salt thereof, to the thus obtained solution. 3. Process as claimed in claim 1, wherein the proportion by weight or ethylenediamine tetraacetic acid and/or a suitable salt thereof, based on the amount of pantoprazole present is from 0.05 to 25%, from 0.25 to 12.5%, or from 1 to 5%. 4. Process as claimed in claim 1, wherein pantoprazole is pantoprazole sodium sesquihydrate. 5. Process as claimed in claim 1 wherein the pH of the aqueous solution is in the range from 10 to 13. 6. Lyophilized pantoprazole preparation obtained by a process as claimed in claim 1 to 5. 7. Pantoprazole injection obtainable by reconstitution of the pantoprazole preparation as claimed in claim 6 in a suitable solvent. 8. Pantoprazole injection as claimed in claim 7, wherein the solvent is physiological saline. 9. Injection kit comprising a lyophilized pantoprazole preparation as claimed in claim 6 and a solvent. Dated this 26th day of April, 2003. HIRAL CHANDRAKANT JOSHI AGENT FOR ALTANA PHARMA AG

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